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       Bulletin of Experimental Therapies for AIDS (BETA); A
       Publication of the San Francisco AIDS Foundation
       *****************************************************

       BETA News Briefs
       Ronald Baker, PhD; editor of BETA.

       New Picture of HIV Pathogenesis

       Recent research results published in the journal Nature offer a
new view of how HIV and the body interact following infection with the
virus. Two studies conducted independently have reached similar
conclusions about HIV replication, how the immune system responds to
it and the implications for drug treatment:

       * HIV replicates profoundly and rapidly throughout all disease
         stages;

       * every day HIV positive individuals produce up to one billion new HIV
particles and 2 billion new CD4
         cells.;

       * drug efficacy should be tested for within days to weeks after
         initiation of therapy by following changes in viral load; if
         viral load increases again, patients and physicians should
         consider changing therapy;

       * immune system defenses respond strongly to HIV infection,
         even in late stage disease.

       The immune systems of HIV positive individuals engage in a
fierce daily struggle to overcome the invading virus throughout the
course of the disease, according to investigators at the University of
Alabama and at New York's Aaron Diamond AIDS Research Center. The
immune system destroys about half the HIV particles in the bloodstream
every 2 days, but newly-produced HIV virions replace those killed.
Both studies conclude that AIDS is primarily a disease caused by the
continuous, high-level replication of HIV, which results in the direct
killing of CD4 T lymphocytes, white blood cells that play a critical
role in immune defense. One important implication of these 2 new
studies is that if HIV replication can be stopped or kept at a low
level for a significant amount of time, the immune system may be able
to recover from the effects of HIV infection, even among people with
advanced AIDS.

       Because the immune system is so resilient, says David Ho, MD,
of the New York research team, researchers should not concern
themselves with trying to repair it with immunotherapies, but rather
focus on attacking HIV early with antiretroviral drugs, before the
virus mutates too many times. If treatment strategies are to be
successful, they should start 'as early in the infection course as
possible,' according to Dr. Ho. See page 68 for a complete report on
the 2 new studies on HIV pathogenesis published in the January 12,
1995 issue of Nature.

       AZT Plus 3TC

       Further evidence of significant and sustained effects of the
AZT/3TC combination on markers of disease progression (viral load and
CD4 counts) emerged at the 2nd National Conference on Human
Retroviruses and Related Infections held in Washington, DC, January 29
- February 2. The results from 2 North American studies showed that
patients using these drugs for the first time experienced a 1.7 log
peak median decrease in viral load (a 98% reduction) and a mean
increase of 66 CD4 cells/mm3. After 24 weeks of therapy, participants
had a 1 log median viral load decrease (90% reduction) and an increase
of 58 CD4 cells/mm3 over baseline.

       The results of the European and American trials of the AZT/3TC
combination are so encouraging that Glaxo, sponsor of the trials, says
it will seek accelerated approval for the combination regimen later
this year. The combination has the most potent and sustained effect on
CD4 counts and viral load of any anti-HIV therapy yet evaluated in
clinical tirals.

       The favorable effects on these markers was less pronounced in
patients who added 3TC after previously using AZT alone. In addition,
among individuals already taking AZT, adding 3TC produced about the
same decrease in viral load as that seen among those taking AZT plus
ddC, although CD4 count increases were more sustained among those on
the AZT/3TC combination. For complete details on these studies, see
page 8. For information on expanded access to 3TC, call
1-800-TRIALS-A.

       Glaxo and Burroughs Wellcome

       Among other therapies, Glaxo manufactures the ulcer drug Zantac
and the new AIDS drug 3TC (lamivudine). Glaxo recently offered $ 14.2
billion in cash and stocks for Wellcome plc, the parent company of
Burroughs Wellcome, manufacturer of Retrovir (AZT; zidovudine) and
Zovirax (acyclovir). The Board of Wellcome plc has recommended
acceptance of the Glaxo offer to all shareholders. The integration of
the 2 businesses will result in formation of the largest
pharmaceutical company in the world.

       IL-2 Significantly Increases CD4 Counts in Some HIV Positives

       Intermittent infusions of recombinant interleukin 2 (IL-2)
produced more than 50 percent (50%) CD4 cell increases after 12 months
in 6 of 10 HIV positive individuals with CD4 counts greater than 200
cells/mm3, according to study results published in the March 2, 1995
issue of The New England Journal of Medicine (NEJM). The other 4
participants with CD4 counts greater than 200 cells/mm3 experienced no
change or a slight decline in their CD4 counts. 'This study provides
the strongest evidence so far that it may be possible to rebuild and
maintain the damaged immune systems of HIV-infected individuals,' said
Clifford Lane, MD, Clinical Director of the National Institute of
Allergy and Infectious Diseases (NIAID) and co-author of the 2-year
study.

       Only 2 of 15 individuals who began the study with CD4 counts
below 200 cells/mm3 experienced a 50% increase in their CD4 counts.
The remaining 13 individuals in this group showed no significant CD4
cell increases. All 15 people with fewer than 200 CD4 cells/mm3 had
more severe adverse side effects than the 10 participants with greater
than 200 CD4 cells/mm3. Side effects of IL-2 may include flu-like
symptoms (headache, body ache and fever), rash, lowered blood
pressure, diarrhea and laboratory abnormalities such as reduced
calcium, albumin and magnesium in the blood.

       bDNA testing showed than intermittent IL-2 therapy produced
transient increases in viral load among 4 of the 10 individuals with
baseline CD4 counts greater than 200 cells/mm3. 'It seems prudent to
use the best possible regimen of antiretroviral drugs, perhaps 2 or
more drugs in combination, as an adjunct to IL-2 therapy,' noted
Joseph Kovacs, MD, of the National Institutes of Health (NIH) and
co-author of the NEJM report.

       In the 4 patients with high increases in CD4 counts, HIV RNA
was undetectable by bDNA testing (below 10,000 copies/ml). However, in
the 15 individuals with fewer than 200 CD4 cells/mm3, IL-2 therapy was
associated with increased viral load as well as significant toxicity
and few or no improvements in immunologic responses. 'If IL-2 therapy
proves to have a beneficial clinical effect in patients with HIV, most
likely it will be in those individuals whose immune systems are not
severely debilitated,' said Kovacs.

       Host Factors Control HIV Infection

       The body's own immune defenses may be more effective than any
antiretroviral drug in controlling HIV infection, says Anthony Fauci,
MD, Director of the National Institute of Allergy and Infectious
Diseases (NIAID). Fauci discussed 'Host Factors in the Pathogenesis of
HIV Disease' at the Human Retrovirus Conference held recently in in
Washington, DC.

       Studies of long-term non-progressors among HIV-positive
individuals show these people have no decline in immune function for
many years, said Fauci, and this demonstrates that 'certain immune
responses can be very effective at containing the replication and
spread of HIV.'

       Fauci and colleagues have focused on how cytokines (chemical
messengers between cells) and the interactions between various immune
system cells induce the replication of HIV, and how this replication
may be controlled. Fauci's research team found that CD8 T cells are
able to block both the cell-to-cell interactions and the cytokine
signals that upregulate HIV expression. They found that adding
interleukin 2 (IL-2) to CD4 T cells from HIV positive individuals
caused little HIV replication when CD8 T cells were present. 'Our
studies show that IL-2 is a potent inducer of the suppressor
phenomenon in CD8 T cells, a function that supercedes its ability to
induce virus production in CD4 T cells,' said Fauci. In contrast, the
researchers found that interleukin 12 (IL-12) did not induce the
suppressing activity of CD8 cells, and instead induced replication of
HIV. Fauci's group also found that when dendritic cells, which present
invading microorganisms (such as HIV) to the immune system for
processing, interact with CD4 T cells in HIV positive individuals, HIV
replication increases.

       Study of Valacyclovir Halted

       A government study of valacyclovir (ACTG 204) was halted
earlier than planned when researchers discovered that people taking
the drug had significantly worse survival time than those taking
acyclovir. A 'prodrug' of acyclovir, valacyclovir converts into
acyclovir once inside the body, and higher doses can be absorbed than
with acyclovir.

       The primary objective of the study was to evaluate whether
valyclovir is effective in preventing cytomegalovirus (CMV) disease
among people with advanced AIDS (fewer than 100 CD4 cells/mm3. The
study was stopped in mid-February because researchers found that there
were significantly more deaths in the valyclovir arm of the study than
in the 2 acyclovir arms (high and low dose acyclovir). Disease
progression appears to have been the cause of death, not the use of
valacylovir. This unexpected finding bolsters the notion that
acyclovir (Zovirax) may have a survival benefit, although no one knows
precisely why. Speculation has centered on the ability of acyclovir to
suppress the activity of several of the herpesviruses (but not CMV) as
a explanation for its possible survival benefit. If the herpesviruses
act as cofactors in HIV disease, then reducing or suppressing their
reactivation may slow disease progression and thus prolong survival.

       Do Positive Women Have Higher Risk of Death than Men?

       HIV positive women are about 33% more likely to die without an
AIDS-defining illness than HIV poitive men, according to a study by
the National Institute of Allergy and Infectious Diseases (NIAID).
Reporting in the Journal of the American Medical Association (December
28, 1994), the researchers could not show why the women had a higher
risk of early death than men, but they offered some possible
explanations, including the following: women may have less access to
health care resources than men; homelessness; domestic violence; and
lack of social support. The government findings derive from a study of
4,500 people enrolled in a prospective study of disease progression
and survival. Note: the cause of death was unknown in 46% of the
women. (See page 43).

       Clarithromycin for MAC

       Results of a randomized, double-blinded, dose-ranging study
published in the Annals of Internal Medicine (December 15, 1994)
demonstrate both the effectiveness and limitations of clarithromycin
(Biaxin) against bacteremic Mycobacterium avium Complex (MAC)
infections. During the 12-week study most participants who took
clarithromycin became blood-culture negative at least once and
MAC-associated symptoms such as night sweats and fever also were
reduced.

       The highest dose (4 grams/day) cleared MAC cultures the
fastest, but also produced more adverse side effects than the lower
doses (1 gram or 2 grams daily). More than half of the study
participants reported gastrointestinal side effects from use of the
drug. During 12 weeks of treatment, laboratory tests revealed that
resistance to clarithromycin developed in 21% of isolates. During
follow-up, 46% of patients developed clarithromycin-resistant MAC
isolates.

       Herpesvirus-Associated Kaposi's Sarcoma (KS)

       BETA published a 'Treatment Alert' in December 1994 describing
a Columbia University research team's findings that a newly-discovered
human herpesvirus may be the cause of Kaposi's sarcoma (BETA Treatment
Alert. December 20, 1994). Principal investigators Patrick Moore, MD,
and Yuan Chang, MD, have added more information to their initial
report (published in Science magazine) suggesting that a new
herpesvirus may be the cause of KS. If these new findings are true,
they could strongly influence strategies for the treatment of KS (see
page 10).

       2 New Treatments for CMV Retinitis

       Both intravenous treatment with HPMPC (cidofovir) and an
intraocular, sustained-release Cytovene (ganciclovir) implant
significantly delay progression of cytomegalovirus (CMV) retinitis,
according to recent studies. HPMPC delays disease progression by a
median of 120 days, while the ganciclovir implant delays progression
by a mean of 226 days.

       Alcohol and Anal Sex May Increase HIV Disease Progression

       Laboratory tests of blood cells collected from individuals
after they were infused with alcohol show that HIV replicates 2 to 4
times more rapidly in these cells than in blood cells collected from
individuals infused with a solution of saltwater.

       Researchers also report that men who had unprotected receptive
anal intercourse with ejaculation experienced an increased risk of a
rapid decline in CD4 counts compared to men who never had receptive
anal intercourse after initial infection (page 13).

       Weightlifting May Slow Disease Progression

       A study at the Naval Medical Center in San Diego found that the
mean CD4 cell percentage decline in 22 weightlifters was 2.1% over a
2-year period, compared with a 2.7% decline among 25 nonexercisors and
a 6.4% decline among runners. All study participants were taking
anti-HIV therapy. These results suggest that weight training may offer
significantly more benefit to HIV positive individuals than intense
aerobic exercising, such as running. Note: the result that running is
more detrimental to CD4 counts than no exercise is confounding, since
other studies show that aerobic exercise is an immune boosting
activity (page 13).

       A Protein in Saliva Inhibits HIV Replication

       In test tube studies, a protein substance, SLPI (secretory
leukocyte protease inhibitor), found in human saliva indirectly
prevents HIV from infecting human blood cells. The finding by dental
researchers may help to explain why the virus rarely has been
documented to spread through saliva or through oral behaviors like
kissing or oral sex (page 14).

       AZT Study in Children Stopped

       Interim results of a government study (ACTG 152) comparing 3
different anti-HIV drug regimens in children aged 3 months to 18 years
show that AZT (zidovudine) monotherapy is the least effective regimen.
Children in the study receiving the other 2 regimens, ddI monotherapy
and ddI plus AZT, experienced significantly better results.

       The children receiving AZT alone had more rapid rates of
disease progression as measured by growth failure, new opportunistic
infections, neurologic deterioration or death. Children receiving AZT
monotherpay also had a significantly higher proportion of side effects
related to blood and chemical abnormalities. The study results
surprised the researchers because earlier findings have shown that
among adults AZT is superior to ddI in delaying disease progression.

       High-Dose Aspirin Study Halted

       The Community Research Initiative on AIDS (CRIA) in New York
City has halted its study of the anti-HIV effects of high-dose aspirin
over concerns about reductions in hematocrit levels and increases in
liver enzymes among 46 patients taking 1,000 mg aspirin with 1,000 mg
sucralfate 4 times daily. The purpose of the study was to ascertain if
high-dose aspirin was safe and if its anti-inflammatory effect would
provide a benefit to HIV positive individuals with 50-350 CD4
cells/mm3.

       Principal investigator Donald Kotler, MD, announced in a
January 21, 1995 press release the recommendation by the study's Data
Safety Monitoring Board (DSMB) to halt the study. The reductions in
hematocrit among those using high-dose aspirin were described as
'slight' and the increase in liver enzymes 'modest.' The CRIA press
release said the New York community-based research group will release
more data from the study at a later date.

       PCP Prophylaxis in Infants and Children

       PCP prophylaxis should be started in all infants born to
HIV-positive mothers at the time of birth, according to new
recommendations from the Centers for Disease Control and Prevention
(CDC). Treatment may be stopped at 6 months of age if PCR testing or
viral culture is negative for HIV infection, say the new
recommendations. These new guidelines were based on new data from the
New York City Perinatal HIV Transmission Collaborative Study Group and
from other studies.

       Thalidomide for AIDS-Related Wasting

       Thalidomide is being tested as a potential therapy for
AIDS-associated wasting among 93 individuals at 6 U.S. medical
centers. The trial is designed to demonstrate whether thalidomide can
help to reverse the significant weight loss experienced by many people
with AIDS.

       Morris Schambelan, MD, UCSF Professor of Medicine, is the
principal investigator of the trial. Schambelan also was the principal
investigator of the Phase III studies of recombinant human growth
hormone (Serostim), a genetically engineered drug recently shown
effective for the treatment of AIDS-associated wasting. Human growth
hormone appears to aid in the development of lean body mass among
individuals with AIDS-related wasting syndrome. Growth hormone is
currently available through a cost recovery Treatment IND program, but
usage will be limited due to the compound's high cost (call
1-800-714-AIDS for eligibility, cost and enrollment information).

       'The advantages of thalidomide are that it's an oral drug that
is relatively inexpensive and attacks the wasting syndrome by a
different route than hormonal therapies,' says Schambelan. Researchers
believe thalidomide works by inhibiting the production of tumor
necrosis factor (TNF), a naturally occuring protein in the body whose
presence in high levels can cause immune system disorders, including
wasting. For more information on thalidomide study sites and
eligibility requirements, call 1-800-TRIALS-A. The trial is sponsored
by Celgene, a biotechnology company in Warren, New Jersey. Several
community-based buyers' clubs may be selling thalidomide in the near
future, if the buyer has a written prescription from his/her
physician. For more information, contact Matthew Sharp at the San
Francisco Healing Alternatives Foundation (415-626-4053).

       Salk Immunogen Trials Will Go Forward

       An FDA advisory panel has recommended that Phase III trials of
the Salk treatment vaccine (Immunogen) should go forward, despite a
lack of convincing data that the product is effective.

       Project Inform Think Tank IV

       San Francisco's Project Inform each year brings together
outstanding AIDS researchers to conceive and prioritize therapeutic
regimens to help restore immune function among individuals with
advanced AIDS. The Think Tank sessions held February 25-27 in San
Francsico drew luminaries such as Drs. Robert Gallo, William Paul,
Gene Shearer and Robert Schooley. Further research into thymic
transplantation ranked as a high priority for the assembled
researchers. For a summary review of the Think Tank proceedings, see
page 28.

       FDA Electronic BBS

       The FDA electronic Bulletin Board System (BBS) is a free online
information service from the FDA's Office of Public Affairs. The new
free service replaces the commercially-provided FDA BBS from British
Telecom/Dialcom. The new BBS allows access to the same FDA
information, but also offers a simplified user interface and enhanced
features not available from Dialcom.

       The new BBS features a wide variety of information, including
news releases, drug and device product approvals lists, FDA medical
bulletin, special section on AIDS information and upcoming FDA
meetings. The BBS operates 24 hours daily, 7 days a week, and is
accessible by dialing 1-800-222-0185 with a computer and modem. For
more information about the FDA BBS, contact the FDA press office at
301-443-3285. If you need technical support, call 301-443-7318 7 am '7
pm Monday through Friday.

       National Cancer Institute Head Will Resign

       Samuel Broder, MD, head of the National Cancer Institute (NCI),
will resign his post in April 1995. Broder is credited with leading a
research team that in 1985 discovered that AZT (zidovudine) inhibits
HIV replication in previously uninfected human cells. As director of
NCI, Broder also supported early government research on other
nucleoside analog drugs such as ddC (zalcitabine) and ddI
(didanosine). After leaving NCI, Broder will take a post at IVAX
Corporation, a large producer of generic drugs and manufacturer of
intravenous drug delivery devices, according to The New York Times.

       New AIDS Research Director Criticizes Current Programs

       William Paul, PhD, the Director of the Office of AIDS Research
(OAR) at the National Institutes of Health, has criticized the
government's AIDS research program and says he will change its
direction. Too much of the $ 1.3 billion AIDS research program has
been tied up in clinical trials of drugs instead of being spent on
basic research, such as the biology of the disease, says Paul.

       'We do not understand major aspects of the virus's interaction
with the infected individual and the nature of the host response to
the virus is far from clear. A turning point has now been reached,'
Paul said in an article published in Science magazine (February 3,
1995). Paul and others want to increase support of research on the
basic mechanisms underlying HIV infection and disease progression and
on the nature of immune responses that might control such progression.

       New legislation has given Paul's OAR the responsibilty for
creating a comprehensive research plan that sets the scientific
priorities to be used in the development of the entire AIDS research
budget. Paul says the OAR will place high priority in making funds
available to support innovative, investigator-initiated research
proposals. 'The critical importance of immune responses both before
and after infection indicates to me that concerted efforts to
understand how the immune system can be mobilized to control HIV is of
the highest priority.'

       Other researchers are downplaying the necessity for research on
immunotherapies in AIDS. Recent findings that the immune system
appears to rebound vigorously when viral burden is significantly
reduced has suggested to some investigators that research resources
ought to be shifted away from immunotherapy and into the search for
more effective antiretroviral agents.

       Treatment Updates from the Second National Conference on Human
       Retroviruses and Related Infections
       Mark Mascolini

       Mark Mascolini is a freelance writer specializing in HIV and
       AIDS issues.

       With no International Conference on AIDS scheduled until the
summer of 1996, the Second National Conference on Human Retroviruses
and Related Infections could prove to be the principal forum for HIV
research in 1995. The meeting, sponsored by the American Society for
Microbiology, was held in Washington, DC, from January 29 through
February 2, 1995. Key presentations, as well as less pivotal but still
intriguing reports, are summarized in this article.

       AZT/3TC Edge over Monotherapy Confirmed in American Trials

       Investigators from 2 North American research teams reported
that combined therapy with AZT (zidovudine) and 3TC (lamivudine) has
significant and sustained effects on markers of disease progression
when compared with single-drug therapy, as French and German
researchers reported last November (see 'A Remarkable Combination: AZT
Plus 3TC' in the December 1994 issue of BETA). However, a study that
compared these 2 nucleoside analogs with AZT plus ddC (zalcitabine)
hinted that the advantage for AZT/3TC may be narrower when compared
with other combinations, at least in people who are already taking
AZT.

       In a controlled trial headed by Joseph Eron, MD, of the
University of North Carolina at Chapel Hill, 2 different doses of 3TC
combined with standard-dose AZT yielded greater and longer-lasting
drops in HIV RNA (a measure of viral load) compared with either drug
used alone in 364 people whose mean CD4 counts were in the mid to high
300-cell/mm3 range. None had taken an antiretroviral drug before the
study began, and 80% had no HIV-related symptoms. People taking 300 mg
3TC plus 600 mg AZT daily had a median drop in HIV RNA of 1.8 logs at
4 weeks and 0.8 log at 24 weeks. (One log equals a 10-fold drop from
the pretreatment level and 2 logs equal a 100-fold drop.) Those taking
600 mg 3TC plus 600 mg AZT daily had a 1.7-log decrease at 4 weeks and
a 1-log decrease after 24 weeks. In comparison, study participants
taking only 600 mg 3TC daily had a median 1.3-log fall in viral load
at 4 weeks and a 0.5-log fall by week 24, and those taking only AZT
had 0.5-log and 0.3-log decreases at weeks 4 and 24, respectively.
Among study participants whose viral loads have been tracked for 1
year while taking 3TC plus AZT, the decrease has remained around 1
log.

       When combined with AZT, the 300 mg daily dose of 3TC produced a
peak mean increase of 70 CD4 cells/mm3 at week 8, which fell to a 36
cells/mm3 gain at week 24. Among people taking AZT plus 600 mg 3TC,
the peak increase was 66 CD4 cells/mm3 at week 20, which fell to 58
CD4 cells/mm3 4 weeks later. But in the 600 mg 3TC monotherapy group,
the peak mean rise was 37 CD4 cells/mm3 at week 8, which dwindled to
15 cells/mm3 by week 24. Among those taking AZT alone, the peak mean
increase was 32 CD4 cells/mm3 at week 20, and at week 24 this group
had a mean increase of 8 CD4 cells/mm3 above baseline levels. Eron
reported that differences in viral load and CD4 counts between the
combination and monotherapy groups have been sustained for 52 weeks
among those whose course has been followed that long.

       The second North American study, headed by John A. Bartlett,
MD, of Duke University, appeared to show less sustained differences
between 2 3TC/AZT combinations and ddC plus AZT when results were
followed for a year. The study population differed from that of the
Eron study in that the median CD4 count at entry was only 211
cells/mm3 and the 254 participants had been taking AZT for 2 years.
Half of the people in this study had HIV-related symptoms when the
trial began.

       Among people taking 300 mg 3TC plus AZT daily, the peak median
decrease in HIV RNA was 1.4 logs after 2 weeks of therapy, compared
with 1.5 logs in those taking 600 mg 3TC plus AZT daily and 0.6 log
among people taking AZT plus ddC. But after 24 weeks, the median
decrease was 0.8 log for low-dose 3TC plus AZT, 0.6 log for high-dose
3TC plus AZT, and 0.6 log for AZT plus ddC. This trend held true
through 48 weeks of follow-up.

       The mean increase in CD4 count peaked at 48 cells/mm3 2 weeks
into the trial in the 300 mg 3TC combination group and stood at 32
cells/mm3 after 24 weeks. In the 600 mg 3TC combination group, a mean
peak CD4 increase of 50 cells/mm3 occurred at 8 weeks and declined to
15 cells/mm3 above baseline at 24 weeks. In the AZT/ddC group, the
mean peak increase was 2 CD4 cells/mm3 at 12 weeks, but that measure
fell to 15 CD4 cells/mm3 below baseline after 24 weeks. Once again,
however, the curves describing CD4 cell responses were clearly merging
after 52 weeks of follow-up. Bartlett cautioned against reading too
much into these 52-week trends, however, because results on only a
handful of study participants were analyzed at the time of his
presentation.

       The principal 3TC-related side effects reported by these
investigators were hair loss and hypoglycemia. Eron J and others. A
randomized double-blind multicenter comparative trial of lamivudine
(3TC) monotherapy vs zidovudine (ZDV) monotherapy vs 3TC + ZDV
combination in naive patients with CD4 200-500 cells/mm3. Second
National Conference on Human Retroviruses and Related Infections.
Washington, DC. January 29-February 2, 1995. Abstract LB34. Bartlett J
and others. A randomized, double-blind multicenter comparative trial
of lamivudine (3TC)/zidovudine (ZDV) combination therapy vs
ZDV/dideoxycytidine (ddC) combination therapy in ZDV-experienced
patients with CD4 100-300 cells/mm3. Second National Conference on
Human Retroviruses and Related Infections. Washington, DC. January
29-February 2, 1995. Abstract LB35.

       Protease Inhibitor Reports Spark Debate on Resistance

       Investigators studying 6 protease inhibitors arrived at the
retrovirus conference armed with new data from clinical and
preclinical trials, but a debate over the import of viral resistance
to these antiretroviral agents threatened to monopolize discussion of
their potential efficacy. Researchers from Merck offered data
indicating that 42 weeks of therapy with their protease candidate
MK-639 prompted the emergence of mutant forms of HIV that resist the
antiviral effects of MK-639. The resistant mutants also inhibit the
effects of Hoffmann-LaRoche's saquinavir, an Abbott drug similar to
one currently in clinical trials, DuPont-Merck's XM-323 and
Vertex-Wellcome's VX-478. Merck's John Condra said that these
findings, based on studies of 4 trial participants, 'raise the
possibility' that combination therapy with protease inhibitors may be
unwise. Protease inhibitor drugs might be better suited to
combinations that do not involve other protease inhibitors, Condra
suggested.

       Other protease researchers argued, however, that the Merck team
is jumping to conclusions about the future clinical use of protease
inhibitors. Roche's Noel Roberts, PhD, said that analysis of viral
strains among people taking saquinavir indicated that recurrent
mutations as seen in the Merck studies were not emerging in clinical
trials of this Roche compound. Martin Markowitz, MD, who is studying
Abbott's ABT-538 at the Aaron Diamond AIDS Research Center, did find
cross-resistance between ABT-538 and saquinavir, Merck's MK-639,
Agouron's AG-1343 and DuPont-Merck's DMP-450 in one set of
experiments. But in the same series of tests, the lack of
cross-resistance with a new Upjohn protease inhibitor called U-104,904
and a novel Searle compound called S-338 encouraged Markowitz to
conclude that there is 'a scientific basis for the use of
non-cross-resistant protease inhibitors in people with HIV-1
infection.'

       Another potential problem with protease inhibitors is how
avidly they bind to a serum protein called alpha-1 A glycoprotein
(AAG). Jean-Pierre Sommadossi, PhD, of the University of Alabama at
Birmingham, said that the binding of Searle's SC-52151 to AAG blocked
its uptake by infected cells and sabotaged its antiviral effect. As a
result, Searle withdrew this protease inhibitor from development last
year. Sommadossi noted that Merck's MK-639 and Roche's saquinavir also
bind to AAG, but not nearly as much as SC-52151, and probably not
enough to greatly decrease their antiviral activity. He urged all
protease inhibitor developers to test their compounds for AAG binding
before forging into clinical trials. Investigators studying individual
protease inhibitors reported the following findings at the Washington,
D.C. meeting:

       Abbott's ABT-538

       In a 12-week placebo-controlled trial reported by the Aaron
Diamond's Markowitz, the Abbott compound ABT-538 decreased levels of
circulating virus by 1.3-2.5 logs in 23 study participants whose
baseline CD4 cell counts ranged from 38-506 CD4 cells/mm3. In most
people, he said, the drop was just above 2 logs. The maximum CD4 count
increase was a 3.3-fold gain. Diarrhea was the most common side
effect.

       Merck's MK-639

       In a 24-week multicenter study involving 73 people whose CD4
cell counts at entry ranged from 50-500 CD4 cells/mm3, John Mellors,
MD, of the University of Pittsburgh, said that MK-639 significantly
increased CD4 counts and decreased viral load compared with AZT,
followed by an optional switch to ddC. A high-dose regimen of MK-639
(400 mg every 6 hours replaced late in the study with 600 mg every 6
hours) had a greater antiviral effect than a low-dose regimen (200 mg
every 6 hours followed later by 600 mg every 6 hours). Bilirubin,
which is normally excreted via the liver and gall bladder, was
elevated in some people taking MK-639, but none had any serious liver
problems. Preliminary results from a study that began therapy at 600
mg every 6 hours in 5 people who had already been taking AZT found a
mean 1.5-log decrease in viral load, according to George Drusano, MD,
of Albany Medical College. The mean CD4 count tripled over 22 weeks of
follow-up in this uncontrolled study, and average body weight rose by
3.5 kg and remained stable.

       Roche's saquinavir

       Saquinavir is being studied in 2 Phase III trials at a dose of
1,800 mg daily. Because side effects at this dose are minimal,
investigators pushed the dose to 3,600 mg or 7,200 mg daily in 40
people with CD4 counts between 200 and 300 cells/mm3 to see if a more
potent effect could be achieved. Jonathan Schapiro, MD, of Stanford
University, said that the 3,600 mg dose yielded more than a 1-log mean
drop in viral load and a mean CD4 cell increase of 100 cells/mm3
before these measures began to return to baseline values. The response
appears to be greater in people taking 7,200 mg daily, according to
Schapiro, but too few people in this group were evaluated by the time
of the meeting to allow him to draw broad conclusions. Some study
participants had elevated liver function tests and neutropenia, but
these problems disappeared when therapy was stopped for a short time.

       Agouron's AG-1343

       Preclinical trials reported by Agouron's Amy Patick, PhD,
suggest that AG-1343 could be synergistic with AZT and ddI
(didanosine), but that cross-resistance between it and other protease
inhibitors may be a limitation. Two small Phase I trials comparing
AG-1343 with placebo indicate that concentrations of the drug in the
blood remain high enough to exert a consistent antiviral effect.
Vertex/Wellcome's VX-478

       Preclinical studies of this VX-478 suggest that it, too, is
synergistic with AZT and ddI, that it is well absorbed in an oral
formulation and is not toxic in monkeys.

        Activist Jules Levin is trying to gather protease inhibitor
experts into a task force that will coordinate more rapid development
of these agents and easier access to them for people in the later
stages of HIV infection. People interested in helping Levin or
checking on his progress may call him at 718-524-8541.

       Sources

       Condra JH and others. Mutations in HIV protease conferring
resistance to inhibitor L-735,524. Second National Conference on Human
Retroviruses and Related Infections. Washington, DC. January
29-February 2, 1995. Abstract 187.

       Markowitz M and others. Evaluation of the antiviral activity of
orally administered ABT-538, an HIV-1 protease inhibitor. Second
National Conference on Human Retroviruses and Related Infections.
Washington, DC. January 29-February 2, 1995. Abstract 185.

       Markowitz M and others. Patterns of specific mutations in HIV-1
protease that confer resistance to a panel of protease inhibitors.
Second National Conference on Human Retroviruses and Related
Infections. Washington, DC. January 29-February 2, 1995. Abstract 188.

       Mellors J and others. A randomized, double-blind study of the
oral HIV protease inhibitor L-735,524 vs zidovudine (ZDV) in
p24-antigenemic, HIV-1-infected patients with less than 500 CD4
cells/mm3. Second National Conference on Human Retroviruses and
Related Infections. Washington, DC. January 29-February 2, 1995.
Abstract 183.

       Painter GR and others. An overview of the preclinical
development of the HIV protease inhibitor VX-478 (142W94). Second
National Conference on Human Retroviruses and Related Infections.
Washington, DC. January 29-February 2, 1995. Abstract LB5.

       Patick AK and others. In vitro antiviral and resistance studies
of AG1343, an orally bioavailable inhibitor of HIV-1 protease. Second
National Conference on Human Retroviruses and Related Infections.
Washington, DC. January 29-February 2, 1995. Abstract 184.

       Quart BD and others. Phase I safety, tolerance,
pharmacokinetics and food effect studies of AG1343, a novel HIV
protease inhibitor. Second National Conference on Human Retroviruses
and Related Infections. Washington, DC. January 29-February 2, 1995.
Abstract LB3.

       Roberts N. Resistance to saquinavir. Protease: Resistance,
Cross-Resistance, Implications for Clinical Study and Use for 1995 and
Beyond. Washington, DC. February 2, 1995. Oral presentation.

       Schapiro JM and others. First efficacy and safety results of
the high-dose saquinavir monotherapy trials. Second National
Conference on Human Retroviruses and Related Infections. Washington,
DC. January 29-February 2, 1995. Abstract LB2.

       Sommadossi J-M and others. A human serum glycoprotein
profoundly affects antiviral activity of the protease inhibitor
SC-52151 by decreasing its cellular uptake. Second National Conference
on Human Retroviruses and Related Infections. Washington, DC. January
29-February 2, 1995. Abstract LB4.

       Stein DS and others. A 24-week open-label phase I evaluation of
HIV protease inhibitor L-735,542. Second National Conference on Human
Retroviruses and Related Infections. Washington, DC. January
29-February 2, 1995. Abstract LB1.

       *****************
       Stronger Evidence Links New Herpesvirus to Kaposi's Sarcoma

       Researchers from Columbia University have added more convincing
evidence to their earlier findings suggesting that a new herpesvirus
may cause Kaposi's sarcoma (KS). Coinvestigators Patrick Moore, MD,
and Yuan Chang, MD, said that they have now mapped out 95% of the
genetic sequences of the virus, which they call Kaposi's
sarcoma-associated herpesvirus (KSHV). Fifteen of the 16 genetic
segments they have defined are closely related to a herpesvirus that
causes cancer in monkeys. In their initial report, published in the
December 16, 1994 issue of Science, Moore and Chang found evidence of
the virus in 25 of 27 samples of KS lesions from HIV positive people.
In Washington they said that they also identified the virus in tissue
samples from 6 of 6 people with classical (non-HIV-related) KS and in
4 of 4 samples from HIV negative gay men with KS. Signs of KSHV could
not be found in 10 control samples of peripheral blood mononuclear
cells or in 10 of 11 skin control samples; all control samples were
from HIV negative persons. (Moore said the one positive result in the
skin control samples can probably be attributed to a laboratory
error.)

       Moore stopped short of claiming that KSHV causes KS, but he
acknowledged that 'we're at least heading in that direction.' Steven
Miles, MD, a KS expert from the University of California, Los Angeles,
was less circumspect. He said he believes that KSHV is 'very
definitely' a new virus that causes KS and that he has confirmed some
of Moore and Chang's findings in his laboratory. Isolation of the
virus means that a blood test to detect it can probably be developed,
and support the logic of testing antiherpes agents such as foscarnet
as therapy (see below).

       But some questions about the new virus remain unresolved.
Herpesviruses are commonly carried by many healthy people and lead to
symptoms only when the immune system is weakened. So far, however,
KSHV has been found only inconsistently in people without either HIV
or KS. Moore P. A new human herpesvirus associated with Kaposi's
sarcoma. Second National Conference on Human Retroviruses and Related
Infections. Washington, DC. January 29-February 2, 1995.

       Taxol, ApoE and Foscarnet Considered for KS Therapy

       National Cancer Institute investigator M. Wayne Saville, MD,
reported that paclitaxel (Taxol) is active against KS in some people
with severe suppression of immunity and advanced KS. In 20 HIV
positive people with a median CD4 count of 16 cells/mm3, intravenous
paclitaxel beginning at 135 mg/m2 as a 3-hour intravenous infusion and
increased to a maximum of 175 mg/m2 produced 13 partial responses
(lesions became smaller but did not disappear). Six people had minimal
responses, 1 had progressive KS and none had a complete response. The
response to paclitaxel in people with advanced KS has lasted only 2
months in this study, but retreatment of 2 people again induced a
response in both. The drug alleviated pulmonary KS, a particularly
severe manifestation, in 4 of 5 people.

       Laboratory studies of apoplipoprotein E3 (ApoE) suggest that
this protein may control KS by stopping the formation of new blood
vessels that feed KS lesions. Phil Browning, MD, of Vanderbilt
University, reported that ApoE reins in the spread of KS cells in a
dose-dependent fashion'the more ApoE used, the greater the inhibition.
This agent is an attractive drug candidate, Browning said, because it
has no toxic effects in the animals in which it has been studied. Many
anti-KS agents now being studied, including paclitaxel and foscarnet,
can have severe side effects. Browning is planning to approach the FDA
for approval to begin safety studies in humans.

       Although there were no presentations on studies of foscarnet
for KS at the Washington conference, this therapeutic strategy was
discussed informally there. The antiherpes agent, which is used to
treat cytomegalovirus (CMV) disease, induced long-term remission of KS
in 3 of 5 people treated in Sweden by Linda Morfeldt, MD. She used a
single 10-day infusion of foscarnet in 4 of the 5 people. One person
whose KS progressed after an initial response to foscarnet responded
again to a second 10-day infusion. Although 2 of the 3 responders had
CD4 counts below 50 cells/mm3, Morfeldt believes foscarnet will be
effective only for mild KS.

       This therapeutic approach has become all the more compelling
since Moore and Chang's discovery that KS is most likely caused by a
herpesvirus. Alvin Friedman-Kien, MD, of New York University, is now
planning to study foscarnet for early KS in 20 people. According to
the January 20, 1995 issue of AIDS Treatment News, Friedman-Kien is
focusing on people who have had KS for no longer than 6 months, who
have not been treated for KS before and whose CD4 count is at least 50
cells/mm3. Among 21 HIV positive people treated with the Abbott
protease inhibitor ABT-538 in an Australian trial, a response to the
drug was seen in the only 2 study participants with KS. In one person,
KS lesions disappeared completely 2 months after therapy with ABT-538,
then returned 5 months later. In the second person, KS lesions became
flatter and lighter but did not disappear. 'I'm not claiming any
miracles here,' said David Cooper, MD, 'but it's evidence that we
should look at protease inhibitors' for KS. Browning P. The effects of
ApoE lipoprotein on Kaposi's sarcoma cells in culture. Second National
Conference on Human Retroviruses and Related Infections. Washington,
DC. January 29-February 2, 1995. Roundtable session. Cooper D. Effects
of ABT-538, an HIV protease inhibitor, on Kaposi's sarcoma. Second
National Conference on Human Retroviruses and Related Infections.
Washington, DC. January 29-February 2, 1995. James J. Kaposi's
sarcoma: possible foscarnet treatment? AIDS Treatment News 215.
January 20, 1995. Morfeldt L and Torssander J. Long-term remission of
Kaposi's sarcoma following foscarnet treatment in HIV-infected
patients. Scandinavian Journal of Infectious Diseases 26: 749-752.
1994.

       Saville MW and others. Use of paclitaxel (Taxol) as therapy for
HIV-associated Kaposi's sarcoma. Second National Conference on Human
Retroviruses and Related Infections. Washington, DC. January
29-February 2, 1995. Abstract 134.

       *******************
       No Advantage to Higher-Dose Chemotherapy for Lymphoma

       Standard chemotherapy followed by treatment with granulocyte
macrophage-colony-stimulating factor (GM-CSF), an agent that boosts
certain white blood cell counts, was no more effective than low-dose
chemotherapy without GM-CSF in people with HIV-related lymphoma.
Lawrence Kaplan, MD, of the University of California, San Francisco,
reported that a randomized study involving 188 people with lymphoma
and HIV infection found no advantage for standard-dose mBACOD (a
combination of the drugs methotrexate, bleomycin, doxorubicin,
cyclophosphamide, vincristine and dexamethasone). The complete
response rate was 46% in the low-dose group compared with 50% in the
standard-dose group in the trial (ACTG 142). Among those who received
the low-dose regimen, 32% had partial responses compared with 28% in
the standard-dose group. Median survival was 34 weeks in the low-dose
group and 31 weeks for those who got standard-dose mBACOD plus GM-CSF.
None of these differences were statistically significant.

       These findings contradict the belief that lymphoma patients
with HIV infection do better with a standard chemotherapy regimen
whose side effects are ameliorated by so-called blood
colony-stimulating factors (CSF), according to Steven Miles, MD, who
chaired the session at which Kaplan spoke. If the low-dose regimen is
just as effective against lymphoma as more intense chemotherapy,
Kaplan said, it has a clear advantage because it is less toxic. Only
21.9% of study participants getting low-dose chemotherapy suffered
neutropenia (a decrease in white blood cells) versus 35.9% in the
standard-dose group. This difference is statistically significant.
Kaplan recommended using the low-dose regimen for lymphoma patients
with fewer than 200 CD4 cells/mm3. For those with higher CD4 counts,
he said, the decision is more difficult. But he believes the standard
dose may be appropriate for some of these people with healthier immune
systems. All people with lymphoma should receive prophylaxis for
Pneumocystis carinii pneumonia (PCP). Kaplan L. ACTG 142: the results
of a randomized clinical trial of low-dose chemotherapy versus full
chemotherapy and cytokine in AIDS lymphoma. Second National Conference
on Human Retroviruses and Related Infections. Washington, DC. January
29-February 2, 1995.

       **********************
       Acyclovir Survival Picture Drifts a Little out of Focus

       Last year an analysis of gay men enrolled in the Multicenter
AIDS Cohort Study (MACS) indicated that those who took acyclovir and
AZT (zidovudine) survived longer than those who took AZT but no
acyclovir (see the June 1994 issue of BETA). Some observers reserved
judgment, however, because a randomized, double-blind clinical trial
of acyclovir plus AZT versus AZT alone (ACTG 063) had yet to be
completed. Such forward-looking controlled trials are considered more
definitive than 'observational' studies such as the MACS, which simply
look back at what has already happened to different groups of people.
ACTG 063 is now complete and the results were reported in Washington,
but even some of the investigators say that acyclovir's influence on
survival remains an open question. Two other studies presented at the
Human Retroviruses meeting add more data for discussion, but offer no
clear-cut answers. The ACTG trial, headed by Ann Collier, MD, of the
University of Washington, found no significant difference in survival
between people who took acyclovir plus AZT (median survival 972 days)
and people who took only AZT (median survival 934 days). But that
result does not clearly contradict the MACS conclusion because many
people in ACTG 063 stopped taking the therapy they had been assigned
long before they eventually died. The median follow-up of study
participants was 562 days, but the median time on therapy was only 310
days, Collier reported. About three-quarters of the deaths occurred
more than 60 days after therapy was stopped. As a result, one could
argue'as MACS investigator Neil Graham, MD, does'that too much time
elapsed after people stopped taking acyclovir to accurately gauge its
effect on survival.

       Another observational study reported at the meeting, headed by
Richard Chaisson, MD, of Johns Hopkins, reflected the ACTG findings
rather than those of the observational MACS study. In Chaisson's study
population of 1,044 people taking AZT, there was no survival advantage
for the 336 who also took acyclovir, either when survival was measured
1 year after they started taking AZT or when it was measured from the
diagnosis of AIDS in those taking acyclovir before an AIDS diagnosis.
In fact, one statistical method these investigators used linked use of
acyclovir to an increased risk of death. However, a third group of
clinicians did weigh in with findings that offered a rationale for the
MACS results. In 8 HIV positive people with herpes simplex virus (HSV)
infection cared for by Larry Mole, MD, and his colleagues at the VA
Medical Center in Palo Alto, California, levels of circulating HIV RNA
rose during herpes outbreaks, then fell after treatment with
acyclovir. But each time these HIV levels fell, they never quite
returned to where they were before the active herpes episode occurred.
Mole concluded that his results coupled with the MACS data 'suggest
that HSV may play an important role in HIV disease progression by
increasing HIV plasma viral load.' But the Palo Alto clinicians said
that their findings do not suggest whether long-term therapy with
acyclovir could have a prolonged effect on HIV viral load. MACS
investigator Graham has said that he believes that all people with CD4
counts below 200 cells/mm3 and all those with evidence of HSV
infection should take acyclovir. Because of the confounding results,
Collier is not ready to make such a recommendation, especially since
the cost of daily therapy with acyclovir adds up quickly over the
course of a year. That part of the equation will change in 2 years,
however, when Burroughs Wellcome's patent on acyclovir expires and
cheaper generic forms of the drug become available.

       Collier AC and others. Prospective comparative study of
acyclovir (ACV) and zidovudine (ZDV) versus ZDV alone in patients with
AIDS. Second National Conference on Human Retroviruses and Related
Infections. Washington, DC. January 29-February 2, 1995. Abstract 383.

       Gallant JE and others. Lack of association between acyclovir
use and survival in patients with advanced HIV disease treated with
zidovudine. Second National Conference on Human Retroviruses and
Related Infections. Washington, DC. January 29-February 2, 1995.
Abstract 382.

       Mole L and others. Plasma HIV RNA levels are increased during
active herpes simplex viral infection. Second National Conference on
Human Retroviruses and Related Infections. Washington, DC. January
29-February 2, 1995. Abstract 239.

       ********************
       Implanted and Oral Ganciclovir Evaluated for CMV Retinitis

       Researchers from the National Eye Institute and Chiron
Corporation offered data showing that sustained-release ganciclovir
implants are effective in preventing progression of cytomegalovirus
(CMV) retinitis, although the strategy is not without risk.
Investigators studying oral ganciclovir spelled out the advantages and
potential disadvantages of long-term prophylaxis with the drug. A
multicenter trial in which 26 people with peripheral CMV retinitis
were randomized to receive either immediate or delayed treatment with
an intraocular ganciclovir implant timed to release 1 microgram of the
drug hourly showed a highly significant difference between progression
in the immediate group (226 days) and the deferred group (15 days).
But because the implanted drug is directed to the site of disease,
nonocular CMV disease developed in 8 of the 26 people. In addition,
the investigators estimated that there was a 50% chance that retinitis
would develop in the untreated eye by 6 months. Another study that
compared the sustained-release implant to standard intravenous
ganciclovir showed a median time to disease progression of 150 days
for the implant group and 72 days for the intravenous group. In this
analysis of 148 people, it was difficult to assess treatment group
differences in development of extraocular CMV or of retinitis in
originally uninvolved eyes because people receiving intravenous
ganciclovir were offered the implant as soon as progression of
retinitis was detected.

       At a symposium on oral ganciclovir held just before the opening
session of the Human Retroviruses conference, Stephen Spector, MD, of
the University of California, San Diego, discussed several
prophylactic strategies that might be considered with the oral drug.
Preventive therapy could simply be started at a predetermined cutoff,
such as 100 or 50 CD4 cells/mm3, or at a low CD4 count only among
people in whom signs of CMV infection can be determined by a CMV
antigen test, polymerase chain reaction (PCR) or blood culture (see
Research Notes in this issue). Other oral ganciclovir investigators,
such as Carol Brosgart, MD, of Berkeley, California, suggested that an
alternative and less expensive strategy would be for people to have
monthly ophthalmologic exams when they cross a certain CD4 cell count
threshold. (The wholesale price of oral ganciclovir is set at $39 per
day.)

       On the basis of results from a placebo-controlled trial of oral
ganciclovir (see 'Oral Ganciclovir' in the December 1994 issue of
BETA), Spector said that prophylaxis with the oral drug would stave
off CMV infection in many people with HIV and so improve their quality
of life. The other side of the coin is that long-term oral prophylaxis
could lead to the emergence of ganciclovir-resistant strains of CMV
that may then fail to respond to intravenous therapies. Spector also
noted that people already taking several drugs for HIV and related
conditions would have to consider the potential additive toxicity of
taking daily ganciclovir.

       Chiron Ganciclovir Implant Study Group. A randomized controlled
multicenter clinical trial of a sustained-release intraocular
ganciclovir implant in AIDS patients with CMV retinitis. Second
National Conference on Human Retroviruses and Related Infections.
Washington, DC. January 29-February 2, 1995. Abstract LB16.

       Martin DF et al. Treatment of cytomegalovirus retinitis with an
intraocular sustained-release ganciclovir implant: a randomized
controlled clinical trial. Second National Conference on Human
Retroviruses and Related Infections. Washington, DC. January
29-February 2, 1995. Abstract LB17.

       Spector SA. Perspectives on prophylaxis for cytomegalovirus in
HIV-infected persons. Theory Into Practice: The Role of Oral
Ganciclovir for CMV Retinitis and CMV Disease. Washington, DC. January
29, 1995. Oral presentation.

       *******************
       Alcohol and Anal Sex Speed HIV Progression; Weight-Lifting May
       Slow It

       Four studies looking at behavioral factors found 2 that appear
to hasten the course of HIV infection, 1 that is linked to an
increased risk of non-life-threatening complications, and 1 that seems
to slow the progression of HIV disease. The good news for
weight-lifters is that pumping, compared with not exercising and with
running, slows the decline in CD4 cell percentage, which is considered
a more reliable marker of immune function than the absolute CD4 count.

       Researchers at the Naval Medical Center in San Diego found that
the mean CD4 percentage decline in 22 weight-lifters was 2.1% over 2
years, compared with a 2.7% decrease among 25 nonexercisers and a 6.4%
drop among 7 runners. For this study, 'weight trainers' were defined
as those who voluntarily exercised at least 3 times weekly, included
weight-lifting as part of their regimen and specifically denied
running. 'Runners' were defined as those who voluntarily ran at a pace
faster than 8 minutes per mile 3 times weekly and specifically denied
weight training. The difference between CD4 percentage declines among
weight-lifters and runners was statistically significant. Members of
all groups were receiving antiretroviral therapy for 'appropriate
indications.' The investigators concluded that weight training 'may
offer benefits superior to intense running' for HIV positive people
who have the motivation and capacity to undertake strenuous exercise.

       However, another study conducted by infectious disease
specialists at St. Michael's Hospital in Toronto, Ontario, suggests
that the relation between exercise and disease progression is not so
clear-cut. They found that moderate exercise (defined as 20 minutes on
an exercise bicycle) by HIV positive people reduced the ability of
their white blood cells to ingest and kill bacteria, 20 minutes after
exercise. (Cell studies were performed only once, 20 minutes after
exercise, so the duration or length of the effect is unknown.) This
result may mean that exercise could make people with HIV more prone to
secondary bacterial infections, at least in the period immediately
following exercise.

       The news for HIV positive smokers was not good. A team from the
Centers for Disease Control and Prevention (CDC) found that smoking
was tied to the development of oral candidiasis, oral hairy
leukoplakia and bacterial pneumonia among 106 long-term smokers
compared with 126 HIV-positive people who had never smoked. But
smoking was not associated with a faster decline in CD4 cells or a
greater incidence of Kaposi's sarcoma, Pneumocystis carinii pneumonia
or other AIDS-defining conditions in the smokers.

       Researchers from Thomas Jefferson University in Philadelphia
found that HIV replicates 2 to 4 times more rapidly in peripheral
blood mononuclear cells (PBMC) collected after people were infused
with 500 mg/kg of alcohol than in PBMC collected from people infused
with a plain saltwater solution. The studies also showed that alcohol
greatly reduced levels of tumor necrosis factor-alpha, gamma
interferon and interleukin 1, signaling molecules that are important
in regulating the function of immune system cells. Anal receptive
intercourse appears to be correlated not only with a greater risk of
HIV infection, but also with a steeper CD4 cell decline once a person
is infected. Analysis of 1,809 men enrolled in the Multicenter AIDS
Cohort Study (MACS) showed that those who had anal receptive
intercourse with ejaculation during the previous 12 months had an
increased risk of a rapid decline in CD4 count compared with men who
claimed that they had never had anal receptive sex. Men who had anal
receptive intercourse with 11 or more partners had an even higher risk
of a sudden plunge in CD4 cells than those who had 10 or fewer
partners. The investigators also found that men who had anal receptive
sex were more likely to be smokers than those who did not.

       References

       Bagasra O and Pomerantz RJ. Effects of acute ethanol infusion
on susceptibility of peripheral blood mononuclear cells to infection
with HIV-1 and on selected cytokine production in vitro. Second
National Conference on Human Retroviruses and Related Infections.
Washington, DC. January 29-February 2, 1995. Abstract 216.

       Conley LJ and others. The effect of cigarette smoking on
selected medical conditions associated with HIV infection. Second
National Conference on Human Retroviruses and Related Infections.
Washington, DC. January 29-February 2, 1995. Abstract 16.

       Fong IW and others. The effect of exercise on leukocyte
function in patients with HIV infection. Second National Conference on
Human Retroviruses and Related Infections. Washington, DC. January
29-February 2, 1995. Abstract 165.

       Olson PE and others. CD4+ correlates of weight training in
HIV-seropositive outpatients. Second National Conference on Human
Retroviruses and Related Infections. Washington, DC. January
29-February 2, 1995. Abstract 544.

       Wiley D and others. Monotonic rapid decline of CD4+ cells
related to anal receptive intercourse with ejaculation in a cohort of
HIV-infected men who have sex with men. Second National Conference on
Human Retroviruses and Related Infections. Washington, DC. January
29-February 2, 1995. Abstract 252.

       **********************
       20-Year AIDS-Free HIV Infection Possible for More than 1 in 10
       People

       Statisticians working with the Multicenter AIDS Cohort Study
(MACS) used data from 1,649 gay men to calculate that a sizable
proportion of people with HIV infection are destined to live without
AIDS-defining symptoms for longer than the 10 years accepted as common
wisdom. Alvaro Munoz, PhD, of Johns Hopkins University, believes that
10 years is the approximate median time to progression. In other
words, half of all infected people will have AIDS within 10 years of
HIV infection and half will have AIDS more than 10 years after
infection. According to Munoz's calculations, 34.5% of infected people
will be free from clinical AIDS 12 years after seroconversion, and
12.7% will have no AIDS-defining symptoms 20 years after
seroconversion.

       References

       Munoz A and others. Estimation of long-term survivors using
different models for the incubation period in homosexual men. Second
National Conference on Human Retroviruses and Related Infections.
Washington, DC. January 29-February 2, 1995. Abstract 555.

       ****************
       Saliva Protein Protects against HIV Transmission

       The mystery behind the apparently low rate of oral transmission
of HIV may have been solved by scientists at the National Institute of
Dental Research (NIDR) in Bethesda. They identified a protein in human
saliva that inhibits HIV and named it SLPI (pronounced 'slippy') for
secretory leukocyte protease inhibitor. The NIDR investigators exposed
white blood cells to SLPI and other salivary proteins but found that
only SLPI protected the cells from HIV, and that it continued to do so
for 3 weeks. SLPI appears to block infection by binding to a cellular
molecule, not to HIV itself. But the cell surface receptor it binds to
is not CD4, which is the primary cellular receptor for HIV.
Researchers have known for some time that there is a secondary
receptor that HIV needs in order to penetrate its cellular targets,
but they have been unable to identify it. The NIDR team plans to track
down the SLPI receptor and see if it has a role in HIV entry into
cells. Much work remains, they said, before scientists learn whether
SLPI can be synthesized and used as an infection blocker.

       Reference

       McNeely B and others. Secretory leukocyte protease inhibitor: a
human saliva protein exhibiting anti-HIV-1 activity. Second National
Conference on Human Retroviruses and Related Infections. Washington,
DC. January 29-February 2, 1995. Abstract 90.

       ************************
       Weakened Immunity and Heart Defect Linked in Children

       Clinicians conducting a 5-center study of 197 children infected
with HIV linked impaired ability to pump blood with the severity of
their immune system defect. The children were all infected via
vertical transmission, and their ages ranged from 0.2 to 14 years.
Steven Lipshultz, MD, of Children's Hospital in Boston, reported that
children whose CD4 counts were more than 2 standard deviations below
normal were more likely than other children to have an abnormal left
ventricle that pumped blood less efficiently. (Statistically speaking,
95% of values'such as CD4 counts'lie within 2 standard deviations of a
mean value.) Progressive failure of the immune system and the
cardiovascular system appear to be related, Lipshultz concluded.

       Reference

       Lipshultz S and others. Cardiac dysfunction in HIV-infected
children correlates with immune dysfunction: the prospective NHBLI
P2C2 study. Second National Conference on Human Retroviruses and
Related Infections. Washington, DC. January 29-February 2, 1995.
Abstract 193.

       ************
       Pain in AIDS
       William Breitbart, MD, and Mathew Lefkowitz, MD

       William Breitbart, MD, is Associate Attending Psychiatrist at
       Memorial Sloan Kettering Cancer Center, New York, NY, and
       Associate Professor of Psychiatry at Cornell University Medical
       College.

       Mathew Lefkowitz, MD, is Clinical Associate Professor of
       Anesthesiology at the State University of New York (SUNY)
       Health Science Center at Brooklyn, and Director and Attending
       Anesthesiologist of the SUNY Pain Management Service.

       This comprehensive article on pain in HIV disease is structured
in 2 parts. Part I presents background information on types,
mechanisms and prevalence of pain. Part II discusses the clinical
management of pain in people with AIDS and highlights the unique needs
of people with AIDS-related pain and a history of substance abuse.

       PART I: NATURE OF AIDS-RELATED PAIN

       Introduction

       Studies have documented that pain is a significant problem for
adults and children with AIDS, associated with psychological and
functional morbidity. Clinicians have neglected pain management in
AIDS patients, focusing instead on treating life-threatening
opportunistic infections, cancers and neuropsychiatric syndromes such
as AIDS dementia complex. Inadequate management of pain in AIDS is
also due to the inability of many clinicians to properly assess pain
in all its dimensions. All too frequently physicians and nurses
presume that psychological variables are the cause of continued pain
or lack of response to medical treatment, when they have not
adequately appreciated the role of medical factors. Conversely,
clinicians often make the mistake of focusing primarily on the
physical aspects of pain and ignoring important psychological and
social factors. Other causes of inadequate pain management include:
lack of knowledge of current pharmaco- or psychotherapeutic
approaches, unsuccessful communication between doctors and patients,
limited capacity of patients impaired by organic mental disorders to
communicate, limited expectations of patients regarding the
achievement of pain relief and doctors' fear of causing
treatment-induced respiratory depression. As the AIDS epidemic has
shifted to include many persons with a history of or active substance
abuse, perhaps the most important barrier to adequate pain management
in AIDS is the fear of worsening addiction or contributing to ongoing
drug abuse by prescribing narcotic analgesics. Healthcare
professionals working with HIV-infected patients must be aware of the
prevalence and types of pain encountered and of the potential role of
pain in initiating and sustaining psychological distress. In addition,
clinicians must be sensitive to the interactions of pain and
psychological factors, as well as psychiatric and substance abuse
disorders in AIDS patients, and involve psychiatric and substance
abuse experts early in the course of pain management. This article
outlines the major issues relevant to the management of pain in AIDS,
including guidelines and principles for treating pain in the person
with AIDS.

       Definition of Pain

       In 1979 the International Association for the Study of Pain
(IASP) defined pain as 'an unpleasant sensory and emotional experience
associated with actual or potential tissue damage or described in such
terms.' This view of pain opened the door to the participation of
psychiatry and psychology professionals in the fields of pain
research, assessment and treatment. Pain is one of the most common yet
complex human experiences. The pain experience is the culmination of
interactions between biological, psychological and social factors. The
main biological factors in pain include tissue damage or injury,
nociception (activation of neural pain pathways via pain receptors)
and non-nociceptive physiological activation of sensory pain pathways.
Psychological factors include attention, perception, cognition,
anxiety, depression, confusion and personality factors, as well as the
individual's understanding of the meaning of the pain. Social factors
include cultural, ethnic, racial and gender differences in pain
perception, secondary gain from disability, positive and negative
reinforcers of pain behaviors in the family and the environment and
finally the impact of pain on the individual, his/her family and
society.

       Types of Pain Mechanisms

       Pain is often classified by mechanism or type (Melzack and
Wall, 1965). There are several mechanisms involved in HIV-related
pain, including: 1) nociceptive pain, 2) neuropathic pain and 3)
idiopathic pain.

       1. Nociceptive Pain is a result of ongoing activation of
          pain-sensitive afferent neural pathways, which can be
          divided into 3 functional groups: skin, deep somatic
          (musculoskeletal) and visceral (Field, H. Pain McGraw Hill,
          New York, 1987).

       2. Neuropathic Pain, also called non-nociceptive pain, results
          from a functional abnormality of the nervous system.

       3. Idiopathic Pain is pain in the absence of organic pathology
          or in excess of the degree of organic pathology; prominent
          emotional factors may be evident.

       An example of nociceptive pain is the pain experienced by
patients with Kaposi's sarcoma that is invading the soft tissues of
their lower extremities and causing tissue damage. An example of
neuropathic pain is the burning, shooting pain experienced by patients
with post-herpetic neuralgia, HIV-related peripheral neuropathy or
diabetic neuropathy in which there is viral or microvascular
destruction of peripheral nerves. Idiopathic pain is pain whose
etiology (cause or origin) is unclear, with no organic pathology (yet)
found; psychological factors may be prominent. Purely psychogenic
pain, i.e., pain presenting as a hallucination or a conversion
syndrome, is very rare (less than 5%), if it even truly exists.
However, pain can be a symptom of depression; pain is reported by
30-60% of those with major depression. In the past the Diagnostic and
Statistical Manual of the American Psychiatric Association (DSM-III-R)
described a pain disorder called somatoform pain disorder. In this
disorder there is a preoccupation with pain for at least 6 months, and
either (1) no organic pathology is uncovered, or (2) excessive
occupational or social impairment results from an identified organic
source of pain. The current edition, DSM-IV, has dropped this disorder
and has replaced it with Pain Disorder Type I (psychological), Type II
(secondary to a medical condition), Type III (combined) and Type IV
(unspecified).

       Temporal Characteristics

       Pain is broadly categorized as being either acute or chronic.
Cancer pain or pain due to malignancies, which also occurs in people
with AIDS, is often categorized as a third type because there are
components of both acute and chronic pain, and because treatment and
management issues are often unique.

       1. Acute Pain is characterized by:

       a. recent onset, short duration;
       b. expectation of resolution;
       c. serving as a warning signal, adaptive;
       d. association with overt pain behavior, rest to heal;
       e. tissue damage, objective physical signs;
       f. sympathetic hyperactivity, autonomic arousal;
       g. anxiety as the primary affect.

       2. Chronic Pain is characterized by:

       a. persistence of pain for 1 month or more beyond usual course
          of acute injury (revised from 6 months duration);
       b. a pattern of recurrence at intervals over months or years;
       c. association with a chronic pathological process;
       d. less well-defined temporal onset;
       e. no adaptive function;
       f. a lack of objective signs or overt pain behaviors commonly
          seen with acute pain;
       g. changes in personality, lifestyle and/or functional ability
          and possible family disruption;
       h. depression as the primary affect, neurovegetative signs;
       i. depression that is often masked by pain preoccupation.

       3. Cancer (AIDS) Pain is characterized by:

       a. features of both acute and chronic pain;
       b. anxiety and depression;
       c. life-threatening nature of illness [fear of death].

       Prevalence of Pain in HIV/AIDS

       There are few systematic studies that examine the prevalence of
pain, describe specific pain syndromes or examine the relationship of
the pain experience and psychological factors in AIDS (Breitbart,
1990). A retrospective chart review of hospitalized patients with AIDS
revealed that over 50% of patients required treatment for pain. Pain
was the presenting complaint in 30%, second only to fever (Lebovits,
et al., 1989). In this study chest pain occurred in 22%, headache in
13%, oral cavity pain in 11%, abdominal pain in 9% and peripheral
neuropathy in 6%. A second retrospective review of pain in a
hospitalized population of AIDS patients reported that abdominal pain,
peripheral neuropathy and Kaposi's sarcoma were the 3 most frequent
pain problems, affecting 15% of hospitalized AIDS patients (Newshan et
al., 1989).

       Schofferman and Brody (1990) described pain in patients with
advanced AIDS. Fifty-three percent of patients surveyed had pain, most
commonly peripheral neuropathy, abdominal pain, headaches and pain
related to Kaposi's sarcoma. At Memorial Hospital the prevalence and
characteristics of pain were examined in a population of HIV-infected
persons receiving medical care in an ambulatory setting (Breitbart, et
al., 1991). Thirty-eight percent of these patients reported
significant pain. Patients had an average of 2 or more pain symptoms
at any given time. Painful sensory neuropathy accounted for up 50% of
pain diagnoses. Kaposi's sarcoma resulted in lower extremity pain in
an additional 45% of patients.

       Patients experiencing pain are more likely to have advanced HIV
disease (i.e., CDC Class IV AIDS) with low CD4 cell counts, a history
of multiple opportunistic infections and lower Karnofsky Performance
Scores (i.e., less able to function independently). Singer and
colleagues (1993) recently reported that in a chart review of 191
ambulatory HIV-infected men, 28% of those who were asymptomatic
seropositives, 55.6% of those with AIDS-Related Complex and 80% of
those with AIDS reported one or more painful symptoms. The most common
pains reported included headache, pain related to herpes simplex,
peripheral neuropathy, back pain, pain related to herpes zoster,
AZT-related headache, throat pain and arthralgia. Pain was associated
with HIV-related peripheral neuropathy in 59% of the men.

       Pain Syndromes in HIV/AIDS

       Table 1 describes a classification system of pain syndromes
seen in HIV disease. HIV-related peripheral neuropathy, which affects
up to 30% of people with AIDS, is often painful and is characterized
by sensations of burning, numbness or 'pins and needles' (Cornblath
and McArthur 1988; Parry, 1988; Levy, et al., 1985; Snider, et al.,
1983). It is important to note, however, that several antiviral drugs
(e.g., ddI, ddC, AZT and d4T), chemotherapy agents used to treat
Kaposi's sarcoma (e.g., vincristine) and other drugs including
phenytoin (Dilantin) and isoniazid (INH) can cause painful peripheral
neuropathy. Granulocyte-macrophage colony stimulating factor (GM-CSF),
used to manage neutropenia, can cause transient bone pain. Barone, et
al. (1986) observed abdominal pain in 12% of AIDS patients. Rabeneck,
et al. (1990) reported 16 cases of painful swallowing due to
esophageal ulcers in HIV-infected men. Reiter's syndrome, reactive
arthritis and polymyositis are other painful conditions reported to
occur during early HIV infection (Kaye, 1989). Other painful
rheumatologic manifestations of HIV infection that have been reported
include various form of arthritis (painful articular syndrome, septic
arthritis, psoriatic arthritis), vasculitis, Sjogren's syndrome,
AZT-related myopathy and dermatomyositis (Berman, et al., 1988;
Dakajas, et al., 1988; Espinoza, et al., 1989; Gant, et al., 1988;
Lange, et al., 1988; Rienhart, et al, 1990; Simpson and Wolfe, 1991;
Wiley, et al., 1989; Stafford, et al., 1991). Children with HIV
infection also experience pain (see Table 2) (Stafford, et al., 1991).
HIV-related conditions in children that cause pain include meningitis
and sinusitis (which may cause headaches); otitis media (middle ear
infection); herpes zoster (shingles); cellulitis and abscesses; severe
Candida-related dermatitis; dental caries; intestinal infections such
as Mycobacterium avium complex (MAC) and cryptosporidiosis;
hepatosplenomegaly; oral and esophageal candidiasis and; spasticity
(painful muscle spasms) associated with encephalopathy.

       Pain in AIDS: Psychological Variables

       Our current conceptual model of pain is multidimensional. This
model emphasizes the contributions of cognitive, motivational,
behavioral and affective components of the pain experience, as well as
the sensory or nociceptive factors. Psychological variables such as
the amount of control people believe they have over pain, emotional
associations and memories of pain, fear of death, depression, anxiety
and hopelessness all contribute to the experience of pain in people
with AIDS and may increase suffering (see Table 3). However, it is
also important to realize that pain has a profound impact on levels of
emotional distress. The patient with HIV disease faces many stressors
during the course of illness including dependency, disability and
fears of pain and/or a painful death. While such concerns are
universal, the level of psychological distress is variable. Stress
levels are affected by social support, individual coping capacities,
personality and medical factors such as extent or stage of illness.
Breitbart et al (1991) found that depression was significantly
correlated with the presence of pain in ambulatory HIV-infected
patients. In addition to being significantly more distressed and
depressed, patients experiencing pain were twice as likely to have
suicidal ideation (40%) as those without pain (20%). HIV-infected
patients with pain had more functional impairment, which was highly
correlated with levels of pain intensity and depression. Those who
felt that pain represented a threat to their health reported more
intense pain than those who did not perceive pain as a threat.
Patients with pain were more likely to be unemployed or disabled and
reported less social support. Singer and colleagues (1993) also
reported an association between the frequency of multiple pains,
increased disability and higher levels of depression.

       Case Vignette

       MS is a 30-year-old HIV positive Hispanic female who presents
to a pain clinic with diffuse body pain that has progressively
worsened over the past 3-4 months. MS has been HIV positive since June
of 1989 and had been asymptomatic until 4 months ago. At that time she
began to develop recurrent vaginal infections (candidiasis) and was
treated for cervical dysplasia. It was also about 4 months ago that
she developed diffuse aching muscular pains. At first MS noticed an
aching sensation in her anterior (frontal) thighs after walking a few
city blocks, climbing stairs or exercising. She felt this might be due
to the AZT therapy which she began at that time. AZT was stopped, and
there was some improvement in the muscle achiness. However, AZT was
restarted several weeks later and the muscle aches and pains returned.
Over the last 2 months the aches and pains have extended to the
muscles of her shoulder, head and neck as well as to her upper
extremities. MS describes an aching sensation in the back of her head
and neck that is barely noticeable in the morning but becomes
'crushing' across the upper neck and between the shoulder blades later
in the day.

       MS has become more anxious and depressed over the last 4
months. She wakes frequently throughout the night, often with
nightmares, and has difficulty falling asleep. She has experienced
attacks of anxiety or panic that have kept her pacing her room; during
these episodes she cannot get thoughts of dying out of her mind. What
triggers these panic attacks are thoughts that her HIV infection is
worsening and that she is developing AIDS and will die. MS starts
having such thoughts when her muscle aches and pains seem to intensify
at night. She believes that these pains are symptoms of AIDS and mean
that her illness is progressing.

       MS is single and acquired HIV infection through heterosexual
contact, possibly with an IV drug-using boyfriend. She has used
cocaine in the past but never used IV drugs. She lives alone and is an
unemployed model/actress/singer. She says that there is little support
available to her since her parents are divorced and live in separate
cities far from her. She has few friends, but does go to the Women's
Support Group in the HIV clinic at Memorial Hospital.

       Physical examination revealed diffuse muscular tenderness, and
laboratory tests showed elevated levels of creatinine phosphokinase
(CPK) consistent with myopathy probably due to AZT therapy. A muscle
biopsy is scheduled to ensure that no infectious etiology for the
myopathy is playing a role. MS was also referred to the AIDS
psychiatric liaison for evaluation and management. MS was felt to have
panic disorder and major depression. She was successfully treated with
antidepressant medication and cognitive behavioral therapy which
focused on her interpretation of the meaning of her pain and physical
symptoms. MS continued in her support group and eventually also became
a volunteer at Memorial Hospital. AZT therapy was stopped and MS was
switched to DDI. A short course of prednisone was also begun. MS's
pain decreased dramatically in intensity.

       The case described above illustrates the interaction between
biological factors (AZT-related myopathy), psychological factors
(anxiety, fear, panic, depression, meaning of pain and past experience
with pain) and social factors (lack of social support, financial
pressures) in the pain experience. It also demonstrates the importance
of identifying psychiatric disorders in patients with pain and the
importance of applying interventions that deal with all of these
factors.

       Psychiatric Disorders and Pain in AIDS

       The person with AIDS must adapt to a set of disease-specific
psychological, social and medical stressors that may include prejudice
against intravenous drug users, homophobia, loss of job, costly
medical expenses and denied or delayed access to the healthcare system
(Tross and Hirsch, 1988). The impact of these stressors and the unique
stressor of pain often lead to psychiatric symptoms such as anxiety
and depression. The high incidence of neurological complications in
AIDS, due to direct effects on the brain of HIV, adds a dimension of
complexity to the neuropsychiatric disturbances seen in HIV-spectrum
illnesses. At least 50% of HIV-infected patients will experience a
psychiatric disorder during the course of their illness (see Table 3).
Tross and Hirsch (1988) found that two-thirds of patients with HIV
infection had an adjustment disorder involving depressed and/or
anxious mood, and about one-fourth develop symptoms of major
depression. Atkinson et al (1988) found that 36% of AIDS patients, 39%
of those with AIDS-Related complex and 18% of asymptomatic HIV
seropositive patients suffered anxiety disorders, including panic
disorder and generalized anxiety disorder. Perry (1990) reports that
the prevalence of organic mental disorders such as dementia or
delirium occurring at some time during the clinical course of AIDS
approaches 65%. Unfortunately no studies of the prevalence of
psychiatric disorders in AIDS has directly examined the relationship
between the presence or intensity of pain and the frequency of
diagnosable psychiatric disorders. In cancer patients, however, it has
been documented that the presence of clinically significant pain
doubles the likelihood of developing a psychiatric complication
(disorder), in particular depression and delirium (Derogatis, et al.,
1983).

       The effective treatment of pain often decreases perceived
psychiatric morbidity and occasionally eliminates a perceived
psychiatric disorder. Conversely, interventions that diminish anxiety
and mood disturbances also can reduce pain. Psychiatric disorders,
particularly organic mental disorders such as AIDS dementia complex
(ADC), can occasionally interfere with adequate pain management in
patients with HIV disease. Opiate analgesics, the mainstay of
treatment for moderate to severe pain, may worsen dementia or cause
treatment-limiting sedation, confusion or hallucinations in patients
with neurologic complications of AIDS. When treating uncontrolled
pain, clinicians should consider that psychological distress may be
the consequence of the pain itself and not of other factors, such as
an adjustment reaction to life-threatening illness.

       Pain and Suicide in AIDS

       Several studies have demonstrated that men with AIDS have a
21-36 times greater risk of suicide relative to the general population
(Marzuk, et al., 1988; Kizer, et al., 1988). Table 4 lists factors
related to suicide risk in persons with AIDS. While pain is likely a
contributing factor, its specific role has not been examined. The role
of pain in suicidal ideation, also dramatically increased in AIDS
patients, has been elucidated (Breitbart, et al., 1991). Our group at
the Memorial Sloan-Kettering Cancer Center has examined the prevalence
of suicidal ideation in an ambulatory population of patients with AIDS
and examined the relationship between suicidal ideation, depression
and pain (Breitbart, et al., 1991). Suicidal ideation in ambulatory
AIDS patients was found to be highly correlated with the presence of
pain, depressed mood (as measured by the Beck Depression Inventory)
and low CD4 lymphocyte counts. While 20% of ambulatory AIDS patients
without pain reported suicidal thoughts, over 40% of those with pain
reported suicidal ideation. Only 2 subjects in the sample (n=110)
reported serious suicidal intent. While only 1 of these 2 men was in
the pain group, both had high scores on measures of depression. No
correlations were observed between suicidal ideation and pain
intensity or pain relief. The mean scores of the pain group on 1
measure of pain intensity were quite comparable to mean pain intensity
levels reported in populations of patients with cancer pain. As with
cancer pain patients, suicidal ideation in AIDS patients with pain is
more likely to be related to a concomitant mood disturbance than to
the intensity of pain experienced (Breitbart, 1989). Our group
recently surveyed the attitudes of AIDS patients towards issues
related to physician-assisted suicide and euthanasia, and examined the
relationship of such attitudes to suicidal ideation, presence of pain
and other factors (Breitbart, et al., 1993). The majority of AIDS
patients in the sample (N=50) were in favor of physician-assisted
suicide (64.4%) and euthanasia (64.4%) as options. The presence of
pain, active suicidal ideation, fears of becoming a burden and having
experienced recent AIDS-related bereavement were highly correlated
with endorsement of physician-assisted suicide or euthanasia.

       Case Vignette

       LM is a 42-year-old male homosexual psychologist with AIDS who
developed severe abdominal pain related to a parasitic infection of
the colon. Despite being cared for by compassionate physicians
specializing in AIDS, LM had a difficult time getting his physicians
to adequately address his pain complaints. His doctors were reluctant
to use opioid analgesics for fear of causing gut motility problems
that would adversely effect the colitis (for which he was receiving
experimental drug therapy). LM consulted a pain specialist who was not
familiar with AIDS pain syndromes. This specialist prescribed Lortabs,
which provided incomplete relief. Despite lack of pain relief the
specialist insisted that there were no further or more aggressive pain
treatments available. LM had no history of drug abuse and had a
long-standing relationship with his healthcare provider. Additionally
he was a 'pillar' of the gay community and a well-known AIDS activist.
At this point LM became despondent and hopeless. He had kept a
collection of medications in his home that were originally intended to
be used by his lover to 'self-deliver' if the ravages of AIDS became
unbearable. His lover had since died naturally, and LM felt that
perhaps the time had come when he too would suffer less if he were to
die at this time. LM expressed this plan to a colleague who had been
working on a study of pain in AIDS at a large urban medical center. As
a last resort, LM sought help from these clinical researchers.

       LM was told that many options for pain control existed. He was
started on a regimen of sustained-release morphine with
immediate-release morphine rescues. The dose was adjusted upwards and
provided relief at about 180 mg/day. LM was comfortable for 3 months.
At that time he had acute spasms of pain that broke through his daily
pain therapy regimen. A celiac block plexus was performed and provided
dramatic pain relief, allowing LM to eventually stop all opioids
except for occasional rescue doses. LM died comfortably at home
several months later with his family and friends around him. Before
dying LM made a videotape to be used for educational purposes. In this
tape he talked about how uncontrolled pain made him feel suicidal and
how pain relief made him feel he could go on living longer. He still
held 'self-deliverance' as an option, but insisted that this option
should be an informed one. He felt that he had been misinformed about
his options for pain control, and that his earlier plan to end his
life had thus not been the result of an informed decision.

       This case illustrates the difficulties in obtaining adequate
pain control for AIDS patients. It also demonstrates the relationships
between pain, depression and suicidal ideation or desire for hastened
death (physician-assisted suicide or euthanasia). Assessment of
suicide risk and appropriate intervention is desirable for the AIDS
patient who expresses suicidal ideation or requests a physician's aid
in dying (although physician-assisted suicide is not legal, patients
still ask doctors for such help). There is danger in the premature
assumption that suicidal ideation in an AIDS patient or a request to
hasten death represents a 'rational' act unencumbered by psychiatric
disturbance or uncontrolled pain or physical symptoms. Work at
Memorial Hospital suggests that a significant percentage of such
patients are suffering from psychiatric co-morbidity related to AIDS
(e.g., depression, confusion) and poorly controlled physical symptoms
including pain (Breitbart, 1993). The clinician working in the AIDS
setting should anticipate that the topic of physician-assisted suicide
or euthanasia may arise with some patients, and should be ready to
respond in a fashion that is most consistent with his or her beliefs.
One should remember, however, that assisted suicide and euthanasia are
not legal in the United States. Active and aggressive pursuit of
maximal palliative (relief-focused) care, focusing on both physical
and psychological symptoms, is the approach that best characterizes
what most clinicians view as their obligation to terminally ill AIDS
patients. Unfortunately this type of care does not always take place.
Clinicians should be cautioned against falling into the trap of
'secret collusion' with a patient regarding suicide or assisted
suicide. The doctor-patient relationship is complex and is subject to
intense emotional forces, particularly when the clinician has been
caring for a patient for a prolonged period of time and when
identification with the patient is strong. Early and comprehensive
psychiatric involvement with high-risk individuals can often avert
suicide in the AIDS patient. Diagnosing depression in AIDS patients,
particularly in late stages of illness, is difficult but possible if
the assessment is made by a psychiatrist who is experienced in working
with the medically ill. It is also advisable to share the management
of such cases with colleagues who have palliative care expertise.
Medical ethicists or medical ethics committees, when available, may be
consulted for help in managing patients where physician-assisted
suicide or euthanasia has been raised as a serious issue.

       PART II: MANAGMENT OF PAIN IN AIDS

       The principles of pain assessment and treatment in the patient
with HIV/AIDS are essentially those that have been proposed and
utilized for the management of pain in cancer, sickle cell disease and
other chronic medical illnesses associated with painful symptoms. This
philosophy regarding pain management in AIDS patients has been
supported by the federal panel of pain experts who developed the
'Clinical Management Guidelines for Cancer Pain Management,' published
by the Agency for Health Care Policy and Research (AHCPR). The
management of acute pain and cancer pain is also well-documented, with
clear guidelines from the World Health Organization (WHO, 1986) and
the American Pain Society (1992). In contrast to pain in cancer, pain
in HIV disease may more commonly have an underlying treatable course
(O'Neill and Sherrard, 1993).

       Assessment Issues

       The initial step in pain management is a comprehensive
assessment of pain symptoms. A description of the qualitative features
of the pain, its time course and any maneuvers that increase or
decrease pain intensity should be obtained. Additionally, detailed
medical, neurological and psychosocial assessments (including a
history of substance use or abuse) should be completed. Family members
or partners should be interviewed when possible. During the assessment
period pain should be aggressively treated, while pain complaints and
psychosocial issues are subject to an ongoing process of re-evaluation
(Portenoy and Foley, 1989).

       The health professional working in the AIDS setting must have a
working knowledge of the etiology and treatment of pain in AIDS. This
would include an understanding of the different types of AIDS pain
syndromes discussed above, as well as a familiarity with the
parameters of appropriate pharmacologic treatment. The pain assessment
may be complicated by co-morbid psychiatric symptoms such as
depression or suicidal ideation. A close collaboration among the
entire healthcare team is optimal when attempting to adequately manage
pain in the AIDS patient.

       An important element in the assessment of pain is the concept
that assessment should be continuous and repeated over the course of
pain treatment. There are essentially 4 aspects of pain in AIDS that
require ongoing evaluation: (1) pain intensity, (2) pain relief, (3)
mood state or psychological distress and 4) drug effects such as side
effects and abuse (Elliott and Foley, 1990). The Memorial Pain
Assessment Card (MPAC) is a helpful clinical tool that allows patients
to report their pain experiences (Fishman, et al., 1987). The MPAC
consists of visual analog scales that measure pain intensity, pain
relief and mood. Patients can complete the MPAC in less than 30
seconds. The patient's report of pain intensity, pain relief and
present mood state provides the essential information required to help
guide their pain management.

       Pharmacological Interventions

       Foley and colleagues have described the indications for and the
use of 3 classes of analgesic drugs that have applications in the
management of pain in AIDS patients: (1) nonopioid analgesics such as
acetaminophen, aspirin and other non-steroidal anti-inflammatory drugs
(NSAID), (2) opioid analgesics, of which morphine is the standard and
(3) adjuvant analgesics such as antidepressants and anticonvulsants
(Foley, 1985; Foley and Inturrisi, 1987; Inturrisi, 1989; Portenoy,
1990). The World Health Organization's (WHO) Cancer Pain Relief
Program (1986) has advocated an approach to the use of these analgesic
drugs which is described as a 3-step 'analgesic ladder.' Patients with
mild pain are managed with nonopioid analgesics such as acetominophen
or an NSAID. Patients with moderate to severe pain move on to the
second step on the ladder and receive a weak opioid (e.g., codeine or
oxycodone) in combination with a NSAID. Patients with severe pain who
fail step 2 go on to step 3 and receive a strong opioid analgesic
(e.g., morphine) with or without an NSAID. Adjuvant drugs (e.g.,
antidepressants) should be used to provide additional analgesia,
enhance the effect of the opioids, treat side effects, regularize
sleeping patterns and provide an antidepressant effect. Breakthrough
pain should be treated with a short-acting opioid drug such as
morphine or oxycodone.

       The nonopioid analgesics are prescribed principally for mild to
moderate pain or to augment the pain-relieving effects of narcotic
analgesics in the treatment of severe pain. Commonly utilized
nonopioid analgesics and the weaker opioids are described in Table 4.
The analgesic effect of the NSAID appears to stem from their
inhibition of cyclooxygenase and the subsequent reduction of
prostaglandins in the tissues (Kantor, 1984).

       Opioid Analgesics

       Opioid analgesics are the mainstay of the pharmacological
treatment of the AIDS patient with moderate to severe pain (see Table
5). Principles useful in guiding the appropriate use of opioid
analgesics for pain include the following: (1) choose an appropriate
drug, (2) start with the lowest dose possible, (3) titrate (adjust)
the dose, (4) use 'as needed' doses selectively, (5) use an
appropriate route of administration, (6) be aware of equivalent
analgesic doses, (7) use a combination of drugs, (8) be aware of
tolerance and (9) understand physical and psychological dependence
(see Table 8) (Portenoy, 1990; Foley and Inturrisi, 1987; APS, 1992).

       Choosing an Appropriate Opioid

       In choosing the appropriate opioid analgesic for cancer pain,
Portenoy (1990) highlights the following important considerations: (1)
opioid class, (2) 'weak' versus 'strong' opioid, (3) pharmacokinetic
characteristics, (4) duration of analgesic effect, (5) favorable prior
response and (6) opioid side effects.

       Opioid analgesics are divided into 2 classes, the agonists and
the agonist-antagonists, based on their affinity to opiate receptors.
Morphine, fentanyl and most of the other opioid analgesics listed in
Table 5 are agonist drugs. Pentazocine, butorphanol and nalbuphine are
examples of opioid analgesics with mixed agonist-antagonist
properties. Agonist-antagonist drugs can reverse opioid effects and
precipitate an opioid withdrawal syndrome in patients who are opioid
tolerant or dependent. They are of limited use in the management of
chronic cancer or AIDS pain where the advantages of the
agonist-antagonist opioids (a lower abuse or addiction potential) are
less relevant. A partial agonist, buprenorphine, in sublingual form
may be appropriate for cancer pain in selected patients who are not
opioid-tolerant (Portenoy, 1990). Oxycodone and codeine are the
so-called weaker opioid analgesics and thus are not first-line agents
for patients with severe, intractable pain. Oxycodone is often
prescribed as a 5 mg oral dose with either aspirin or acetaminophen.
More severe pain is best managed with morphine or another of the
stronger opioid analgesics such as hydromorphone, methadone, single
entity oxycodone or levorphanol.

       Pharmacologic Considerations

       The general principles of pain management in AIDS patients are
similar to those developed in cancer patients, but with some notable
differences. AIDS patients are usually younger and psychologically
unprepared for the consequences of the disease. Analgesic guidelines
are based on the WHO analgesic ladder designed for the escalating
control of malignant pain. All drugs are given on a time-contingent
basis.

       A basic understanding of the pharmacokinetics of the opioid
analgesics is important for the mental health professional treating
the cancer patient or AIDS patient with pain (Inturrisi, 1989). Opioid
analgesics with long half-lives, such as methadone and levorphanol,
require approximately 5 days to achieve a steady state. Despite their
long half-lives, the duration of pain relief that they provide is
considerably shorter (i.e., most patients will require administration
of the drug every 4-6 hours). As both methadone and levorphanol tend
to accumulate with early initial dosing, delayed effects of toxicity
can develop (primarily sedation, and more rarely respiratory
depression). Because of this unique profile, methadone is not
recommended as a first-line pain management agent, especially in the
elderly cancer patient.

       The duration of analgesic effects of opioid analgesics varies
considerably as outlined in Tables 4 and 5. Oxycodone will often
provide only 3 hours of relief and it must be prescribed on an every 3
hours, around-the-clock basis (not 'as needed'). Methadone and
levorphanol may provide up to 6 hours of analgesia. There is
individual variation in the metabolism of opioid analgesics, and there
can be significant differences between individuals in drug absorption
and disposition. These differences lead to a need for alterations in
dosing, route of administration and scheduling for maximum analgesia
in individual patients. While parenteral administration (intravenous,
intramuscular, subcutaneous) will yield a faster onset of pain relief,
the duration of analgesia is shorter. For example, a patient started
on intramuscular morphine might require administration every 3 hours.
Once pain is under better control, it may be desirable for various
reasons (e.g., discharge home) to have the patient switch to oral
morphine. The patient might then require the drug every 4 hours.
Longer-acting oral morphine preparations such as Oramorph SR or MS
Contin, are available that provide up to 8-12 hours of analgesia,
minimizing the number of daily doses required for the control of pain.
Fentanyl in a transdermal system (Duragesic) can deliver stable doses
(25-100 micrograms/hour) for 2-3 days. It provides an alternative to
oral dosing.

       The adequate treatment of pain in AIDS also requires
consideration of the equianalgesic doses of opioid drugs, which are
generally calculated using morphine as a standard (see Table 5).
Cross-tolerance is not complete among these drugs, therefore one-half
to two-thirds of the equianalgesic dose of the new drug should be
given as the starting dose when switching from one opioid to another
(Foley and Inturrisi, 1987). For example, if a patient receiving 20 mg
of parenteral morphine is to be switched to hydromorphone, the
equianalgesic dose of parenteral hydromorphone would be 3.0 mg. Thus,
the starting dose of parenteral hydromorphone should be approximately
1.5-2 mg. There is also considerable variability in the parenteral to
oral ratios among the opioid analgesics. Both levorphanol and
methadone have 1:2 intramuscular/oral ratios, whereas morphine has a
1:6 and hydromorphone a 1:5 intramuscular/oral ratio. Failure to
appreciate these dosage differences in route of administration can
lead to inadequate pain control.

       Regular ('standing') scheduling of the opioid analgesics is the
foundation of adequate pain control. It is preferable to prevent the
return of pain as opposed to treating pain as it recurs. 'As needed'
orders for chronic cancer or AIDS pain often create a struggle between
the patient, family and staff that is easily avoided by regular
administration of opioid analgesics. The typical prescribing of
methadone is a notable exception. It is often initially prescribed on
an 'as needed' basis to determine the patient's total daily
requirement and to minimize toxicity (due to its long half-life).

       Opioid Side Effects

       While the opioids are extremely effective analgesics, their
side effects are common and can be minimized if anticipated in
advance. Sedation is a common central nervous system side effect,
especially during the initiation of treatment. Sedation usually
resolves after the patient has been maintained on a steady dosage.
Persistent sedation can be alleviated with a psychostimulant such as
dextroamphetamine, pemoline or methylphenidate. All are prescribed in
divided doses in the early morning and at noon. Additionally,
psychostimulants can improve depressed mood and enhance analgesia
(Bruera, et. al., 1987; Breitbart, 1992). Delirium, of an either
agitated or somnolent variety, can also occur while on opioid
analgesics, and is usually accompanied by attentional deficit,
disorientation and perceptual disturbances (visual hallucinations and,
more commonly, illusions). Myoclonus and asterixis are often early
signs of neurotoxicity that accompany the course of opioid-induced
delirium. Meperidine (Demerol) when administered chronically in
patients with renal impairment can lead to delirium due to the
accumulation of the neuro-excitatory metabolite normeperidine (Kaiko,
et al., 1983). Opioid-induced delirium can be alleviated through the
use of 3 possible strategies: (1) lowering the dose of the opioid drug
presently in use, (2) changing to a different opioid or (3) treating
the delirium with low doses of high-potency neuroleptics such as
haloperidol. The third strategy is especially useful for agitation and
clears the sensorium (Breitbart, 1989). For agitated states,
intravenous haloperidol in doses starting at 1-2 mg is useful, with
rapid dose escalation if no effect is noted. Gastrointestinal side
effects of opioid analgesics are common. The most prevalent are
nausea, vomiting and constipation (Portenoy, 1987). Concomitant
therapy with prochlorperazine, dronabinol, odansetron, scopolamine or
chlorpromazine for nausea may be effective. Since all opioid
analgesics are not tolerated in the same manner, switching to another
narcotic drug can be helpful if an antiemetic regimen fails to control
nausea. Constipation caused by opioid effects on gut receptors is a
problem frequently encountered. It tends to respond to the use of
senna derivatives or prokinetic antimetics such as metochlopramide or
cisipride. A careful review of medications is imperative, since
anticholinergic drugs such as the tricyclic antidepressants can worsen
opioid-induced constipation and can cause bowel obstruction.
Respiratory depression is a worrisome but rare side effect of the
opioid analgesics. Respiratory difficulties can almost always be
avoided if 2 general principles are adhered to: (1) start opioid
analgesics in low doses in opioid-naive patients and (2) be cognizant
of relative potencies when switching opioid analgesics, routes of
administration or both.

       Adjuvants

       Adjuvant analgesics are the third class of medications
frequently prescribed for the treatment of chronic pain, and have
important applications in the management of pain in AIDS (see Table
6). The most commonly used adjuvant analgesics are the tricyclic
antidepressants (TCA) (Breitbart, 1989; Breitbart and Holland, 1990;
Breitbart, 1992). The tricyclic antidepressants (amitriptyline,
nortriptyline, imipramine, desipramine, clomipramine, doxepin), the
heterocyclic and the noncyclic antidepressants (trazadone,
maprotiline, as well as the new serotonin reuptake inhibitor
paroxetine) have potent analgesic properties and are widely used to
treat a variety of chronic pain syndromes. They may have their most
beneficial effect in the management of neuropathic pain (pain due to
nerve damage) such as the peripheral neuropathies common in AIDS
patients. While studies of the analgesic efficacy of these drugs in
HIV-related painful neuropathies have not yet been conducted, the
drugs are widely applied clinically using the model of diabetic and
post-herpetic neuropathies. Psychostimulants such as dextroamphetamine
and methylphenidate are useful antidepressants in patients with HIV
infection or AIDS who are cognitively impaired, and are also helpful
in diminishing sedation due to narcotic analgesics (Fernandez and
Levy, 1990; Bruera, et al., 1987). Psychostimulants also enhance the
analgesic effects of the opioid drugs (Bruera, et al., 1989).

       Neuroleptic drugs such as methotrimeprazine, fluphenazine,
haloperidol and pimozide may play a role as adjuvant analgesics in HIV
positive patients with pain (Beaver, et al., 1966; Gomez-Perez, et
al., 1985; Maltbie, et al., 1979; Lechin, et al., 1989). However,
their use must be weighed against what appears to be an increased
sensitivity to the extrapyramidal side effects of these drugs in AIDS
patients with neurological complications (Breitbart and Marotta,
1988). Anxiolytics such as alprazolam and clonazepram may also be
useful as adjuvant analgesics, particularly in the management of
neuropathic pains (Fernandez, et al., 1987; Swerdlow and Cundhill,
1981; Caccia, 1975).

       Psychological and Psychiatric Interventions for Pain Control in AIDS

       The psychiatric management of HIV-related pain involves the use
of psychotherapeutic, cognitive-behavioral and psychopharmacologic
techniques. A psychotherapist can offer short-term, supportive
psychotherapy based on a crisis-intervention model, and can provide
emotional support, continuity of care, information about pain
management and assistance to patients in adapting to their crises.
This often involves working with non-traditional families that may
include gay lovers, estranged spouses or parents and fragmented or
extended families. People with HIV disease may also require treatment
for substance abuse.

       Cognitive-behavioral techniques for pain control such as
relaxation, imagery, hypnosis and biofeedback are effective as part of
a comprehensive multimodal approach (see Table 7). These techniques
are particularly appropriate for patients with AIDS who may have
increased sensitivity to the side effects of centrally-acting
medications. Non-pharmacologic interventions, however, must never be
used as a substitute for appropriate analgesic management of pain. The
mechanisms by which these non-pharmacologic techniques work are not
known; however, they all seem to share the elements of relaxation and
distraction. Additionally, patients often feel a sense of increased
control over their pain. Ideal candidates for the application of these
techniques are mentally alert and have mild to moderate residual pain.
Confusion interferes significantly with a patient's ability to focus
attention, and thus limits the usefulness of cognitive-behavioral
interventions.

       Psychotropic drugs, particularly the antidepressants and the
psychostimulants (see Table 6), are useful in the management of
depressive disorders in AIDS patients. As adjuvant analgesics they
enhance the effects of opioids. They may also function as primary
analgesics in the management of neuropathic pain (Breitbart, 1992).

       Pain Management and Substance Abuse in AIDS

       Individuals who inject drugs make up an AIDS exposure category
with one of the highest rates of increase over the past 5 years,
especially in large urban centers (CDC, 1993). Pain management in the
substance-abusing AIDS patient is perhaps the most challenging
clinical goal. Fears of addiction and concerns regarding drug abuse
affect patient compliance and physician management of pain using
narcotic analgesics, and often lead to the under-medication of
HIV-infected patients with pain. Studies of patterns of chronic
narcotic analgesic use in patients with cancer, burns and
post-operative pain have demonstrated that although tolerance and
physical dependence commonly occur, addiction, that is, psychological
dependence, and drug abuse are rare and almost never occur in
individuals who do not have histories of drug abuse (Kanner and Foley,
1981; Porter and Jick, 1980; Perry and Heidrich, 1982). More
problematic, however, is managing pain in the growing segment of
HIV-infected patients who are actively abusing drugs. The use of
drugs, specifically opiates, for pain control raises several pain
treatment questions, including: how to treat pain in people who have a
high tolerance to narcotic analgesics, how to mitigate this
population's drug-seeking and potentially manipulative behavior, how
to deal with patients who may offer unreliable medical histories or
who may not comply with treatment recommendations and how to counter
the risk of patients transmitting HIV while high and disinhibited. In
addition, clinicians must rely on a patient's subjective report, which
is often the best or only indication of the presence and intensity of
pain and of the degree of pain relief achieved by an intervention.
Physicians who believe they are being manipulated by drug-seeking
patients often hesitate to use appropriately high doses of narcotic
analgesics to control pain. Most clinicians experienced in working
with this population recommend that practitioners set clear and direct
limits. While this is an important aspect of the care of IV drug-using
people with HIV disease, it is by no means the complete solution. As
much as possible, clinicians should attempt to eliminate the issue of
drug abuse as an obstacle to pain management by dealing directly with
the problems of opiate withdrawal and drug treatment. Clinicians
should err on the side of believing patients when they complain of
pain, and should utilize knowledge of specific HIV-related pain
syndromes to corroborate the report of a patient perceived as being
unreliable.

       Case Vignette

       LL is a 21-year-old African American female with AIDS and
Kaposi's sarcoma which invaded her left maxillary sinus and orbit (eye
socket), causing severe pain. LL has been abusing heroin, cocaine,
marijuana and alcohol since age 13. While undergoing radiotherapy at
Memorial Hospital for her sinus tumor, LL abruptly left treatment and
disappeared for 2 months. She had been told that the tumor was
progressing despite radiotherapy and that future options for treatment
were limited. This news led to a period of prolonged drug binging.
Upon exhausting all of her funds, LL attempted to gain admission to a
drug rehabilitation program that she had attended 2 years earlier and
which resulted in 18 months of abstinence. The program would not admit
her because of her medical problems and lack of insurance coverage. LL
returned at this point to Memorial Hospital in a disheveled,
malnourished state, presenting with a painful, protuberant, red and
severely infected left eye.

       LL was admitted to the hospital for pain management and
treatment of infection. The psychiatrist who had been consulted at the
time because of obvious relapse of drug use arranged for this medical
admission through extensive meetings with the Immunology, Infectious
Disease and Pain services. A detailed plan for care and pain
management was outlined and discussed with the team, including the
floor nursing staff. A plan for limit setting, including the use of a
private room, visitor restrictions, restriction of excursions by the
patient off of the floor, urine toxicology screens and periodic
searches of the room, was outlined with the patient and staff and
written down. Consequences for continued abuse in the hospital were
spelled out, i.e., that the patient would be discharged if medically
stable. LL was assured that she would be given adequate pain relief
and that particular attention would be given to preventing withdrawal
from both opioids and alcohol (LL had been drinking extensively). LL
was also assured that treatment for psychological distress would be
provided. LL was managed with a regimen of 90 mg of orally
administered methadone every 6 hours and 2 mg orally administered
clonazepam three times a day. In addition nortriptyline was added to
treat depression and neuropathic pain caused by tumor progression. LL
did well in the hospital and was ultimately transferred to an AIDS
hospice.

       Experience from the cancer pain literature suggests that it is
possible to adequately manage pain in substance abusers with
life-threatening illness, and to do so safely and responsibly by
utilizing opioid analgesics and several sound principles of pain
management outlined here (see Table 8) (Macaluso, et al., 1988;
McCaffery and Vourakis, 1992; Portenoy and Payne, 1992; APS, 1992).
Perhaps of greatest concern to clinicians is the possibility that they
are being lied to by a substance-abusing AIDS patient complaining of
pain. The fear is that the clinician is being 'duped' into prescribing
narcotic analgesics which will then be abused or sold. Clinicians do
not want to contribute to or help sustain addiction. This leads to an
immediate defensiveness on the part of the clinician and to an impulse
to avoid prescribing opioids and even to avoid full assessment of a
pain complaint. Unfortunately, the existence or severity of pain
cannot be objectively proven. The clinician must accept and respect
the patient's report of pain in spite of the possibility of being
duped, and must proceed in the evaluation, assessment and management
of pain. The clinician must be familiar with and understand the
current terminology relevant to substance abuse and addiction. It is
important to distinguish between the terms tolerance, physical
dependence and addiction. Tolerance is a pharmacologic property of
opioid drugs defined by the need for increasing doses to maintain an
(analgesic) effect. Physical dependence is characterized by the onset
of signs and symptoms of withdrawal if narcotic analgesics are
abruptly stopped or a narcotic antagonist is administered. Tolerance
usually occurs in association with physical dependence. Addiction or
abuse (also often called psychological dependence) is a psychological
and behavioral syndrome in which there is drug craving, compulsive use
(despite physical, psychological or social harm to the user), other
aberrant drug-related behaviors and relapse after abstinence (APS,
1992). The term pseudo-addiction has been coined to describe the
patient who exhibits behavior that clinicians associate with
addiction, such as requests for higher doses of opioids, but which is
in fact due to uncontrolled pain and inadequate pain management
(Weissman and Haddox, 1989).

       The clinician must also distinguish between the 'former' addict
who has been drug-free for years, the addict in a methadone
maintenance program and the addict who is actively abusing illicit
and/or prescription drugs. Patients with pain who are actively using
or are on methadone maintenance must be assumed to have some tolerance
to opioids. They may require higher starting and maintenance doses of
opioid analgesics. Prevention of withdrawal is an essential first step
in managing pain in this population. In addition, active addicts with
AIDS will understandably require more in the way of psychosocial
support and services to adequately deal with the distress of their
pain and illness. Former addicts may pose a challenge by refusing
opioids for pain because of fears of relapse. Such patients can be
assured that opioids, when prescribed and monitored responsibly, can
be an essential part of pain management, and that the use of these
drugs for pain relief is quite different from their use when the
patient was abusing similar drugs. Portenoy and Payne (1992) emphasize
the importance of conducting a comprehensive pain assessment in order
to define the pain syndrome. Specific pain syndromes often respond
best to specific interventions (i.e., neuropathic pains respond well
to antidepressants or anticonvulsants). Adequate assessment of the
cause of pain is essential in all AIDS patients and particularly in
the substance abuser. It is critical that adequate analgesia be
provided while diagnostic studies are underway. Often treatments
directed at the underlying disorder(s) causing pain are very effective
as well (e.g., headache due to central nervous system toxoplasmosis
responds well to primary treatments and steroids).

       Portenoy and Payne (1992) point out that it is critical to
apply appropriate pharmacologic principles for opioid use. One should
avoid using agonist-antagonist opioid drugs. Adequate doses and dosing
intervals as well as around-the-clock dosing for constant pain are
essential. The use of 'as needed' dosing often leads to excessive
drug-centered interactions with the staff that are not productive.
While patients should not necessarily be given the specific drug or
route they request, every effort should be made to give patients more
of a sense of control and a sense of collaboration with the clinician.
Often a patient's report of beneficial or adverse effects of a
specific agent are useful to the clinician. The management of pain in
substance abusing AIDS patients requires a team approach. Early
involvement of pain specialists, psychiatric clinicians and substance
abuse specialists is critical. Non-pharmacologic pain interventions
should be appropriately applied, not as a substitute for opioids but
as an important adjunct. Realistic goals for treatment must be set,
and problems related to inappropriate behavior around the handling of
prescriptions and interactions with the staff should be anticipated.
Hospital staff need to be educated and made aware that such difficult
patients evoke feelings that if acted upon could interfere with
providing good care. Clear limit setting is helpful for both the
patient and the treating staff. Sometimes written rules about what
behaviors are expected, what behaviors are not tolerated and the
consequences of breaking the rules should be provided. The use of
urine toxicology monitoring, restrictions of visitors and strict
limits on the amount of drug provided per prescription can all be very
useful. It is important to also remember that rehabilitation or
detoxification from opioids is not appropriate during an acute medical
crisis and should not be attempted at that time. Once more stable
medical conditions exist, referral to a drug rehabilitation program
may be useful. Constant assessment and re-evaluation of the effects of
pain interventions must also take place in order to optimize care.
Special attention should be given to points in treatment where routes
of administration are changed or where opioids are being tapered. It
must be made clear to patients which drugs or regimens will still
control pain when opioids are tapered or withdrawn, and what options
are available if a non-opioid regimen is ineffective.

       Finally, it is important to recognize that substance abusers
with AIDS are quite likely to have co-morbid psychiatric symptoms as
well as multiple other physical symptoms, which can all contribute to
increased pain and suffering. Adequate attention must be paid to these
physical and psychological symptoms if pain management is to be
optimized.

       Summary

       Pain in AIDS is a clinically significant problem that
contributes greatly to psychological and functional morbidity. Pain
impacts negatively on the quality of life of patients with AIDS, and
psychological and social issues impact on the experience of pain.
Since pain can be adequately treated, it must be a focus of care.
Substance abusers with AIDS who experience pain are a particularly
undertreated segment of the AIDS pain population and need special
attention. Psychiatrists and substance abuse specialists can play
useful roles in the management of the AIDS patient with pain.

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Organization, Geneva, Switzerland. 1986.

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       Immune Restoration Think Tank IV
       Mark Bowers

       Mark Bowers is HIV Treatment Hotline Manager at Project Inform
       in San Francisco.

       For most of the AIDS epidemic, there has been little research
on new treatments for individuals with fewer than 100 CD4 cells. In
response to this need, San Francisco Project Inform organizes, hosts
and facilitates yearly meetings to bring together many of the most
respected researchers in immunology, virology, oncology and genetics
from the National Institutes of Health, academia, the community and
industry. The general topic of each 'think tank' is to conceive and
prioritize methods to restore immune function in persons with advanced
HIV disease. The focus varies from year to year as new collaborations
are formed to study emerging new areas of interest and as the basic
scientific understanding of the pathogenesis of AIDS deepens.

       The most recent think tank was held February 25-27, 1995, in
Oakland, California, at the Claremont Hotel. The name 'The Dobson
Project' was given to the ongoing series of collaborative
brainstorming sessions, in memory of the first director of the Project
Inform Immune Restoration Think Tank, Jesse Dobson, who died of AIDS
in 1993. Many of the more than 40 assembled researchers had become
personal friends of Dobson; they promised to redouble their efforts to
'make the system move faster.' William Paul, Director of the Office of
AIDS Research, Gene Shearer, one of the first to emphasize the
importance of the TH1 to TH2 shift in humans and Irv Weissman,
international authority on thymic structure and function, were only a
few of the accomplished scientists who attended. Members grappled with
the problems of setting priorities for testing gene therapy for AIDS,
thymic transplantation, and novel combinations of cytokines and
antiretroviral drugs.

       Much discussion centered on the recent reports in Nature by
Drs. Wei and Ho. These researchers independently discovered that HIV
replicates far more rapidly in the body than was previously suspected,
and that the immune system responds by producing vast numbers of CD4
cells to attempt to control the viral infection. Researchers were
divided as to whether this was groundbreaking news, but agreed that
investigation into reconstitution of the immune system and
immunotherapies should be intensified. All agreed that interventions
should begin earlier in the course of disease, given the new data on
viral replication.

       The think tanks are noted for identifying important research
priorities and quickly solving problems, thus advancing AIDS research
and the entire field of biomedical research by giant steps. This think
tank ranked thymic transplantation in advanced disease as a very high
priority. The thymus is known to be the organ where vast numbers of
thymocytes, including CD4 cells, mature and are 'educated' to perform
their physiologic tasks. More information must be gathered about the
thymus before any transplantation is attempted. Scientists first need
to know whether the thymus is involuted or enlarged in individuals
with HIV, and what that means. Techniques for preserving thymic
transplant tissue and causing it to engraft in a recipient have
advanced to a stage where transplantation in advanced HIV disease is
not only thinkable, but reasonably feasible. Collaboration is underway
to craft a transplantation study as this issue of BETA goes to press.

       Other areas that will advance significantly in the near future
include the development of gene therapy vectors (novel ways to deliver
anti-HIV genes to cells at risk of becoming infected) and new cytokine
interventions. While the spirit of the think tanks encourages
researchers to openly share their knowledge and expertise,
collaborative efforts frequently must await regulatory approval before
they may begin. Therefore, not all of the planned collaborations are
immediately made public.

       Much progress was made on the 2 ongoing plans developed by
previous think tanks. The first of these is a 1-year salvage plan
designed to rescue people whose immune systems are severely damaged.
The second is a more detailed and ambitious 3-year plan that allows
for the careful consideration and management of novel combination
intervention strategies. In the effort to obtain a wide range of input
to plan development, investigators outside the think tank are
regularly contacted to work on both plans.

       Project Inform has scheduled another think tank for November
1995. The possibility of a 'junior researcher think tank,' convened to
grapple with the same problems confronted by the senior scientists, is
also envisioned for 1995. BETA will keep you apprised of the results
of the research planned at the Fourth Project Inform Immune
Restoration Think Tank as they emerge.

       The Protease Inhibitors: Science and Activism Memo to Merck

       To:     Merck and Company
       From:   The HIV/AIDS Community Re:
               An Urgent Call to Save Lives!

       Results of human studies of the Merck protease inhibitor MK-639
suggest that it is one of the safest and most effective AIDS drugs yet
developed. Edward Scolnick, president of Merck research, told The Wall
Street Journal in a recent interview that the Merck protease inhibitor
'looks better than anything else tested.'

       Access to MK-639 and to other promising protease inhibitor
drugs represents the best hope for prolonging life and delaying
disease progression among tens of thousands of people living with HIV
infection and AIDS who have exhaused the limited benefit of available
AIDS treatments.

       Failure to make the protease inhibitors widely available to
people with AIDS in the near future violates the fundamental right of
all people with life-threatening illnesses for speedy access to safe
drugs that show promise of benefit.

       The HIV/AIDS community calls on Merck, the largest
pharmaceutical company in the world, to take the following actions:

       * Create immediately a 'compassionate use' program to provide
         MK-639 to at least 3,000 people with advanced AIDS who have
         no other treatment options. Your offer to sponsor such a
         program by June 1995 for 300 people is inadequate.

       * Apply to FDA for accelerated approval of MK-639 as a
         prescription drug before the end of 1995, when interim data
         from the Phase III trials of the drug become available.

       As a supporter of people living with HIV infection and AIDS, I
urge you to accomplish these objectives at the earliest moment
possible.

       Signature (optional)

       Fax or mail this memo to: Merck and Company, One Merck Drive,
       P.O. Box 100, WSIA-37, Whitehouse Station, NJ 08889.  FAX:
       908-735-1843.

       ************************
       The Protease Inhibitors: Science and Activism Summit Meeting on
       Protease Inhibitor Drugs Ronald Baker, PhD

       Ronald Baker is editor of BETA.

       Baker attended a special meeting of the National Task Force on
AIDS Drug Development, which held public hearings February 23-24,
1995, in Washington, D.C. Baker testified before the Task Force as the
representative of the San Francisco AIDS Foundation and BETA. (see
policy statement on page 39). The 2-day Task Force meeting focused on
development of the protease inhibitor compounds, a new class of AIDS
drugs that has shown promise in the treatment of HIV infection.

       Protease inhibitor drug development held the spotlight at a
February 1995 summit meeting of top government drug regulators,
scientists, manufacturers and AIDS treatment community advocates. The
U.S. Food and Drug Administration (FDA) and the National Task Force on
AIDS Drug Development hosted the event, which drew an estimated 250
participants over 2 days of public hearings.

       Presentations and discussions among the 18-member Task Force
took up most of the approximately 20 hours of meeting time. There were
also presentations by researchers, clinicians, drug company CEO and
brief testimonies from the public and from AIDS advocates and AIDS
community representatives.

       Three community-based AIDS educational and service agencies
sent representatives to testify at the Task Force summit meeting on
protease inhibitors: The San Francisco AIDS Foundation, Gay Men's
Health Crisis and Project Inform. Other AIDS groups and individuals
also testified, including Jules Levin of ACT-UP New York, Spencer Cox
and Gregg Gonsalves of New York City's Treatment Action Group (TAG),
John James of AIDS Treatment News, Linda Grinberg of the Grinberg
Foundation of Los Angeles, Brenda Freiberg of the Los Angeles AIDS
Commission and James Driscoll of Direct Action for Treatment Access.

       AIDS community representatives were displeased that the Task
Force scheduled only 1 hour for public testimony during the 20-hour
event. 'All of us had to fight just to ensure that the agenda would
allow for any discussion of our issues. How sad,' protested David Barr
of the Gay Men's Health Crisis (GMHC) in his public testimony.

       To make matters worse, the public testimony came at the end of
the first day, at about 6 pm, and followed almost 10 hours of
discussion and testimony. By that time, most of the exhausted
audience, company executives and several Task Force members had long
since abandoned the meeting room. Community representatives wondered
aloud whether the meeting's organizers had delayed the public
testimony session and restricted it to 60 minutes as a means to reduce
community and activist influence on the outcome of the hearings.

       The 20 hours of discussion and testimony that comprised the
2-day summit meeting covered a wide spectrum of protease inhibitor
drug development and policy issues, including accelerated approval,
drug resistance and cross-resistance, expanded access, compassionate
use/salvage therapy programs, Phase III and postmarketing trial design
and FDA regulations.

       The following text summarizes some of what was said on these
subjects, but is by no means an exhaustive review of the proceedings.
A complete transcript of the meeting is available from FDA through the
Freedom of Information Act. [For a complete transcript, write to: FDA,
Freedom of Information Staff (HFI-35), 5600 Fishers Lane, Rockville,
MD 20857. There is a charge for search and review time, photocopying,
certifications and computer charges. You will receive a bill after
sending in the written request. Expect to pay about $100 for the
complete transcript.]

       Accelerated Approval of Protease Inhibitor Drugs

       In a rare show of unity, almost all community representatives,
scientists and clinicians at the Task Force meeting spoke in favor of
accelerated approval for the Roche, Merck and Abbott protease
inhibitor drugs. However, there was considerable disagreement about
the appropriate timing for early marketing approval for the 3
compounds. In addition, there was extensive debate about how best to
evaluate the potential clinical benefits of the protease inhibitor
drugs in Phase III and in post-marketing trials following accelerated
approval.

       A Consensus Statement endorsed by Project Inform, San Francisco
AIDS Foundation and BETA, ACT-UP New York, ACT-UP Golden Gate and many
other community-based organizations called for the manufacturers of
the 3 leading protease inhibitor drugs to file for accelerated
approval before the end of 1995.

       About 250 signed Consensus Statements, endorsed by over 50
community-based organizations and by numerous individuals, were
presented during the public testimony session to FDA Commissioner
David Kessler by Jules Levin, who represented the coalition of
community groups that endorsed the accelerated approval statement.
Accelerated approval of the protease inhibitors in 1995 is the
centerpiece of an ongoing campaign by the San Francisco AIDS
Foundation and BETA to achieve widespread access to this new class of
AIDS drugs through 4 specific actions:

       * create immediately 'compassionate use' programs to provide
         the Merck, Abbott and Roche protease inhibitor drugs to at
         least 10,000 people with advanced AIDS who have no other
         treatment options;

       * approve as prescription drugs (through the accelerated
         approval process) the Roche, Merck and Abbott protease
         inhibitor drugs as early in 1995 as possible;

       * establish a Protease Inhibitor Drug Task Force to stimulate
         collaborative research and to address patient-related issues;

       * convene a Consensus Conference to recommend new, innovative
         designs for human studies of the protease inhibitor drugs and
         other experimental AIDS treatments.

       For more information on this campaign, and how you can help
       achieve these objectives, see the memo to Merck on page 30 of
       this issue of BETA.

       ******************************
       Viral Load as a Marker of Drug Effectiveness

       The potential role, utility and reliability of polymerase chain
reaction (PCR) and branched chain DNA (bDNA) tests in the drug
development process emerged as a central topic of discussion at the
Task Force meeting. PCR and bDNA tests already have become significant
tools in AIDS research. These powerful new assays measure the amount
of HIV RNA present in the bloodstream of HIV positive individuals. The
result is referred to as 'viral load,' 'viral burden' or 'HIV load.'
Both the reliability of these tests and their practical applications
have expanded dramatically recently, although work remains to be done
to ensure that they give accurate and repeatable results.

       Several studies using these tests suggest that viral load
predicts clinical outcome, e.g., low viral load due to drug treatment
correlates with a clinical benefit, whereas a significant increase in
viral load presages disease progression. These new diagnostic tools
are changing the treatment of HIV disease at a fundamental level. Many
researchers believe that PCR and bDNA testing are valuable methods for
demonstrating how well a particular drug or drug regimen is working in
individual patients. As a result, recommendations can be made about
continuing, halting, changing or adding drug treatment early, before
patients experience significant CD4 cell loss and clinical decline.
PCR and bDNA assays of viral burden also may significantly shorten the
amount of time necessary to test the effectiveness of experimental
therapies. In so doing, millions of dollars in research costs may be
saved. If these tests can reliably predict clinical outcome, they
would have a dramatic effect on FDA's drug approval regulations. Using
these tests, it may be possible to evaluate the clinical effectiveness
of an individual drug or drug regimen in far less time, with far fewer
trials and at a much lower cost than currently is the case. As might
be expected, this is a hotly debated subject within the scientific,
regulatory and activist communities concerned with AIDS drug research
and development.

       At the February Task Force meeting, a number of researchers and
FDA personnel addressed the issue of the appropriate role of viral
load testing in the accelerated approval process. FDA policy on this
matter may be gleaned from remarks made at the meeting by David
Feigal, Director of the Division of Antiviral Drug Products at FDA:
'PCR will be allowed as a surrogate marker. You don't need to validate
viral load as a surrogate marker [for clinical benefit] in order to
get accelerated approval [from FDA]. That is a long-term question that
does not have an impact on the registrational status of the protease
inhibitors,' said Feigal.

       'One of the features of accelerated approval is that you know
less [about candidate drugs],' continued Feigal. He added that FDA
labeling for drugs licensed on an accelerated approval basis contains
no description of a clinical benefit. FDA requires sponsors of drugs
receiving accelerated approval to conduct post-marketing (Phase IV)
studies to confirm, through clinical endpoint markers, that the drugs
produce a clinical benefit.

       For more information on how viral load testing may affect the
drug approval process and early access to new therapies, see the BETA
interview with researcher Michael Saag, MD, page 40.

       The following section reviews scientific data and other
information on the Roche, Merck and Abbott protease inhibitor drugs
drawn from drug company presentations at the Task Force meeting,
activist meetings with the companies and other sources.

       Roche's Saquinavir

       Hoffmann-La Roche (Roche) is the only protease inhibitor drug
developer that has announced plans to apply for accelerated approval
of its product, saquinavir (Invirase) before the end of 1995,
following an analysis of interim data from the Phase III trials of the
drug. The Phase III trials of saquinavir, already underway in the
U.S., Canada and Europe, have enrolled about 4,000 people at various
stages of HIV disease. Miklos Salgo, MD, director of the department of
clinical virology at Hoffmann-La Roche, said at the Task Force meeting
that Roche will apply for early approval of saquinavir by October
1995. Roche will seek approval of the drug as monotherapy and in
combination with AZT and ddC, according to Salgo. Two important
concerns have arisen in the AIDS community regarding saquinavir: (1)
saquinavir's potential cross-resistance to the other protease
inhibitors and (2) the optimum dose of saquinavir.

       Optimum Dose of Saquinavir

       The optimum dose of saquinavir is not yet known. The 1,800 mg
dose used in the ongoing Phase III trials of the drug may be
suboptimal, i.e., may not produce the maximum anti-HIV effect.
Preliminary data from a Stanford University study of 'high-dose'
saquinavir (3,600 and 7,200 mg daily) suggest that these higher doses
reduce viral load more significantly than the 1,800 mg dose.

       Roche is developing a new oral formulation of saquinavir to
make it more bioavailable and thus more active than the current
formula, which is only 4% bioavailable. Roche officials have suggested
that because the 1,800 mg daily dose reduces viral activity by 90%, it
may not be necessary to increase dosing (beyond 1,800 mg/day) if
saquinavir is used in combination with other antiretroviral agents.

       A randomized study (ACTG 229) completed last year showed that
the 3-drug combination of AZT/ddC/saquinavir produced a stronger
anti-HIV effect (i.e., decreased viral load more significantly) and
better immunologic effects (i.e., increased CD4 counts more
significantly) than the 2-drug combinations of AZT/ddC or
AZT/saquinavir.

       Saquinavir and Resistance

       The following information on saquinavir and resistance has been
drawn from personal communications with Roche researchers and from
unpublished documents furnished to BETA by Roche. The principal
sources of this information are Noel Roberts, PhD, and Ian Duncan,
PhD, of the Department of Preclinical Biology at Hoffmann-La Roche in
Welwyn, England.

       Resistance to saquinavir at 600 mg 3 times daily does not
develop rapidly or at a high incidence level. After one year of
treatment, about 50% of patients using the drug show some sign of
resistance. Most of the resistant virus isolated has only a single
critical mutation at L90M or, less commonly, at G48V. These single
mutations generally lead to a modest (typically 3-to 10-fold)
reduction in sensitivity.

       By comparison, after 16 to 36 weeks, patients treated with the
Merck protease inhibitor (MK-639) show 16- 60-fold decreases in
sensitivity. With the DuPont-Merck protease inhibitor, XM-323,
multiple mutations produce up to a 500-fold decrease in sensitivity.
With the nucleoside analog 3TC, a single mutation yields a greater
than 100-fold decrease in sensitivity.

       Because the target enzymes differ, no cross-resistance occurs
between reverse transcriptase inhibitors and protease inhibitors.
There also is no known cross-resistance between saquinavir and most of
the other protease inhibitor drugs in development, according to Roche
researchers Roberts and Duncan. They say that saquinavir-resistant
virus retains full sensitivity to the Merck and the DuPont Merck
protease inhibitors. The only significant cross-resistance found with
saquinavir occurs between saquinavir and the Agouron protease
compounds, which are close analogues of saquinavir.

       Merck scientists have said that patients using MK-639 for 40
weeks or more became resistant not only to MK-639 itself, but also to
other protease inhibitors sensitive to changes at position 82 (e.g.,
Abbott's ABT-538) and also, unexpectedly, to saquinavir. Roberts and
Duncan of Roche counter that, after examining the data from 100
patients treated with saquinavir, no evidence could be found from the
genotypic studies that saquinavir generates resistance to MK-639.

       It was discovered that 10% of the saquinavir-treated patients
carry the MK-639 mutations V82A or I84V, which could indicate
resistance to MK-639. But the same incidence of these mutations was
found at baseline and there is no correlation with the saquinavir
mutations G48V or L90M, Roberts and Duncan told BETA. Baseline data
show no G48V or L90M in any patients studies to date, they said.

       Taken together, these data suggest that resistance to
saquinavir should develop less readily than to MK-639, BMS-186318 or
to any other protease inhibitor sensitive to V82A and I84V changes,
according to the Roche scientists. This information points to a
special attribute of Roche's saquinavir that is not indicative of the
Merck and Abbott protease inhibitors: it may be possible to use
saquinavir successfully in combination with either MK-639 or ABT-538,
as well as with nucleoside and non nucleoside drugs. In contrast, the
Merck and Abbott protease inhibitors appear to be cross-resistant and
therefore probably unsuitable for use in combination. For more
information on protease inhibitors and resistance, see page 37 of this
issue of BETA.

       Saquinavir and Compassionate Use/Salvage Therapy/Expanded
       Access

       During the Task Force meeting, community representatives and
drug company managers clashed over the need for increased enrollment
in 'compassionate use/salvage therapy' programs to provide protease
inhibitor therapy to seriously ill patients with no treatment options.

       To its credit, Roche has committed to sponsor an expanded
access program to provide saquinavir to people with advanced AIDS.
Roche says it will start a limited expanded access program in the
third quarter of 1995, pending the completion of a bioequivalence
trial of a new formulation of saquinavir. The expanded access program
will begin with an enrollment of 4,000 people worldwide (approximately
half of this number in the U.S.) and increase in size as greater
quantities of saquinavir are manufactured.

       Merck's MK-639

       Merck and Company's protease inhibitor drug, MK-639 (formerly
called L-735,524), in clinical trials for 2 years, has demonstrated
potent anti-HIV activity. For 12 weeks, at a dose of 2,400 mg/day,
MK-639 produces a dramatic drop in viral load (a median maximum of 2
logs, a 100-fold decrease. After 24 weeks of treatment, viral load
returns to near baseline levels and low-level resistance develops. Yet
the median maximum CD4 cell increase is 110 cells/mm3.

       Merck scientists have discovered that virus with high-level
resistance to MK-639 also shows some level of resistance to the
Abbott, Vertex/Wellcome, Searle, Roche and DuPont-Merck protease
inhibitor drugs. The clinical significance of this is not known. At
the Task Force meeting, Merck representatives said that a few of 18
individuals using MK-639 for over a year have not developed
significant resistance.

       Merck claims its protease inhibitor is the most effective AIDS
therapy yet tested, according to a February 23, 1995 article in The
Wall Street Journal (WSJ). 'Based on our preliminary data, [MK-639]
looks better than anything else tested,' said Edward Scolnick,
president of Merck research. Despite Scolnick's bold claim, most
experts agree that it's too early to know the comparative efficacy of
any of the protease inhibitors. To be maximally effective, these drugs
likely will be used in combination with other agents. At the Task
Force meeting, Merck drew fire from community activists on several
fronts. New York City's TAG sharply criticized the design of Merck's
trials in a report, Problems with Protease Inhibitor Development
Plans, co-published by TAG and the Gay Men's health Crisis (GMHC).
Other activists were concerned more with lobbying Merck for faster and
greater access to MK-639 than with trial design issues.

       The San Francisco AIDS Foundation has lobbied for 2 treatment
policy objectives regarding the Merck protease inhibitor: (1)
immediate creation of a 3,000 person 'compassionate use' program for
MK-639; and (2) accelerated approval of MK-639 as soon as possible.
The primary function of 'compassionate use' programs is to provide
promising experimental drugs to seriously ill people with AIDS who
have no other treatment options.

       MK-639 and Accelerated Approval

       At the Task Force meeting, Merck said the company likely will
apply for accelerated approval of MK-639 in 1996. The Community
Consensus Statement calls on Merck to apply for early approval of
MK-639 before the end of 1995, when interim  data become available
from Phase III trials of the drug.

       No Expanded Access of MK-639 in 1995

       Merck says it does not have enough drug supply to operate an
expanded access program of any size in 1995: 'While there can be no
expanded access in 1995, due to limited drug supplies, Merck will work
toward the goal of having enough drug for an expanded access program,
which would bridge from early 1996 until drug approval.'

       Compassionate Use/Salvage Therapy Program for MK-639

       Some community activists are skeptical of Merck's claim
regarding its supplies of MK-639, even though 2 independent
consultants hired by community members reported that Merck was
manufacturing the drug as fast as possible. Although no one expects
Merck to launch a large expanded access program for MK-639, enough
drug ought to be available in 1995 for a 3,000-person 'compassionate
use' program for severely ill people with CD4 counts less than 50
cells/mm3.

       Phase II and Phase III Trials of MK-639

       Merck is continuing Phase II trials to further evaluate MK-639
as monotherapy (protocols 006 and 021), combination therapy with AZT
(protocol 019) and with AZT and ddI (protocol 020). A study to
evaluate the safety and effectiveness of higher-dose MK-639 in
combination with AZT is also underway (protocol 024).

       Merck expects that Phase III trials of the drug will be
underway by the spring of 1995. Phase III studies to test the safety,
tolerability and effectiveness of MK-639 at a dose of 800 mg 3 times
daily will begin in the next few weeks:

       * a clinical endpoint (new opportunistic infections and death)
         study in 750 AZT-naive patients with CD4 counts between
         50-250 cells/mm3. Patients will be randomized to MK-639, AZT
         or the combination. An interim analysis of CD4 counts occur
         at 6 months. Scheduled to begin in March 1995 in Brazil,
         results of this study will form the basis for the accelerated
         approval filing.

       * a surrogate marker (CD4 and viral load) study in 780
         AZT-naive patients with CD4 counts between 50-500 cells/mm3.
         Participants will be randomized to MK-639, AZT or the
         combination. Study will begin in March or April 1995 in the
         U.S. and Europe, and possibly in Canada and Australia.

       * a surrogate marker study in 450 AZT-experienced patients with
         CD4 counts between 50-500 cells/mm3. Participants will be
         randomized to MK-639, d4T or the combination. Study will
         begin in the April or May 1995 in the U.S. and Europe.

       * a pilot surrogate marker study in 90 AZT-experienced patients
         with CD4 counts between 50-400 cells/mm3. Participants will
         be randomized to MK-639, AZT/3TC or the triple combination.
         Study will begin in March or April 1995 in the U.S.

       * a surrogate marker study in 150 patients with CD4 counts less
         than 50 cells/mm3. The trial includes 4 arms. In 3 arms,
         patients will be randomly assigned to AZT plus 3TC, AZT plus
         3TC plus MK-639, MK-639 monotherapy or, if randomization
         proves medically inappropriate, the patient will be put into
         a fourth arm of open-label MK-639.

       * Merck may start a 900 - 1,200 person clinical endpoint study
         in AZT-experienced individuals, using d4T or AZT/3TC as the
         control arm. The study will be conducted in the U.S. and
         Europe, and possibly in Canada and Australia.

       Merck's Future As an AIDS Drug Developer

       Merck released the following statement regarding its AIDS
research program at the Task Force meeting on February 23: 'Merck is
dedicated to AIDS research and the pursuit of new treatments for HIV
infection and AIDS. Since 1986 we have invested more than $400 million
in AIDS research, making it the largest basic research program in
Merck's history....'

       'Although our basic research continues, Merck does not have
other product candidates for AIDS [emphasis added]. Merck's back-up
protease inhibitor failed in late pre-clinical studies last year
because it was too toxic. In addition, Merck terminated its clinical
development program for non-nucleoside reverse transcriptase
inhibitors (NNRTI) in the fall of 1993. Four Merck NNRTI entered human
trials, but all 4 eventually failed because they were ineffective or
because the virus rapidly developed resistance to them.'

       Abbott's ABT-538

       The Abbott protease drug is a potent inhibitor of HIV
replication, and produces on average a 2.1-log reduction in HIV load,
according to study results released recently at the Human Retrovirus
Conference in Washington, DC (January 1995). Researchers report that
some patients on ABT-538 have experienced dramatic increases in CD4
counts. One individual reportedly went from a CD4 count of 60 to 600
cells/mm3. Another report documents the rapid disappearance and
shrinking of KS lesions in 2 individuals while on the drug. For a
review of the available data on ABT-538, see page 9 of this issue of
BETA as well as the December 1994 issue of BETA, pages 3-4.

       After 24 weeks of monotherapy with ABT-538, patients show signs
of resistant virus. ABT-538 appears to be cross-resistant to the Merck
protease, but may be suitable for combination with saquinavir, the
Roche protease inhibitor. In its current elixir formulation (which
will be used for the Phase III trials), the Abbott protease inhibitor
is unstable and requires constant refrigeration to avoid spoilage.
Abbott representatives say they are working to produce an oral capsule
that will not require refrigeration. Based on the results of Phase II
studies, Abbott has chosen 600 mg twice daily as the optimum dose of
ABT-538 (1,200 mg/day).

       Adverse side effects from ABT-538 appear to be minimal. The
most commonly reported adverse events are bad taste, perioral
paresthesias and diarrhea. Laboratory abnormalities associated with
use of the drug include elevated triglycerides and elevated ALT.

       Abbott Laboratories' development timetable for ABT-538 remains
unclear at this date (early March 1995), but Abbott representatives at
the Task Force meeting said that the company likely will not apply for
accelerated approval before mid-1996. Enrollment in the Phase III
trials has begun at some sites (call 312-755-1241 for more
information). Abbott has planned a 3-arm Phase III study for 300
AZT-naive patients with 100-500 CD4 cells/mm3. Participants will be
randomized to ABT-538 monotherapy, AZT monotherapy or ABT-538 plus
AZT. Scheduled to begin in March 1995, the study will evaluate the
effect of therapy on viral load. An interim data analysis is planned
at 16 weeks.

       For 700 patients with fewer than 100 CD4/mm3 who are
AZT-experienced, Abbott has designed an unusual 36-week, 2-arm trial.
Participants will be allowed to take any anti-HIV monotherapy or
combination (except 3TC). One arm will add ABT-538 to their individual
regimen. The second arm will add nothing. Viral load and CD4 counts
are the primary endpoints, although clinical events also will be
noted. This is Abbott's answer to the AIDS community request for a
'salvage therapy' program for individuals with advanced disease and no
treatment options.

       Some AIDS advocates, including this author, consider this
protocol unethical, because half the participants, in effect, are on
placebo'their existing therapy. In addition, individuals on 3TC are
excluded from the study. Activists concerned with these programs for
seriously ill people consider patient access to alternative therapy
(Abbott's protease inhibitor) as the primary goal. Abbott apparently
regards these 'compassionate use' protocols as a means of providing
useful data to the company.

       A third trial among AZT-experienced patients with 200-500 CD4
cells/mm3 will have 3 arms: one arm will consist of those already
using AZT. When any of these individuals experience a 'clinical event'
(i.e., a recurrent or new opportunistic infection), they then will go
to open label ABT-538 monotherapy (arm 2). The third arm will consist
of participants receiving both AZT and ABT-538.

       Protease Inhibitor Drugs from Agouron and Vertex/Burroughs
       Wellcome

       These 2 compounds have just emerged from preclinical testing.
Human studies will begin in March 1995. Both the Agouron drug
(AG-1343) and the Vertex/Burroughs Wellcome product (VX-478) appear to
be synergistic with AZT and ddI, an observation that bodes well for
combination regimens. Roche scientists say that saquinavir and the
Agouron compound are cross-resistant. Information on saquinavir's
interaction with VX-478 is not available.

       Proposal to Create a Protease Task Force

       Jules Levin of ACT-UP New York's Treatment and Data Committee
proposed before and during the protease meeting that the National Task
Force on AIDS Drug Development create a subcommittee to focus
exclusively on protease inhibitor drug issues. This body, comprised of
researchers, regulators, clinicians and community activists, would
meet regularly to identify obstacles and facilitate progress in the
future development of this new class of AIDS drugs.

       Many issues and concerns about the protease inhibitor drugs and
their development, although identified and discussed at the February
23-24 Task Force meetings, are neither resolved nor even yet clearly
delineated. These include such subjects as drug resistance,
cross-resistance, combination studies, trial design and salvage
therapy protocols. An independent Protease Inhibitor Task Force or
perhaps a Protease Inhibitor Working Group that meets regularly to
address these and other concerns could help to overcome impediments to
the development of these new agents.

       The FDA and Protease Inhibitor Drug Development

       FDA Commissioner David Kessler, MD, played an important role at
the February meeting of the National Task Force on AIDS Drug
Development. David Feigel, MD, of the FDA antiviral division also
contributed much to the discussions (see 'Viral load,' above). Kessler
presided over the program throughout much of the 2 days of hearings,
and directed salient questions to Task Force members and
pharmaceutical company CEO. Many AIDS activists present at the meeting
were relieved to hear Kessler and Feigel publicly endorse accelerated
approval of the protease inhibitor drugs. He also scored points among
some activists by continuing to press the pharmaceutical industry to
sponsor expanded access programs for these drugs. It was Kessler who,
under pressure from AIDS activists in 1992, guided FDA adoption of the
accelerated approval regulations that allows the agency to approve for
marketing drugs for life-threatening illnesses before complete
information on their effectiveness is known.

      Kessler and his agency have been criticized by some, most
particularly New York City's TAG, for not forcing companies granted
accelerated approval to conduct adequate postmarketing studies to
prove definitively the clinical effectiveness of their drugs. TAG has
criticized FDA repeatedly for not requiring Bristol-Myers Squibb and
Hoffmann-La Roche to conduct adequate follow-up studies of ddI and
ddC, respectively.

       The Protease Inhibitors: Science and Activism

       Resistance and Cross-Resistance among Protease Inhibitor Drugs

       The following are excerpts from a symposium entitled 'Protease:
Resistance, Cross-Resistance, Implications for Clinical Study and Use
for 1995 and Beyond.' Sponsored by ACT-UP New York and Hoffmann-La
Roche, the symposium took place February 2, 1995, in Washington, DC,
immediately following the close of the Second National Conference on
Human Retroviruses and Related Infections.

       Included here are remarks by Noel Roberts, PhD, Director of
Virology at Hoffman-La Roche, Emilio Emini, PhD, Executive Director of
Antiviral Research for Merck Research Laboratories, and Martin Delaney
of Project Inform.

       ROBERTS (Roche): The experience of a lot of people now, 4 or 5
different groups, who have [cultured] virus resistant to saquinavir
[Roche's protease inhibitor] in vitro, is that the 48 mutation comes
up first and the 90 mutation comes up later. That is the general
pattern. There have been few deviations from this profile, which is
different from that of most of the other protease inhibitors that are
either in the clinic or in early-stage development.

       I think these data are encouraging. They open the door for
treatment with saquinavir and other protease inhibitors, and perhaps
of most importance to patients for combination treatments using more
than one protease inhibitor.

       We have found that 48 and 90 are the common mutations [for
saquinavir], both in vitro and in vivo. In vivo, the L90M mutation
predominates. The double mutant [48 and 90] is rare. It's still only
been seen in 2 out of 73 patients [on saquinavir] we've looked at. The
total incidence rate of mutation is only about 50% at 1 year. The
populations are still mixed'in other words, most of these patients
still carry wild-type virus as well as the mutant(s). Phenotypic
changes are modest.

       I must qualify this. I quoted about 10-fold. The data, as I
said, are being done in test centers, between which there's sort of a
divergence, not qualitatively but quantitatively. The United Kingdom
and the French centers are giving us lower figures for phenotypic
changes than the centers in Italy. But overall, I think that a factor
of 10-fold is representative. We also have indications that use of
combinations may reduce the incidence rate of emergence of resistance
either to saquinavir or to AZT in double or triple combination.

       I think it's important to place the term 'resistance' in
context. We can very sensitively measure a lot of changes that pertain
to resistance in vitro, and I fear we are perhaps in danger of
overinterpreting these changes as far as clinical outcome is concerned
and scaring people who might want to take these compounds.

       I think the only real test, when we've got sufficiently large
prospective rather than retrospective studies on the emergence of
resistance, will be to relate long-term changes to marker changes and
eventually to clinical outcome changes. We're now engaged in 2 large
Phase III studies. We are taking samples prospectively for genotypic
and phenotypic data. We hope to compile a database of several hundred
patients and their matched phenotypic and genotypic changes over time.

       These data should enable us to look closely and powerfully at
the correlation between changes, be it a half-log change, a 1-log
change, 1 mutation, 2 mutations (e.g., 48 and 90, or just 90) and
cross-correlate these with clinical outcome and with marker changes. I
think that when we've collected these data we can then really talk
about resistance in a clinically meaningful way rather than just
theoretically, based on changes that we can measure in the test tube.

       EMINI (Merck): There will be some disagreement between Noel and
myself, but there is one point Noel made that I want to emphasize
because I agree very strongly with him. That point is that we must put
the whole issue of resistance in context. It is clear that given the
genetic variability of this virus, and given the virus life cycle in
infected individuals, it is unfortunately an almost perfect
evolutionary machine. Resistance is something that we're going to have
to tackle with most, if not all, antiretroviral agents that will be
developed against the virus.

       There is structural diversity among the protease inhibitors,
yet we have been able to isolate variants in the clinic that are
multiply resistant or express a fair degree of loss of susceptibility
to all of these compounds. I have data from a series of individual
patients; it's very difficult to look at this data in a representative
fashion because of the extreme variability in terms of genotype, in
terms of amino acid substitutions within the protease from patient to
patient, etc.

       Regarding the question of cross-resistance, after 36 weeks [on
the Merck protease inhibitor, MK-629] we see
cross-resistance'cross-loss of susceptibility'to the Dupont-Merck
compound (XM-323) and to a prototypic Abbott compound (ABT-80987), but
no cross-resistance with saquinavir, the Vertex compound (VX-478) or
SE-52151 [the Searle protease inhibitor]. When we looked at the week
40 isolate, for which we see a much greater loss of susceptibility to
MK-639, we saw, very much to our astonishment when we first got these
data, a loss of resistance that went across the other compounds,
including saquinavir, VX-478 and SE-52151.

       It is obviously very difficult at this early point to draw
conclusions. One of the things this means from our perspective is that
there is a fair degree of flexibility within the protease enzyme and
the genetic pathways that it can undertake (at least in the case of
MK-639) to achieve clinically significant resistance; cross-loss of
susceptibility and cross-resistance are certainly not just
possibilities, but are facts. It is difficult to draw any conclusions
about what this may mean in terms of combination use or sequential use
of different protease inhibitors, short of doing the actual
experiments.

       DELANEY (Project Inform): I had some prepared remarks, but I'm
inclined to go off on some other tangents after having seen the 2
contradictory data presentations. But first, I think that the
community point of view on all this is that it's not about dueling
scientists and codon mutations, but about the real world. What is the
impact of these findings in a clinical setting? I don't think we have
much of that kind of information coming to us today. Instead, a lot of
the information we're getting is scaring people out of even
participating in those clinical settings [trials].

       From a patient's point of view, I think we need to come up with
methods that will distinguish the degree of resistance that takes
place to these drugs and in what populations, something I believe has
been completely absent from this discussion. We keep hearing about the
same 4 famous Merck patients that have been analyzed to death. What
kind of people were these? Did they have early- or late-stage disease?
Were the patients AZT-resistant? Who they were, I think, has a big
impact on the significance of this data.

       We need scientists to give us a sense of what all this means,
relative to the production of viral RNA as measured by existing PCR
tests. My understanding is that these tests do not distinguish between
productive viral RNA and defective viral RNA. If viral load is going
up, is it productive viral load? I don't know if we know that, and I
think that until we do, we need to be very careful about making
projections from relatively obscure laboratory observations.

       Additionally, I think we need information on the interactions
among these drugs, their potential interactions and synergy. I'm
struck by Doug Richman's recent comments about how HIV resistance is
not so much a phenomenon of rapidly mutating virus as it is simply a
reflection of viral turnover. If we're talking about the potential for
synergy among some of these drugs, that implies that there's a lower
degree of viral turnover. Will that not also result in a slower pace
of development of resistance? I think we need to look at the issues of
synergy right alongside the issues of resistance and cross-resistance.

       I also want to do a little scolding here. I think Merck and
Abbott have done something that no drug companies have done so far in
this epidemic, and that is putting out individual case data. This is
the kind of data that we, as patient advocate groups, would get
clobbered for presenting.

       I think in many ways it amounts to anecdotal data, and I want
to acknowledge that Roche has not put out anecdotal data or
case-by-case data on saquinavir. The only kind of data we've seen on
saquinavir has been controlled study data. It is indeed more modest
and not as exciting, but I know from having worked with some of the
investigators that if you look at saquinavir data on a case-by-case
basis, you can find some really enormous responses. You can find
people with 2- and 3-log drops in viral load and 500-600 CD4 cells/mm3
increases, but a decision was made not to put that kind of data out.

       I am also struck by the repeated phrase about the
unpredictability of the interaction of resistance patterns. I think I
heard that from Emilio [Emini] and others. If that's the case, then it
seems to me that the data that counts is the clinical data, not
projections from laboratory data. The lab data may be a place to start
when making some early decisions about what clinical trials to
undertake using what combinations'the essential thing is to get the
drugs into studies, alone and in combination, and to get real clinical
data out of those studies and see what the real results are. Until
that happens, I think putting out that kind of case-by-case data is
having a very negative impact.

       For example, I know an awful lot of people who have been
frightened away from participating in the saquinavir trials because
they read in community newsletters that taking saquinavir will make a
person resistant to the Merck drug. There's a perception that Merck's
MK-639 is a better drug, so people reason that they shouldn't get into
a saquinavir trial because they'll be spoiled for the Merck drug.

       We don't know that this is true! But that's the kind of thing
that is growing from misinterpretation of this information. At these
meetings, I think we all need to achieve better clarity about what
this data means and to realize that it should not be [although it may
be] impacting anybody's clinical choices or impacting whether or not
to go into clinical trials. The real story on all of this is yet to
come.

       EMINI (Merck): Let me respond to each of Martin's points
individually. First, we agree that it is critically important to
establish how these resistance findings translate into real clinical
experience. We're looking at that right now. In fact, all the viral
resistance data that I presented were drawn from patients in ongoing,
controlled clinical studies. As these studies continue, we hope to
correlate the patients' eventual clinical outcomes to the viral
resistance that I just reported. Second, the only time we discuss
individual patient data is to illustrate certain points or to show how
specific viral resistance patterns correlate with a specific patient's
antiviral activity. By definition, we have to show individual patients
in order to make these points. Furthermore, the way we present our
clinical data is far more conservative than others, and has in fact
been criticized as being too conservative. Third, we know that when
the viral RNA rebounds in patients, the viral RNA does indeed
represent infectious virus. We have demonstrated this by actually
isolating the virus in the serum of patients and showing that the
virus is infectious, and that the infectious pattern correlates with
viral RNA patterns. Finally, the patients that I presented today all
had CD4 counts below 250.

       The Protease Inhibitors: Science and Activism

       San Francisco AIDS Foundation Policy Statement on Protease
       Inhibitor Drug Development Ronald Baker, PhD

       The following are excerpts from the public testimony given by
BETA editor Ronald Baker before a special meeting on protease
inhibitor drugs sponsored by the National Task Force on AIDS Drug
Development, held February 23-24 in Bethesda, Maryland.

       'What are we to say to those who are dying for lack of an
effective therapy? There is only one reasonable response to their
calls for help: creation of 'compassionate use' programs to provide
immediately the promising protease inhibitor drugs to seriously ill
individuals who have no other treatment options; this should be
followed by accelerated approval of these drugs as soon as possible.'

       'Providing these promising drugs to this patient population at
the earliest moment possible is the highest treatment policy priority
of the San Francisco AIDS Foundation.'

       'Early access to the protease inhibitor drugs represents the
best hope for delaying disease progression and prolonging life among
people who no longer benefit from available anti-HIV therapies.'

       'We must be mindful of the discouraging but all too real fact
that tens of thousands of people who have taken nucleoside analogs for
several years are now living without treatment options. Many of those
who have exhausted the limited benefit of available therapies are
gravely ill and have an urgent need for alternative treatment.'

       'Many of us here today believe that the demonstrated capacity
of these agents [protease inhibitors] to significantly decrease viral
load in people with AIDS correlates with the ability to produce a
clinical benefit for these individuals.'

       'The exciting data we now have on these drugs are primarily
from monotherapy studies. It is not unreasonable to suggest that, when
used in combination with drugs of different classes, the combined
anti-HIV effect of the combination regimens may be synergistic and
more sustained.'

       'The San Francisco AIDS Foundation urges FDA and the
pharmaceutical companies to work together to bring the protease
inhibitors to market as soon as possible and thereby provide the
HIV/AIDS community with the broadest possible access to these
promising drugs.'

       Viral Load and Clinical Outcome: the Search for Correlation An
       Interview with Michael Saag, MD Ronald Baker, PhD

       It is important for the immediate and long-term future of AIDS
treatment research to answer the question: Is viral load a reliable
marker for clinical outcome? BETA interviewed Michael Saag, MD, of the
University of Alabama about this question, which emerged as a critical
issue at the meeting on protease inhibitor drugs sponsored by FDA and
the National Task Force on AIDS Drug Development.

       BETA: How have the new data on HIV pathogenesis affected your
views on patient care and drug development?

       SAAG: The recent insights in biodynamics clearly show that HIV
is replicating from day one of infection throughout the entire course
of disease, even through terminal stages. With that in mind, I think
it's important to remember that for each individual the virus and
quasi-species are different. The host response to the virus is also
different for each person. The emergence of resistance to any
permutation created by drugs is different from person to person.
Therefore, it raises the question whether large population studies of
a single agent or a single intervention will be able to provide us
with the answers that we need for HIV infected individuals in the long
run.

       If every individual's response is unique, then 2 individuals in
the study can be 2 extremes. The dramatic, initial 2-week response is
lost in terms of viral burden and CD4 response. The other is the
sustained response over the 2-year period. You're going to follow them
both for 2 years and by the intent-to-treat analysis they are treated
equally, whether or not they remained on therapy or their response was
lost physiologically. Then, after the 2-year period, they are analyzed
together. To me, that runs counter to the physiology of the situation.
Though we can get a generic assessment, that assessment does not
capture each individual person.

       We practice medicine by looking at individuals and making a
decision for them. What we do in traditional drug development is look
at populations of people, find a result, choose a regimen and apply
that to individuals. When one has a relatively uniform pathogenesis,
that system works. In the paradigm of a virus being different in every
host, or the host response being different every time, the emergence
of resistance is variable depending on how that viral population
responds and what its level of replication is. In my opinion, a
population-based approach to drug development falls short. If we
assume that viral burden correlates to clinical outcome, how do we act
on that assumption with our current set-up?

       One option is to create a large study using viral markers as
endpoints and either allow information to go through to the
practitioner and let them make a decision, or nor. The variable there
is that measuring viral burden will direct changing therapies, instead
of using traditional means of following a clinical sense of when
someone might be failing. The relative value of measuring viral burden
may not necessarily answer the question of whether viral burden is a
good surrogate marker. The clinicians who are making decisions in the
'control' arm are still getting hints about how their patients are
doing'such as CD4 count or symptoms. Clinicians may switch therapy
regimens based on those things and not necessarily validate the viral
burden.

       I propose we address several things at once: that we try to get
relatively uniform guidelines for clinical trials across the country,
and maybe even internationally; and that we agree to a well-defined
schedule of measuring viral burden and processing and storing
specimens uniformly. We can establish a national databank within
different studies that we can use as a resource. We can set up several
small intervention trials in which it doesn't matter how the
intervention affects viral burden. We can then analyze the cases of
bad clinical outcomes, however that is defined, e.g., development of
an opportunistic infection or even survival while on a new therapy. We
can compare these individuals' viral burden to those who did not reach
a clinical endpoint over the same time period and see what the viral
burden suggests. Maybe better yet, we can see what the clinical
outcome is of those who had a sustained response, however that's
defined, in viral burden versus those who didn't.

       Again, the concept of intervention outcome is secondary to the
primary focus on the viral burden. If we can prove that viral burden
correlates to clinical outcome, we can solve enormous problems for
ourselves. It may be one of the most important discoveries since this
epidemic began. It would speed up drug development, so that all a
company would have to show regarding a given drug is (1) whether it's
safe'what is its safety profile and what are its side effects?'(2)
what its relative antiviral activity is, in terms of viral burden, and
how sustained it is, and (3) what are its drug interactions,
especially with other agents, so that we know what to anticipate if we
use a new drug with AZT, ddI, ddC, etc. We need to have some sense of
the potential pharmacologic and clinical drug interactions or safety
profile changes if we're using the drug in combination. Once we have
established these things it's not a question of accelerated approval
but of straight-out approval.

       A parallel situation is hypertension. Many studies have shown
that high blood pressure, sustained over a long period of time and not
treated, is significantly associated with such outcomes as stroke or
heart attack. If we can lower an individual's blood pressure,
generally those individuals will be better. Not all people do; some
may still have a heart attack.

       In general, if we can shift the balance in favor of a better
clinical outcome, ultimately we will have safer, more effective
compounds that clinicians can mix and match based on their individual
patients' response, and thus we'll have better patient care.
Clinicians can use these markers to tell when a drug or regimen is
failing and it's time for a change. We desperately need these markers
to get more drugs approved. This is all critically dependent upon
proof that viral burden correlating to clinical outcome is correct. If
it is incorrect, then we're back to where we were from the get go.

       BETA: How long will it take to verify that correlation?

       SAAG: Well, we have a lot of storage specimens from a number of
our trials units throughout the country. The problem is that I don't
think we can be fully assured that other specimens are collected in
the same way. One trial may be serum-based, another plasma-based, one
may have been processed overnight or one may have been processed in 3
hours. What we have to do is ensure that each specimen is processed
similarly; otherwise we will get variations in the viral burden
marker.

       BETA: How much reliable data is available now?

       SAAG: There already is some data from the VA cooperative study.
Other examples are ACTG 116A, 116B and 117. There are other ACTG
studies undergoing that type of analysis, 241 for example. We can get
the answer faster by having the ICC, the ACTG, the CPCRA and all the
major trials networks internationally adopting a similar approach. We
should be collecting specimens in a uniform way. Once we start doing
that, and as soon as we reach a critical mass of specimens, with
well-collected clinical outcome data validated through the appropriate
mechanisms, then we get to our answer fastest. All of these groups are
capable of doing this, but it's going to take a strategic approach. We
ultimately will be able to establish a large simple trial with the
twist being that the studies can be small and individual. The viral
burden is the common thread that allows the cross comparison.

       In essence, it is a large meta-analysis but better because most
meta-analyses allow for differences between studies in terms of
inclusion criteria and specimens. I would like to see us streamline
this with a uniform approach of having key data points collected on
most all of the persons in all of these studies. What happens
in-between is up to the individual study. We agree that certain key
things in every trial are done a specific way. Again, it is critically
important that viral burden correlate to clinical outcome. We
absolutely need to prove that correlation. In my opinion, this is the
leading scientific agenda item in the ACTG and clinical trials across
the world. I think it is time for a concerted effort. There will be a
meeting in the next couple of weeks at which these issues can be
addressed. We've raised them in the ACTG and we have different groups
that are looking at this. I'm going to see about getting a proposal
together to create a task force within the ACTG to address this issue.

       BETA: Don't the tests need to be standardized so that we know
they give consistent results?

       SAAG: Companies are working very hard and that's happening.
I've been impressed with their efforts in that direction and in many
ways they are a few steps ahead of us. They have focused on quality
assurance of kits and batches. In the Roche and Chiron tests, when
viral burden is above 5,000, certainly 10,000, the variability is
really quite low and the tests are quite good. Recently, an ACTG study
reported on in Washington, DC, showed a comparison of several
different assays. We looked at the performance of several different
laboratories performing these assays within the ACTG and they were
good. There is some new ming-boggling terminology, like false
difference detected (FDD) and true difference undetected (TDU). We can
now pick out false positives and false negatives. This terminology can
get twisted when you're talking about tests, but the labs are sending
out panels and seeing whether one can detect a difference. Sometimes,
for example, one might detect a difference that isn't really there, so
that's a false difference detected. If a true difference is
undetected, there may be a 50,000 difference in the standard and the
lab missed it; that's a TDU. The pilot has been established within the
ACTG, and that's another contribution to this effort. A lot of good,
smart people are focusing on this. We need to pull together and this
conference for the FDA task force is right on target.

       BETA: Assuming that a consensus develops about how to correlate
viral load to clinical benefit, and that the structure is present, how
long will it take to get the answer you're looking for?

       SAAG: I hope we can get some data within a year and a half.

       BETA: In the meantime, doesn't it make sense to assume that
there is a correlation, so that things can move forward?

       SAAG: It depends on the consequences of the decision being
made. In an individual person I think it's easier because it's a
judgment, like a lot of things in clinical medicine. Test data is
gathered to tell us about the person. We're talking about a kind of
sanctioning. I think that's what the FDA Task Force is wrestling with.
I bet if you polled all the people here and asked them their gut level
reaction they'd assume it to be correct. The reasoning is strictly
based on the fact that if we are seeing dramatic responses with a new
class of agents, i.e protease inhibitors, then not to approve we'd
have to think of the consequences.

       By not approving or allowing access, much harm is done to those
who could have benefitted but do not have the time to wait for the
clinical trial. On the other hand if we withhold approval, we might be
keeping a potential snake-oil substance from the public. They may
spend a lot of money on something that doesn't have any effect in the
long term on their health. That has been the traditional approach that
the FDA has taken, for good reason. There's the potential for
releasing or sanctioning things as effective when they really have not
proven to be. Everyone can think about this issue and come up with
different answers. My answer would be that the harm is greater to the
individuals who currently need the therapy.

       BETA: Do you think there is enough data on the 3 leading
protease drugs to warrant approval now?

       SAAG: I think there is enough promising data from the protease
inhibitors as monotherapy, and I have seen a lot of anecdotal data. I
hope that combination therapy will be even better. The second argument
in favor of approval is that we are seeing good, small studies that
indicate viral burden correlates to better clinical outcome.

       BETA: You spoke of 2 important meetings'

       SAAG: There's going to be a conference at Cold Spring's Harbor
that will draw scientists from around the country to address different
issues. I suspect that viral and surrogate markers will be discussed.
The International AIDS Society USA (IS USA) will be conducting a
small, relatively closed round table discussion for people to come up
with a set of recommendations. The plan for Cold Springs Harbor is to
identify an agenda for the future, while IS USA's plan is to get
people who use these markers to come together to state an
opinion'where we are with these markers, and how we could be using or
interpreting them in clinical practice. The opening statement is that
we do not know how to use this, yet we realize that people are using
them in practice. People are unsure about what to do with the data
when it comes back. We're going to come up with rough guidelines with
the caveat that these are going to change as more data comes out. This
is a starting point and shouldn't be written in stone. We can get
something out there for people who have dealt with these issues. That
meeting will happen in late April in San Francisco and will be
sponsored by the International AIDS Society USA.

       ************
       WOMEN AND HIV/AIDS

       Gender & HIV
       Leslie Hanna

       Leslie Hanna is associate editor of BETA.

       As the incidence rate of AIDS among women in the U.S. continues
to rise, healthcare providers will be faced with increasingly large
numbers of HIV-infected female patients, with whom they will have to
make vital treatment decisions. Current therapeutic guidelines are
derived largely from observations of HIV disease progression in
infected persons, or studies of the natural history of HIV infection.
Past natural history studies have primarily involved cohorts of gay
and bisexual men; it has been difficult to enroll significant numbers
of women into prospective cohort studies. Some studies have evaluated
disease progression in one gender or the other (without other-gender
comparison groups); others have considered gender differences only
among women and men with AIDS diagnoses, and thus could not gather
information on the broader spectrum of HIV disease manifestations. In
some studies, important prognostic information simply was unavailable
(e.g., CD4 cell counts). More limited findings have been generated by
other types of studies, such as retrospective chart reviews or
surveillance data.

       Four recently published studies concerning gender and HIV
disease are among the latest official entries in the ongoing
discussion about gender-related aspects of HIV infection. One of the 2
large studies reported on here is American (prospective
observational); the other is European (retrospective chart review).
The third is a small retrospective study of people with AIDS conducted
in London. A fourth study from New York evaluated clinical
manifestations of HIV disease in asymptomatic female and male
injection drugs users.

       Past studies that have considered gender differences in HIV
disease have produced conflicting conclusions about whether or not
women are at relative risk for increased mortality. While the
objectives of the 4 studies reviewed here are very similar'does
survival and disease progression differ between women and men?'their
responses are different. Although each study purports to evaluate sex
differences in survival, differences in study design and features such
as population characteristics (e.g, HIV disease stage and transmission
risk behaviors) at least in part contribute to apparently incongruent
results. Ultimately, because of differences in study populations and
designs, the results may be incomparable.

       One very important theme pervades all these natural history
studies, underlying conflicting results and influencing a myriad of
incompletely understood covariates (e.g., socioeconomic status, area
of geographic origin): access to health care. Differential access to
health care impinges indirectly, perhaps, but significantly upon
studies such as these, and most definitely plays a key role in
morbidity and mortality among women with HIV.

       In the absence of a unifying metanalysis of gender studies,
refraining from hasty conclusions about gender, biology and HIV
disease is probably the best course of action. Much remains to be
learned, particularly about HIV disease manifestations and survival
among women. Continued research and data collection are critical to
the development of appropriate medical strategies for seropositive
women.

       Survival and Disease Progression According to Gender

       The Terry Beirn Community Programs for Clinical Research on
AIDS (CPCRA) study on survival and HIV disease progression according
to gender sought to 'compare mortality and disease progression at
different stages of HIV disease between large groups of women and
men.' Multiple sites and investigators as well as participants around
the country contributed to this study. The primary finding was that
although women were much more likely to survive for a shorter length
of time than men, the rates of HIV disease progression were comparable
between the 2 groups. Expressed another way, women were one-third more
likely to experience death as their first study event.

       This prospective multicenter cohort study enrolled over 4,500
HIV-infected people (768 women and 3,779 men) and followed them over
time. All subjects were participants in other CPCRA clinical trials
from September 1990-September 1993. Important baseline data about the
participants' medical histories, current health, current use of
treatments, HIV risk factors and demographics were collected at entry.
Follow-up visits and examinations occurred every 2-6 months thereafter
for a median of 15 months. There was a median of 5 study visits for
both women and men. Differences between women and men were analyzed at
the beginning (baseline data) and at the end of the study.

       Study women were slightly younger than men; the median ages
were 36 years for women and 38 years for men. Women were more likely
to be of color: 78% of women were either African-American or Latina,
compared to 44% of the men. Specifically, 59% of the women were
African-American, 19% were Latina and 22% were Caucasian or other. The
corresponding racial/ethnic figures for men were 30.8%, 23.9% and
56.4%, respectively. Women were more likely to report having used
injection drugs at any time since 1977. Forty-nine percent (49%) of
women in the study reported injection drug use, compared to 27% of the
men. Furthermore, 70% of the women reported sex with an injection drug
user (IDU) or a bisexual male and 45% reported both. Two percent (2%)
of the women reported having had sex only with women (history of drug
use was not analyzed for this subgroup) and 10% reported having had
sex with both women and men. At entry, 74% of the men in the study
reported a history of sex with men, 27% reported injection drug use
and 9% reported both. (Note: the CPCRA protocol allowed participants
to enter with more than one official risk behavior, unlike studies
that use the 'hierarchical' system, which records 1 category per
participant, regardless of how many total risk behaviors a participant
reports. This is the sort of difference that makes comparing study
results problematic.) Baseline CD4 counts were obtained for all
participants within 90 days of enrollment. The range of CD4 cell
counts varied greatly, with entering women having about 100 cells/mm3
more than entering men. For women at entry, the median CD4 cell count
was 240 cells/mm3; 44% had fewer than 200 cells/mm3, 37% had 200-499
cells/mm3 and 19% had greater than 500 cells/mm3. For men, the median
was 137 CD4 cells/mm3; 62.7% had fewer than 200 cells/mm3, 26.6% had
200-499 cell/mm3 and 10.7% had greater than 500 cells/mm3.

       With respect to both CD4 cell count and history of disease
progression, women were slightly healthier at entry than men.
Approximately 25% of the women at entry reported a history of disease
progression (i.e., a diagnosis of an HIV-related medical condition or
an AIDS-defining diagnosis) at their initial visit, compared to 33% of
the men. History of opportunistic infections (OI) varied by baseline
CD4 cell count. Overall, women tended to have higher rates of oral
thrush and progressive multifocal leukoencephalopathy (PML). Eleven
women reported cervical cancer. Men had higher incidence rates of
Pneumocystis carinii pneumonia (PCP), invasive herpes simplex virus
(HSV) infection, Kaposi's sarcoma (KS) and oral hairy leukoplakia.

       Use of antiretroviral drugs was reported by 61% of women and
66% of men. Among people with less than 200 CD4 cells/mm3, 71% of
women and 70% of men were taking antiretroviral drugs. Among those
with CD4 cell counts in the 200-499 cells/mm3 range, 69% of women and
70% of men reported using antiretroviral treatment. Use of some type
of PCP prophylaxis was reported by 44% of women compared to 61% of
men, overall. Among those with less than 200 CD4 cells/mm3 at entry,
74% of women and 81% of men used PCP prophylaxis. These proportions
changed over time, as women whose CD4 cells dropped below 200
cells/mm3 between visits accordingly began taking PCP prophylaxis.

       For the study definitions of disease progression events and
AIDS, investigators used the 1987 Centers for Disease Control and
Prevention (CDC) definitions. (Data collection ended just a few months
after the 1993 CDC AIDS definition became official, and it was not
possible to retrospectively fill in histories of pulmonary
tuberculosis, bacterial pneumonia and cervical cancer. Nor was it
feasible to go back through the records to use CD4 counts as
AIDS-defining, since entry CD4 counts were based on 1 observation
only.) In addition to the usual AIDS-defining events, CPCRA included
oral and vaginal candidiasis and other conditions indicative of HIV
disease progression.

       After considering baseline differences and similarities,
investigators established a list of important factors as covariates to
be examined in addition to gender, the primary predictor variable, in
the subsequent analyses. Covariates included CD4 cell count, age,
race/ethnicity, history of injection drug use, Karnofsky score (of
everyday functioning), disease progression history, antiretroviral
treatment and PCP prophylaxis. To enable meaningful gender comparisons
regarding survival and disease progression, 6 CD4 cell stratifications
were created. For each of the 6 CD4 cell categories, and adjusting for
other factors, the mortality rates were higher among women. Disease
progression rates also were adjusted to consider the covariates
mentioned previously (age, race, history of injection drug use,
history of OI, use of anti-HIV therapy and PCP prophylaxis).
Regardless of the variable considered, the relative risks for disease
progression according to gender remained equal.

       With respect to opportunistic illnesses, or infections that
developed during follow-up, women were much more likely to develop
bacterial pneumonia than men (about 40% more likely), particularly
female IDU, who had a 53% greater risk for developing this condition
than male IDU. Women also had more mycobacterial infections. Men
experienced higher rates of oral hairy leukoplakia and KS.

       During the study, vaginal candidiasis developed for the first
time in 128 of the 768 women (17 cases per 100 woman-years). Cervical
cancer was reported in only 4 women; however, since the 1987
definition of AIDS was being used and since routine gynecological
exams were not part of the protocol, this condition was not actively
surveyed. The survival difference was seen most clearly in a subset of
study participants who died before ever developing any AIDS-associated
condition: 27.5% of female participants who had never had any
AIDS-defining OI died, compared to 12.2% of the males. For these
people, death was the first observable event while in the study. Among
survivors, however, women were not more likely than men to experience
a disease-progression event. Investigators note that many participants
died outside of a clinical setting and that cause of death in these
cases is not infrequently difficult to establish. Cause of death was
unavailable or unknown for 46% of women who died and 36% of men.

       In summary, 'the principal finding of this report is that women
had a poorer survival than men during a 15-month interval of
observation, even though disease progression rates did not differ
significantly between women and men.' Investigators found that neither
history of injection drug use nor race, 2 large baseline differences,
could be used to predict survival or progression. In fact, 'for
patients both with and without a history of disease progression at
entry, death rates were higher in women than men after adjustment for
baseline differences.'

       The reasons for the relatively elevated mortality rate observed
for women in this study are unclear. The possibilities may provide
investigational directions for future studies. A singular strength of
this study is that it was able to analyze differences in progression
rates and survival between women and men at different disease stages,
as well as to control for potential baseline differences. The
inability to identify cause of death for a relatively large number of
those who died, perhaps the largest limitation of the study data,
inhibits the formulation of preventive measures.

       Investigators postulate that 'observed survival differences may
reflect a differential access to or utilization of health care
resources by gender.' Relevant factors include social class, social
support systems and 'awareness of when to seek care.' This seems
particularly likely when considering that although death rates were
higher in women, disease progression rates were similar. Increased
risk of death among women also may be related to conditions associated
with IV drug use, 'with HIV infection but one more concomitant
complication' for these women. More detailed information on IV drug
use, defined in the study as use at any point since 1977, might have
illuminated some of these findings.

       Follow-up of the surviving women and men in this cohort may
reveal additional important information. Investigators recommend that
factors not addressed by this study but potentially important to
survival, such as pregnancy, socioeconomic status, domestic violence
and access to health care, be included in other studies.

       Gender and HIV Disease

       According to Sandra Melnick, MD, lead author of the CPCRA
study, it is clear that 'women must be made aware of when to seek care
from their providers.' Since women who are better informed still
sometimes fail to seek care, 'providers should encourage their female
patients to seek care for themselves despite competing demands on
their time and energy. Both women and providers should be alert to
subtle complications of their HIV infection that might not be readily
detectable.' Dr. Melnick also exhorts researchers to 'continue efforts
to replicate among women findings found for HIV disease progression,
non-progression and rapid progression among men, and to continue to
seek out conditions which have not been either proven to be associated
with HIV infection in women or, if already proven, worked into the
general standard of care for women in this country.' Ancelle-Park R
and De Vincenzi I. Epidemiology and natural history of HIV/AIDS in
women. In HIV Infection in Women. Churchill Livingstone. London, UK.
1993.

       Melnick SL. The rates of HIV disease progression and mortality
in women and men from the Terry Beirn Community Program for Clinical
Research on AIDS (CPCRA). HIV Infection in Women Conference: the First
National Scientific Meeting on HIV Infection in Adult and Adolescent
Women. Washington, DC. February 22-24, 1995. TC3-146.

       Melnick SL and others. Survival and disease progression
according to gender of patients with HIV infection. The Journal of the
American Medical Association 272(24): 1915-1921. December 28, 1994.
European Retrospective

       Study of Gender, Morbidity and Mortality

       In June 1994, the AIDS in Europe Study Group published findings
from a study with objectives similar to the CPCRA study just
described. In the European study, retrospective analyses were made of
charts and case information collected on 2,554 people with AIDS (566
women and 1,988 men) for the development of new AIDS-defining
conditions. Participants were part of the multicenter AIDS in Europe
study, which included people diagnosed with AIDS between 1979 and 1989
at 52 centers in 17 European countries. One of the study parameters
was to compare men and women with similar probable routes of HIV
transmission. The primary behavioral risk factors for these
participants were injection drug use (72% of the men and 59% of the
women) and heterosexual sex (15% of the men and 31% of the women);
homosexual/bisexual men were not included in the study. Most of the
women in the study (47%) were from central Europe (Belgium, France,
southern Germany, Hungary, Luxembourg, Switzerland), compared to 25%
of the men. The majority of the men, 62%, came from southern Europe, a
region which for the purposes of this study included Greece, Israel,
Italy, Portugal and Spain.

       The median age was 28 years for women and 29 years for men. The
average CD4 cell count at the time of AIDS diagnosis was 78.9
cells/mm3 for women and 86.5 cells/mm3 for men; however, CD4 cell
count at diagnosis was available for only 46% of the subjects.
Researchers analyzed the rates of occurrence of different
AIDS-defining diseases at 2 timepoints: at the time of AIDS diagnosis
and during the follow-up interval. At the time of AIDS diagnosis,
women had less toxoplasmosis and extrapulmonary tuberculosis (TB),
which researchers believe may be the result of underdiagnosis of these
conditions in women due to clinicians' tendency to underestimate
women's risk for HIV infection. The second measure compared the
development of disease after an AIDS diagnosis in women and men, and
consequently is probably more accurate. After adjusting for factors
that might influence rate of disease occurrence (including age, year
of diagnosis, geographic region and AZT use), women had higher rates
of both toxoplasmosis and HSV ulcers. Adjusting for CD4 cell count did
not change the findings. However, since CD4 cell counts were available
for less than half of the participants, this analysis included a much
smaller number of people.

       Similar proportions of women (64%) and men (65%) died during
the study interval. Adjusting for other factors did not change the
finding that the survival interval after AIDS diagnosis was similar
for women and men.

       Investigators hypothesize that the overall similarities in the
incidence and occurrence rates of AIDS-defining diseases between women
and men resulted in part from the fact that the study compared women
and men infected via the same transmission routes (injection drug use
and heterosexual sex). They note that OI incidence rates at the time
of AIDS diagnosis varied more by geographic region than by gender;
people in the north (the U.K., Scandinavia, the Netherlands and
northern Germany) had higher rates of PCP and people in the south had
higher rates of extrapulmonary TB. Even after adjusting for geographic
region, women were found to be at higher risk than men for
toxoplasmosis and for HSV ulcers. Investigators could not explain the
higher risk for toxoplasmosis in women, and postulate that the higher
incidence of HSV ulcers may be related to possible higher rates of HSV
infection among all women (as reported in 1989 in a study by Robert
Johnson and colleagues), throughout the general population, and not
related to HIV. With regard to the similar rates of survival after an
AIDS diagnosis for men and women, researchers state that 'any
differences that do exist are not substantial, at least among European
AIDS patients.' Access to healthcare and the types of healthcare
delivery systems in Europe may play roles in these patterns and are
factors to bear in mind when comparing European and American studies.

       Finally, investigators note 3 main study limitations: (1) the
restrospective study design involves a certain risk of inaccurate and
incomplete data, (2) the large number of clinicians involved presents
a risk of different diagnostic methods and, ultimately, different
diagnoses and (3) gynecologic causes of morbidity were excluded. In
summary, investigators found that men and women survived about the
same length of time after an AIDS diagnosis, and that the only
differences were that women had higher relative risks than men of
developing toxoplasmosis and HSV ulcers. Note that the definition of
AIDS used by researchers in this study is based on the presence of
certain AIDS-defining conditions rather than on CD4 cell count.

       Reference

       Phillips AN and others. A sex comparison of rates of new
       AIDS-defining disease and death in 2554 AIDS cases. AIDS 8(6):
       831-835. June 1994.


       British Retrospective Study of Gender and AIDS

       A letter to the editor in a recent issue of the journal
Genitourinary Medicine relates to the variable findings of studies of
survival differences between men and women with AIDS. The authors,
British researchers, disclosed the results of their London-based
retrospective study of 41 women with AIDS. They analyzed the records
of women diagnosed with AIDS between 1990 and 1992 from 3 major
treatment centers, and compared the results with those from a group of
men with AIDS. The men were matched for year of diagnosis, age and CD4
cell count.

       The following information was gathered: age at AIDS diagnosis,
route of acquisition, ethnicity, CD4 cell count at diagnosis,
AIDS-defining diagnosis and types of treatments and prophylaxes used.

       The mean ages were 33 years for women and 35 years for men.
Thirteen (13) women and 7 men received primary PCP prophylaxis.
Twenty-seven (27) women and 22 men used AZT at some point. Thirteen
(13) women and 19 men died during the study interval, and there was no
difference in survival between the 2 groups. The proportion of women
who presented with AIDS was noted to decrease each year, from 47% in
1990 to 14% in 1992. The proportion of women presenting with PCP as
the AIDS-defining diagnosis decreased from 70% in 1990 to 50% in 1992.
In conclusion, 'the reduction in the number of women presenting
initially with an AIDS-defining diagnosis is encouraging, and suggests
earlier diagnosis of HIV infection in this group....The reduction in
PCP as an index diagnosis may reflect the increasing usage of
effective PCP prophylaxis.'

       Reference

       Iatrakis GM and others. Survival of men and women with AIDS: a
       comparative study. Genitourinary Medicine 70: 290-293. 1994.


       Gender and Clinical Manifestations in Injection Drug Users

       Researchers in New York City compared a group of male and
female HIV positive but AIDS-free injection drug users (IDU) with
similar CD4 cell counts for significant gender-related differences.
The study group consisted of 118 women and 444 men whose median ages
were 33 years and 35 years, respectively. Median CD4 cell counts were
480 cells/mm3 for women and 490 cells/mm3 for men. Most participants
were African-American. Investigators evaluated clinical symptoms and
results of laboratory blood tests and physical examinations. The
primary findings were that oral candidiasis and the use of antifungal
medications occurred with increasing but equal frequency in both men
and women as CD4 cell counts decreased, and that physical symptoms
such as diarrhea and fatigue were unrelated to gender or CD4 cell
count. In men, hematocrit levels were higher and platelet counts were
lower, but the observation of the same patterns in HIV negative
controls suggests that the differences between values in HIV positive
men and women were probably unrelated to HIV.

       Although women reported having more recent outbreaks of genital
herpes than men, physical examinations failed to detect any signficant
difference in herpes occurrence rates between women and men. At higher
CD4 cell counts (greater than 500 CD4 cells/mm3), men seemed to have
more fungal infections of the skin or nails. At lower CD4 cell levels,
fungal infection rates were similar for both sexes. Overall, the study
found that 'no significant interactions between sex and CD4 cell count
were detected for any physical findings.'

       This study suggests that men and women in the early stages of
HIV infection have similar symptoms. Investigators conclude that 'it
is important to recognize that there are few clinical differences
between men and women early in HIV infection, except for those related
to the genital tract....Differences between men and women...will
probably be in gynecologic disease related to HIV, and in more serious
HIV-related manifestations....It remains to be determined whether
differential rates of signs and symptoms by sex appear with the
progression of HIV infection to later stages.'

       Reference

       Vlahov D and others. Comparison of clinical manifestations of
       HIV infection between male and female injecting drug users.
       AIDS 8(6): 819-823. June 1994.

       Gender and AZT Pharmocokinetics

       Information about the pharmacokinetics of AZT (the way a drug
behaves in the body: how it is absorbed, distributed, eliminated and
affected by factors such as disease stage) is still being gathered 8
years after the drug's approval. A team of researchers in the
Netherlands recently evaluated the influence of several clinical
factors on the pharmacokinetics of AZT. Their findings appear in the
December 1994 issue of the journal AIDS.

       This prospective pharmacokinetic study involved 68 people with
HIV. All participants took AZT in a strictly regulated, uniform
manner'after fasting overnight, at a specific time in the morning,
without food. Blood samples were drawn 9 times over a 3-hour
postdosing period and tested for AZT concentration. Based on plasma
concentration and time measurements, investigators evaluated the rate
of clearance, bioavailability and volume of distribution of AZT.
Statistical analyses were performed to determine the influence of
patient characteristics and drug interactions on AZT clearance.

       Multivariate analysis revealed that body weight, disease stage
and gender are significant influences on the action of AZT in the
body. As body weight decreases, so does AZT clearance. As HIV disease
progresses, AZT clearance also decreases (25% lower in participants
with AIDS than participants with ARC or no symptoms).

       AZT clearance was 42% lower in women than in men. This
difference was unrelated to other influences like body weight, disease
stage, liver function or use of other drugs. The volume of
distribution was also lower in women, although the rates of
elimination from the blood (elimination half-lives) were similar for
both women and men. Various other drugs are known to be cleared more
slowly in women than in men. Female sex hormones (such as estrogen or
oral contraceptives) are believed to inhibit the metabolism of many
drugs; male hormones (androgens), on the other hand, stimulate drug
metabolism. Other study findings were that liver or kidney dysfunction
did not significantly influence AZT clearance, use of rifampin
increased clearance, and methadone and ganciclovir both decreased
clearance. Investigators concluded that the lower rates of AZT
clearance seen in women, and in those with lower body weight and
advanced HIV disease, lead to higher plasma concentrations and may
lead to more toxicity. At present, however, there is no clear evidence
about the relationship between plasma concentration and clinical
effect. Once a better pharmacokinetic profile of AZT is established,
researchers suggest that 'patient-individualized antiretroviral
therapy' may be more beneficial. They also comment that 'the fact that
only very limited data are available in the literature on the
pharmacokinetics of AZT in non-pregnant women is another example of
the neglect of this rapidly growing subpopulation of HIV-infected
people.'

       Reference

       Burger DM and others. Pharmacokinetic variability of zidovudine
       in HIV-infected individuals: subgroup analysis and drug
       interactions. AIDS 8(12): 1683-1689. December 1994.

       ******************
       Notes on Research for HIV Positive Women
       Leslie Hanna

       Leslie Hanna is associate editor of BETA.

       Obstetrics/Pediatrics
       Maternal Factors that Influence Vertical HIV Transmission

       In New York, pregnant women and new mothers at risk for HIV
infection and their children were enrolled for study in obstetric and
pediatric care centers. From 1986 to 1992 investigators collected
demographic and behavioral data, medical histories and laboratory
reports on immune blood markers (e.g., CD4 cell counts, immunoglobulin
levels) from the mothers. Children were followed for at least 15
months.

       The rate of vertical transmission for 172 HIV-1-infected women
was 28%. Analysis of subgroups revealed that women with fewer than 280
CD4 cells/mm3 collectively had a vertical transmission rate (TR) of
48%, whereas those with greater than 280 CD4 cells/mm3 had a TR of
22%. Furthermore, a 'marginally higher TR was seen among women with
CD8 cell percentage greater than or equal to 51% than among those with
CD8 cell percentage less than 51% (TR = 41% vs 24%),' although CD8
cell counts themselves were not predictive of vertical transmission.
The highest transmission rate was seen in the subgroup of women who
had both low CD4 cell counts and high CD8 cell counts. The
transmission rate was twice as high for women who had been
hospitalized for pneumonia within the previous year (53%). Finally,
women who delivered their infants by cesarean section were less likely
to transmit HIV than those who delivered vaginally (18% vs 32%);
however, this difference was not statistically significant.

       Reference

       Thomas PA and others. The New York City Pediatric HIV
       Transmission Collaborative Study Group. Maternal predictors of
       perinatal human immunodeficiency virus transmission. Pediatric
       Infectious Disease Journal 13(6): 489-495. June 1994.

       Viral Factors Encourage Perinatal HIV-1 Transmission

       Maternal factors known to increase the likelihood of vertical
transmission include a low CD4 cell count, advanced HIV disease stage
and high viral load. San Francisco researchers who analyzed HIV taken
from HIV-infected mothers and their children found that there are
certain viral factors that facilitate mother-to-child HIV
transmission. The 18 women and 6 children were members of the Bay Area
Perinatal AIDS Center cohort, and participants in a comprehensive
study of vertical transmission.

       In this smaller study, virus was isolated from the serum of 12
HIV-infected mothers who did not transmit HIV to their infants, and
from 6 mothers who did transmit and their HIV-infected children.
Several virologic and immunologic findings were made. First,
transmitting mothers had virus that tended to replicate at rapid or
high levels in peripheral blood mononuclear cells (PBMC), in contrast
to the 'slow/low' virus type isolated from nontransmitting mothers.
Second, viral isolates from transmitting mothers showed 'T-cell [CD4
cell] line tropism,' or a high affinity for replicating in different
CD4 cell lines. Together, these 2 factors 'provide a basis for high
viral load as a factor for the vertical transmission of HIV-1.'

       Serum samples from both transmitting and nontransmitting
mothers contained antibodies to HIV proteins, and various degrees of
antibody-binding affinity were seen among both groups. However, virus
from transmitting mothers was less likely to be neutralized by
autologous HIV-1 antibodies (i.e., antibodies present in the mother's
own serum samples). Furthermore, all virus isolates from seropositive
infants were completely resistant to neutralization by the maternal
serum samples (mother's antibodies) or autologous serum samples (the
infant's serum). Isolates from 2 infants were enhanced (one by the
mother's serum, one by autologous serum). Investigators found that
'regardless of the neutralization status of the maternal viruses,
neutralization-resistant or enhancement-sensitive viruses were
transferred to the infants.' This suggests that particularly virulent
'escape' variants may be what infants acquire, through a process of
immunological escape or selective transmission.

       Overall, HIV strains that replicate strongly and that can
infect multiple CD4 cell lines are likely to encourage perinatal
transmission. Investigators hope that this information will 'provide
direction for further evaluation in intervention strategies.'

       Reference

       Kliks SC and others. Features of HIV-1 that could influence
       maternal-child transmission. The Journal of the American
       Medical Association 272(6): 467-474. August 10, 1994.


       Vertical Transmission Rates: HIV-1 vs HIV-2

       The French Collaborative Study Group compared the rates of
vertical transmission between new mothers infected with HIV-1 and new
mothers with HIV-2. The women were part of a large prospective cohort
study in which, by 1994, 1,589 women with HIV-1 had given birth to
1,758 infants, 1,115 of whom had at least 18 months of follow-up. Of
the HIV-1 positive mothers, 419 were of African origin; 260 of their
children were followed up. In the same cohort, also by 1994, 68
predominantly African women with HIV-2 had given birth to 86 children;
41 of their children were available for follow-up.

       Diagnoses of children were based on serologic status at 18
months. The HIV transmission rate for 260 infants born to African
mothers with HIV-1 was 21%. The transmission rate for HIV-2 infected
mothers, most of whom were West African, was 0%. The HIV-1
transmission rate remained significantly high even after HIV-1
positive French mother-child pairs were included in the analysis.
HIV-2-infected mothers were older and had a higher median CD4 cell
count, as well as more children, than HIV-1-infected mothers.
Investigators note that higher transmission rates of HIV-1 occurred
without regard to the mothers' transmission risk category (injection
drug use or sexual transmission), and thus conclude that 'reported
differences in the replication of the 2 viruses probably account for
the lower mother-infant transmission rate of HIV-2.'

       Reference

       HIV Infection in Newborns French Collaborative Study Group.
       Comparison of vertical human immunodeficiency virus type 2 and
       human immunodeficiency virus type 1 transmission in the French
       prospective cohort. Pediatric Infectious Disease Journal 13(6):
       502-506. June 1994.

       HIV in Breast Milk

       A preliminary study of HIV in breast milk indicates that p24
antigen and DNA levels, if present, are highest immediately after
childbirth. Breast milk specimens were obtained from HIV positive
mothers immediately after birth and at intervals thereafter for up to
1 year (postpartum). Samples were tested for the presence of HIV p24
antigen and HIV DNA using the antigen capture and polymerase chain
reaction (PCR) tests. p24 antigen was present in 24% of samples taken
from 37 HIV positive women within 4 days after birth but was not
detected in samples collected after that point. HIV DNA, detected in
70% of specimens drawn 0-4 days after delivery from 47 women, was
found in 50% of specimens drawn from the same women at 6 and 12 months
postpartum. The presence of HIV DNA or p24 antigen was not correlated
with CD4 cell count, clinical disease stage or beta 2-microglobulin
level. This study, which was unable to analyze any relationships
between the presence of either measure and infectiousness in the
women, emphasizes the need for further study to elucidate the real
risk of breastfeeding for perinatal HIV transmission.

       Reference

       Ruff AJ and others. Prevalence of HIV-1 DNA and p24 antigen in
       breast milk and correlation with maternal factors. Journal of
       Acquired Immune Deficiency Syndrome 7(1): 68-73. January 1994.


       Gynecologic Research Cervical Cancer Plus Pelvic Inflammatory
       Disease

       Invasive cervical cancer, now an AIDS-defining condition, has
been reported to develop aggressively and unusually in HIV positive
women. A case report of an HIV positive woman with pelvic inflammatory
disease (PID) and recently diagnosed cervical cancer that was
unresponsive to chemotherapy suggests that concurrent PID may help
create an environment in which the carcinoma flourishes. The report
highlights the need for new treatment strategies appropriate for the
aggressive type of cervical cancer and concomitant complications seen
in women with HIV.

       Reference

       Singh GS and others. Metastatic cervical cancer and pelvic
       inflammatory disease in an AIDS patient. Gynecologic Oncology
       54(3): 372-376. September 1994.


       Cervical Disease and Screening Recommendations

       Canadian researchers  reviewed current literature on cervical
disease in women with HIV, such as dysplasia, cervical intraepithelial
neoplasia (CIN) and cancer, as well as cervicovaginal screening
recommendations.

       Data was collected by searching MEDLINE and AIDSLINE for all
relevant articles published in English and/or French between 1987 and
1993, reviewing abstracts from international AIDS conferences from
1989-1993 and consulting 'pertinent agencies and organizations.' Of 92
total reports on gynecologic disease in HIV-infected women, 32 studies
evaluated cervical dysplasia, cervical cancer and/or CIN. The
researchers conducting the review analyzed the studies on the bases of
design, sample size, type of subject, markers and whether there were
concurrent vaginal infections.

       Researchers found scant data associating HIV-related
immunosuppression and cervical disease pathogenesis. They also found
that official recommendations for cervicovaginal screening in women
with HIV were remarkably similar to those for HIV negative women and,
apparently, inadequate.They urge further research and submit that,
because of the dire consequences for HIV positive women of inadequate
or delayed treatment of cervical disease, 'more frequent
cervicovaginal screening through Papanicolaou testing and colposcopy
in women with HIV infection is warranted.'

       Reference

       Hankins CA and others. Cervicovaginal screening in women with
       HIV infection: a need for increased vigilance? Canadian Medical
       Association Journal 150(5): 681-686. March 1, 1994.


       Increased Risk of Genital Candidiasis

       An Italian research team recently quantified increased risk for
genital Candida in HIV positive women. The researchers enrolled 84 HIV
positive and 384 HIV negative women who presented to a gynecologic
outpatient clinic for sexually transmitted diseases (STD). All of the
women had symptoms of vulvovaginitis, i.e., infection of the vulva
(external genitals) or vagina. Presenting symptoms included itching,
irritation and/or discharge. Vaginal, rectal and oral specimens from
cases and controls were cultured for Candida species.

       The overall prevalence of vaginal candidiasis was 61.9% (52/84)
in the cases and 32.3% (124/384) in the controls. Results were
adjusted for confounding factors, which included age at first
intercourse, lifetime sexual partners, new partner(s) in the last 6
months and type of contraceptive used. After adjustment, HIV positive
women were found to be at a 2.5-fold greater risk for Candida
albicans, and also were at a 3.5-fold greater risk for Torulopsis
glabrata vaginitis. Both of these findings reached statistical
significance.

       Compared with controls, the HIV positive women also had
increased rates of oral and rectal colonization with Candida species.
Lastly, the time to recurrence of vaginal infection was significantly
shorter in the HIV positive women than controls and significantly
correlated with the severity of immune depression. [Harvey S. Bartnof,
MD]

       Reference

       Spinillo A and others. Clinical and microbiological
       characteristics of symptomatic vulvovaginal candidiasis in
       HIV-seropositive women. Genitourinary Medicine 70(4): 268-272.
       August 1994.

       ******************
       Psychoneuroimmunology: An Interview with Jeffrey Leiphart, PhD
       Mark Bowers

       Mark Bowers is HIV Treatment Hotline Manager at Project Inform
       in San Francisco.

       BETA interviewed Jeffrey Leiphart, PhD in psychology, in his
office at the Lesbian and Gay Men's Center in San Diego, where he is
Clinical Director. In the course of psychotherapy with numerous HIV
positive and AIDS-diagnosed patients, Leiphart found several common
threads. These threads have been carefully woven into a popular and
successful psychotherapeutic strategy called the Learning Immune
Function Enhancement (LIFE) program.

       The LIFE program is divided into 3 distinct phases. In the
first phase, an assessment of each individual's performance on an
exhaustive questionnaire determines a percentile for each of 19
cofactors. In the next phase, participants work one-on-one with mental
health professionals to increase their scores on measures of cofactors
on which they scored low or in the 'danger zone.' The third phase is
reinforcement of positive behaviors through participation in groups.

       A clinical evaluation of the program has begun. Investigators
will compare individuals who have received counseling with those who
are on a waiting list. Measurements of immune system functioning will
be compared between the 2 groups; it is expected that successful
intervention will slow, stop or reverse HIV disease progression, and
that this will be reflected in measures of immune functioning.

       Leiphart sketches the history and nature of the counseling
program that he has developed to help others learn about
immune-boosting strategies employed by long-term survivors and
long-term non-progressors.

       BETA: You saw your first patient with Kaposi's sarcoma (KS) in
1982. What were you doing at that time?

       LEIPHART: I was working as a clinical psychologist in the gay
medical clinic at the Medical Arts Building in San Francisco. People
with opportunistic infections (it was primarily KS in the beginning)
were referred there for psychological assistance because they were
flipped-out and panicked. Since then I have seen about 525 people
during 13 years of the HIV epidemic. I have followed their
psychological and disease progression pathways in a clinical
psychology practice that is derived from the theory of
psychoneuroimmunology (PNI) as developed by Dr. George Solomon.

       BETA: Who is George Solomon?

       LEIPHART: George Solomon is an MD who developed the field of
psychoneuroimmunology in 1964. At that time he was working on the
personality correlates of chronic rheumatoid arthritis. Before AIDS
ever appeared on the scene, the medical subspecialty of
psychoneuroimmunology had over 1,200 published studies that linked
psychological variables and issues with immune system functioning.
Researchers had begun to map out the mechanisms of brain functioning
through autonomic nervous system connections, and cytokine and
endocrine influences on the ways psychological processes can impact
immune system functioning. Now at the University of California at Los
Angeles (UCLA) Medical School, Solomon is the authority on PNI and
HIV.

       BETA: Does Solomon have a program like the one that you have
created here?

       LEIPHART: PNI is currently designated a 'research only' medical
specialty. Up to this point there have not been any clinical
applications of PNI. The LIFE Cofactor Counseling Program is one of
the first programs to derive a clinical application based on PNI
research in HIV/AIDS. I know of 2 others: one at the HIV Wellness
Hospital at Deaconess Hospital, operated through the Harvard Medical
School in Boston, and the second at the University of Miami Medical
School, where enormous amounts of PNI research takes place.

       BETA: Are the other programs also based on specific identified
cofactors?

       LEIPHART: They are based on cofactors that have been identified
as related to either immune system functioning or HIV infection or
progression of HIV infection. Their lists of cofactors are not as
extensive and not as precisely detailed. Their cofactors are more
generally related to overall health, stress and nutrition.

       BETA: Could you describe the history and evolution of this
particular psychological intervention program?

       LEIPHART: It became clear to me by about 1985 that stress, and
possibly other psychological factors, had an impact on immune system
functioning and on disease progression. There also was a large body of
significant research in PNI, so I attempted to create a variety of
venues for teaching these findings to people. In San Francisco I led a
PNI HIV/AIDS group that met every Saturday for 2 hours for about a
year. That group provided a very early prototype of the current LIFE
program. I organized a 3-day retreat at Wildwood that provided an
intensive short-term training. I presented the psychological aspects,
a masseur provided physical reinforcement and a nutritionist provided
sound, practical survival advice.

       In 1991 I moved to San Diego and became Clinical Director of
the AIDS Response Program of the San Diego Lesbian and Gay Men's
Community Center. The AIDS Response Program has 4 treatment components
ranging from very traditional mental health services to homeopathy,
acupuncture, meditation and chiropractic. The AIDS Response Program
operates out of the designated mental health agency for HIV/AIDS in
San Diego County. The LIFE program is an immune-based therapy centered
on teaching people to assess and manage both psychological issues and
health behavior patterns that have been demonstrated to either enhance
or suppress immune system functioning. We teach our clients to
maximize their own immunity.

       BETA: To what do you attribute the popularity of the program?

       LEIPHART: Although we have never advertised to get people into
the cycle, the program has indeed become immensely popular. The cycles
fill up quickly, largely through referrals by previous HIV positive
clients. One reason for clients' satisfaction is that the program is
something positive and hopeful in a landscape where there isn't much
else that is positive. Also, what clients are supposed to do is very
clear and direct and self-empowering. We give them something realistic
that they can do themselves. They say, 'I understand it, I can do it,
I can control it and it's reasonable.' Now, 2 and a half years later,
we're about to begin cycle II.

       BETA: What exactly is a cycle?

       LEIPHART: A cycle is like a traditional class. Each cycle is
composed of 20-25 people who start the program together. In Phase I,
clients attend psycho-educational classes that meet weekly for 3
months. We provide lectures and educational materials explaining the
19 cofactors and how they relate to immunity and HIV positive health.
Participants engage in small group discussions and experiential
exercises. Bonding among the members of each cycle is incredibly
important; by the end of the 3 months they are a closely-knit group of
20 people who know what the cofactors are and how they affect their
lives.

       Then clients go into Phase II, which is individual cofactor
counseling once a week for 12 weeks or 3 months; by this time they are
equipped with the information and experience gained from Phase I.
Clients sit down with a counselor and identify specific cofactors that
need individual attention. Working from a treatment manual, the
counselor provides strategies to help individuals improve their scores
for a given cofactor. One strategy is comprised of activities that the
therapist and client can do during the session. An example might be
teaching a deep relaxation exercise or guided imagery to access
unresolved grief about a lover's death 2 years ago; unresolved grief
can be immunosuppressive. The interventions might be things that
clients can go out and do on their own, somewhat like homework
assignments. Or they might be holistic modalities available in the
center's Heart Program or other programs available in the community.
Another kind of strategy, for those who want to dig deeper, is to
access a reference library. The client presents previously identified
cofactor deficiencies and plans treatment interventions in a
relatively structured manner. While in Phase II, clients can also
attend weekly support groups. Phase III is 6 months of participation
in support groups.

       BETA: The total obligation of time is a year?

       LEIPHART: We ask for a commitment of 6 months. If at the end of
that time clients want to attend groups on a weekly basis, they are
welcome to do so. They can attend on any schedule they want; there is
no obligation.

       We're doing formal research on the impact of this program on
immune system functioning. The research design requires blood testing
pre-treatment, post-treatment and at 6-month follow-up intervals.
There are several types of data that we collect during the study. One
type is performance on cofactor issues. To measure that, we have
constructed a 250-item questionnaire that produces a profile that is
used clinically in the individual counseling.

       BETA: Would you say that your assessments are useful for
fine-tuning the individual program being followed by the HIV-infected
individual?

       LEIPHART: Based on the data that we collect at 3-month and
6-month follow-up visits, we postulate that people with a high
cofactor performance rating also have high immune system functioning
and high HIV health status.

       BETA: And a corollary would be that low performance on the
cofactors as stated and defined would correlate, by your hypothesis,
with disease progression?

       LEIPHART: Right'low cofactor performance correlates with
decreased immune system functioning and markers of immune system
impairment, and highly correlates with increased HIV symptoms. The
specific symptoms are measured by adapting the University of
California at San Diego HIV Neurobehavioral Research Center (HNRC)
symptom checklist to measure health problems. This is compared to the
Centers for Disease Control and Prevention (CDC) classification. The
last measure is the psychological profile; we're using a personal
problems checklist and the Profile of Mood States.

       The primary hypothesis is that immune system functioning
deficits are correlated with progression of HIV symptoms. What we're
proposing is that the cofactor performance is equally, intimately
linked with AIDS. The cofactor performance that creates immune system
dysfunction in HIV is as important as the viral component, in terms of
impact on immune system functioning.

       Immune function is checked at baseline, at 6 months and at 12
months. We would like to add other datapoints at 18 months and even at
24 months. These later measures become important because PNI research
at UCLA has shown that the immune boosting capabilities of
psychological interventions often don't show up until a year or so
after the intervention is over, when the groups separate.

       To date there haven't been any traditionally defined control
groups. In the proposed design there is a waiting list control group
with a huge reserve of candidates. They will be matched on certain key
variables and randomly assigned to certain control groups. This will
be done so that no one is deprived of useful interventions [the
control group receives delayed intervention].

       So far our clinical program has been highly popular. It has
become clear to me over the years that programs like this will go
absolutely nowhere unless there is a very thorough and tight research
piece done on it. The research must be highly sophisticated. To do
this we need money, which we don't have. So what we're doing is
research prototypes and research pilots and research development,
getting the program presentation and the instruments fine-tuned, and
working out issues with the blood lab.

       BETA: What is the central laboratory for the proposed study and
which measures of immune function are you collecting?

       LEIPHART: We work with Nichols Institute in San Diego because
they have blood draw stations everywhere. All blood draws are done in
the same 2-hour window so that there is no diurnal (over the course of
the day) fluctuation to confound the data, which you may get when you
measure T-cells and cortisol levels. We are also collecting beta-2
microglobulin and neopterin. We're also counting natural killer (NK)
cells, which to my knowledge has not been done for clinical use. In
standard medical practice with an HIV positive person, NK cell levels
are not taken and used for treatment. And the physicians I've talked
with in town don't know how to interpret them or what to do with the
information.

       A UCLA study of NK cell levels in healthy long-term survivors
with CD4 counts under 50 cells/mm3 shows that they have moderately to
maximally elevated NK cell levels. So there is at least an initial
indication that if you have a low CD4 cell count you, may be able to
compensate and protect yourself with an elevated NK cell level. The
same is true for CD8 cells. So we're measuring NK cells, the absolute
number of B-lymphocytes, p24 antigen and serum cortisol levels.

       BETA: Do you have any preliminary data from your collections?
Do you intend to provide a subset analysis at an interim point before
you finally publish?

       LEIPHART: Right now there are maybe 1 or 2 subjects that are
lagging on getting their blood draw in, but we've just about collected
all the post-treatment data: the psychological measures, the cofactor
questionnaire, the symptoms check list and the blood draw. That data
has not yet been analyzed. We've done preliminary analysis on the
pre-treatment data and we're doing correlations among these measures.
We have gotten some interesting correlations.

       BETA: Do you have plans to export this program outside of San
       Diego County?

       LEIPHART: Because the program is pro-immune system and
self-empowering and is relatively clear and hopeful, it has a lot of
appeal. Consequently, potential clients have knocked on our door
saying that they want this program. While we respect people's right to
treatment, that demand has put us in a dilemma because the research
isn't completed. The plan for a multi-site research project is to
extend the program to those people who want it as much as we are able,
provided they are willing to be research partners and complete all the
research measures. In that case, one site might be an individual
consumer's house; he or she would agree to complete the research
measures and to seek mental health counseling on those issues for
which support and guidance are needed. Let's say there is someone who
has the background manual for this program and a basic understanding
of psychoneuroimmunology, and they know the kinds of factors that are
immune-enhancing and immune-suppressing in HIV infection. If they have
that basic background they can then select a mental health
professional. They don't have to educate the mental health
professional in psychoneuroimmunology or on any of the background of
the program. They can simply go to the mental health professional and
say, 'I want to learn how to be assertive. I have discovered recently
that I am really low on assertiveness and I want you to teach me
assertiveness. Can you do that?' This is a perfectly fine contract,
and the therapist does not have to agree or disagree with the role of
assertiveness in immune system functioning.

       BETA: They do have to agree that HIV does not equal AIDS and
that HIV does not equal death. If you're going to go the clinical
psychologist with that specific deficiency in your belief system, you
need to have contact with a psychologist who does not have that
conviction. But the psychologist is not going to be able to make yout
accept that conviction if you don't already believe it.

       LEIPHART: That's true. If your mental health professional is
basing interventions on the premise that you have a short time to live
and need empathy because you are dying, they're not going to be useful
in teaching psychological strategies for long-term survival. So their
attitude is important. Perhaps one of the most important things a
mental health professional can provide are the psychological
strategies that long-term survivors have developed and that anyone can
put to use.

       The table on the previous page lists the 19 cofactors that are
addressed by the LIFE program in San Diego.

       BETA LIVE!

       Report from the Second National Conference on Human
Retroviruses and Related Infections

       The following is an edited transcript of 2 BETA LIVE!
teleconferences broadcast live on January 31 and February 1, 1995,
from the Second National Conference on Human Retroviruses and Related
Infections in Washington, DC.

       BAKER: Good afternoon everyone, and welcome to the January 1995
BETA LIVE! I'm Ronald Baker, editor of BETA. Today's teleconference is
being broadcast to you live from the Sheraton Washington Hotel in
Washington, DC, where over 2,000 people are attending the Second
Annual Conference on Human Retroviruses and Related Illnesses,
sponsored by the American Society of Microbiology. BETA LIVE! has no
affiliation with the conference or its sponsor. Our objective is to
bring you a comprehensive news report on important new treatment
developments that are being presented here today and throughout the
week by top AIDS researchers from all over the world.

       Five distinguished AIDS researchers and caregivers are here
with me this afternoon to discuss new information on AIDS treatments
and to answer your questions. They are Michael Saag, Melanie Thompson,
Jay Lalezari, Eric Darr and Cal Cohen. Dr. Saag is Associate Professor
of Medicine in the Infectious Diseases Department of the University of
Alabama. Dr. Thompson is Principal Investigator of the AIDS Research
Consortium of Atlanta. Dr. Lalezari is Co-Director of the HIV Research
Program at Mount Zion Hospital in San Francisco. Dr. Darr is Director
of AIDS Research at Cedars-Sinai Medical Center in Los Angeles. Dr.
Cohen is Research Director of the Community Research Initiative in
Boston.

       Dr. Saag, let's begin with a question for you. There's been a
great deal of discussion at this conference and elsewhere on new
information about the pathogenesis of HIV disease, particularly about
an article that appeared recently in the journal Nature. You were a
contributing author to that article. Would you describe this new
information and its significance for AIDS treatment strategies?

       SAAG: There are several pieces of information that have been
coming together over the last 3-4 years concerning viral load or viral
burden, meaning the amount of HIV that can be measured in the plasma
or circulating blood of patients who are HIV-infected. We instituted a
study about 8 months ago that watched what happened to the viral load
when antiretroviral therapy was added to patients' regimens, and
followed this viral burden change over time. What we noted in using
some of the more potent inhibitors such as the Abbott and Merck
protease inhibitors and nevirapine, is that the viral burden dropped
precipitously in the bloodstream. In a matter of a week we saw around
an 80-90% decrease in viral load, which persisted over a period of
time. We had noticed this before with other retroviral therapeutic
interventions, but we had never really thought about the dynamics.

       There's something called a 'steady state,' which means that
virus production and virus clearance is roughly equal. If you're
measuring virus in the blood of a patient, at any given time you'll
see a fairly steady level from day to day. So we asked a few simple
questions. How fast does the viral burden change? How long does it
take for virus to be produced and replaced in the bloodstream? How
does this really happen in patients? When we applied fairly simple
mathematical models to the situation, we found a very astonishing
result: the virus turns over about every 2 days. Every 2 days, new
virus is produced and older virus is cleared.

       This means that within any infected individual, 30% of the
virus that we measure in the bloodstream today was not here yesterday.
And conversely, 30% of it will be gone tomorrow. That is a pretty
astonishing and significant fact.

       We found a couple of additional things. Most of the virus that
was being affected by agents such as nevirapine and protease
inhibitors was coming from cells that were newly infected. Translated,
that means that 98% of the virus in the bloodstream that's produced
daily is coming from cells that were infected in the last several
days.

       This is critically important to our understanding of what we
call viral pathogenesis, or how the virus causes disease. The
take-home points from this are several. The first is that viral
turnover and viral replication occur at every stage of HIV infection
at an incredibly rapid rate. On a hopeful note, CD4 cell responses,
and the immune system response in general, are quite substantial, and
the body's ability to repair itself and produce new cells continues
even in the late stages of disease. The clinical take-home point is
that we shouldn't give up on patients simply because their CD4 counts
have dropped. Our goal is to try to suppress viral replication with
antiviral agents, preferably in combination, and change therapies when
a given regimen is not working any longer to keep the viral burden
low.

       LALEZARI: I'd like to add another perspective on the data that
Michael just reviewed. There's been a tendency to despair in advanced
HIV. It's common for patients to start despairing over low numbers of
CD4 cells if they're down in the 5-10 cells/mm3 range. But the data
actually show that these individuals are replacing their CD4 cells at
an even higher rate than patients with earlier disease. I think it
speaks to the possibility of an enormous reserve of the immune system
and potential capacity for the regeneration of the immune system.

       COHEN: We've also seen related evidence from long-term
nonprogressors. Somewhere around 5-10% of people, perhaps, are able to
stabilize, or create stalemate, and maintain their own CD4 counts at
high levels. It remains unclear if antivirals are needed for this
population. It's entirely possible that this is a subset of people
whose CD8 cells are perhaps so effective at controlling the virus that
they don't need help from the kinds of drugs that we have to offer at
this moment. But once somebody sees that they are slipping, I think
that the logic is to assist the immune system as soon as possible.

       BAKER: That's an important point. A study was presented here
about long-term, disease-free survivors of HIV infection that showed
that 13% of HIV positive individuals will probably remain AIDS-free
for 20 years after initial infection. This means that 13% of these
individuals will not develop an AIDS-defining illness nor will they
see their CD4 counts drop below 200 cells/mm3 for 20 years.

       THOMPSON: That's very optimistic; I think it underscores the
difficulty in making decisions about treating as soon as someone is
diagnosed with HIV or even after acute serconversion. We don't know
how to predict who's going to be a long-term non-progressor or
survivor and we really don't know whether, as Mike pointed out, we're
going to be able to have enough drugs to treat people over the long
haul. If we're talking about a 20-year latency for some people, then
we really don't know how soon we'll use up all of our armamentarium.

       BAKER: It might be important for clinicians to talk to their
patients about making use of these new viral load tests to measure the
viral burden, particularly in asymptomatic individuals, and then to
make a decision about whether therapy is warranted or not.

       LALEZARI: I support that point. For the past decade and a half
we've been using very crude measurements of what's actually going on
within an individual in terms of their HIV load. CD4 counts are not a
reliable predictor of how much virus there is. Now we have these much
more sensitive and specific markers that tell us exactly how much
virus is present in the blood. For the first time, I think we can
actually craft therapeutic regimens to address an individual patient's
situation. That's going to have as much of an impact on the care of
individual patients as any of the new drugs that are now out.

       THOMPSON: I would offer a bit of caution on that, though. As
data presented at Yokohama have been looked at a little more closely,
it's clear that viral burden is not the sole predictor of progression
or treatment effect, that is, whether the drugs we use really are
going to be helpful. I think we've seen some more evidence at this
meeting that we need to look at both CD4 cells and viral burden, and
probably other things that we're not even aware of at this point. I
don't think it's prudent to hang our hats on any one number.

       SAAG: I think we really ought to be focused on the change in
viral burden as it responds to therapy. You establish a baseline for a
given individual patient and then watch and see what type of effect
the antiviral therapy has. If over time you see that the viral burden
goes back to baseline, or even rises, you can be pretty confident that
the viral therapy is no longer working and that you ought to think
about using another agent.

       COHEN: This leads us to other controversies and confusions,
based on our observations with what happens with interleukin 2 (IL-2).
We certainly have evidence that the immune system can actually
increase its replication capacity in late-stage patients, relative to
earlier-stage patients. In some ways this is not what we would have
intuitively predicted, based on declining CD4 numbers. We also know
that we can exogenously increase the number of circulating CD4 cells
and yet simultaneously see an increase in viral burden.

       So it gets complicated. How do we use these numbers? Does the
burst in viral burden with IL-2 predict that the drug is bad, or does
the CD4 increase predict that it's beneficial? We're still just
beginning to understand how to use these markers.

       BAKER: Yes, I think it is important to remember that these
tests are still experimental. On the other hand, they are commercially
available and useful. We might mention that there are 2 different
types of these tests that are now readily available for clinicians as
well as researchers to use. One is called the branched DNA (bDNA)
test, which comes from the Chiron Corporation; the other is the
polymerase chain reaction (PCR) test, from Roche Laboratories. These
tests cost about $220 a pop, which certainly is not inexpensive. We're
hearing from patients and clinicians across the country that insurers
are sometimes reimbursing for these tests and sometimes not. Until
these tests are FDA-approved, it's unlikely that all insurers will pay
for them.

       Let's talk for a few minutes about the protease inhibitor
drugs. There were several presentations on this new class of drugs
throughout the week here at this conference, including presentations
on the Merck protease inhibitor, the Roche protease inhibitor
saquinavir, the Abbott protease inhibitor and a new protease inhibitor
from Agouron Pharmaceuticals. Dr. Saag, which presentations impressed
you?

       SAAG: What impresses me most is that we are on the verge of
identifying a new class of compounds that really will offer additional
therapeutic options for patients. Most of the saquinavir data has been
presented at previous meetings. The triple drug combination of AZT,
ddC and saquinavir was found to be most active, underscoring the
concept of combination therapy.

       The data that were presented at this meeting about the Merck
protease inhibitor came from a multicenter study in Pittsburgh. That
study evaluated the Merck drug at 2 different doses: 200 mg 4 times
per day or 400 mg 4 times per day. A fairly dramatic drop in HIV RNA
levels was noted, on the order of about 10'100-fold or 1'2 logs. There
were CD4 count increases initially above 50 cells/mm3 in the majority
of patients, and sometimes increases over 100'112 cells/mm3 in a
number of patients. The problem, at least at these doses, was a loss
of effect in a number of the patients around 24 weeks. Increasing the
dose to 600 mg every 6 hours didn't bring any additional benefit.
However, the Merck protease inhibitor is a very potent agent that has
a lot of promise for the future. The dose that will probably be used
in later studies will be 800 mg 3 times per day, which is what I think
will be the ultimate dose.

       The Abbott protease inhibitor data was also presented at this
meeting by Marty Markowitz from the Aaron Diamond Center at New York
University Medical Center. This group found that the Abbott protease
inhibitor, given at a number of varying doses, caused on the order of
a 2'2.5-log decrease. That's about a 100'250-fold decrease in viral
burden from baseline that was quite rapid. CD4 count increases were
noted in the majority of patients, some quite remarkable. One patient
in particular went from a CD4 count of 60 cells/mm3 to about 600
cells/mm3. That was with monotherapy. Again, after about 24 weeks of
therapy the magnitude of that response disappeared in some of the
patients. Still, there was a substantial proportion of patients who
had a reduction in viral burden at 24 weeks and a sustained CD4 count
increase. Early data show that the drug is well absorbed, which is
encouraging. Absorption has been a problem with these agents.

       Altogether, I think there is a lot of hope. These agents may be
available to us in the near future. The cautionary notes are that
there's a lot of what we call 'protein binding,' which means that when
the drug gets into the body, it binds tightly to protein and may not
be released to the cells in question. That was the undoing of one of
the protease inhibitors, the Searle drug. Despite reaching very good
levels in the bloodstream, it had no antiviral effect because of the
tight protein binding. The second problem we have to be on guard
against is resistance. Resistance has raised its head in almost every
treatment situation so far in this disease, and indeed is happening
with these agents. The good news is that these agents, at least as
monotherapy, appear to be more potent than almost any other agent
we've seen to date.

       BAKER: The Abbott investigator mentioned that resistance was
persistent but very low-level. This issue of HIV resistance to
protease inhibitors has come up often in questions about whether these
drugs are going to be clinically useful. Do any of you see resistance
emerging as a serious problem?

       SAAG: Viral resistance has been a problem with all of the
nucleoside analogs that interact with reverse transcriptase (RT). I
think one thing you have to remember is that the RT enzyme of HIV,
against which our drugs have been targeted, is flexible and capable of
tolerating mutations; the virus can survive in the face of the
pressures exerted by those drugs. The protease enzyme has a much less
flexible, more rigid structure. It's less able to tolerate a series of
mutations that would allow the virus to become resistant. As we move
to the protease as a target for antiretroviral therapy, the hope is
that the virus won't have as many options to develop resistance to
multiple agents.

       BAKER: I think it's encouraging that the Roche protease
inhibitor, the Merck protease inhibitor and even the Abbott protease
inhibitor, may be submitted to FDA for accelerated approval this year.
So we could conceivably have 3 new protease drugs available, at least
for some patients, within the next 6 months.

       THOMPSON: I wanted to add that although saquinavir doesn't seem
to be as potent as some of the other protease inhibitors, there is a
new formulation in progress. Data were presented at the conference
showing that very high doses of saquinavir caused an increased effect.
If the product can be improved so that it is better absorbed, there
may be some increased benefit from that drug.

       BAKER: Let's take a couple of questions from the audience.

       BRISTOL, FL: Someone advised me to get on Bactrim [TMP-SMX]
even though I have 901 CD4 cells/mm3. Do I need to be taking anything?

       BAKER: Dr. Darr, would you like to talk about PCP prophylaxis?

       DARR: When we initiate Bactrim therapy we're trying to prevent
some of the opportunistic infections associated with HIV disease. We
have pretty good data about when people are at risk for developing
these complications. In other words, we don't need to start everybody
who's HIV positive on all forms of prophylactic therapy. In the case
of Bactrim we're primarily trying to prevent Pneumocystis carinii
pneumonia [PCP]. The data indicate that you usually don't need to
worry about developing this complication until the CD4 cell count is
around 200 cells/mm3 or unless a person has some evidence of
symptomatic disease such as thrush, unexplained persistent diarrhea,
fever or wasting.

       SAN FRANCISCO, CA: Relative to the Abbott protease inhibitor,
the data suggests a 2.75-log drop in viral load at 12 weeks. Is that
the highest impact that's been seen for the protease inhibitors? How
does that compare to the Merck drug? Also, what information is there
on manufacturing and expenses relative to the Abbott protease
inhibitor?

       SAAG: We've actually worked with the saquinavir product from
Roche, the Merck protease inhibitor and the Abbott protease inhibitor.
Because we haven't done a head-to-head comparison, I can't give you a
direct answer. I can tell you that in general the Merck and Abbott
drugs are absorbed a lot better than the Roche drug. Most of these
drugs are well tolerated. The Abbott drug has been associated with
perhaps slightly greater decreases in viral burden, but not enough to
call it a significant difference from the Merck drug. It looks like
the Merck and Abbott drugs are both a little bit more active than the
Roche protease inhibitor since the Roche drug is not as well absorbed.
So, the Merck and Abbott drugs seem to be pretty much in line with one
another and the data that you are quoting is pretty much on target.

       We're seeing on average about a 2-log or 100-fold decrease in
viral burden with either the Merck or the Abbott protease inhibitor.
The question is, how durable is that effect? And that's what I think
has most of us concerned. Ron asked a question earlier about
resistance. There is perhaps less flexibility with the protease gene
product, but I think there's enough flexibility that the virus will
mutate, and indeed it has already been shown to develop resistance in
a matter of 12-24 weeks.

       In my experience, these are the most potent agents I've ever
seen as monotherapy. But I don't think in the future we will be
treating patients with monotherapy much any more. Consider the viral
burden data; even when patients are clinically well, like the caller
who has a CD4 count of 900 cells/mm3, active viral replication is
still going on. Even though the recommendations currently are not to
treat such an individual with antiretroviral therapy, at least from a
theoretical standpoint you could argue that we should be treating most
people, regardless of their CD4 count. In the future we'll be leaning
towards earlier intervention because of those pathophysiologic
reasons, and toward earlier, more aggressive intervention with
combination therapy.

       BAKER: Dr. Saag, you're suggesting that there appears to be a
growing consensus that the most effective strategy would be to combine
drugs with different mechanisms of action. I guess one big question
that's on everyone's mind is how early should people who have HIV
infection begin combination treatment?

       SAAG: The problem boils down to one of philosophy, almost. All
the drugs available, including the protease inhibitors, have a limited
durability of effect. When you treat early with AZT monotherapy you'll
get about 3 years of effectiveness, which might be lost after that.
Nevirapine as monotherapy appears to be effective for just a couple of
weeks.

       The point is that to prevent resistance or to give more
coverage we are going to have to use combinations. With regard to
early intervention, the philosophy I'm referring to relates to whether
or not we believe that there will be better therapies coming down the
pike in the future. A conservative approach would be to wait until the
CD4 count gets to some magical number, say 500 cells/mm3, and begin
therapy at that point. These are the standard treatment
recommendations. On the other hand, if someone believes that there
will be better therapies down the road, then it makes some sense, at
least from a physiologic standpoint, to treat as early and
aggressively as possible. That would involve understanding that if you
play all your cards now, there may not be anything left if resistance
occurs. To start treatment above 500 CD4 cells/mm3 is a delicate
decision that people have to make for themselves. Personally, I think
we will have better agents, therefore I generally lean towards
suggesting earlier treatment.

       LALEZARI: I think it's clear that the future of HIV therapy is
combination therapy. In particular, that may mean combinations of
protease inhibitors because, although some of these agents have
demonstrated that they are capable of inducing resistance after a
period of 3-6 months, it is at least theoretically conceivable that
the protease enzyme is not that flexible or capable of functioning
with multiple mutations when it's subjected to the pressure of several
protease inhibitors simultaneously. So the studies evaluate protease
inhibitors either individually or in combination with nucleoside
analogs.

       One of the hopes I have for expanded access is to see what
happens when we begin to use these protease inhibitors in combination
therapy. One of the frustrating things I would add is that even though
there's a great deal of hope and enthusiasm about these drugs, it's
still going to be 6 or 12 months, realistically, before my patients in
San Francisco have ready access to these compounds. In the meantime,
the message coming out of this conference is, 'it's the virus, it's
the virus.' Whatever we can do now to stem viral replication should be
done. It's also clear in retrospect that AZT is a very potent compound
and, in combination with a drug like 3TC, there's something we can use
now, even before the protease inhibitors become available; I'm
certainly going to be recommending this to my patients in San
Francisco.

       COHEN: I think one of the other hopeful messages from this
conference has to do with access to HIV RNA PCR-type testing for viral
load. We're all embarking on a new strategy which involves the ability
to do short screening tests of combinations'2 drugs, 3 drugs, maybe
even 4 drugs'and taking a look at these measures in the short term.
The rate of change of viral load within 2-4 weeks gives evidence of
activity; within 6 months we already can see evidence of how long that
activity might last. All of the research networks are really gearing
up to test various combinations and compounds. This work will allow us
to start to prioritize these very interesting compounds.

       BAKER: Dr. Thompson, just a couple of months ago at a
conference in Glasgow, Scotland, investigators presented data which
suggested that the combination of AZT and 3TC produced significant,
sustained increases in CD4 counts and also significantly reduced the
viral load in patients who were taking this combination. Tomorrow, at
the conference here in Washington, results of studies that you have
been participating in will be presented on patients who are using this
same combination. I know you can't discuss these results until the
paper is given tomorrow, but what can you tell us about the possible
clinical significance of the European studies of people using AZT plus
3TC? Also, would you be able to tell us perhaps how the European
studies of this combination differ from the U.S. studies?

       THOMPSON: There were 2 studies presented in Glasgow, Scotland,
this past November. One was a study that mainly involved folks who had
less than 4 weeks of AZT use; that study looked at AZT alone compared
with AZT plus 3TC. The dose of 3TC was 300 mg 2 times per day. Keep in
mind that this was a short study aimed at achieving an outcome in 24
weeks. The study did not measure how many people survived or for how
long or whether they got diseases'it just measured viral burden and
CD4 cell counts. After this short study it was very apparent that the
combination of 3TC and AZT raised CD4 cell count more than AZT alone.
At the 24-week point, there was about a 85 cells/mm3 rise in those who
had taken AZT and 3TC compared with a 34 cells/mm3 increase for those
who had taken AZT alone. The people who were on AZT alone had actually
lost 7 cells/mm3. There was a significant difference between people
who had taken 2 drugs compared to 1. The other study, which followed
folks who'd been on AZT for more than 6 months, also showed a change
in CD4 cells, but not quite so strong an effect. That's not surprising
because these people had already been on AZT.

       We saw a significant drop in viral burden with AZT and 3TC
together, on the order of 1.5 logs. That change is not quite as
impressive as the protease inhibitors' 2-log drops, but it's better
than any of the other combinations we've seen such as AZT/ddC or
AZT/ddI. At the end of the study there was still a 1-log drop. Again,
in the more experienced patients, the difference was not quite so
great but was still very encouraging. Another encouraging thing about
this study was that there was a cross-over point for both studies at
24 weeks when everyone was given AZT and 3TC together. The people who
had been on AZT alone also showed quite a bit of benefit. It's
interesting to speculate why this is. It looks as though when the
virus mutates to become resistant to 3TC, it may actually become more
sensitive to AZT.

       There are also 2 American studies of this combination. One
study enrolled people who had very little prior AZT use, less than 4
weeks. The other looked at people who had longer AZT use, say 6
months. The earlier study was for folks with CD4 cell counts of
200-500 cells/mm3 and the later study was for people with CD4 cell
counts of 100-300 cells/mm3.

       Now, lest this get confusing, let's talk first about the
earlier patients who've not had much AZT use. Data from the American
studies was very similar to the data from the European studies. I
think it's very encouraging we have 2 separate studies that confirm
the same findings. In the American studies we were comparing AZT alone
versus 3TC alone versus 2 different doses of AZT plus 3TC. There
really was no difference between the 2 doses of 3TC and AZT in any of
the 4 studies. So the dose of 3TC from now on probably will be 150 mg
2 times per day. In the naive patient study people entered with a CD4
cell count over 300 cells/mm3, on average, and a viral burden level
around 31,000 copies.

       We saw a very dramatic decrease in the level of viral burden.
In fact, it was sort of surprising, but the maximum decrease seen with
AZT and 3TC together was almost as much as has been seen in some of
the protease inhibitor studies. The maximum decrease was 1.8 logs. The
other interesting thing was that this decrease was sustained. Although
it was not always quite so dramatic as 1.8 logs, there was still a
1-log drop in viral burden at the end of 24 weeks. In fact, that
decrease was sustained over a 52-week period.

       That's very encouraging and something that we're not seeing in
some other studies, including protease inhibitor studies. This result
was compared to AZT alone and 3TC alone (which looked pretty similar,
actually); those drugs were associated with a much smaller drop in
viral burden and by the end of the study really showed no sustained
benefit. This is very similar to the way AZT has looked in other
studies. In naive patients we have good reason to think that the
combination is a very potent suppressor of the virus. Also, whereas
the AZT-only and the 3TC-only arms did not show an overall benefit in
terms of CD4 cell count, the AZT/3TC arm showed a sustained increase
of about 80 cells/mm3. The combination also was very well tolerated.

       Now the story for folks who had had some AZT in the past was
also very encouraging, but the design of the study was a little
different. This study compared AZT and 3TC in 2 different doses to
AZT/ddC, which is a combination that many people are taking. The
interesting thing was that the AZT/3TC arms looked pretty much like
the AZT/ddC arm in terms of actual viral burden decrease. The effect
against viral burden was not as great as in the previous study, but
there was a greater benefit in terms of CD4 cell count in the AZT/3TC
arms. That benefit was sustained over 24 weeks and probably over 52
weeks, although the data are not yet in. So I think we saw again that
there is apparently a CD4 cell benefit in the AZT/3TC combination that
is a little out of sync with what we see with viral load. That also
makes us have to think about how we're going to use viral load
markers. Are we getting a benefit, and is the benefit longer-lasting
than the actual blip we see in viral load?

       BAKER: For the benefit of people who may be new to this
terminology, I wondered if one of you would define what we mean by
'log reduction,' as in a reduction of 1 log, and also by the word
'naive.'

       SAAG: Generally, what we're talking about is a reduction in
'log base 10.' Thinking back to high school math, what that means is a
10-fold reduction. If viral load drops 2 logs, that's a 100-fold
reduction (which is really phenomenal). In fact, that's what has
actually been seen in some of the protease inhibitor studies that were
reported at this meeting. At least for a short period you could get
that type of response. As opposed to someone 'experienced,' someone
who is 'naive' has never had any treatment with retroviral agents'AZT,
ddI, ddC, etc. They are naive to retroviral drugs as opposed to
'experienced' patients who have been treated at some point in the
past. You generally see a much more profound antiviral effect when you
give any agent that's effective to a population of patients who
haven't been treated before. A lot of listeners, if they're patients,
probably fall into the category of being 'experienced.' Many people
have been through a number of different agents or combinations of
agents. Studies of experienced patients are vital for uncovering other
options for treatment for people whose viral burden is coming back up,
or whose CD4 counts may be starting to drift downward despite therapy.

       BAKER: Here at the conference Columbia University researchers
are going to present more information on the discovery that a new
herpesvirus may be the cause of Kaposi's sarcoma [KS]. Dr. Steven
Miles of UCLA said at a press conference that he is personally
convinced that this is, in fact, a new herpesvirus and that it is
likely the cause of KS. If this turns out to be true, I'd like to ask
our panelists to comment on what the implications of this discovery
may be for people with HIV infection.

       LALEZARI: There are many questions that remain to be answered
about whether or not this is indeed a new herpesvirus. We still don't
know anything about the mode of transmission of this agent or what
drugs we might be able to use to treat it. Certainly, we've known for
a long time that KS is a sexually transmitted disease. The current
chemotherapy we're using for KS involves a lot of toxicity that we
would all be glad to get rid of. We clearly need to know a lot more
about this discovery and its implications, but it does potentially
open up an avenue for new treatment and prevention approaches.

       BAKER: What might be one of these new treatment approaches?

       LALEZARI: I'm not aware of any demonstration to date showing
that ganciclovir, acyclovir or foscarnet, the currently available
anti-herpes drugs, have had any impact on the evolution of KS in our
patients. These studies clearly need to be done.

       SAAG: If this is indeed a herpesvirus of some sort, it's
probably not the typical HSV-1 or HSV-2 that commonly cause sexually
transmitted disease. It's probably a different herpesvirus, as
everyone has said. But the potential good news is that a test could be
developed to look for antibodies against this virus in the
bloodstream. You could test to see who might be at risk to develop KS
and who might not be. If you can isolate the herpesvirus, you can test
a lot of different drugs, some of which already exist, to try to
prevent this virus from expressing itself and thereby prevent KS
altogether, which would be very exciting. For those who have actually
developed KS, it would mean better ways of treating it.

       About a year and a half ago there was a lot of discussion about
patients in whom researchers were trying to prevent CMV
[cytomegalovirus] disease with acyclovir. Unfortunately, acyclovir
didn't prevent CMV disease but, almost miraculously, the patients in
those trials who received acyclovir tended to live on the order of
8-12 months longer than those who were getting placebo. Several
studies showed this. Since we know that acyclovir works almost
exclusively on herpes-related viruses, we thought that there may be
some occult or hidden herpesviruses that stimulate HIV production,
especially in later-stage HIV disease, and that perhaps acyclovir
slows this process. It might be that acyclovir is active against one
of those herpesviruses that we hadn't yet discovered. I'm not saying
that acyclovir is a cure for KS; the point is that we suspected for a
while that there might be other herpesviruses present and significant
for HIV disease progression.

       BAKER: It might be useful to do some initial laboratory studies
to see if agents such as acyclovir or ganciclovir have any effect
against this new virus in the test tube.

       SAAG: As we've been talking about this, I've tried to think
about patients who I've seen recently who have had CMV disease and
have been on foscarnet or ganciclovir, and whether any of them have
developed KS. Off the top of my head, I can't think of any. How about
you guys? Have you seen that happen?

       LALEZARI: It's really hard to say. I've probably treated 200
individuals with CMV retinitis in the last 3 years and probably 20% of
them had KS. I don't know that their KS has advanced while they
received anti-CMV therapy.

       SAAG: Right, but I think the question is, did any of those who
did not have KS before develop KS while you were treating them for
CMV?

       LALEZARI: Off hand, I'd say no.

       HOUSTON, TX: I have 2 questions. In a recent issue of BETA
there was an article dealing with 4-drug combinations. Can you update
us on these? Second, is there anything new on GEM 91?

       SAAG: I can comment on GEM 91 [an antisense molecule that binds
viral RNA and thus blocks HIV replication]. In Birmingham we are doing
a study right now that's also going on at New York Hospital, Brown
University, the University of Texas in Dallas and the University of
Washington in Seattle. It's a Phase I/II dose escalation study of both
the safety and the relative antiviral activity of GEM 91. We've just
finished our second dosing group. We will be going back to FDA next
week to get permission to go to the next dosing level, and we'll
continue until we've studied another 4 or 5 groups. The beauty of this
study is that it will tell us fairly quickly not only the safety but
whether the drug has promise in the first 2 weeks. Hopefully, we will
have some data by the first part of June as to the promise of GEM 91.
Briefly, the downside of GEM 91 is that it requires intravenous
administration right now. For these studies patients are in the
hospital for 15 days and given what's called a continuous infusion, in
which they get the drug around the clock for 24 hours. That's clearly
not going to be feasible in the long run.

       BAKER: In regard to 4-drug therapy mentioned in the last issue
of BETA, that was in reference to the fact that 3-4 drug regimens
appear to have been successful in the treatment of tuberculosis and
certain forms of cancer. Three to 4 drug combinations of different
classes of anti-HIV drugs may, in the future, prove to be of the most
benefit to people with HIV infection. Unfortunately, right now
patients do not have the option of using 4-drug therapy against HIV
infection. When more drug options become available to patients, that
will be possible. For example, were FDA to approve one or more of the
new protease drugs and one of the non-nucleoside reverse transcriptase
inhibitors such as nevirapine in the coming months, then we would be
able to use a 4-drug regimen combining drugs from different classes.
There are a few ongoing studies using 3-drug combinations such as AZT
plus ddI plus nevirapine or AZT plus ddI plus saquinavir. These
studies are being conducted by the Intercompany Collaboration of
pharmaceutical companies.

       THOMPSON: Actually there is a 3-drug combination that has been
looked at in the lab that is available, and that is AZT, 3TC and ddI.
This combination seems to have a fairly powerful effect on viral
burden. While it's not really been looked at in clinical trials, I do
think it's worthwhile to think about combining existing drugs as well.

       Still, I think it's very important for patients to resist the
temptation to go wild with the drugs that are currently available.
Because with what we have now'AZT, ddI, ddC and d4T'there's a
tremendous amount of overlapping toxicity. The possibilities for drugs
antagonizing each other aren't clear yet either, particularly with
some of the newer agents. When we talk about combination therapy
beyond 2 drugs right now, we're really talking about in the future
with some of the newer agents like 3TC and perhaps some of the
non-nucleosides or protease inhibitors.

       Let me also clarify that 3TC is not generally available. I
think of it as being available because there's a very large expanded
access program for people with CD4 count less than 300 cells/mm3, but
it is not yet licensed.

       BAKER: At the Yokohama AIDS conference last summer, and then
again here this morning, findings were presented about a genetically
engineered drug from Serono Laboratories called human growth hormone.
Dr. Darr, what exactly is recombinant human growth hormone, and why
are some people calling it a breakthrough treatment for AIDS-related
wasting syndrome?

       DARR: First, it's very important to understand that
AIDS-related wasting syndrome is probably a mixed bag. As people are
remaining healthy longer, receiving antivirals and prophylactic
therapy, more and more of our patients are suffering from relentless
or intermittent bouts of weight loss. People with HIV disease seem to
selectively lose actual muscle or lean body mass, not just fat. Some
individuals relentlessly lose weight, particularly lean muscle mass,
regardless of how much they eat. Another subset of individuals
probably aren't getting adequate calories, either because they are
unable to eat enough or because they have problems with their gut.
They have some type of pathogen that prevents them from absorbing
nutrients. The idea for growth hormone really comes from the former
group, people who, regardless of how much they eat, are unable to gain
weight.

       Several studies have tried different approaches to wasting. One
study was of parenteral nutrition, where we gave calories
intravenously. Several other studies were of drugs, including one
called Megace, that increase appetite. What these studies have
consistently shown is that although weight was sometimes gained, it
tended to be mostly, if not all, fat.

       Growth hormone is a natural hormone poduced by the body that
promotes growth and is particularly important in children. If given in
excess to adults, growth hormone can increase lean muscle mass; it has
been used by body builders for this purpose. The thinking was that
perhaps we could reverse the HIV-related wasting process with a drug
such as recombinant human growth hormone, and that would it bring
different benefits than parenteral nutrition or Megace.

       A relatively large placebo-controlled trial sponsored by Serono
recently looked at recombinant human growth hormone in people who had
lost a substantial amount of weight, about 15% of their previous
weight. They were otherwise able to eat and didn't have obvious
evidence of malabsorption or inability to absorb calories, meaning
they weren't having a lot of diarrhea. The results were that these
people did indeed gain weight. Those who got treatment gained on
average about 2 kg, while those who got placebo remained stable or
lost a little bit of weight. As I mentioned, growth hormone actually
increases muscle deposition and burns fat; in the treatment group,
lean body mass or muscle mass gain was 3 kg, with a net loss of about
1 kg of fat.

       The drug was also very well tolerated. About 15-20 people out
of about 90 in both groups dropped out of the study. None of the
growth hormone patients had to drop out because of growth
hormone-related toxicity. The most common side effect was a sense of
fullness in the hands or feet, but there was no evidence of gross
edema or swelling.

       We also looked at CD4 cell counts to see if there was either a
positive or a negative effect, but there was no real difference in CD4
counts over a 12-week period. Finally, we also looked at viral load.
If growth hormone was going to have a good or a bad effect on viral
load, we'd likely see it over a 12-week period. Using sensitive
techniques to measure viral load, looking for viral RNA in plasma, we
saw essentially no change in either the placebo or the growth hormone
group. This is considered a major breakthrough, because growth
horomone is really the first treatment for wasting that's been shown
in a randomized trial to actually increase, or reverse the loss of,
lean body mass.

       BAKER: Patients or physicians who want information on growth
hormone and how to obtain it may call Serono toll-free at
800-714-AIDS.

       CHICAGO, IL: What do you think about d4T? It seems like it was
approved with little fanfare or attention. Is it successful? Can it be
compared to AZT? Can it be used in combination with other drugs?

       SAAG: We actually know quite a bit about d4T. The first time I
saw a poster on it was in 1988 in Stockholm, Sweden. Since that time
the drug has been available in a number of clinical trials that looked
at dose levels and effectiveness. I'll be interested to hear what the
rest of the panel says, but in our experience in Birmingham the drug
seems to be generally better tolerated than ddI. The one thing you
want to watch out for is some neuropathy, but I've noticed that less
frequently than with ddC. It seems to me that we're getting better
response in terms of viral burden decreases and CD4 count increases
than we get with either ddI or ddC, even as monotherapy. We haven't
had enough experience with d4T in combination therapy. Because AZT and
d4T are both thymidine [a genetic building block] analogs (notice the
'T' in AZT and d4T) there was concern that when added together they
might counteract one another or cause more side effects or toxicities.
In fact, a lot of people have been combining them. So far there
doesn't seem to be a problem. It may be that this combination will
work well'we don't know yet.

       Let me give you my personal philosophy about where we might be
headed with drug approval. There's a number of clinical trials that
will allow us to evaluate as many agents as rapidly as we can, prove
their safety as best we can, and then once the safety and activity are
proven, allow us to make those drugs available to patients on a wider
scale than we've done previously. In other words, I'm very much
supportive of the FDA expanded access program and I think it should
definitely continue. This is especially true in light of the new data
on viral burden changes. More data is being presented at this and
other meetings that show that reduced viral burden correlates with
improved clinical outcome. We aren't going to need the so-called large
simple drug trials to prove this.

       BAKER: I agree with Dr. Saag and would just add that I think
it's very important and very necessary that FDA approves more anti-HIV
drug options sooner rather than later. It's been important that d4T
has become available.

       LALEZARI: I've been concerned about using d4T in combination
with other drugs. As monotherapy, I'm increasingly comfortable with
it. I think my patients generally feel good on the drug, and I haven't
seen a lot of toxicity. There really are 2 other areas of concern,
though. One is the caution against using d4T in combination with AZT
because they share a common activation pathway and it is at least
theoretically possible that they will tend to cancel each other out.
The other is in terms of the toxicity profile. The main toxicity with
d4T is peripheral neuropathy, which occurs at a dosage of 40 mg 2
times per day. It's less frequent at a dosage of 20 mg 2 times per
day, but it does occur. The concern would be that because ddI and ddC
have peripheral neuropathy as their most common toxicity, you would be
inviting more neuropathy than you'd bargained for by combining these
drugs with d4T. So I don't think we have a lot of information about
d4T in combination therapy, and there are certainly reasons to be
concerned.

       COHEN: The data on AZT and d4T interaction is actually
conflicting. Some studies are being launched to finally figure it out.
Since we do have conflicting in vitro data, I think you're right, d4T
and ddI aren't being explored as a combination. The other combination
that many are using is d4T with 3TC, which unfortunately we know very
little about. But, on the basis of some of the drug susceptibility or
viral susceptibility studies, there are at least reasons to be hopeful
that the effects of the drugs might be additive. We're still at the
learning stage.

       ATLANTA, GA: My question is about HIV-related use of
hydroxyurea and whether there is any information on whether it can be
used sporadically. I've heard that it may continue to inhibit viral
replication even after someone stops taking it.

       BAKER: I think very little is known about its use in HIV
infection. It has been used as a cancer treatment for a long time, but
it was only fairly recently that I believe Dr. Robert Gallo suggested
that it might have a role in HIV infection. But to the best of my
knowledge there is no data available on its use in HIV infection. Dr.
Saag?

       SAAG: There was one abstract at this meeting that compared, at
least in the test tube, what happens when you add hydroxyurea to AZT.
The bottom line seems to be, not much. So it may not be an agent that
can be of clinical utility. Melanie?

       THOMPSON: I think other people have looked at hydroxyurea with
ddI and noticed a differential effect with the different nucleoside
analogs, and a more beneficial effect with ddI. I don't think it's
clear yet. We're talking about small studies that are predominantly
laboratory studies. There's a protocol in development in the American
Foundation for AIDS Research community-based clinical trials network
to look at hydroxyurea and ddI. But I don't think there really is any
clinical data. People should be very cautious about using hydroxyurea
because it can suppress bone marrow and should be given under the
supervision of a physician.

       SAAG: Just a last comment about hydroxyurea. Probably the most
important thing about this study is that it raises the idea of looking
at novel ways of treating this disease. The hydroxyurea studies point
to some other pathways and mechanisms involved in HIV disease,
particularly at the cellular level. The least important thing right
now is for people to go out and try to get their hands on it just
because it's available. As was mentioned, it has some toxicity. There
aren't any data in patients. People need to wait for the clinical
studies.

       ORLANDO, FL: Throughout history, for every disease we have ever
cured, we stopped looking at the effects and started looking at the
cause. We also know that the number of CD4 cells in a person's body
doesn't necessarily reflect the amount of virus, the viral load
itself. So why are we so concerned about CD4 cell counts?

       SAAG: Your point is well taken: it is the virus that's
important. Without the virus, people wouldn't be sick. If we can find
a way to stop the virus from replicating, I suspect that we will
control this disease. On the other hand, the target of the virus is
the immune system, and one of the best markers of immune system
health, at least from natural history studies, is the CD4 cell count.
CD4 counts are correlated with risks of developing certain
opportunistic infections and act as a barometer of the relative
strength or weakness of the immune system. When the CD4 cell count
falls below 200 cells/mm3, as everyone knows, people are at higher
risk of PCP, etc. But you're right, the primary focus ought to be on
the virus and finding a way to inhibit its replication. It now seems
like the immune system is more capable of reconstituting itself and
improving its ability to respond to things than we had perhaps
previously recognized.

       SAN FRANCISCO, CA: I want to know about the use of ganciclovir
for CMV for prophylaxis and for treatment, including for non-retinal
CMV.

       LALEZARI: I don't know if there's any area of HIV care that's
changing more rapidly or dramatically than the prevention and
management of CMV in the setting of AIDS. There's a lot of good news
at this conference. Before I summarize some of these studies, I would
like to articulate our 4 goals in handling CMV with HIV infection.
First of all, we want to prevent CMV disease in patients who are
infected. For those individuals who develop CMV disease (in general
we're talking about retinitis), there are 3 other goals: first, to
provide good local control of the CMV within the eye; second, to
provide treatments that prevent the spread of CMV from the eye into
other organ systems; and third, to provide treatments that are both
well-tolerated and that allow patients to receive treatment without a
permanent indwelling catheter. Although none of the treatments that
are emerging at this conference individually satisfies all these
criteria, I think it's relatively easy to play a game of mix-and-match
so that we can come up with a treatment regimen that in fact meets
these goals.

       To begin with, oral ganciclovir has now been shown in a large
study by Syntex to be effective in reducing the incidence of CMV
disease by half in a cohort of over 700 patients with fewer than 50
cells/mm3. In fact, the average CD4 cell count in that population was
about 25 CD4 cells/mm3. So for the first time we're going to have an
oral drug available as a prophylaxis for CMV infection. It's not
perfect, but it will be the first time we have a prophylactic regimen.

       In addition, oral ganciclovir has now been shown to be
effective as a maintenance treatment regimen for CMV disease,
following initial IV [intravenous] induction treatment. Oral
ganciclovir will be available starting this week in pharmacies in the
United States for that purpose. On the plus side in this area, oral
ganciclovir is effective. It's not as effective as IV ganciclovir in
controlling retinitis, but it's much safer than IV ganciclovir. It's
clearly effective in preventing the spread of CMV from the eye to
other organ systems. Of about 400 patients with CMV disease who have
been treated with oral ganciclovir, there's only 1 documented case of
someone developing CMV disease outside the eye. And finally, beyond
being an oral drug and being well-tolerated, it also has the virtue of
not requiring a permanent indwelling catheter. So there's a lot of
pluses to oral ganciclovir.

       On the downside, I do have some concerns about oral ganciclovir
not being as effective as IV ganciclovir. I hesitate to endorse the
oral drug as a maintenance treatment for anybody who has CMV infection
that's toward the center of the eye and who therefore has immediately
sight-threatening CMV disease. But oral ganciclovir can become an
important part of our treatment regimen for CMV.

       We've also heard about the ganciclovir implant at this
conference. This is a small 2 mm pellet that is surgically placed in
the eye in a relatively easy surgical procedure. As several papers
presented here have described, the implant offers extraordinarily good
local control of CMV disease. Average time to progression is the 6-8
months that the pellet actually releases ganciclovir within the
chamber of the eye. On the downside, with the implant there's very
poor control of the spread of CMV to the other uninfected eye or to
other organ systems. So unlike oral ganciclovir, the advantages of the
implant are very good local control but very poor systemic coverage.

       Finally, we also heard one paper on a new drug in the pipeline
called HPMPC. This drug showed very good control of CMV retinitis.
Since this drug is potent, it can be administered infrequently, once
every 1-2 weeks. On the downside of HPMPC, even though we see that
it's quite effective in controlling retinitis, we're not sure how well
patients will be able to tolerate maintenance treatment because it has
a number of toxicities.

       There are multiple scenarios that one might generate with these
emerging therapies. If I had access to all of these drugs and a
patient came to me with CMV retinitis, I could imagine providing some
initial induction therapy with either ganciclovir or HPMPC which could
be done over a 2-3 week period without a permanent catheter. During
that period we could place a ganciclovir implant in 1 or both affected
eyes and then, after the retinitis is stable, give the option of oral
ganciclovir maintenance therapy. This would prevent the spread of CMV
to other organ systems and provide a relatively well-tolerated
treatment that again doesn't require a permanent catheter. The good
news is that a lot of options are emerging for the prevention and
treatment of CMV, which will give patients the opportunity to tailor
treatment regimens to suit their own needs.

       BAKER: Although oral ganciclovir has not yet been approved for
the prevention of CMV disease, it is now available through a special
program provided by the manufacturer, Syntex, or Roche Laboratories.
Patients who think they may be at risk for developing CMV disease can
ask their physicians to call 800-569-4630 toll-free to get more
information on how to enroll in this program.

       ATLANTA, GA: Dr. Saag made a statement a few minutes ago that I
found very interesting. He said if a drug has any effect on HIV we'll
know it in a couple of weeks. My question is directed to all
panelists. What effect will the new understanding of HIV pathogenesis
have on the design of clinical trials?

       SAAG: I think it's already had an effect on clinical trials. As
you know, we've been measuring viral burden for the last 2 years and
assessing whether antiretroviral therapy has activity that's worth
pursuing. Sometimes we've seen dramatic activity, as with the protease
inhibitors, and sometimes we've seen virtually no activity, as with
recombinant soluble CD4 which we studied 2 years ago. So I think viral
burden measurement actually does 2 things. First, it tells us very
quickly which regimens are going to work and which ones aren't, as far
as anti-HIV activity. And that speeds drug development, which is
obviously critical. The second thing is that it tells us when a given
regimen is no longer working, which may be used in the future in
day-to-day clinical management. Right now that's a 'best guess' based
on CD4 cell count and overall clinical picture. In my opinion,
clinical trials in the future will be more geared towards following
viral burden and changing regimens based on viral burden, and away
from using an arbitrarily fixed time point, e.g., following a
population for 2-3 years to see what happens to them. I think we're
going to be much more physiologic in our assessment of drugs. Again,
that should speed drug development and ultimately improve patient
care.

       PAWTUCKET, RI: I have 3 questions. First, is 3TC being used at
all for monotherapy? Next, are there any new drugs other than
chemotherapy for treatment of Kaposi's sarcoma? Finally, I was
wondering if saquinavir would be available outside of clinical trials?

       THOMPSON: I can comment on a couple of these questions. 3TC is
available through expanded access. Many people take it as monotherapy
when they can't tolerate any of the other anti-HIV drugs. However, I
think that 3TC is going to be most helpful in combination. It's clear
from clinical trials that the combination is where it's at with 3TC.
HIV develops resistance very rapidly when exposed to 3TC alone. And
yet I would have to say that some patients clearly get clinical
benefit from being on only 3TC. The jury is still out, but I'd
certainly lay my bet on combination therapy for most patients who are
able to tolerate it.

       Regarding saquinavir, I don't think that we have a real clear
plan for expanded access yet. Drug production is a real problem; it's
very difficult to make. All the protease inhibitors are difficult to
make, and so providing a supply for the current clinical trials is the
priority of the company. But Roche is making plans for some sort of an
expanded access, possibly by the end of the year. They may have to do
some sort of screening in order to have enough drug for patients. I
think saquinavir is likely to be the first protease inhibitor that is
available through an expanded access program.

       As an element in combination therapy, saquinavir certainly
showed considerable activity in ACTG 229, which looked at triple
therapy with AZT, ddC and saquinavir, compared with 2-drug
combinations. The triple therapy arm clearly seemed better. I also
think that there is a formulation change in the works at Roche to
improve the bioavailability of saquinavir. Data was presented at this
conference showing that if you can get more of the drug in, then there
is more effect.

       BAKER: I can offer a little more information on the expanded
access program for saquinavir. Roche has been in contact with AIDS
community groups across the country about the upcoming expanded access
program for saquinavir. We're being told that approximately 4,000
people worldwide will be able to get the drug by July of this year. As
more drug becomes available, the number of people able to get the drug
will increase. Also, Roche announced a few months ago that it is the
company's intention to apply for accelerated approval of saquinavir
before the end of 1995.

       THOMPSON: I don't think we answered the question about KS and
treatments other than chemotherapy. Although I'm not going to answer
that question per se, I did want to mention DOX-SL or liposomal
doxorubicin [doxorubicin encapsulated in a liposome, or lipid bubble],
which is actually a type of chemotherapy. It's an old drug that's been
reformulated, and so far it is looking very good in clinical trials in
terms of having less toxicity, which with chemotherapy is our main
concern. There is considerable hope that DOX-SL will be less toxic
than the other regimens and that DOX-SL may be used alone. We
certainly have seen some significant improvement in KS lesions in
patients who are on DOX-SL alone.

       BRATTLEBORO, VT: I have a question about the HIV integrase
structure that was recently discerned, and also about possible
vaccines. What does the vaccine picture look like?

       SAAG: Integrase is an enzyme that is responsible for taking the
viral DNA (after HIV enters a cell and converts its viral RNA into DNA
by means of reverse transcriptase) and integrating it, or making it an
actual part of the host cell's DNA. There have been a lot of efforts
to crystallize the integrase enzyme and look at its structure.
Recently this was accomplished. It's an enormously important step
because once you identify the structure of an enzyme, you can identify
targets to attack that structure. Computer modelling allows us to
design drugs that actually interfere in a very rational way. I think
we should be seeing, hopefully, integrase inhibiting compounds coming
down the pipeline in the next 3-4 years.

       As far as therapeutic vaccines go, I'll be controversial. I
personally do not see any role for a therapeutic vaccine in HIV
disease, especially in light of all the new information that we're
seeing about viral turnover, that the virus is producing on the order
of 100-200 million new virions per day. I can't imagine that a single
injection of a protein is going to compare in any way to what the
virus is doing naturally in vivo every second of the day. I'm
underwhelmed by the clinical data, and I don't think we'll ever see
that a therapeutic vaccine will work, although I may be wrong.

       ANANDALE, VA: Earlier one of the physicians was talking about
advanced HIV. What do you consider advanced HIV? Would you consider an
individual who is free of any opportunistic infections but who has a
low CD4 cell count as advanced?

       SAAG: That's a great question. I'm glad you brought that up
because we tend to use terminology that really should be more clearly
defined. When I refer to any stage of HIV disease, I'm referring not
so much to the length of time that someone's been infected, but rather
to the relative ability of the immune system to continue to protect
the host from the opportunistic infections and other problems that
people get as their immune system weakens. Early infection, then,
basically means that a patient is asymptomatic and has relatively
normal CD4 counts, let's say above 400-500 cell/mm3. Middle stages of
disease would be more in the range of 150-300 cells/mm3. I would refer
to later stages of disease as having a CD4 count in the 25-200
cells/mm3 range. 'Advanced stages' in my terminology refers to someone
who has less than 25 CD4 cells/mm3. The reason I refer to patients
with advanced disease in that way is because they are at a much higher
risk of Mycobacterium avium disease [MAC], cytomegalovirus disease and
other problems such as wasting, which all occur with much greater
frequency as CD4 counts drift lower.

       But I think that the message is not to focus so heavily on CD4
count as on the quality of life. I've had plenty of patients who have
had low CD4 counts, and I'm talking less than 10 cells/mm3 for 2-3 or
even 4 years, who have gotten by pretty well. By my definition they
still have 'advanced disease,' but are nonetheless doing quite well. I
think our goal as treaters and clinicians is to make sure that
patients stay as healthy and as active as they possibly can for as
long as they can, regardless of whatever label is placed on them.
Those labels just help us anticipate what types of problems they may
have based on their CD4 count and on what we know about the natural
history of HIV disease.

       MIAMI, FL: What can you tell me about gene therapy?

       SAAG: Let me just try to give a general description of what it
is and predict what might happen in the future.

       When people refer to gene therapy, it's almost like referring
to the 'Star Wars' Strategic Defense Initiative: there's a lot of
logic behind the strategies, but not a whole lot of practical
experience or reality yet. Some aspects may pan out and some may not.

       The concept is to apply our knowledge of how HIV replicates.
Potentially, we could interfere with the activity of unique viral
genes in ways that are as varied as the ways these genes interact with
each other and with the host cell. So the idea, in very general terms,
is to design approaches to treatment that allow us to interfere with
the mechanisms of viral reproduction on a genetic level.

       In Birmingham, for example, we are currently working with a
drug called GEM 91, which is a kind of gene therapy. We're basically
using a small fragment of genetic material that can bind to the
genetic material [RNA] of HIV and hopefully shut down its replication.
GEM 91 exemplifies the general approach of gene therapy, but we've got
a long way to go before these things become available.

       VENTURA, CA: My question relates to viral burden. We always
make the assumption that the lower the viral burden, obviously the
better for the patient. In measuring the CD4 count, I've always found
that the best way to raise it was just to repeat the test or to send
the patient to another lab. What is the normal fluctuation in viral
burden in an untreated HIV positive patient over a period of several
years, particularly in somebody who already has progressive disease,
so that we know we're not just seeing normal variation? The second
part to the question is, if CD4 counts drop or CD4 cells are becoming
non-functional, can that in and of itself lower the measurable viral
burden in the serum?

       SAAG: You're asking a very good question. I think we need to
divide it up into a couple of segments. The first is how good is the
viral burden test itself. The test is actually quite good, using
either the PCR or the branched DNA method. If you take one sample,
split it up and run the same test over and over again, even in a
blinded fashion, the variability in the test is at most about 15-20%.
There's very little test-to-test variability for the most part, and
that's quite good.

       The second part of your question is how stable is the value in
an individual patient. Again, the test is actually quite good and the
value is quite stable over the short run. I'm talking about a period
of weeks or so, assuming that the patient hasn't gotten ill and that
the patient hasn't started new antiretroviral therapy. If someone gets
ill or receives a vaccine or takes IL-2 or something, viral burden
will increase. But assuming the patient is fairly stable, then viral
burden values are remarkably stable over the short run.

       Now the final part to the question is what about over time,
over a period of years. There is a very strong correlation between
viral burden and stage of disease. When somebody presents with acute
seroconversion, the viral burden is at its absolute highest'on the
order of several million to 20 million copies of virus per milliliter
of plasma, which is an enormous viral burden. Then when the patient's
immune system kicks in and they go to more quiescent or quiet stages
of disease for a period of years, the usual copy number is on the
order of 1,000-10,000, or perhaps 20,000, copies per milliliter. If
someone develops later-stage disease, the levels in that individual
are more on the order of 400,000-500,000 copies, and can be up to 1-2
million copies per milliliter.

       I think the take-home point is that these markers are a direct
reflection of antiviral activity. The CD4 count is as much a response
to viral infection as it is to antiviral activity. CD4 counts can vary
a bit partly because the test itself might have some problems every
now and then. But probably more often it's just that the immune system
is not a steady, static kind of thing. It's a very dynamic process
where the immune system is kicking out a billion new CD4 cells a day
and lots of things could have an effect on the absolute number of CD4
cells.

       BROOKLYN, NY: What about AZT in children under 3 years old?

       SAAG: Well, the general recommendation in children is to use
AZT. A couple of studies have nailed down the dose. AZT really is
effective in children. It comes as an elixir.

       There's actually something very important at this meeting that
we should mention with regard to kids about PCP prophylaxis. It was
said initially by Harold Jaffe, and has since been augmented by a
couple of other presentations. The new recommendation for treating
children born to HIV-infected mothers is to start all of them on PCP
prophylaxis from the time of birth until 6 months of age, at which
time you can be more confident that the child isn't HIV-infected
before you stop PCP prophylaxis. This is very important. Before, when
we waited for a magical CD4 count before starting PCP prophylaxis,
there was a lot of breakthrough PCP in kids, sometimes leading to
death. Now the recommendation is to use PCP prophylaxis across the
board for any child born to an HIV-infected mother, and to continue it
until either a PCR assay or a culture comes back negative at 6 months.
If it comes back positive and the child is infected, then you continue
PCP prophylaxis.

       BAKER: As many of you know and may have learned several months
ago, AZT use decreases transmission of HIV from mother to fetus or
mother to child among otherwise healthy HIV positive pregnant women.
Here at the conference this week a study was reported that suggests
that AZT is also effective in preventing HIV transmission from mother
to fetus or newborn among women who have very advanced HIV disease.

       PAWTUCKET, RI: I was curious if there was any information at
this conference on supportive, alternative or holistic therapies, or
acupuncture. Does anything in this arena sound hopeful?

       SAAG: There have been a few reports at this meeting about a
number of alternative therapy issues. I have to tell you I didn't
personally go to them so I don't feel comfortable commenting. The gist
of what I was hearing was that patients who smoke generally have more
difficulty than those who don't smoke. Exercise was generally
discussed as being a good thing for patients to do, but resistance
training is perhaps in some ways better than aerobic training. I'll
have to let Ron carry this further because I didn't go to that session
myself.

       BAKER: According to the abstract, lifting weight has a greater
benefit or a greater effect on increasing CD4 counts than running.

       SAAG: That was a study that was sponsored by Soloflex, I think.

       THOMPSON: Actually, in response to your question about
acupuncture, I don't have any data, but there is a study going on in
the CPCRA looking at acupuncture as a possible treatment for
peripheral neuropathy, which of course can be very painful. We don't
really have very good treatments for peripheral neuropathy. It
compares acupuncture to Elavil or amitriptyline.

       SOMERVILLE, MA: I believe that I've had HIV for 17 years. I've
had a CD4 count of 7 cells/mm3 for 3 years. I've never taken an
antiviral and I've been perfectly healthy. I'm curious what treatment
regimen we'd talk about at this point. Would anyone suggest that I try
antivirals?

       SAAG: Your situation illustrates a lot of very important things
about the natural history of this disease. One is that people can do
very well with HIV infection for a prolonged period of time. This
doesn't just apply to the 'long-term non-progressors' whom we've heard
so much about, who have normal CD4 cell counts after 10-15 years, but
also to many people who have very low CD4 cell counts. You say that
you've had very low CD4 cell counts, less than 10 cells/mm3 for 3
years, and remain healthy. I think we've all had that type of
experience with patients. Unfortunately, in our goal of preventing
complications and managing people's disease, we as physicians spend a
lot of time focusing on CD4 cells. But we need to remind patients that
CD4 cells are not the end-all, and that just because someone's CD4
cells are low doesn't automatically mean that bad things are going to
happen.

       As far as therapy is concerned, there's a lot that we don't
know about treating people with very advanced disease. My bias is that
there is still obviously an enormous amount of viral replication going
on. I encourage people who can tolerate therapy to be on as aggressive
an antiretroviral regimen as possible. In this day and age, that's
probably a combination that includes drugs like AZT and one of the
other nucleoside analogs, perhaps 3TC or d4T. I can't emphasize enough
the importance of the tolerance issue. It certainly isn't worth
impairing somebody's quality of life for the benefits we may gain from
the drugs that are available. So I think if an individual can tolerate
the form of therapy, they should probably be on it with the idea of
suppressing the virus and controlling the disease.

       LALEZARI: I agree that there's certainly room to negotiate and
tolerate a number of perspectives when it comes to anti-HIV therapies.
Your success speaks to the variability that's inherent in HIV disease.
One thing that I'd be concerned about is PCP prophylaxis; that's one
area where I tend to be a little less flexible with my patients in San
Francisco. Even though AZT et al have not really demonstrated much of
a survival benefit, there's no question that preventing PCP has had a
major impact on survival. I'm not sure from your question whether no
therapy meant no PCP prophylaxis. If nothing else, I ask that all my
patients who are at risk for PCP give Septra a try.

       THOMPSON: I'd have to agree with that. I also wanted to make a
point about viral burden and rapid turnover and the amazing immune
system activity that goes on constantly. I was very impressed by one
of the slides Dr. David Ho showed in his presentation several days
ago. People with advanced disease, meaning low CD4 cells, actually may
be producing 75 times as many CD4 cells as people in earlier disease.
The immune system is really cranking to try to control the virus.
Unfortunately, people in later disease usually have more virus. But I
think it really is encouraging that the immune system is still
actually working extremely hard, and perhaps we could intervene to get
the viral burden down and give the immune system a chance to control
the infection better than it's already doing, even in late-stage HIV
infection.

       I've been very encouraged by the fact that we've seen some
significant CD4 cell changes in people who have been on drugs like
protease inhibitors, even if they have advanced disease. I think it's
something that you have to consider very carefully and discuss with
your doctor. I wouldn't write off therapy at this point, especially as
we get newer drugs or combinations like AZT and 3TC. However, quality
of life is important. It would be a different story if you're not on
drugs because you have problems with them. I also would say we're
really talking about antiretroviral therapy and not about prophylaxis,
so I hope that you are taking prophylaxis for PCP.

       SAAG: No matter what infectious disease we're talking about,
the immune system is always our best drug. Always. And with HIV
disease it's no exception. When we give antiretroviral therapy, we're
just helping the immune system do its thing. We're giving support for
the infantry, and as long as the infantry is out there fighting, I
think we ought to do what we can to help support it. That's what
antiretroviral therapy is all about.

       I would also make a point about the survival advantage, which I
think is often overlooked. There is no question that from the early
trials back in 1986-87 of patients who had CD4 counts less than 200
cells/mm3 and who were randomized to receive either AZT or placebo,
there was a clear survival advantage'an unequivocal, absolute survival
advantage with antiviral therapy. So I would recommend at least trying
antiretroviral therapy if you haven't done so in the past. If you're
successful with it, I would continue. If you have toxicity, you can
try dose reduction or another agent. I would personally recommend
fairly strongly that you consider antiretroviral therapy.

       LALEZARI: When the Concorde study results from Europe came out,
there was a lot of debate about the value of AZT. The activist press
in San Francisco was very aggressive about putting AZT down. But I
really think that study and the reaction to it in some ways did a
disservice to the benefit our antiviral drugs can have for people with
AIDS. As Dr. Saag said, it's not a question of faith or belief'there
really is no doubt that antiretroviral drugs can prolong the quality
of life and survival in advanced HIV. In my practice, although all
therapy is negotiated, I tend to push to try to get my patients to at
least try those drugs.

       BAKER: Speaking of survival benefit, as many of you know,
several studies have been published over the last couple of years
which show that taking acyclovir in combination with anti-HIV
treatment has provided a significant survival benefit to patients. At
this conference we've heard different reports on that subject. I
wondered if any of our panelists would like to comment on this.

       LALEZARI: There have actually been 5 reports in the past
suggesting that there was a survival advantage with acyclovir. Doses
studied range from as little as 1,200 mg per day up to 3,200 mg per
day. This was observed in studies that really weren't designed to
directly ask whether acyclovir prolonged survival, but rather were
more incidental observations that were made at the end of the study.
If there's 1 area that I think is more confounded now, at the end of
the conference, it is the whole role of acyclovir in the treatment of
HIV.

       The ACTG presented their large multicenter study specifically
and prospectively looking at the question of whether acyclovir
provided a survival advantage. There are all sorts of confounding
aspects to the study that make it difficult to understand. The bottom
line is that the study did not show any survival advantage, or even
any trend toward a survival advantage, with the use of acyclovir. I
believe the dose was 4 grams per day. The problem is that the study
specifically excluded patients who might require frequent acyclovir
treatment or prophylaxis because of frequent occurrences of herpes
(HSV). So by the design of the study they may have ended up excluding
the very patients that were deriving the benefit that was observed
retrospectively in the 5 other studies.

       BAKER: They were excluding patients with herpes simplex?

       LALEZARI: Yes, or those who were taking acyclovir
prophylactically to prevent frequent herpes recurrences. Related to
this, there were a couple of other posters and presentations at the
conference that showed a very interesting relationship between the
activation of herpes and the cross-activation of HIV. Specifically,
when someone had an outbreak of HSV there was a very sharp temporally
related increase in the amount of HIV in the blood that tended to
fairly rapidly subside with the onset of acyclovir therapy. So there's
at least some evidence in some patients that HSV is turning on HIV. It
provides a very nice rationale for why acyclovir might provide a
survival advantage in HIV disease. You have these 5 other studies
which retrospectively and incidentally suggested a benefit from
acyclovir. I think we're walking away from this conference not really
knowing what to do about the issue of acyclovir.

       THOMPSON: I'm not sure that we'll ever really know the answer
to that question. At the CPCRA we've been talking about how to design
a study that might answer that question, but we keep running into
problems. For example, if you consider a very traditional,
prospective, placebo-controlled study of acyclovir, then you might
have to exclude people who have herpes and run into the same problems
as the study we just discussed.

       LALEZARI: I still believe that acyclovir provides a survival
advantage. I don't believe the study presented today precludes that
possibility, particularly now that we can see that there's a dramatic
correlation between the activation of HSV and the activation of HIV. I
think that this provides a very solid rationale for taking acyclovir
prophylactically. I don't think that just because 1 large study
doesn't show a benefit, that's any reason to dismiss the notion.

       BAKER: I would agree. The weight of the evidence so far
suggests that acyclovir does provide a survival benefit in people who
are also taking anti-HIV treatment such as AZT, d4T or ddI.

       This might be a good note on which to close today. The next
BETA LIVE! teleconference will take place in early March. The subject
will be 'Immune-Based Therapies in AIDS.' These teleconferences will
air on Tuesday, March 7th and again on Thursday, March 9th. Please
call 800-707-BETA for the exact times of these teleconferences in your
time zone.

       ***************
       Research Notes Harvey S. Bartnof, MD

       Dr. Bartnof is a clinical faculty member at the University of
       California at San Francisco School of Medicine where he has
       been Course Director of 'AIDS-HIV: Overview and Update' since
       1985. Dr. Bartnof has been a member of the San Francisco AIDS
       Foundation Scientific Advisory Committee since 1987.

       Treatment for HIV

       HIV Positives Produce 100 Million to 1 Billion New HIV
Particles Daily and 2 Billion New CD4 Lymphocytes Daily

       Researchers suggest that HIV treatment:

        should start soon after initial HIV infection,

        should be measured for effectiveness within days,

        should occur at all stages of HIV infection,

        should include a combination of anti-HIV drugs.

       Two prominent research groups have determined that people
infected with HIV produce 100 million to one billion individual HIV
virus particles (virions) each day. They also have measured that HIV
positive individuals produce an average of 2 billion CD4 lymphocytes
daily. Their studies indicate that the human immune system is able to
respond significantly in attempting to fight off HIV.

       David Ho, MD, and colleagues from the Aaron Diamond Research
Center at the New York University School of Medicine represent the
first group. Drs. Xiping Wei, Michael Saag, George Shaw and colleagues
from the University of Alabama School of Medicine represent the second
group. The 2 research teams have reported their landmark findings in
the January 12, 1995 issue of Nature. The 2 groups were able to make
their determinations on the basis of mathematical calculations during
drug therapy trials of HIV positive patients. Each research group
arrived at essentially the same numerical conclusions.

       Dr. Ho's group enrolled 20 HIV positive patients with a
pretreatment mean CD4 cell count of 180 cells/mm3 and a mean viral
load of 134,000 virions per milliliter (ml). All 20 patients were
given the experimental protease inhibitor ABT-538 in doses of
600-1,200 mg daily. Within a 2-week period, every patient had a rapid
decline in plasma viremia, with a mean reduction of 66-fold (range 11-
to 275-fold reduction). This represents a mean reduction equivalent to
98.5% inhibition.

       The loss of virus particles ('decay slope') led to the
calculation of the half-life of an HIV virion to be from 1.3 to 3.3
days. Half-life is the amount of time required for half of an original
amount to be destroyed or broken down. This number indicates that half
of the blood plasma virus particles turn over every 2 days, on
average. This translates into a daily production and clearance rate of
a mean 680 million HIV particles (+/- 13 million). The researchers
infer that almost all (98.5%) of plasma virus particles in the blood
at any given time are new and have come from recently infected cells.
(Note: due to resistance, the virus levels returned to their
pretreatment levels within a short time.)

       Dr. Ho's group also was able to determine the rapid turnover of
the CD4 lymphocyte pool in blood plasma. They calculated that before
treatment with the protease inhibitor, the entire population of blood
CD4 lymphocytes completely turns over in approximately 15 days
('doubling time'). That fact led them to state that 'the CD4
lymphocyte depletion seen in AIDS is primarily a consequence of the
destruction of these cells, not a lack of their production.'

       After the ABT-538 therapy was given, a reduction in
virus-induced destruction of CD4 lymphocytes occurred. This led to a
temporary increase in the CD4 cell numbers (as in most anti-HIV
therapies). The observed increases in CD4 cells allowed the authors to
calculate the pretreatment CD4 lymphocyte production rate. They found
that the minimum numbers of blood CD4 cells manufactured and destroyed
daily are a mean 35 million (range 4 to 108 million). Since the blood
lymphocyte pool has been calculated to be 2% of the total body
lymphocyte population, this translates into an overall daily
production and destruction of 1.8 billion CD4 lymphocytes in each
patient.

       The report stated that the calculations provide significant
insights into the understanding of HIV and CD4 cell kinetics. They
made an analogy of the CD4 cell depletion in HIV/AIDS to a sink with a
tap and a drain, wherein the tap represents wide-scale lymphocyte
production, the drain represents wide-scale lymphocyte destruction and
the sink water represents the pool of CD4 lymphocytes. Dr. Ho states:

       'The CD4 lymphocyte depletion seen in advanced HIV-1 infection
may be likened to a sink containing a low water level, with the tap
and drain both equally wide open. As the regenerative capacity of the
immune system is not infinite, it is not difficult to see why the sink
eventually empties...(the) primary strategy to reverse the
immunodeficiency ought to be to target virally-mediated destruction,
i.e., plug the drain rather than to emphasize lymphocyte
reconstitution, i.e., put in a second tap.'

       Dr. Ho and his colleagues conclude that, 'Treatment strategies,
if they are to have a dramatic impact, must therefore be initiated as
early in the infection course as possible, perhaps even during
seroconversion...Replication of HIV-1 in vivo is continuous and highly
productive, driving the rapid turnover of CD4 lymphocytes. (This)
rapid turnover of HIV-1 in plasma also suggests that current protocols
for monitoring the acute antiviral activity of novel compounds must be
modified to focus on the first few days following drug initiation.'

       Dr. Wei's study enrolled 22 HIV positive subjects with a mean
pretreatment CD4 lymphocyte count of 102 cells/mm3. The mean entry
plasma viral load (RNA) was 5 million particles/ml. Eighteen patients
were treated with an HIV protease inhibitor, either ABT-538 or
L-735,524, and 4 were treated with the reverse transcriptase inhibitor
nevirapine (NVP) as part of Phase I/IIA clinical trials. Within 2 to 4
weeks, the plasma RNA levels fell with a mean 90-fold reduction for
each of the ABT-538 and L-735,524-treated patient groups and a mean
60-fold reduction for the NVP-treated patients. This represents an
average decrease in plasma virus of 99%.

       Just as the Ho group found, Dr. Wei's group determined that the
lifespan of plasma virus was rather short: a half-life of
approximately 2 days. They found no differences in the viral clearance
rates between the 3 different treatment groups. There was also no
correlation between the rate of viral clearance from blood and either
baseline CD4 lymphocyte count or baseline viral RNA load. They
conclude that the pretreatment wild type virus in plasma was
completely replaced by drug-resistant variants after only 14 to 28
days.

       Their calculations allowed them to estimate the half-life of
peripheral blood mononuclear cells, which include all lymphocytes,
monocytes and basophils. (Lymphocytes and monocyte/macrophages
represent major reservoirs for HIV.) Since the half-life of those
white cells was estimated to be approximately 50-100 days, they
conclude that blood lymphocytes and monocytes do not contribute much
virus to the blood plasma viral load. Instead, other mononuclear cells
within the lymph organs must be the major source of virus production,
the researchers believe. They calculated that the lifespan of those
(non-blood) virus-producing white cells was approximately 2 days, the
same as the HIV virion lifespan. Just like Dr. Ho's group, the Wei
group calculated that the CD4 lymphocyte cell turnover rate is 2
billion produced and destroyed daily.

       Dr. Wei's group also conclude that 'HIV-1 viremia is sustained
primarily by'continuous rounds of'virus infection and replication and
rapid cell turnover.' Also, they suggest the 'possibility of
successful immunological reconstitution even in late-stage (HIV)
disease if effective control of viral replication can be sustained.'

       Dr. Simon Wain-Hobson from the Institut Pasteur in Paris,
France, reviewed the 2 articles for Nature. He points out:

       'Given that the virus is replicating 24 hours a day from day
one (after initial infection), anti-viral treatment is called for at
all stages of disease. Any means to reduce viral spread will
ultimately be beneficial. (Since) an asymptomatic patient can harbor
at least a million genetically distinct variants of HIV, and for an
AIDS patient the figure is more than a billion...monotherapy cannot
succeed'only combinations of drugs have the potential to outgun the
virus.'

       References

       Ho DH and others. Rapid turnover of plasma virions and CD4
       lymphocytes in HIV-1 infection. Nature 373: 123-126. January
       12, 1995.

       Wei X and others. Viral dynamics in human immunodeficiency
       virus type 1 infection. Nature 373: 117-122. January 12, 1995.

       Wain-Hobson S. Virological mayhem. Nature 373: 102. January 12,
       1995.


       Slower HIV Progression Rate with AZT/ddC Combination Therapy

       Margaret Fischl, MD, and her colleagues with the AIDS Clinical
Trials Group (ACTG), under the auspices of the National Institute of
Allergy and Infectious Diseases (NIAID) have reported on the
beneficial effects of combination therapy of AZT (zidovudine,
Retrovir) with ddC (zalcitabine or Hivid) versus monotherapy with
either. Their report has been published in the January 1, 1995 issue
of Annals of Internal Medicine.

       The trial was randomized, double-blind and controlled. Study
participants included 1,001 patients with either symptomatic HIV
disease and 300 or fewer CD4 cells cells/mm3 or asymptomatic disease
and 200 or fewer CD4 cells cells/mm3 who had tolerated AZT for 6 or
more months. Patients were randomized to receive monotherapy of either
AZT 600 mg/day or ddC 2.25 mg/day, or combination therapy with both.
The primary endpoint of the study was time to disease progression or
death.

       The median follow-up time was 17.7 months. The 12-month
event-free rates were 70%, 67% and 73%, respectively, for the AZT, ddC
and combination groups. However, a trend analysis showed significantly
slower progression rates for combination therapy compared with AZT
monotherapy as the pretreatment CD4 cell count increased. For patients
with 150 or more CD4 cells cells/mm3, those who received combination
therapy were half as likely (relative risk 0.51) to have disease
progression or to die than were those who were receiving AZT
monotherapy. There were no observed differences between the AZT and
ddC monotherapy groups. For patients with 50-100 CD4 cells cells/mm3,
there were no observed differences among the 3 groups. Severe toxic
effects were observed less frequently among patients with 150 or more
CD4 cells cells/mm3.

       The authors conclude that even though there were no overall
observed statistical benefits of ddC used alone or with AZT, a trend
analysis suggested a better outcome for combination therapy compared
with monotherapy, as the pre-treatment CD4 cell count increased.

       Reference

       Fischl MA and others. Combination and monotherapy with
       zidovudine and zalcitabine in patients with advanced HIV
       disease. The NIAID AIDS Clinical Trials Group. Annals of
       Internal Medicine 122(1): 24-32. January 1, 1995.


       Prolonged d4T Therapy Causes Less HIV Resistance than AZT

       d4T (stavudine or Zerit) was recently licensed by FDA for
people with AIDS who are failing or are intolerant to approved
antiretroviral therapies. However, its true location in the anti-HIV
armamentarium is not yet known. Researchers at the Bristol-Myers
Squibb Pharmaceutical Research Institute in Connecticut reported in
the November 1994 Journal of Infectious Diseases a relatively low rate
of resistance developing among patients treated with d4T monotherapy.
The development of HIV resistance has been a problem in AIDS patients
treated with AZT.

       A total of 13 HIV positive patients were treated with d4T
monotherapy for 18-22 months. An analysis of the pre- and
post-treatment pairs of HIV isolates from 11 of the patients indicated
only 2 with a decreased sensitivity to d4T. This was seen even though
genetic analyses revealed mutations in the reverse transcriptase gene
from all 13 pairs of isolates. The authors note that the low frequency
and modest degree of change in d4T sensitivity after prolonged therapy
was significantly encouraging.

       Reference

       Lin PF and others. Genetic and phenotypic analysis of human
       immunodeficiency virus type 1 isolates from patients on
       prolonged stavudine therapy. Journal of Infectious Diseases
       170(5): 1157-1164. November 1994.


       Initial Therapy: AZT Better than ddC for Daily Functioning

       In the 1990s, more clinical studies include patient daily
functioning in their outcome measurements, in an attempt to determine
quality of life while on therapy, in addition to the usual endpoints
of disease progression, toxicities, CD4 cell count changes, etc. The
Roche 3300/ACTG 114 Study Group did just that in a trial comparing AZT
(zidovudine, Retrovir) with ddC (zalcitabine, Hivid) as the initial
therapy for HIV disease. The report was published in the January 25,
1995 issue of the Journal of the American Medical Association. The
lead author is Samuel A. Bozzette, MD.

       The randomized controlled multicenter trial included 338 HIV
positive participants with CD4 cell counts <200 cells/mm3 and a
history of Pneumocystis carinii pneumonia (PCP) or symptoms of HIV
infection. The 76-week observation period allowed comparison of: (1)
ddC 0.75 mg every 8 hours plus inactive capsules identical in
appearance to AZT to (2) AZT 200 mg (later changed to 100 mg) every 4
hours plus inactive tablets identical in appearance to ddC.

       The main outcome measurements included the periodic completion
of self-reported symptoms, disability, work, functioning and
utilization. More specific questions were asked about: days feeling
less well than usual, days of reduced activity, bed days, days of work
missed and earned income.

       The results indicated that participants who took ddC reported
greater than 40% more symptoms that interfered with activity and
greater than 50% more disability days than participants who took AZT.
In addition, ddC recipients had a 7% lower employment rate and a 35%
lower monthly income than their AZT counterparts. ddC recipients also
were twice as likely to undergo an invasive procedure or to be
admitted to the hospital than were AZT recipients.

       The authors conclude that AZT has significant advantages over
ddC in the initial monotherapy of AIDS in terms of functional status
outcomes, including symptom impact, work, disability, utilization and
health status. They also state that including daily functional
outcomes as endpoints can improve the information available from
clinical drug trials.

       Reference

       Bozzette SA and others. Health status and function with
       zidovudine or zalcitabine as initial therapy for AIDS. Journal
       of the American Medical Association 273(4): 295-301. January
       25, 1995.


       Is Triple Therapy Better than Double Therapy?

       The ACTG 241 protocol team has announced the interim results of
a Phase II randomized, multicenter, double-blind clinical trial
designed to compare the laboratory and clinical effects of triple
anti-HIV therapy with double therapy. The 3 drugs used were all
reverse transcriptase inhibitors. The 3-drug arm included nevirapine
(NVP 400 mg/day), AZT (600 mg/day) and ddI (400 mg/day). The 2-drug
arm included AZT and ddI, each using the same doses as in the triple
therapy arm, plus a placebo (i.e., each group received 3 agents).
There were 398 enrollees in the study. Entrance criteria included CD4
cell counts ≤350 cells/mm3 and ≥6 months prior nucleoside therapy with
either AZT, ddI or ddC. The median duration of prior nucleoside analog
(reverse transcriptase inhibitor) therapy was 25 months.

       Primary measures for comparing the 2 treatment arms included:
time to HIV progression or death; long-term changes over 48 weeks in
CD4 cell counts, p24 antigenemia and viral infectivity in mononuclear
cells and; adverse effects. Long-term changes in plasma viral load
were also considered.

       At the 48-week analysis point, the triple therapy group had CD4
cell counts which were 25% higher than those in the double therapy
group; a similar benefit was noted in increased CD4 cell percentage.
Regarding viral infectivity in mononuclear cells in vitro, the triple
group had a 50% lower rate than the double group. The lowered viral
infectivity rate was sustained over the 48-week period. Regarding
viral load, the triple group had a statistically significant lower
plasma HIV-1 RNA copy number than the double group within 8 weeks,
although the difference decreased over time. At the 48-week mark,
there were no significant differences between the 2 groups in levels
of viral load, serum p24 antigen changes or in disease progression.
The authors note that the study was not designed to have high enough
statistical power to detect differences in clinical progression
between the 2 treatment arms. There were no significant differences in
death rate between the 2 groups, which were 2% vs 1% for the triple-
and double therapy groups, respectively. The triple therapy group had
a greater prevalence of severe rashes (8%) compared to the double
therapy group (2%). However, there were no significant differences in
the rates of other side effects or toxicities between the 2 groups.
The authors conclude that the triple therapy regimen with reverse
transcriptase inhibitors (NVP plus AZT plus ddI) is associated with
better immunologic and virologic activity than the double therapy
regimen (AZT plus ddI) in patients with moderately advanced HIV
infection and prolonged prior nucleoside analog therapy. They also
note that another triple therapy Phase II trial led to similar
results. ACTG 229 had 3 arms: AZT plus ddC; AZT plus saquinavir
(Invirase, a protease inhibitor); or AZT plus saquinavir. They also
indicate that the results should not lead to any recommendations for
changing current anti-HIV therapeutic regimens or any current adult
ACTG trials, including ACTG 193A and 244.

       Reference

       ACTG 241 Trial Protocol Team. ACTG 241: Executive Summary,
       pages 1-14. November 16, 1994.

       Hydroxyurea Synergistic with ddI, AZT and ddC

       Three research reports published in the medical literature in
October and November 1994 have examined an increased anti-HIV effect
in vitro by combining hydroxyurea with either AZT, ddI or ddC.
Hydroxyurea is an FDA-approved therapy used as an adjunctive aid for
treating several different types of cancers. It is relatively
inexpensive and has good oral bioavailability. Robert Gallo, MD, from
the National Cancer Institute addressed the feasibility of hydroxyurea
as an anti-HIV compound in plenary sessions at the last 2
International AIDS Conferences.

       The first report appeared in the journal Science in November
1994, authored by Drs. Franco Lori, Gallo and co-workers. They
describe the mechanism of hydroxyurea's action as inhibition of DNA
synthesis by blocking the enzyme ribonucleotide reductase. In
peripheral blood lymphocytes, hydroxyurea inhibits HIV-1 DNA synthesis
by limiting the number of available DNA building blocks
(deoxynucleotides). Hydroxyurea has been shown to block HIV-1
replication in vitro in acutely infected lymphocytes and macrophages.
In addition, it will block HIV-1 replication in vitro in lymphocytes
infected in vivo before removal from an a person with AIDS. They note
that the inhibitory concentration of hydroxyurea is less than that
required for its established anti-cancer effect. Combining hydroxyurea
with ddI produced a synergistic (multiplied effect) anti-HIV effect
than with either alone, without increasing toxicity. In some cultures
the inhibitory effect lasted for several weeks, even after suspending
the hydroxyurea treatments.

       The second report appeared in the Proceedings of the National
Academy of Sciences in November 1994. The research group from the
Institut National de la Sante' in Lyon, France was headed by Dr. Serge
Malley. The researchers performed in vitro studies of the anti-HIV
effects on lymphocytes of several reverse transcriptase inhibitors
(AZT, ddI, ddC) alone or in combination with either hydroxyurea or
other hydroxyamates. They found a synergistic anti-HIV effect when
combining ddI with any of the hydroxyamates, including hydroxyurea.
The 2 drugs together also prevented HIV-cytopathic effects without
altering the lymphocyte's ability to replicate.

       The third report appeared in Molecular Pharmacology in October
1994, by Dr. Wen-Yi Gao and colleagues from the Experimental
Retrovirology Section of the National Cancer Institute. They also
found synergistic anti-HIV effects in vitro, using hydroxyurea and
each of the reverse transcriptase inhibitors. They documented the
greatest inhibitory effect when combining hydroxyurea with ddI, with
lesser inhibitory effects when combining hydroxyurea with either AZT
or ddC.

       The authors of all 3 studies indicate that reducing the number
of DNA building blocks (deoxynucleotide triphosphate levels)
represents a potential therapeutic approach for HIV treatment and that
initial Phase I trials combining hydroxyurea with ddI are indicated.
In vitro effects may or may not translate into clinical benefits in
vivo, and toxicities and/or side effects are possible and even
probable. Hydroxyurea has also been in the news recently for having
been shown to be an effective treatment to prevent the pain crises in
sickle cell anemia.

       References

       Lori F and others. Hydroxyurea as an inhibitor of Human
       Immunodeficiency Virus-type 1 replication. Science 266(5186):
       801-805. November 4, 1994.

       Malley SD and others. Synergistic anti-human immunodeficiency
       virus type 1 effect of hydroxyamate compounds with
       2',3'-dideoxyinosine in infected resting human lymphocytes.
       Proceedings of the National Academy of Sciences 91(23):
       11017-11021. November 8, 1994.

       Gao WY and others. Anti-human immunodeficiency virus type 1
       activity of hydroxyurea in combination with
       2',3'-dideoxynucleosides. Molecular Pharmacology 46(4):
       767-772. October 1994.


       AZT Has Beneficial Effect on CD8 T-cell Anti-HIV Activity

       Carl Mackewicz, MD, Jay A. Levy, MD, and colleagues from the
University of California at San Francisco School of Medicine have
measured a finite beneficial effect of AZT (zidovudine, Retrovir) on
CD8 T-cell anti-HIV activity. The report was published in the October
1994 issue of Clinical Immunology and Immunopathology. Dr. Levy's
laboratory group has determined that the CD8 T-cell population
produces a soluble factor that helps suppress HIV replication.
Extremely difficult to isolate, the factor appears strong early in the
course of HIV disease (asymptomatic phase) and in certain long-term
non-progressors.

       The researchers evaluated the CD8 anti-HIV effect over 1-2
years in vitro from 12 HIV-infected individuals (11 men and 1 woman)
who were receiving daily AZT therapy. The mean CD4 lymphocyte count
was 224 cells/mm3. The control group consisted of 9 untreated HIV
positive individuals with a mean CD4 lymphocyte count of 647 cells/mm3
(range 194-198 cells/mm3). In the 12 AZT-treated patients, the CD8
anti-HIV activity increased 6.6-fold above pre-treatment levels. In 6
of the subjects the increases were transient, returning to
pretreatment levels or lower during the observation period. In 4
subjects, the increase persisted throughout the observation period.
The average level of CD8 anti-HIV effect for all 12 subjects during
the 1-2 year period was more than a 2-fold increase above baseline,
compared with a more than 3-fold reduction in CD8 anti-HIV effect in
the control group. The results are quite significant, considering that
the mean entry CD4 count for the control group was much greater than
the AZT-treated group.

       Untreated individuals sustained a gradual reduction in the CD8
anti-HIV effect over time, reaching as low as a 16-fold reduction. In
the AZT-treated group, the changes in CD8 response did not correlate
with either changes in the CD4 or CD8 T-lymphocyte number or
percentage. The research team also found that the CD8 anti-HIV
activity could not suppress HIV replication when AZT resistance was
present.

       The authors conclude that AZT can mediate an increase in the
CD8 anti-HIV effect in vitro, even if the increase is only temporary.

       Reference

       Mackewicz CE and others. Effect of zidovudine therapy on CD8
       t-cell anti-HIV activity. Clinical Immunology and
       Immunopathology 73(1): 80-87. October 1994.

       New Drugs Effective against AZT-Resistant HIV

       Dr. Douglas Mayers and colleagues from the Walter Reed Army
Institute of Research have reported in the January 3, 1995 Proceedings
of the National Academy of Sciences that a novel class of anti-HIV
drugs appear to be effective in blocking replication of AZT-resistant
HIV-1 strains in vitro. The class of drugs, called the
3-deazanucleosides, are molecularly-altered versions of nucleoside DNA
analog building blocks and belong to the same broader class of drugs
that includes AZT, ddC, ddI and d4T. The 2 drugs they tested in vitro
included DZNep (3-deazaneplanocin A) and plain neplanocin A. The
experiments examined the effects of either drug on paired HIV-1
isolates drawn from blood samples of HIV-infected patients, before and
after they were treated with AZT. When compared to their anti-HIV
effectiveness in vitro on isolates from patients before AZT treatment,
their anti-HIV effectiveness in vitro on isolates from patients after
AZT treatment indicated an increase of 3- to 18-fold in their potency
against AZT-resistant HIV-1 isolates. The authors conclude that the
3-deazanucleoside drugs belong to an unusual class of anti-HIV drugs
which have unique abilities to block growth of HIV resistant to AZT.
This new class may have significant importance if these beneficial
therapeutic effects can also occur in vivo, without toxicities.

       Treatment of AZT-resistant virus is becoming an increasing
problem in the HIV pandemic. Recent studies indicate that
approximately one-fifth of newly infected persons carry AZT-resistant
strains of HIV.

       Reference

       Mayers DL and others. Anti-human immunodeficiency virus 1
       (HIV-1) activities of 3-deazaadenosine analogs: increased
       potency against AZT (3' -azido-3' -deoxythymidine)-resistant
       HIV-1 strains. Proceedings of the National Academy of Sciences
       92(1): 215-219. January 3, 1995.


       Laboratory Markers Predicting Future Risk of Developing
       Kaposi's Sarcoma

       Drs. Philip Browning, Robert Gallo and colleagues from the
National Cancer Institute have reported on the presence of Kaposi's
sarcoma-like spindle cells circulating in the blood of 25 HIV positive
homosexual men with KS and in 27 HIV positive homosexual men without
clinical KS. Their research appears in the October 15, 1994 issue of
Blood. They found that the number of KS-like spindle cells in
circulating blood from gay men with clinical KS was increased 78-fold
when compared with HIV negative controls. Also, the number of KS-like
spindle cells from gay men without KS lesions was increased 18-fold
when compared with HIV negative controls. The percentage of such cells
from the blood of HIV positive heterosexual injection drug users (men
and women at low risk for KS) and HIV-negative controls (men and
women) was very low and not significantly different.

       Kaposi's sarcoma represents the most common proliferative
(cancer-like) condition in AIDS. In epidemiologic studies,
AIDS-related KS has been closely linked with a sexually transmitted
cofactor. AIDS-related KS occurs most commonly among men with a
history of gay/bisexual sexual contact, somewhat less commonly among
the female sexual partners of bisexual men, and least commonly among
other heterosexually transmitted AIDS cases, blood component
recipients and pediatric AIDS cases. Recently, a herpes-like viral
component was isolated from AIDS-related KS cells. (See BETA Treatment
Alert, December 20, 1994 and, in this issue of BETA, Treatment
Updates, page 10.)

       The abnormal cell in KS is felt to be the spindle cell,
associated with an abnormal proliferation of blood vessels. The
researchers found adherent-cells with a spindle shape and many
characteristics of the Kaposi's sarcoma spindle cell among circulating
mononuclear cells in the blood of people with AIDS and KS. After first
culturing these cells, they determined that the cells produced a blood
vessel growth factor. This was shown when the culture fluid containing
the growth factor was able to promote growth of normal vascular
endothelial (blood vessel lining) cells in vitro. The same fluid
produced angiogenesis (new blood vessel growth) when injected
subcutaneously into athymic nude mice, an animal model for KS.

       The findings are significant in that a laboratory blood test
eventually could be developed to identify individuals at imminent risk
of developing KS lesions. Theoretically, such individuals could then
take a prophylactic therapy to prevent KS from developing. First,
however, the findings would need to be expanded to larger numbers of
patients. Also, natural history studies would need to take place to
confirm a progressive increase over time in the number of KS-like
spindle cells circulating in the blood of men who thereafter develop
clinical KS. Such studies could be performed retrospectively from
stored blood samples of patients enrolled in natural history studies.
The sensitivity and specificity of the findings also would need to be
determined to rule out false negative and false positive results. The
findings also add to the evidence that AIDS-associated KS is a
systemic disease, even in those individuals who have only 1 or 2 KS
lesions.

       Reference

       Browning PJ and others. Identification and culture of Kaposi's
       sarcoma-like spindle cells from the peripheral blood of human
       immunodeficiency virus-1-infected individuals and normal
       controls. Blood 84(8): 2711-20. Oct 15, 1994.


       Predicting Future Risk of CMV Retinitis

       Researchers from Denmark have determined that the presence of
cytomegalovirus (CMV) DNA in blood, as measured by polymerase chain
reaction (PCR), is a good predictive marker of future CMV retinitis, a
severe AIDS condition that often causes blindness. The authors
measured CMV DNA from 5 consecutive blood serum samples drawn from 52
HIV positive patients. Nineteen of the 52 had a clinical diagnosis of
CMV retinitis at some point. The report has been published in the
November 1994 issue of Journal of Infectious Diseases. The lead author
is Dr. K. Hansen.

       The researchers found that the presence of CMV DNA in serum
preceded development of clinical disease. Eleven patients who
developed CMV retinitis were positive for CMV DNA in serum 3 months
prior to developing CMV retinitis. Three retinitis patients who
initially were negative for CMV DNA became positive at the onset of
their retinitis. In contrast 29 of 33 HIV positive patients without
clinical retinitis (matched for age and CD4 cell counts) were negative
for CMV DNA in all 5 of their consecutively drawn blood serum samples.

       The authors indicate that the presence of CMV DNA in the serum
of HIV positive patients supports the clinical diagnosis of and is a
predictor of CMV retinitis. The study would need to be expanded to
larger numbers of patients followed over even longer time periods to
determine the true sensitivity and specificity of the test. (See BETA
Bulletin, October 21, 1994, regarding prophylaxis for CMV retinitis
with oral ganciclovir.) The authors also indicate that the test might
be used to monitor the efficacy of anti-CMV therapy, with an expected
decrease in CMV DNA.

       It should be noted that most gay/bisexual men with HIV
infection are already infected with CMV, as measured by blood antibody
tests, specifically IgG (immunoglobulin class G). However, a DNA test
would not be expected to be positive unless a CMV-infected person had
a chronic CMV infection or unless the person had severe
immunosuppression associated with HIV disease. Persons with HIV due to
other transmission risks would be expected to have a lower prevalence
of past CMV infection. The immune globulin test (IgG) for CMV, if
positive, would indicate past or ongoing infection. If the CMV IgG
test is negative, then a CMV DNA test would be expected to be negative
(unless CMV infection was very recent and the immune system had not
yet manufactured enough CMV antibodies to result in a positive IgG
test).

       Reference

       Hansen KK and others. Detection of cytomegalovirus DNA in serum
       correlates with clinical cytomegalovirus retinitis in AIDS.
       Journal of Infectious Diseases 170(5): 1271-1274. November
       1994.


       Treatment for Opportunistic Infections Eye Implant of Ganciclovir
       Effective in Treating CMV Retinitis

       A study of an experimental eye implant device manufactured by
Chiron Corporation for the treatment of CMV retinitis was reported by
researchers at the National Eye Institute, a part of the National
Institutes of Health (NIH) in the December 1994 issue of Archives of
Ophthalmology. The device delivers a steady flow of ganciclovir
(Cytovene) into the eye to provide high levels of drug directly to the
end-organ, the retina, or back of the eye, thereby helping to prevent
blindness. The device would not be expected to prevent or treat CMV at
other locations in the body, but the retina is the most common
end-organ in the body to be affected by CMV in HIV positive patients.

       The study was randomized and controlled. Patients with
previously untreated CMV retinitis were randomly assigned to either an
immediate (treatment with the device) group or a deferred (treatment
with the device) group. Every 2 weeks, retinal photographs were taken
and analyzed anonymously. The endpoint of the study was retinitis
progression based upon photograph analysis.

       Twenty-six (26) patients enrolled, with a total of 30 eyes with
an initial diagnosis of CMV retinitis (4 patients had both eyes
affected). Throughout the study, a total of 39 first-time implants and
12 exchange implants were placed into immediate treatment eyes,
deferred treatment eyes that progressed and opposite-side eyes that
developed CMV retinitis.

       The treatment group experienced a significant delay to
progression of retinitis disease. The median time to progression in
the immediate treatment group was 226 days (14 patients) compared to
15 days in the deferred treatment group (16 patients). This is
significantly better than time-to-progression studies with intravenous
(IV) ganciclovir or foscarnet, approximately 7 weeks for either.

       Vision was near normal (20/25) or better at the end of the
study in 34 of 39 treated eyes. The median survival was 295 days in
patients treated with the implant(s). Complications after the implants
included 7 sight-threatening retinal detachments and one retinal tear.
This is not significantly different from the incidence of retinal
detachments in natural history studies of untreated CMV retinitis.

       The calculated risk of developing CMV retinitis in the
opposite-side eye was 50% at 6 months. CMV developed in other organs
in 8 of 26 (31%) patients, verified by biopsy. To help prevent further
spread of CMV, some physicians may choose to treat with systemic
therapy in addition to the implants. Syntex Corporation is currently
involved in studies to evaluate the utility of systemic therapy
addition to the implants. Syntex is currently seeking patients who may
desire to enroll in a study using the implant in addition to oral
ganciclovir therapy for CMV retinitis. For more information,
interested persons may call Syntex (415-855-6021). Even though the
implant is not yet approved by the FDA, Chiron has permission on an
experimental basis to make the eye implant available to people with
AIDS who have failed or are intolerant to either IV foscarnet or IV
(or oral) ganciclovir. Chiron's phone number is 800-CHIRON-8. (See
related article in this issue of BETA, Treatment Updates, page 12.)

       Reports of injecting ganciclovir directly into the eye to treat
CMV retinitis have appeared in the medical literature since 1990. It
is clear that prevention and treatment of HIV-related CMV disease,
particularly retinitis, is making significant strides.

       Reference

       Martin DF and others. Treatment of cytomegalovirus retinitis
       with an intraocular sustained-release implant. Archives of
       Ophthalmology 112(12): 1351-1359. December 1994.


       Bacterial Bronchitis in HIV Positive Patients

       Dr. Abraham Verghese and colleagues from the Texas Technology
University Health Sciences Center have reported that treatable
bacterial bronchitis and bronchiectasis (abnormal dilation of
windpipes) may be more common among HIV positive individuals than
previously believed by clinicians. Recurrent bacterial pneumonia and
sinusitis are known to be common infections among HIV positives, but
the physicians heading this study believed that they were seeing more
bacterial bronchitis among their HIV positive patients.

       The researchers' definition of bacterial bronchitis included:
symptoms of productive cough without fever, no evidence of pneumonia
on chest x-ray, a positive laboratory stain for white cells
(neutrophils) on sputum collected from the patient during bronchoscopy
and identification of one or more predominant bacterial species on
sputum staining, confirmed by culture. Bronchoscopy is the insertion
of a tube through the mouth into the windpipe while the patient is
sedated.

       Ten patients were evaluated and found to have 18 episodes of
bacterial bronchitis. The mean CD4 lymphocyte count was 61 cells/mm3.
The 10 patients underwent bronchoscopy to rule out other causes of
bronchial inflammation. The cultures generally grew common bacteria
which are treatable with standard antibiotic therapies. Fourteen of
the 18 episodes of bacterial bronchitis grew out: Hemophilus
influenzae and Streptococcus pneumoniae (5 episodes of each) and
Pseudomonas aeruginosa (4 episodes each). Response to antibiotic
treatment was good, although recurrences were common. H. influenzae
and S. pneumoniae are known to be common bacteria in the blood among
both adults and children with AIDS.

       Among the 10 patients, the authors also identified 3 with
bronchiectasis, an abnormal dilation of the windpipes felt to be due
to repeated bacterial bronchitis. Bronchiectasis was diagnosed by CT
(computerized tomography) scan.

       The researchers conclude that recurrent bacterial bronchitis
should be included among the types of bacterial infections considered
to occur among HIV positive people. It is readily treatable with
common antibiotics, but recurrence is common. They also conclude that
bronchiectasis may be more common during HIV infection than has been
previously reported in the medical literature. This study was
uncontrolled and observational. Hence, there may be some bias in terms
of patient recruitment and conclusions.

       Verghese A and others. Bacterial bronchitis and bronchiectasis
       in human immunodeficiency virus infection. Archives of Internal
       Medicine 154(18): 2086-2091. September 26, 1994.


       Clarithromycin plus Pyrimethamine or Minocycline for
       Toxoplasmosis

       Toxicity due to the standard treatment of
pyrimethamine-sulfonamide for AIDS-associated central nervous system
(CNS) toxoplasmosis brings the issue of finding alternative therapies
to the forefront. Also, finding therapies to treat toxoplasmosis that
overlap with treatments for other common AIDS-associated opportunistic
infections will be of benefit. Dr. J. Alder and co-workers from Abbott
Laboratories Anti-Infective Research Division are attempting to
accomplish both of these objectives in their report published in the
November issue of Journal of Acquired Immune Deficiency Syndromes.

       The researchers used an experimental mouse model of
toxoplasmosis to test the efficacy of combining clarithromycin
(Biaxin) with either pyrimethamine or minocycline. Mice were infected
experimentally in their brains with Toxoplasma gondii. Combining
clarithromycin with pyrimethamine led to a significantly greater
reduction in mortality than either drug used alone. A similar effect
was observed in mice treated with clarithromycin and minocycline. The
enhanced effects with the combinations were synergistic; that is, a
multiplied effect was observed by combining the individual drugs when
compared to the expected added effect of either drug alone. A 100%
cure rate of active and latent infection was achieved by the
clarithromycin-based combination therapies. The researchers also found
a comparable efficacy rate with either clarithromycin-based therapies
and the standard treatment of pyrimethamine and sulfamethoxazole.

       The authors indicate that 'clarithromycin combined with
minocycline or pyrimethamine could allow greater flexibility for
treatment of (toxoplasmosis) patients predisposed to the toxicity
associated with standard pyrimethamine-sulfonamide therapy...(and)
could be especially useful since clarithromycin-based therapy provides
safe and effective treatment against M. avium infections associated
with AIDS.'

       Reference

       Alder J and others. Treatment of experimental Toxoplasma gondii
       infection by clarithromycin-based combination therapy with
       minocycline or pyrimethamine. Journal of Acquired Immune
       Deficiency Syndromes 7(11): 1141-1148. November 1994.

       Low-Dose Steroid Effective Adjunct for Treating Disseminated MAC

       Effective treatment of disseminated Mycobacterium avium complex
(dMAC) infection in AIDS can be difficult, despite multi-antibiotic
regimens. Dr. G. Wormser and colleagues from New York Medical College
have reported in the September 1994 issue of Antimicrobial Agents and
Chemotherapy on the successful adjunctive use of low-dose steroids to
treat dMAC.

       The researchers report on 5 HIV positive persons with dMAC
infection who had progressive weight loss and persistent fever despite
multidrug antimicrobial therapy. All 5 were given daily low-dose oral
dexamethasone (Decadron) 2 mg/day as an experimental adjunctive
therapy. Thereafter, all 5 had 'substantial and significant weight
gain' (a 12-50% gain of pre-steroid treatment weight). They also had
substantial reduction of fever, and an improved sense of well-being.
The low mean serum albumin (protein) level increased from 3.06 g/dl to
3.9 g/dl after decadron treatment. The high mean serum alkaline
phosphatase (liver/bile duct enzyme) decreased from 368 units/liter to
128 units/liter. Both latter laboratory improvements were
statistically significant. The 5 patients involved represent too small
a group to measure dMAC disease outcome or mortality improvement.

       The authors conclude that 'further studies of the potential
role for corticosteroids in the management of dMAC infections in HIV
infected patients are warranted.' Since steroids are immune
suppressants, there would be some concern that using such drugs might
increase the risk of reactivating other latent infections. However,
clinicians have learned that a partial block of the immune response
sometimes can be favorable, e.g. in the adjunctive treatment of
moderate-to-severe PCP with standard antibiotics. The reasoning is
that the immune system's inflammatory response to the Pneumocystis
organism is partially blocked, and the clinical outcome is improved.
If the same mechanism exists with dMAC infection, then a clinical
improvement also may be possible by adding steroids to the treatment
regimen for dMAC.

       Reference

       Wormser GP and others. Low-dose dexamethasone as adjunctive
       therapy for disseminated Mycobacterium avium Complex infections
       in AIDS patients. Antimicrobial Agents and Chemotherapy 38(9):
       2215-2217. September 1994.


       Treatment for Malignancies/Cancers
       Antisense Gene Therapy for Kaposi's Sarcoma

       Drs. Barbara Ensoli, Robert Gallo and colleagues from the
National Cancer Institute have performed laboratory experiments using
a genetically engineered therapy which could represent a potential new
therapy for AIDS-associated Kaposi's sarcoma (KS). Recombinant
technology allowed for the development of an antisense nucleotide
directed against the messenger RNA of basic fibroblast growth factor.
That factor is highly expressed by KS spindle cells and is a potent
promotor of new blood vessel growth in KS lesions. The report appears
in the November 1994 Journal of Clinical Investigation.

       The antisense therapy inhibited growth in vitro of
AIDS-associated KS cells derived from different patients. It also
inhibited growth of both new blood vessels and KS cells in nude mice
after they were injected subcutaneously with human AIDS-associated KS
cells.

       The nude mice represent an animal model for KS. The observed
growth inhibition was due to the blocking of production of basic
fibroblastic growth factor. The effects were specific, dose-dependent
and were not toxic to the mice. The effects were reversed by adding
back the growth factor. The authors conclude that the antisense gene
therapy represents a potential new treatment for AIDS-associated KS.
The implications of their findings also could apply to inhibiting
growth of other cancers, both HIV- and non-HIV-related.

       Reference

       Ensoli B and others. Block of Kaposi's sarcoma (KS) cell
       growth, angiogenesis, and lesion formation in nude mice by
       antisense oligonucleotide targeting basic fibroblast growth
       factor: a novel strategy for the therapy of KS. Journal of
       Clinical Investigation 94(5): 1736-46. November 1994.


       FDA Panel Rejects Liposome Doxorubicin for Kaposi's Sarcoma

       The FDA Cancer Advisory Committee has decided against
recommending liposome doxorubicin (stealth liposome doxorubicin,
DOX-SL) for FDA approval to treat AIDS-related Kaposi's sarcoma (KS).
Only 6 out of 77 patients with advanced HIV disease experienced some
clinical benefit, including either a reduction in lesion size or
associated pain. The committee did recommend that the manufacturer
consider submitting an application for approval of DOX-SL under the
accelerated approval mechanism, restricted to life-threatening
illnesses. Under that process, less information is required for the
FDA to approve a new drug. Liposomal technology is a process whereby
drugs are suspended in a lipid (fatty) formulation, thereby allowing
them to remain in the bloodstream longer than without the liposomes.

       Reference

       Associated Press. FDA panel rejects cancer drug. San Francisco
       Chronicle: C2. February 15, 1995.

       Relevant Laboratory Research Structure of HIV Integrase Discovered

       The structure of the third key HIV enzyme has been discovered
by Dr. Fred Dyda and colleagues from the National Institute of
Diabetes and Digestive and Kidney Diseases at the National Institutes
of Health. The first 2 are (1) reverse transcriptase which is
inhibited by AZT and others and (2) protease which is inhibited by
saquinavir (Invirase and others). Their findings appear in the
December 24, 1994 issue of Science. The third enzyme is called
integrase and its structure had remained elusive for some time. The
integrase enzyme allows the HIV DNA to 'integrate' into the human
cellular DNA between the genes of the chromosome. They were able to
characterize its 3-dimensional structure using x-ray crystallography
techniques. Dr. Dyda and another group led by Dr. Stephen Goff at
Columbia University reported in the same Science issue that they had
to make mutants of the integrase protein in order to make it soluble
and thereby easier to crystallize.

       Now that the structure of integrase is known, the synthetic
chemists will have an easier time designing drugs to block its
activity. Specifically, they will be more likely to design an
inhibitor drug that will bind to and inhibit the catalytic binding
site, like a lock-and-key mechanism.

       Development of integrase inhibitors will add to the types of
anti-HIV drugs available to treat HIV/AIDS. Many leading HIV/AIDS
researchers believe that the key to controlling HIV progression in
HIV-infected individuals will be to use several different types of
anti-HIV therapies simultaneously, thereby minimizing the likelihood
of developing resistance to any one drug. For example, such an
anti-HIV 'cocktail' could include a reverse transcriptase inhibitor, a
protease inhibitor and an integrase inhibitor. A direct analogy exists
in the treatment of active tuberculosis, whereby 4 different types of
antibiotics are used simultaneously to effectively treat the disease
and minimize the development of antibiotic resistance. If only one
drug is used, the tuberculosis organism often becomes resistant to
that drug.

       Reference

       Dyda F and others. Crystal structure of the catalytic domain of
       HIV-1 integrase: similarity to other polynucleotidyl
       transferases. Science 266: 1981-1986. December 23, 1994.

       Kalpana GV and others. Binding and stimulation of HIV-1
       integrase by a human homolog of yeast transcription factor
       SNF5. Science 266: 2002-2006. December 23, 1994.

       O'Brien C. HIV integrase structure catalyzes drug search.
       Science 266: 1946. December 23, 1994.


       HIV and MAC Each Increase the Other's Growth

       Researchers have determined by in vitro studies that HIV
increases the growth of Mycobacterium avium complex (MAC) and that M.
avium in turn increases the growth of HIV. Dr. Mahmood Ghassemi and
co-workers from the University of Illinois used the U937 monocytoid
cell line for the set of experiments, since macrophages are
target-cells for both HIV and M. avium. When compared with cultures
infected only with HIV, coinfected cultures at day 6 demonstrated more
than a 3-fold increase in HIV replication. When cells were infected
with HIV prior to infection with M. avium, a significant increase in
MAC growth was observed, when compared with control cultures infected
with MAC only. (HIV infection prior to MAC infection is thought to
occur in most persons with AIDS-related MAC.) In addition, cell death
was accelerated in co-infected cultures, when compared with either
singly infected control. The research was reported in the January 1995
issue of Journal of Infectious Diseases.

       Reference

       Ghassemi M and others. Human Immunodeficiency Virus and
       Mycobacterium avium complex coinfection of monocytoid cells
       results in reciprocal enhancement of replication. Journal of
       Infectious Diseases 171(1): 68-73. January 1995.


       HIV Tat Protein and KS Growth Factor Enhance KS Growth

       Drs. Robert Gallo and Barbara Ensoli from the National Cancer
Institute have found that administering both HIV tat protein and basic
fibroblast growth factor has a synergistic effect towards inducing
Kaposi's sarcoma (KS)-like lesions in nude mice. Synergy is a
situation wherein a multiplied effect is observed by adding 2 factors
together, compared to a much smaller observed effect when either is
added alone. The nude mice represent an animal model of
AIDS-associated KS. Extracellular HIV tat protein, tat receptors and
basic fibroblast growth factor are all present in HIV-1-associated KS.
The findings are significant in that they could be exploited to find
new potential therapies for AIDS-related KS, specifically by
manufacturing inhibitors to either protein. The authors believe their
findings may explain why KS can be so aggressive in the presence of
HIV compared to classical (pre-HIV/AIDS) KS, which grows slowly and is
rarely life-threatening. The report appears in the October 20, 1994
issue of Nature.

       Reference

       Ensoli B and others. Synergy between basic fibroblastic growth
       factor and HIV-1 tat protein in induction of Kaposi's sarcoma.
       Nature 371(6499): 674-80. October 20, 1994.


       Vaccines Safer Vaccine Possible with Drug-Sensitive HIV

       Stephen M. Smith, MD, and colleagues from the National
Institute of Allergy and Infectious Diseases (NIAID) have reported
that a drug-sensitive HIV clone created there may enable HIV
experimental vaccines to be safer. The experimental vaccines are based
on live but attenuated (weakened) forms of HIV. After being used in
the vaccine, the clone could be eliminated from the body.

       Up to this time, researchers have been reluctant to use
experimental attenuated live-virus vaccines to prevent HIV/AIDS out of
concern that they were too hazardous, since HIV is ultimately fatal
for the vast majority of those infected. Several other diseases are
prevented by using licensed attenuated live-virus vaccines, e.g.,
polio.

       Dr. Smith and co-workers removed the thymidine kinase (TK) gene
from herpes simplex type 1 (HSV-1), the virus which causes cold sores.
Then they replaced the HIV nef gene with the HSV-1 TK gene.
HIV-infected human cells that produce the TK enzyme could then be
selectively killed by adding ganciclovir (Cytovene), the drug used to
treat cytomegalovirus. In vitro, the researchers found that
ganciclovir eliminated cells infected with HIV-TK. They also found no
increased cell death due to HIV and no rise in HIV reverse
transcriptase enzyme, indicating no HIV activity. However, in
HIV-TK-infected cultures not treated with ganciclovir,
significant-cell death was observed with concomitant increases in
reverse transcriptase.

       Dr. Smith said, 'This result suggests that after [the vaccine]
has had a chance to work, an attenuated vaccine based on the HIV-TK
clone could similarly be eliminated by co-administration of
ganciclovir, reducing the concern about long-term adverse side
effects...By killing infected cells before virus production occurs,
ganciclovir interrupts the spreading of HIV infection without
influencing uninfected cells.'

       Reference

       Smith SM and others. Drug-sensitive HIV could make safer AIDS
       vaccine. NIAID News. January 31, 1995.


       Experimental Chimpanzee Vaccine Model Effective

       Researchers from NIAID have reported some success in a
chimpanzee model for an experimental HIV-1 vaccine. The group is
headed by Riri Shibata, PhD. Although chimpanzees can be infected with
HIV-1, they do not manifest disease, unlike humans. The researchers
hypothesized that chimpanzees inoculated with 1 HIV-1 strain would be
immune to infection by another HIV-1 strain. With the strains tested,
they found that their hypothesis was correct.

       Dr. Shibata states, 'In this study, the first infection
simulated the effect of a successful attenuated HIV-1 vaccine. The
virus induced protective immunity against a subsequent HIV-1
infection. Scientists now have a model system that can help develop an
attenuated HIV-1 vaccine for humans.'

       In 1986 and 1990, one chimpanzee per year was infected
successfully with the HIV-1 strain IIIB, grown in the laboratory. In
1993 and 1994, the researchers attempted to 'superinfect' the chimps
with increasing doses of a different HIV-1 strain, DH-12, which can
easily infect chimpanzee cells. At that time, DH-12 had been recently
isolated from a person with AIDS. In 1993, the scientists injected one
chimp with a DH-12 dose that can induce infection in a chimp. In the 4
months after the DH-12 injection, repeated polymerase chain reaction
(PCR) tests found evidence only of the IIIB strain, but not any DH-12
strain. This suggested that the chimp, after having been infected with
the IIIB strain years before, was immune to infection by the DH-12
strain.

       In 1994 both IIIB strain-infected chimps were given a DH-12
dose 10 times larger than the 1993 dose. Again, repeated PCR tests
during the subsequent 4 months detected evidence of IIIB infection but
not DH-12 infection. After the PCR tests, one of the chimps was
injected with yet another dose of DH-12, 100 times larger than the
first: still no evidence of DH-12 infection by PCR. Then the other
IIIB-infected chimp was injected with 10cc (2 teaspoons) of blood from
a third chimp which had been experimentally infected with a DH-12
strain 4 months earlier. This was done in attempt to 'mimic the type
of exposure an injection drug user' may have over time. So far,
neither HIV-1-IIIB-infected chimpanzees shows any evidence of
infection by the DH-12 strain by PCR or other virus isolation
techniques.

       The researchers believe that the cell-mediated component of the
immune system prevented the infection by the DH-12 strain, since both
chimpanzees had neutralizing antibodies against the IIIB strain before
1993, but not against the DH-12 strain.

       In a related experiment, the researchers determined that the
strength of an attenuated virus may be important in preventing
superinfection with a second strain. They inoculated 2 different
chimpanzees with a weaker strain than IIIB, the HIV-1 SF2 strain. SF2
leads to lower levels of virus in the chimps than the IIIB strain. In
1994, the 2 SF2-infected chimps were inoculated with a low dose of
DH-12. Contrasted with the IIIB-infected chimps, the SF2-infected
chimps did become infected with DH-12 within 4 weeks after exposure.
However, the levels of DH-12 viremia was 35- to 50-fold lower than an
unvaccinated chimp exposed to DH-12.

       The authors indicate that 'chimpanzees can be protected from a
subsequent challenge (of a different strain of) HIV-1, provided the
animals are first immunized with a potent attenuated live-virus
vaccine.' The researchers are continuing their experiments, with the
eventual implications for prophylactic and therapeutic vaccines for
humans.

       Reference

       Shibata R and others. Chimpanzee vaccine model protects against
       HIV-1 infection. NIAID News. February 1, 1995.


       Surgery Emergency Surgery Outcome in People with AIDS
       Considered Satisfactory

       Over the course of the HIV/AIDS pandemic, surgeons have
sometimes determined that surgery in the person with AIDS was 'not
indicated' due to the impression that either: (1) it was
'experimental,' (2) the patient would have a poor post-operative
course and/or (3) that an AIDS diagnosis was associated with an
imminent death. Some surgeons did not want to assume the low but
finite risk of accidental exposure to HIV during surgery, thereby
avoiding their professional responsibility. Researchers at UCSF San
Francisco General Hospital have addressed the first 2 issues in a
retrospective study of emergency abdominal surgery in people with AIDS
in the American Journal of Surgery. The lead author is Timothy
Whitney, MD.

       The study included 57 patients undergoing a total of 63
emergency abdominal exploratory surgeries at 4 UCSF hospitals.
Ninety-six percent (96%) were gay/bisexual men, and 68% had been
treated for an opportunistic infection. Indications for exploratory
abdominal surgery included: uncontrolled hemorrhage, intestinal
blockage or leakage (perforation), to rule out appendicitis, gall
bladder/bile duct infection or blockage or peritonitis
(life-threatening infection of abdominal wall lining).

       Mortality during or shortly after surgery was 12%. Fifteen
participants (26%) experienced major complications. Those
complications included pneumonia, sepsis, intra-abdominal abscess (pus
collection) and multi-organ failure. Chronic antibiotic or cancer
chemotherapy was significantly associated with survival. Forty-five
(45) of 50 survivors (90%) were receiving some kind of antibiotics
(including anti-HIV and other anti-microbial therapies), compared to
only 2 of the 7 (28%) patients who died. Decreased post-operative
complications and death were associated with each of the following:
ongoing AIDS-related prophylaxis, lack of sepsis or an active
opportunistic infection and a more benign classification of HIV
disease (lower Walter-Reed staging).

       The authors indicate that an AIDS diagnosis should not prevent
necessary abdominal exploratory surgery, since the outcome in the
patient group is generally satisfactory. Recently, there have been
other reviews in the medical literature suggesting that aggressive
surgery can decrease disease and death associated with abdominal
emergencies in people with AIDS, and that such surgery should not be
considered experimental.

       Reference

       Whitney TM and others. Emergent abdominal surgery in AIDS:
       experience in San Francisco. American Journal of Surgery
       168(3): 239-243. September 1994.

       ****************
       Selected Open Clinical Trials for HIV/AIDS Treatments
       Leslie Hanna

       For further information, call the number provided with the
individual listing or call the AIDS Clinical Trials Information
Service (ACTIS), toll-free, at 1-800-874-2572 (1-800-TRIALS-A). This
government-sponsored service can provide information about most of the
following trials, but can only provide information about privately
sponsored  trials when the sponsor has elected to give that
information to ACTIS.

       Treatment for HIV Infection

       ABT-538 (Abbott protease inhibitor)

       A Phase III dose-ranging study is scheduled to begin in March.
Eligible participants have 200-700 CD4 cells and are
antiretroviral-naive. At press time, the protocol was being finalized.
Twenty sites are projected. For more information, call Mabrey Whigham
at 312-755-1241.

       MK-639 (formerly L-735,524, Merck protease inhibitor)

       Merck plans to begin several Phase III trials to test the
safety, tolerability and effectiveness of MK-639. For information
about upcoming trials, see 'Summit Meeting,' on page 31 of this issue
and/or call 1-800-379-1332.

       saquinavir (Hoffman La-Roche protease inhibitor) and ddC

       FDA 229A is a Phase III study that will involve 1,000
participants. The trial is open to people with HIV with 50-300 CD4
cells/mm3 who have failed on AZT. Prior use of ddC, ddI or d4T must
not be greater than 2 weeks. There are 3 treatment arms: (1)
saquinavir monotherapy, (2) ddC monotherapy and (3) ddC plus high-dose
saquinavir. (A fourth arm, ddC plus low-dose saquinavir, has been
dropped.) For more information about international and North American
trials of saquinavir, call 1-800-526-6367. saquinavir, AZT and ddC

       In this Phase III double-blind, placebo-controlled trial,
people with 50-350 CD4 cells/mm3 will be randomized to receive various
combinations of these anti-HIV agents. The 4 treatment arms are: (1)
saquinavir plus AZT plus ddC, (2) saquinavir plus AZT, (3) AZT plus
ddC and (4) AZT. Prior use of antiretrovirals other than AZT is
excluded, and previous use of AZT must not exceed 4 months. This is a
large study with many sites.

       combination vs alternating antiretroviral treatment for
       advanced HIV infection

       ACTG 193A is a Phase II/III double-blind study comparing
combination nucleosides to alternating nucleosides to triple-drug
therapy for people with fewer than 50 CD4 cells/mm3. Investigators
will evaluate efficacy and the relative abilities of the different
regimens to minimize toxicity as well as resistance. Participants are
randomized to (1) AZT plus ddC, (2) AZT plus ddI, (3) AZT alternating
monthly with ddI, or (4) AZT plus ddI plus nevirapine. There are
multiple sites.

       hydroxyurea

       This Phase I open-label trial will evaluate the safety and
tolerability of hydroxyurea as monotherapy vs hydroxyurea combined
with either AZT or ddI (3 arms). The study is open to people with 300
or more CD4 cells/mm3. For more information, call Dr. Galpin at the
Shared Medical Research Foundation in Tarzana, CA, at 818-345-2172.

       sulfasalazine

       Sulfasalazine is approved for the treatment of arthritis, an
autoimmune disease. Like aspirin, it reduces pain and inflammation;
unlike aspirin, it is not known to cause gastrointestinal problems.
This placebo-controlled dose-ranging study will evaluate the potential
of the drug to elevate CD4 cell counts in people with HIV and seek to
establish optimal doses. The study lasts 16 weeks. Participants must
not have arthritis, severe liver or kidney disease, or active major
opportunistic infection(s). In New York, call Dr. Eddy Disla at
Cabrini Medical Center at 212-995-6996.

       sulfasalazine vs hydroxychloroquine

       This Phase II open-label safety and efficacy trial will
evaluate the anti-HIV potential of these 2 agents alone and in
combination. Participants will be randomized to 1 of 3 arms. The
treatment and trial last 6 months. The study is open to people with
fewer than 200 CD4 cells/mm3. Call Dr. Szebenyi at the Albany (NY)
Medical College at 518-262-4381.

       salasalate

       An anti-inflammatory agent, salasalate is chemically related to
aspirin but does not cause the gastric upset that aspirin does. This
placebo-controlled study will evaluate its potential anti-HIV effects.
In New York, call the AIDS Treatment Data Network ('the Network') at
212-260-8868 or 800-734-7104 for more information. The Project for
Aspirin Research and Education can provide additional information on
the potential use of aspirin for treating HIV infection
(310-659-6965).

       glutathione

       Glutathione is a naturally occurring protein that detoxifies
waste in the body; deficiencies of it are associated with HIV
infection. This study will test the safety and pharmacokinetics of
different doses of glutathione (up to 1.5 g twice daily), to evaluate
its potential to counteract HIV-related deficiencies. Study
requirements include having a CD4 cell count higher than 500 CD4
cells/mm3, no prior use of antiretrovirals and no cigarette smoking.
For more information call Paul Prosser at the Pacific Oaks Medical
Group at 818-906-6279.

       935U83 plus ddI

       This Phase I/II multidose study will evaluate the safety,
tolerance and pharmacokinetics of the combined antivirals 935U83 and
ddI, a combination that other research suggests is synergistic. The
study is open to people with 100-500 CD4 cells/mm3 and no prior use of
anti-HIV drugs except AZT, ddI and/or ddC. 935U83 will be taken 3
times daily in doses ranging from 100-500 mg; a 200 mg dose of ddI
will be taken twice daily. The 12-week study may be extended an
additional 12. In the San Francisco (SF) Bay Area, call Peter at ViRx
at 415-353-5623.

       GEM 91

       This open-label Phase IB/II trial will evaluate the safety,
pharmacokinetics and anti-HIV properties of GEM 91, an antisense drug.
Sixty people will receive intravenous GEM 91 for 2 to 4 weeks. Viral
RNA plasma concentrations will be measured by bDNA. This trial
requires 2 weeks of hospitalization. In New York, call Dr. Giordano at
212-746-4177. In Birmingham, Alabama, call Dr. Saag at 205-934-7349.

       delavirdine, AZT and ddI

       This Phase I/II, multicenter, open-label study will compare
delavirdine as monotherapy versus AZT or ddI monotherapy. The 24-week
study will evaluate the safety, tolerance and efficacy of delavirdine
as monotherapy. Eligible participants have between 200 and 500 CD4
cells/mm3 and have not taken any antiviral drug other than AZT (no
ddI, ddC, d4T or 3TC). Exclusion criteria include pregnancy or
breastfeeding; acute or chronic treatment for any of several
opportunistic infections and; past use of delavirdine.

       HIV-IT (V) gene transfer therapy

       This study of the safety and efficacy of HIV-IT (V) involves
use of a disabled mouse virus similar to HIV that can genetically
change some uninfected cells and cause them to produce some of the
proteins that HIV-infected cells make. Participants will receive
either HIV-IT (V) or placebo for 2 years. Every 4 months, both HIV-IT
(V) and placebo are injected 3 times into thighs and arms.
Participants on antiretrovirals (AZT, ddI, ddC, d4T, etc.) must stop
for 4 days before and 2 days after each series of injections. Study
requirements include greater than 100 CD4 cells/mm3 and antiretroviral
use for at least 90 days. There are 16 sites nationwide. In the SF Bay
Area, contact Peter Knapp at ViRx at 415-353-5623.

       OPC-8212

       OPC-8212 is an oral medication used in Japan to treat
congestive heart problems. This Phase I study evaluates the safety,
tolerance and antiviral potential of 3 different doses of OPC. The
study lasts for 12 weeks and is open to people with asymptomatic HIV
infection. Call UCLA's Center for AIDS Research and Education (CARE)
at 310-206-1960.

       In Atlanta, a similar Phase I study but with 4 different doses
of OPC is enrolling people with 50-300 CD4 cells/mm3. Call the AIDS
Research Consortium of Atlanta at 404-876-2317.

       SC-49483 vs AZT for inhibition of syncytia formation

       ACTG 259 is a Phase II double-blind multicenter study of
SC-49483, a new drug that may help prevent the formation of syncytia,
which are clumps of infected and healthy immune cells that the immune
system targets for elimination from the bloodstream. Syncytia
formation is associated with disease progression. Participants will be
randomized to receive either (1) low-dose SC-49483 plus AZT, (2)
high-dose SC-49483 plus AZT or (3) AZT plus placebo. Entrance
requirements include 50-350 CD4 cells/mm3 if no prior antiretroviral
use and 150-350 if participants have past antiretroviral use.
Treatment lasts 16-24 weeks.

       BMS 180194 for HIV and CMV

       This Phase I/II study will compare the safety, tolerance,
anti-CMV and anti-HIV activity of the new oral antiviral drug BMS
180194. Two visits are required each week for 8 weeks, plus 3 hospital
stays of 1 day each. Requirements include a CD4 count below 200 CD4
cells/mm3 and no history of CMV disease. In San Francisco, call Mt.
Zion Hospital at 415-476-6356; in Minnesota, call 612-624-6489; and at
John Hopkins University in Maryland, call 410-955-7704.

       PMEA plus AZT

       The National Cancer Institute (NCI) is conducting a Phase I/II
dose-ranging study of the safety and efficacy of the combination of
AZT and PMEA, a nucleoside analog like AZT, known to be active against
herpesviruses and HIV. PMEA is given in IV form 3 times a week.
Participants have less than 500 CD4 cells/mm3. Call Sergio Bauzo at
the NCI at 301-496-8959.

       PMEA for advanced HIV disease

       This Phase I/II study looks at the safety, tolerance,
pharmacokinetics and anti-HIV effect of PMEA in people with advanced
HIV disease. PMEA is administered daily by intravenous (IV) or
subcutaneous (SC) injection. Twenty participants will receive a single
IV or SC dose once a day for 4 weeks. Entry requirements include less
than or equal to 100 CD4 cells/mm3 and p24 antigen levels greater than
40. This study will take place at the University of Washington School
of Medicine in Seattle. For more information call Dr. John Nienow, at
206-223-3184.

       GS-840

       A Phase I study of an oral drug known as GS-840 (also called
BIS-PON PMEA) is underway. Manufactured by Gilead Sciences, GS-840 is
a prodrug of another Gilead Sciences product, GS-393, or PMEA, which
is in ongoing Phase I/II clinical trials. GS-840 is designed to be
efficiently converted in the body into GS-393 and to achieve the
highest possible bioavailability. Ongoing trials of GS-393 or PMEA
have shown that taking the drug is associated with decreased levels of
p24 and increases in CD4 cell counts. Call Dr. Lietmann at Johns
Hopkins University at 410-955-9707.

       alferon N for HIV infection

       This 16-week, Phase II, randomized, dose-ranging study will
evaluate the safety and anti-HIV potential of alferon N. Participants
will receive 1 of 3 doses of alferon N 2 or 3 times a week by
subcutaneous injection. Treatment lasts 4 weeks. Requirements include
greater than 250 CD4 cells/mm3 and a minimum of 2 months on any
nucleoside inhibitor currently being taken. Exclusion criteria include
use of protease inhibitors. There are many national sites. In the SF
Bay Area, contact Brian Camp, RN, at the AIDS Community Research
Consortium (ACRC) at 415-364-6563.

       AZT effect on viral load in lymph nodes

       This 9-week study will evaluate the effect of AZT on the amount
of HIV in blood and lymph tissue. All participants will receive AZT
for 8 weeks and will have 2 lymph nodes biopsied, at the beginning of
the study and then 8 weeks after treatment ends. The 2 lymph node
biopsies will not cause long-term health problems. Study requirements
include having 100-500 CD4 cells/mm3. Exclusion criteria include prior
use of any antiretroviral drugs, chemotherapy and current
opportunistic infections (except mild Kaposi's sarcoma or
candidiasis). This is a multicenter study. In the SF Bay Area, contact
the ACRC at 415-364-6563. sustained-release AZT

       Aztec is a sustained-release formulation of AZT, developed by
Verex Laboratories. The study will evaluate the safety and
effectiveness of the sustained-release product compared to the
standard formulation of AZT. The 18-week, double-blinded study is open
to people with HIV and 200-500 CD4 cells/mm3. Participants who
complete the study will be eligible to enroll in a 3-year open-label
study of Aztec. In the SF Bay Area, call Brian Camp at ACRC at
415-364-6563.

       Treatment for Opportunistic Infections

       candidiasis (thrush) treatment: itraconazole and fluconazole

       This third-party blind, randomized pilot study will evaluate
the safety and efficacy of itraconazole and fluconazole for
oropharyngeal candidiasis. Participants will receive 1 of 2 doses of
oral itraconazole or oral fluconazole for 2 weeks. Periodic physical
exams and routine blood tests will be performed throughout the 5-7
week study and 4 weeks after treatment. Participants must have oral
candidiasis (thrush or oropharyngeal candidiasis) and at least 100 CD4
cells/mm3. Exclusion criteria include esophageal or disseminated
candidiasis. This is a multicenter study.

       candidiasis treatment: liquid itraconazole

       This Phase III open-label safety and efficacy study will
evaluate the use of itraconazole for oral Candida infections (thrush)
that cannot be treated successfully with fluconazole. Liquid
itraconazole is administered like a mouthwash for 14-28 days. Study
length depends upon treatment efficacy. Participants must have thrush
that has not responded to fluconazole for 14 days. Several sites
across the U.S.

       cryptosporidiosis/diarrhea treatment

       This study will prospectively evaluate the ability of bovine
immunoglobulin concentrate (BIC) to alleviate severe diarrhea
resulting from cryptosporidial infection or other causes, that has
failed to respond to other treatments. Participants are randomized to
receive either BIC powder or BIC capsules. The study lasts 7 weeks.
Entrance requirements include 10 days of diarrhea within the past
month and exclude milk protein or severe lactose intolerance. In the
SF Bay Area, call Dr. Paul Greenberg at 415-206-8824.

       cytomegalovirus (CMV) retinitis: ISIS 2922

       This ISIS Pharmaceuticals-sponsored study compares immediate vs
delayed treatment with intravitreal injections of their antisense
compound ISIS 2922. The study is open to anyone (over the age of 18)
with AIDS and previously untreated CMV retinitis in one eye. In the SF
Bay Area, call Brenda Cayme, RN, at ACRC at 415-364-6563.

       CMV retinitis: ganciclovir and intravitreal implants

       This Phase III study will evaluate the safety and efficacy of
ganciclovir in conjunction with intravitreal ganciclovir implants.
Participants will be randomized to 1 of 3 treatment arms: IV
ganciclovir; implant plus oral ganciclovir; or implant plus placebo.
The study lasts 1 year. Participants must have had CMV in only 1 eye.
Exclusion criteria include current or past presence of CMV disease in
other parts of the body, and more than 2 induction phases of therapy
for CMV retinitis. This is a multicenter study.

       CMV peripheral retinitis: AM 285

       This open-label, randomized, multicenter, Phase I/II study will
determine the safety and tolerance of AM 285 in people with HIV and
CMV peripheral retinitis. AM 285, which has anti-inflammatory
properties, blocks energy production in CMV-infected cells. This study
lasts 8 weeks and consists of 3 to 5, 3-hour infusions per week. Six
dose levels will be studied. If retinitis stabilizes, there is a
possibility of treatment extension for up to 1 year. There are no CD4
requirements or restrictions on antiretroviral use for participation
in this study. For more information in the SF Bay Area, contact ViRX
at 415-353-5623. refractory CMV retinitis: HPMPC

       FDA 216B is an open-label study of the safety and efficacy of
intravenous cidofovir, or HPMPC. Entrance requirements include
ophthalmologically proven CMV retinitis and unsuccessful ganciclovir
and/or foscarnet treatment (for at least 4 weeks). During a 2-week
induction phase, everyone will receive 5 mg/kg once weekly. After
that, participants will take either 5 or 3 mg/kg once every other
week. Everyone receives concomitant probenecid and saline hydration.
Retinal photographs will be used to evaluate efficacy. Approximately
100 people will be enrolled at 6 sites in the U.S. and 1 in Great
Britain. azithromycin (Zithromax), clarithromycin (Biaxin) plus
ethambutol (Myambutol) for treating Mycobacterium avium complex (MAC)

       This double-blind study compares 2 combinations of anti-MAC
agents for the treatment of disseminated MAC. Participants will be
randomized to take 250 or 650 mg azithromycin plus 800-1200 mg
ethambutol daily (based on body weight) or clarithromycin 500 mg twice
daily and 800-1200 mg ethambutol once a day. At the end of the regular
24-week study, participants may be evaluated for entry into an
open-label maintenance protocol. The study is open to people with HIV
and a positive MAC blood culture within 2 months prior to study entry.
Exclusion criteria include therapy for MAC after the positive culture
that qualified for study entry, known sensitivity to any of the
macrolide antibiotics or use of another investigational drug within 1
week of study entry. A total of 300 people will be enrolled at 25-30
sites nationwide. In the SF Bay Area call the ACRC at 415-364-6563.

       thalidomide (Synovir) for mycobacterial infections and/or HIV

       FDA 133A is a Phase I/II trial of the safety and efficacy of
thalidomide in people with HIV and/or mycobacterial infections,
including MAC and tuberculosis. Clinical examinations and laboratory
tests will be used to evaluate the impact of thalidomide on reducing
symptoms and improving immune responses in participants. The trial is
open to people with proven mycobacterial infection (culture or smear),
with or without documented HIV infection. HIV positive participants
must have fewer than 500 CD4 cells/mm3 and must be taking one or more
antiretroviral. Recent fever, weight loss and night sweats are also
required. Participants will be randomized to receive oral thalidomide
or placebo the night before beginning anti-tuberculosis treatment, to
continue for 7 nights. Follow-up continues for a total of 28 days.
Pneumocystis carinii pneumonia (PCP) treatment: trimetrexate
glucuronate (TMTX) plus

       leucovorin (LCV) plus dapsone vs trimethoprim/sulfamethoxazole
       (TMP/SMX)

       This randomized, Phase I multicenter study will compare the
safety and efficacy of the combination TMTX, LCV and dapsone to
TMP/SMX (Bactrim or Septra) for the treatment of PCP. Participants
will be hospitalized for the first 10 days of the 24-day study.
Requirements include AIDS and active PCP. Exclusion criteria include
more than 24 hours of systemic anti-PCP therapy within 2 weeks of
start of study, pregnancy and anti-HIV drugs (AZT, ddI, ddC, d4T). In
the SF Bay Area contact Lisa Turner at San Francisco General Hospital
(SFGH) at 415-476-9296 extension 84092.

       PCP prevention: dapsone vs atovaquone

       ACTG 277 is a multi-site, double-blind Phase III study that
will compare daily dapsone to atovaquone for the prevention of PCP in
people who are intolerant to trimethoprim-sulfamethoxazole (TMP/SMX).
The study is open to people with a history of but without active PCP,
and fewer than 200 CD4 cells/mm3, who are not taking TMP/SMX.

       Treatment for Malignancies and Cancers anal cancer prevention:

       isotretinoin, interferon alfa-2a

       This dose-escalating multicenter study of isotretinoin in
combination with interferon alfa-2a will assess the ability of the
combination to prevent anal neoplasia (secondary to anogenital human
papillomavirus infection) in people with HIV infection. Participants
will be taught to self-inject. Treatment will last 12 weeks.
Requirements include biopsy-confirmed Grade I or treated Grade II or
III anal intraepithelial neoplasia (AIN, a type of anal cancer). No
opportunistic infections or cancers requiring chemotherapy are
allowed. In the SF Bay Area contact Sue Forstat at  415-476-3226.

       tecogalan sodium for Kaposi's sarcoma (KS) and solid tumors

       This Phase I, dose-escalating multicenter study will evaluate
the safety, efficacy and pharmacokinetics of tecogalan sodium.
Tecogalan sodium will be infused 2 times a week for 3 weeks.
Participants will be hospitalized for the first infusion, and will
continue treatment on an outpatient basis. Requirements include
confirmed KS with at least 4 skin lesions. Exclusion criteria include
prior anti-KS therapy for 3 weeks or more, an opportunistic infection
other than KS within 4 weeks before the study, a history of acute or
chronic GI bleeding or inflammatory bowel disease. In the SF Bay Area
call George Bosse, RN,  at 415-476-9296, extension 84099.

       tretinoin (AR-623) for the treatment of KS

       This Phase II/III dose-escalating study will evaluate the
safety and efficacy of tretinoin for KS treatment. Tretinoin will be
injected 1 or 3 times a week for 24 to 32 weeks. To participate one
must have diagnosed KS of the skin but no chemotherapy, immunotherapy,
hormone or radiation therapy, and no opportunistic infections (except
candidiasis) within 3 weeks. This is a multicenter study. topical gel
for KS

       This Phase I/II, multicenter study is looking at the efficacy
of a topical medicine called LGD1069. People with KS can apply the
medicine, which comes in gel form, to their lesions themselves. A
natural retinoic hormone (9-cis-retinoic acid), LGD1069 is related to
vitamin A, which plays various roles in immune system responses and in
protecting body tissues. The study will last for 4 weeks. If
appropriate, participants may be eligible to continue using the agent
after the end of the study. In the SF Bay Area call St. Francis
HIVCare at 415-353-6215.

       OPC-8212 for KS

       OPC-8212 is an oral medication that is also being studied for
its antiviral properties. This study will evaluate the ability of 2
different doses of the agent to cause regression of KS tumors, and is
open to people with HIV and KS, without other current opportunistic
infections. Use of antivirals is disallowed during the study. Call the
UCLA CARE Center at 310-206-1960.

       interleukin 4 (IL-4) for KS

       ACTG 224 is a Phase I/II open-label, dose-ranging study of IL-4
for treating KS. In Boston call Dr. Scadden at 617-632-8895 and in Los
Angeles call Dr. Miles at 310-206-6414. For more information about a
Phase II open-label trial of IL-4 for KS, call Dr. Gill in Los Angeles
at 213-343-8275.

       Treatments for Wasting Syndrome and Myopathy

       thalidomide (Synovir) for wasting syndrome

       FDA 230A is a Phase II placebo-controlled study of the safety
and efficacy of thalidomide for treating HIV-related wasting syndrome
(i.e., reducing weight loss and antiviral and anti-tumor necrosis
factor-alpha potential). The study is open to people with HIV and
wasting, or greater than 10% loss of normal/prewasting body weight in
the absence of another infection that might account for such weight
loss. Participants will be randomized to receive low- or high-dose
thalidomide (100 mg or 200 mg/day) or placebo for 8 weeks.

       San Francisco nutrition study

       This study will prospectively evaluate changes in body
composition and energy metabolism as HIV infection progresses. Body
fat, bone density, dietary intake, energy expenditure and viral burden
will be measured. For information call Viva Tai, RD, at 415-206-4090
or Dr. Kathy Mulligan at 415-206-5882.

       diethylhomospermine (DEHSPM) for refractory AIDS-related diarrhea

       This is a Phase I study of the efficacy of DEHSPM for treating
refractory AIDS-related diarrhea. To participate one must have
uncontrolled diarrhea (defined as more than 500ml/day of liquid stool
for 4 weeks duration despite high-dose, non-specific antidiarrheal
therapy). Exclusion criteria include use of antidiarrheal drugs. For
more information, contact Dr. Charles Sninsky or Barbara Fitz-Williams
at the University of Florida Clinical Research Center, at
904-392-2877.

       enzymes for treating diarrhea related to HIV-associated fat
       malabsorption

       This study will evaluate the effect of exogenous enzymes on
people with HIV and severe diarrhea that has no identifiable,
treatable cause but is related to fat malabsorption. Pancrelipase
supplements are already approved for the treatment of non-HIV-related
fat malabsorption. The study involves a special diet and 12 days of
hospitalization. Body composition tests will be performed. In San
Francisco call Yvette Garcia at 415-206-4748 or Johannes Koch at
415-206-4753.

       oral rehydration therapy for chronic diarrhea

       Chronic diarrhea results in depletion of water and nutrients.
This study will compare the efficacy of 2 oral rehydration solutions
(ORS): a standard glucose formula vs a newer one containing
oligosaccharides, 'shorter' sugars that may reduce diarrhea in
addition to rehydrating the participant. Chronic diarrhea, an entrance
requirement, is defined as 3 or more episodes, 3 times a week, for 3
weeks. For more information, call the Network in New York at
800-858-2111.

       glutamine for bowel syndrome

       Glutamine is an amino acid that may help repair damaged
intestinal linings (contributing to 'leaky bowel syndrome,' associated
with HIV infection). Participants will be randomized to receive 1 of 2
doses of glutamine or placebo for 28 days. Various tests are performed
to measure the integrity of intestinal linings as well as absorption
and treatment efficacy. Call the Network at 1-800- or 212-260-8868.
L-carnitine for myopathy

       (muscle weakness/degeneration)

       L-carnitine is a natural biochemical that stimulates the
oxidation and synthesis of fatty acids. The National Institutes of
Health (NIH) is conducting a Phase II placebo-controlled trial to
evaluate L-carnitine as a treatment for myopathy, which sometimes is
associated with use of AZT. Call Dr. Cupler at the National Institute
of Neurological Disorders and Stroke (NIND), a division of NIH, at
301-402-4479.

       Immune Enhancement recombinant human interleukin-12 (rhIL-12)

       This Phase I study will evaluate the safety of single doses of
rhIL-12, a natural protein involved in regulating the cell-mediated
immune response. Participants have 100-500 CD4 cells/mm3, are
currently taking an antiretroviral (for at least 6 weeks), and are
asymptomatic or slightly symptomatic. In the SF Bay Area, call UCSF at
415-476-9296, extension 84598. In Southern California, call the UCLA
CARE Center at 310-206-6414.

       thymopentin (TP5)

       Thymopentin, or TP5, is derived from a natural hormone and
stimulates the immune system. This Phase III double-blind,
placebo-controlled trial will evaluate the safety and efficacy of
thymopentin (Timunox) in HIV positive individuals taking one or more
anti-HIV drugs. Participants are randomized to receive thymopentin
with AZT or ddI, or AZT combined with ddI, or AZT combined with ddC. A
previous study indicated that the combination of thymopentin and AZT
was more effective than AZT alone in slowing HIV disease progression.

       A related Phase II placebo-controlled trial will look at the
impact of various doses of thymopentin on viral load; the study is
open to people with less than 400 CD4 cells/mm3.

       HIVIG plus AZT vs IVIG plus AZT for pregnant women

       HIVIG, a solution of concentrated antibodies, is a type of
passive immunotherapy. ACTG 185 is a Phase III trial that compares
HIVIG to IVIG for efficacy in preventing transmission of HIV from
mother to infant. Participants are randomized to take either HIVIG or
IVIG; all participants take AZT. Infants receive the same treatment as
mothers. Mothers are given AZT intravenously during labor. Newborns
also receive either IV HIVIG or IVIG within 12 hours of birth, and a
syrup formulation of AZT for 6 weeks. There are numerous sites
nationwide.

       Children and Adolescents

       Virgina Parks, an AIDS treatment activist living in San
       Francisco, contributed to the Children and Adolescents section
       in this issue.

       accessing experimental therapies not in pediatric trials

       Although most adult studies are only open to persons over the
age of 18 years, several adult studies now also include adolescents
13-17. Representatives at 1-800-TRIALS-A can identify which adult
studies permit adolescents. For children with limited therapeutic
options, many pharmaceutical companies will allow compassionate use of
therapies not yet in pediatric trials. Such use is determined on a
patient-by-patient basis and may depend upon the availability of
dosing information or a liquid formulation of the drug. Your
pediatrician should contact the company directly and request the
department or investigator handling the drug in question.

       3TC and AZT

       Approximately 600 children ages 3 months to 15 years, with less
than 56 days previous use of an antiretroviral will be enrolled in
this double-blind efficacy study. Children will be randomized to
receive either 3TC and AZT or placebo and AZT. The study, considered
pivotal for FDA approval of the drug, may be revised if data from
current pediatric studies suggest that the combination of AZT and ddI
is preferable to AZT alone (see below). Clinical endpoints include
growth failure, onset or progression of central nervous system
problems and major opportunistic infection(s) or AIDS-defining events.
This study is scheduled to begin enrolling in April at 74 sites
nationwide including all ACTG and National Institute of

       Child and Human Development (NICHD) sites.  VP 3TC, AZT and ddI

       This study will evaluate the safety, efficacy and
pharmacokinetics of 3TC, AZT and ddI in children with HIV.
Participants enrolled in Arm A will receive all 3 drugs concurrently,
but will be assigned to 1 of 2 different AZT dose levels. Patients in
Arm B will be assigned treatment based on their past medical history
as follows:

        Patients with toxicity to ddI receive AZT and 3TC.
        Patients with toxicity to AZT receive ddI and 3TC.
        Patients with toxicity to AZT and ddI with progressive HIV
         will receive all 3 drugs concurrently, but the AZT dose will
         be 90 mg/m2.

       Participants must be between 3 months and 18 years old.
Exclusion criteria include opportunistic infections requiring
treatment. For more information, contact Susan Sandelli, RN, at NCI at
301-402-1391.

       off-study access to 3TC

       Glaxo, the manufacturer of 3TC, will provide free drug to
patients for whom other antiretrovirals have failed. This expanded
access program includes adults and children over the age of 2 years.
Glaxo also has been receptive to requests for compassionate use in
children less than 2 years old. Call 1-800-248-9757 for more
information on expanded access or compassionate use of 3TC. VP

       oral ganciclovir

       ACTG 225 is a study of oral ganciclovir in children with
asymptomatic CMV infection and low CD4 cell counts. Four different
doses will be evaluated for pharmacokinetics and long-term safety in
children. The study will enroll 32 children at several ACTG sites.  VP

       antibiotics for prevention of multiple opportunistic infections

       ACTG 254 will compare trimethoprim/sulfamethoxazole (TMP/SMX)
to the combination of azithromycin and atovaquone as prophylactic
regimens against PCP, MAC and other AIDS-related infections. The study
seeks to enroll 680 children aged 2 to 13 years whose imune status
indicates prophylaxis. Several sites nationwide.  VP

       AZT for encephalopathy

       This study will determine if continuous infusion AZT will
improve neurodevelopmental deficits associated with HIV infection or
decrease encephalopathy rate. Eligible participants must be between 3
months and 18 years old with persistent HIV-related encephalopathy
despite optimal oral AZT therapy. Exclusion criteria include use of
immunomodulatory agents within 4 weeks. For more information, contact
Susan Sandelli, RN, at NCI at 301-402-1391.

       AZT, ddI and nevirapine

       ACTG 245 will evaluate the safety and efficacy of the
combination of AZT, ddI and nevirapine in children 6 months to 18
years of age who have persistently elevated or rising p24 antigen
levels while receiving AZT and ddI in combination. Requirements
include 12 weeks of AZT and ddI treatment, and a positive p24 antigen
after 12 weeks of therapy. Opportunistic infections requiring
intervention are not permitted, but prophylaxis for PCP and MAC is
allowed. Note: Rash is a possible side effect of nevirapine. Although
treatable, the rash may sometimes progress into a more serious and
painful dermatologic condition known as Steven's Johnson syndrome.
Children with HIV sometimes develop this disorder independently of
nevirapine treatment. All HIV positive children with body rash should
be closely monitored, especially those taking nevirapine.  VP

       AZT and ddI

       ACTG 152 compares AZT or ddI vs AZT plus ddI in children with
previous AZT experience. Based upon interim data, the monotherapy AZT
arm has been closed; children on that arm will be unblinded and
offered the best available care as determined by parent/guardian and
physician. Children on the ddI monotherapy or AZT/ddI combination arm
will remain on study until it ends in August 1995.  VP

       protease inhibitor (KNI-272)

       The National Cancer Institute (NCI) is conducting a Phase I
study of the safety, toxicity and antiviral potential of a new
protease inhibitor, KNI-272, in HIV positive children ages 3 months to
18 years. Children with no prior antiretroviral treatment will
comprise arm A, and children intolerant to antiretroviral therapy will
comprise arm B. The study will use 5 dose levels to establish maximal
tolerated and minimally effective doses. Initial and final doses will
be single IV or oral, with 12 weeks of oral administration in between.
Call 301-402-1391 for more information.

       recombinant human growth factor vs growth hormone

       This Phase I/II NCI study compares the safety and tolerance of
recombinant human insulin-like growth hormone (rhGH), in combination
with antiretroviral therapy, in children with HIV and failure to
thrive or grow. Investigators will also collect preliminary data on
the effects of the growth factor and growth hormone on growth, immune
function and viral burden. Eligible children are 6 months to 18 years
old, have used antiretroviral therapy in the past, and have
experienced growth failure. Exclusion criteria include diabetes and
malnutrition. Initially, all children will receive AZT and ddI for 12
weeks. They will then be randomized to receive either rhIGF-1 or rhGH
for 12 weeks. Children who benefit may continue for another 12 weeks
(36 total). Call the NCI at 301-402-1391 or 301-402-1387.

       non-Hodgkin's lymphoma

       The NCI is conducting a pilot study of 2 drugs, systemic
cyclophosphamide and methotrexate, for the treatment of HIV-related
non-Hodgkin's lymphoma in children aged 3 months-18 years. The drugs
under study are considered the 2 most effective drugs for treating
childhood lymphomas. During the 2-month study, participants will
continue to use antiretrovrial therapy as well as IV gamma globulin,
acyclovir and PCP prophylaxis to minimize the risk of complicating
infection. For more information, call the NCI at 301-496-2321.

       Women

       natural history of HIV infection in women

       Sponsored by the National Institute of Allergy and Infectious
Disease (NIAID), the Women's Interagency HIV Study (WIHS, pronounced
'wise') is a large prospective observational study of the natural
history of HIV infection in women. Investigators will be evaluating
clinical manifestations, immunologic markers and virologic parameters,
the roles in disease progression of cofactors such as nutrition,
endocrine influences (hormones), socioeconomic status and substance
use, and more.

       Designed to last 4 years, the study involves clinic visits
every 6 months. Each visit, participants will have
physical/gynecological exams and blood draws (for laboratory tests).
Eligible HIV positive women are 13 years or older. (Enrollment is also
underway for an HIV negative control group of 'high-risk' women ,
i.e., injection drug-using, having multiple sex partners, etc.) The 6
study sites are New York (2 sites), Washington, D.C., Chicago, San
Francisco and Los Angeles. For information in English and Spanish,
call the National WIHS Hotline at 1-800-665-1855.

       cervical dysplasia

       ACTG 200, a phase II/III open-label multicenter trial, is
enrolling HIV positive women with cervical dysplasia. Investigators
will evaluate the safety and efficacy of 5-FU for maintenance
treatment of cervical dysplasia. Participants will be randomized to a
treatment or an observation arm. Those in the treatment arms will
apply topical 5-FU twice a week for 6 months.

       cervical intraepithelial neoplasia (New York only)

       In New York, this information-gathering study will look at the
relationship between HIV-related immunosuppression and cervical
intraepithelial neoplasia, or CIN. Clinical data will be collected
through the provision of routine gynecological care to female
participants. For more information, call Mary Jo Hoyt, principal
investigator, at 212-604-8038.

       Miscellaneous

       thalidomide (Synovir) for aphthous ulcers

       ACTG 251 is a multicenter study of the safety and efficacy of
thalidomide for the treatment of oral and esophageal aphthous ulcers
and HIV viremia. Investigators will look at viral load and tumor
necrosis factor (TNF) levels. To participate, people with HIV need to
have had a biopsy within 8 weeks prior to study entry that documents
the presence of aphthous ulcers lasting at least 2 weeks, as well as a
negative culture for herpes (within the same period). Participants
will be randomized to receive 4 weeks of either 200 mg oral
thalidomide or placebo once daily.

       acitretin for severe psoriasis

       In New York, there is an open-label, dose-escalating trial of
the efficacy of oral acitretin for the treatment of psoriasis in
people with HIV. Acitretin is known to clear psoriasis and is
considered an effective treatment in HIV negative people; this will be
the first thorough study of its use in people with HIV. Eligible
participants are 18-55 years of age with psoriasis that affects at
least 10% of their bodies (as measured by the Psoriasis Area and
Severity Index, or PASI). Everyone will begin with a minimum dose of
25 mg/day. Various assessments will be performed at regular intervals
during the 20-week study, including x-ray, skin biopsy, blood tests,
PASI evaluations and photographic studies. For more information,
contact Dr. Bradford Katchen at the Department of Dermatology, Beth
Israel Medical Center, at 212-420-2184.

       tuberculosis (Tb) prophylaxis

       ACTG 177/CPCRA 004 is a phase II open-label trial that will
evaluate the safety and efficacy of 2 different drug regimens for the
prevention of Tb. Participants will be randomized to receive either
rifampin and pyrazinamide for 2 months, or isoniazid and vitamin B6
for 1 year. Persons with active Tb, acute hepatitis and/or severe
peripheral neuropathy and pregnant women will be excluded. There are
multiple sites.

       delavirdine for AIDS dementia complex (ADC)

       This Phase II placebo-controlled study will look at the safety
and efficacy of delavirdine (DLV) for treating ADC. DLV, a
non-nucleoside antiretroviral also under study for its anti-HIV
effects, may improve neurological function. There are no CD4 cell
requirements. People using AZT, ddI or ddC must have been doing so for
a minimum of 90 days before the study begins. If the treatment appears
promising, participants may be eligible to take DLV indefinitely.

       neutropenia prevention: filgrastim (Neupogen)

       This randomized, controlled trial will evaluate the efficacy of
filgrastim for the prevention of serious (Grade IV) neutropenia, or
low numbers of white cells in the blood. Participants will receive 1
of 2 doses of filgrastim or placebo by subcutaneous injection.
Requirements include a white blood count between 750 and 1000
cells/mm3. No treatment with filgrastim or growth factors for 14 days,
active CMV retinitis or cancer (except for stable KS), allowed.
Participants receiving ganciclovir must wait 3 weeks after starting
ganciclovir. This is a multicenter study.

       Chinese herbal medicine and immune enhancement

       This 1-year study seeks to determine the efficacy of 2 herbal
formulations (an antiviral and an immune enhancer) in maintaining the
immune system and improving quality of life in HIV positive
individuals. This study is a collaborative effort between the Pacific
Oaks Medical Group and the Oriental Medical Center. Participants must
have 300-500 CD4 cells/mm3 and must discontinue use of any
antiretroviral(s) for at least 30 days before entering as well as
throughout the study. For more information contact Paul Prosser at the
Pacific Oaks Medical Group at 818-906-6279.

       standard antibiotics vs Chinese medicine for chronic sinusitis

       This 12-week study compares the efficacy of traditional Chinese
medical to standard antibiotic treatment of HIV-related chronic
sinusitis, a condition often unresponsive to standard Western
treatments. Participants will be randomized to receive acupuncture and
Chinese herbs or an antibiotic for 8 weeks. Eligible participants have
CT scan-confirmed sinusitis and have used neither acupuncture nor
herbs in the month before the study begins. In the SF Bay Area contact
Thomas Sinclair or Elyse Graham at the Immune Enhancement Project at
415-252-8711.

       testosterone patch

       This Phase I study will measure the effectiveness of Testoderm
Testosterone Transdermal System (Testoderm-TTS) in HIV positive men
with low testosterone levels. Eligible participants have less than 200
CD4/mm3 or a history of an AIDS-defining illness, and must have been
taking AZT, ddC, ddI and/or d4T for a minimum of 60 days prior to
study entry. No previous or current testosterone treatment will be
allowed. The study lasts 2 months. For more information contact Paul
Prosser at the Pacific Oaks Medical Group at 818-906-6279.

       intravenous testosterone replacment

       This pilot study evaluates the safety and efficacy of
intravenous testosterone replacement in men with HIV and loss of sex
drive or depression. In New York, call Judith Rabkin, PhD, at the NYS
Psychiatric Institute at 212-960-5762.


       Clinical Trials Information by Region

       SOUTHERN CALIFORNIA
       HIV TREATMENT DIRECTORY
       213-469-5888

       AIDS/HIV TREATMENT DIRECTORY
       FOR NEW ENGLAND
       617-566-4004

       NEW YORK,
       CONNECTICUT,
       NEW JERSEY AND PHILADELPHIA
       212-268-4196

       AIDS Institute
       Experimental Treatment Infoline
       in New York state: 800-MEDS-4-HIV
       outside New York: 212-239-5523

       DIRECTORY OF WISCONSIN
       HIV/AIDS CLINICAL TRIALS
       in Wisconsin: 800-359-9272
       outside Wisconsin: 414-291-2799

       NORTHERN GEORGIA and ALABAMA
       404-874-7926

       SOUTH FLORIDA
       Community Research Initiative of South Florida, Inc.
       305-667-9296

       GULF COAST REGION
       504-584-3605

       HOUSTON CLINICAL TRIAL NETWORK
       713-520-2083

       CANADIAN HIV TRIAL NETWORK
       604-631-5327

       ACTIVELY RECRUITING U.S. TRIALS
       AmFAR Treatment Directory
       212-682-7440

       SAN FRANCISCO BAY AREA
       415-476-9554


       Glossary

       3TC (LAMIVUDINE): a nucleoside analog drug that has less
serious toxicities than other nucleoside analogs. When used as
monotherapy resistance develops rapidly, but in combination with AZT,
3TC has shown sustained, strong anti-HIV activity.

       A

       ACCELERATED APPROVAL: FDA regulations governing early marketing
 approval of promising drugs for life-threatening illnesses such as
 AIDS. To receive accelerated approval a drug need not show evidence
 of clinical benefit (e.g., increased survival or decreased disease
 progression), but rather 'reasonable promise' of benefit based on
 surrogate marker data.

       ACUTE: rapid in onset, aggressive; opposite of chronic.

       ACYCLOVIR (ZOVIRAX): an antiviral drug used to treat herpes
 simplex virus 1 and 2 and herpes zoster (shingles). When used in
 combination with AZT, acyclovir has been shown in some studies to
 prolong survival in persons with HIV disease.

       ADDICTION: psychological dependence on a drug. See dependence.

       ADJUVANT ANALGESIC: a drug (e.g., antidepressant, steroid)
 which increases the pain-relieving effects of opioid analgesics or
 which is used as a principal analgesic for pain due to nerve damage.

       AFFERENT: nerves that travel from the rest of the body (e.g.,
 skin, muscles, organs) to the brain and spinal cord.

       AGONIST: an agent that binds to a receptor on a cell's surface
 and promotes a specific cellular activity. Agonists mimic or
 reproduce the activity of the body's own neurotransmitters and other
 regulatory chemicals or drugs.

       AGONIST-ANTAGONIST: an agent which has a mixed effect on cells
 by acting on different types of receptors, some of which stimulate
 cellular activity (agonist) and some of which inhibit cellular
 activity (antagonist).

       AIDS CLINICAL TRIALS GROUP (ACTG): a NIAID-sponsored group of
 medical centers, known as AIDS Clinical Trials Units (ACTU), that
 evaluate treatments for HIV disease and associated illnesses. There
 are 36 adult ACTG sites and 24 ACTG pediatric sites.

       AIDS-RELATED COMPLEX (ARC): a term used to describe the
 condition in which a person is HIV positive and has a variety of
 symptoms that are related to HIV disease (e.g., night sweats,
 diarrhea) but that do not qualify as AIDS-defining illnesses.

       AMBULATORY: able to walk and move about without assistance.

       ANALGESIA: relief from pain. An analgesic is a drug that
 reduces sensibility to or perception of pain.

       ANDROGEN: a hormone (e.g., testosterone) that has masculinizing
 effects, including stimulation of the male reproductive organs and
 development of secondary sex characteristics.

       ANEMIA: an abnormally low number of red blood cells or a
 decreased concentration of hemoglobin, resulting in a reduction of
 the supply of oxygen to cells and tissues. Anemia is often
 accompanied by fatigue and weakness.

       ANERGY (adjective ANERGIC): the lack of an immune response to a
 foreign antigen that would be expected to produce a reaction in a
 person with normal immunity. Anergy may indicate an inability to
 mount a normal allergic or immune response.

       ANGIOGENESIS: the growth and proliferation of blood vessels.

       ANOREXIA: the lack or loss of appetite for food.

       ANTAGONIST: an agent that prevents or reverses the action of
 another agent. An antagonist prevents the activation of a specific
 cellular function by binding to a cell's receptors and blocking their
 use by other drugs or chemical messengers.

       ANTIBODY (AB): an immunoglobulin protein secreted by activated
 plasma cells, which evolve from B-cells, in response to an
 antagonistic substance (antigen) in the body; specific antibodies
 bind to and act upon specific antigens. The antigen/antibody reaction
 forms the basis of humoral (TH2) immunity. Neutralizing antibodies
 destroy or inactivate infectious agents while enhancing antibodies
 promote infection.

       ANTICHOLINERGIC: an agent that affects parasympathetic neural
 transmission, causing symptoms such as dry mouth, blurred vision,
 constipation and increased heart rate. Some drugs (e.g., tricyclic
 antidepressants) have anticholinergic side effects.

       ANTICONVULSANT: a drug that reduces or prevents convulsions
 (seizures or fits).

       ANTIDEPRESSANT: a drug that acts to elevate the mood and prevent, cure
or alleviate mental depression; antidepressants are also
 sometimes used to relieve pain. Heterocyclic, noncyclic and tricyclic refer
to specific chemical structures of antidepressant drugs.
 Other classes include MAO inhibitors and serotonin reuptake inhibitors.
ANTIEMETIC: an agent that relieves nausea and vomiting.
ANTIGEN: any agent or substance that stimulates an immune response. Antigens
are often foreign microorganisms such as bacteria
 or viruses, or the substances they produce.
ANTIGENEMIA: the presence of an antigen in the blood.
ANTIRETROVIRAL: an agent (e.g., AZT, d4T) used to suppress the activity or
replication of retroviruses such as HIV.
ANTISENSE: a complementary piece of genetic material (DNA or RNA) that binds
to another piece of DNA/RNA by base-pairing
 and thus prevents that DNA/RNA from being used to synthesize new proteins.
HIV antisense therapy (e.g., GEM 91) binds to viral
 messenger RNA and blocks viral replication.
ANTIVIRAL: an agent that interferes with the life cycle of a virus and
suppresses its replication.
ANXIOLYTIC: a drug (e.g., diazepam) that counteracts or reduces anxiety.
APOPTOSIS: premature programmed cell death.
ARTHRALGIA: pain in a joint.
ARTICULAR: relating to a joint.
ASSAY: a test used to detect the presence and/or concentration of a drug,
substance or microorganism in the blood and/or other body
 fluids or tissues.
ASTERIXIS: involuntary jerky tremors, especially of the hands.
ASYMPTOMATIC: not feeling or showing outward signs of disease despite the
presence of a disease-causing agent.
ATHYMIC: lacking a thymus gland.
ATROPHY: progressive degeneration or wasting; often refers to the loss of
muscle tissue.
ATTENUATE: to weaken, to reduce the level of virulence.
AUTOIMMUNE RESPONSE (AUTOIMMUNITY): a condition in which an individual's
immune system fails to recognize its own
 biochemical markers as being 'self,' and thus attacks body tissues as if
they were foreign matter.
AUTONOMIC NERVOUS SYSTEM (ANS): the branch of the nervous system that
primarily controls non-voluntary bodily processes
 such as heartbeat, intestinal motility and non-endocrine gland secretion.
The ANS has two branches, sympathetic and
 parasympathetic.
AZT (ZIDOVUDINE, RETROVIR): a nucleoside analog that suppresses replication
of HIV.
B
BACTEREMIA: the abnormal presence of bacteria in the blood.
BASELINE: a known value to which later measurements can be compared, e.g.,
baseline CD4 cell count.
BASIC FIBROBLAST GROWTH FACTOR (bFGF): a chemical that promotes angiogenesis
(blood vessel proliferation), which is
 essential for the development of Kaposi's sarcoma and other neoplasms.
B-CELL (B-LYMPHOCYTE): an immune system cell that carries out the humoral
immune response. B-cells are 1 of 2 major classes
 of lymphocytes and are produced in the bone marrow and spleen. B-cells
mature into plasma cells that produce antibodies against
 specific pathogens.
BECK DEPRESSION INDEX: a written self-report questionnaire used to measure
the level of clinical depressive symptoms.
BETA-2 MICROGLOBULIN (B2M): a cell surface protein that is released into the
bloodstream when cells die. Elevated blood levels
 are associated with immune activation and HIV replication.
BILIRUBIN: a pigment released by red blood cells when they are removed from
circulation and broken down. High serum levels of
 bilirubin may indicate stress on the liver.
BIOAVAILABILITY: the extent to which a substance (e.g., a drug) is absorbed
and circulated in the body; the physiological
 availability of a drug, as distinct from its chemical potency.
BRANCHED DNA ASSAY (BRANCHED CHAIN DNA, bDNA): a test for measuring viral
load in plasma or tissue by detecting a
 chemical signal produced by viral RNA. The bDNA test is faster and
potentially more accurate than traditional methods.
C
CACHEXIA: a condition of body wasting and general ill-health.
CANDIDIASIS: a fungal disease caused by the yeast-like fungus Candida
albicans. Candidiasis can affect the skin, nails and mucous
 membranes throughout the body including the mouth, esophagus, vagina,
intestines and lungs. Oral and vaginal candidiasis are often
 early signs of an impaired immune system in HIV positive individuals.
CARCINOMA: a malignant tumor that may spread throughout the body.
CARIES: decay or destruction of parts of the tooth; cavities.
CD4 CELL (CD4 LYMPHOCYTE, T-HELPER CELL, T4 CELL): an important subset of
white blood cells that carry the CD4 surface
 marker and help the body fight infection. CD4 cells engulf and process
invaders (e.g., viruses) and display pieces for recognition by
 disease-fighting cells (e.g., cytotoxic T-lymphocytes). CD4 cells release
cytokines that coordinate a broad range of immune activity
 including killer cell activation and antibody production. HIV invades CD4
cells, typically resulting in their dysfunction or destruction.

CD4 CELL COUNT (T-HELPER CELL COUNT): the number of CD4 lymphocytes present
in a cubic millimeter (mm3) of blood. The
 CD4 count is one indicator of the severity or progression of HIV disease and
is sometimes used as a surrogate marker. In healthy
 adults CD4 cell counts range from 400-1800 cells/mm3 and vary over the
course of the day; counts are considerably higher in healthy
 children. In adults, severe immune suppression is associated with CD4 cell
counts below 200 cells/mm3.
CD4 (OR CD8) CELL PERCENTAGE: the number of CD4 (or CD8) cells as a
percentage of all lymphocytes. Cell percentage is a
 more consistent and reliable measure than absolute cell count.
CD4/CD8 RATIO: the ratio of CD4 cells to CD8 cells. In healthy individuals
the CD4/CD8 ratio is about 2; in individuals with HIV
 disease the ratio typically eventually drops below 1.
CD8 CELL (CD8 LYMPHOCYTE, T8 CELL): a type of white blood cell that helps
regulate and/or carry out the body's immune
 response. There are 2 major subsets of T-cells that express the CD8 surface
marker: T-suppressor cells and cytotoxic T-lymphocytes
 (CTL).
CELIAC PLEXUS BLOCK: use of anaesthetic techniques to numb or destroy a web
of nerves in the abdominal cavity that surrounds
 the celiac branch of the aorta; the procedure is used to control severe,
intractable pain.
CELL-MEDIATED IMMUNITY (CELLULAR IMMUNITY, TH1 RESPONSE): a type of specific
immune response mediated by the
 TH1 subset of CD4 cells and carried out by CD8 cytotoxic T-cells (CTL) and
macrophages. Cell-mediated immunity is stimulated by
 the cytokines IL-2, IL-12 and gamma interferon. Contrast with humoral
immunity.
CELLULITIS: inflammation of subcutaneous connective tissue.
CENTERS FOR DISEASE CONTROL AND PREVENTION (CDC): the U.S. federal government
agency within the Department of
 Health and Human Services that monitors disease occurrence and develops
policies for preventing diseases and maintaining the
 health of the population.
CENTRAL NERVOUS SYSTEM (CNS): the brain and spinal cord.
CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN): abnormal growth of cells of the
uterine cervix; may be an early stage of
 cervical cancer.
CERVICOVAGINAL: relating to the uterine cervix and the vagina, parts of the
female reproductive system.
CHEMOTHERAPY: the use of chemical agents to treat disease.
CHRONIC: less intense, slow, persisting over a long period of time; opposite
of acute.
CODON: a sequence of 3 nucleotides or bases that encode the information for
a particular amino acid (the building blocks that make
 up proteins).
COFACTOR: a substance, microorganism or environmental factor that activates
or enhances the action of a disease-causing agent.
 Some possible cofactors in AIDS are mycoplasma, herpesviruses and age.
COLITIS: inflammation of the colon.
COLONY-STIMULATING FACTOR (CSF): a cytokine responsible for controlling the
production of white blood cells. Types include
 granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage
colony-stimulating factor (GM-CSF) which are used to
 relieve neutropenia caused by drugs such as AZT and ganciclovir.
COLPOSCOPY: examination of a tissue surface, typically the uterine cervix,
with a low-power microscope (a colposcope) to identify
 abnormal cell growth and, if necessary, remove a piece of tissue for biopsy.

COMBINATION THERAPY: simultaneous or alternating administration of 2 or more
therapies.
COMMUNITY PROGRAMS FOR CLINICAL RESEARCH ON AIDS (CPCRA, TERRY BEIRN CPCRA):
a community-based clinical
 trials network sponsored by NIAID with 17 units in 15 U.S. cities. CPCRA
conducts Phase II and III studies in community-based
 settings with a focus on new treatments for opportunistic infections,
particularly in underserved populations.
COMPASSIONATE USE: an FDA classification that allows the use of an
experimental drug for a serious illness for which there is no
 other suitable treatment, even though data are lacking regarding the drug's
effectiveness.
CONTROLLED TRIAL: a clinical trial in which the group receiving an
experimental therapy is compared with a control group that is
 not given the intervention being studied. In a placebo-controlled trial the
control group is given an inactive substance (placebo); in
 an active control trial the control group is given the best existing proven
therapy.
CORTISOL: a steroid hormone secreted by the adrenal cortex as part of the
body's response to stress. Cortisol promotes the
 breakdown of bodily tissues and high levels are associated with reduced
immune function. Synthetic cortisol (hydrocortisone) is used
 to reduce inflammation and allergic reactions.
CREATINE PHOSPHOKINASE (CPK): an enzyme essential for muscle contraction.
Blood levels of CPK are typically elevated in
 muscle diseases (myopathies), and CPK levels can be used to monitor toxicity
to the muscles.
CROSS-TOLERANCE: a situation in which tolerance to one drug carries over to
another related drug, so that the similar drug has
 reduced effects.
CRYPTOSPORIDIOSIS: a disease caused by the protozoa Cryptosporidium parvum.
The parasite is transmitted to humans by direct
 contact with the feces of an infected animal, ingestion of contaminated food
or water or oral-anal sexual contact (rimming). The
 protozoa grows in the intestines and bile ducts and causes severe, chronic
diarrhea, gas, weight loss and lymphadenopathy.
 Cryptosporidiosis may be persistent and life-threatening in immunosuppressed
individuals.
CYCLOOXYGENASE: an enzyme involved in oxygen metabolism. Cyclooxegenase is
part of the pathway that mediates bodily
 response to infection and injury (e.g., inflammation and pain) via
substances such as histamine and prostaglandins.
CYTOKINE: a chemical messenger protein released by white blood cells,
including macrophages, monocytes and lymphocytes.
 Cytokines facilitate communication among immune system cells and between
immune system cells and the rest of the body.
CYTOMEGALOVIRUS (CMV): a virus of the herpes family. CMV infection often
occurs in healthy individuals without causing
 symptoms. In individuals with HIV disease, CMV may reactivate and cause
serious illness including retinitis, pneumonia, colitis and
 encephalitis. CMV infection may result in blindness or death.
CYTOTOXIC T-LYMPHOCYTE (CTL, T-KILLER CELL): an immune system white blood
cell that targets and kills cells infected
 with viruses, bacteria, parasites and other microorganisms. The action of
CTL is coordinated by CD4 cells via the production of
 cytokines.
CYTOTOXICITY: the quality of being toxic to or killing cells.
D
DELIRIUM: a state of mental confusion, usually acute and rapid in onset; may
be caused by disease, drugs, high fever, etc.
DEMENTIA: chronic loss of mental capacity that affects a person's ability to
function in a social or occupational setting. Dementia
 involves the progressive deterioration of thinking, behavior and motor
skills. AIDS-related dementia may be caused by HIV, drugs
 or opportunistic infections.
DEMOGRAPHICS: the characteristics of a population, e.g., sex, race, age and
geographical location.
DEPENDENCE: a state in which a person is reliant on a drug. Physical
dependence is characterized by the onset of physical
 symptoms of withdrawal (e.g., sweating, tremors) if a drug is abruptly
stopped. Psychological dependence or addiction is a
 psychological and behavioral syndrome characterized by drug craving,
compulsive use, abberant drug-related behaviors and relapse
 after abstinence.
DERMATOMYOSITIS: combined skin and muscle inflammation resulting in muscle
weakness.
DNA (DEOXYRIBONUCLEIC ACID): a molecule found in the nucleus of cells as a
twisted double-stranded chain that encodes
 genetic information. The particular sequence of the 4 chemical building
blocks (nucleotides) that make up a DNA chain determines
 the unique genetic code of an individual. See also RNA.
DOUBLE-BLIND: a type of clinical trial in which neither the subject nor the
observer knows what treatment, if any, the subject is
 receiving. At the end of the experiment the 'code' is broken and data are
analyzed by the type of treatment received.
 Double-blinding is done to minimize bias due to the expectations of the
patient, the investigator and/or healthcare providers.
DSM IV: the Diagnostic and Statistical Manual, a compendium of psychiatric
and mental disorders published by the American
 Psychiatric Association. The current edition is IV; the previous edition was
III-R.
DYSPLASIA: abnormal development or growth of cells and tissues; precancerous
tissue changes.
E
EDEMA: swelling caused by an abnormal accumulation of fluid in body tissues.
EFFERENT: nerves that travel from the brain and spinal cord to the rest of
the body.
EMPIRIC TREATMENT: evaluation and treatment based on observation and
experience alone, without relying on laboratory results.
ENCEPHALITIS: inflammation of the brain.
ENDOCRINE GLAND: a ductless gland that regulates bodily functions via
hormones secreted into the bloodstream. The endocrine
 glands include the hypothalamus, pituitary gland, thyroid, adrenal glands
and gonads (ovaries and testes).
ENDOTHELIUM (adjective ENDOTHELIAL): a layer of cells that line blood
vessels, the heart and body cavities.
ENDPOINT: a direct marker of disease progression, e.g., disease symptoms or
death. The effectiveness of drug therapies is often
 determined by observing the clinical endpoints that develop over time in a
group of patients undergoing experimental treatment.
 Contrast with surrogate marker.
EPIDEMIOLOGY: the study of the frequency, distribution and behavior of a
disease in a population.
EPSTEIN-BARR VIRUS (EBV): a virus of the herpes family. EBV infection is
common and usually asymptomatic in childhood, and
 may cause infectious mononucleosis in young adults. EBV is associated with
hairy leukoplakia, some types of lymphoma and
 AIDS-related muscle cell tumors.
EQUIANALGESIC: providing equivalent amounts of pain relief.
ESCAPE VARIANT (ESCAPE MUTANT): a strain of a microorganism (e.g., a virus)
that has mutated so as to escape sensitivity to a
 drug; a drug-resistant strain.
ESTROGEN: female sex hormone; a natural or synthetic substance (e.g.,
estradiol) that stimulates the development of secondary sex
 characteristics and regulates the reproductive cycle in women.
EUTHANASIA: deliberate ending of life to reduce pain and suffering; 'mercy
killing'.
EXOGENOUS: originating or produced outside of the body.
EXPANDED ACCESS: an FDA program that distributes experimental drugs free of
charge through physicians to people with
 life-threatening illness who have failed on or are intolerant of approved
therapies and have no other treatment options.
EXTRAPYRAMIDAL TRACT: a central nervous system tract (bundle of nerves) that
lies outside of the pyramidal tracts and controls
 body tone and posture.
F
FIRST-LINE TREATMENT: the preferred standard therapy for a particular
condition.
FOOD AND DRUG ADMINISTRATION (FDA): the agency of the federal government
responsible for regulating the development,
 use and safety of drugs, medical devices, food, cosmetics and related
products.
FOSCARNET (FOSCAVIR): an antiviral drug used to treat cytomegalovirus disease
and acyclovir-resistant herpesvirus infection.
 Adverse side effects may include kidney toxicity, muscle twitching, nausea
and skin ulcers.
FUNGUS: a class of organisms that includes yeasts, molds and mushrooms,
several of which (e.g., Candida albicans, Pneumocystis
 carinii) can cause opportunistic infections in humans.
G
GANCICLOVIR (CYTOVENE): an antiviral drug used to treat cytomegalovirus (CMV)
infection. Ganciclovir may be administered
 intravenously via a central catheter; an oral form has recently been
FDA-approved as maintenance therapy for CMV retinitis.
GEM 91: an experimental anti-HIV compound; GEM 91 is an antisense
(complementary) strand of nucleotides that can bind to HIV
 RNA and thus block viral replication.
GENE: the unit of heredity. A gene contains hereditary (genetic) information
encoded in the form of DNA and is located at a specific
 position on a chromosome in a cell's nucleus. Genes determine many aspects
of anatomy and physiology by controlling the
 production of proteins.
GENE THERAPY: an approach to preventing and/or treating disease by replacing,
removing or introducing genes or by otherwise
 manipulating genetic material. Examples include adding a gene to a cell to
produce a specific missing protein and using antisense
 molecules to prevent viral replication.
GENOTYPE: the specific genetic makeup or 'blueprint' of an individual; see
also phenotype.
GERMINAL CENTER: a part of the lymph node in which immune cell proliferation
takes place.
GLYCOPROTEIN (GP): a small unit made of a sugar and a protein molecule, often
part of a cell's membrane. Glycoproteins make
 up the outer envelope of HIV (e.g., GP41, GP120).
GROWTH HORMONE (GH, SEROSTIM): a peptide hormone secreted by the anterior
pituitary gland in the brain. GH enhances
 growth by stimulating metabolism and protein synthesis and also stimulates
the immune system. rHGH refers to recombinant
 human growth hormone, a genetically-engineered drug under study for the
treatment of HIV-related wasting syndrome.
GYNECOLOGY: the study of the genital and reproductive system of women.
H
HAIRY LEUKOPLAKIA: a condition caused by the Epstein-Barr virus (EBV) and
characterized by small, white, hair-like projections
 on the sides of the tongue.
HALF-LIFE: the time required for half the amount of an agent (e.g., drug,
virus, cell) to be eliminated from the body.
HELPER T-CELL: see CD4 cell.
HEMATOCRIT (HCT): the percentage of red blood cells in whole blood; a drop
in hematocrit may indicate bone marrow
 dysfunction.
HEPATITIS: an inflammation of the liver that may be caused by several agents,
including viruses and toxins. Hepatitis is
 characterized by jaundice, enlarged liver, fever, fatigue and abnormal liver
function tests. Types include hepatitis A (infectious
 hepatitis), hepatitis B (serum hepatitis), hepatitis C and alcoholic
hepatitis.
HEPATOSPLENOMEGALY: enlargement of the liver and spleen.
HERPES SIMPLEX VIRUS (HSV): a herpes group virus that causes blisters and
recurring disease. HSV-1 usually produces lesions on
 the lips or in the mouth ('cold sores'). HSV-2 is usually sexually
transmitted and its lesions generally occur in the anal and/or
 genital area. In healthy individuals blisters usually resolve without
treatment in 2-3 weeks; in immunocompromised persons lesions
 may last longer and be more frequent and severe, and the virus may become
disseminated. Symptomatic disease outbreaks occur at
 unpredictable intervals of weeks, months or years. HSV lies dormant
(inactive) in the nerves; reactivation may result from
 emotional stress, hormonal changes or other illnesses.
HERPESVIRUS: a group of viruses that includes herpes simplex virus type 1
(HSV-1) and 2 (HSV-2), cytomegalovirus (CMV),
 Epstein-Barr virus (EBV), varicella zoster virus (VZV) and human herpesvirus
types 6 and 7 (HHV-6, HHV-7). Herpesviruses may
 act as opportunistic pathogens and/or cofactors in HIV pathogenesis.
HERPES ZOSTER (SHINGLES): a skin condition characterized by painful blisters
that appear in a linear distribution following nerve
 pathways. Shingles is caused by reactivation of the varicella-zoster virus
(VZV) that causes chickenpox; VZV lies dormant in the
 nerves and reactivates when immune defenses are weakened.
HLA (HUMAN LEUKOCYTE ANTIGEN): see major histocompatibility complex.
HORMONE: a chemical messenger that is carried in the blood and is involved
in the regulation and coordination of bodily functions.
HUMAN PAPILLOMAVIRUS (HPV): a member of the papova family of viruses. HPV
causes warts, including the sexually transmitted
 disease Condylomata acuminata (genital warts). Certain strains of HPV are
associated with cervical, anal and oral cancer.
HUMORAL IMMUNITY (ANTIBODY IMMUNITY, TH2 RESPONSE): the immune response that
is mediated by the TH2 subset of
 CD4 cells and carried out by plasma cells (derived from B-cells) which
produce antibodies. Humoral immunity is stimulated by the
 cytokines IL-4 and IL-10. Contrast with cell-mediated immunity.
HYDROXYUREA (HU): an agent FDA-approved for treating leukemia and ovarian
cancer; HU inhibits the synthesis of viral DNA
 and may block HIV replication.
HYPERVARIABILITY: an extremely high rate of genetic variability or mutation.
HYPOGLYCEMIA: a low level of glucose (sugar) in the blood.
I
IDIOPATHIC: referring to a disease or condition of unknown cause.
IDU (INJECTION DRUG USER): a person who uses a drug (e.g., heroin) that is
administered with a needle and syringe. Also known
 as IVDU or intravenous drug user.
IMMUNE MODULATOR (IMMUNOMODULATOR): a substance capable of modifying
functions of the immune system. Immune
 modulators include cytokines (e.g., IL-2, gamma interferon) and broad-acting
agents (e.g., hormones such as endorphins).
IMMUNE MODULATING THERAPY (IMMUNOTHERAPY, IMMUNE-BASED THERAPY): therapy that
attempts to modify or
 enhance the immune response or reconstitute a damaged immune system.
IMMUNE SYSTEM: the body's natural defense system that protects against
foreign invaders (e.g., microorganisms) and cancerous
 cells. Some immune defenses are general or nonspecific (e.g., phagocyte
activity). Defenses against specific antigens are of 2 types:
 cell-mediated (TH1) and humoral (antibody-based or TH2). Organs of the
immune system include the lymph nodes, spleen, thymus,
 tonsils and bone marrow.
IMMUNIZATION: a process by which a person is protected against the adverse
effects of infection by a disease-causing
 microorganism. Active immunization (vaccination) involves innoculating a
person with an antigen and relying on their body to
 produce an immune response. Passive immunization involves giving a patient
exogenous antibodies, which may be either
 manufactured or produced by individuals with active immunity.
IMMUNOCOMPROMISE: reduced function of the body's immune system.
IMMUNOGEN: an antigenic agent or substance that stimulates an immune
response.
IMMUNOGLOBULIN (IG): see antibody.
IMMUNOSUPPRESSION: reduced function of the immune system; a state in which
the immune system defenses have been
 suppressed or weakened.
INFLAMMATION: the body's response to tissue injury or infection; inflammation
typically includes increased vessel dilation and
 permeability resulting in redness, swelling, heat and pain.
INTEGRASE: an enzyme produced by HIV that allows the integration of HIV DNA
into the host cell's genetic material.
INTERCOMPANY COLLABORATION FOR AIDS DRUG DEVELOPMENT (ICC): a cooperative
effort of 16 large pharmaceutical
 companies to share drugs and data and to collaborate on trials of
experimental HIV/AIDS drug combinations.
INTERFERON: a cytokine (messenger protein) that plays a role in immune
response. Interferons are secreted by infected cells and
 help protect other cells from infection. There are 3 major classes: alpha,
beta and gamma. Synthetic interferons are under study as
 treatments for HIV infection and other diseases; beta interferon is being
studied as a treatment for human papillomavirus infection.

INTERLEUKIN (IL): a cytokine (chemical messenger) secreted by immune system
cells. Various interleukins (e.g., IL-1, IL-2, IL-10,
 IL-12) regulate a range of immune system functions. See also TH1/TH2 immune
response.
INTOLERANCE: inability of the body to appropriately metabolize an agent or
drug.
INTRAOCULAR: administered into the eye. An intraocular implant is embedded
in the eye and releases a drug slowly over time.
INTRAVENOUS (IV): injected directly into a vein.
INVASIVE CERVICAL CANCER: an aggressive type of cancer of the uterine cervix
that has spread beyond the surface cell layers.
 Invasive cervical cancer is more common and spreads more rapidly in women
with HIV disease, and is an AIDS-defining illness.
INVESTIGATIONAL NEW DRUG (IND): an FDA classification applied to experimental
drugs undergoing trials to assess safety and
 efficacy prior to marketing approval. See also Treatment IND.
IN VITRO: Latin for 'in glass'; refers to experiments done in a test tube or
culture medium in the laboratory.
IN VIVO: Latin for 'in the body of a living organism'; refers to experiments
using human (or animal) subjects.
K
KAPOSI'S SARCOMA (KS): an abnormal proliferation of incomplete blood or lymph
vessels of the skin, mucous membranes and/or
 internal organs. KS typically appears as pink or purple flat or raised
lesions on the skin or in the mouth. The cause of KS is
 unknown, but has recently been associated with a new herpesvirus. KS is
typically treated with chemotherapeutic drugs.
KAPOSI'S SARCOMA-ASSOCIATED HERPESVIRUS (KSHV): a newly discovered virus
apparently of the herpesvirus family that
 is found in samples of tissue from KS lesions and may be a causal agent or
cofactor.
KARNOFSKY PERFORMANCE SCORE: a measure determined by a test of a person's
ability to perform various routine everyday
 tasks.
KILLER T-CELL: see cytotoxic T-lymphocyte.
L
LESION: any abnormal change in tissue caused by disease or injury.
LEUKOCYTE: any white blood cell, including monocytes, CD4 cells, etc. Many
leukocytes are involved in the body's defense against
 infection and disease.
LEUKOPENIA: an abnormally low number of white blood cells in the circulating
blood.
LIPOSOME (LIPID VESICLE): a spherical particle of fat suspended in a liquid
medium. Liposomes may be used to carry drugs or
 other substances to cells or tissues.
LIVER ENZYME: a protein produced by the liver. Abnormally high levels of
liver enzymes in the blood indicate liver damage or
 disease (e.g., hepatitis, drug-related liver toxicity). Liver enzymes
include alanine transaminase (ALT, SGPT) and aspartate
 transaminase (AST, SGOT).
LOG: refers to quantities in factors of 10. One log change is a 10-fold or
order of magnitude increase or decrease (e.g., 10 to 100 is a
 1-log increase; 100,000 to 1,000 is a 2-log decrease).
LONG-TERM NON-PROGRESSOR (LTNP): an individual who has been infected with HIV
for many years (usually defined as 7-10
 or more years) but who does not exhibit immune system decline or
opportunistic diseases. About 5% of persons with HIV disease
 seem to be LTNP. LTNP may have unusually strong immune responses (e.g., CD8
cell activity), may be infected with a weakened
 strain of HIV or may have genetic factors (e.g., HLA/MHC markers) that
protect them.
LONG-TERM SURVIVOR (LTS): an individual who has been infected with HIV for
a long period of time (typically 7-10 or more
 years). The term long-term survivor may include both long-term
non-progressors and individuals who live for many years with a
 damaged immune system and/or opportunistic infections.
LYMPH NODE (LYMPH GLAND): a small, bean-sized organ located throughout the
body along lymph-carrying vessels, with
 concentrations in the neck, groin and armpits. Lymph nodes are the sites of
antigen presentation and immune activation.
LYMPHATIC SYSTEM (adjective LYMPHOID): a network of capillary-like vessels,
ducts, nodes and organs that help maintain the
 fluid environment of the body and coordinate immune response. The lymphoid
organs include the lymph nodes, spleen, thymus,
 tonsils and adenoids.
LYMPHOCYTE: a type of white blood cell responsible for specific immune
defenses (i.e., against a particular antigen). T-cells and
 B-cells are types of lymphocytes.
LYMPHOKINE: a chemical messenger (e.g., interferon, interleukin) produced by
lymphocytes that directs and regulates immune
 responses.
LYMPHOMA: a malignant disease (cancer) originating in the lymph nodes.
LYSIS: rupture and destruction, e.g., of a cell.
M
MACROPHAGE: a large scavenger white blood cell that ingests degenerated cells
and foreign particles and secretes monokines
 (messenger proteins) involved in a variety of immune system responses. The
long-lived macrophages are a major reservoir of HIV
 infection.
MAINTENANCE THERAPY (SECONDARY PROPHYLAXIS): preventive therapy that follows
successful initial treatment of an
 illness. Generally maintenance therapy continues for the lifetime of the
patient to prevent disease reactivation.
MAJOR HISTOCOMPATIBILITY COMPLEX (MHC): cell surface markers (also known as
HLA markers) which determine receptor
 shape and allow immune cells to recognize components of the body (i.e., to
distinguish 'self' from 'non-self'). Each individuals has
 one of a variety of genetically-determined MHC/HLA patterns. MHC molecules
are necessary for antigen presentation and
 recognition of antigens by immune system cells.
MALIGNANCY (adjective MALIGNANT): cancer; a neoplasm or tumor growing in an
uncontrolled fashion, either spreading to other
 sites through the bloodstream or invading nearby normal tissues.
MENINGITIS: inflammation of the meninges, the membrane envelopes that cover
the brain and spinal cord.
METABOLISM: the process of building the body's molecular structures from
nutrients (anabolism) and breaking them down for
 energy production (catabolism).
METASTASIS (adjective METASTATIC): secondary cancer that has spread from the
primary or original site.
METHADONE: an oral narcotic drug used for the treatment heroin and other
opiate addictions and for pain therapy.
MICROVASCULAR: relating to the smallest, finest blood and lymph vessels.
MONOCYTE: a type of white blood cell that plays a role in immune defense.
Monocytes leave the bloodstream and migrate into the
 tissues where they become macrophages.
MONONUCLEAR CELL: a cell that has one nucleus, used to refer to a subset of
white blood cells, i.e., lymphocytes and monocytes.
 Peripheral blood mononuclear cells (PBMC) are mononuclear cells circulating
in the blood.
MONOTHERAPY: use of a single agent or drug for treatment.
MORBIDITY: affected by disease.
MORPHINE: a narcotic analgesic derived from opium that has major effects on
the central nervous system and the bowel; morphine
 is used for the relief of acute or chronic severe pain.
MUCOUS MEMBRANE (MUCOSA): a moist layer of tissue lining the
gastrointenstinal, respiratory and genitourinary tracts; mucosal
 tissue is more permeable than skin and may permit invasion by
microorganisms.
MULTICENTER AIDS COHORT STUDIES (MACS): a set of longitudinal studies of
5,000 gay and bisexual men in 4 U.S. cities;
 long-ranging data going back 10 or more years are available for men in this
cohort.
MULTIVARIATE ANALYSIS: a technique of statistical analysis in which multiple
variables are analyzed separately to determine the
 contribution made by each variable to an observed result.
MUTATION: a change in the character of a gene that is perpetuated in
subsequent cell divisions.
MYCOBACTERIUM AVIUM COMPLEX (MAC): a disease caused by Mycobacterium avium
or Mycobacterium intracellulare (sometimes
 referred to as Mycobacterium avium-intracellulare or MAI), bacilli found in
soil. In immunosupressed persons the bacteria can
 spread through the bloodstream to infect lymph nodes, bone marrow, liver,
spleen, spinal fluid, lungs and the gastrointestinal tract.
 Symptoms of MAC include diarrhea, wasting, fever, fatigue and spleen
enlargement. MAC is difficult to treat successfully.
MYOCLONUS: violent, uncontrollable contractions of a muscle or muscle group,
either localized or occuring throughout the body.
MYOSITIS: inflammation of a skeletal muscle; may involve muscle degeneration
and weakness.
N
NAIVE: inexperienced. Used to describe an individual who has never taken a
certain drug (e.g., AZT-naive).
NARCOTIC (OPIOID): a class of drugs that dull the senses, relieve pain and
induce sleep; drugs derived from opium or having
 opium-like characteristics and effects (e.g., morphine, heroin, codeine).
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES (NIAID): one of the
components of the National Institutes
 of Health (NIH), NIAID supports federally-funded research aimed at
preventing, diagnosing and treating illnesses such as AIDS
 and tuberculosis. NIAID conducts the majority of HIV/AIDS research in the
U.S., including the AIDS Clinical Trials Group
 (ACTG), Community Programs for Clinical Research on AIDS (CPCRA) and the
AIDS Vaccine Evaluation Group (AVEG).
NATIONAL INSTITUTES OF HEALTH (NIH): a large biomedical research organization
that is part of the federal U.S. Public
 Health Service (PHS). NIH includes 24 institutes, centers and divisions,
several of which perform AIDS-related research.
NATURAL KILLER CELL (NK CELL): a type of lymphocyte that attacks and kills
cells infected with microorganisms (e.g., HIV).
 Unlike cytotoxic T-lymphocytes (CTL), NK cells are non-specific and attack
infected cells without regard to their receptor
 configuration.
NEOPLASIA: see cervical intraepithelial neoplasia.
NEOPLASM: a tumor or growth; tissue that develops abnormally or grows more
rapidly than normal. A neoplasm that does not
 spread to other tissues is called benign; a neoplasm that has the potential
to spread (metastasize) is called malignant or cancer.
NEOPTERIN: a substance produced by macrophages in response to a foreign
agent. Neopterin levels are elevated as a result of
 immune system activation and have been used to predict HIV disease
progression.
NEURALGIA: a sharp, shooting pain along a nerve pathway.
NEUROLEPTIC: a drug that acts on the nervous system and modifies psychotic
behavior.
NEUROLOGIC (NEUROLOGICAL): pertaining to the central nervous system (brain
and spinal cord) or the peripheral nervous
 system.
NEUROPATHY: any abnormal, degenerative or inflammatory state of the nervous
system; damage to the nerves. See also peripheral
 neuropathy.
NEUROTOXICITY: destructive of or toxic to the tissues of the nervous system.
NEUROVEGETATIVE: a state characterized by physical symptoms of depression
(e.g., insomnia, fatigue, loss of appetite).
NEUTROPENIA: an abnormally low number or a decrease in the number of
neutrophils.
NEUTROPHIL: the most common type of white blood cell. Neutrophils release
chemicals involved in inflammation and are the
 primary defense against bacteria, which they ingest.
NEW DRUG APPLICATION (NDA): an application made by a drug sponsor to FDA to
request marketing approval. An NDA is
 made after a drug completes Phase III clinical trials. The approval process
for an NDA typically takes 6-12 months.
NOCICEPTION: the perception of pain or injury. A nociceptor is a pain
receptor.
NONOPIOID ANALGESIC: a pain reliever (e.g., aspirin, ibuprofen) that is not
derived from opium and does not have opium-like
 characteristics and effects.
NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NNRTI): a drug (e.g.,
delavirdine) that inhibits the action of the
 retroviral reverse transcriptase enzyme, thus blocking viral replication,
yet works in a different way than nuceloside analog drugs.
NON-STEROIDAL ANTI-INFLAMMATORY DRUG (NSAID): a drug that relieves pain and
reduces inflammation and fever, but
 which is not a steroid or a narcotic.
NUCLEOSIDE ANALOG (NA): a synthetic compound (e.g., AZT, ddI, ddC, d4T, 3TC)
that mimics one of the building blocks of
 DNA. These compounds suppress retroviral replication by interfering with the
reverse transcriptase enzyme; the synthetic
 nucleosides cause premature termination of the viral DNA chain.
NUCLEOTIDE (NUCLEOSIDE): one of the building blocks (e.g., adenine, cytosine,
thymine) that make up genetic material (DNA or
 RNA).
O
OBSTETRICS: the medical specialty concerned with pregnancy and birth.
OFFICE OF AIDS RESEARCH (OAR): a new federal agency created to coordinate
AIDS research done by various federal
 departments, institutes and agencies.
OFF-LABEL: use of an FDA-approved drug for an indication other than that for
which the drug was approved.
OLIGODENDROCYTE: a type of brain cell that produces myelin, a protective
covering necessary for proper neural transmission.
OPEN LABEL: a drug trial in which both participants and investigators know
which drug is being tested and what dose is being used.
OPIATE ANTAGONIST: an agent (e.g., naltrexone) that binds to the body's
opiate receptors thereby blocking the activity of opioid
 drugs and endorphins.
OPIOID (OPIATE): a drug that is derived from the opium poppy plant, contains
opium, or is produced synthetically and has
 opium-like characteristics and effects.
OPHTHALMOLOGY: the medical specialty relating to the treatment of diseses and
disorders of the eye.
OPPORTUNISTIC INFECTION (OI): an illness caused by a microorganism that
usually does not cause disease in persons with
 healthy immune systems, but which may cause serious illness when the immune
system is suppressed. Common OI in HIV positive
 people include MAC, CMV and PCP.
ORAL CANDIDIASIS (THRUSH): an infection in the mouth caused by Candida
albicans, which typically appears as white or red
 patches on the oral mucosa, tongue, palate or back of the throat.
P
p24: a core protein of HIV produced by the gag gene. The p24 antigen test
detects the p24 protein fragment in blood or tissues; a
 positive result indicates that HIV is actively replicating and predicts
disease progression. The p24 antibody test measures the
 amount of antibodies against the p24 antigen; high levels of p24 antibody
in the absence of p24 antigen may indicate that the
 immune system is successfully suppressing the virus.
PALLIATIVE: offering relief (e.g., of pain), but not a cure.
PANCREATITIS: inflammation of the pancreas, a digestive gland in the
abdominal cavity. Pancreatitis is a possible side effect of
 some anti-HIV drugs (e.g., ddI).
PAP SMEAR (PAPANICOLAOU SMEAR): a specimen of cells taken from the uterine
cervix or anus, prepared on a slide and
 examined under a microscope for abnormal cell growth and development
(dysplasia); an abnormal Pap smear suggests increased
 risk of developing cancer.
PARALLEL TRACK: a system of distributing experimental drugs to individuals
who are unable to participate in ongoing clinical trials.
 Parallel track drugs have completed Phase I safety testing and show enough
evidence of efficacy to merit wider release.
PARASYMPATHETIC NERVOUS SYSTEM: part of the nervous system that tends to
induce secretion, increase the tone and
 contraction of smooth muscle and cause dilation of blood vessels. See also
autonomic nervous system.
PARENTERAL: infusion by injection, bypassing the enteral (gastrointestinal)
system.
PATHOGEN (adjective PATHOGENIC): any disease-causing agent, especially a
microorganism.
PATHOGENESIS: the development of a particular disease, including the specific
events involved, bodily tissues or systems affected,
 mechanisms of damage, timing of the course of disease, etc.
PATHOLOGY (adjective PATHOLOGIC): the study of disease, especially with
regard to the causes of disease, the development and
 progress of disease and how the body is affected.
PBMC (PERIPHERAL BLOOD MONONUCLEAR CELL): see mononuclear cell.
PEAK LEVEL: the highest concentration of a drug achieved in the body.
PELVIC INFLAMMATORY DISEASE (PID): a condition affecting the upper female
reproductive tract including the uterus, fallopian
 tubes and ovaries. PID is often the result of untreated chlamydia or
gonorrhea infection. Without treatment PID can become
 chronic and may lead to extreme pain, infertility, and death.
PERINATAL: referring to the period around the time of birth.
PERIPHERAL NEUROPATHY: a disorder of the nerves usually involving the feet,
hands and sometimes the legs, arms and face.
 Symptoms may include numbness, a tingling or burning sensation, sharp pain,
abnormal reflexes, weakness and partial paralysis.
 Peripheral neuropathy is a side effect of some anti-HIV drugs (e.g., ddC,
ddI and d4T).
PERITONITIS: inflammation of the peritoneum, the lining of the abdominal
wall.
PHARMACOKINETICS: the action of drugs in the body, including the processes
of absorption, transformation, distribution to tissues,
 duration of action and elimination.
PHARMACOLOGY: the science of drugs, their sources and how they work; the
specialty of preparing and dispensing drugs.
PHASE I TRIAL: the first step in human testing of a new drug; these trials
evaluate drug safety and toxicity at different dose levels in
 a small number of volunteers.
PHASE II TRIAL: the second step in the evaluation of a new drug in humans;
these trials evaluate drug effectiveness and involve
 more participants than Phase I studies. Phase II studies proceed only if
Phase I studies have shown that a drug is acceptably safe.
PHASE III TRIAL: the third step in human drug testing; these trials are
designed to support and verify information gathered in Phase
 I and II trials and involve many more volunteers, up to several thousand.
Phase III trials may compare the drug being tested to
 other therapies or to placebo.
PHENOTYPE: visible characteristics and behavior that result from a
combination of an individual's genetic 'blueprint' (genotype)
 and their environment.
PLACEBO-CONTROLLED TRIAL: a trial of an experimental therapy in which an
inert, inactive substance (placebo) is given to one
 group while the treatment being tested is given to another; the results
obtained in the different groups are then compared. Placebo
 is used to make the experience of the treatment and control groups as
similar as possible and to minimize bias due to the
 expectations of the patient.
PLASMA (SERUM): the clear, amber-colored fluid that carries blood cells and
nutritive substances throughout the body, removes
 metabolic waste products and is a medium for chemical communications between
different parts of the body.
PLATELET: see thrombocyte.
PNEUMOCYSTIS CARINII PNEUMONIA (PCP): a life-threatening type of pneumonia
thought to be caused by a protozoa. PCP is a
 common opportunistic infection in people with AIDS and a leading cause of
death. First-line treatment and primary prophylaxis is
 TMP-SMX (Bactrim, Septra).
POLYMERASE CHAIN REACTION (PCR): a highly sensitive test that can detect
minute amounts of DNA or RNA in blood or
 tissue samples using an amplification technique that multiplies existing
DNA/RNA so that it can more easily be detected.
POLYMYOSITIS: inflammation and weakness of several muscles at the same time.
POSTPARTUM: the period following childbirth.
PRIMARY INFECTION: the initial introduction of an infectious agent into the
body. Primary (or acute) HIV infection may be
 characterized by flu-like symptoms including fever, malaise, enlarged lymph
glands and possibly a sore throat or rash.
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): a progressive brain disease
thought to be caused by the JC
 papillomavirus. PML infects oligodendrocytes and leads to defective nerve
signal transmission. Symptoms include change in mental
 status, speech and vision defects and weakness and/or loss of coordination.
PML is often fatal; there is no known treatment.
PROKINETIC ANTIMETIC: a drug that relieves nausea by promoting
gastrointestinal motility, i.e., speeding up the digestive and
 excretory processes.
PROPHYLAXIS: a treatment that helps to prevent a disease or condition before
it occurs (primary prophylaxis) or recurs (secondary
 prophylaxis).
PROSPECTIVE STUDY: a study that looks forward in time. Patients are selected
and their progression is followed. A prospective
 cohort study follows a specific group of patients over a period of time.
Contrast with retrospective study.
PROSTAGLANDIN: a locally-acting chemical messenger that is produced by many
types of cells. Prostaglandins have a wide variety
 of effects including vasodilation and smooth muscle regulation;
prostaglandins have a role in allergic reactions, uterine contraction,
 inflammation and pain signalling.
PROTEASE (PROTEINASE): an enzyme that facilitates the breakdown of proteins.
HIV protease breaks up the large proteins
 produced from viral RNA so that the component pieces can be assembled into
new viral particles; protease is essential for viral
 replication.
PROTEASE INHIBITOR: a drug (e.g., saquinivir, L-735,524, ABT-538) that blocks
the action of the protease enzyme and thereby
 prevents viral replication. Unlike reverse transcriptase inhibitors,
protease inhibitors can inhibit HIV replication in cells that are
 already infected.
PSORIASIS: a common chronic skin condition characterized by reddish scaly
patches, primarily on the scalp, elbows, knees and trunk.
 Psoriatic arthritis is a form of arthritis accompanied by psoriasis
symptoms.
PSYCHOGENIC: a sensation or state (e.g., pain) that has a psychological or
mental origin.
PSYCHONEUROIMMUNOLOGY (PNI): the study of how psychological process, mental
state and the nervous system affect the
 functioning of the immune system.
PSYCHOPHARMACOLOGY: use of drugs that affect the psyche or personality.
PSYCHOSTIMULANT: a drug that causes increased responsiveness of the mind.
PSYCHOTROPIC: an agent (e.g., thorazine) that affects psychic or mental
functioning, behavior or experience.
PYRAMIDAL TRACT: one of 4 columns of motor fibers (nerves) that run in pairs
along the spinal cord and originate in the brain.
Q
QUANTITATIVE COMPETITIVE POLYMERASE CHAIN REACTION (QC-PCR): a refined and
more sensitive version of the PCR
 assay used to detect DNA or RNA.
R
RANDOMIZED TRIAL: an experiment arranged to produce a chance distribution of
subjects into different treatment groups or arms.
 Randomization is intended to cancel out factors that aren't specifically
being studied in an effort to obtain unbiased data.
RECEPTOR: a specific protein-binding site on a cell's surface or interior.
When chemical messengers bind to receptors, various
 cellular functions are activated or inhibited. Many drugs exert their
effects by binding to receptors and altering normal cellular
 communication.
RECOMBINANT: produced by genetic engineering in the laboratory. Recombinant
products are designated by a lower-case r, e.g.,
 rHGH.
REFRACTORY: resistant to treatment.
REITER'S SYNDROME: an autoimmune disorder characterized by the simultaneous
occurence of urethritis (inflammation of the
 urethra), arthritis, and conjunctivitis (inflammation of the outer membrane
of the eye). The syndrome may occur following other
 diseases such as chlamydia or salmonellosis; no known cure exists.
RELAPSE: recurrence of disease symptoms following a period of improvement.
REMISSION: a lessening of the severity of disease symptoms; a period of time
during which symptoms are abated or eliminated.
REPLICATION: duplication or reproduction.
REPLICATIVE ENZYME: an enzyme that is necessary to the reproductive process;
replicative enzymes for HIV include reverse
 transcriptase, integrase and protease.
RESERVOIR: a site where an infectious agent collects and multiplies, e.g.,
the macrophages and lymph nodes are reservoirs for HIV.
RESISTANCE: the ability of a microorganism (e.g., a virus) to lose its
sensitivity to a drug. Microorganisms mutate in a way that
 allows them to function and reproduce despite the presence of a drug.
RETINITIS: inflammation of the retina, the light-sensitive tissue at the back
of the eyeball that transmits visual impulses via the optic
 nerve to the brain.
RETROSPECTIVE STUDY: a study based on the medical records of patients,
looking backward in time at events that happened in
 the past. A retrospective cohort study uses the records of a specific group
of patients. Contrast with prospective study.
RETROVIRUS: a class of enveloped viruses (e.g., HIV) that have their genetic
material in the form of RNA. Retroviruses have an
 enzyme, reverse transcriptase, that allows the virus to translate its RNA
into DNA, which is then inserted into the genetic material
 of the host cell.
REVERSE TRANSCRIPTASE (RT): a viral enzyme that allows a retrovirus to
translate its genetic material, in the form of RNA, into
 DNA which is then integrated into the host cell's chromosomes.
REVERSE TRANSCRIPTASE INHIBITOR (RTI): a drug that blocks retroviral
replication by interfering with the reverse
 transcriptase enzyme; RTI drugs are not effective after a cell has already
been infected. RTI include nucleoside analogs (e.g., AZT,
 ddI) and non-nucleoside reverse transcriptase inhibitors (e.g.,
delavirdine).
RHEUMATOLOGY: the study of various conditions (e.g., arthritis, polymyositis)
involving pain or other disorders of the joints,
RNA (RIBONUCLEIC ACID): a single-stranded nucleic acid made up of
nucleotides. RNA is involved in the transcription of genetic
 information from DNA; the information encoded in DNA is translated into
messenger RNA (mRNA), which controls the synthesis
 of new proteins. RNA takes the place of DNA in retroviruses such as HIV.
S
SALVAGE THERAPY: emergency treatment with an experimental drug for a disease
or illness that has not responded to standard
 therapy.
SAQUINAVIR (INVERASE): a protease inhibitor drug currently undergoing
clinical trials.
SECOND-LINE TREATMENT: the second preferred therapy for a particular
condition used when a patient fails or cannot tolerate
 the side effects of first-line treatment.
SECRETORY LEUKOCYTE PROTEASE INHIBITOR (SLPI): a protein found in saliva that
blocks HIV infection by binding to a
 surface receptor on host cells.
SENSITIVITY: the ability of an organism to be affected by a drug or other
agent, e.g., a virus is senstive to AZT if AZT is able to
 prevent viral replication.
SENSORIUM: consciousness of sensation.
SEPSIS: the presence of pathogenic organisms or their toxins in the blood or
tissues, and the associated bodily reactions.
SEPTIC ARTHRITIS: infection in a joint.
SEPTICEMIA: the physiological response to the presence of bacteria in the
blood. Symptoms include increased cardiac and
 respiratory rates and fluctuations in body temperature.
SEPTIC SHOCK: a condition characterized by a significant decrease in blood
pressure along with symptoms of septicemia.
SEQUELAE: conditions resulting from a disease or injury.
SEROCONVERSION: the change in a person's antibody status from negative to
positive.
SEROSTATUS (ANTIBODY STATUS): the presence or absence of antibodies in the
blood serum. If antibodies are present, a person
 is said to be seropositive; if no antibodies can be detected, they are said
to be seronegative.
SERUM: see plasma.
SIDE EFFECT: an action or effect of a drug other than that which is intended.
The term usually refers to undesired or negative
 effects such as headache, skin rash or liver damage.
SINUSITIS: inflammation or infection of the sinuses, cavities behind the
forehead and cheekbones.
SJOGREN'S SYNDROME: an autoimmune disorder characterized by dryness of the
mucous membranes, enlarged salivary glands
 and facial lesions; the syndrome may also be associated with pancreatitis
and kidney disease.
SOMATOFORM: having or following the form of the body.
SPASTICITY: a condition characterized by increased muscle tone, exaggerated
reflexes and increased resistance to passive movement.
STANDARD THERAPY: a therapy that is FDA-approved for a given condition and
is widely used as first-line treatment.
STEM CELL: a precursor cell from which all blood cells are derived. As they
mature in the bone marrow, stem cells evolve into
 various types of red and white blood cells.
STEROID: a family of substances that share a similar chemical structure,
including many hormones (e.g., testosterone), Vitamin D
 and various drugs. Steroid drugs are used to lessen inflammatory reactions.
STRAIN: a specific genetic variant of a particular organism.
SUBCUTANEOUS: beneath the skin; subdermal.
SURROGATE MARKER: a marker or sign that can serve in place of a clinical
endpoint. Surrogate markers for HIV disease may be
 virologic (e.g., p24 antigen level, viral load), immunologic (e.g., CD4 cell
count, cytokine levels) or clinical (e.g., weight loss).
SYNCYTIUM (plural SYNCYTIA): a mass of cells which fuse together to form one
'giant cell.' Strains of HIV are classified as either
 syncytium-inducing (SI) or non-syncytium-inducing (NSI).
SYNERGY (SYNERGISM): the action of 2 or more agents (e.g., drugs) used
together that produce an effect greater than the
 combined effect of the same agents used separately.
SYSTEMIC: affecting the whole body; not localized.
T
T-CELL (T-LYMPHOCYTE): a type of white blood cell derived from the thymus
that participates in a variety of cell-mediated
 immune responses. There are 3 major types of T-cells: T-helper (CD4),
T-suppressor (CD8) and T-killer (cytotoxic T-lymphocyte or
 CTL).
TERATOGENICITY: the ability to cause malformation of the fetus.
TH1/TH2 IMMUNE RESPONSE: 2 branches of the immune system. The TH1 response
involves a subset of CD4 lymphocytes called
 TH1 cells that secrete IL-1, IL-2 and gamma interferon, which enhance the
cell-mediated immune response and inhibit both TH2
 cell activity and the humoral (antibody-based) immune response. The TH2
response involves the TH2 subset of CD4 cells that
 secrete IL-4 and IL-10, which inhibit cell-mediated immune response and
enhance the humoral immune response.
T-HELPER CELL: see CD4 cell.
THROMBOCYTE (PLATELET): a type of blood cell that facilitates normal blood
clotting.
THRUSH: see oral candidiasis.
THYMOSTIMULIN: one of several hormones produced by the thymus gland that are
involved in the regulation of immune function.
THYMUS (adjective THYMIC): a lymphoid organ in the upper chest cavity. The
thymus is the source of lymphocytes in children and is
 the site of lymphocyte differentiation where lymphocytes 'learn' to
recognize antigens.
T-KILLER CELL: see cytotoxic T-lymphocyte.
TOLERANCE: a condition in which the body becomes accustomed to a drug so that
the previous dose no longer produces the desired
 effects and a progressively larger dose is needed to achieve a previously
observed effect. See also cross-tolerance.
TOPICAL: pertaining to the surface of the skin; a medication applied to the
skin.
TOXICITY (adjective TOXIC): the state of being poisonous or harmful.
TOXOPLASMOSIS: an opportunistic infection caused by the microscopic parasite
Toxoplasma gondii, found in raw or undercooked
 meat and cat feces. Symptoms may include headache, lymphadenopathy, malaise,
muscle pain, fever and dementia. Toxoplasmosis
 may lead to brain swelling, coma and death in persons with suppressed immune
systems.
TREATMENT ARM: a group of participants in a research trial who receive the
same treatment (or placebo).
TREATMENT IND: an FDA classification that allows physicians to prescribe
certain promising experimental drugs prior to marketing
 approval to patients with life-threatening diseases who lack satisfactory
alternative treatments.
TRIAL (STUDY): an experiment involving the collection, analysis and
interpretation of data, e.g., a clinical trial to determine the
 safety and efficacy of a new drug.
TROPISM: affinity for or the tendency to move toward something; the specific
attraction of a virus or other microorgansim to a
 particular host tissue, e.g., HIV has a tropism for CD4 cells.
TROUGH LEVEL: the lowest concentration of a drug reached in the body between
doses.
T-SUPPRESSOR CELL: a type of T-cell bearing the CD8 surface marker that helps
to regulate the immune response.
TUBERCULOSIS (TB): an infectious disease caused by Mycobacterium tuberculosis
that typically affects the lungs but may occur in
 other organs (extrapulmonary TB). Transmission generally occurs through
inhalation of aerosolized sputum droplets. A combination
 of 4 chemotherapeutic drugs is standard therapy; multidrug-resistant
tuberculosis (MDR-TB) is resistant to some of the standard
 drugs and requires more aggressive treatment.
TUMOR NECROSIS FACTOR (TNF, CACHECTIN): a cytokine produced by activated
macrophages that can destroy tumors. When
 chronically elevated, TNF may promote wasting. In laboratory tests TNF has
been shown to stimulate HIV replication.
U
UNCONTROLLED TRIAL: research studies in which there are no participants
taking a placebo or non-experimental therapy.

       V

       VACCINE: a preparation that contains an infectious agent or its
 components which is administered to stimulate an immune response that
 will protect a person from illness due to that agent. A therapeutic
 (or treatment) vaccine is given after infection and is intended to
 reduce or arrest disease progression. A preventive vaccine is
 intended to prevent initial infection.

       VARICELLA-ZOSTER VIRUS (VZV): a virus in the herpes family that
 causes chickenpox (varicella). VZV may lie dormant for years and
 reactivate later in life to cause herpes zoster (shingles),
 especially in immunosuppressed individuals.

       VASCULITIS: inflammation of blood or lymph vessels.

       VERTICAL TRANSMISSION: the transmission of HIV from a mother to
 a fetus or neonate (newborn). Vertical transmission may occur in
 utero (in the womb), during the birth process or following birth via
 breastfeeding.

       VIRAL LOAD (VIRAL BURDEN): the amount of virus in the blood or
 other tissues. The presence of HIV RNA indicates that the virus is
 replicating; changes in viral load may be used to gauge drug
 effectiveness and disease progression. Viral load is measured using
 assays such as QC-PCR or branched DNA, and is expressed as the number
 of copies of RNA per cubic millimeter of blood (mm3); increases and
 decreases are expressed as log (10-fold) changes.

       VIREMIA: the presence of virus in the blood. Plasma viremia can
       be measured using assays such as PCR and branched DNA.

       VIRION: a complete viral particle.

       VIRUCIDE: a substance that can kill or destroy viruses.

       VIRULENCE (adjective VIRULENT): aggressiveness, ability to
       cause disease.

       VIRUS: a group of minute organisms that are unable to grow or
 reproduce outside the body of a host. During replication a virus
 releases its genetic material (DNA or RNA), integrates that material
 into the host cell, and takes over the host cell's biological
 mechanisms to reproduce new virus particles. Many viruses are
 pathogenic in humans and animals.

       VIRUSTATIC: a substance that has the ability to inhibit growth
       and/or reproduction of viruses without killing them.

       VULVOPERINEAL: relating to the area of the female body that
 includes the vulva, the urethral and vaginal openings, and the
 perineum (the area between the vagina and the anus).

       W

       WASTING SYNDROME: a condition characterized by atrophy of lean
 body mass and involuntary weight loss of more than 10% of normal body
 weight. Other symptoms may include chronic diarrhea, fatigue,
 weakness and fever.

       WILD TYPE: the normal, typical phenotype of a virus or other
       organism before genetic mutation and/or manipulation takes
       place.