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AIDS TREATMENT NEWS Issue #211, November 18,1994
   phone 800/TREAT-1-2, or 415/255-0588

Contents:

Strategy of Hope: Small, Rapid Viral-Load Trials

Viral Load, Small Trials, and Immune Recovery

Nevirapine Triple Combination: Preliminary Results Released
November 17

Hydroxyurea -- Call for Information

The Elections: What AIDS Organizations Need to Do Now.
Interview with Tom Sheridan, Sheridan Associates

AIDS TREATMENT NEWS Talent Search: Board Members for
Charitable, Internet Work


***** Strategy of Hope: Small, Rapid Viral-Load Trials

by John S. James

There is more despair in the AIDS community now than probably ever
before. The bad news -- often misreported, misinterpreted, and
misunderstood -- is heard again and again, and reaches the minds of
people everywhere. Medical and scientific presentations are largely
empty of important good news, and people sense that little is
happening in AIDS treatment development.

We do not share the pessimism, because there are also excellent
opportunities to move forward, given the will and the organization to
do so. The potential good news is largely unreported in the media, and
missing in the ongoing public conversation which largely determines
peoples' views. But new developments are starting to save lives now,
and could save many more lives in the near future. How many lives will
depend on whether people pay attention, understand what is happening,
and effectively support its development.

Recently AIDS TREATMENT NEWS has published a series of
articles with a common focus: developing certain emerging
opportunities into a strategy for moving forward, a strategy
we can apply today, a strategy which will pay off now and in
the near future, as well as the distant future. This is our
tenth article this year in this series; for a list of the
earlier ones, see below.

Last week, at the New Directions in Antiviral Chemotherapy
conference (November 10-12 in San Francisco), both the
despair and the grounds for hope were evident. After Friday's
sessions, what stood out most was the lack of new
information. Earlier that day, while one of the speakers
droned on, a prominent physician in the audience commented to
us that the leading researchers (with most of the medical
profession following) were going to continue treating AIDS
like hepatitis, and continue to accept the death of all of
their patients.

But those who showed up early Saturday morning heard Douglas
Richman, M.D., one of the leading AIDS researchers, in an
aside from his talk on antiviral drug resistance, cite
studies from around the world showing that, "In a two-week
study, you can show whether a drug works or doesn't work, and
you can do a dose-response curve. Now it doesn't tell you
what's going to be a useful drug, because it's a chronic
disease, so it doesn't tell you what's going to happen long
term... In terms of being a useful drug, we need longer
studies. But in phase I studies to ascertain whether you've
got a drug that works or not, you only need a two-week
study." (For more of this transcript, see "Viral Load, Small
Trials, and Immune Recovery," below.)

What is important in Dr. Richman's talk is:

* The concept of small, rapid trials to look for antiviral
activity in people;

* Evidence that if viral load, as measured by plasma HIV RNA,
could be kept down, the immune system could recover
spontaneously (see transcript below); and

* The rapidly increasing momentum these ideas are getting in
the professional community.

The ideas are not new. But Dr. Richman's discussion -- a 5-
minute aside in a longer talk on resistance to antiviral
drugs -- brings together strong evidence in their favor, a
coherent interpretation of the evidence, and a clear path for
moving forward.

Some other researchers have shown a mental split on this
issue. On one hand, they say it is unproven that reducing the
plasma HIV RNA and keeping it down will benefit the patient,
that this must be proven by prospective studies (which in
practice will take years to design, conduct, analyze, and
publish). But on the other hand, the same people can be seen
to be basing their own thoughts and plans on the working
assumption that lowering this viral load is the central goal.
Many researchers do agree that trials to learn how to lower
the HIV RNA is what we should be doing now -- although
everyone also knows that we also need more studies on what
this marker means for clinical practice. And pharmaceutical
companies, which bet money on drug-development strategies,
are now including HIV RNA in almost all their trials of new
antivirals, providing de facto acceptance of viral load
measurement in early human trials to screen new drugs.

But in Dr. Richman's talk, as in almost all talks by
professional researchers, the only drugs mentioned are those
being developed by pharmaceutical companies. If these were
the best candidate drugs -- if pharmaceutical companies were
efficient in selecting what to develop -- then this
limitation might not make much difference. But the industry's
selection process is not efficient, because it only looks in
certain places; it only considers drugs where the company
has, or can readily acquire, exclusive proprietary rights.
Usually this means new chemicals, which will take years to
develop because they have to go through laboratory testing,
animal tests in different species, pharmacodynamic tests in
people, phase I dosage tests in people, etc., all the time
with many committees and reviews. Another problem is that it
usually takes so long to build management and financial
momentum for a new product idea, that years are likely to
pass between the time a few scientists realize that a new
approach is important, and the time that management decides
to go ahead and develop an innovative drug. And during this
time the data, and often even the existence of the project,
are generally secret. This means that innovations are
routinely delayed for years, for no scientific or medical
reason -- not only delaying the drug in question, but often
impeding other projects which could benefit from the
information. Industry is usually fixated on getting
individual proprietary drugs through the FDA -- which is only
part of the job of giving doctors the tools they need to be
effective.

Meanwhile, natural products, traditional medicines used in
cultures around the world, and readily available prescription
drugs approved for other uses and often long off patent, are
not considered as potential HIV treatments, even when there
are excellent reasons to study them. Yet if any one of these
were found to be useful in treating HIV disease, that finding
would have great public-health importance, since these drugs
are readily available, usually inexpensive, and well known in
human use. Basic information on dosage, risks, precautions,
etc. is already there; the financing of a major development
project, the convincing of management, the laboratory and
animal tests, etc. are not necessary. There are seldom any
supply or manufacturing issues, nor need to fight with
companies or the FDA over expanded-access programs.

What is needed instead is (1) to find out if there is
scientific evidence that an available drug shows antiviral or
other potentially beneficial activity in people, and if so,
(2) to learn how to use the treatment most effectively -- for
example, learning which patients may benefit, what doses are
best for HIV treatment, and what additional safety
precautions may be required for persons with HIV. While this
work is proceeding, the drug can also be tried as an element
in combinations, which can include existing approved HIV
treatments, experimental drugs under development, and other
already-available drugs which have shown promise. The first
test for scientific rationale may look for reduction in HIV
RNA; or other tests could measure markers of immune function,
for example.

These other tests may be equally important; we have
emphasized HIV RNA because it has several advantages at this
time. It has a central rationale in HIV disease, since it
directly measures the amount of virus in the blood -- which
also appears to be a good indicator of the activity (although
not the amount) of the virus in lymph nodes and throughout
the body. Tests for HIV RNA have been well standardized, and
are known to be highly reproducible from sample to sample;
also, early data on average day-to-day variation in patients
has been published. The test is commercially available,
meaning that researchers and physicians can order it when
they need it, instead of spending months in negotiations or
years in assay development and standardization, which is
often necessary for research tests.

Overcoming Drug Resistance

HIV resistance to antiviral drugs is a major and growing
problem. The conventional approach to overcoming resistance
is to combine drugs, either targeted against the same viral
protein (for example, AZT plus ddI plus a non-nucleoside
reverse transcriptase inhibitor such as nevirapine), or
against different proteins (for example, AZT combined with a
protease inhibitor). This approach is important, but it is
too early to know how successful it will be.

There is another approach which may be more successful in
overcoming resistance, but which unfortunately is largely
being ignored. This is to combine drugs like AZT or protease
inhibitors, with different kinds of drugs which inhibit HIV
without targeting viral proteins at all. There are many
different kinds of such potential drugs, many different
mechanism of action. Here are four of them:

* Immune-based therapies. An ideal treatment would be a way
to restore the body's ability to keep HIV under control. This
is because the immune system can control HIV much better than
any known drug. Eventually, in most people, it loses this
ability, for reasons which are unknown, but which are
probably related to some injury to the immune system caused
by the virus -- an injury which appears to be reversible, at
least in large part, if the virus can be stopped (see "Viral
Load, Small Trials, and Immune Recovery," below). If we knew
specifically what caused this loss of immune function, it
would probably be possible to intervene pharmaceutically,
creating a new HIV treatment entirely separate from antiviral
drugs -- which could still be used in addition, if necessary.

* Hydroxyurea, etc. Another approach is to reduce the level
of substances which HIV needs, but which are produced by
human cells, not by the virus. Viruses always rely on many
substances which they cannot produce themselves. Of course it
is necessary to find a drug which can inhibit the virus
without harming the human cells, which often need the same
substances. But once such a drug is found, it will probably
be difficult for the virus to work around it, as there is no
viral protein which is being directly targeted and can evade
the drug through mutations.

One such drug now in the news is hydroxyurea, which has been
used for decades in treating certain cancers (see
"Hydroxyurea -- Call for Information," below.) In laboratory
tests, it greatly inhibits HIV at concentrations which are
easily achievable in the blood. Laboratory tests also
indicate that it might work especially well when combined
with ddI. So far only a handful of people have tried
hydroxyurea as a treatment for HIV, apparently with quite
promising results; because of safety concerns, however, most
physicians understandably want trials to be run first, before
they prescribe the drug for their patients. But, in a tragedy
which would also be a scandal if it were not so common, no
trials have been run (except for a small study recently
started in France), despite great efforts by researchers to
get a trial going. The problem seems to be that the clinical-
research system is built around the assumption that drugs
will be developed by well-financed pharmaceutical companies;
and in this case, no company has an incentive, since the drug
is off patent. The critical need is for the first, small
study, to get credible data which will provide momentum for
further research, as well as data about safety and side
effects in persons with HIV. Such a trial would not need to
be very expensive. But neither government nor private
research organizations have succeeded in getting a study
going, and activists have not followed the situation or
raised an alarm about the lack of research.

* LTR inhibitors. A third approach is to reduce viral
activation of the LTR (long terminal repeat) of HIV, which
acts as a master switch which makes the virus more active.
AIDS TREATMENT NEWS has reported on this mechanism of action,
which has been largely ignored in conventional drug
development. Some treatments which work this way will
probably be susceptible to HIV drug resistance, but might
still be useful in combinations with other classes of drugs.
Other approaches, less susceptible to resistance, may slow
HIV progression by reducing abnormally high levels of certain
substances, such as TNF (tumor necrosis factor), which are
naturally present in the body and known to stimulate HIV.

* It appears to be possible to slow HIV progression by
aggressive diagnosis and treatment, suppression, or
prophylaxis of certain opportunistic infections, which may
stimulate HIV. If it is true that continuous acyclovir use
can extend average survival in persons with AIDS, as some
evidence suggests, it may be working indirectly by
suppressing certain herpes viruses which may activate HIV.

Drug Mechanism of Action,

and Viral Load

With small, rapid trials, many leads can be followed up
quickly, and new combinations can be rapidly developed.
Whenever a treatment does look promising, the trials set up
to test it should, of course, be followed indefinitely. The
first challenge is to reduce the viral load; but the most
difficult challenge will be to keep it down.

Testing for viral load (usually by measuring plasma HIV RNA,
which is the most feasible viral-load test today) is clearly
useful for trials of antivirals which directly target viral
proteins; in this case, we know what to expect if the drug
works (see "Viral Load, Small Trials, and Immune Recovery,"
below). It now seems clear that hydroxyurea greatly reduces
the level of HIV RNA in people, so the same test should be
able to measure its activity -- although less is known about
this drug, since no trials have been done.

For drugs with other mechanisms of action, however, viral
load tests will need to be used with care, sometimes in an
exploratory mode where researchers are looking to see what
happens, rather than trying to confirm or deny a pre-existing
hypothesis. For example, an immune-based therapy may reduce
viral load indirectly, by helping the body control the virus.
But at first, certain immune-based therapies may actually
increase viral load temporarily, by causing immune
stimulation which can activate HIV.

There might also be treatments which reduce the damage that
HIV causes to cells, but do not reduce the level of virus. In
this case the treatment could be beneficial, even if nothing
at all is seen on the viral-load tests.

Or consider the case of acyclovir, which does not have any
direct effect against HIV. If this drug does improve average
survival of persons with late-stage HIV disease -- and the
evidence which suggests it does is controversial -- it is
probably doing that by suppressing other viruses which
activate HIV. If so, then it is possible that some patients
might be getting a large benefit, while others who do not
have those viruses might be getting none at all. Viral-load
and other blood tests could be used to explore this
hypothesis. For example, a controlled trial could assign one
group of patients to use acyclovir continuously, while others
used it only when necessary for suppression of herpes; the
latter group would have HIV viral load measured whenever a
herpes recurrence occurred but before acyclovir treatment was
started, and then have repeated viral-load measurements while
the acyclovir treatment continued. Such a trial might help
researchers understand the mechanism of action (if any) of
acyclovir in improving AIDS survival, and perhaps make it
possible to identify groups of patients most likely to
benefit.

Some Drugs to Test

One cause of the prevailing pessimism about AIDS treatments
is the sense that there are no drugs to test. So we started a
list of candidate drugs which are already in use in people,
and have some rationale suggesting that they should be tested
for possible use in treatment of HIV disease.

The list of 27 potential treatments below is just a
beginning. We only included drugs, nutrients, etc. which are
already in human use for other purposes. And we only included
the drugs which came to mind in the last two weeks; we have
not yet done literature searches, nor talked to experts in
micronutrients, or in Chinese or other systems of traditional
medicine, etc. As we do these things, the list below will
certainly grow longer. (Also, this list only includes
potential treatments for HIV disease, not for opportunistic
infections.)

Note that most of these drugs are not antivirals; in some
cases, the mechanism of action, if any, is unknown. For such
drugs, results of viral load and other tests will have to be
interpreted especially carefully.

We will add to this list in the future. You can help by
suggesting other treatments which should be considered. For
this particular list, we are interested in treatments which
are already in human use for some purpose, so that they can
be tested quickly for possible use in HIV, without the need
to go through animal studies, etc. Also, we have not included
drugs which are already in major development projects, since
in that case the testing which we are proposing is already
being done.

Note that this is a list of research possibilities, not
treatment options. Some of these drugs can be quite
dangerous; and while there is a rationale for further
research, the evidence in hand showing actual benefit to
patients is usually slim to non-existent. We were reluctant
to publish the list, at least without first completing the
library and phone-interview research on each of the drugs, to
gather the information which is already known. But that
process would take months or years, and by then there would
be new drugs to list anyway. So we expect to keep an ongoing
list of drugs needing research as possible treatments for HIV
disease, and publish it from time to time. We hope this will
encourage public interest and advocacy, to get the necessary
research done. If even one of these 27 drugs is found to be
useful in HIV treatment, that finding would be immensely
important. (Our guess is that several will be found useful --
if the studies are done.)

Initial list of drugs already in human use which need small,
rapid trials to look for possible activity as HIV treatments
(in alphabetical order):

Acyclovir (indirect effect); aspirin; cimetidine; co-enzyme
Q; curcumin; DHEA; doxycycline; DNCB; glycyrrhizin; HCG;
hydroxyurea; hypericin; isoprinosine; NAC; papaverine;
pentoxifylline; peptide T; ranitidine; ribavirin;
sulfasalazine; thalidomide; thymomodulin, etc.; topotecan;
tricyclic antidepresants; vitamin B6; vitamin C; warfarin.

Strategy of Hope: Previous Articles

 in AIDS TREATMENT NEWS

Our most important previous articles on the AIDS treatment
development strategy discussed here are:

* Research Strategy Proposal: High-Tech Exploitation of the
Unexpected, issue #190, January 7, 1994;

* Antivirals and Immune Recovery: Interview with Michael S.
Saag, M.D., issue #200, June 3, 1994;

* AIDS Research Strategy: Rapid, Small Trials for Promising
Treatment Leads, issue #201, June 17, 1994;

* HIV RNA: New Blood Test for Individualized Therapy and
Faster Trials, issue #204, August 5, 1994;

* AIDS Pathogenesis: New Understanding, issue #206, September
2, 1994;

* Why AIDS Drug Development Has Failed, issue #206, September
2, 1994;

* "Surrogate Markers": Current Status, Future Directions
(Part I), issue #209, October 21, 1994;

* Maternal Transmission and Viral Load, issue #209, October
21, 1994; and

* HIV RNA -- Time to Wake Up and Save Lives, issue #210,
November 4, 1994.]


***** Viral Load, Small Trials, and Immune Recovery

The following is our transcript of a section of a talk by
Douglas D. Richman, M.D., on viral resistance, given November
12, 1994 at the recent New Directions in Antiviral
Chemotherapy conference in San Francisco. This presentation
is important because it cites studies from many researchers
which strongly support the feasibility of small, very rapid
trials to screen drugs and combinations to find out which
ones have initial antiviral effect in humans, and to learn
the doses required. Such trials do not prove that a treatment
is useful, since it may stop working later; but they can
rapidly and flexibly provide a rational basis for planning
further research.

This talk also makes the point that lowering viral load, as
measured by HIV RNA count in blood plasma, is likely to
result in immune-system recovery, even without special
therapies for immune reconstitution.

This information changes the outlook for AIDS research,
creating opportunities for much faster progress.

Note: We were unable to run this transcript by Dr. Richman,
as he was out of the country as we went to press. To avoid
changing his meaning inadvertently, we did not edit the oral
presentation for readers who do not have access to the slides
he was using. As a result, the following text is sometimes
difficult to follow.

Dr. Richman: "Shifting gears a bit, this is a point almost
related to pathogenesis, something that Mike Saag brought up
yesterday. These are two patients given nevirapine, and
almost like a PK [pharmacokinetic] study looked at daily
plasma HIV RNA levels. Here's a person with 8,000, and here's
a person with 35,000, at baseline; at 24 hours after the
administration of drug, no change here, slight change here.
48, 72 hours, an incredible drop; basically by day four or
five, everything that the drug is going to do has been done.
The same sorts of data have been shown by Clive Loveday in
London with AZT, and Charles Boucher in Amsterdam with 3TC,
and David Ho with protease inhibitors, also; the same
phenomenon is occurring with all of the antiretroviral drugs.

"There are two major take-home lessons that I think are very
important about this. One is, as Mike mentioned yesterday,
the turnover rates, the half-lives here, even if you assume
that the drug is inhibiting replication 100 percent, which is
a worst-case phenomenon, probably unlikely, the half-life
here is 24 hours, or even less. So that these ten to the five
levels of plasma RNA that we're seeing, those hundred
thousand copies, weren't there yesterday; those are today's
virus. The implication is that, with this high turnover, if
you can stop the production, you significantly down-shift
what's going on.

"And in terms of pathogenesis, a similar phenomenon has been
shown; the very nice data with the Abbott compound that David
Ho showed in Atlanta, that unfortunately we didn't get to see
yesterday, showed that with more potent drugs, as with the
Merck protease inhibitor and the Abbott compound, this same
phenomenon occurs, but you get two and three log drops,
instead of a one or one and a half log drop. And in
association with drops of that magnitude, instead of getting
75 or 100 [T-helper] cell rises, they were seeing two, three,
four, five hundred CD4 cell rises, in a couple of weeks. The
implications of that are (and I think somewhat different from
the Ashley Haas model that Mike was talking about) -- my
perception is that there's a stem-cell population, CD34 cell
population, that is producing CD4 cells; and if you can
arrest the replication, the high turnover rate of new cells
will reconstitute the immune system. The implications of that
are that immune reconstitution is not necessary if you can
block virus production. That also means that the stem cell
population isn't being infected -- and there are other
studies showing that the CD34 cell population is not CD4
positive, is not susceptible to the virus. And that's good
news, we have a stem-cell population that is not infected. If
it were, I would argue that this wouldn't be a chronic
disease.

"There's one other implication of all of this. And that is,
with all of these drugs we're seeing the same kinetics. That
means that in a two-week study, you can show whether a drug
works or doesn't work, and you can do a dose-response curve.
Now it doesn't tell you what's going to be a useful drug,
because it's a chronic disease, so it doesn't tell you what's
going to happen long term. And this virus -- and we're doing
studies with Scott Eastman, to do the allele-specific
characteristics of this virus -- we've shown in seven days a
drug resistant virus emerging. So that this is going to be
resistant virus, this is sensitive virus. So in terms of
being a useful drug, we need longer studies. But in phase I
studies to ascertain whether you've got a drug that works or
not, you only need a two-week study; and there is a protease
inhibitor that we've just finished evaluating in which the
decision to stop the development of the drug was based on
two-week studies, and 48 patients who had plasma RNA levels,
sequentially, not one of them had more than a three-fold
variation. So that with a half-log change, you only need
[few] patients and if you have half-log changes, that's
different than you're going to see in the natural course over
a short period of time in the patients."

Note: The audio tape of Dr. Richman's talk, "Antiviral Drug
Resistance: Genetic and Phenotypic Mechanism -- Clinical
Significance," is available from J. Schimmel Associates,
10251 Granada Lane, Shawnee Mission, Kansas 66207, 913/649-
5743; ask for tape #94-14 from the New Directions in
Antiviral Chemotherapy conference. The price is $10, which
includes shipping. You can also get a list of the 16 audio
tapes available from the conference; while few of the talks
have new information, they do have useful reviews on a number
of topics, including combination therapy, early intervention,
delavirdine, nevirapine, the Abbott and Merck protease
inhibitors, cytokine therapy for HIV, gene therapy for HIV,
treatment for CMV, and treatment for hepatitis.]


***** Nevirapine Triple Combination: Preliminary Results
      Released Nov. 17

by John S. James

In early 1993 there was great excitement about the
"convergent combination" approach to antiviral treatment.
This theory holds that there may be limits to how much a
virus can mutate and still be able to reproduce, and
therefore there might be certain drug combinations, targeted
against THE SAME viral protein, which could stop the virus
permanently by preventing the development of resistance.
(Traditional combination therapy seeks drugs which target
DIFFERENT steps in the life cycle of the virus, bacterium,
etc.)

It turned out that some of the early data supporting the
convergent combination approach was in part the result of
laboratory error; but even so, the idea remained worth
testing. (AIDS TREATMENT NEWS covered these developments in
issue #170, March 5, 1993, and issue #181, August 20, 1993.)
A clinical trial was quickly organized, and it began in May
1993; it was fully enrolled by July. The trial lasted 48
weeks, then data analysis began, and a preliminary report was
released this week. Much more analysis is still to be done,
however, and some of the more interesting results may come
later.

This study enrolled a total of 398 subjects. They had T-
helper counts less than or equal to 350; the median count at
entry was 138. All had at least six months of prior treatment
with AZT, ddI, or ddC; the median prior treatment was 25
months. These volunteers were randomly assigned to either
receive AZT plus ddI, or AZT plus ddI plus nevirapine, an
experimental HIV treatment. All three drugs target the
reverse transcriptase enzyme of HIV; when used alone,
nevirapine has a very strong anti-HIV effect at first, but
then the effect diminishes as the virus develops resistance
to the drug.

At 48 weeks, the main preliminary results were:

* T-helper counts were 25 percent higher for patients
assigned to the triple combination, compared to those
assigned to AZT plus ddI.

* The infectivity of PBMCs (peripheral blood mononuclear
cells) was lowered by 50 percent more in the triple
combination arm than in the AZT plus ddI control arm. [Note:
viral measures were only done on a subset of 198 of the 398
subjects.]

* HIV RNA showed a significant difference in favor of the
triple combination at first, but according to the November 17
executive summary, the difference was not statistically
significant at 48 weeks. [However, after the executive
summary was finalized, it was learned that the reason the
PBMC virology but not HIV RNA virology remained statistically
significant at 48 weeks may have been because of the
different ways these numbers were collected and analyzed.]

* There was no indication of a survival or disease-
progression benefit. Seventeen percent of those on triple
combination died or experienced HIV disease progression (as
defined by the study), vs. 14 percent of those on AZT plus
ddI. This difference, which was not statistically
significant, was in the wrong direction. While the study was
not designed to detect clinical benefit in death or disease
progression, and did not have enough patients to do so
reliably, still it seems unlikely, in view of these results,
that there is any substantial clinical benefit of the triple
combination.

* There were more side effects from the triple combination.
The biggest difference between the groups was in skin rash,
with severe rashes affecting 8 percent of those on triple
combination, vs. two percent of those on AZT plus ddI. The
overall rate of severe adverse reactions was high: for signs
and symptoms, 30 percent on triple combination vs. 24 percent
on the two-drug combination; for hematology and chemistry
abnormalities, 30 percent on triple combination vs. 26
percent in the AZT plus ddI control arm. These overall rates
were not significantly different between the arms.

This study collected important data, and there is much more
to be learned from it. For example, it is possible that
certain subsets of patients may have responded differently to
the treatments -- those with less advanced disease, for
example, or those who began the study with or without AZT-
resistant or ddI-resistant viruses.

Comment

This study is likely to be cited to argue that viral load and
other blood tests cannot be trusted to tell what drugs are
working. We think it is too early to draw that conclusion.
The viral load differences appear to be marginal; with plasma
HIV RNA, whether the difference is even statistically
significant at 48 weeks seems to depend on how you look at
the data -- and usually it is easy to get statistical
significance using this measure, even with far fewer
patients, provided that there is any substantial effect to
measure. Also, it is likely that many patients had AZT-
resistant viruses before they started, so they were never
effectively on a triple combination; and nevirapine
resistance can develop quite rapidly. If the side effects of
this drug balanced a relatively minor virological benefit,
then the difference between clinical progression and viral-
load changes could easily be explained -- with no need to
postulate that viral load does not show drug benefit. Further
study of the existing data may help to explain what was
actually going on in this trial.

The main lesson we draw from this example is that we need
more flexible research strategies, with many small trials
which can be designed and run rapidly, to quickly check out
promising leads which suggest the possibility of big gains in
viral-load reductions, in measures of immune health, or in
other indicators of activity. Then the larger, confirmatory
trials could be better focused, because they would be based
on data from human experience, not just on laboratory
studies.


***** Hydroxyurea: Call for Information

by John S. James

Hydroxyurea is a prescription drug which has been used for
about 30 years in treating certain cancers, and for a few
other diseases. Theory suggests that hydroxyurea might be
active against HIV, and that if it is, the virus would be
unlikely to develop resistance to it. Laboratory results at
the U.S. National Cancer Institute were promising enough that
Robert Gallo, M.D., explained this work at his major talk at
the Ninth International Conference on AIDS in Berlin, in June
1993; AIDS TREATMENT NEWS covered his presentation in issue
#178, July 9, 1993.

Earlier this month researchers at the NCI published a
detailed report of their laboratory findings with this drug
(Franco Lori, M.D., and others, "Hydroxyurea as an Inhibitor
of Human Immunodeficiency Virus--Type 1 Replication,"
Science, November 4, 1994, pages 801-805). THE NEW YORK TIMES
interviewed Dr. Lori and published an article on November 8.
The published articles are based only on laboratory studies;
almost nothing has been done in the last year and a half to
follow up the laboratory work with a clinical trial. A small
trial has been approved by the FDA but not started because of
lack of funding; another small trial has started in France.

AIDS TREATMENT NEWS is now trying to find out about clinical
experience with hydroxyurea as an anti-HIV treatment. So far
we have detailed reports of only two patients, both of whom
had large drops in viral load; we have heard indirectly about
others. Physicians have been reluctant to prescribe the drug,
which can cause serious but reversible suppression of the
white blood count, until trials have studied its safety and
activity in persons with HIV.

If you know of anyone we should talk to about effects of
hydroxyurea in HIV disease, let us know immediately at
800/873-2812. We hope to get this article into the next
issue, which goes to press on November 29.


***** The Elections: What AIDS Organizations Need to Do Now.
      Interview with Tom Sheridan, Sheridan Associates

by John S. James

The November elections created a difficult and dangerous time
for those working for an effective U.S. response to AIDS. To
look at what should be done now, AIDS TREATMENT NEWS
interviewed Tom Sheridan, a professional lobbyist, AIDS
organizer, and founder of The Sheridan Group, a government
and public-relations organization in Washington.

ATN: In view of the elections, what should those concerned
about AIDS do now?

Sheridan: Organize, organize, organize. I mean three very
specific things.

First, we must organize internally. We must make sure that
our programs are well run; the people we represent are well
served; that the work we do is very much in the public
interest. Sometimes we forget, on the front lines, that we
have to justify our work to the general public.

Second, grassroots organizing is a very effective way to
combat Congressional complacency and to win over reluctant
allies. Some politicians would like to put a "special
interest" label on AIDS, and we can't let that happen. Some
of them are not disposed to be our friends. But we have to
approach these politicians and convince them, in whatever way
necessary, that AIDS care, prevention, and research are
important to this country, to their states and districts, and
that AIDS should be a priority.

In the early AIDS movement, we did grassroots organizing very
well. More recently, we have been less successful. If ACT UP
was our early grassroots organization, we can point to it as
a source of effective action. Now we are facing an entirely
new strategy, and a whole new level of grassroots organizing.
We need to mature and develop a certain political savvy -- to
hold members of congress accountable -- and it is vital that
we do it now. For too long, our movement has looked like a
brownie pan -- wide, but not too deep. Grassroots organizing
can provide that depth and assure accountability.

The third level of organizing is political -- we must
communicate with those new members of Congress. We must find
out who the new players are and which old players have new
positions. We need to figure out how much money it will take
to support our friends and challenge our enemies We need to
have a very aggressive political agenda, but we have to
develop that capacity. You can't watch people like Dan
Hamburg lose his election for lack of money, and that's why
he lost it; he didn't have the money he needed to beat a
right-wing opponent.

AIDS advocates need to think about retooling our resource
pool, and have real political resources available for
friends, and some resources to fight our enemies.

We must avoid the politics of division; there are Republican
friends who will need our support, and our work, to keep our
agenda moving forward: people like Connie Morella, Steve
Gunderson, Mark Hatfield, Arlen Specter, John Porter. These
are people who have been supportive, who will be in important
positions; we need to work with them. Look at Orrin Hatch on
Ryan White; he was our original cosponsor, with Ted Kennedy,
and remains the program's enthusiastic champion.

These will be difficult days, no doubt about it. Some of our
biggest enemies are now in positions of great power; and we
have very little structural barricades to fight against them.
Jesse Helms has opportunity now that he's never had before.
The Clinton Administration is going to be very hard-pressed
to make sure that they keep a focus and a priority on AIDS,
and not to let it go in the face of other things. The
Administration is our safe harbor; we will need a lot of
extremely tough work with them.

One of our biggest losses concerns our institutional base of
staff support. Will key people be able to retain their jobs
in the Senate and the House, and therefore retain our history
in that institution? They are so important to everything we
do, they have institutionally carried us through almost every
fight we have had.

ATN: Aside from the consequences of the elections, what else
must we watch out for?

Sheridan: We need to join ranks and avoid being caught up in
competitive -- zero-sum gain -- discussions on AIDS
priorities. I am troubled by potential off-sets in the ACTG
(AIDS Clinical Trials Group) program to get better bench
science. If we need better bench science we must advocate for
it, not transfer it from other program areas. I believe we
may face our first full-scale debates on AIDS funding vs.
other funding areas. Our solidarity is our survival.

ATN: What is the bottom line for the AIDS community?

On those three levels of organizing we should get immediately
to work. There is a certain discipline that is required. We
cannot compete against each other, at a program level or at a
community level or at a national level -- research at the
expense of care, or care at the expense of prevention. First,
those are completely ridiculous constructions; and second, we
will get killed politically if we put ourselves into that
position.

If there is any good news, sometimes a common crisis can pull
people together. This community hasn't been together in some
years.


***** AIDS TREATMENT NEWS Talent Search: Board Members for
      Charitable, Internet Work

by John S. James

AIDS TREATMENT NEWS is starting a new, nonprofit organization
to expand our free work in providing AIDS treatment
information to underserved communities. This will include
more subscriptions for anyone in need, as well as support to
organizations serving specific communities including
minorities, women, prisoners, the geographically isolated,
and the economically disadvantaged. We will use the Internet
and other computer communication for low-cost delivery of
targeted, practical information to service organizations, and
to individuals

This will be a fundraising, working board; however, no
computer or treatment expertise is required, nor is it
necessary to live in the Bay Area, as we expect to conduct
most meetings by telephone. If you know someone who would be
an ideal candidate to help us support this project, you could
help by suggesting that they call John S. James at AIDS
TREATMENT NEWS, 415/255-6259.



***** AIDS TREATMENT NEWS
      Published twice monthly

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Editor and Publisher:
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Statement of Purpose:
AIDS TREATMENT NEWS reports on experimental and
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Treatment News does not recommend particular
therapies, but seeks to increase the options available.

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ISSN # 1052-4207

Copyright 1994 by John S. James.  Permission granted for
noncommercial reproduction, provided that our address
and phone number are included if more than short
quotations are used.