info-aids@apple.com (INFO-AIDS MAILER) (08/26/89)
AIDS TREATMENT NEWS Issue # 85, August 11, 1989
Contents:
R-HEV: Better Test for New AIDS Treatments?
DDI, Parallel Track Negotiations
Los Angeles Hunger Strike for Treatment Access;
28 Organizations Form Coalition for Compassion
San Francisco: New Clinical Trials Treatment Directory
San Francisco: Quan Yin Chinese Herbal Program
Deadline September 1
Update: Community-Based Trials and San Francisco's
Community Research Alliance
*****
R-HEV: BETTER TEST FOR NEW AIDS TREATMENTS?
by John S. James
A new blood test developed in France may allow testing of
proposed AIDS treatments in clinical trials much more rapidly
than is now being done -- and to give individuals early informa-
tion about how well a particular treatment is working for them.
AIDS TREATMENT NEWS interviewed the test's principal developers,
Jacques Leibowitch, M. D. and Dominique Mathez, M. D., clinical
immunologists at the Raymond-Poincare Hospital/University Rene-
Descartes, Paris-Ouest. Leibowitch stressed that these results
must be considered very preliminary as they have not yet been
confirmed by peer review. (The work has been submitted for pub-
lication, but not yet formally published; a short, early poster
was presented at the June 1989 AIDS conference in Montreal.)
A retrospective study using frozen blood samples examined
how the test performed in predicting disease progression.
Researchers tested 131 samples from 57 HIV+ patients followed
over five years; none of the patients received any anti-HIV
treatment during this time. Because the test can be run on
frozen blood, it is possible to study its prognostic value
quickly, without waiting for years to see how AIDS/HIV progresses
in the patients tested, as would be necessary if fresh blood were
required. The new test, called R-HEV, performed much better than
the P24 antigen test in predicting who would do badly or do well
in the future.
In a separate study, the R-HEV test clearly showed the
antiviral effect of AZT -- an effect which was partial and tem-
porary -- and also the effect of alpha interferon. (Some of the
57 patients whose blood was tested in the earlier study were
later treated with these drugs, and frozen blood samples col-
lected after treatment began were tested.) These results suggest
that R-HEV may allow researchers to determine very quickly
whether and to what extent a new drug is working. Also, much
might be learned quickly and inexpensively about the efficacy of
existing drugs by studying stored blood samples of patients who
have already been treated, without needing to wait for new clini-
cal trials to be funded, organized, and conducted.
WHAT IS THE R-HEV TEST?
R-HEV, an abbreviation for "radiation-resistant HIV expres-
sion ex vivo," is based on a technique which has been used in
viral research for over 20 years (Henle and others, 1967), but
has not previously been applied to HIV. It basically consists of
viral cultures on cells which have been treated with radiation.
The goal is to measure the HIV expression levels of the patient's
virus, on the theory that radiation will suppress cells carrying
HIV but not expressing it in the patient, and with the assumption
that viral expression in the person is required for HIV disease
to progress.
Ordinary viral cultures are unreliable as a measure of
disease progression. Part of the reason is that latent virus,
which is not causing any immediate problem, can be stimulated to
become active by the culturing process itself, causing a positive
result which does not reflect disease progression or poor prog-
nosis for the patient.
In the R-HEV test, the radiation treatment causes the cells
to die shortly after the time that culturing begins. If the
virus was latent at the time the blood was drawn from the
patient, the cells containing the latent virus die without being
able to infect cells in the culture medium. But if the virus was
active in the patient, some of the infected cells will just have
time to transmit the infection to cells in the culture medium.
Eight separate wells are cultured for each test, and the result
reported by the R-HEV test is the percentage of wells which do
grow virus.
Hundreds of sites in the U. S. already have the equipment
needed to do the R-HEV test. The radiation can be provided by a
machine already used in blood banks to irradiate blood before
transfusion to persons with immune deficiencies. HIV cultures
are somewhat expensive today -- just the materials for each R-
HEV test cost $40 -- but the technology is already available to
reduce the cost enough to allow regular use of the test in medi-
cal practice, not only in research.
THE AIDS PROGRESSION STUDY
Of the 57 HIV+ patients whose frozen blood and five-year
followup results were available, 22 already had AIDS or ARC, or
T-helper cells under 400, at the time of their first visit. The
other 35 had few or no symptoms, and T-helper cells over 550, at
their first visit.
Of the latter 35 (the apparently healthy patients), 13
remained well and had T-helper counts which remained above 500.
These 13 were called slow progressors. The other 22 had rapid
clinical deterioration or rapid fall in T-helper cells (the fast
progressors). How well did the R-HEV test do in distinguishing
who was already ill, and more importantly, in predicting who
would become ill in the future?
Of the 131 specimens available from the 57 HIV+ subjects, 91
tested positive on R-HEV; the other 40 were negative. Of these
40, all but one came from 15 patients with few or no symptoms and
high T-helper cells. Among these 15 were ten who remained R-HEV
negative for an average of 32 months; all ten of them remained
well, and their T-helper counts remained over 500.
On the other hand, 43 of the 44 patients with serious ill-
ness or bad prognosis (the 22 with AIDS or ARC, and the 22 fast
progressors) tested R-HEV positive. (And the one who tested
negative did test R-HEV positive on alveolar lavage cells.)
Of the 22 apparently-healthy patients who were fast progres-
sors, 17 were R-HEV positive at their first visit -- an average
of one year before clinical symptoms or falling T-helper cells
were seen; the others became R-HEV positive eventually (in one
case, only when alveolar cells were tested.) By contrast, P24
antigen was positive in only eight of the 22 patients at their
first visit. All together, 33 percent of the 44 patients who
were seriously ill at some point in the five years were P24
antigen negative, vs only one of those patients who was R-HEV
negative (and that patient was R-HEV positive when alveolar cells
were tested).
These results suggest that R-HEV is much better than P24
antigen in correlating with disease state, and in providing early
warning of poor prognosis -- long before T-helper cells decline.
If future work confirms these results, then R-HEV will be the
best test available for HIV-disease status, and an excellent HIV-
specific "surrogate marker" to use in clinical trials to find out
quickly whether or not a drug is working.
R-HEV AND ANTIVIRALS
How good is the R-HEV test for showing how well an antiviral
is working? The very preliminary results now available appear
promising.
Eighteen of the 57 patients mentioned above were later
treated with AZT. While we do not have the exact figures, R-HEV
scores were greatly reduced in almost all of them within six
months of AZT treatment. However, between six and 12 months
after the patients started AZT, their R-HEV scores were back to
an average close to their original value.
Three patient was treated with alpha interferon; one
improved greatly, going into a long clinical remission. Ordinary
viral cultures decreased initially, but then produced as much
virus as they had before, even though the patient was in remis-
sion and did not have P24 antigen -- illustrating that R-HEV
correlated with this patient's condition, whereas a conventional
viral culture was not. (The other two patients treated with
interferon did not show as complete or as prolonged a remission.)
DISCUSSION
The R-HEV test is still very preliminary; until the early
results outlined above are confirmed by other researchers, we
cannot be sure that the test will prove useful. But if future
work confirms the results obtained so far, then this test will
have great importance in speeding the clinical trials of new AIDS
drugs, by providing an objective, specific measurement of disease
status which can be followed to see how well a treatment is work-
ing. A few weeks of testing in a small number of patients may
provide a better measure of a new drug's efficacy than current
trials -- which require hundreds of patients and commonly take
two years or more, because they do not have a good measure of
efficacy and have to wait for deaths or opportunistic infections
to accumulate instead.
A detailed report on R-HEV will be presented at a scientific
meeting in Bethesda, Maryland, later this month.
On September 11-12, a crucial meeting in Washington, DC will
attempt to reach professional consensus on "surrogate markers" --
meaning results other than deaths or opportunistic infections
which can be used as endpoints of clinical trials to determine
whether treatments work. At this time, there is much scientific
debate about whether existing blood tests -- especially P24
antigen and T-helper counts -- are meaningful enough to use as
rapid proof of efficacy of a drug, without needing to wait for
statistically significant numbers of "clinical events" -- deaths
and major opportunistic infections -- which require the large,
slow trials now causing bottlenecks and great delays in AIDS drug
testing. While some leading scientists -- such as Samuel Broder,
M. D., the principal developer of both AZT and DDI -- believe
that new drugs could be tested using existing measurements such
as P24 and T-cell subsets, it appears that most of the scientists
involved doubt that those tests are good enough, and that clini-
cal trials must therefore continue to recruit hundreds of sub-
jects and take years to prove efficacy, as they have in the past.
AIDS TREATMENT NEWS has argued that statistical indices of
patients' overall health should be used in clinical trials to
determine whether drugs are working. But few physicians and
scientists have been willing to accept this approach. They argue
that measures of clinical condition are often "subjective" and
are not HIV specific, and that AIDS does not follow a steady
course, with patients' health often improving or deteriorating
unpredictably. Because of these concerns, there is no chance
that the approach we have proposed will emerge as a consensus
from the October meeting.
We also fear that there may be no consensus on existing
markers of HIV progression either -- that many scientists will
not accept P24 antigen, T-helper counts, beta-2 microglobulin,
etc., as good enough for proving efficacy in drug trials. In
that case we would be left with the current "body count" clinical
trials as the only accepted designs -- trials which cannot possi-
bly test drugs fast enough to prevent tens of thousands, if not
hundreds of thousands, of AIDS deaths.
This is why the R-HEV test, if its early promise is con-
firmed, would be so important. It is the kind of test which the
scientific community might accept, and which could greatly speed
AIDS treatment research. It is urgent that this approach to drug
efficacy testing get prompt, objective consideration.
REFERENCES
Henle, W. and others. Herpes-type virus and chromosome marker in
normal leukocytes after growth with irradiated Burkitt cells.
SCIENCE, vol. 157, pages 1064-1065, September 1, 1967.
Leibowitch, J; Mathez, D; Cesari, D; Belilovsky, C; Gorin, I;
Deleuze, J; and Paul, D. Morbidite systemique et expression
retrovirale (infection productive) chez le porteur HIV. V Inter-
national Conference on AIDS, Montreal June 4-9, 1989, poster
number W. C. P. 72.
*****
DDI, PARALLEL TRACK NEGOTIATIONS
by John S. James
During the last week a series of meetings and conference
calls, arranged by different organizations and individuals, has
brought diverse groups concerned with DDI and with proposed
"parallel track" treatment access to the discussion table. Part
of the urgency of these discussions was the deadline of a meeting
on August 17 to advise Assistant Secretary for Health James O.
Mason about the parallel track. We have not attended these meet-
ings, but have spoken with some of the participants. Some obser-
vations, based on what we have heard:
* A major meeting August 8 in Washington brought together
most of the groups involved. Ten persons represented Federal
agencies -- including Anthony Fauci from NIH, and Ellen Cooper
from FDA. Several came from Bristol-Myers, including at least one
of the principal writers of the DDI protocol. There were several
representatives from patient and advocacy groups, three community
physicians, three clinical researchers, and a representative of
the Pharmaceutical Manufacturers' Association.
The AIDS patient advocates were Paul Boneberg from Mobiliza-
tion Against AIDS, Jim Eigo from ACT UP/New York's Treatment and
Data Committee, Jay Lipner (who has worked closely with Lambda
Legal in New York, and with Martin Delaney of Project Inform),
and Earl Thomas of NAPWA (National Association of People with
AIDS). The community physicians were Bernard Bihari of New York,
Neil Schram of Los Angeles, and Melanie Thompson of Atlanta.
The information below came not only from that meeting, but
also from a New York meeting on the following day called by Jay
Lipner and attended by physicians from NYPHR (New York Physicians
for Human Rights), and by Ellen Cooper, M. D., of the FDA. Later,
a conference call coordinated by the American Foundation for AIDS
Research (AmFAR) included additional participants in these dis-
cussions.
* Despite major unresolved issues (see below), and specific
concerns about process in these discussions, the fact that they
occurred at all is a major advance. One FDA representative was
heard to comment on the advantage of talking to physicians who
see many AIDS patients, instead of only to those who are experts
in trial design but see few patients.
It appears that until now, protocols for multicenter AIDS
trials have not even been seen by the major private-practice phy-
sicians (much less by the patients who will put their lives on
the line for them) until after the protocols have hardened into
concrete -- been submitted to Institutional Review Boards across
the country, which makes even the slightest change impossible, as
it would require re-approval of the study by all these boards.
Apparently for the first time, the physicians who must refer
patients if the trials will be successful, and representatives of
patients themselves, have had a chance to look at a study while
changes are still possible, and point out the kinds of practical
problems that could make the trial unworkable but often could
easily be corrected by the trial designers if they knew about
them in time.
* Some examples of the kinds of problems that can be worked
out (or at least addressed) by bringing the different parties
together:
- PWAs are concerned about what would happen to persons ran-
domized to receive either DDI or AZT, probably for two years, and
who then did poorly. Would they be left to get a major oppor-
tunistic infection or die, or would they be allowed to try the
other drug?
This issue is still unresolved, and apparently was not dis-
cussed in the meetings except for one trial -- the "AZT worri-
some", those who responded well to AZT and can still tolerate the
drug, but are showing early signs that AZT is beginning to fail
for them. This group is not included in the three trials already
planned, apparently because the idea for it came later; but this
trial could be very important, because it could obtain statisti-
cal proof of efficacy of DDI faster than any of the other trials.
And the issue of treatment failures is most important here,
because everybody going into such a study would already be start-
ing to fail on AZT, and half of them would be randomized to con-
tinue the same drug. There seems to be a developing consensus
that criteria could be devised under which the code would be bro-
ken for patients who continued to deteriorate, and if they had
been receiving AZT, they could change to DDI.
But for the three trials, planned to start in September,
this issue of great importance to the PWA community is still
unresolved. The question should also be important to the trial
designers, because if volunteers who do poorly on the study medi-
cation are not allowed to try other options within the trial,
they are likely to obtain treatments outside of the trial
instead, perhaps without telling the investigators. And patients
will be reluctant to volunteer -- and physicians reluctant to
recommend that they enter trials -- if there is no provision for
changing their treatment if they do poorly.
- AIDS community representatives insisted on allowing com-
passionate provisions for persons who clearly need an antiviral
but could not use AZT because they are already using ganciclovir,
which like AZT has hematologic toxicity. (These persons will not
be eligible for any of the formal trials.) Since DDI does not
have the same toxicity, there is no reason to think that persons
using ganciclovir could not also take DDI. But because no one has
yet tried the combination, there is no proof that it is safe.
If ACT UP and Jay Lipner had not raised the issue, these
patients would have been told to wait for DDI until a safety
study of the combination had been done. But from the discussion
which developed in the meeting, it quickly became clear that it
would in practice be a long time before this study could be fin-
ished. So an alternative, apparently proposed by the FDA and
acceptable to everyone, was to allow these people compassionate
access to DDI, and also to put a small number (perhaps eight to
15) of such patients into a new trial at one of the ACTG sites
which has previously done the phase I study of DDI, to find out
quickly about any unknown dangers in the combination. If prob-
lems are found, then the compassionate access for persons also
using ganciclovir could be re-evaluated.
- Community physicians suggested that useful data could be
collected from parallel-track access by community-based clinical
trials organizations working together with Bristol-Myers.
Bristol-Myers has agreed to supply DDI for at least five thousand
people within a year (the number could go higher if justified),
in addition to those in the trials; but it has not yet decided
how to obtain data from these patients. Community- based
research organizations could collect data from about two thousand
or more of them; the others (for example, those too far from any
such organization) would receive the drug without data collec-
tion. The cost would be small, and the data would be collected
by organizations with a track record in research, rather than by
individual physicians who would usually not be interested. Then
later, in case the formal studies were slow in recruiting, data
would be available; if, perhaps a year from now, the FDA is wil-
ling to accept surrogate markers (blood tests, etc., instead of
deaths or OIs) as proof of efficacy, the drug could be licensed
much earlier than otherwise.
- One physician was concerned that DDI may be blamed for
cases of pancreatitis which have been found in some of the people
using it, when the drug might not be responsible. He pointed out
that New York physicians have seen increasing numbers of cases of
pancreatitis recently, in patients who have never used DDI.
- AIDS activists expressed concern about recent moves to
limit parallel track to those who cannot get into any trial.
There are a number of moribund trials, which fail to recruit
patients because they are poorly designed, or because they are
testing drugs which do not look good but made it into trials
because somebody had the money to pay for them. There is fear
that restrictions on access to experimental treatments will be
used to blackmail the AIDS community into filling these dead-end
trials.
However, Dr. Bernard Bihari of the Community Research Ini-
tiative, who attended the meetings, told us that the idea of lim-
iting access in this way was brought up but was clearly rejected,
and that it will not happen, at least not for DDI.
* Specifics of the trials -- according to the memory of one
participant:
- The three DDI trials to start soon -- hopefully by late
September -- will be named ACTG 116, ACTG 117, and ACTG 118. It
is hoped that they will enroll 1800 volunteers total.
- The trial considered most important will be DDI vs AZT,
for persons with AIDS or advanced ARC. In some ways this trial
will try to replicate the early phase II trial which led to
approval of AZT. It hopes to have 400 patients in each arm. Some
prior use of AZT (up to two months) is OK.
- Another trial is for persons who have taken AZT for a year
or more, and are tolerating it well. This study is to find out
whether these people do better staying on AZT, or switching to
DDI. It is hoped that this trial will produce the earliest con-
clusive evidence.
- The third trial is for those who have had to stop AZT due
to hematologic toxicity. Since these people cannot be randomized
to AZT, and a placebo would not be acceptable, they will be ran-
domized to receive one of two different doses of DDI. The low
dose will be the lowest which showed efficacy in phase I
(apparently 100 mg twice a day), and the high dose will be the
standard DDI dose for all three of these trials, (apparently 375
mg twice a day). There is concern that these doses are similar
enough that it will take a long time for this trial to prove that
there is a statistically significant difference between them.
- Later, there are plans to organize a trial for the "AZT
worrisome," those who are on AZT and not intolerant, but show
signs that the drug is beginning to fail, short of a major oppor-
tunistic infection. There will also be a pediatric trial.
- Two different existing programs for early access -- "com-
passionate use" and "treatment IND" -- for those who clearly need
an antiviral and cannot use AZT or enter the trials, should begin
at the same time as the trials. The competing "parallel track"
concept will not be used for DDI at this time -- partly because
parallel track is not yet fully defined, and partly because in
the turf wars between FDA and NIH, the FDA is in the position to
make this decision. Parallel track may be the more far-reaching
proposal, returning more choice to patients and their physicians
when patients cannot enter trials, whereas compassionate access
is for those who clearly cannot use AZT effectively and have no
other choice.
* As we went to press, we received a two-page consensus
statement on the parallel track prepared by 15 organizations:
AIDS Action Council, ACT UP/New York, ACT UP/San Francisco, AIDS
Project Los Angeles, American Association of Physicians for Human
Rights, American Foundation for AIDS Research, Community Research
Alliance, Gay Men's Health Crisis, Human Rights Campaign Fund,
Lambda Legal Defense and Education Fund, National Association of
People with AIDS, National Gay & Lesbian Task Force, National Gay
Rights Advocates, Project Inform, and the San Francisco AIDS
Foundation. This statement calls for the creation of an indepen-
dent panel to make "decisions regarding the definition and imple-
mentation of the parallel track." This panel "must include full,
voting representation by AIDS primary care physicians, represen-
tatives of community-based research groups, and people with AIDS,
HIV infection and their advocates" -- as well as representatives
from government agencies and the pharmaceutical industry. The
statement points to the lack of decision-making representation by
the AIDS community as a key factor in impeding previous efforts
(compassionate use, and the treatment IND) to make AIDS treat-
ments more available.
The statement also calls on this panel to "consider mechan-
isms for assuring that any person with HIV infection who has a
demonstrable medical need for a parallel track treatment could
obtain access regardless of economic circumstances."
* A major concern we have heard about the developing program
for DDI involves the responsibility of the AIDS community.
Bristol-Myers and other participants have taken risks to handle
this drug much better than others have been handled, moving very
rapidly at this time to get trials going, consulting with commun-
ity physicians and patients, and planning to make their drug
available free. But DDI is not the last drug, and other com-
panies will be watching to see how well this policy works. If it
fails, access to other drugs will be harder in the future.
One fear in the AIDS community is that patients who could
qualify for the formal trials, or their physicians, may fudge
records to get patients DDI through compassionate access or
treatment IND instead, in order to avoid the chance of being ran-
domly assigned to AZT, and to be able to receive the drug
directly from one's physician and have the physician know which
drug it is. On the other hand, the trials will have the advan-
tage of offering excellent testing for free -- and none of them
will give AZT to patients who clearly will not benefit from it.
We hope that fudging records to stay out of trials will not
be a serious problem, as it is important for many reasons that
the trials be able to recruit effectively -- both to get the
efficacy data quickly, and to avoid future restrictions on treat-
ment access.
Another concern, which we have heard from persons in the
Community Research Initiative in New York, is that the great
attention to DDI is leading to an irrational rush to this partic-
ular drug, with people avoiding other trials, or calling off
other treatment plans, to get DDI. Not only could a stampede for
DDI damage other trials and make it more difficult to get legal
access to treatment in the future, but also it does not make
sense medically, because the case for this drug is not yet very
strong. Only about 90 patients have taken DDI in trials, and
there are many questions remaining about risks and benefits. DDI
may prove to be more useful and less toxic than AZT -- but at
this time the uncertainties are much greater. DDI may be espe-
cially valuable to those who cannot use AZT effectively, and it
is important that the AIDS community make sure they have the
option. But those who can use AZT should weigh the choice care-
fully, and not overemphasize DDI just because it is new or in the
news.
Other new drugs now entering clinical trials, such as D4T
and AZDU, may be at least as good as DDI. We hope that DDI will
show the way to an effective compromise, in which well- designed
clinical trials can be quickly enrolled and conducted, while at
the same time patients' options are maximized and there is some
provision for everybody.
MAJOR UNRESOLVED ISSUES:
* How will data be collected when treatments are released
for compassionate use or parallel track access?
Ideally, data collection from early access could provide
valuable experience about how drugs are working in the real
world, outside of the artificial, controlled conditions of the
trials. Patients want more data collection, and so do community-
based clinical-trials organizations, which see a role for them-
selves in collecting it.
But pharmaceutical companies often fear that in today's
regulatory climate, this data could only hurt a drug's licensing,
not help it. The concern is that the FDA is unlikely to take
seriously results obtained outside of a rigorously controlled
clinical trial, meaning that data from parallel track, treatment
IND, or compassionate use could not help the drug be licensed.
But adverse effects reports are taken seriously. The fear, then,
is that results from early release can only hurt -- a fear which
makes companies reluctant to allow use their drugs, no matter how
medically justified and urgent the case for doing so.
Unfortunately many FDA employees do not believe in any early
access -- perhaps because they fear that exceptions to the regu-
lar licensing process cast doubt on the rationale of their work.
If their standard drug-licensing procedures are sound, then why
are exceptions necessary?
Fauci's parallel-track proposal has added a new element to
the debate -- an authoritative statement that it is possible to
relax some restrictions on treatment access without harming clin-
ical trials. But the FDA has more than research to worry about.
Like a circus lion trainer, in a cage with entities more powerful
than itself, it must not lose control for a moment. This fight
to keep control has led to cruel and irrational outcomes, which
are increasingly becoming a mainstream political issue.
This is the basic problem which has stood in the way of ear-
lier access to treatments. The FDA has not wanted to find ways
to allow data from pre-licensing use (other than through trials
which most patients cannot qualify for) to help a drug get
licensed. If early access can only harm their interests, pharma-
ceutical companies will not provide their drugs for any form of
compassionate treatment use. Bristol-Myers may have made an
exception for DDI because otherwise it would have faced enormous
bad publicity. Instead, by agreeing to provide the drug subject
to FDA approval, it put the ball in the FDA's court, where it
belongs. But the great majority of drugs do not capture the
public's imagination. The only sound solution we see is to
insist on a full, ongoing examination of the scientific and
public-policy assumptions underlying the drug-approval process.
In addition, pharmaceutical companies are understandably
reluctant to have others collecting data about their products
outside of their control, because they fear being held responsi-
ble for adverse effects which may have nothing to do with their
drugs. Most private-practice physicians who are not associated
with research organizations do not want to do data collection,
either. To them it is just more paperwork.
One possible solution to this problem is for the pharmaceut-
ical company to fund data collection by community-based or other
research organizations, under the sponsoring company's control,
through negotiated protocols. Data would be collected only for
those patients who volunteered (the free blood work would be an
incentive), and were geographically convenient to a monitoring
organization.
* A major disagreement is what to do for "AZT refuseniks,"
those who do not want to try AZT but do want access to DDI.
Patients and some physicians see it as wrong to force somebody to
use a drug they do not want and get sick from it in order to
qualify for treatment. But at this time the other side seems to
have little sympathy -- as if those who refuse AZT are to be pun-
ished for their distrust of the system, or as if the doors are to
be closed to "economic refugees" who come to DDI because they
cannot afford AZT, or as if patients must do their share of sac-
rificing themselves for some greater good in the future.
One suggestion is to develop standards for documenting who
is a "real" refusenik, for example by chart notes over a period
of time, so that there will not be a huge number of people who
receive DDI this way.
This issue shows that we have a long way to go to reach con-
sensus that treatment decisions should be made by patients and
their physicians, on medical grounds, in the patient's interest.
There are excellent arguments for being cautious with DDI until
more is known, for not using it if other viable options are
available. The case against accepting unknown risks as prefer-
able to known ones must be well stated. But when there are legi-
timate medical grounds for choosing a drug, the ultimate deci-
sions should be made by patients and their physicians, rather
than by scientists, officials, or committees who make rules in
advance with no knowledge of each specific case.
PHYSICIAN ACCESS
Bristol-Myers has made plans to distribute DDI rapidly. Phy-
sicians will be able to call an 800 number, then receive and
return forms by fax, or by express delivery for physicians who do
not have fax machines. Then a 30-day supply of the drug can be
shipped immediately.
NEED FOR CAUTION
Persons considering using DDI should realize that not every-
body in the AIDS community thinks that this drug is beneficial.
There are growing questions and concerns. The history of new
drugs suggests caution, as serious side effects of AZT and DDC
were not noticed in early trials.
The best information we are hearing at this time is that DDI
may add a year of life to persons who are burned out on AZT (or
who never took AZT), but that it will not replace AZT. Research-
ers are finding the same pattern of rising T-helper cells, then a
interrupt
plateau, then falling T-cells, so that after about a year or
eighteen months, patients will probably be back where they
started. DDI is becoming available underground, but it must not
be considered harmless, as there are side effects including rash,
rise in liver function tests, pancreatitis, and peripheral neuro-
pathy. So far the neuropathy has caused the most concern, as a
few patients have had severe pain in the feet after 30 to 40
weeks of the drug at doses about equal to those which will be
used in the trials; in extreme cases the pain can be debilitating
and not responsive to optiates, and it can take weeks to recover
after the drug is stopped. At higher doses, the neuropathy has
occurred as soon as ten weeks; the problem may depend on total
cumulative dose. DDI might prove most useful when taken in
cycles alternating with AZT, instead of taken continuously.
Questions have also been raised about the evidence for effi-
cacy. Rebecca Smith of the AIDS Treatment Registry in New York
pointed to the report that patients on four higher doses did
better than those on four lower doses (recent article in Science,
June 28). But the graphs on page 413 of that article show that
patients on the lower doses started with about half the T-cells
of those on the higher doses. This difference should be con-
sidered when evaluating the fact that all but one of the six
opportunistic infections which developed occurred in patients on
the lower doses. (Other indications of efficacy are more clear,
however, such as the fact that every one of the 13 patients on
the four higher doses had T-helper cell increases.)
This article has looked at the the current status of the
negotiations concerning the issues and mechanisms of early access
to experimental drugs including DDI, but only briefly at the
arguments for or against the drug itself. We plan to follow all
of these issues as they develop.
*****
LOS ANGELES HUNGER STRIKE FOR TREATMENT ACCESS;
28 ORGANIZATIONS FORM COALITION FOR COMPASSION
Hunger strikers urging the Food and Drug Administration to
speed the release of safe experimental drugs moved their protest
to a site in West Hollywood after 20 of them were arrested "for
reasons of encampment" outside the Federal building at the Los
Angeles Civic Center.
The strikers are supporting the demands of the Coalition for
Compassion, a coalition of 28 gay and lesbian community and AIDS
service organizations. The Coalition launched it "Compassion =
Life" campaign "to focus upon responsive use of drugs and to
alert the nation to the immediate need to make medical treatment
available to people with AIDS. "
The hunger strike had been planned to consist of 24-hour
shifts of concerned citizens and celebrities at the Federal
building, to bring attention to treatment development and access
issues. But in addition to the rotating shifts, two persons with
AIDS have fasted for three days, and are continuing. They are
being monitored by physicians.
The hunger strike began at 10 AM on August 9 outside the
Federal Building. Federal officials ordered the people to leave
by 6 PM that day. After 20 arrests on August 9 and 10, the
strikers were granted sanctuary in the City of West Hollywood and
moved to their current location at Crescent Heights and Santa
Monica Boulevards, while negotiating to return to the Federal
Building site.
The hunger strike is only one aspect of the Coalition for
Compassion campaign, a movements which hopes to spark similar
organizing in other cities. So far we have seen no press cover-
age outside of Los Angeles, where the protest has been reported
by the Los Angeles Times and on local television. But word
spread nationally, since AIDS Project Los Angeles is both associ-
ated with the Coalition for Compassion and also one of the 15
national organizations which drafted the consensus statement on
the parallel track (see "DDI, Parallel Track Negotiations," in
this issue).
For more information about the hunger strike or the Coali-
tion for Compassion, and about how you can help, contact Rodney
Scott, West Hollywood Cares project director, at 213/659-4840.
You may need to leave a message as he is usually at the site.
*****
SAN FRANCISCO: NEW CLINICAL TRIALS TREATMENT DIRECTORY
The County Community Consortium has released a new edition
of its directory of AIDS/HIV clinical trials in the San Francisco
area. (The previous edition was published in BETA -- the Bul-
letin of Experimental Treatments for AIDS, published by the San
Francisco AIDS Foundation. The new version will also be distri-
buted by mail.)
To obtain the new edition, write to the County Community
Consortium, Ward 84, Building 80, San Francisco General Hospital,
995 Potrero Ave., San Francisco, CA 94110.
The Consortium is also making copies available to all AIDS
service organizations in the San Francisco area, and to organiza-
tions elsewhere which want it.
*****
SAN FRANCISCO: QUAN YIN CHINESE HERBAL PROGRAM
DEADLINE SEPTEMBER 1
The next cycle of Quan Yin's research and treatment program
using traditional Chinese herbs begins September 6 and lasts for
12 weeks; deadline for enrollment is September 1. Currently
there are 160 people in the program. For more information, call
Quan Yin at 415/861-4963.
Note: for background on Quan Yin, see AIDS TREATMENT NEWS
issue # 68, November 4, 1988.
*****
UPDATE: COMMUNITY-BASED TRIALS
AND SAN FRANCISCO'S COMMUNITY RESEARCH ALLIANCE
By John S. James
In a development unprecedented in the history of medicine,
persons with AIDS or HIV and their physicians have begun to
organize and run their own clinical trials of potential treat-
ments, conducting this human research in ways which meet all FDA
and other legal requirements. One of about 20 such organizations
is the Community Research Alliance (CRA), which AIDS TREATMENT
NEWS covered in issue #70, December 1, 1988. This writer is one
of the founders of the CRA and is currently a member of the
board; we chose to focus our report on this particular organiza-
tion because we are closest to it and know it best.
WHAT IS COMMUNITY-BASED RESEARCH?
Clinical research traditionally takes place in major medical
centers, usually academic institutions, and is paid for by phar-
maceutical companies or by the Federal government. Some
research, especially tests of new chemicals never before taken by
humans, can only be done in specialized institutions. But other
studies, such as "monitoring" trials designed to collect con-
sistent, reliable data on a new use of a treatment already well
known in medicine, can usually be done more rapidly in the less
formal setting provided by a community organization working
together with front-line physicians in private practice or at
public clinics.
Research initiated by persons with AIDS or HIV or their phy-
sicians, and conducted under the professional guidance of physi-
cians and scientific specialists, can:
* Test immediately practical treatment options, which other-
wise might not be tested at all if they lack commercial incentive
or elegant scientific appeal;
* Design trials which will get results quickly (in contrast
to the "body count" designs usually used in mainstream research,
which usually take two years or more to produce results, due to
the wait for persons not being treated to get sick);
* Negotiate trial designs which are attractive to the parti-
cipants and their physicians, as well as scientifically sound,
greatly reducing recruitment delays and the danger of invalid
results due to cheating;
* Build an in-depth knowledge base, allowing the PWA commun-
ity to make sure its interests are represented when decisions are
made in mainstream research.
The public has not realized the extent to which the specific
interests of institutions and professionals have shaped medical
research in ways which differ from patients' interests. One
example came to light over a year ago, when Dr. Anthony Fauci,
director of the National Institute of Allergies and Infectious
Diseases, which runs most of the Federal government's AIDS treat-
ment research, had to tell a Congressional committee that some of
the most promising treatments, including aerosol pentamidine pro-
phylaxis, had been delayed for a year or more due to lack of a
single staff person to "shepherd" each one through the research
and regulatory labyrinth (see The New York Times, April 30, 1988,
page 1). Because the community- based research movement had been
small until that time, no one knew what was happening, except
those too dependent on the system to make a public issue. There-
fore, nobody raised the warning early, and a year was lost.
(Aerosol pentamidine received full FDA approval last month, based
on data from studies begun by the two oldest community-based
research organizations, the County Community Consortium in San
Francisco and the Community Research Initiative in New York.
Emergency funding was provided by pentamidine licensee LyphoMed,
Inc., after the U. S. National Institutes of Health had unexpect-
edly refused to fund the study.) This incident illustrates the
fact that treatment and prevention of opportunistic infections
has often fallen through the cracks of mainstream research, as
there are usually too few patients to generate much commercial
interest, and government scientists have preferred to study
high-tech antivirals which relate to genetic research and the
growing biotechnology industry.
Today's movement for community-based research exists to make
sure that the interests and patients and their physicians are
better represented in the future.
The groups developing today are modeling themselves on one
of the two pioneering organizations in the community-based trials
movement -- the Community Research Initiative in New York, and
the County Community Consortium in San Francisco -- the same
organizations which conducted the studies leading to the approval
of aerosol pentamidine. These original organizations developed
separately, creating two different flavors of community-based
research:
The Community Research Initiative was first suggested in a
position paper by Joseph Sonnabend, M. D., Michael Callen of the
PWA Coalition, Dr. Mathilde Krim of the American Foundation for
AIDS Research (AmFAR) and others. The organization started with
a five thousand dollar grant from New York's PWA Coalition --
beginning the tradition of extensive PWA involvement. Two more
physicians -- Bernard Bihari, M. D. and Nathaniel Pier, M. D. --
joined the group in its earliest stages, and administrator Tom
Hannan did the lengthy paperwork required to establish an organi-
zation meeting all legal requirements to conduct human research.
For the first year the group attracted little attention.
But after favorable comments by the Presidential Commission on
the HIV Epidemic (see The New York Times, March 15, 1988), the
organization and the concept on which it was based attained wide
acceptance. Today the CRI has 190 participating physicians, and
a scientific advisory committee headed by Donald Armstrong, M.
D., Chief of Infectious Diseases, Director of the Microbiology
Laboratory, and head of the AIDS Clinical Trial Group (ACTG) at
Memorial Sloan Kettering Cancer Center. (Two other members of
the scientific advisory committee are also ACTG researchers.)
Nine trials are now underway or completed, with over 500 patients
participating; the organization has an annual budget of slightly
over a million dollars. (For more background on the Community
Research Initiative, see AIDS TREATMENT NEWS #70, December 1,
1988.)
The other pioneer in community-based research, San
Francisco's County Community Consortium (CCC), did not begin as a
research organization, but as a forum for communication between
physicians with AIDS practices, and AIDS researchers at San Fran-
cisco General Hospital. Almost all AIDS physicians in San Fran-
cisco are members of the CCC, although many are primarily
interested in sharing information, rather than conducting
research.
In addition to its information-sharing function, CCC now has
five clinical trials underway, is building an infrastructure to
provide research-nurse support to help physicians throughout the
San Francisco area participate in research within their prac-
tices, and has published a directory of clinical trials in the
San Francisco area (see "San Francisco: New Clinical Trials
Treatment Directory," elsewhere in this issue for information
about the directory and how to receive a copy). (For more back-
ground on the history and development of the County Community
Consortium, see AIDS TREATMENT NEWS issues # 54, April 8, 1988,
and # 56, May 6, 1988.)
These two organizations have established two different
styles of community-based research:
(1) The Community Research Initiative emphasizes patient
involvement, with PWA participation on the governing board and on
the institutional review board (IRB) which must review and
approve any trial's ethical treatment of human subjects. Studies
can take place either in the offices of primary-care physicians
or at a central location, with the physician consulted. Much of
the CRI's research takes place at its clinical center, however,
as physicians are usually too busy to do the additional paperwork
required for research.
(2) The County Community Consortium emphasizes technical
support to enable primary-care physicians to conduct AIDS treat-
ment research. Physicians with large HIV practices are usually
the first to see the potential of available, immediately practi-
cal treatment options. But few practicing physicians have the
time, training, or inclination to organize their own clinical
research projects without assistance. Technical support provided
by organizations like the Consortium allows the knowledge and
experience of leading physicians to lead to credible scientific
data which can be used everywhere to improve medical practice.
Studies take place within the practices of the physicians, with
the Consortium providing technical support and assuring quality
control of the data.
The CRI model applies when patients want to be involved not
only as subjects, but also in the development and decision- mak-
ing of research. The Consortium model applied when an existing
(or new) group of physicians, in private practice or in a public
or private hospital or clinic, want to begin participating in
clinical trials. Both models are crucially important for organ-
izing practical research to make new treatments available faster.
THE COMMUNITY RESEARCH ALLIANCE
AIDS TREATMENT NEWS described the formation and early his-
tory of the Community Research Alliance last December (issue
#70). At that time the scientific advisory committee had not
met, and the institutional review board had not been formed.
This article will focus on current projects, instead of the
details of the rapid organization building which has taken place
since then. We should point out, however, that developing an
organization which meets all legal requirements for conducting
human research is not only a matter of completing paperwork and
complying with regulations, but more centrally is a process of
developing working relationships with scientific and medical pro-
fessionals, and with other organizations and community leaders.
Over 30 volunteers are involved as members of the various boards
and committees.
The Community Research Alliance is currently conducting a
hypericin monitoring project which has been running for two
months and has 30 patients participating. This study went from
proposal to operation in three months. It provides a model for
what could become a series of studies by the organization.
Hypericin is a substance found in a plant (St. John's wort)
long used in herbal medicine. Recently researchers at New York
University and elsewhere have found that hypericin appears to be
an excellent antiretroviral, not only active against HIV in the
test tube, but also against two other retroviruses in mice.
(Since animals do not get AIDS, it has not been possible to run a
direct animal test of hypericin as an anti-AIDS treatment.) For
more background on hypericin, see AIDS TREATMENT NEWS issues
numbers 63, 74, 75, 77, 79, and 80; the major scientific report so
far was published in the Proceedings of the National Academy of
Sciences, USA in July 1988, and five abstracts were published at
the Montreal AIDS conference in June 1989 (including number M. C.
P. 115, not listed under "hypericin" in the subject index).
But approval and regular human use through the mainstream
research system will probably be years away. At this time, chem-
ists are developing better methods for synthesizing large quanti-
ties of the pure chemical. Then there must be more animal tests
before human trials can begin. The human trials can take years,
despite recent efforts to speed the process.
Meanwhile herbal extracts are available. No one is sure if
they can be useful. How can we find out?
A randomized controlled trial (today's gold standard of
clinical research) would probably be impossible, at least in the
United States. Such studies are difficult to run, and expensive
-- and herbal extracts have very poor prospects for patent pro-
tection and therefore do not attract investors. Besides, it
would probably be legally impossible to do the study, as the FDA
is very unlikely to give an IND (Investigational New Drug appro-
val) for the herbal extracts available. The FDA does not like
crude plant extracts since they are not completely characterized
chemically, and vary from batch to batch. The FDA exists to
regulate (and protect) the pharmaceutical industry -- not herbal-
ists, who are not taken seriously in the U. S. mainstream.
Without an IND, it is not legal to give an unapproved drug to
people.
What, then, can be done, besides waiting several years for
large-scale synthesis of pure hypericin and animal and human
tests of the chemical?
One option is to conduct a survey -- such as the one AIDS
TREATMENT NEWS distributed in our June 2 issue, which we are now
analyzing. A survey is better than nothing, but it has the major
limitation of having no uniformity in data collection. People get
different blood tests, or none at all, and on completely dif-
ferent schedules. Because of such problems, our survey will only
be a study of peoples' beliefs about whether herbal extracts con-
taining hypericin are helping them. What objective evidence does
get reported (such as blood results, or clear appearance or
disappearance of symptoms) is so diverse and scattered that it is
difficult or impossible to draw reliable conclusions from it.
Between the survey and the randomized controlled trial is
the monitoring study, such as the one the Community Research
Alliance is doing with hypericin. A monitoring study avoids the
need for an IND by not giving anybody a drug. Instead, it only
collects data -- by doing blood work, physical examinations, and
medical histories. But it collects the data under a strict,
scientifically designed protocol, to maintain uniformity and
quality control.
In the hypericin monitoring study now being run by the Com-
munity Research Alliance, patients are not told what kind of
hypericin to use, or how much. They are not told to stop or
change any other treatment. Of course they are asked to report
every treatment they are using.
As we described in our June 2 issue, which announced the
start of this monitoring study, baseline (before starting hyperi-
cin) and four monthly blood tests are given. Tests (not all
given every month) include P24 antigen, T-cell subsets, the CMI
skin test, CBC, ESR, and SMA 25. Before and after physical exams
are given, and a medical history is taken. All blood work for
all patients is done by the same laboratory, to reduce inter-lab
variations.
This kind of monitoring study cannot control or standardize
the treatments people are using -- for both legal and ethical
reasons. But it can rigorously control the data collection. As
as result, it can quickly collect much better data than is avail-
able from any other source about many, if not most, of the non-
approved treatments now being used.
Since there is no control group for comparison, this kind of
study cannot obtain statistical "proof" of whether the treatment
works better than no treatment, or better than some other treat-
ment. Instead of seeking such proof, this study aims to keep
very good records of what happens to people who are using the
treatment. The rationale is that since every patient's health
status going into the study is well documented, any major or
dramatic effects should be evident to physicians when they com-
pare the histories of these patients, during the trial or after-
ward, with the histories of other patients they have known.
Therefore monitoring studies do not aim to prove a drug
effective, but rather to produce quality information which can
support treatment decisions. Note that almost any result of a
well-conducted monitoring study can support such decision- making
to some degree. If the treatment shows dramatic effects, of
course that would be interesting. But if it shows nothing at
all, or only ambiguous, debatable results, this information would
also be helpful to patients and physicians, in supporting the
case against using the treatment.
Monitoring studies are relatively inexpensive and easy to
administer, because they do not give treatments, or change what
the patient is doing anyway. The main expenses are for blood
tests, and staff time. This kind of study can quickly obtain the
best information available on treatments which are coming into
use but have not been formally studied -- either food supple-
ments, etc. which patients can obtain on their own, or drugs
formally approved for other purposes and prescribed by physi-
cians.
FUTURE PROSPECTS
Here are examples of the kinds of projects which the Commun-
ity Research Alliance may pursue in the future:
(1) The CRA might develop many small monitoring studies,
like the hypericin trial currently underway, and focus on doing
this particular kind of research well. Funding would come mainly
from individual donations, fund-raising events, and foundation or
corporate grants, rather than from pharmaceutical company spon-
sorship of particular projects. The treatments studied would be
those already available; and because funding would be from com-
munity and other public sources, treatments could be selected
only on the basis of medical merit and public-health importance,
without regard to their commercial prospects. This research arm
of the organization will operate entirely in service to the AIDS
community and the larger public.
(2) Some of the most important studies, however, could only
be done with pharmaceutical-company sponsorship. Collaboration
between pharmaceutical companies and community-based research
organizations has worked well in the past, and the companies have
been happy with the results. More time may be required up front
to negotiate a protocol acceptable to people with AIDS and their
physicians, as well as to the other parties involved -- a step
usually omitted by academic research centers. But the care taken
to include their interests is repaid many times over by easier
and faster recruiting of volunteers for the trial.
Community-based organizations have a reputation for getting
top-quality results much faster and less expensively than other
alternatives. And today there are more drugs to test than
research facilities available to test them (for background on
this problem, see "The Trials of Conducting AIDS Drug Trials,"
Science, May 26, 1989). Therefore community-based organizations
not only have opportunities to contribute to the mainstream
research process, but by doing so they can help relieve a major
bottleneck in the system, in addition to the qualitative contri-
butions they can make by being close to the PWA community.
At this time the two most important drugs which could be
studied by community-based research organizations are compound Q
and DDI. Genelabs, the developer of compound Q, is exploring the
possibility of organizing some phase II trials through
community-based groups. For DDI, the phase II trials will be
through NIAID's ACTG system, but there may be a role for
community-based organizations in collaborating with Bristol-Myers
to collect data from patients who receive drugs through compas-
sionate use, treatment IND, or (later) the parallel track.
No final decisions have been made at this point, but these
are some of the projects the Community Research Alliance is
exploring as possible industry-sponsored trials.
(3) A number of other potential avenues are also being exam-
ined, including:
* Studying treatments for opportunistic infections, an area
which has been neglected by the AIDS research mainstream. The
treatments would be used by physicians in their usual practice,
with the Community Research Alliance doing paperwork to facili-
tate access, data collection, and reporting of results;
* Participating in multicenter community-based trials, car-
ried out by a developing network of community-based research
organizations around the country, focusing on prophylaxis of
opportunistic infections;
* Opening doors for full participation in clinical trials
people of color and other groups which so far have been under-
represented -- both in the decision-making process and as
volunteers -- speeding AIDS trials by reducing recruitment
delays, at the same time as the trials are made more equitable.
HOW CAN YOU HELP?
Community-based research organizations need public support.
The biggest immediate need is money. The Community Research
Alliance, for example, has had its office space and almost all of
its office equipment donated, as well as the efforts of many
volunteers, but it must have some paid staff in order to move as
rapidly as possible to negotiate future trials, as well as com-
pleting the one already going. The hypericin study is completely
financed by the CRA itself, as there is no pharmaceutical company
sponsor for it.
The Community Research Alliance has received a $30,000 grant
from AmFAR (the American Foundation for AIDS Research), and indi-
vidual gifts totalling over $60,000. But expenses at the current
rate of growth and activity are about $12,000 per month. The CRA
did not originally ask the public for money, as it wanted to
establish a track record first. Now it needs contributions
within the next two months, or its growth must be greatly cur-
tailed.
The Community Research Alliance also needs volunteers, espe-
cially people with professional skills and/or who can develop or
manage long-term projects.
If you can help in any way, contact administrator Tom Wilcox
or his assistant Drew Catapano at 415/626-2145. Physicians
should call the medical director, William Cooper, M. D., at the
same number. Contributions can be sent to the Community Research
Alliance, 273 Church St., San Francisco, CA 94114.
*****
STATEMENT OF PURPOSE
AIDS TREATMENT NEWS reports on experimental and complementary
treatments, especially those available now. It collects informa-
tion from medical journals, and from interviews with scientists
physicians, and other health practitioners, and persons with AIDS
or ARC.
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.
We also examine the ethical and public-policy issues around AIDS
treatment research.
HOW TO SUBSCRIBE TO AIDS TREATMENT NEWS BY MAIL
Send $100.00 per year for 26 issues ($150.00 for businesses and
organizations), or $30.00 reduced rate for persons with AIDS or
ARC who cannot afford the regular rate, to: ATN Publications,
P.O. Box 411256, San Francisco, CA 94141. A six-month subscrip-
tion (13 issues) is $55.00 ($80.00 for businesses or organiza-
tions), or $16.00 reduced rate. For subscription information and
a sample issue, call (415) 255-0588.
For the complete set of over 70 back issues, send $75.00 ($18.00
for persons with AIDS or ARC) to the above address. The back
issues include information on hypericin, dextran sulfate, foscar-
net, passive immunotherapy, DTC (Imuthiol), naltrexone, DHEA,
lentinan, propolis, coenzyme Q, monolaurin, egg lecithin lipids,
fu zheng herbal therapy, DNCB, aerosol pentamidine, fluconazole,
ganciclovir (DHPG) and other experimental or complementary treat-
ments.
To protect your privacy, we mail first class without mentioning
AIDS on the envelope, and we keep our subscriber list confiden-
tial.
Outside North America, add $20.00 per year for airmail postage,
and $18.00 airmail for back issues. Outside U.S.A., send U.S.
funds by International Postal Money Order, or by travelers
checks, or by drafts or checks on U.S. banks.
Copyright 1989 by John S. James. Permission granted for non-
commercial reproduction.
-----------------
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