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[Electronic distribution for GENA by AEGIS/San Juan 714.248.2836]

 Volume 8 no. 4

 Gay Men's Health Crisis: Treatment Issues

 > Cover letter
 > The ICC's New Combo Trials
 > Commentary: Another Day, Another Trial
 > The Torturous Development Path of Alpha-Thymosin
 > Delavirdine Enters Efficacy Trials
 > Highlights from the Fourth European Conference on AIDS
   >> New Diagnostic Techniques for Cytomegalovirus Infections
   >> Oral Ganciclovir To Prevent Cmv Retinitis Recurrence
   >> Famciclovir for Herpes Zoster
   >> Toxoplasmosis Suppression
   >> European Tuberculosis Studies
   >> Visceral Leishmaniasis
   >> Terbinafine for Nail Fungal Infections
   >> Aspergillus Infections Associated with Hospital Renovation
   >> Vitamin B12 and Folate Supplements
   >> Zinc and Opportunistic Infections
   >> Clotting Disorders in HIV-Positive Patients
 > Drug company watch
   >> SmithKline Blocks Investigation of AIDS Drug
   >> First Human Data on Effectiveness of Antisense Drugs
   >> First U.S. HIV Antisense Trial Starts
   >> Bristol Meets with Activists on d4T
   >> Viagene Begins New Gene Therapy Trial
   >> Lilly Leaves HIV Research
   >> Price Competition for Acyclovir (Zovirax)
 > Treatment Briefs
   >> Oral Ganciclovir Access Plan (Sort of)
   >> Hyperthermia Trial to Start
   >> Pentoxifylline: Disappointing Data and a Warning
   >> Hydrogen Peroxide Therapy
   >> Poppers and the Immune System
   >> New Drug Tested for Genital Warts
   >> Depression and HIV
   >> Correction


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 [Cover letter]

 Dear readers:

Your subscription payments, renewals and generous
contributions have enabled us to provide vital treatment
information to people all over the world. It has made
possible our advocacy work aimed at creating a more
proficient and productive HIV/AIDS research effort. If you
have not yet renewed your subscription or are able to make
another donation, please complete the form below and return
it to us in the enclosed envelope. Your continuing support
means a great deal to us.

We would like to take this occasion to bring you up to date
on Treatment Issues and the work of the new Treatment
Education and Advocacy Department at Gay Men's Health Crisis:
GMHC has reorganized its treatment education program. In
January of this year, Jeff Richardson, the Executive Director
of GMHC, created a new Department of Treatment Education and
Advocacy (TEA) in order to expand GMHC's impact on national
and corporate HIV/AIDS research policy. TEA also will broaden
GMHC's treatment education programs to ensure that people
with AIDS and their care providers have access to the best
information possible when making difficult treatment
decisions. The new department is headed by David Barr,
formerly of the GMHC Policy Department.

We are committed to providing objective HIV treatment
information and making Treatment Issues available to whomever
needs it. Treatment Issues remains the centerpiece of GMHC's
treatment information program. The newsletter neither accepts
nor solicits money from drug companies or government
agencies. Since we began publishing in 1987, everyone who has
requested a subscription to Treatment Issues has received one
regardless of his or her ability to pay. Our monthly
circulation of over 20,000 includes individuals and
organizations from all over the world - North and South
America, Europe, Asia, Africa and Australia. Our articles are
reprinted in hundreds of other community publications.

We are planning more special editions of Treatment Issues. We
published a 32-page special edition of TI devoted to
"Alternative Therapies for HIV" as well as a special edition
on the Concorde Study results concerning early intervention
with AZT. In the coming year, we are projecting special
editions devoted to "Current Standards of Care for HIV,"
"Therapies for Advanced HIV Disease" and a complete glossary
for TI readers.

We also are expanding Treatment Issues. Treatment Issues has
been expanded in both size and frequency. We now publish
monthly instead of nine times per year. We often publish 16
page editions in order to provide more information to our
readers. Last year such features as Washington Watch, Drug
Company Watch, the TI Interview, editorials, and commentaries
all began making regular appearances in TI. We now are
considering adding other columns that would make TI a more
accessible publication.

We are introducing a series of Treatment Issues fact sheets.
This month we will publish the first set in a series of
"Basic Fact Sheets" on HIV-related opportunistic infections.
They will appear in both English and Spanish These fact
sheets will present information in a simple, easy-to-read
format. We also will be offering "In-Depth Fact Sheets" that
enable readers to obtain all the information ever published
in Treatment Issues on any specific HIV-related therapy or
condition. These fact sheets will significantly improve our
ability to respond to requests for information from the
public.

Our "Treatment Forums" series is providing the community with
a wide range of up-to-date information. Over the last year we
have put together a regular series of community treatment
forums to increase awareness of state-of-the-art medical
therapy and focus attention on promising areas of AIDS
research. These forums have covered such topics as long-term
survival, future directions in the treatment of Kaposi's
sarcoma, alternative therapies for HIV, risk of HIV
transmission through oral sex, reports from the IX
International Conference on AIDS, and prevention of
opportunistic infections. We have initiated regular treatment
forums in Spanish, too. Both the English and Spanish forums
are presented in collaboration with many other AIDS
organizations, including the Community Research Initiative on
AIDS, Treatment Action Group, Latino AIDS Treatment Issues
Group, Latino Commission on AIDS, Elmhurst Hospital and
Columbia University. Tapes and summaries of many of these
forums are available to TI readers.

Our Treatment Library continues to grow. The GMHC AIDS
Treatment Library has enlarged its size and scope. It is now
open to the public four days a week from 10 a.m. to 1 p.m.
and provides Medline and AIDSline computer services, the
latest medical journals, newsletters, reference materials and
our comprehensive files on all medical aspects of HIV/AIDS.
The library has received substantial donations from a number
of publishing companies and has become a member of the
prestigious METRO Medical Network made up of New York area
hospital and university medical libraries.

In an effort to use our resources even more effectively, we
have reduced our printing and mailing costs substantially in
the course of the past year. Nevertheless, your continuing
support is essential to our expanding effort. Please take a
moment of your time to send us a renewal or contribution with
the form below. Note that, as always, all Treatment Issues
subscription lists are kept strictly confidential. We do not
even allow them to be part of the general GMHC mailing lists.
Thank you in advance for your assistance. We would appreciate
any comments you might have as to how we could better fulfill
our goals. A business reply envelope is enclosed for your
convenience.

 David Gold, Executive Editor ; Dave Gilden, Editor; Gabriel
Torres, M.D., Medical Consultant; Paul Warren, Technical
Coordinator

 [GMHC
  129 W. 20th Street
  New York, NY 10011]

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The ICC's New Combo Trials
 by Derek Link

The Inter-Company Collaboration for AIDS Drug Development
(popularly known as the ICC), a private consortium that
includes sixteen major drug companies involved in AIDS
research, announced its "master protocol" for triple-drug
combination therapy to a meeting of activists in New York on
April 26. According to its chief architect and proponent, Dr.
David Barry of the Burroughs Wellcome Company, the master
protocol is designed to find a "home-run" triple drug
combination that for 52 weeks restores CD4 cell levels back
to an immunologically normal state (above 800 cells/mm3 of
blood) and eliminates detectable viral replication. The
study's sponsors do not plan to collect clinical data (such
as symptoms and disease progression) on study participants.

The plans for the trial were greeted with substantial
criticism by the activists in New York, many of whom regarded
the potential for finding a "home-run" treatment from any of
the proposed combinations as negligible. The critics
questioned whether the trials would produce meaningful data
to clearly determine whether any of these combinations have a
more modest benefit in treating HIV infection.

Trial Design

The protocol, designed as a pilot study, will enroll 100
asymptomatic patients with 200 to 500 CD4 cells and no prior
HIV treatment in each study arm. The study will sequentially
enroll patients. The first 100 patients will receive the
first combination regimen, the next 100 patients will receive
the second regimen, and so forth. The ICC initially will use
two approved drugs and one unapproved drug to create the
three-drug combinations.

The ICC will begin with four triple-drug regimens, enrolling
patients at "10 to 20" sites nationwide. Sites have not yet
been selected, but accrual could begin sometime this summer.

The four regimens selected for earliest evaluation are:
 Arm 1: AZT + ddC + Saquinavir (the Roche protease inhibitor)
 Arm 2: AZT + ddI + Nevirapine
 Arm 3: AZT + ddI + 3TC
 Arm 4: AZT + ddC + Nevirapine

All drugs will be used at standard monotherapy doses. Dr.
Barry anticipates that accrual into each regimen will take
two to three months. If a "home-run" effect occurs, it could
be noted as early as 26 weeks into the study because regular
interim analyses are planned.

Although the ICC hopes to score a home-run with this
strategy, it recognizes that a less dramatic therapeutic
effect may also occur. Thus a graded scale has been developed
to record a range of therapeutic responses that fall short of
a home run. Four types of response will be examined:
immunological markers, HIV levels, adverse effects and
emergence of drug-resistant HIV strains. Each of these areas
will be graded. For immunological markers, a "Grade A"
response is CD4 cells returning to normal (above 800) in 90
percent of patients. A "Grade D" response is no CD4 effect at
all.

Criticisms of the Trial Design

The first criticism of this trial design concerns
randomization, the process by which patients in a clinical
trial are "randomly" assigned to different treatments.
Randomization minimizes the differences among groups by
equally distributing people with particular characteristics
among all the arms. It also allows for certain statistical
methods to be applied to the data.

But the ICC master protocol is not randomized. The failure to
randomize the study means that the data generated by it will
lack both confidence and sophistication. It may be open to
substantial bias if the different groups do not have
equivalent characteristics that affect their response to
therapy.

Then too, the study has no "control arm" (e.g. a placebo or
even a standard therapy regimen) against which the effect of
triple-drug combination is compared. Instead, the master
protocol will compare triple-drug combination to an
historical control - i.e., surrogate marker data from
similar patients in previous studies.

Historical controls do have some advantages. Fewer patients
are required for a study, resulting in easier recruitment.
The trials also are much cheaper and simpler to conduct.
Historical controls have some significant disadvantages,
though. In the specific case of anti-HIV therapies, little is
known about two-drug combination therapy in patients who have
never before taken anti-HIV drugs. It is hard to imagine how
the ICC can arbitrarily establish standard comparison data
for this patient group. Not only are immunological markers,
such as CD4 cell counts, open to considerable uncertainty for
these people, but the effect of antiviral drugs on newer
virological markers (like PCR or branched-chain DNA assay)
has not been established.

In general, trials utilizing historical controls tend to
over-estimate the therapeutic effect of treatment.
Uncontrolled studies generally yield a much higher percentage
of positive results than controlled studies.[1,2]
All criticisms of the trial are not scientific. Only
"nucleoside analog naive" volunteers (no history of taking
AZT, ddI, ddC, etc.) are eligible for the study, which raises
a difficult issue. People who have faithfully followed
government, industry and (in some cases) community
recommendations that "it's never too early" to start
nucleoside analog treatment now find that the presumed
cutting edge of research is unavailable to them. Is this
anyway to treat one's best customers?

The most significant criticism of the trial is the drugs
themselves. Three of the four regimens selected for initial
investigation include only reverse transcriptase inhibitors,
with the combination of AZT, ddI and 3TC being particularly
dubious. Few virologists believe that a "home-run" is
possible with a regimen that includes just reverse
transcriptase inhibitors or even any of the drugs currently
available. The trial appears in some respects to be a renamed
repeat of the notorious "convergent combination therapy."
The obvious, sad reality is that there are few new drugs to
plug into the master protocol. This situation underscores the
desperate need for new agents. Accordingly, the ICC must open
up membership to the biotechnology industry, which is at the
cutting-edge of drug discovery.

Strengths of the Trial

The master protocol has some important strengths that should
not be overlooked. For treatment-naive asymptomatic patients,
this trial represents a new option that some may find highly
desirable. Despite the study design's scientific weaknesses,
the protocol is probably adequate to detect a "home-run"
treatment. A dramatic "cure," a treatment that brings
patients back to normal and eliminates viral replication, is
not difficult to observe. The problem, of course, is that
treatments up to now have not shown such a dramatic,
overwhelming effect.

The ICC protocol is a good sign that the drug industry is
serious about cooperation. By explicitly going after a home-
run strategy, the industry also has taken an important step
toward defining its role in clinical research of HIV disease.
Up to this point, no research group (government, industry or
academic) has so clearly defined its mission. One hopes that
other organizations, particularly those that are publicly
funded, will follow the ICC's example and clarify their own
missions.

And here's a final point not to be dismissed lightly: ICC
members are spending their own money on these trials.

1 Sacks H, et al. American Journal of Medicine, 1982;
72(2):233-40.

2 Sacks H, et al. Archives of Internal Medicine, 1983;
143(4):753-5.


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Commentary: Another Day, Another Trial
 by Dave Gilden and David Gold

Low dose oral alpha interferon (LDAI) - including Kemron and
similar products - attracted a great deal of attention almost
five years ago when Davy Koech, M.D., of Kenya announced a
stunning reversal of the AIDS disease process in patients who
let lozenges containing the substance dissolve in their
mouths. Dr. Koech also claimed a series of controversial
"serodeconversions," in which HIV-positive patients became
HIV antibody-negative after Kemron therapy. Not surprisingly,
these results received widespread publicity, creating
significant demand for oral alpha interferon at AIDS buyers
clubs, and even a number of physicians began selling various
oral alpha interferon products.
In 1992, the National Institute of Allergy and Infectious
Diseases (NIAID) reviewed thirteen different LDAI studies
here and abroad. The Institute concluded, "The initial claims
which have been made on behalf of Kemron ... have not been
confirmed.... People with HIV infection will be best served if
they receive treatments which have been shown efficacious in
well controlled studies."[1]
At the 1993 International Conference on AIDS, Elly Katabira,
M.D., of Uganda announced the results of a 560-person
placebo-controlled trial.[2] The study, which was sponsored by
the World Health Organization, found no difference between
Kemron and the placebo. There was no evidence of any effect
on CD4 cells, viral load, disease progression, survival or
"quality-of-life" indicators.

Nevertheless, officials at NIAID, the division of the
National Institutes of Health (NIH) that receives almost half
of all U.S. government AIDS research dollars, are proceeding
with plans for another large oral alpha interferon trial.
Taking the lead in planning and funding the study is the
Community Programs for Clinical Research on AIDS (CPCRA), a
unit of NIAID.

Why Another Trial?

Even those planning the study do not believe that oral alpha
interferon works. Dr. Lawrence Deyton, Director of the CPCRA,
readily admits that "scientific evidence proves [the LDAI]
products give no benefit in fighting HIV or in improving the
immune system of persons with HIV infection."[3] Why then
proceed with an expensive new test that only prolongs
uncertainty over the substance? Dr. Deyton argues that
continued community use of LDAI, particularly in the African-
American community, requires yet more definitive testing of
the substance.

Why not just publicize the results of the WHO/Ugandan study
then? "We accept the immunological and virological data from
the WHO/Ugandan study," Deyton told Treatment Issues, "but
the quality of life issues are clouded. The Ugandan people
were very sick to start with." Additionally, deficient care
may have obscured the results. The new LDAI trial will
primarily investigate whether the therapy causes any
reduction in clinical symptoms related to the HIV-associated
decline in immunity.

Small trials in Los Angeles and New York did find some slight
symptomatic relief, mainly in terms of restored energy and
weight. But with enough studies, some positive data will
always appear, just from random variation. These results are
specifically countered not by just the WHO/Ugandan study, but
by a trial conducted through the Community Research
Initiative of Toronto in 149 HIV-positive individuals,[4] in
addition to all the other oral alpha interferon studies that
found no significant effect from the drug.

Most researchers do not believe that oral alpha interferon
can have any effect because the interferon protein is broken
down and rendered useless by fluids in the stomach. That is
why all interferons approved for therapeutic use are injected
subcutaneously (into the skin). The conjecture that alpha
interferon directly affects immune cells in the mouth and
sparks an improvement in immune system responsiveness remains
highly speculative with no supporting data.

Wasting Precious Dollars and Goodwill

The new trial, which will enroll 800 people and compare three
versions of LDAI, is to begin later this year. The cost of
the study may be in the millions (not including the cost of
NIAID staff time in planning and overseeing the trial). Dr.
Deyton claims the cost will be less, but refused to be quoted
on a specific figure.

In addition, the smaller and more difficult a drug's benefit
is to measure, the larger and more extensive a clinical trial
must be to document that benefit. There is no reasonable
assurance that this trial will prove large enough to show any
quality-of-life benefits from the drug. Failure of this trial
to document an effect from LDAI may only elicit calls for
another, still larger trial.

Besides consuming valuable research funds and staff time, the
proposed trial will waste human resources. People who enroll
in a clinical trial are contributing the most valuable thing
they have - their bodies. It is unconscionable to enroll
people in a clinical trial, particularly one sponsored by the
U.S. government, when there is no reasonable evidence that
the therapy being tested is of benefit. Individuals
participating in this study may forego other therapeutic
options, or render themselves ineligible for more appropriate
clinical trials. They also may become further disenchanted
with the clinical trial system when the false hopes played
upon to draw them into the trial are dashed.

Rather than improve relations between the scientific and
African-American communities through this trial, as has been
hoped, the gap between the two may only grow more
insurmountable.

Making Sense of Research Priorities

Many observers, including The New York Times, report that
LDAI is being kept alive by political pressure, especially
from medical clinics connected with the Nation of Islam,
which has helped popularize LDAI in the African-American
community.[5] But LDAI has also received support from the
National Medical Association, the well-established
organization of African-American physicians in the United
States.

The chair of the LDAI protocol team, Lawrence Brown, M.D., of
Brooklyn argues, "Things are not driven by pure science,
there's politics on all sides: Who believes in what data?
Look at all the effort put into AZT, and with such little
yield."

Dr. Brown is exactly right. Too much government funding has
gone towards studying AZT and its sister drugs, ddI and ddC
(although these drugs at least can reduce viral load and
provide modest increases in CD4 levels - oral alpha
interferon does neither). Let's not do the same with LDAI,
while leaving promising experimental therapies and areas of
basic virological and immunological research starved for
funds. LDAI keeps reappearing precisely because the medical
establishment has nothing really effective to offer people
with HIV - especially those in disenfranchised and poor
communities, who have the least access to care and promising
therapies.

The LDAI saga sums up much of what is wrong at NIAID: endless
trials of mediocre drugs without any clear insight into what
strategies could yield effective therapies and an all too
pervasive acceptance of wasteful and redundant clinical
studies. Let people take Kemron - if they want it. NIAID
resources should be used for more productive lines of
research.

This is the first in a series of commentaries that will
appear in Treatment Issues on AIDS research at the NIH.

1 National Institutes of Health. Interim Report: Low-dose
oral interferon alpha as a therapy for human immunodeficiency
virus infection (HIV-1): completed and on-going clinical
trials. April 1992.

2 Katabira E, et al. IX International Conference on AIDS,
1993; abstract PO-B26-2056.

3 Deyton L. Letter to CPCRA Steering Committee. October 5,
1993.

4 Hulton, MR et al. Journal of Acquired Immune Deficiency
Syndromes, 1992; 5(11):1084-90.

5 The New York Times. March 4, 1994.

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The Torturous Development Path of Alpha-Thymosin
 by Dave Gilden and Jay Levin

One of the great hurdles that any anti-HIV drug must overcome
is the lack of a persistent immune response that combats HIV.
A successful antiviral treatment will have to clear the virus
from the body in the face of an increasingly dysfunctional
immune system.

A number of immune modulators have been tested in conjunction
with anti-HIV drugs in an attempt to improve the immune
response. Yet, results have been inconclusive and the side
effects often severe. Recently, a small, unblinded Italian
study reported that a substance known as alpha-thymosin
(thymosin), when used in combination with alpha-interferon
and AZT, provided more sustained increases in CD4 cells than
AZT alone.

Just announced results from another, larger study of thymosin
suggest that the drug is not effective as a treatment for
chronic hepatitis B, however. The question now is whether
Alpha 1 Biomedicals, the small, underfunded biotech firm
developing thymosin, has the resources to mount new,
redesigned trials.

Natural Thymic Hormones

The thymus gland has been identified as a key immune system
organ. It is thought to be responsible for the development
and regulation of the immune system cells that mature in that
organ (such "T-cells" as CD4 helper cells and CD8 cytotoxic
cells). The thymus seems to exert its regulatory functions
through the secretion of various hormone-like products called
thymic peptides. Although the importance of thymic peptides
remains in dispute, several investigators have reported that
thymic peptide products can assist development of immature,
precursor cells into fully competent T-cells. They also
regulate the functioning of T-cells once they have matured.

Alpha-thymosin is a thymic peptide that adjusts an
individual's immune responsiveness when aberrations occur.
Thymosin boosts the number of receptors on T-cells,
especially for alpha-interferon and IL-2. It also increases
the efficiency of T-cells' response to signaling agents and
causes cells to produce more of them.[1]

Intercellular signaling molecules ("cytokines") like alpha-
interferon and IL-2 commonly have severe adverse effects.
These agents are released during disease to help bolster the
inflammatory response, which causes a variety of flu-like
symptoms. Thymosin, in contrast, circulates in the blood at
comparatively constant levels. In a series of clinical trials
involving a total of nearly 1,000 people, no serious side
effects have been noted.[1] Since thymosin promotes the action
of alpha-interferon and IL-2, combining it with these
products could allow lower dosages to be used, resulting in
both greater safety and more efficacy.

Thymosin in HIV

This year, an Italian research group led by Enrico Garaci
published encouraging results from a small trial comparing
various combinations of thymosin, alpha-interferon and AZT in
people with HIV.[2] The trial enrolled 40 HIV-positive men and
women with CD4 cell counts of 200 to 500 per cubic milliliter
of blood and without previous treatment for HIV infection.
(The trial was randomized, but unblinded - everybody
involved knew who was receiving which treatment.)
Unfortunately, the dropout rate in this already small trial
was high: by the end of twelve months, only 28 patients were
available for evaluation, and by eighteen months only 23
remained.

Trial volunteers were assigned to one of four groups. The
first received 500mg of AZT twice daily. The second group
received AZT plus two million units of natural human alpha-
interferon twice weekly, and the third group received AZT
plus 1mg thymosin subcutaneously twice weekly. The fourth
group had the complete combination - AZT, thymosin and
alpha-interferon.

Over the first ten months, CD4 counts rose by an equivalent
amount in the AZT plus interferon group and in the triple
combination group. In the AZT only group and the AZT plus
thymosin group, CD4 counts fell or were stable, respectively.
But then CD4 counts in the AZT plus interferon group on
average dropped back to baseline whereas the triple-drug
people saw their CD4 counts continue to rise. At twelve
months, the average increase amounted to 187 CD4 cells per
cubic millimeter of blood. At eighteen months, the average
increase was 237 CD4 cells while the counts for the other
three treatment groups were close to the original, baseline
averages.

The small size and high drop-out rate of this trial make it
difficult to have confidence in these results. Those who
discontinued were not followed, and without this data, it is
difficult to draw even tentative conclusions. Be that as it
may, the Italian government subsequently funded a much
larger, more definitive trial of the thymosin-interferon-AZT
regimen. This 100-person study is now two-thirds enrolled.
Investigators will present an update on this trial at the
"Fourth International Conference on Combined Therapies," to
take place next month in Sardinia, Italy. No confirmed data
is available at present from this trial.

The investigators hope to release preliminary data on the
first six months of treatment by the end of the year.
Measurements will include assays of CD4 and CD8 counts, HIV
p24 antigen, beta2 microglobulin (an index of immune
activation), HIV levels in the blood, and a lab test for
immune cell proliferation response. Crucial clinical data on
the rate of opportunistic infections also will be available.
(A reduced rate of opportunistic infections would confirm
that the improvements seen in laboratory tests, if any,
actually have functional value in improving people's health.)

A Disappointing U.S. Trial for HIV

Thomas Merigan, M.D., the director of the Center for AIDS
Research at Stanford University, has been conducting an
initial study of thymosin combined with PEG IL-2 (IL-2 joined
to polyethylene glycol for increased stability) and AZT. Dr.
Merigan, who has studied IL-2 for some years with
disappointing results, says, "Thymosin has had some
interesting results in Italy and with hepatitis [see below].

The point of this trial is to see how thymosin boosts the
effect of IL-2 in patients with 50 to 200 CD4 counts, where
IL-2 just starts to have an effect." Merigan is following
changes in trial participants' CD4 counts and HIV levels.

The fourteen volunteers for this study started out on AZT
alone (500mg per day) for eight weeks. Then they went on AZT
plus IL-2 (one million units per square meter of body surface
every other week) for another eight weeks. In the final
twelve weeks, an escalating dose of thymosin was added.
Merigan will not yet comment on the results of this trial,
which enrolled its first volunteer a year ago. (The final
analysis of the data will not be available until late summer,
he says.)

Several informed sources have told Treatment Issues, though,
that the trial has not found any benefits from the triple
combination regimen. Some suggest that the participants were
not receiving thymosin long enough to make a difference or
that, alternatively, since patients in the U.S. trial, who
had more advanced disease than those in the Italian trial,
may have been too sick for thymosin to have an effect. A
final possibility is that thymosin plus IL-2 is just the
wrong combination for fighting HIV.

Discouraging Results with Hepatitis B

In the United States, Alpha 1 Biomedicals has concentrated on
developing the product for chronic hepatitis B, which affects
at least 300 million people worldwide. Chronic hepatitis C is
also under study.

Of course, a safe treatment for chronic hepatitis would be of
great interest to people with HIV, many of whom are co-
infected with hepatitis B or hepatitis C. Progression of
hepatitis disease may trigger progression of HIV or vice
versa. Alpha-interferon, the only approved treatment for
chronic hepatitis B, induces sustained disease remission in
only 25 to 30 percent of those treated, and side effects
often dictate stopping treatment.

Data from a phase II study of chronic hepatitis B suggested
that thymosin might be a significant advance.[3] Nine of the
twelve of the "thymosin treated" volunteers responded
favorably to treatment, and seven (58 percent) had a
sustained remission with normal liver tests and negative
hepatitis B antigen status after four years.

However, recently announced results of a phase III, placebo
controlled study indicate that thymosin was no better than
placebo as a treatment for chronic hepatitis B. The 99
patients in the study received either thymosin or placebo for
six months, with another six months of follow-up. After one
year, eleven of the 49 people in the thymosin arm tested
negative for hepatitis B virus DNA, compared to twelve of 50
people in the placebo arm.

Unraveling the Contradictions

The hepatitis B trial is extremely disappointing. The Italian
group, meanwhile, is conducting a combined alpha-interferon
plus thymosin study for hepatitis B and C in 30 people.
Researchers are reporting high rates of remission, even in
people who previously had not responded to interferon alone.
Thymosin's main hope is now likely to be new trials using
interferon and thymosin together.

But Alpha 1 may not be financially able to mount more trials,
let alone large, definitive ones. The day the recent
hepatitis B results were announced, Alpha 1 Biomedicals'
stock fell by two-thirds.

The company has been further weakened by a dispute with the
company's marketing licensee for outside North America and
Europe, which is now before an arbitrator. That licensee,
SciClone Pharmaceuticals, is demanding and may well get
damages and greater rights to alpha-thymosin because Alpha 1
has not been able to provide the drug due to a breakdown in
the manufacturing agreement with a Belgian company. The
damage award alone could bankrupt cash-starved Alpha 1.

SciClone is moving aggressively to sell thymosin in Asia,
which has an enormous population of hepatitis B carriers.
(Thymosin is already approved in Singapore.) The day Alpha
1's stock price fell, SciClone bought 15 percent of the
shares, making it Alpha 1's largest shareholder. This only
adds to the uncertainty concerning alpha-thymosin's future
development.

Meanwhile, Alpha 1's Italian licensee, Sclavo, has been
caught up in Italy's general financial scandal, and progress
in bringing thymosin to market in Italy (where it is approved
as a vaccine additive) has been retarded.

Because of these difficulties, thymosin is not available
outside of clinical trials anywhere in the world, although
Italian supplies are expected to exist eventually. Thymosin
may soon appear in the U.S. underground market, too, but wide
availability awaits future positive trial data. Lacking
quick, convincing results from the Italian HIV trials,
funding will be a serious problem.

Despite the problematic aspects of past thymosin trials, some
believe that the drug merits further scientific attention.
The Los Angeles-based Search Alliance wants to conduct a
rigorous study combining AZT, alpha-interferon and alpha-
thymosin in HIV-positive individuals.

Chuck Chesson, Search Alliance's clinical trial coordinator,
says, "Thymosin results have been interesting. The question
has to be answered - people need to know whether thymosin
works or not."

Although Search Alliance is a community organization, the
total cost of this medium-size trial still will amount to
$200,000, not counting the cost of the medicine. Encouraging
findings from this economical option (or the current Italian
government funded HIV study) may offer thymosin its only
chance for garnering the grassroots and financial support.
Without that support, its continued development is
questionable, regardless of the compound's value.

1 Goldstein, A. personal communication, April 24, 1994.

2 Garaci E, et al. International Journal of Clinical and
Laboratory Research, 1994; 24(1):23-8.

3 Mutchnick MG, et al. In: Graci E and Goldstein AL. Combined
Therapy: Biological Response Modifiers in the Treatment of
Cancer and Infectious Diseases, 1992; Plenum Press.


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Delavirdine Enters Efficacy Trials
 by Gabriel Torres, M.D.

Delavirdine (also known as U-90152) is a new anti-HIV drug
manufactured by Upjohn Company. It belongs to the class of
compounds called non-nucleoside reverse transcriptase
inhibitors (NNRTIs). These compounds block HIV replication by
inhibiting the same enzyme, reverse transcriptase, that is
blocked by nucleoside analogs like AZT, ddI, ddC and d4T.
NNRTIs strongly protect uninfected cells from HIV, but they
have been plagued by HIV's ability to rapidly develop
resistance to them.

It is hoped that delavirdine, when combined with other drugs
such as AZT, ddI, other NNRTIs, or protease inhibitors, can
slow down emergence of viral resistance. Precisely because of
this resistance, delavirdine is unlikely to be effective as a
single agent. Combining the drug with additional antiviral
agents, though, might so reduce HIV replication that
resistance to any of the components in the combined regimen
will take much longer to evolve. Also, the development of
resistance to delavirdine seems to increase HIV's sensitivity
to other NNRTIs.

Delavirdine's long-term side effects still need to be
evaluated, as does its activity during pregnancy. The
influence of the drug on fetal development and its ability to
reduce mother-to-child HIV transmission remain unknown.

Laboratory Studies

In the test tube, very low concentrations of delavirdine can
totally stop HIV-1 from infecting new cells and causing cell
death. It is also more potent than AZT and is effective
against AZT- and ddI-resistant strains of HIV in the
laboratory.[1] In AZT- or ddI-sensitive strains, delavirdine
has been found to be synergistic with AZT or ddI (the effect
of the combined treatment is greater than the sum of the
individual drugs' effects).[2] The compound is synergistic with
the first version (now canceled) of Upjohn's protease
inhibitor, too.[3] Delavirdine can also reduce the formation of
syncytia (clumping of cells which leads to rapid T cell
destruction).[1]

Unfortunately, when delavirdine is introduced to HIV-infected
cell cultures, viral strains that are ten- to 100-fold less
sensitive to the drug emerge. This drug resistance is
triggered by single changes (or point mutations) in the amino
acid sequence of the reverse transcriptase enzyme. One such
mutation (at amino acid number 236) causes high-level
resistance to delavirdine but sensitizes the virus to other
NNRTIs such as nevirapine, TIBO compounds and Merck & Co.'s
L-drug (L-697). Yet, it does not change sensitivity to
nucleoside analogs such as AZT and ddC.[4]

Animal Studies

Animal studies using delavirdine have focused on determining
its toxicities and adverse effects. The lowest dose in
animals in which notable toxicity has been observed is 50mg
per kilogram of body weight per day. This dose produced
inflammation of blood vessels (vasculitis) in dogs over a two
week period. Higher doses caused gastrointestinal
ulcerations, bone marrow toxicity and lung inflammation. The
drug also led to birth defects in pregnant rats at extremely
high doses. Since the drug is so potent, there is a wide
margin of safety - low doses can be effective in achieving
levels in the body that inhibit the virus.

Phase I Human Studies

Two clinical studies in normal healthy male volunteers have
been completed. These placebo-controlled studies showed that
the drug was tolerated in single doses of up to 300mg and
multiple doses of up to 100mg four times daily without side
effects; headache occurred frequently in both the delavirdine
and placebo groups. Two multiple-dose safety, tolerance, and
pharmacokinetic studies in 87 HIV-positive volunteers have
been completed. It appears that the drug is well tolerated
when given orally in amounts up to 400mg three times daily in
combination with AZT and up to 300mg four times daily in
combination with AZT and ddI. The most frequent side effect
is a rash that appears after one week on the drug. The rash
occurred in 27 percent of patients who took delavirdine in
combination with AZT and in 38 percent of those who took it
in combination with AZT and ddI. Most patients were
subsequently rechallenged with a lower dose once the rash had
resolved. They were able to tolerate their original assigned
doses after two weeks on the lower dose. Increases in liver
function tests occurred in two patients and resolved after
all antiretroviral agents were discontinued. A new crystal
form of delavirdine has also been developed by Upjohn that
seems to be more heat-stable. The new form is being used for
the large scale clinical trials initiated this spring.

New Delavirdine Clinical Trials

Upjohn is launching three new clinical trials of delavirdine
in multiple centers throughout the United States. The first
trial is a double-blind randomized study of three doses of
delavirdine in combination with AZT versus AZT alone.
The trial will measure delavirdine's efficacy based on
changes in HIV viral load, CD4 cell counts, and disease
progression. HIV-positive persons with CD4 cell counts of 200
to 500 who have had less than six months of prior AZT therapy
are eligible for this two-year trial. According to trial
plans, 1,200 to 1,500 participants will be enrolled. It is
hoped that women will make up 20 percent of the participants.
The delavirdine doses used will be 200, 300 or 400mg three
times daily in combination with AZT at 200mg three times
daily. The addition of ddI will be allowed in all treatment
groups if a study participant experiences a fall in CD4 count
to below 50 percent of baseline on two consecutive occasions
or develops an AIDS-defining illness.

The study will exclude persons with previous ddI, ddC, 3TC or
d4T therapy, patients unable to take AZT, and those who have
received therapeutic vaccines. The use of drugs that can
interact with delavirdine and lower its blood levels will not
be allowed within 21 days of study entry. These include a
large number of drugs used to treat opportunistic infections
and other conditions, including ketoconazole, fluconazole and
itraconazole for fungi; isoniazid and rifampin for
tuberculosis, rifabutin for mycobacterium avium complex
(MAC); and astemizole and loratadine, which are anti-
histamines.

A second parallel study will compare delavirdine in
combination with didanosine (ddI) versus ddI alone. This
trial will follow people with HIV who have CD4 counts less
than 300 and previous experience on AZT but less than four
months on ddI. Plans are to enroll between 800 and 950
patients for a two-year time period.

This study, too, will exclude patients with prior ddC, d4T or
NNRTI therapy. There is some concern that such people will
develop HIV strains resistant to ddI in addition to ddC. This
will be a problem for those in the ddI-only arm. The trial
also will exclude patients requiring therapy with rifampin,
rifabutin or the anti-histamine terfenadine (seldane).

Both studies will compare the emergence of drug-resistant HIV
in patients on the delavirdine combinations versus those on
nucleoside analog monotherapy. One interesting aspect of
these studies is that they will also measure the cost-
effectiveness and quality of life effects of adding
delavirdine to AZT or ddI monotherapy.

Finally, a third study is being conducted by Upjohn for
patients who have participated in previous delavirdine
studies. It will evaluate and compare the use of delavirdine
in triple combination with ddI and AZT or ddC and AZT. This
third trial is expected to enroll over 4,000 people.

For information on the delavirdine trials contact 800/TRIALS-
A. A number of trial sites will be located in the New York
area at various sites, including the Community Research
Initiative on AIDS (contact Bette Smith at 212/924-3934), St.
Vincent's Hospital (contact Daisy Soto, R.N., 212/604-8920),
Beth Israel Medical Center (contact Carsandra Sanders, P.A.,
at 212/420-4519), Mt. Sinai Medical Center (contact Eileen
Chusid, Ph.D., at 212/241-3933).

1 Dueweke TJ, et al. Antimicrobial Agents and Chemotherapy,
1993; 37(5): 1127-31.

2 Chong KT, et al. Ninth International Conference on AIDS,
1993; abstract PO-A25-0606.

3 Chong KT, et al. Ninth International Conference on AIDS,
1993; abstract PO-A25-0557.

4 Dueweke TJ, et al. Proceedings of the National Academy of
Science USA, 1993; 90(10):4713-7.

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Highlights from the Fourth European Conference on AIDS
 by Gabriel Torres, M.D.

The Fourth European Conference on Clinical Aspects and
Treatment of HIV Infection was held in Milan, Italy on March
16-18, 1994 and was attended by over 2,000 delegates from
Europe and the United States. The conference focused on
clinical issues in the management of HIV infection and its
complications rather than on basic or social sciences or
epidemiology. Last month we highlighted conference reports on
anti-HIV therapy. This month we give an account of the
presentations concerning AIDS-related opportunistic
infections.

New Diagnostic Techniques for Cytomegalovirus Infections

Various studies presented new methods for diagnosing CMV
infections, especially those of the central nervous system.
In one Swedish study,[1] 148 patients with encephalopathy had
their cerebrospinal fluid examined with PCR for detection of
viral genome (DNA). Diagnoses of herpes simplex, varicella
zoster, Epstein Barr virus, JC virus (which causes PML) and
CMV were made using this PCR technique in 39 to 42 percent of
patients. One presentation[2] showed how CMV encephalitis could
be diagnosed by detection of CMV DNA by in-situ hybridization
from cerebrospinal fluid and cells. Another technique used by
an Italian group[3] utilized a CMV pp65 antigen test as a blood
or cerebrospinal fluid marker of active CMV infection in HIV-
positive patients with painful peripheral neuropathy. The
development of these new diagnostic tests for CMV is crucial
in making a prompt diagnosis of CMV encephalitis or
neuropathy, which would otherwise require a brain or nerve
biopsy.

Oral Ganciclovir To Prevent Cmv Retinitis Recurrence

A multicenter European-Australian study reported data
comparing the use of oral and intravenous ganciclovir in
preventing the recurrence of CMV retinitis.[4] Following
induction with intravenous ganciclovir for two to three
weeks, 159 patients were randomized to receive either oral
ganciclovir (3 grams per day) or intravenous ganciclovir (5mg
per kilogram of body weight once daily). Using photographic
(fundoscopic) evaluation, the mean time to progression was
109 days for the intravenous group and 86 days for the oral
group. These results are not too different from those of the
trials in the United States and confirm that the oral drug is
almost as effective in delaying disease progression as the
intravenous drug. It is certainly less toxic.

Famciclovir for Herpes Zoster

A randomized placebo-controlled study found that
famciclovir,[5] a new potent oral anti-herpes drug, was
effective in the treatment of herpes zoster (shingles). Two
doses of famciclovir (500 and 750mg) showed comparable
efficacy and superiority over placebo in reducing the
duration of virus recovery from zoster lesions as well as
time to healing of lesions. A significant decrease in the
duration of pain was detected for famciclovir-treated
patients with severe rashes. The drug was well tolerated and
had minimal side effects. A poster presentation reported that
famciclovir also reduced the duration of post-herpetic
neuralgia (pain which develops after the shingles have
healed) from 128 days to 55 to 62 days.[6]

Toxoplasmosis Suppression

A randomized trial conducted by the ENTA Toxoplasmosis study
group in France and Belgium[7] showed that the combination of
pyrimethamine and clindamycin is clearly less effective for
long term suppression of toxoplasmosis than the combination
of sulfadiazine and pyrimethamine. Of 175 patients who had
completed acute therapy for toxoplasmic encephalitis and who
were randomized to one of the two suppressive regimens, 28
percent relapsed on the clindamycin group compared to 7
percent in the sulfadiazine group. A quarter of patients in
each group had to discontinue therapy because of adverse
effects, most commonly rashes in the sulfadiazine group and
diarrhea in the clindamycin group. Other options for
suppressive therapy of toxoplasmosis include atovaquone alone
or in combination with pyrimethamine, azithromycin or
rifabutin.

European Tuberculosis Studies

A multicenter European study[8] testing a three-drug against a
four-drug regimen for the treatment of tuberculosis in HIV-
infected patients was reported by a large consortium of
researchers. The treatment regimen included isoniazid,
rifampin, pyrazinamide with or without ethambutol.
Of the 611 patients under study, 475 had TB confirmed by
culture. The treatment failure rate was similar in both
groups, as was overall mortality. The level of TB resistance
to more than one drug was low (6 percent). In this population
of TB patients with low levels of drug resistance, the
addition of ethambutol did not seem to be justified.

A Spanish tuberculosis study[9] described an outbreak of
hospital acquired, multidrug resistant tuberculosis (MDRTB)
at a facility in Madrid. Twenty cases of MDRTB were diagnosed
between December 1992 and October 1993. The majority (85
percent) of the patients died, 53 percent within the first
month of diagnosis.

In a Rome hospital, 31 percent of the cases of TB were
resistant to at least one drug.[10] Drug resistance was more
common among patients with TB who had received previous anti-
TB therapy and had been noncompliant.

A blood test measuring adenosine deaminase (ADA) is being
studied in Spain[11] for rapid diagnosis of tuberculosis and
may prove useful in cases where there is a need to make an
immediate treatment decision. Other rapid TB tests include
PCR, the tuberculostearic acid assay and the luciferase gene
detection method.

Visceral Leishmaniasis

A relatively uncommon opportunistic infection in the United
States was described by groups from three European countries
(France, Spain and Italy). The disease, visceral
leishmaniasis,[12] is caused by the Leishmania infantum
protozoan which disseminates throughout the body and leads to
high fever, liver and spleen enlargement and bone marrow
disorders (leading to low red blood cell, neutrophil and
platelet counts). The disease responds poorly to
amphotericin, pentamidine or antimony drugs such as
meglumine. Patients often relapse and the average survival is
only 10.6 months. Resistance to meglumine was reported by one
group of researchers in patients who had received several
courses of the drug.[13] Immigrants from these European
countries, as well as from Asia and South America who present
with these symptoms should be evaluated for visceral
leishmaniasis since it can be rapidly fatal if untreated.

Terbinafine for Nail Fungal Infections

Toe nail fungal infections are very common in HIV-positive
persons and may be the first sign of an impaired immune
system. A British group reported that five of fifteen HIV-
positive patients with nail fungal infections caused by Tinea
rubrum were successfully treated with a new antifungal drug
called terbinafine.[14] Terbinafine is an allylamine antifungal
agent that in the trial was given once daily at a dose of
250mg for twelve weeks. The five patients who were cured did
not relapse after 48 weeks of follow-up. But terbinafine was
not effective in the treatment of oral thrush in another
study reported at the conference.[15]

Aspergillus Infections Associated with Hospital Renovation

A cluster of thirteen cases of an invasive fungal infection
called aspergillosis was reported by a group of Italian
investigators.[16] The cases were associated with exposure of
patients to the fungal spores in a hospital ward undergoing
reconstruction. The cluster confirms the dangers of hospital
acquired infections for AIDS patients during construction or
renovation, which may release fungi such as Aspergillus
fumigatus into the air.

Vitamin B12 and Folate Supplements

A group from Spain studied 75 patients with CD4 cell counts
under 500 who were randomized to receive AZT (500mg per day)
alone or in combination with folate (15mg per day) and
vitamin B12 (1,000 micrograms per month, injected
intramuscularly).[17] The study attempted to determine whether
the vitamin supplements prevented AZT-related suppression of
blood cell production in the bone marrow. After one year of
follow-up, there were no differences in the hemoglobin,
hematocrit, white blood cell, neutrophil or platelet counts
between the two groups. The researchers concluded that these
vitamins were not effective in preventing AZT-related
hematological effects. Other studies have reported a
beneficial effect of vitamin B12 in HIV-related peripheral
neuropathy.

Zinc and Opportunistic Infections

A poster presentation reported on the use of zinc sulfate
supplementation as preventive of opportunistic infections.[18]
Thirty volunteers received 200mg of the supplement a day in
combination with AZT and were compared to a group of eleven
patients who received AZT alone. The frequency of
opportunistic infections in the next two years was reduced in
the group who received the zinc supplementation (nine
infections versus 26 in the control group). The opportunistic
infections in which zinc may have played a role included PCP,
toxoplasmosis, cryptococcus, salmonella and tuberculosis; no
effects were seen for CMV and esophageal candidiasis.

Clotting Disorders in HIV-Positive Patients

A French group reported 35 episodes of unprovoked thromboses
(clots) among twenty patients in three hospitals.[19] Nineteen
of the clots were in the deep leg veins, fourteen in the
pulmonary vessels and two in cerebral vessels, leading to
strokes. A deficiency of free protein S had been noted in a
previous study of HIV-positive patients, and was recorded in
six of eight of the patients who developed clots and had
levels of Protein S measured. Protein S is involved in
preventing spontaneous formation of clots, and a deficiency
predisposes to thrombotic (clotting) episodes. It is unclear
why some HIV-positive persons have protein S deficiency and
are consequently at higher risk of unprovoked thrombotic
episodes.

1 Cinque P, et al. abstract O20. Fourth European Conference
on Clinical Aspects and Treatment of HIV Infecton, 1994.

2 Manicardi G, et al. abstract P138.

3 Volpi A, et al. abstract P137.

4 Knopse V, et al. abstract O21.

5 Tyring S, et al. abstract O24.

6 Tyring S, et al. abstract P159.

7 de Wit S, et al.; abstract P192.

8 European Tuberculosis Study Group. abstract O54.

9 Moreno V, et al. abstract 355.

10 Palmieri F, et al. abstract 356.

11 Fernández-González F, et al. abstract 360.

12 Rosenthal E, et al. abstract O27.

13 Gambarelli F, et al. abstract O28.

14 Nandwani R, et al. abstract P233.

15 Cartledge JD, et al. abstract O31.

16 Libanore M, et al. abstract P234.

17 Falguera M, et al. abstract P264.

18 Mocchegiani E, et al. abstract 306.

19 Pulik M, et al. abstract O62.

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Drug company watch
 by David Gold and Dave Gilden

SmithKline Blocks Investigation of AIDS Drug

Alan Pardee, M.D., and his group at Harvard University's
Dana-Farber Institute has found that the experimental
anticancer drug topotecan is also a potent inhibitor in the
test tube of HIV replication. General rights to topotecan are
owned by its manufacturer, SmithKline Beecham, but Dana-
Farber proceeded to file a use patent for HIV applications.
SmithKline in response has stopped supplying topotecan for
any HIV experimentation and refuses to negotiate any payment
to Dana-Farber. One prominent researcher is said to have been
ready to begin a trial using topotecan in HIV-positive people
with lymphoma, but SmithKline delayed it at the last moment.
The company reportedly now insists that all future topotecan
trials for whatever purpose exclude anyone who tests HIV-
positive.

First Human Data on Effectiveness of Antisense Drugs

Isis Pharmaceuticals of San Diego is reporting encouraging
preliminary data on its antisense compound aimed at CMV,
blocking a gene necessary for the virus's reproduction. The
drug, ISIS 2922, is injected weekly into the patients' eyes
to arrest CMV retinitis. CMV-associated retinal lesions
resolved (leaving inactive patches) in all five members of
the ISIS 2922 trial's high-dose arm. The same happened to two
of three volunteers receiving the medium dose. There have
been no relapses so far in up to four months of treatment.
All these patients had failed or become intolerant of the
standard CMV therapies, ganciclovir and foscarnet. Despite
these positive results (which were publicized by the
company's PR department), Isis insists that it is premature
to begin a compassionate use program for people outside of
the Isis trials who are doing poorly on the approved CMV
retinitis medications.

First U.S. HIV Antisense Trial Starts

Hybridon, a Worcester, Massachusetts based biotechnology
company, received FDA approval to test its antisense product,
GEM-91, which disrupts a sequence on the HIV gag gene
essential for constructing the core of new virus particles.
Trials are to begin by the end of April at the University of
Alabama and will include six HIV-positive patients. Michael
Saag is the principal investigator. GEM-91 is administered
intravenously. The drug has been studied in 23 patients in
France without side effects. However, in primates, serious
cardiovascular side effects were seen. In test tubes, GEM-91
inhibits HIV replication.

Bristol Meets with Activists on d4T

Officials from Bristol-Myers Squibb met with activists to
discuss the company's new drug application for d4T. Bristol
officials suggested that the company's AIDS drug development
program would be negatively affected if community
representatives did not support FDA approval of the drug. By
the end of the year, the company will release results from a
trial comparing d4T and AZT in 813 patients with at least six
months of previous AZT therapy. Bristol also is commencing a
d4T/ddI combination trial, even though the combination
enhances the risk of peripheral neuropathy.

Viagene Begins New Gene Therapy Trial

A 20-person trial of Viagene's HIV gene therapy product has
begun in HIV-infected individuals with CD4 counts between 200
and 500 at the University of California San Diego.
Participants will receive three injections over six weeks.
The injections contain the participants' own cells
genetically altered to express HIV protein on their surfaces.
It is hoped these cells will stimulate immune system
cytotoxic "killer cells" to attack HIV-containing cells. An
ongoing study is following the therapy in HIV-positive
patients with over 500 CD4 cells. Green Cross, a Japanese
company has agreed to continue funding development of this
immune therapy through 1996.

Lilly Leaves HIV Research

The Eli Lilly Corporation has announced that it is
discontinuing its HIV research. The company is in the midst
of restructuring its clinical program. Lilly had worked with
Agouron in developing the company's protease inhibitor.

Price Competition for Acyclovir (Zovirax)

SmithKline's famciclovir received approval as a treatment for
shingles (herpes zoster) in England. The drug is priced about
eight percent less than acyclovir. Most people expect that
the U.S. will approve famciclovir in the near future.
Approval will mean greater price competition for zovirax, it
is hoped.

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Treatment Briefs
 by David Gold

Oral Ganciclovir Access Plan (Sort of)

The Syntex Corp. of Palo Alto, California has announced a
program to make oral ganciclovir available to PWAs with CMV
who are unable to receive ganciclovir through central
catheter due to catheter infections or thrombosis (clotting
of veins). Physicians should call 800/569-4630. Activists
criticized the open label program because of the amount of
time it took to develop and, more importantly, because it
requires that patients must have a history of having a
catheter removed two or more times due to catheter infection
or thrombosis within the six months prior to enrollment.
Kevin Frost of ACT UP and TAG called the program "laughable."
Syntex plans to meet with community representatives to
"discuss these issues."

Hyperthermia Trial to Start

The FDA has allowed a six-patient trial of hyperthermia as a
treatment for Kaposi's sarcoma in people with AIDS. Dr.
Kenneth Alonso, who conducted hyperthermia on a number of
patients, will be overseeing the trial.

Dr. Alonso's hyperthermia procedure involves withdrawing
blood from the patient, then heating it to 110 degrees
Fahrenheit and returning the blood to the patient.
Hyperthermia attracted widespread attention in 1990 when a
few patients with AIDS claimed a "remission" after undergoing
the procedure. Some individuals were reportedly charged
upwards of $30,000 for the treatment. At the time, the
National Institutes of Health stated that it found no benefit
to hyperthermia therapy. Concerns about hyperthermia include
the fact that a significant number of patients died from the
procedure (seven percent in one trial) as well as the
procedure's high price. In addition, it is unlikely that
removing blood and "treating" it will affect the lymph
system, where much of the early HIV replication occurs.
Nevertheless, Biocontrol, a Pittsburgh-based company, is
developing the hyperthermia procedure. The company claims
that "favorable results" were seen from the hyperthermia
procedure on KS patients.

In what is no doubt a bit of an understatement, Senator Frank
Lautenberg (D-New Jersey), who pushed the FDA to allow the
trial to proceed, suggested "we are far from announcing a
cure for AIDS."

Pentoxifylline: Disappointing Data and a Warning

Pentoxifylline (also called trental) is an approved treatment
for a circulation disorder caused by a narrowing of the
arteries. The drug is also being used by HIV-infected people
based on preliminary data that suggests it reduces tumor
necrosis factor (TNF), an immune system protein that may
increase HIV replication and contribute to wasting syndrome.
However, a three week study by researchers from the Veteran's
Administration Medical Center in Palo Alto, California
reported that pentoxifylline produced no immediate benefits
in terms of CD4 counts, viral load or clinical status (May
1994; Journal of AIDS; 7:5(5)19-20). In addition, significant
side effects were seen at the dose given (2,400mg per day).
Of nine HIV-positive patients (CD4 count less than 400) given
the drug, one patient had to be reduced to 1,200mg per day
and three others could not tolerate the drug at either dose.
Reported side effects included fevers, gastrointestinal
upset, headaches, and nausea. No antiretroviral therapy (AZT,
ddI or ddC) was given.

The six remaining patients were followed for three weeks of
therapy. Viral load (as measured by HIV plasma RNA and p24
antigen) did not change in five of six patients. In addition,
no overall effects on TNF levels were seen.

In a reply to the published results, Dr. Bruce Dezube, a
researcher from Beth Israel Hospital in Boston who has done
extensive studies of pentoxifylline, noted that
antiretroviral therapy such as AZT was not included in the
study regimen. Dr. Dezube believes that if pentoxifylline is
to play a role in the overall treatment of HIV disease, it
will be in combination with an antiretroviral agent.
The VA study comes on the heels of a request by the BGA,
Germany's drug regulatory agency, that doctors report any
changes in the retina in patients treated with
pentoxifylline. According to Scrip, a drug industry
newsletter, the advisory was issued because a patient on
pentoxifylline developed retina bleeding and detachment. The
BGA emphasized that no causal relationship has been
established between the drug and retinal disorders.
Pentoxifylline is known to cause bleeding of the skin,
mucosal areas and stomach.

Hydrogen Peroxide Therapy

Treatment Issues has received a number of questions regarding
the use of hydrogen peroxide as a therapy for HIV. There is
no evidence that injecting hydrogen peroxide will provide any
benefit for HIV disease and there is some evidence that it is
quite dangerous. A recent letter in the Annals of Internal
Medicine (April 15, 1994;120: 694) reported the death of a
PWA who injected hydrogen peroxide into his catheter. He
subsequently developed nausea, dark urine, and a rapid heart
beat. Kidney problems soon developed and the patient died
five days after injecting the hydrogen peroxide.

Poppers and the Immune System

Isobutyl nitrite inhalers or "poppers" can reduce the
functional ability of T-cells in mice, according to a
researcher from the University of Arkansas (Toxicology
Letters, February 15, 1994; 70:319-29). Mice in the study
were exposed to three doses of isobutyl nitrite (900 parts
per million, 600 ppm and 300 ppm) for 45 minutes a day for
fourteen days. By comparison, one of the leading "popper"
products, "Probe," releases over 1,500 ppm of isobutyl
nitrate.

The study found that mice given the two higher doses had T-
cell mediated responses that were reduced by 37 percent.
However, three days after the last exposure to isobutyl
nitrate, T-cell functions returned to normal. In a
conversation with Treatment Issues, the lead investigator of
the study, Dr. Lee Soderberg, concluded that the reduction in
T-cell functioning in mice after exposure to isobutyl nitrate
was statistically significant, but reversible. He also noted
that the mice exposed to isobutyl nitrate showed reduced
tumor killing capabilities which returned to normal levels
more slowly than T-cell functioning.

New Drug Tested for Genital Warts

A topical formulation of HPMPC, an anti-CMV drug being
developed by Gilead Sciences, is now being studied as a
treatment for anal and genital warts in HIV-infected
patients. The trial is ongoing at three sites: the Conant
Medical Group, the University of Washington at Seattle, and
the Houston Clinical Research Network.

An intravenous (IV) version of HPMPC is now in phase II/III
trials for CMV. The drug is believed to work against strains
of human papilloma virus (HPV) which are associated with
genital warts. HPV has been linked to increased rates of
cervical cancer in HIV-positive women and anal cancer in gay
and bisexual HIV-positive men. The topical formulation of
HPMPC is being administered once a day. It is also being
studied in acyclovir-resistant herpes.

According to Dr. Conant's office, early indications from the
study for genital warts are "promising." In the first three
patients treated (all with anal warts), one patient had a
complete clearing, one had "extensive reduction," and one had
a self-described 50 percent reduction in warts per day. It
should be noted, however, that genital warts clear
spontaneously in about 25 percent of cases when a placebo is
given. Nevertheless, HPMPC is the first therapy tested
against HPV that attacks the virus itself and, according to
the company, protects uninfected cells against HPV.

Depression and HIV

Two studies on depression and disease progression among HIV-
positive individuals were recently published in The Journal
of the American Medical Association (JAMA, 1993; 270: 2563-
74).

One group of researchers, Lyketsos, et al. from the
Multicenter AIDS Cohort Study (MACS), found that depression
was not associated with increased disease progression or
death. However, another study, published in the same edition,
by Burack, et al. from San Francisco General Hospital,
concluded that "depression predicted a more rapid decline" in
CD4 counts. The first study, which did not find an
association, was significantly larger than the second. It
measured not only CD4 counts but "at least five assessments"
of disease progression. An editorial entitled "Depression and
HIV: How Does One Affect the Other?" accompanied the two
reports. It noted, "We are reminded by both studies that most
HIV-infected subjects are not depressed."

The editorial continued, "We continue to urge clinicians to
view depression in this population as a psychopathological
condition warranting treatment to reduce suffering and to
improve functioning. But we also recommend that clinicians be
cautious in suggesting that HIV-infected patients should
reduce their depression because of its direct effects on
their T-cells. Such a stance is not well substantiated and
may foster self-accusation when disease progression occurs."

Correction

March's edition of Treatment Issues incorrectly stated that
the on-going trial of Abbott Laboratories lead protease
inhibitor, A-84538, required participants to visit the clinic
every day for their daily dose. Actually, trial participants
will receive a cooler to transport their supply of the drug,
which comes in pill form and has to be stored at temperatures
below freezing. Other conditions for entering the trial
remain restrictive: Participants must have no opportunistic
infections and forego all other medications except for
prophylaxis for pneumocystis carinii pneumonia. They also
must have a CD4 count of more than 50. These criteria exclude
most people at the low end of the CD4 range. Volunteers also
must have substantial HIV levels in their blood, as measured
by the branched-chain DNA assay. This requirement excludes
many people with higher CD4 counts - a CD4 count of up to
500 is allowable in the trial.