        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 Rhne-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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