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AIDS TREATMENT NEWS #215, January 20, 1995
   phone 800/TREAT-1-2, or 415/255-0588

CONTENTS:

New Information on HIV Rapid Turnover - What Does It Mean?

Kaposi's Sarcoma: Possible Foscarnet Treatment

1995 Outlook: Research Strategy

Protease Inhibitor Task Force: Opportunity for Participation

KS, DOX-SL: FDA Hearing February 14

FDA Advisory Committees: Hotline for Upcoming Meetings

International Conference for People Living with HIV and AIDS, 
Cape Town, South Africa, March 6-10; Pre-Conference for 
Women, March 4-5


***** New Information on HIV Rapid Turnover - What Does 
      It Mean?

by John S. James

On January 12, many newspapers carried page-one stories about 
a major scientific advance in understanding AIDS. Some of the 
reporting has been unclear and confusing to readers, however. 
This article will outline what the discovery is and why it is 
important to people with HIV or AIDS. We will also explain 
our concern that this new understanding, while indeed 
important, shows signs of being misunderstood in ways that 
could seriously harm AIDS research.

The occasion of the recent press coverage was the publication 
of two articles and a commentary in the January 12 issue of 
Nature,(1,2,3) which is one of the most prestigious 
scientific journals. The two articles are by two well-known 
research groups which independently arrived at essentially 
the same conclusions. AIDS researchers worked with 
mathematicians to help them reach a deeper understanding of 
the data -- which came from blood tests of patients with 
advanced HIV disease as they started taking certain 
experimental antivirals in small clinical trials.

The discovery announced in the newspapers on January 12 was 
not news to the scientific community, which has heard the 
central idea at a number of public conferences during the 
last year. We published a preview last November, in an 
extensive quote from Douglas D. Richman, M.D., who spoke on 
November 12 to a physicians' conference in San Francisco (see 
"Viral Load, Small Trials, and Immune Recovery," AIDS 
TREATMENT NEWS #211, November 18, 1994).

New Understanding of HIV

The new understanding of how HIV behaves in the body was made 
possible by the development of better antiviral drugs, which 
can now shut off HIV reproduction almost completely (although 
so far only for a short time since resistant virus develops 
in a few weeks) -- and also by the new blood tests which 
measure plasma HIV RNA, a much more accurate indication than 
the old p24 antigen tests of how much virus is in the blood. 
The three antiviral drugs used were the Abbott protease 
inhibitor (ABT-538), the Merck protease inhibitor (L-524, 
also called L-735,524), and Boehringer Ingelheim's nevirapine 
(which is a non-nucleoside reverse transcriptase inhibitor); 
all three of these drugs are experimental and currently in 
clinical trials. AZT, ddI, and other approved anti-HIV drugs 
do not stop the virus well enough to make the new discovery 
obvious. [Note: the HIV RNA blood tests used are today 
available to physicians; for background, see "HIV RNA: New 
Blood Tests for Individualized Therapy and Faster Trials," 
AIDS TREATMENT NEWS #204, date August 5, 1994, and later 
issues.] 

Both the research teams measured the HIV RNA frequently (at 
least weekly) when patients started taking the new 
experimental antivirals. They found that once the 
reproduction of new virus was shut off, the viral level in 
the blood declined very rapidly; about 30 percent of the 
virus is cleared from the blood each day (and this percentage 
may be about the same regardless of stage of the disease). 
Since blood levels are fairly stable from day to day when the 
patient is not taking an antiviral, about as much new virus 
must be produced every day as is destroyed. The essence of 
the new discovery is that the "turnover" of new virus in the 
body is far more rapid than people had believed -- in just a 
few days, most of the virus in the blood has been removed and 
replaced with fresh virus.

Also, these drugs work by stopping the infection of new cells 
-- not by shutting off viral production from chronically 
infected cells -- and still they often cause the amount of 
virus in the blood to drop by 99 percent or more. This means 
that almost all of the enormous amount of virus being 
produced continuously during HIV infection is coming from 
newly infected cells.

The researchers also measured the recovery of CD4 cells (T-
helper cells) while the reproduction of HIV was temporarily 
shut off. They found that CD4 cells increased very rapidly 
during this time. This seems to mean that they are also being 
destroyed equally rapidly when the virus is not shut down. 
(Although an alternative possibility, which we do not believe 
is ruled out by the new Nature articles, is that active HIV 
infection produces something that suppresses production of 
new CD4 cells; if this is the case, CD4 cell turnover in HIV 
disease may be less than now thought.)

[Note on terminology: Until now AIDS TREATMENT NEWS has 
preferred the term "T-helper cell" to "CD4 cell," as being 
better for communicating with the public. But now the more 
accurate term "CD4 cell" (or "CD4+ cell," which is the same 
thing) is coming into wider use, and will be our preferred 
usage in the future.]

Through simple calculations based on this data, the 
researchers estimated that about 100 million virions 
(individual virus particles) are normally being produced and 
destroyed each day. (Note that this applies only to patients 
with fairly advanced HIV disease, who were studied in this 
research; they had a median CD4 count of 102 in one of the 
papers, a mean of 180 in the other. In earlier stages of 
asymptomatic HIV infection, the number of virions would 
usually be much less.) Also, the researchers estimated that 
about two billion CD4 cells are also being created and 
destroyed each day in these patients. Each infected cell can 
produce many copies of the virus; the researchers suspect, 
therefore, that most infected CD4 cells are destroyed by the 
immune system before they ever have a chance to produce 
complete virus.

Importance

These findings are important to people with AIDS/HIV because:

* They strongly suggest that if HIV reproduction could be 
largely stopped for a longer time, and kept at a very low 
level indefinitely, then the immune system would have much 
more ability to recover, even without immune-based treatment, 
than most physicians and scientists had believed.

Note that this does NOT mean that the virus will be 
eradicated. Huge reservoirs of latent virus will still likely 
remain, in the DNA of cells in lymph nodes and elsewhere. 
While it is latent, it is not doing damage. But some of the 
latent virus may become activated later and re-establish the 
active infection. It will probably still be necessary to take 
drugs to keep the virus suppressed -- although if the immune 
system recovers, it may be an important help in this process.

* It is now clear that researchers can test potential 
antiviral drugs and combination treatments in people in 
small, rapid trials -- which get results in weeks. This means 
that it is feasible to test many new treatments quickly, 
greatly speeding the development of better AIDS/HIV 
treatments.

Of course it will be necessary to continue testing the 
treatments which do show antiviral activity, to see how long 
they work before viral resistance develops. This should not 
be hard to do, since patients will naturally want to continue 
taking a treatment which is working.

Other steps are also necessary before FDA approval. [We 
analyze the critical bottleneck in the whole process -- the 
need to prove actual clinical benefit to patients -- in "1995 
Outlook -- Research Strategy," below.]

* They emphasize again the major problem of HIV developing 
resistance to drugs. The very rapid turnover of HIV in the 
blood means that in just two to four weeks, the drug-
susceptible viral population in a patient can be replaced by 
a drug-resistant population, meaning that the drug will no 
longer work, or at least not work as well.

The researchers emphasized the need to use combination 
treatments to prevent drug resistance. Drug combinations help 
to prevent resistant viruses from developing, because only a 
small fraction of the virus will initially be resistant to 
any candidate drug. If a second drug is added, only a small 
fraction of that small fraction will be resistant to both. 
The more drugs that are added to the combination, the less 
likely it will be that any virion will be resistant to all of 
them. But with billions of virions in the body, it may take a 
number of drugs in combination to stop all of them.

Some researchers have suggested that combination treatments 
should be used early in infection, when the viral load in the 
body, and also the variation of the virus, is less. (It is 
generally believed that HIV infection starts with only one 
variant of HIV, but as the disease progresses, this one 
strain evolves into a great many different "quasispecies" 
within the individual patient. In each patient, this 
evolution is different.)

Comment: What This Discovery Does Not Explain

The most important unanswered question about HIV disease may 
be how it progresses from early, asymptomatic infection to 
late-stage illness. For years the immune system controls the 
virus to a degree, and blood levels stay relatively low. But 
somehow the body gradually loses this ability (in most 
people, but not in all), allowing the virus in the blood to 
increase by as much as hundreds of times, leading to the 
development of AIDS.

Many theories have been proposed to explain how HIV 
suppresses the immune system -- including, for example, 
direct killing of CD4 cells, and also indirect mechanisms 
such as molecular mimicry, cytokine or possibly endocrine 
dysregulation, autoimmunity, abnormal apoptosis, loss of CD8 
cells, etc. If researchers knew why the immune system 
gradually loses its ability to control HIV, then it might be 
possible to treat HIV infection by correcting this specific 
problem, and keep people healthy indefinitely, perhaps 
without the need for antivirals.

We are concerned by indications that some researchers, as 
well as medical reporters, may uncritically assume that the 
new understanding of HIV also explains how the infection 
progresses from the early, asymptomatic stage, to the later 
stages of greatly increased HIV levels and clinical illness. 
Such a premature conclusion could suppress interest and 
research in other potential mechanisms of progression.

The new information recently published in Nature was based 
only on studies of persons with advanced HIV infection. And 
each patient was studied only for a brief snapshot of time; 
there was no long-term data on how infection progresses over 
time.

The Nature papers do not claim to have shown how HIV 
infection progresses. But they are often being implicitly 
interpreted that way. Some of these interpretations do not 
stand close scrutiny:

* One assumption is that, due to the great number of CD4 
cells infected and destroyed, the immune system eventually 
becomes exhausted and unable to keep up, and then the disease 
progresses because the body cannot produce enough CD4 cells 
to replace those that are lost.

But this theory ignores the fact that HIV disease progression 
occurs also at earlier stages, when the level of HIV 
infection and destruction of T-cells is a small fraction of 
what the body will be able to keep up with later. For 
example, there is data showing that in persons with a CD4 
count around 200, the level of virus in the blood may be ten 
to a hundred times more than the level when the CD4 count is 
500.(4) How could this exhaustion theory explain the 
progression from a CD4 count of 500 to 450 or 400, if at 500 
the body still has at least ten to a hundred times the 
capacity needed to replace the cells which are lost at that 
stage?

* Another assumption -- seen repeatedly in the January 12 New 
York Times article -- is that HIV infection progresses 
because the virus has a "slight statistical edge" over the 
immune system, leading to its eventual victory. But this 
theory is unlikely to hold up to an analysis of the dynamics 
of stability vs. instability. The levels of both the opposing 
sides in the battle -- the virus, and the CD4 cells -- can 
change greatly in a time frame of days or weeks. It seems 
unlikely that these two opposing forces, which each can 
change in days, will just happen to stay approximately 
balanced for the much longer time period of years that it 
takes for HIV disease to progress.

To visualize the problem, imagine an acrobat on a high wire 
who momentarily loses balance, and fights in an attempt to 
regain it. Usually only seconds will pass until either 
balance is regained, or the acrobat falls off. We do not 
expect to see the struggle go on for ten years.

In other words, some mechanism other than a slight 
statistical edge must be controlling the timing of HIV 
disease progression. No one knows what sets this clock; it 
should be a central goal of AIDS research to find out. The 
statistical-edge theory, by giving false confidence that the 
answer is already known, could distract research from this 
key goal.

Note that in most viral and other infections, the dynamics of 
the interaction between the replicating organism and the 
immune system does not lead even temporarily to a 
homeostasis, to a balance or steady state. Instead, the 
immune system either eradicates or almost eradicates the 
disease-causing organism, or the infection progresses until 
the person dies. (Nor does the limited supply of cells to 
infect explain the limited growth of HIV, except perhaps at 
end-stage illness; at earlier stages, the supply of CD4 cells 
would clearly allow more viral growth, as shown by the fact 
that viral levels will substantially increase later, when 
there are fewer such cells available.) No one knows why HIV 
reaches a certain blood level and then stops (until the level 
changes over months or years). When we discover the mechanism 
by which this control becomes established and maintained, but 
then gradually lost, we will very likely have a new way of 
controlling HIV disease.

* One of the recent Nature articles(1) noted, "The difference 
in lifespan between virus-producing cells and latently 
infected cells (PBMCs) suggests that virus expression per se 
is directly involved in CD4+ cell destruction. The data do 
not suggest an 'innocent bystander' mechanism of cell killing 
whereby uninfected or latently infected cells are indirectly 
targeted for destruction by adsorption of viral proteins or 
by autoimmune reactivities."

We are concerned that readers may take away from this 
statement something different from what it actually says. 
While the data cited may not support indirect mechanism for 
the decline of CD4 cells, they do not rule out such 
mechanisms, either. Again, our concern is that important 
research could be prematurely downgraded or closed off, due 
to the rush of enthusiasm which has greeted the new findings.

(And if it turns out that active HIV infection somehow 
suppresses development of new CD4 cells, or suppresses their 
release into the blood -- and CD4 counts increase rapidly 
when the infection is stopped, not because they are usually 
being created and destroyed that fast, but because the 
suppressive effect is removed -- then the whole issue of the 
turnover and lifespan of infected CD4 cells will have to be 
rethought.)

Research Strategy Summary

The most important impact of the new understanding of HIV 
disease, published in two articles and a commentary in the 
January 12 Nature, will be on the strategy of research and 
development of new AIDS treatments. We see the following 
consequences:

* The new work validates the use of small, rapid screening 
trials, in a few patients, to learn which potential drugs 
have antiviral activity in people.

* It also shows that if the virus can be suppressed 
completely enough, the immune system has much more ability to 
recover than many had suspected.

* It also confirms the belief that overcoming drug resistance 
is likely to be the biggest challenge to making anti-HIV 
treatments work.

* On the minus side, possible misinterpretation of the new 
findings (in the current atmosphere of great attention and 
enthusiasm for them) may impede important work of learning 
how HIV infection progresses -- work which could lead to a 
completely different class of treatments which do not attack 
the virus directly, but preserve the immune system's ability 
to control it.

References

1. Wel X, Ghosh SK, Taylor ME and others. Viral dynamics in 
human immunodeficiency virus type 1 infection. Nature. 
January 12, 1995; volume 273, pages 117-122.

2. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, and 
Markowitz M. Rapid turnover of plasma virions and CD4 
lymphocytes in HIV-1 infection. Nature. January 12, 1995; 
volume 273, pages 123-126.

3. Wain-Hobson S. Virological mayhem. Nature. January 12, 
1995; volume 273, page 102.

4. Phillips AN, Sabin CA, Elford J, and others. Viral burden 
in HIV infection. Nature. January 13, 1994; volume 367, page 
124.


***** Kaposi's Sarcoma: Possible Foscarnet Treatment?

by John S. James

Foscarnet (Foscavir) is an antiviral used to treat CMV 
(cytomegalovirus) infection; it is also used in serious cases 
of acyclovir-resistant herpes simplex. It is active not only 
against CMV (which is a member of the herpesvirus family) and 
herpes simplex, but also against all other known 
herpesviruses; in addition it has some anti-HIV activity, 
although it is not generally used as an anti-HIV treatment. 
Foscarnet is often the initial choice of anti-CMV treatment 
in Europe, while ganciclovir is usually the initial choice in 
the United States; this difference appears to be due to 
historical reasons, as foscarnet was developed by Astra, a 
Swedish company, while ganciclovir was developed in the U.S. 
Foscarnet must be given intravenously with an infusion pump, 
and can cause many serious side effects -- especially kidney 
toxicity, which occurs to some degree in many patients 
treated; the drug must be used by a physician who has 
experience with it. Another disadvantage is that the drug is 
very expensive.

Until recently there was no reason to think that foscarnet 
would have any use in treating Kaposi's sarcoma (KS). But 
last year a laboratory study, published in December 1994, 
found evidence that KS might be caused by a previously-
unknown herpesvirus(1) (see AIDS TREATMENT NEWS #213, 
December 23, 1994). And another article, also published in 
December 1994,(2) reported on a pilot study of five patients, 
which was conducted after physicians noticed that KS 
regressed in two patients who were treated with foscarnet for 
other purposes. Three of the five patients in the pilot study 
had a long-term remission of KS, after a single 10-day 
treatment (or in one case, two 10-day treatments) with 
foscarnet; the lesions disappeared slowly over several 
months. In the other two patients, the disease progressed 
despite the treatment. KS regressions without treatment are 
fairly rare. (These five cases were the ones reported at the 
recent conference in Glasgow, Scotland, as mentioned in AIDS 
TREATMENT NEWS #213.)

The five patients in the pilot study had low CD4 (T-helper) 
counts (24, 26, 270, 6, and 24) when treatment began. The two 
who progressed had ongoing, active opportunistic infections 
at the time; the three who had long-term regression did not. 
All five were also being treated with AZT following the 
course of foscarnet.

We talked to Linda Morfeldt, M.D., Dr. Med. Sc., of the 
Karolinska Institute in Sweden, who organized the pilot 
study. She said that the results so far suggest:

(1) The effect of foscarnet on KS is not proven; however, 
other small studies are now being designed to confirm or to 
rule out the early findings;

(2) The researchers suspect that the drug may be effective in 
relatively early KS which is confined to the skin and mucous 
membranes (even if the CD4 count is low) -- but not 
effective, or less effective, in advanced KS; and

(3) Patients who also have ongoing active infections, such as 
CMV organ disease, pneumocystis, MAC, or fevers of unknown 
origin, may not respond to foscarnet as a KS treatment; but 
the KS may possibly respond if the opportunistic infections 
are successfully treated first.

AIDS TREATMENT NEWS (December 23 issue) asked our readers to 
let us know of any experience of persons with KS who used 
foscarnet, regardless of the outcome; so far three people 
have contacted us as a result. One had fairly mild KS since 
June 1992, but he was still getting new lesions, and those 
treated with liquid nitrogen would re-appear. He started 
foscarnet for CMV retinitis in mid January; by early March 
the KS had mostly disappeared. After six weeks on foscarnet, 
there were no new lesions, and those treated with liquid 
nitrogen did not return.

Another person, before he started using foscarnet, had about 
20 KS lesions; these had been removed successfully with 
Velban or liquid nitrogen. Since he started using foscarnet, 
no new lesions have appeared.

The third person had only one small KS lesion, which was 
removed and biopsied in 1992. For three years since he has 
been on foscarnet, and no new lesions have appeared.

Early KS Foscarnet Study Now Recruiting in New York

A 20-patient study of foscarnet treatment for early KS is 
planned at New York University Medical Center by Drs. Alvin 
Friedman-Kien, Miriam Keltz, Abraham Chachoua, Geoffrey 
Chazen, Linda Morfeldt, and others. The goal is to confirm 
whether or not foscarnet can have any therapeutic benefit in 
treating KS.

To answer this question most effectively, this study is 
seeking patients with early KS -- approximately five lesions, 
and for no longer than six months, and with no prior 
treatment for KS. Also, they must have a CD4 count of at 
least 50.

References

1. Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, 
Knowles DM, and Moore PS. Identification of herpesvirus-like 
DNA sequences in AIDS-associated Kaposi's sarcoma. Science. 
December 16, 1994; volume 266, pages 1865-1869.

2. Morfeldt L. and Torssander J. Long-term remission of 
Kaposi's sarcoma following foscarnet treatment in HIV-
infected patients. Scandinavian Journal of Infectious 
Diseases. December 1994; volume 26, number 6, pages 749-752.


***** 1995 Outlook: Research Strategy

by John S. James

As 1995 begins, we have more opportunities for progress 
toward major improvement in AIDS/HIV treatments than ever 
before. And we have clear, feasible paths to follow -- of 
safe, rapid, low-cost, high-quality treatment trials in 
people, to get solid preliminary information on how certain 
potential treatments work in practice. Researchers now have 
better tools to run these trials than in the past -- and some 
of the new tools, especially tests for plasma HIV RNA, are 
also available to individual physicians and patients.

Also, we are hearing more cases of unexpected improvement in 
people with HIV or AIDS -- sometimes beyond what would be 
thought possible. The most dramatic examples are usually from 
clinical trials of experimental treatments such as protease 
inhibitors. But there are others who are lucky enough to do 
quite well with approved treatments or treatment combinations 
which happen to work for them. And some do well with 
"alternative" treatments, or their own combinations of 
approved, experimental, and/or alternative approaches. We 
have long believed that the best strategy available is to try 
many different treatments, keeping the ones that seem to work 
for oneself, and discarding the ones that seem not to work.

Strategy, Part I: Small, Rapid Screening Trials

These success stories are not the answer, however. They do 
not work for everyone, and usually there is no way to predict 
who will benefit. Also, no one knows how long the successes 
will last -- although often they seem to work for years, with 
no evidence of failure in sight.

These success stories, instead, should be seen as treatment 
leads, entry points for further research. For each lead, 
physicians and scientists should use their best judgment to 
try to define a class of patients who might reproducibly 
benefit. The next step is to run a small, rapid "proof of 
principle" trial -- usually in only a few patients, perhaps 
ten to 20 -- looking for consistent changes in measurable 
indicators of improvement. There might or might not be a 
control group in this trial.

What would happen then? Most of the proposed treatments 
tested this way, perhaps 80 or 90 percent, would probably be 
found not to work. But there are dozens of good-quality leads 
waiting for such a test, and a number of them would come out 
with strong support. These would then have the 
social/political momentum needed to move rapidly into further 
research.

This proposal for many short, rapid screening trials is not 
controversial, but is generally accepted as something that 
can and should be done. The cost and other resource 
requirements would be modest. The problem today is finding 
the political and institutional will to make the research 
happen.

Strategy, Part II: A New Way to Prove Clinical Benefit

The next step after the screening trials is more 
controversial. Those short trials will look for a measurable, 
reproducible improvement, usually in blood work. But what 
then? Change in a blood test may not prove that the treatment 
actually benefits patients. Usually we need other kinds of 
trials to show this.

Here we face a serious problem. The prevailing thinking so 
far has focused on a kind of clinical-benefit trial design 
which will take hundreds of patients for each drug studied, 
and take years to produce conclusive answers. This kind of 
trial randomly assigns the treatment being tested to some 
patients, while others are assigned to standard treatment 
instead. Then both groups are observed to see which one gets 
sick faster. It takes a long time because AIDS progresses 
slowly; even if the new treatment being tested were a 
complete, instant cure, the trial might still take years, 
because it would have to wait for a statistically significant 
number of those on the standard treatment to get sick or die. 
And even aside from the time required to run the study 
itself, it usually takes years to politic for, finance, 
design, organize, and recruit for such a large trial (in 
addition to the time to analyze the data, distribute the 
results, and get them into standard medical practice). Even 
aside from the problem of making people wait for years to get 
better treatments, it is clear that there will not be enough 
patients available, let alone enough money or trained 
researchers, to test more than a few of the treatments which 
are likely to pass the small screening trials.

There is a better approach. The treatments which pass the 
small screening trials in all probability do benefit patients 
-- the difficulty is in finding a feasible way to prove that 
conclusively. What we suggest is combining a number of 
treatments which work well in the screening trials, until the 
cumulative benefit of all of them is great enough to be 
clearly visible -- not only in delaying illness, which takes 
a long time to see, but also in getting sick people well, 
which usually happens much more quickly. When patients 
regularly get out of bed and go back about their lives, when 
those who were disabled can work again, when chronic 
infections disappear with no further need for antibiotics or 
other specific treatments, then the value of the AIDS/HIV 
treatment will be unambiguous. Statistical proof could be 
rapidly obtained, through small, rapid trials (much like the 
screening trials) which compare immediate vs. delayed therapy 
-- for example, randomly assigning volunteers to either start 
the treatment now, or to start it in six weeks. Long-term 
followup would of course be included, to make sure that the 
benefits last, and to watch for long-term side effects.

This research strategy offers definitive proof of clinical 
benefit in small, rapid, inexpensive trials -- instead of the 
huge years-long trials that are usually believed necessary to 
prove clinical benefit. It may not prove the benefit of each 
individual treatment -- only of a certain, partly-arbitrary 
combination. But the information available today suggests 
that this strategy could quickly provide relief and save 
lives; those who want more refined information could pursue 
it later.

This approach to proving clinical benefit, unfortunately, is 
not yet part of the ongoing conversation on how to improve 
AIDS research. We have never heard it discussed or proposed 
anywhere. Hopefully our readers will help to get this idea 
onto the table, to be considered professionally and accepted 
or rejected on its merits. None of the alternatives offers an 
acceptable outcome.

This proposal for proving clinical benefit turns the small, 
rapid screening trial into part of a complete strategy for 
going from where we are now to where we need to be to save 
lives. Let's further develop and improve this strategy, and 
use it as an organizing tool to get the research done.

Strategy, Part III: New Mechanisms of Action

A third potential research strategy would seek to develop 
treatments which control HIV through new, previously-unknown 
mechanisms of action.

This could be done through intensive research into what might 
be called mystery treatments -- accidental or lucky 
discoveries of drugs or other treatments which seem to be 
helping in some way, but which have no known mechanism of 
action. Mystery treatments may include prescription drugs 
(one possible example is sulfasalazine), certain nutrients 
(see "Some Vitamins Associated with Decrease Risk of AIDS and 
Death," AIDS TREATMENT NEWS #214, January 6, 1995), or other 
approaches such as exercise. The goal is not so much to 
develop these treatments themselves, as to discover how they 
might work. If a new mechanism of action is found, then a 
whole new approach to AIDS treatment would become possible.

The key is to direct more research attention and resources 
into investigations of mystery treatments, which could lead 
to potentially major advances in understanding and treating 
HIV disease. This is the opposite of what happens now, which 
is that potential treatments without a known mechanism of 
action are largely ignored.

How does one begin to study a possible treatment with no 
known mechanism of action? One way is to look for consistent 
changes in any of the virological, immunological, and other 
tests which are available. Any repeatable, predictable 
treatment effect could serve as a lead or clue. And of course 
this research would be done in collaboration with 
specialists, usually outside the AIDS field, with expertise 
in the treatment being studied; they can help to identify and 
evaluate research leads.

Political Strategy: Organizing National Will

AIDS research and AIDS prevention have always suffered from a 
lack of full national commitment to AIDS. Today this problem 
is becoming more critical than ever before. As it affects 
research, it takes many forms:

* AIDS research has long overemphasized large, high-tech, 
complex, and product-oriented projects, because those are the 
ones people get paid to do, the ones that build a politically 
powerful constituency (lobby). Corporate research is almost 
always oriented toward proprietary products; in theory, 
government and foundation research should fill in the gaps by 
doing necessary work which companies will not do -- including 
basic research, and also including the small trials that we 
suggested above, for those treatment leads which are not 
products that corporations will study. But due to conflict of 
interest, revolving-door employment, and increasing reliance 
by academic institutions on entrepreneurial funding, non-
corporate institutions have not adequately set their own 
agendas. As a result, academic, government, and foundation 
researchers have tended to study the same drugs and 
approaches that corporations already are studying, or should 
be.

Part of the problem is the ever-increasing difficulty of 
making anything happen in clinical research (due to ever-
growing costs and regulatory requirements, as well as 
increasing scarcity of funds). This creates a conservative 
bias, by making it hard to get any trial off the ground 
unless it has a large, pre-existing constituency. Since new 
ideas almost never come into being with a large constituency, 
they almost always suffer great delays while the necessary 
professional/commercial/regulatory momentum develops.

In other circumstances, it would be possible to correct these 
structural defects. But due to the widespread attitudes 
around AIDS, the nation has not found the will to do so. 

* The recent elections have created new and serious problems. 
Many members of Congress seem to be interested in 
representing only one group of people -- white, heterosexual 
men with good incomes -- and have little interest in anyone 
else's concerns. (A more accurate statement would be that 
they represent the frustrations of certain voters, and the 
interests of multinational big business.) Since relatively 
few such people have AIDS, money may be taken from AIDS for 
tax reduction, military spending, and other rewards for those 
who financed the recent political campaigns.

* Recently we spoke with two business reporters not connected 
with AIDS, and found a well-developed ideology of fatalism 
tailor-made to justify not bothering with AIDS research. One 
compared AIDS research to a swamp, in that the farther you go 
in, the deeper you get, without end. The other compared AIDS 
to the common cold -- more serious, he acknowledged, but 
similar in that despite ongoing progress, we do not expect to 
ever see a time when people do not get colds (or, by obvious 
analogy, a time when people do not die of AIDS).

These images did not come from their personal experience, but 
from somewhere else. This ideology does not reflect anyone's 
experience, but appears to have been constructed for a 
purpose -- to justify abandoning people with AIDS or HIV.

* Other national-will problems are closer to home. AIDS 
service organizations have never shown much interest in 
research -- and neither has organized medicine. And public-
policy experts, in Washington and elsewhere, seldom 
understand science and technology issues, or have any serious 
interest in them.

* Also close to home is the lack of popular mobilization on 
AIDS. Most people affected by HIV do nothing, ever, to help 
the cause of AIDS research. One major reason is that 
organizers have not created effective channels for them to 
use in doing so. In most locations, the only options, the 
only ways to interact with the issue, are to send a check to 
a distant national organization -- or possibly to sit through 
many hours of high-tension, ego-battle meetings, before the 
new person is allowed to actually do anything which 
contributes. Many people want to meet with friends and 
neighbors to write and call Congress to support AIDS funding 
-- perhaps the most important thing they could be doing now 
-- but nobody has organized to give them the information they 
need. 

The public motivation certainly does exist; as we pointed out 
in the last issue of AIDS TREATMENT NEWS, at least 50 million 
people in the U.S. alone have a relative, friend, or 
acquaintance whom they know has AIDS or HIV. What must be 
done is to establish a social movement so that these millions 
of people can make their voices heard, instead of remaining 
silent as is almost always the case today.

In summary, we now have excellent opportunities for progress 
in treating AIDS. But they are not being exploited 
effectively. Solutions have been identified; it is up to us 
to organize and insist that they be implemented.


***** Protease Inhibitor Task Force: Opportunity for 
      Participation

The February 23-24 meeting of the National Task Force on AIDS 
Drug Development (NTFADD), especially February 23, may be a 
pivotal moment in the development of protease inhibitors. 
Activists want the NTFADD to appoint an official protease 
inhibitor task force which can work effectively to find ways 
to make the drugs accessible to patients; to facilitate 
research in combination therapies, cross resistance, etc.; to 
facilitate collaboration and sharing in research; and to 
overcome corporate and regulatory barriers. Note that those 
who want to speak at the meeting should make advance 
arrangements by February 9 (see AIDS TREATMENT NEWS #214, 
January 6, 1995, page 8).

For background on the proposed protease inhibitor task force, 
see AIDS TREATMENT NEWS #210, November 4, 1994. If you can 
help, call Jules Levin at 718/624-8541.


***** KS, DOX-SL: FDA Hearing February 14

The Oncologic Drugs Advisory Committee will consider approval 
of DOX-SL, for persons with AIDS-related Kaposi's sarcoma who 
have failed systemic chemotherapy, either because of toxicity 
or because of disease progression. This meeting, which is 
open to the public, will be at the FDA's Parklawn Building, 
in Rockville, Maryland. Persons interested in speaking should 
call Adele Sefried at the FDA, 301/443-4695, by February 10. 
It is particularly important for physicians or patients with 
personal experience with DOX-SL to address the committee.

Later in that meeting, the committee will also consider 
approval of Zoladex (goserelin acetate) for palliative 
treatment of advanced breast cancer in pre- and peri-
menopausal women.


***** FDA Advisory Committees: Hotline for Upcoming Meetings

You can find out about upcoming meetings of any FDA advisory 
committees through a voicemail system run by the FDA. 
Information is updated as soon as it becomes available, and 
is often more current than meeting notices in the Federal 
Register.

To use the voicemail system, call 800/741-8138, or 301/443-
0572.

There are several dozen different advisory committees; you 
can select the one you want through the voicemail system. 
However, you can save time if you have the five-digit code 
for the committee you want, as you can enter the code 
immediately and bypass the voice menus. The codes for the 
advisory committees most involved with AIDS are:

Antiviral Drugs Advisory Committee (code 12531);

Oncologic Drugs Advisory Committee (code 12542);

Vaccines and Related Biological Products Advisory Committee 
(code 12388).

Also, the National Task Force on AIDS Drug Development (code 
12602) announces its meetings on this system.


***** International Conference for People Living with HIV and 
      AIDS, Cape Town, South Africa, March 6-10; Pre-
      Conference for Women, March 4 and 5

The Seventh International Conference for People Living with 
HIV and AIDS, sponsored by the Global Network of People 
Living with HIV and AIDS (GNP+), will be held in Cape Town, 
South Africa, March 6-10, 1995. March 6 includes registration 
and opening plenary, March 7 has a theme of health, March 8 
of human rights and identities, March 9 skills building and 
technical assistance, and March 10 is a business day for 
GNP+.

For more information, contact the Conference Secretariat, 
P.O. Box 27262, 8050, Rhine Road, Cape Town, South Africa, 
phone 27-21-4181011, fax 27-21-4181015, email 
sn0298@connectinc.com.

Note: On March 4 and 5, the ICW (International Community of 
Women Living with HIV and AIDS) will hold a pre-conference 
for HIV-positive women, in Cape Town. For information, 
contact the conference secretariat in Cape Town, or contact 
the London office of the ICW, phone 44-171-222-1333, fax 44-
171-222-1242.


***** Notice: Next Issue Delayed One Week

Our next issue, scheduled for publication on February 3, will 
be delayed a week so that we can include coverage of the Jan. 
29 - Feb. 2 Second National Conference on Human Retroviruses 
and Related Infections, as well as the HIV Immune-Based 
Therapies Workshop, and the CPCRA 16th Group Meeting. We will 
return to our regular schedule with the February 17th issue.



***** AIDS TREATMENT NEWS
      Published twice monthly

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Editor and Publisher:
   John S. James
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   Thom Fontaine
   Tadd Tobias

Statement of Purpose:
AIDS TREATMENT NEWS reports on experimental and 
standard treatments, especially those available now. We 
interview physicians, scientists, other health 
professionals, and persons with AIDS or HIV; we also 
collect information from meetings and conferences, 
medical journals, and computer databases. Long-term 
survivors have usually tried many different treatments, 
and found combinations which work for them. AIDS 
Treatment News does not recommend particular 
therapies, but seeks to increase the options available.

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ISSN # 1052-4207 

Copyright 1995 by John S. James.  Permission granted for 
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