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        Treatment Issues, Vol 9, No. 2 - February 1995
        Gay Men's Health Crisis, New York
        ----------------------------------------------

        Reports from the National Retrovirus Conference
        by Dave Gilden, David Gold, and Gabriel Torres, M.D.

        In this issue we present some of the highlights of the Second
National Conference on Human Retroviruses and Related
Infections, held in Washington, D.C. on January 29 to
February 2. The conference is well on its way to establishing
itself as the major conference for presenting new research on
HIV and AIDS. Next month's Treatment Issues will include a
more detailed report on the Conference, including such issues
as drug resistance, the treatment and prevention of
opportunistic infections and clinical trial design.

        Viral Dynamics

        Viral dynamics -- the rate of HIV particle production and
clearance within the body -- was a key issue dominating the
Second National Conference on Human Retroviruses and Related
Infections. Two leading AIDS researchers, David Ho, M.D.,
from the Aaron Diamond AIDS Research Center in New York and
George Shaw, M.D., from the University of Alabama started off
the proceedings with oral presentations on this topic. Their
findings -- that production of HIV virions and CD4 cells both
can exceed a billion per day -- indicate the massive struggle
occurring during HIV infection. Those findings also indicate
the difficulties involved in relying on antiviral drugs to
eliminate the virus, especially given the number of mutant,
drug-resistant variants that viral production of this
magnitude makes possible.

        Dr. Ho reported on twenty patients with high viral loads
(over one million copies of HIV RNA per milliliter of plasma)
who received Abbott Laboratories' protease inhibitor. This
compounded lowered study participants' plasma HIV levels by
98 percent within two weeks. The virus's exponential rate of
decline indicated that the half-life of virus particles was
on average approximately 2.1 days. This means that one-half
of the HIV in an infected person is renewed every two days,
for a daily production of 680 million HIV particles per day.
This rate of renewal appears relatively constant throughout
all stages of chronic HIV infection.

        This is a conservative estimate of viral turnover, since all
virus production is not shut off by the Abbott drug. Residual
virus may be due to inadequate drug penetration of tissues,
drug-resistant virus, long-lived virus-producing cells and
gradual activation of latently infected cells. Using a
similar model, Dr. Ho calculated the rate of CD4 production
and clearance based on the CD4 responses to the Abbott drug.
He estimated that each day anywhere from 35 to 53 million new
CD4 cells appear in the blood. Given that the lymph system
contains nearly 50 times more CD4 cells than the blood,
approximately 1.8 billion CD4 cells are produced in the human
body per day during HIV infection.

        Dr. Ho's group inferred from these figures that even in
persons with low CD4 counts, the loss of CD4 cells is not due
to lack of production, but rather to excess destruction. He
concluded from these experiments that the continuous high
viral replication is the engine driving the pathogenesis of
AIDS.

        In experiments by Dr. Shaw's group, patients were treated
with the Merck or Abbott protease inhibitor, and similar
viral and CD4 kinetics were seen. The Shaw team also used
nevirapine, an antiretroviral agent that leads to the rapid
emergence of resistant HIV. The researchers noted the
appearance of mutant, nevirapine-resistant virus within two
weeks.

        In the Ho and Shaw studies, resistance to both the Abbott and
Merck protease inhibitor were observed, although some
patients still had sensitive virus after six months of
therapy. Also, cases of marked, although usually short-lived,
CD4 increases were seen, with one patient who received the
Abbott compound going from a CD4 count of 68 to 680.
The implication of both of these studies is that aggressive
treatment with a combination of more than one drug should be
started as early as possible. Keeping HIV levels and
replication at a minimum would delay the emergence of
resistance to particular therapies. Dr. Ho plans to conduct a
study of aggressive combination therapy, including protease
inhibitors, for people experiencing initial, acute HIV
infection. His goal is to assess whether lowering viral load
as early as possible may alter the course of, or even
eradicate, HIV infection.

        Protease Inhibitors

        ABT-538: Abbott's compound, ABT-538, continues to appear the
most potent protease inhibitor now being tested in HIV-
positive individuals. Dr. Martin Markowitz from the Aaron
Diamond Research Center in New York presented phase I data on
ABT-538. At week four, viral load reductions had decreased by
an average of two logs (99 percent), and by week twelve, HIV
levels were still an average of 70 percent below baseline.
CD4 counts were 75 to 95 percent above baseline at week
twelve in the higher doses. The maximum antiviral effect
occurs within weeks of beginning therapy. It was not clear
from the data how long viral load reductions are maintained
on ABT-538.

        Australian researcher David Cooper presented additional data
from a 21-patient study of ABT-538. As reported in Treatment
Issues last month, two patients in this study had short-term
remissions in Kaposi's Sarcoma lesions after beginning ABT-
538. Other reported clinical improvements included:
regression in oral hairy leukoplakia (two patients) and
weight gain of over fifteen pounds (two patients). One
patient had remission of thrombocytopenia (low platelet
count), and one patient experienced a clearance of
cryptosporidiosis. The current formulation of ABT-538 is a
cherry syrup which, company officials admit, "tastes
terrible." Reported side effects include headaches, diarrhea
and a cluster of symptoms including lightheadedness and
fatigue, which were most common at the higher doses.
According to researchers, some patients on the highest doses
of ABT-538 "felt real lousy" for the first week.

        In a meeting with community activists, Abbott officials
described two placebo-controlled trials of ABT-538 that will
begin enrolling within a month. One study will enroll 250
AZT-naive patients and will measure surrogate markers (viral
load and CD4 cells). The other will look for clinical
benefits (differences in progression or survival) in 700
patients with less than 100 CD4 cells. In this trial patients
will be allowed to take the standard of care (i.e., whatever
nucleoside analog therapy they wish). The dose will be 600 mg
twice a day.

        Abbott researchers hope to file for FDA approval of ABT-538
within four months after beginning these studies. Another
study, of 900 AZT-experienced, asymptomatic people, will
begin at a later date. Abbott is also doing a dose escalating
study using 700 mg twice a day at Duke Medical Center in
North Carolina. Some suggest that drug interactions may be a
problem with ABT-538 (particularly with rifabutin and
fluconazole).

        Saquinavir: Stanford University researchers reported
preliminary data from a phase I/II study of 40 people treated
with higher doses of saquinavir (3,600 and 7,200 mg per day).
The findings indicated greater reductions in HIV levels and
increases in CD4 levels than the 1,800 mg dose being used in
phase III studies of the drug. Even at the higher doses,
saquinavir was reasonably well tolerated and there was a
direct relationship between blood level of saquinavir
attained and greater reductions in HIV levels. The anti-HIV
effect is still probably less potent than the Abbott protease
inhibitor, though. Interestingly, the Stanford researchers
noted that resistance to saquinavir seemed to develop at a
point after HIV RNA levels had already started to rebound.
Roche representatives claim that they are confident that the
1,800 mg dose of saquinavir taken in combination with
nucleosides analogs will provide a "meaningful antiviral
effect." The company plans to file for FDA approval of the
drug by December of 1995.

        AG-1343: Agouron researchers presented early phase I data on
AG-1343 in HIV-negative volunteers. The results showed that
the drug was extremely well absorbed and well tolerated. In a
meeting with activists, company officials outlined plans for
a phase I study including 25 HIV-positive people in London.
In the study, patients will be randomized to 100 and 300 mg
three times per day for four weeks.

        If all goes well, a phase II study will begin in the US
shortly thereafter. Agouron's data was considered reasonably
impressive, but activists are concerned that the company is
moving too cautiously and that the company has not outlined
studies to determine the optimum dose of AG-1343.
Agouron is also working on developing protease inhibitors for
CMV, hepatitis C and rhinovirus (the common cold).

        Resistance to Protease Inhibitors

        Dr. Markowitz also presented work by Aaron Diamond
researchers on resistance to protease inhibitors. The test
tube studies suggest HIV can develop cross-resistance to the
Abbott, Agouron, Roche and Merck compounds with long term
use. But the resistant HIV is still susceptible to the
Upjohn's protease inhibitors and a novel compound from
Searle. While this study provides some more sobering news
about drug resistance, it should encourage drug companies to
focus more effort on developing protease inhibitors which
require unique viral mutations to create resistance.

        New Data Provides a Second Look at 3TC

        Previous studies: The December, 1994 edition of Treatment
Issues reported extensively on antiviral therapy with 3TC and
AZT. We noted that this two-drug combination did seem to
produce a "comparatively robust" effect, with HIV levels in
blood plasma falling off dramatically and CD4 counts rising
significantly. But questions remained as to how long-lasting
and profound this response was. The conclusion that benefits
from 3TC/AZT still existed a year after therapy began or that
adding 3TC to preexisting AZT monotherapy preserved the
latter's effect turned out to be based on meager information.

        Newly presented studies: At the Washington retrovirus
conference, US researchers presented new data from two large
studies conducted in North America. Joseph Eron, M.D., of the
University of North Carolina-Chapel Hill reported on a trial
of 364 persons without prior experience on AZT (oral
presentation no. LB34). The group was divided into four arms:
93 were on AZT alone, 85 were on 3TC alone, and 186 received
AZT/3TC combination therapy with two different doses of 3TC
(150 and 300 mg twice daily). The median initial CD4 count
was 351. At week four, both combination therapies had
triggered a 98 percent reduction in plasma HIV levels whereas
AZT alone decreased virus levels by 70 percent and 3TC alone
resulted in a 95 percent drop. By week 24, virus levels in
the monotherapy groups had climbed back considerably toward
their original values. The combination therapy groups, in
contrast, retained an 84 to 90 percent viral load decrease.

        The pattern was similar as far as CD4 counts go, although
there was a time lag between changes in HIV levels and CD4
cell numbers in the blood. By week 24, the AZT and 3TC
monotherapy groups had fallen on average almost back to their
initial CD4 count while the combination therapy groups were
still above baseline: People on AZT plus high dose 3TC had an
average CD4 count of 58 over baseline (at week eight they
averaged 66 over baseline) and the low dose 3TC combination
group had an average CD4 count gain of 37 at week 24
(compared to 70 over baseline at week eight). This 40 to 60
cell superiority may be modest in the overall scheme of
things (especially compared to some of the first data coming
out of protease inhibitor trials), but it seemed to persist
out to one year. As Dr. Eron pointed out, though, no firm
conclusion can yet be drawn beyond six months because
information on study participants after that point is still
largely lacking.

        The second trial (oral presentation LB35) involved 254 people
with an average of two years' prior experience on AZT and a
median CD4 count of 211. The trial compared AZT plus 3TC
therapy to AZT plus ddC. The results, described by John
Bartlett, M.D., of Duke University, were much more
disappointing in this population, which had more advanced
disease than the first trial. Despite some initial
superiority, AZT plus 3TC performed little better than the
more traditional AZT/ddC combination. Decreases from baseline
virus load were nearly the same by week 24 (and were almost
below the sensitivity of the PCR assay). CD4 cell count
differences were marginal: Up 32 for the low dose 3TC
combination, up fifteen for the high dose 3TC combination and
down fifteen for AZT/ddC. All these CD4 values were reduced
somewhat from their peak values early in the trial.

        Analysis: The data comparing AZT/3TC and AZT/ddC in AZT-
experienced individuals is particularly puzzling in that
there are strong theoretical reasons, based on laboratory
experiments (oral presentation no. LB33), to think that the
AZT/3TC combination should represent a therapeutic
breakthrough. In persons treated with 3TC, HIV becomes
resistant to the drug within a matter of weeks, through a
single amino acid change in the reverse transcriptase enzyme.
This single mutation appears to reverse other changes in the
enzyme that enable it to resist the effect of AZT. In the
laboratory, it is impossible for HIV to be resistant to both
drugs at the same time.

        Yet, giving 3TC to people on long-term AZT proved little
better than adding ddC to the regimen. In the first study,
3TC alone actually performed at least as well as AZT alone
even though developing resistance to AZT seems to be a
longer, more drawn-out genetic process than for 3TC. High-
level resistance to AZT takes months to develop and requires
several genetic mutations.

        It would be interesting to further test combination
nucleoside analog therapies such as AZT /ddC against AZT/3TC,
especially in AZT-naive persons, to check if the latter
combination really possesses any special magic. But theory
aside, the final proof is whether combinations including AZT
and 3TC provide added clinical benefit (i.e., fewer
opportunistic infections) than other combinations.
A one-year trial looking at these issues is now starting up
in Europe. It includes 1,200 people with CD4 counts of 50 to
250, and will compare the clinical effect of remaining on
current treatment (either AZT or AZT/ddI or AZT/ddC) to
current treatment plus 3TC or current treatment plus 3TC and
loviride (an experimental compound under development by
Janssen Pharmaceuticals that blocks reverse transcriptase but
is not a nucleoside analog). The problem here is that the
"current treatment" rubric obscures the differences between
the various regimens that do not include 3TC. Also, adding
loviride, a second drug of uncertain effect throws a wild
card into the proceedings.

        In the meantime, the 3TC expanded access program (call
800/248-9757 to register ), continues to enroll patients at
the rate of 2,000 per month. Since the studies showed no
additional benefit to the 300 mg dose, all patients will be
given the 150 mg dose. Glaxo plans to file for FDA approval
of 3TC by June of this year.

        Other Reports

        Acyclovir for HIV: While a number of studies have suggested a
survival benefit from continual acyclovir (Zovirax) therapy
in HIV-positive individuals, two studies presented at the
conference, a placebo-controlled ACTG study (oral
presentation 383) and an observational study conducted by
Johns Hopkins University (oral presentation no. 382), failed
to find such a benefit. A more detailed analysis of the
acyclovir results will appear in the March Treatment Issues.

        Flu vaccinations and HIV: A number of poster presentations
reported that influenza or pneumoccocus vaccines can
temporarily increase the levels of HIV in HIV-positive
individuals. Researchers from the University of Nebraska said
that pneumoccocus vaccines resulted in a rapid, and in some
cases profound increase in viral burden (poster 240). A
consortium of medical centers in San Francisco reported that
"a substantial, yet transient increase" in HIV RNA was
observed in 78 percent of 30 HIV-positive individuals who
were given influenza vaccines and then closely monitored for
changes in viral load (poster 151). It is still unclear
whether these transient increases in HIV levels have any
clinical meaning at all. Moreover, the possible risks from
vaccination have to be weighed against the serious dangers
that influenza or pneumonia may cause in HIV-infected
individuals.

        Saliva's anti-HIV protein: Researchers from the National
Institute of Dental Research said they have identified a
protein in saliva that inhibits HIV (poster 165). The test-
tube studies suggest that the protein, called SLPI (secretory
leukocyte protease inhibitor), attaches to white blood cells
and prevents HIV from infecting those cells. Amgen, a
California based biotech company, is studying whether SLPI
has application as an anti-HIV treatment or as a viricidal
adjunct to safer sex.

        Good news for gym queens: An observational study at the Naval
Medical Center in San Diego suggested that HIV-positive
individuals whose workouts consisted primarily of weight-
lifting lost fewer CD4 cells over a 24 month period than
those whose exercise came mostly from running (poster 544).

        HIV Integrase: A New Therapeutic Target
        by Vincent Pieribone, Ph.D.

        The surging interest in new viral targets has brought about
the first scientific meeting dedicated exclusively to the HIV
enzyme integrase (January 19 to 20 at the National Institutes
of Health in Bethesda, MD).

        What is Integrase?

        HIV integrase is the virus's third enzyme (the other two are
reverse transcriptase and protease). HIV uses integrase to
incorporate its genes into a host cell's DNA. (The DNA form
of the viral genes is produced by reverse transcriptase.)
Inhibition of HIV integrase is an attractive therapeutic
strategy since it would potentially protect healthy cells
from infection thereby helping to bolster the immune system.

        Promising Reports

        At the conference, several laboratories presented ongoing
work that may lead to agents that could block integrase's
action. Notably, workers at the National Institute of
Diabetes and Digestive and Kidney Diseases have determined
the three dimensional structure of the central catalytic
region of the enzyme. By knowing the structure of the
enzyme's active site, scientists can begin to "design"
compounds that bind to and possibly inhibit the enzyme. This
"rational" approach proved successful in producing inhibitors
of HIV protease.

        Sometimes merely knowing the structure of the enzyme reveals
a similarity of other related enzymes for which cross-
specific inhibitors may already exist. Researchers have found
that integrase resembles the structure of cellular RNAase H
and another DNA binding protein termed mu-transposase.
Dr. Stephen Goff of Columbia University has used a novel
molecular biologic technique to identify a host protein that
binds to integrase and dramatically enhances its activity.
Working with HIV integrase, the protein seems to help the
viral genes to join properly with cellular DNA.

        In screening the National Cancer Institute's drug library,
Dr. Yves Pommier's laboratory has discovered three classes of
compounds that are effective at blocking HIV integrase. These
include DNA binding molecules, polyhydroxylated aromatic
compounds and various nucleotides. Polyhydroxylated aromatic
compounds naturally occur in a variety of plants. One active
form is found in nectar from flowers and is used by bees to
improve their hives. Some synthetic derivatives are ten times
more potent at blocking integrase and have exhibited some
anti-HIV activity in an NCI in vitro screening test.
Another promising lead reported at the meeting was a short
inhibitory peptide that was extracted from a synthetic
"combinatorial peptide library." These libraries consist of
millions of different peptides with known sequences. By
systematically testing mixtures with progressively fewer
numbers of different peptides, one can identify the exact
sequence of a peptide (or peptides) that has inhibitory
activity.

        Using a collection of compounds synthesized by Houghten
Pharmaceuticals in San Diego, Dr. Ronald Plasterk's group
from the Netherlands Cancer Institute found several lead
peptides that inhibit HIV integrase. While these peptides are
too large to be clinically relevant, they do provide
structural constraints that chemists can use to create second
generation molecules with more therapeutic potential.
Finally, the French company RhÖne-Poulenc Rorer has been
screening their large chemical collection and have identified
several lead compounds. Probably the most exciting outcome of
the conference was the fact that so many large pharmaceutical
companies attended the meeting. This indicates a growing
interest on their part in developing compounds active against
integrase.

        Potential Drawbacks

        Integrase as a therapeutic target does have several possible
pitfalls. While HIV reverse transcriptase and protease are
required to act for a significant period of time during the
viral life-cycle, integrase acts for only one brief step
during infection of the cell. This reduces the chances that a
drug will interfere with integration. Conversely, however,
the intracellular levels of integrase may be extremely small,
and this scarcity works in favor of an integrase inhibitor.
Also, interfering with the integration step would not affect
the yield of viable virus from infected cells. Since HIV
seems to produce a great deal of mutations throughout its
genes, inhibition of existing HIV integrase may merely cause
the rise of drug-resistant mutant versions.

        The hope is that a combination of therapies targeting
different enzymes, including integrase, will convey lasting
benefit to the infected person by reducing HIV's replication
rate, and therefore the emergence of mutant strains.

        Another Look at IL-2 Therapy for HIV
        by Craig Sterritt

        Over the past dozen years, a major effort has been under way
to develop the natural immune system stimulant IL-2
(interleukin-2) as a therapeutic weapon against HIV. IL-2
induces the multiplication of CD4 (T-helper) cells in the
test tube. If the same effect can be achieved in the human
body, CD4 cells destroyed by HIV could be replaced, and the
immune system perhaps reconstituted.

        There is also a substantial body of evidence suggesting that
HIV is controlled in the body during the early period of
infection by a strong response by the cell-mediated arm of
the immune system (chiefly suppressor and cytotoxic CD8 T-
cells activated by IL-2 released by CD4 cells). The cells
involved in this response gradually lose their ability to
effectively respond to HIV and other pathogens, possibly
owing to a decline in IL-2 production by CD4 cells.

        Intermittent Continuous IL-2

        IL-2 trials in the past found that the molecule's positive
influence on CD4 cell numbers disappeared after a few weeks
of continuous infusion therapy. Cells seemed to become
refractory to IL-2 after chronic exposure to the compound.
But an as yet unpublished study of IL-2 conducted by Joseph
Kovacs, M.D., and H. Clifford Lane, M.D., at the Laboratory
of Immunoregulation (part of the NIH's National Institute of
Allergy and Infectious Diseases -- NIAID) for the first time
observed substantial and prolonged IL-2-induced CD4 cell
increases.

        The NIAID trial employed a unique cyclical dosing regimen
rather than administering IL-2 on a steady weekly schedule as
previous trials have. Every eight weeks, study participants
received a five-day continuous IL-2 infusion of six to
eighteen million international units (IU) per day. This
regimen of intermittent continuous infusion lasted for eleven
to 25 months.

        In the course of the study, sustained CD4 cell rises of
greater than 50 percent were seen in six out of ten patients
who started with over 200 CD4 cells per cubic millimeter of
blood and were on stable antiretroviral therapy. Three
patients experienced three- to four-fold increases in CD4
counts over the course of the trial. In addition, Dr. Lane
now reports that three initial responders whom he has
followed for nearly three years have been able to maintain
CD4 counts in the high normal range of greater that 1,000 by
receiving "booster" five-day infusions whenever their CD4s
drop below 1,000 (every seven to twelve months). (It should
be emphasized that these patients who remained on therapy are
the IL-2 "success stories." They do not necessarily represent
the average patient's experience with IL-2.)

        A new, larger trial is following 60 participants with CD4
counts greater than 200. The trial is comparing intermittent
continuous IL-2 (18 million IU/day for five days every eight
weeks) combined with antiretroviral drug therapy to
antiretroviral therapy alone. The trial is still underway and
results are not yet available. Two separate informed sources,
however, have told Treatment Issues that CD4 responses
similar to those in the first trial are occurring.
One source also reported that several participants who
received between three and six infusions in the ongoing study
have had CD4 counts of over 1,000 for as long as seven to
eleven months since their last infusions. As in the follow-up
of the first trial, these participants will receive
additional five-day courses of IL-2 whenever their CD4 counts
drop below 1,000. The source added that CD4 increases in many
individual cases are detectable only after several infusions.
Rather than diminishing over time, the increase observed
after infusion tends to become greater with additional
courses of IL-2.

        Advanced Disease and Viral Load

        Results from experiments using the same IL-2 regimen in
patients with lower baseline CD4 counts have been less
encouraging. Earlier IL-2 studies had indicated that
treatment benefits were less likely to be seen in patients
with AIDS or with low numbers of circulating CD4's, and the
NIAID data confirmed these findings. Only two of six patients
with baseline CD4 counts of 100 to 200 have demonstrated
significant CD4 increases (greater than 50 percent) while
none of the six patients with CD4 counts lower than 100 had
such increases.

        The majority of study participants with low CD4 cell counts
also had significant, lasting rises in their HIV levels in
the blood (as measured by p24 antigen and viral RNA assays).
In contrast, the participants in the higher T-cell group had
transient increases in HIV RNA just after IL-2 infusion (up
to six-fold). Their HIV levels returned to their original
point before the next infusion. Those higher CD4 cell
participants who added an additional antiretroviral drug
during the study had reduced increases in viral load and
improved CD4 responses.

        There has always been a grave concern that IL-2 stimulates
HIV along with T-cells. The virus reproduces in infected,
activated CD4 cells, and HIV-free activated CD4 cells are
especially vulnerable to becoming infected. The NIAID
observations suggest that IL-2 boosts both CD4 counts and
viral levels, and that IL-2's treatment effect may be
determined by a tradeoff between the ability of IL-2 to
stimulate CD4 cells and the ability of increased amounts of
HIV to destroy CD4 cells. In addition, NIAID director Anthony
Fauci, M.D., has suggested that IL-2 stimulates "CD8
suppressor cells" which block HIV replication within infected
cells. These suppressor cells are lost in advanced disease,
and this may help explain the different responses to IL-2 in
the high and low CD4 cell groups.

        Immune Function

        Researchers have presumed that a boost in CD4 cells is a good
sign. There is, however, no way of knowing at this time if an
IL-2-induced CD4 count of 1,000 is as good -- or anywhere
near as good -- as a naturally occurring CD4 count of 1,000.
We cannot assume that IL-2-induced CD4 increases will
translate into any clinical benefit, such as delayed disease
progression or prolonged survival.

        The NIAID trials unfortunately have not observed the
qualitative immune improvements seen in previous IL-2 trials
with various regimens. Such markers include increased natural
killer (NK) and lymphokine activated killer (LAK) cell
function. Indication of heightened cell-mediated immunity --
greater CD8 and cytotoxic lymphocyte (CTL) numbers and
activity and a more intense reaction to delayed-type
hypersensitivity (DTH) skin tests -- also were lacking. Some
of the cell-mediated immunity tests (CTL, DTH) were not
carried out during the NIAID trials while others (CD8
numbers) remained unchanged in trial participants.

        In a telephone interview, Dr. Lane reported that during lab
tests, T-cell replication upon exposure to certain test
proteins increased in some patients, and this improvement may
correlate with the observed increase in IL-2 receptors on
cell membranes. No patients whose CD4 cells were unresponsive
in these proliferation tests prior to IL-2 became responsive
following IL-2 therapy, though.

        Dr. Lane could only speculate as to why indices of NK and LAK
cell activity were unchanged by IL-2, which ordinarily
stimulates such cell populations. The absence of information
about CTL and CD8 activity is particularly worrisome given
that this might be the immune system's strongest anti-HIV
response.

        Clinical Symptoms

        Dr. Lane and Dr. Gwen Fyfe (of Chiron Corporation, the
manufacturers of Proleukin brand IL-2) expressed concern that
once IL-2 therapy is begun, CD4 count and slope (the rate at
which CD4 counts are going down) no longer have any value as
a prognostic marker or as a tool for making treatment and
prophylaxis decisions.

        One patient in the NIAID trials (who received IL-2 but was
not considered a responder) subsequently developed
Pneumocystis carinii pneumonia (PCP) with a relatively high
CD4 count of about 400 as well as an extremely high viral
burden. In addition, two HIV-positive patients in the
Washington, D.C. area developed PCP with CD4 counts over 300
after receiving intermittent continuous IL-2 from their
private doctors. (See below for other cautions about
community use of IL-2.)

        IL-2 may either boost or preserve CD4 numbers without
necessarily making those cells competent. Alternatively, IL-2
may simply cause a "retrafficking" of CD4 cells, in which
cells enter the blood from the lymph system, where 95 percent
of them are concentrated. Dr. Lane is currently examining
lymph node and tonsil biopsies before and after IL-2 therapy
to ascertain to what extent IL-2 induces CD4 cell increases
there as well as in the blood. More exacting methods will
probably be necessary to accurately determine the
retrafficking phenomenon's extent.

        Safety and Toxicity

        The original IL-2 dose for these studies was 18 million IU
per day, but the majority of patients required dose
reductions to either twelve or six million IU, primarily
because of the debilitating side-effects that historically
have accompanied high-dose IL-2 therapy. These include fever,
severe flu-like symptoms, capillary leakage, lung congestion
and swelling, liver, kidney and gall bladder disorders,
neutropenia (low neutrophils, a type of white blood cell),
thrombocytopenia (low platelets), glucose intolerance and
irritating dermatologic problems such as psoriasis flare-ups.
Some participants have dropped out of the NIAID trials due to
the severity of the symptoms. But most found that the side-
effects, though very unpleasant, were at least temporary
under the intermittent regimen. One participant in the
ongoing trial noted that a recovery period of two to three
days following the five-day infusion in most cases restored
completely normal daily functioning.

        Community Use of IL-2

        There are various reports that people with HIV and their
doctors are obtaining commercial IL-2 (brand name:
Proleukin), which is approved for the treatment of renal cell
carcinoma, and trying to mimic the NIAID protocol. All of the
findings discussed here are preliminary, and there is no
indication as yet that IL-2 can yield any clinical benefit to
people with HIV. Some community sources also are attempting
to administer IL-2 by injecting it under the skin rather than
infusing it into a vein. This technique is particularly
problematic (see below).

        Drs. Lane and Fyfe are wary that patients most likely to seek
out an unapproved AIDS therapy, especially a toxic one like
IL-2, are those who are failing currently available treatment
options and consider themselves to have a poor prognosis.
According to the data from the NIAID and earlier trials, such
persons are the least likely to reap any immunologic benefit
from IL-2 therapy. The NIAID studies further imply that IL-2
can accelerate disease progression in patients with CD4
counts below 200 by substantially increasing HIV levels.
Dr. Kovacs has hastened to add on several occasions that the
HIV-promoting nature of IL-2 is probably worst among patients
in whom HIV has developed resistance to the antiretroviral
drugs they are taking. It is possible that drug-resistance in
the lower CD4 cell groups, besides higher viral burdens to
begin with, contributed to the sustained increases in viral
levels.

        The current consensus among investigators is that if there is
any recipe for success with IL-2, it includes higher baseline
CD4 counts, lower baseline HIV levels, and the presence of a
strong antiretroviral drug effect during IL-2 therapy. It is
hoped that future analyses of ongoing and upcoming trials
will be able to determine the specific factors that determine
an individual's response to IL-2 therapy -- such as CD4
count, percentage, HIV characteristics and virus level.
Persons with HIV who insist on trying IL-2 should have their
doctors procure information on contraindications, safety and
viral monitoring from investigators involved in ongoing IL-2
trials (See box).

        Future Directions

        Dr. Lane stated that his lab's first goal, to discover if IL-
2 can be used to sustain significant CD4 increases, has been
accomplished in a preliminary fashion. The larger, randomized
trial described above is pursuing more detailed data along
these lines.

        A second goal is to see if the same effects can be
accomplished in patients with more advanced HIV disease when
IL-2 is administered in conjunction with a potent, new
antiretroviral drug -- namely, the Merck protease inhibitor.
Preliminary studies of the Merck drug indicate that unlike
the nucleoside analogs, it may have a very strong antiviral
effect in later-stage HIV infection. As a brand-new drug, HIV
resistance to the compound is not an immediate problem
either.

        Dr. Lane believes that by strongly suppressing viral
replication during IL-2 therapy, CD4 responses may be much
more pronounced in late-stage patients. A small trial in
persons with CD4 counts lower than 100 is currently enrolled,
and Dr. Lane is hopeful that this approach can be expanded in
a larger follow-up study.

        Another goal is to discover ways to achieve the same CD4
effects without the onerous, risky and expensive five-day
infusions every eight weeks. As mentioned above, it is
possible that following an initial phase of three to six
infusion cycles, individuals may be able to maintain normal
to above normal CD4 counts with less frequent dosing --
possibly only once or twice a year. Another possibility is to
reduce the infusion period to three or four days rather than
five -- this will be the subject of a Chiron-sponsored trial.

        In a very different approach, investigators are examining the
efficacy of IL-2 injected subcutaneously (under the skin). An
efficacious subcutaneous regimen is a major goal of Chiron. A
company study is evaluating a two-week on/two-week off
treatment cycle in which twelve million international units
are injected once daily for five days in each "on" week. This
study is still underway, but already many participants have
had their daily doses reduced to nine or six million IU.
Sources told Treatment Issues that the regimen is not meeting
with profound success, possibly due to either the brevity of
the treatment intervals or the lack of continuous exposure to
IL-2.

        NIAID investigators have also found discouraging results with
once daily injections of IL-2. They are now seeking to
determine if IL-2 blood levels and CD4 rises comparable to
those obtained in the intermittent IL-2 infusion trial can be
achieved with two to three subcutaneous injections daily for
five days every eight weeks.

        Another study, conducted by Applied Immune Sciences in
California, has yielded data on the effects of twice daily
subcutaneous injections for five days every four weeks (with
and without concomitant infusion of proliferated CD8 cells
taken from the patient). Injected doses of two or four
million IU per square meter of body surface per day each
caused a 1.4-fold mean CD4 cell increase for the duration of
the trial (over nine months). The CD8 infusions gave no extra
benefit.

        A third goal is to reduce the severity of side-effects
associated with higher doses of IL-2. Some suggest that most
of the toxic effects of IL-2 therapy are caused by elevated
levels of tumor necrosis factor (TNF), an immune system
modulator released by cells in response to IL-2, which is
also known to increase HIV replication. There are plans to
explore intermittent continuous IL-2 in conjunction with such
TNF inhibitors as pentoxifylline (PTX), thalidomide and the
Centocor anti-TNF monoclonal antibody (MAb). Drs. Lane and
Fyfe say PTX and the Centocor MAb will probably be studied in
NIAID-sponsored trials, while the thalidomide/IL-2 trial is
under consideration by Chiron and investigators in the United
Kingdom. Findings from studies of PTX alone, as well as
reports from a few patients who have received PTX in
conjunction with IL-2, indicate that PTX is not that
effective in decreasing TNF levels. Thalidomide and the
Centocor MAb (besides newer TNF-inhibitors under development)
are now more promising candidates.

        Conclusion

        Despite the remaining unknowns, there is considerable
excitement among IL-2 researchers over the intermittent
continuous IL-2 findings. NIAID's Division of AIDS has just
commenced working on a comprehensive, long-term development
plan for IL-2 in collaboration with Chiron. The plan's
purpose is to delineate the fastest and most accurate way to
determine if IL-2 should be taken into large-scale efficacy
trials and then to envision how to conduct such trials.
A logical next step will be to couple long-term follow-up of
patients in current and upcoming IL-2 trials with in-depth
analyses of IL-2's biologic effects. There is an immediate
need to determine what IL-2's exact effects upon the immune
system are and whether those effects are likely to slow the
progression of HIV disease. A precise evaluation of the
amount of real T-cell proliferation that occurs compared to
the amount of T-cell retrafficking is of particular
importance. Another objective is a broad determination of the
specific types and usefulness of all the immune cells
influenced by IL-2 therapy.

        IL-2-induced CD4 increases ultimately will need to be
correlated with explicit improvements in immune function for
the therapy to proceed into large, expensive efficacy phase
III trials. Improvements in immune function will then need
correlation with clear health and survival benefits in order
for IL-2 to be validated and approved as a treatment for HIV
infection.

        Issues to Consider Before Starting IL-2

        IL-2 therapy is not approved for HIV disease. But because it
is approved for other conditions, a number of doctors around
the country are currently offering IL-2 to HIV-positive
patients. Some of these doctors are giving patients injected
IL-2, while others are offering infusions of IL-2 similar to
those used in the NIH trials. Both doctors and patients
should consider the following issues before initiating IL-2
treatment:

        1. IL-2 therapy can be very toxic, particularly in high doses
(3-18 million IU/day). It can cause severe flu-like symptoms
that will interfere with normal daily functioning. During IL-
2 infusions, you should have someone with you in the event
that respiratory or other complications arise. Liver and
kidney function and blood pressure should be monitored during
therapy. Individuals with heart problems or active
opportunistic infections should not experiment with IL-2.

        2. IL-2 therapy has been shown to increase levels of HIV.
These levels often go back to baseline in a matter of days or
weeks. Nevertheless, all patients given IL-2 must remain on
antiretroviral therapy. Antiviral therapy should include at
least one new agent to which your virus is not resistant. New
antiviral drugs should not be started at the same time as IL-
2 since it may be impossible to distinguish between side
effects from IL-2 and the new drug.

        3. HIV levels must be monitored closely in all patients given
IL-2. New methods of measuring HIV RNA in the blood, such as
PCR or branched DNA tests, should be used both before
starting therapy, to establish a baseline level, and several
weeks after each infusion. These new HIV tests cost more than
$200 a piece. Increasing virus levels are a warning that IL-2
therapy is failing or is counterproductive.

        4. It is not clear whether the large increases in CD4 counts
often seen with IL-2 therapy have biological significance or
translate into any benefit to patients.

        5. IL-2 does not appear to increase CD4 cells in patients
with low CD4 counts (less than 100). In fact, these patients
are far more likely to get an increase in HIV levels from IL-
2. Studies completed so far do suggest that patients with
over 200 CD4 cells have a good chance of receiving a CD4
boost from IL-2 therapy.

        6. IL-2 infusions are extremely expensive around $2,000 per
four or five day cycle. These cycles are repeated every eight
weeks. Patient advocates at Chiron, the manufacturer of IL-2,
can talk to your insurance company about the cost of the
actual drug and will provide it free of charge if your
insurer will not pay. This does not include the cost of
infusions, which are the most expensive part of IL-2
treatment.

        7. If you use IL-2, you may be excluded for clinical trials
of new therapies.

        8. ACTG 248, a trial of low dose, injected IL-2, will soon
begin enrolling individuals with CD4 counts of over 300 at
several sites across the country (including New York).
Patients will receive IL-2 therapy for at least six months.
All necessary blood work and medical monitoring will be
included at no cost. For more information, call 800/TRIALS-A.
There will be a forum on IL-2 therapy for HIV on March 20,
1995 at 8p.m., at St. Vincent's Hospital, Cronin Building,
tenth floor auditorium, Seventh Avenue and Eleventh Street,
New York City.

        Larry Kramer on the Politics of AIDS Research
Larry Kramer co-founded GMHC and founded ACT UP. In 1986,
Kramer began publicly pressuring GMHC to start a treatment
newsletter and hire Dr. Barry Gingell, a noted physician and
PWA, as editor. Shortly thereafter, in 1987, Treatment Issues
began publication with Barry Gingell as its first editor.
Since that time, Kramer's AIDS activism has focused primarily
on AIDS research and, as he describes it, "the fight for a
cure." He maintains a wide network of contacts among AIDS
researchers, physicians, activists, government officials and
those in the media and has not hesitated to attack, often in
bitter and personal terms, individuals and organizations
(including GMHC) with whom he may disagree.

        Larry Kramer is described in The Gay 100: A Ranking of the
Most Influential Gay Men and Lesbians, Past and Present
(Citadel Press, 1995) as, "Rude, opinionated, inconvenient,
invaluable, and irreplaceable, he is the most influential gay
man in America today. The organizations he helped found have
become some of the most important institutions in
contemporary gay America's struggle to survive. If the
community does in fact survive, it will owe that survival in
no little degree to Larry Kramer."

        Dave Gilden and David Gold of Treatment Issues spoke with
Larry Kramer in his Manhattan apartment and got his views on
the politics of AIDS research.

        Overall AIDS Research

        TI: Where do you think we are in terms of the AIDS research
effort?

        KRAMER: It's hard to know because there's no one in charge
and it seems to be worse under Clinton. He has been
grotesquely and tragically useless on AIDS. In terms of AIDS
research, we were actually better off under Bush. Everything
seems more fractured and splintered. There's less
communication than ever.

        The Office of AIDS Research [OAR] has been an enormous
disappointment. It's split whatever NIH effort was going on
into different camps that don't seem to get along well.
Fauci, Gallo, Paul and Broder -- nobody talks to anybody
else.

        The most interesting research is being done outside of the
government at places like the Aaron Diamond Center, the Salk
Institute, Dr. Cecil Fox's Molecular Histology Lab, and at
various drug companies. All this has little to do with
government. So one wonders what we get from the $13 billion a
year that goes to the NIH. Did you know there's never been a
cure for any major illness that has come out of the NIH?

        TI: What about William Paul [Director of the OAR]?

        KRAMER: Bill Paul is a nice man and a smart scientist, but he
has no sense of urgency. He is a wimp. This would not have
happened but for the lessening of ACT UP's energy.

        TI: But before the OAR reforms no one at NIH was looking at
how AIDS research dollars were being spent.

        KRAMER: The OAR changes killed our only friend down there --
Tony Fauci [Director of NIAID, the NIH institute with the
largest AIDS research program]. He invited us in. It was a
courageous and generous act that allowed the activist
community to get what power it does have.

        TI: What about the Director of NIH, Harold Varmus?

        KRAMER: Harold Varmus, like William Paul, has been an
enormous disappointment. He is not interested in AIDS and
does not appear capable of making everybody sit down at the
same table and talk -- of being the general.

        TI: What are your current thoughts on Tony Fauci?

        KRAMER: Well, your publication has been harsh on Tony, and
there are things to be harsh about. But emasculating Tony,
which is what has happened because of the OAR reforms,
resulted in us getting something worse. When we got rid of
Dan Hoth [former assistant to Fauci and director of the
Division of AIDS -- DAIDS] what did we get? Jack Killen
[current Director of DAIDS].

        TI: But Tony Fauci's job is to attract quality people to
NIAID and oversee operations such as the ACTG [AIDS Clinical
Trials Group], which is a mess.

        KRAMER: Tony hasn't been a very good administrator, but he's
a brilliant scientist. And it's hard to get anybody to work
for the NIH because the salaries are so low and because the
place is such a cesspool of mediocrity. Why has Tony become
the lightning rod of all the anger? Why did nobody go after
Sam Broder [the outgoing Director of the National Cancer
Institute -- NCI]. Or Varmus? The same thing happened here in
New York. We spent so much energy going after Ed Koch and
never went after Cuomo, D'Amato or Moynihan. These people, in
some instances, were more important than Ed Koch.

        TI: What about Robert Gallo's work?

        KRAMER: Some very important work has come out of Gallo's
laboratory at the NCI and we need him to continue. Two of the
most important people in AIDS research, Bob Gallo and David
Baltimore, have been crucified by Congressman John Dingel for
exceedingly petty reasons. We've lost two of the smartest
brains in AIDS research because some idiot Congressperson who
doesn't know anything about humanity has killed them. David
Baltimore should have been in charge of all AIDS research in
this country.

        TI: What about the AIDS Drug Development Task Force that was
announced with great fanfare last year?

        KRAMER: It meets once every three months, which is shocking.
A number of members would like it to meet every month.
They've asked Kessler [FDA Commissioner David Kessler] to
meet every month and he has refused. So I called David and he
said there simply isn't enough stuff to push through for a
monthly meeting, which is kind of scary. Secondly, he wants
to get the Abbott protease [inhibitor] out fast and doesn't
want to upset the apple cart. So let's see what he does with
the Abbott compound. If the members themselves can't get the
damn committee to meet every month, how can I do it? [But]
Kessler is the least of our problems at this point.
Approving AIDS Drugs

        TI: So you think the protease inhibitors are ready for
accelerated approval?

        KRAMER: Absolutely. Why aren't we fighting for the Abbott
protease the way we fought to get aerosolized pentamidine
approved? We fought so hard in the early days of ACT UP to
get a bunch of lousy drugs released. Now, when there are
decent drugs on the horizon, nobody is fighting for access.
You're talking to someone who could make a good case that we
don't need an NIH, an FDA or an ACTG. We know more about AZT
and how it works from patients taking it than we have learned
from a billion dollars' worth of trials. This is what makes
me so angry with groups like TAG [Treatment Activist Group],
which are advocating a return to a rigid system of drug
approval that we spent so much time dismantling.

        TI: Some would suggest that we don't know how to use these
drugs or if they are beneficial.

        KRAMER: Well, large simple trials may not give you the
answer. Chemotherapies for cancer have been in existence for
40 years and still haven't produced consistent results.
Doctors can learn more about how to use a drug from personal
experience on their patients than from clinical trials that
may take ten years.

        TI: So, if a drug has anti-viral effect and a known toxicity
profile it should be approved?

        KRAMER: Yes.

        TI: But just because a drug is safe, doesn't mean that it
works.

        KRAMER: You'll find out soon enough. And "safe" is a very
loaded word. Chemotherapy is not always safe. "Effective" is
the better word. There are very few drugs that work across
the board and do not have side effects in somebody.

        TI: But if a person is taking a bunch of drugs we may not
know whether one drug is useful or not.

        KRAMER: Enough is known about the Abbott drug for it to be
available right now, period. It is criminal to withhold that
drug.

        We are in desperate straits and we need drugs out there
faster. Researchers who we all respect think that the Abbott
protease is good, including David Ho [director of the Aaron
Diamond Center]. I would rather listen to David Ho than to
the 25 mediocre doctors who are going to do an ACTG trial
that will take four years.

        I have no faith in the drug delivery system in this country,
as it presently stands. That includes the NIH, which is a
cesspool of utter mediocrity, the ACTG which is $68 million
down the toilet every year, and the FDA. There are cheaper
and more efficient ways to collect data, such as using small
quick trials and private physicians as data collection
points.

        TI: But what if the effects of the Abbott protease inhibitor
as a single agent are only for three to six months?

        KRAMER: Well, so that's three or six more months than most
people have. It's probably not the cure but it's the next
step, at a time when AZT isn't working on a lot of people.

        TI: Are you concerned about raising false hopes with the
protease inhibitors?

        KRAMER: There's nothing wrong with hope that may not pan out.
Hope keeps you alive. No hope, you slit your wrist. Both hope
and panic can be useful and humane tools.

        Overhauling AIDS Research

        TI: Are things going to get worse, in terms of AIDS research,
under the Republican-controlled Congress?

        KRAMER: I don't think it makes any difference who's in office
-- who's the President or who's running Congress, Republican
or Democrat. It's taken me fifteen years to come to this
dreadful conclusion. What people don't understand is that you
have to change the system, but the system doesn't change. It
is run by civil service bureaucrats and laws on the books
since 1776. No one ever bothers to change the system of how
research is done, grants are funded or people are hired.

        TI: So how would you change the system?

        KRAMER: It will require a revolution and it's simply not
going to happen. The more sensible question is, what can we
do, that is possible, to make things go faster?
Prevention education does not seem to work. Rates of HIV
infection among young gay men continue to go up. That does
not mean we should give up educating, but we must spend more
time pressuring the system so that research moves faster. And
if you want some suggestions I've got them.

        TI: Go right ahead.

        KRAMER: To begin with, the people who are important in AIDS
research have to meet on a regular basis. The important ones
in government, Fauci, Varmus, Paul, Kessler, Phil Lee
[Assistant Secretary of Health], and Patsy Fleming [the new
White House AIDS Coordinator] have to meet once a week and
somebody has got to push them into establishing clear goals
-- and meeting them.

        These people, believe it or not, do not speak to each other
on a regular basis. Everybody has their own little fiefdom
and that's grotesque. If I'm running a large corporation
that's going to be any good, all my department heads would
have to meet with me on a regular basis and show results.
All these people report to Bill Clinton and Donna "Do-
Nothing" Shalala. So, the apparatus is there. Hopefully,
Patsy Fleming will somehow bring this about. But I'm told she
feels she can't step into AIDS research. If that's true, and
I hope it isn't, then Patsy Fleming is useless.
Second, combinations of anti-viral drugs must be studied more
quickly and aggressively.

        Third, why isn't anybody doing any major research on monkeys?
This has been advocated by Dr. Cecil Fox. When it was put to
Bill Paul and Tony Fauci both said, "Oh, yes, we're rushing
to work on monkeys." Well, nothing has started on the
monkeys. Why isn't combination therapy being studied on the
monkeys? Or immune therapies like cyclosporine? It's just
ludicrous. There's been a monkey model for this illness for
how long? Why aren't GMHC and other groups providing pressure
in this area? This is probably the biggest oversight going
right now.

        Fourth, research on monkeys must be done by virologists, not
by veterinarians. Evidently, part of the problem is that a
lot of the monkey work is being controlled by veterinarians
who do entirely different kinds of experiments than
virologists. They do not understand AIDS the way a virologist
does.

        Fifth, why isn't more work being done with infected babies?
This is an ideal chance to use early intervention. How much
earlier can an intervention be than in an infected baby? Here
again is a population of patients that we're overlooking.
Sixth, we need to get more drugs into the pipeline. Drug
companies must be convinced to screen their chemical
libraries. I'm grateful to David Ho for explaining this to
me. The large companies, which have libraries with more than
100,000 compounds, should be screening their compounds
against assays to study anti-HIV effect. This is one reason
there are so few drugs in the pipeline. Why aren't we
pressuring companies to do this? Some kind of apparatus has
to be set up whereby companies are encouraged to do this,
through tax credits or whatever. And, again, you come up
against the terrible lack of somebody in charge who can
convince the drug companies to do this work.

        Seventh, we need to make better use of data from the AIDS
cohort studies. People who have data from the cohort studies,
like those in San Francisco or at the New York Blood Center,
have refused to share this data with other researchers. It is
simply tragic that the New York Blood Center doesn't
automatically provide these samples when a reputable
scientist comes along and needs access to them. And no reason
is given. These studies were funded by the government. What
kind of attitude are we dealing with here?

        Eighth, we still don't know enough about pathogenesis of this
illness -- how does the virus get into a person, step by
step? What type of immune response do we need for a vaccine?
Why aren't we making greater use of monkeys for this type of
basic research?

        Ninth, it's wrong that the smartest researchers are forced to
spend 30 to 40 percent of their time running after money.
There's got to be some emergency mechanism set up so that the
brightest scientists are allowed to have more free time to
research. The dreadful thing about the current system is that
it rewards the mediocre and punishes the smart. We're never
going to get any kind of cure that way. Again, this is an
area where private foundations should step in more. The
Howard Hughes Institute, which has a gigantic amount of
money, should take even more of a lead in this.

        Tenth, we've got to figure out how to attract promising
researchers into AIDS. In this respect, the NIH can learn
from the drug companies. Corporate people set goals, pay
people a decent salary and give them decent benefits to
achieve those goals. If those goals aren't reached, then they
are out of a job. That's why the most exciting AIDS research
is taking place outside of government.

        Now,these things are not impossible to do. The fact that they
are not being done brings us back to the same problem --
nobody is in charge. There's no person with guts, persuasive
powers, administrative skills and scientific knowledge who is
in charge. Fauci, Varmus, Phil Lee, these are people who are
not particularly strong at being leaders.

        TI: Who, in your mind, is this kind of leader?

        KRAMER: We tried Lowell Weicker, Lee Iacocca, Roy Vagelos and
Admiral Watkins. The world is not short of these kinds of
people. Major corporations around the world are run by them.
These people are identifiable, and they're not controversial.
Admiral Watkins did an amazing job on the AIDS Commission
with a bunch of people who hated each other. So did the late
David Rogers. Why is this useless President refusing to cast
a net for someone like this?

        The Community Response

        TI: Why has the community been ineffective in the area of
AIDS research?

        KRAMER: I have come to the terrible and sad realization that
I don't know why people don't fight when their lives are
threatened. We don't and we haven't. A few of us have died
fighting. There's been an effort, but certainly not
commensurate with the power and money that this community has
at its disposal. I will obviously go to my death not knowing
why.

        TI: You've criticized major AIDS service organizations such
as GMHC and APLA [AIDS Project Los Angeles] for not devoting
enough resources to treatment advocacy.

        KRAMER: I have, and I continue to do so. It is an abdication
of these organizations' primary responsibility, which is to
fight for the lives of their clients. The leaders of all of
these organizations need to be more visible in the area of
fighting for AIDS research.

        TI: But the core work of these organizations is to provide
direct services to people with HIV, most of whom are in
desperate need of such services.

        KRAMER: Why does it have to be either/or, direct services or
fighting for a cure? GMHC and APLA get a lot of money. These
organizations were not started just to be one thing!

        TI: But some suggest that it's easy for Larry Kramer, who
lives on Fifth Avenue and East Hampton, to say we shouldn't
spend so much money on direct services.

        KRAMER: I've never said that at all. I've said that you
should spend more money and energy fighting the system and
fighting for AIDS research. These organizations rarely seem
to confront the system.

        TI: What about our organizations in Washington, such as AIDS
Action Council?

        KRAMER: Who are they? AIDS Action Council has been like so
many other AIDS organizations -- a waste of money. It has
been run by people who are not very good and has achieved
very little. It was set up initially by Paul Popham and
myself to be a Washington presence separate from GMHC because
in those days GMHC was looked upon as hogging everything and
other AIDS organizations around the country resented it.
So we attempted to set up an organization that would
represent everybody. But it turned out to be mostly funded by
GMHC -- and still is, as far as I know. The fact that GMHC
continues to give money to it is something that I've never
understood. GMHC would be better off funding its own
Washington lobbyist. [Editor's note: Derek Hodel has recently
been hired by GMHC in a newly created position, Director of
Federal Affairs.]

        It's a never-ending pattern with our Washington
organizations. We send people to DC to fight the system, they
get invited to lots of lunches and become part of the system.

        TI: So how do you avoid that?

        KRAMER: You avoid it by asking for a return on your money. If
GMHC is funding AIDS Action $200,000 a year, you say, "I want
to know what I'm getting for my $200,000 a year." You set
goals and demand results, like in any corporate environment.
And quite frankly, if that were the case, you would have
stopped funding AIDS Action long ago.

        TI: How do we get more government monies allocated for AIDS
research?

        KRAMER: Everybody fights for more money, but the real issue
is making sure the money is well spent. You can get more
money for the ACTG, Bill Paul, and for an awful lot of
inferior entities but it's not going to solve the problem.
The problem is seeing that the money is spent wisely and
given to smart people so that things move faster. Again I use
the example of the monkeys. Do you know that because of the
bureaucracy and red tape, it takes two years to requisition a
monkey at the NIH? So it's irrelevant that the money is
there. You can't get the monkey because of red tape. So AIDS
Action, Patsy Fleming, the OAR, GMHC or APLA must all exert
pressure to eliminate these delays.

        The "right wing" and the "religious right" never give up.
They know that they are going to have to fight until the day
they die. And there's no wavering. We give up very quickly.
We must get a different mind-set on this, that you just
simply cannot stop fighting.

        TI: So, what needs to be done? ACT UP is kind of burned out.

        KRAMER: I don't know whether what ACT UP does works anymore.
You can make the system work by raising our voices and
reaching increasing numbers of people. For a while ACT UP was
able to do that. We're weak now because our voices are not
heard. So organizations like GMHC, which have the money to
mount campaigns and fund lobbyists, must be more aggressive.
And other tactics have to come in. We should begin a series
of protests against the media. The New York Times still does
not have an AIDS reporter investigating this issue like they
would a USAir crash.

        TI: The Wall Street Journal just transferred their AIDS
reporter out of AIDS.

        KRAMER: That's appalling. The important media sources don't
write about AIDS. McNeil/Lehrer and Nightline never do AIDS
stories. I've long advocated nonspecific underground
guerrilla activities. This is a war, a plague, and we're
treating it as if it's not. On a community-response level, we
are exceedingly passive and docile. I get particularly angry
when we have resources that we don't use. By that I mean
boards of directors. I have gone after GMHC in print any
number of times because you have powerful people on your
Board, people who have connections with powerful people. Why
are these contacts not utilized? I was overwhelmed with anger
when I recently discovered that the President of the Board of
Harvard AIDS Institute is Maurice Templesman, who was Jackie
Kennedy's friend. I called Max Essex [Director of the Harvard
AIDS Institute] and asked if he ever requested Templesman to
speak out or do a benefit. He said, "No, maybe I should ask
him to do something." It's that kind of attitude. Scientists
are wimps when it comes to politics.

        You have the same kind of important people on your Board. And
you don't use them. The corporate world works because
companies have powerful boards. No gay organization ever uses
its board effectively.

        Treatment Decisions

        TI: How do you make your own treatment decisions?

        KRAMER: It's hard and it's not comfortable because doctors
don't agree with each other. And that's very confusing for
everyone. But people have access to more information than
they think. It's vitally important that everybody who's HIV-
positive take charge of his or her illness powerfully. And
that is not impossible to do. It just requires a lot of work.
It requires reading publications like your own excellent one,
which I tell everybody to subscribe because you put out stuff
that nobody else does. And reading John James' newsletter
[AIDS Treatment News] and the stuff that comes from PWA
groups, as well as talking to doctors and other patients who
are plugged in. It's like researching a term paper and going
to all the sources you possibly can and then making your own
decision. I know it's not easy.

        It's not easy with any serious illness, particularly where
there are different points of view. So you have to learn how
to read your own blood work, ask your own questions and
realize that your doctor, whoever he or she may be, is not
going to be on top of your case with the thoroughness that is
required. You have to see when things go up and down on the
medicine you take, how you feel from it and what it does to
your blood over a period of time. Find a doctor you feel
comfortable with. Be assertive and tell your doctor
everything. But it's not easy.

        TI: Tell us about your plans, aside from activism.

        KRAMER: Stephen Gendin recently said to me, "It's all your
fault because you gave us such hope. You said there was
cure." Well, I still believe there's a cure. And I've never
lost hope. That helps keep me going.

        But I have this perennial conflict between being an activist
and wanting to be an artist. And I'm embarked on a very long
novel. I also have a lover for the first time in a long time
and that's made me exceedingly happy. We bought a house in
the country and I want to live there with him, write my book
and play house. But I feel guilty that I'm not out there
being what everybody wants me to be. Like most of us, I don't
have that kind of energy anymore.

        I outlined ten things that would help the system go faster.
Yes, it would be wonderful if there was a leader to appear
who could push all these things. But, there are things we all
can do. We have to keep pushing and pressuring a research
system which moves far too slow.

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