International Conference: Antiretrovirals (Part I)

This article will provide an overview of the conference sessions most
relevant to antiretroviral treatment. In selecting what to cover, we
will be guided by the conference program, selecting those research
reports which the conference organizers and advisory committees thought
worthy of special attention in oral presentations. (We will not ignore
the majority of submissions selected for poster- presentation only, nor
those published in the conference abstract books but not given even a
poster; the more innovative ideas are likely to appear here. We will
cover some of these in other articles. But this conference was well
organized, better than previous ones, in that the oral sessions were
more consistently designed around the best research reports that came
in, instead of around superstar speakers or preconceived categories.
The conference organizers have seen the material longer than anyone
else, and their selection is helpful for a first cut at selecting what
is most important.)
The conference documentation does not list degrees (M.D., Ph.D., etc.)
and titles of the speakers. We have followed this convention in our
conference coverage.
The following sessions are most relevant to antiretroviral treatment.
Usually, each session consists of several oral presentations. (The
session number is for finding abstracts in the volumes published by the
conference; the tape number refers to the audiotape, which has more
complete and more current information for these sessions.)
Overview Session: Drug Therapy and Pathogenesis (session 1, tape 4)
This first technical session of the conference consisted of overview
talks by Samuel Broder of the U.S. National Cancer Institute, and Luc
Montagnier of Institut Pasteur. Broder gave a quick overview of some of
the leading treatment research areas, mentioning many drugs and
approaches, highlighting certain ones he considered particularly
important. These included:
* PMEA, which Broder described as a very important drug which will soon
begin human trials.
* A new class of protease inhibitors being developed by collaboration
between researchers at the U.S. National Cancer Institute and two
organizations in Japan. (AIDS TREATMENT NEWS will have more coverage of
this research, which was presented at the conference in poster # PoA
2282.)
* Combination antiretroviral therapy, suggesting that we don't need to
wait for radical scientific advances, but meanwhile can use the
knowledge we have to keep patients alive and healthy.
Broder concluded by listing some unanswered research questions. Does
early use of AZT or related drugs improve survival, compared to later
use? Could early combination therapy improve survival? Are HIV strains
which become resistant to several drugs likely to be less pathogenic?
Can the immune system be brought to the point where it can control HIV
without long-term antiretroviral treatment? Broder said that his own
personal optimistic belief, without data, is that the answer to all
these questions will be yes.
Montagnier's more technical talk reviewed some of the theories of
pathogenesis and AIDS, especially the role of cofactors -- other
infections which might greatly accelerate the development of AIDS, or
may even be necessary, along with HIV, for AIDS to develop. [His theory
that mycoplasma infection may be a cofactor has met considerable
skepticism, in the U.S. at least. Most researchers accept the idea that
there may be cofactors, but there are many different guesses as to what
they might be.]
One theory Montagnier discussed which is generating much interest
lately is that many T-helper and also CD8 cells are killed by a process
called apoptosis, or programmed cell death. Since Montagnier did not
explain apoptosis in this talk, non-scientist members of the audience
had trouble following it. The necessary background is that this kind of
programmed cell death occurs normally before birth, and is part of the
way the immune system learns to tell self from non-self. When the
immune system is developing, different cells are created, by random
chance, to recognize millions of different shapes of proteins. Some of
these cells would recognize the body's own proteins, which would cause
autoimmune disease. But at a certain point in development, a self-
destruct mechanism is turned on, and then any immune- system cells which
are activated (because they have recognized a protein) are killed. The
only cells left, therefore, are those which do not recognize the body's
proteins, although they will recognize others, such as from invading
bacteria. Naturally this self-destruct mechanism must later be turned
off, or the immune system could not function. Some researchers believe
that somehow this mechanism is turned on again in HIV disease, and then
those immune cells which recognize foreign substances are killed,
leading to the loss of many more cells than are directly infected with
HIV. (Two articles on apoptosis, one relating directly to HIV, appeared
recently in Science, July 10, 1992).
** New Antiretrovirals: Non Reverse Transcriptase Inhibitors (session
11 tape 14)
1. Pentoxifylline
An important talk in this session by Bruce Dezube of Beth Israel
Hospital, Dana-Farber Cancer Institute, in Boston, concerned
pentoxifylline (brand-name Trental, a prescription drug which has been
used worldwide for over a decade), which is being tested in a trial by
the AIDS Clinical Trials Group (ACTG) because it might be able to
reduce excessive levels of tumor necrosis factor (TNF). TNF can
increase the replication of HIV, cause wasting syndrome, and, in
laboratory studies, almost completely reverse the antiretroviral effect
of AZT or ddC (ddI was not tested in that study). Several years ago it
was learned that concentrations of pentoxifylline which could be
achieved in patients could reduce TNF levels in cells in laboratory
tests. Pentoxifylline was also shown to decrease HIV activity in
laboratory cells, apparently by lowering TNF.
A separate poster at the international conference indicated that
pentoxifylline enhanced the activity of ddI in a laboratory test
(poster # PoA 2326).
The report at the Amsterdam conference presented a preliminary analysis
on 17 patients who had completed eight to 16 weeks of a phase I trial.
This trial was a non- randomized, open-label test with a dose of 400 mg
three times a day -- a dose approved by the FDA for treating vascular
disease. All patients had T-helper counts less than 300 -- but 15 of
the 17 had counts of about 100 or less. All patients were on AZT, ddI,
ddC, or a combination of these drugs.
TNF levels fell in 11 of the 13 patients analyzed so far, but it never
fell below normal levels (this is important because low levels of TNF
may have a beneficial effect). Also, fasting triglycerides were
measured, because high triglyceride levels, which have been found in up
to a third of AIDS patients, can indicate excessive activity of TNF,
interferon, and other cytokines. (Triglycerides are much easier to
measure than TNF.) There was a "dramatic" decrease of excessive
triglyceride levels.
Quantitative HIV titers also fell. In the six patients with the highest
HIV titers, the levels fell in all six -- in five of the six, to less
than a tenth of the pretreatment value. The average decrease in all
patients was 33 fold -- a 97 percent decrease.
Weight loss slowed down during treatment, but this effect was not
statistically significant in this data.
Only one adverse effect -- recurrent fevers on the drug, in one patient
-- was found.
Dezube called for a larger controlled study to confirm these
preliminary results. Meanwhile, the researchers are trying twice the
dose to see if even better effects are found. (The higher dose level
trial is being conducted at the AIDS Clinical Trial Units at Beth
Israel Hospital, Boston, and at Case Western Reserve University, in
Cleveland. For more information, call 800/TRIALS-A.)
One unidentified questioner reported his negative experience in
treating 17 patients with pentoxifylline; only two had T- helper count
improvements. Dr. Dezube told us that for each such negative anecdotal
report they have heard, they get many positive ones. These differences
underscore the need for additional studies to learn more about the
drug, to make sure it can be useful and learn how and when to use it.
Two Other Pentoxifylline Trials Recruiting in New York and Boston;
Wichita Soon?
The Community Research Initiative on AIDS (CRIA) is now running a
controlled trial of pentoxifylline in New York City. This 16-week trial
has about ten more openings; about thirty volunteers are already on the
study. Volunteers are randomly assigned to pentoxifylline (the same
dose as reported above) or a placebo; TNF, weight, and viral culture
will be measured. This trial also is for persons with T- helper counts
of 300 or less. For more information, call Bette Smith, CRIA, 212/889-
1958.
Also, the Community Research Initiative of New England (CRI/NE) is
actively recruiting for their controlled trial of pentoxifylline. Their
study design is unique, as participants receive the drug during four
out of five months; during the other month, selected at random, they
receive a placebo. A total of 60 volunteers are needed; only five of
them are on the trial already. This is the only study that is measuring
indicators of quality of life, in addition to laboratory markers such
as fasting triglycerides. For more information, contact Jeanne Day at
CRI/NE, 617/424-1524.
This study may also open an arm in Wichita, Kansas.
** Comment
Pentoxifylline could be important because it is generally safe, readily
available by prescription, and inexpensive (U.S. price, $300 to $350
per year). A number of physicians are using it already, especially in
Eastern U.S.; it has been slower to come to public attention in
California. Trials are needed to learn more about this treatment. We
hope that people will be willing to volunteer, at the risk of a short
time on a placebo for pentoxifylline (they will still be on their other
treatments, such as AZT or ddI), even though they could get
pentoxifylline without joining a study.
(to be continued)