info-aids@apple.com (INFO-AIDS MAILER) (07/31/89)
AIDS TREATMENT NEWS Issue # 83, July 14, 1989
DDI: Compassionate Access Announced
Pneumocystis Seminar Televised July 25
Foscarnet Information Numbers
San Francisco DDC Study -- KS Diagnosis Is Allowed
National Conference On AIDS and Minorities Slated For August
Computer System Recommendations For Community-Based
Research Organizations
AZT, Acyclovir, and the Case for Early Treatment
DDI: COMPASSIONATE ACCESS ANNOUNCED
by John S. James
On July 13, Bristol-Meyers Company announced that it would
make the experimental anti-HIV drug DDI available to persons with
AIDS who did not meet the criteria for clinical trials and had a
"critical" need for the drug. This program, described by the
company as "compassionate use", follows the "parallel track"
ideas of NIAID director Dr. Anthony Fauci (see "Fauci Proposes
'Parallel Track' Treatment Access," AIDS TREATMENT NEWS # 82,
June 30, 1989). However, many important details are not yet
available.
DDI OVERVIEW AND IMPORTANCE
DDI emerged from the June Montreal AIDS conference with
widespread professional consensus that it is the most important
new AIDS antiviral at this time. The drug appears to be much
less toxic than AZT, and the toxicities it does have are
different- -opening doors to more effective doses, as well as
combination therapies.
Like AZT, DDI is not a cure, and will have to be used as a
maintenance treatment. It can be taken less frequently than AZT,
probably twice a day.
Although the drug is in the same general class as AZT, there
does not appear to be cross resistance -- meaning that strains of
the virus which have become resistant to AZT are not automati-
cally resistant to DDI. Therefore, DDI may be effective for peo-
ple for whom AZT no longer works well. DDI may also be synergis-
tic with AZT, meaning that the combination may work even better
than would be expected by adding the efficacies of the two
separate drugs together. But no one knows for sure, because as
far as we know there have been no human tests of the combination.
Eventually AIDS virus strains will probably develop resis-
tance to DDI, as with AZT. But the new drug should at least work
for some time for people who cannot use AZT, or for whom AZT is
no longer effective. And laboratory tests have suggested that
when different drugs attack the virus in different ways (as sug-
gested here by lack of cross resistance), it may take much longer
for the virus to develop resistance to the combination than to
any of the drugs separately.
Some scientists also suspect that bone-marrow toxicity from
prolonged use of AZT might make it more difficult for the immune
system to recover, even if the virus causing the immune defi-
ciency can be stopped. DDI may provide evidence of whether or
not this theory is true, by allowing AZT to be compared with an
antiviral which has no bone-marrow toxicity. It will be important
to see whether T-helper cells (for example) recover fastest with
DDI alone, AZT alone, or a combination of the two.
In short, DDI will be most important for those who cannot
use AZT. But also it may open doors to a whole range of new
treatment possibilities, making possible creative research which
can advance HIV management for the benefit of everyone.
These potential benefits, however, may be slowed or blocked
by the ineffectual system of clinical research now in power. For
example, no matter how clearly DDI works, the drug will have to
go through a two-year ritual in which a statistically significant
number of deaths and serious infections must accumulate in those
in a control group not receiving the treatment. Trials to look
directly at which patients do or do not improve while using the
drug could be conducted much more rapidly, and would provide
exactly the information patients and physicians want to know --
but such trials would not be accepted for drug approval, because
it is hard to measure patient improvement scientifically.
Since important antivirals will take years to go through the
approval process, and patients cannot wait for reform of the
current unproductive research system and the entrenched interests
behind it, immediate discussion has focused on programs to make
drugs available before full approval to those who need them most
-- after the drugs have passed safety tests and shown some evi-
dence that they work. The basic fact shaping this discussion is
the conflict between the interests of patients, who want to have
more and better treatment options available, and the interest of
institutions which, for differing reasons, want to restrict
access.
Today there are increasing efforts to establish dialog among
the different parties involved in treatment-access issues. Much
of this dialog is focusing on the immediate and obvious point for
negotiation -- the specific rules on which groups of patients
will or will not be allowed certain treatment options.
DDI NEGOTIATIONS
What made the recent Bristol-Meyers announcement possible
was the near-unanimous professional consensus coming from the
Montreal conference that DDI looked good. (The only doubt we
have heard so far was from a medical expert who questions whether
HIV -- which is inhibited by DDI -- causes AIDS.) It would be
hard for a company or for the FDA (U. S. Food and Drug Adminis-
tration) to flatly deny access to a treatment when the medical
profession is convinced that it could save lives. However, prac-
tical early access is not guaranteed, because there is still no
consensus that the system should provide early access, even if
the drugs clearly seem to work. And the all- important details
of who will be able to get DDI have not been determined.
Bristol-Meyers made its announcement after intensive nego-
tiations involving the company, the FDA, Dr. Anthony Fauci of
NIAID (the U. S. National Institute of Allergy and Infectious
Diseases), and the AIDS community, primarily represented by the
Treatment + Data Committee of ACT UP New York (the city where
Bristol-Meyers is based). ACT UP's Treatment + Data Committee
has done an outstanding job; without its work the current opening
for DDI might not exist.
The Treatment + Data Committee defined four categories of
patients who should have access to DDI:
* The AZT-intolerant, meaning those who cannot take AZT due
to drug toxicity;
* The AZT-resistant, those for whom AZT is no longer working
well, probably because the virus has developed resistance to it;
* The protocol-intolerant, including those too ill to qual-
ify for the formal trials, those who need to stay on another
medicine which disqualifies them, and those with symptomatic HIV
infection but T-cells too high for the trial; and
* The protocol-inaccessible, including those living too far
from a trial site, those who could not enroll because the trial
was full, and those whose physicians were unable to enroll them
and who could not change physicians (for example, those whose
primary care was at a public-hospital emergency room where physi-
cians could not take the time to get them enrolled in trials).
This list reflects the fact that those who most urgently
need a new treatment are those who cannot effectively use any
standard one. It also reflects the requirement of Fauci's
"parallel track" access proposal, that use of experimental treat-
ments must not be allowed to interfere with ongoing trials (see
AIDS TREATMENT NEWS # 82, cited above).
It is unclear at this time who will be allowed to use DDI.
We have heard (but not confirmed) the following:
* At this time the only group fairly well assured of getting
access is the AZT-intolerant -- because the FDA is likely to
insist that if a standard therapy is available it must be used in
preference to an experimental one, unless, due to toxicity, the
standard therapy cannot be administered.
* Informal discussions with FDA officials have raised some
hope that four other groups might also be included: those too
sick to qualify for the trials, those who must stay on another
medicine which disqualifies them, those who live too far from a
trial site, and those who cannot enter a trial because the trials
are already full.
* The problem with the "AZT-resistant" group may be the dif-
ficulty of defining it. For example, one trial design being con-
sidered for AZT-resistant patients would accept anyone who has
been on AZT for a year or more, since it is believed that the
AIDS virus may develop resistance after that time. Even for a
formal scientific study it is not feasible to do viral cultures
for every potential subject to prove that viral resistance to AZT
has in fact developed.
The potential difficulty in getting access to DDI for
patients who can tolerate AZT but do not benefit from it recalls
the example of trimetrexate, a pneumocystis treatment which at
first was allowed only to those who could not tolerate the stan-
dard treatments, but not to those who could take them but did not
respond and had no other alternative except death (see
"Trimetrexate With Leucovorin: Decisions That Save Lives, Deci-
sions That Kill, AIDS TREATMENT NEWS #52, March 11, 1988). Fol-
lowing public outrage, these patients were also allowed access to
trimetrexate. But what is not well known is that they were
included through special procedures intended to avoid setting a
precedent for the future. (We do not know why a special effort
was made to preserve so clearly inhumane a procedure. One possi-
ble motive is that each early-access exception highlights a
failure of the overall approval process, meaning that those who
operate and support that process have reason to ration the excep-
tions as tightly as possible.)
THE POLITICS OF EARLY TREATMENT ACCESS
Ideally, persons facing a life-threatening illness should,
with their physicians, be able to choose treatments based on med-
ical merit, taking their whole medical situation into account.
How can abstract, general rules make better decisions than those
who know the specific, often unusual or even unique facts of a
particular case? But the political reality is that institutions
have more power to pursue their interests than patients do.
How do the different groups involved view the issue and per-
ceive their interests? It would be difficult to answer this ques-
tion fully. The insights and viewpoints below are some which
have helped us in understanding what is happening. They refer to
the general issue of access to treatments before full marketing
approval, not specifically to DDI.
* Pharmaceutical companies. One clinical-trials expert
described the position of pharmaceutical companies (toward the
FDA) as, "Tell us what we must do, and that if we do it we will
get the NDA." The NDA, or new-drug application approval, gives
the company permission to market the drug -- permission often
worth hundreds of millions of dollars. Everything the companies
do is seen in the light of whether it will help them get the NDA,
or not.
Providing access to experimental drugs before the NDA
(through "compassionate use," "treatment IND," or "parallel
track,") is an expense and bother to companies. They must pay
not only for the drug, but also for associated research and
administrative expenses, and they can seldom be reimbursed, let
alone profit from this activity. There may also be manufactur-
ing, quality assurance, and liability concerns.
But the overriding issue is whether providing early access
will help the company get the NDA. Early access primarily for
treatment use could also provide data to help prove the drugs
effective, and therefore support the NDA. But historically, the
"compassionate use" system has provided poor data, probably
because it relied on busy physicians to fill out forms which they
would rather not deal with.
Starting almost two years ago, on October 26, 1987,
compassionate-use access to drugs (at least for AIDS) became much
more difficult to obtain. On that date an FDA advisory committee
recommended against approval of ganciclovir (DHPG), and the phar-
maceutical industry interpreted this rejection as punishment of
Syntex for making its drug available to thousands of patients
through compassionate use. Only recently, when NIAID's Dr.
Anthony Fauci proposed his "parallel track" for access to certain
treatments during trials, has the misinterpretation been
corrected. When company officials said that they could not use
the parallel track because they feared that what happened to Syn-
tex would happen to them, Fauci pointed out that Syntex got in
trouble not for making its drug available, but for failing to do
scientific trials early.
A key difference between the old "compassionate use" system
and the newer "treatment IND" or "parallel track" is that the
newer systems provide access under a protocol, so that better
data can be collected. Community-based research organizations
may be able to monitor patients, collecting data according to the
protocol and relieving primary-care physicians of unwanted paper-
work.
(Why then did Bristol-Meyers use the older term "compas-
sionate use" in its announcement on DDI? Apparently the company
did not want to be seen as taking sides in a fight between NIAID,
with its "parallel track" proposal, and the FDA, which wants to
revive its "treatment IND", which already exists but has not been
used much because it has been interpreted so conservatively.)
For pharmaceutical companies, the bottom line is getting
their NDA, which is granted by the FDA. Therefore, the most
important factor determining whether or not these companies will
be willing to provide their drug before marketing approval is the
rules, often unwritten, set by the FDA. The public and the AIDS
community have often failed to recognize this fact, in part
because pharmaceutical companies and the FDA have an inner rela-
tionship between them which is hard for outsiders to penetrate.
For example, which party takes the heat for an unpopular decision
can be decided as part of a larger negotiated arrangement. For
this reason, when treatments are not available, it is often hard
to know whether the real problem is with the company which holds
the exclusive rights to the drug, or with the FDA.
* The FDA. In discussions with FDA officials, the word
"thalidomide" is likely to come up. Thalidomide was a drug
disaster that led to the birth of thousands of deformed children
in Europe in the early 1960s. No animal or other tests gave any
advance warning of the problem. Fortunately, an FDA official
noticed an obscure report suggesting other toxicity, and withheld
U. S. approval long enough that the danger became known before
the drug was distributed here.
After thalidomide, Congress amended Federal law to require
proof of efficacy as well as safety before a drug could be mark-
eted. This new law would not have stopped thalidomide, but in
practice it has made new-drug approvals enormously more diffi-
cult. The current cost of drug development in this country is
about $120 million for each new drug. And even aside from AIDS,
analysts have questioned whether the current system saves as many
lives as it destroys (see "FDA Reform: Major New Position Paper,"
AIDS TREATMENT NEWS #58, June 3, 1988).
The FDA has taken its mission from thalidomide and the
resulting Congressional mandate -- to protect the public against
dangerous or worthless drugs. Neither the FDA nor any other
institution evaluates the risks or costs of not approving a drug
which should be approved. People forget that thalidomide was a
sleeping pill, and casually apply the standards appropriate for a
new cold, cough, or baldness remedy for the development of life-
saving treatments for diseases like cancer and AIDS. Thousands if
not millions of people with diseases which are or should be
treatable are sent away to die on their own, and there is no
institutional responsibility. But if anyone is hurt by the other
kind of mistake -- approving a bad drug -- then the FDA, the com-
pany, the researchers, and everyone else involved can expect to
be blamed. The result is more than a distortion; it is a situa-
tion where half of the decision-making process does not take
place at all.
The bottom line is not that we should weaken drug regula-
tion, but rather strengthen it by balancing the costs of both
kinds of errors. The rules of drug approval have immense and
often hidden effects, not only on individual patients denied
existing treatments, but also on the speed and creativity of the
entire enterprise of medical research and development. Federal
regulation largely controls the ability of medicine to respond
quickly to new emergencies like AIDS, and to develop new treat-
ments for old diseases like cancer.
* We do not have a clear picture of the other major institu-
tion in AIDS treatment development, namely NIAID (the National
Institute of Allergy and Infectious Diseases), a branch of the
National Institutes of Health. At this time the AIDS community
is grateful that NIAID director Dr. Anthony Fauci proposed a
"parallel track" system of allowing access to important new drugs
while formal efficacy trials proceed. However, we are hearing of
resistance to early access by some of the AIDS principal investi-
gators working through NIAID contracts at sites around the coun-
try. Apparently these researchers fear that early access will
deprive them of subjects for their trials, and as a result they
are pressing to restrict such access. These reports have not yet
been confirmed, but they have been greeted with anger in the AIDS
community, which sees the NIAID research effort as unproductive
in view of the time and money it has had, and which sees the
notorious recruiting problems at academic research centers as
being caused by poorly designed trials (that people cannot
volunteer for even when they want to), not by the existence of
other options for patients. This situation must be watched,
because it could threaten access to lifesaving treatments.
WHAT SHOULD BE DONE?
Pharmaceutical companies and government agencies alike have
been unenthusiastic if not hostile toward early treatment
release. The old "compassionate use" system, for example, was
supposed to apply to only a few patients. The "treatment IND"
applied to groups, but the FDA has used this system after the
full burden of proof has already been met, when only paperwork
remains before approval of the NDA. And pharmaceutical companies
have had little incentive to use either system.
What is needed instead is a flexible burden of proof that
takes account of the uniqueness and potential value of a drug and
the urgency of the need for it. For example, consider DDI:
* It will take probably two years or more to get statistical
proof that DDI (or any antiviral) increases AIDS survival or
reduces the frequency of major infections.
* During this time, 50,000 people will die in the United
States alone, unless better treatment becomes available.
* Of the new treatment possibilities, DDI looks best at this
time.
In this emergency the FDA should waive the requirement to
prove reduced death or opportunistic infections. Instead, it
could work with Bristol-Meyers to design much faster trials using
p24 antigen, T-helper count, and clinical measures such as weight
gain to show drug efficacy, in a program of clinical trials
involving perhaps several hundred patients, testing different
doses and testing the drug in different patient populations. Pla-
cebos could ethically be used in some cases, because patients
would not be on the trial for long -- and after the trial would
have the option of using the drug. If these rapid trials showed
that the drug was useful, and the long-term experience available
did not show serious problems, then the developer should get its
NDA and be allowed to market the drug -- provided that post-
marketing studies continued. (The approval might be called an
"emergency NDA", to alert physicians that the drug was approved
with less testing than usual because of the urgent need, and
therefore should be used cautiously.) No legislation would be
needed to implement this approach; the FDA has the power to start
tomorrow.
This system would be clean to administer, and would provide
enough incentive to insure that pharmaceutical companies con-
ducted their trials rapidly. Then the medical community could
evaluate the evidence available and make recommendations to guide
practicing physicians. Patients and physicians could then decide
whether to use the drug or to choose other options instead.
Why hasn't such an approach been used already? The reason is
that the outcome measures available -- p24 antigen, T-helper cell
count, and overall health of patients -- all have flaws and
therefore are not technically attractive in the academic world
which sets the tone for these decisions. Fantastic scenarios can
be concocted in which drugs could look good after the trials sug-
gested above, but really not give any benefit to patients. But
the small chance of mistakenly approving such a drug must be bal-
anced against the certainty of tens of thousands of deaths caused
by the built-in, two-year delay of the kinds of trials currently
required.
*****
PNEUMOCYSTIS SEMINAR TELEVISED JULY 25
On July 25 the Physicians' Association for AIDS Care (PAAC)
will broadcast an interactive video conference on pneumocystis
diagnosis, treatment, and prophylaxis. Produced in cooperation
with NIAID, the seminar will be presented by five experts: Henry
Masur, M. D., Judith Feinberg, M. D., David Feigal, M. D., Mar-
garet Fischl, M. D., and John Phair, M. D. Members of the audi-
ence can ask questions.
The interactive broadcast is via AIDS Satellite Television
Network (recently developed by PAAC, in conjunction with MediVi-
sion of Houston, TX). Institutions must be able to receive
either C-Band or Ku-Band satellite television to participate.
The two-hour conference will take place at 1:00 to 3:00 PM
Eastern Time. Your hospital, university, or other institution
can register as a site for this broadcast by calling 800/262-0834
or 713/779-7494. There is no charge for institutions to partici-
pate.
In San Francisco, the public can see a tape of the seminar
at 7:00 PM at Ralph K. Davies Medical Center, Castro and Duboce
Streets, in conference rooms B-2 and B-3 near the cafeteria. We
do not know of any live broadcast site in San Francisco open to
the public.
The symposium is the third program in PAAC's AIDS Satellite
Television Network series.
(AIDS TREATMENT NEWS thanks Morgan Fine of PANT -- Patient
Advocates For Necessary Treatment, 415/431-4843 -- who helped
publicize this seminar and brought it to our attention.)
*****
FOSCARNET INFORMATION NUMBERS
Many people with CMV retinitis are interested in the experi-
mental treatment foscarnet, some because they did not obtain an
effective response from the approved treatment, ganciclovir
(DHPG), and others because they want to avoid the side effects of
ganciclovir as well as make use of foscarnet's possible anti-HIV
activity. In June, issue #80 of AIDS TREATMENT NEWS printed the
number of an ACT UP foscarnet organizing committee in San Fran-
cisco. The activists on this committee have done an excellent
job of maintaining pressure on the Food and Drug Administration
and the manufacturer of foscarnet, Astra, to develop wider access
to the drug. The current alternatives for many people are to
stay on ganciclovir but give up the option to use AZT because of
the unacceptable combined bone marrow suppression, or to give up
ganciclovir in order to stay on AZT. The first choice is life-
threatening and the second one guarantees irreversible blindness.
(For more background information, see AIDS TREATMENT NEWS #71
and #77.)
Thanks to the efforts of activist Terry Sutton who died in
April, more people who want to try foscarnet may be eligible for
a "salvage" trial, and should call Astra's hotline number:
800/225-6333. This number may be useful for other questions
regarding foscarnet as well. But the organizing committee still
maintains a phone line to connect with people who are interested
in challenging the basic restrictions on foscarnet: 415/431-6088.
*****
SAN FRANCISCO DDC STUDY: KS DIAGNOSIS IS ALLOWED
Our last issue (AIDS TREATMENT NEWS #82) included an
announcement that a trial of the antiviral DDC is seeking
volunteers in San Francisco. We had been told that persons with
KS would not be accepted. But the protocol was still being
developed at that time, and the final version does allow persons
with KS in the study, if they are not using chemotherapy or radi-
ation when they enter it.
Volunteers must have a T-helper count lower than 200, and
either have had pneumocystis within four months before starting
the trial, or have certain other AIDS-related symptoms. They must
not have used AZT, and not have used acyclovir for extended
periods.
For more information, call Elena Swann, 415/565-6272.
*****
NATIONAL CONFERENCE ON AIDS AND MINORITIES SLATED FOR AUGUST
Washington, D. C. will be the site of a conference from
August 13-17 to discuss the impact of HIV and AIDS on minority
communities in the U. S. and to develop a plan to empower these
communities with information that can save lives. The conference
is sponsored by fourteen different agencies of the U. S. Public
Health Service, including the Centers for Disease Control, Office
of the Surgeon General, the Indian Health Service, and the Office
for Civil Rights. There is no registration fee, although to
avoid overcrowding the conference is limited to 3,000 partici-
pants. AIDS TREATMENT NEWS will attend the conference and parti-
cipate in panel discussions of treatment access for minority com-
munities. For information, write Ms. Edith Ross, National
Conference on HIV Infection and AIDS, TASCO Associates Inc., 4733
Bethesda Avenue, Suite 725, Bethesda, MD 20814.
*****
COMPUTER SYSTEM RECOMMENDATIONS FOR COMMUNITY-BASED RESEARCH
ORGANIZATIONS
by John S. James
On July 7-9 a major conference on community-based research,
sponsored by the Community Research Initiative of New York and
the County Community Consortium of San Francisco and funded by
the American Foundation for AIDS Research (AmFAR) and NIAID,
brought together representatives of community-based research
organizations, government agencies, and pharmaceutical companies.
(For more information about this conference, see articles in THE
NEW YORK TIMES, July 9, 1989 and THE WASHINGTON POST, same date.)
Plans were begun to set up electronic communication networks
among organizations interested in community-based research, using
conference calls, electronic mail, fax, and perhaps voicemail. A
number of groups are buying computer equipment at this time, and
it is important that a standard be suggested so that the groups
will purchase compatible equipment and software to facilitate
electronic mail and the sharing of text files and research data.
No official umbrella organization was formed at this time,
so there was no body to decide on a standard. However, it is
almost certain that the community-based trials organizations will
follow the standard already set by NIAID's Community Programs for
Clinical Research on AIDS. That is because many of the organiza-
tions involved have applied to that organization for funding, and
those who receive contract awards will be required to purchase
the specified computer equipment and software. (And from our own
background in computers, we can tell that the recommended stan-
dard was clearly well selected and appropriate for the task.)
The following specifications are from instructions to
community-based research organizations applying for NIAID grants:
"Equipment will be required for computer-to-computer elec-
tronic mail communications, report generation, and data
analysis. Specifically:
* MS-DOS/PC-DOS microcomputer IBM compatible PC/AT or
equivalent,
* Monochrome display,
* Minimum of 20 megabyte hard disk and 640 K memory; the
3.5" diskette drive is recommended,
* A 2400 baud modem and cable (to be specified by AIDS Pro-
gram),
* 132-column printer and cable (Epson LQ-1500 or
equivalent),
* Communications software to be specified by AIDS Program,
* WordPerfect word processing software (version 5.0 is pre-
ferred)."
The NIAID recommendations for communication software are not
final, but they will probably include MCI Mail and Lotus Express.
The modem specified will probably be any which is 2400 baud and
Hayes compatible.
Any organization buying computer equipment for the purpose
of community-based research should strongly consider following
the recommendations outlined above. But if you already have a
computer which is not compatible with these specifications, it
might be OK for a time, so there is no need to rush to buy new
equipment.
*****
AZT, ACYCLOVIR, AND THE CASE FOR EARLY TREATMENT
by Denny Smith
Regulatory issues are not the only obstacles to access to
care. Even when treatments are legally available, many patients
will not benefit because of lack of standards of care, and lack
of insurance reimbursement even in many cases when physicians
agree. Such problems are especially apparent on the issue of
whether antiviral or other treatments should be started before
symptoms have appeared or T-helper cell counts have fallen below
200.
For several years the San Francisco-based organization Pro-
ject Inform has developed a pioneering treatment strategy dealing
with HIV infection. The key premise of this strategy asserts
that HIV and AIDS are chronic, manageable conditions, not the
death sentences bemoaned by the media/medicine/government com-
plex. The prescription for action which grew from this premise
is 1) early testing for the presence of HIV or immune dysfunc-
tion, and 2) flexible antiviral or immune-boosting treatment
before the appearance of symptoms, possibly without waiting for
the approval of a promising treatment by the Food and Drug
Administration (FDA). Though much of the medical establishment
still dismisses or ignores it, the message proposed by Project
Inform is proving correct with the passage of time and with the
accumulation of pointless deaths. Health officials from govern-
ment and academia alike have been slow to advocate any plan of
action, or standard of care, to account for everyone with HIV,
symptomatic or not.
Even within the limits of FDA-approved drugs there are
treatment opportunities now available to seropositive asymp-
tomatic people to optimize their chances of staying healthy. Two
of them are AZT (Zidovudine) and acyclovir (Zovirax). Since its
initial approval by the FDA, AZT has remained the most prom-
inently discussed and intensively studied treatment for HIV and
related infections. At the recent International Conference on
AIDS in Montreal, for example, there were over 370 sessions which
discussed some aspect of AZT. Despite pervasive and often
unfounded mistrust of its efficacy, and despite its very real
toxicity and the limits of its antiretroviral activity, AZT has
proven to be of immune- preserving and life-prolonging usefulness
for many people with HIV. In addition, its capacity to reach the
central nervous system makes AZT useful for treating HIV neuro-
pathy, and the neurologic impairment sometimes called AIDS demen-
tia complex (ADC).
Side effects on the other hand, especially from the "high"
dose of 1200 mg daily, completely prevent many people from using
AZT. And for people who can tolerate the drug, long-term studies
indicate that prolonged use of AZT on the originally approved
dosing schedule often leads to unacceptable bone marrow suppres-
sion. Prolonged use may create AZT-resistant virus as well,
although laboratory tests have shown that isolates of HIV which
have become resistant to AZT are still susceptible to other
anti-retrovirals such as DDI and DDC. AZT-induced anemia can be
reversible if the drug is temporarily discontinued, or may be
managed with periodic blood transfusions, or may possibly be
prevented by also taking erythropoietin (EPO), a red cell growth
factor recently approved by the FDA.
There are HIV and AIDS-related treatments which appear to
enhance AZT. This has meant that the same anti-retroviral
potency might be achieved by combining such an agent with lower,
less toxic amounts of AZT. One possibility, reported in AIDS
TREATMENT NEWS #79, is the anti-clotting drug dipyridamole (Per-
santine). This is a prescription drug which extended the
activity of AZT in the test tube. But there is no evidence yet
that it will do the same, or do it safely, in people. The benefi-
cial combination best studied is AZT and acyclovir (reported in
AIDS TREATMENT NEWS #47, December 4, 1987, although much more
work has been published since then). Acyclovir is relatively non-
toxic and two European studies presented at the Montreal confer-
ence (Walger, P and others, abstract W. B. P. 318, and Weber, R
and others, abstract W. B. P. 321) suggested that AZT with acy-
clovir was superior to AZT alone. Acyclovir is also used to
suppress latent infections of the herpes viruses, including
herpes simplex, CMV, and herpes zoster, all of which have been
discussed as factors that may facilitate the growth of HIV.
One small but illustrative AZT/acyclovir study, conducted by
Harry Hollander and others at the University of California in San
Francisco, began with 20 HIV+ asymptomatic participants almost
two years ago. Ten of the participants were placed on 100 mg of
AZT (half the dose originally recommended by the manufacturer,
Burroughs-Wellcome) with 400 mg of acyclovir (twice the dose
recommended for treating initial herpes infections) five times
daily. The other ten participants received the same amount of
AZT, with 800 mg of acyclovir.
Three participants withdrew from the study (two after 10
weeks and the other after 38 weeks) because of subjective toxici-
ties (side effects that the patients told the physicians about,
but were not measured by laboratory tests). Unfortunately, three
other participants developed AIDS (at weeks 6, 8, and 62). These
six participants had entered the study with a lower median T4-
helper cell count than the other fourteen participants (210
versus 544), and the three who developed symptoms had each tested
positive with the first p24 antigen results. The remaining par-
ticipants continue to tolerate this drug combination without
serious side effects and remain asymptomatic. Three have had at
least one positive p24 titer, all below 25 pg/ml, and one parti-
cipant who began the study with low titer antigenemia now tests
negative. Helper cells have remained stable -- from a baseline
median of 503 to 588 at week 78.
The investigators concluded that the combination of AZT with
acyclovir is generally well-tolerated, with no statistical conse-
quences seen between the two acyclovir doses (although the three
participants who withdrew for subjective toxicity were all on the
higher dose). They added that larger trials are necessary to
determine the efficacy of the combination.
Nevertheless, some implications may be useful for people now
considering whether to treat an asymptomatic HIV infection, with
or without AZT. The combination was apparently better tolerated
by participants with a higher T4-helper cell count. Additionally,
progression to illness was uniformly seen in those participants
with the poorest laboratory predictors: depressed helper cells
and elevated p24 antigen levels. A reasonable conclusion, one
reflected by the Project Inform strategy, is that early interven-
tion in HIV infection is easier to cope with, and more effective
therapeutically, than applying an equivalent treatment after
helper cells have been seriously depleted or AIDS-related symp-
toms have developed.
This was not a placebo-controlled study, fortunately, since
there is ample epidemiological evidence that without any treat-
ment intervention most people with HIV will eventually progress
to illness. AIDS TREATMENT NEWS has spoken to many people who
are currently asymptomatic but watching their T4-helper cells
fall or p24 antigen level rise (if they're lucky enough to get
these tests). Many physicians would defend not treating these
asymptomatic patients, with a rationale mentioned below. Other
physicians are tending to treat earlier than the appearance of
symptoms by following such progression markers as thrombocyto-
penia and elevated beta 2 microglobulin, in addition to helper
cell counts and p24 antigen levels.
If most or all HIV infections eventually progress to ill-
ness, what is the basis for telling an asymptomatic seropositive
person to "leave well enough alone" or "if it ain't broke, don't
fix it"? And if the treatments now available for HIV are more
effective the earlier they are initiated, what is the point of
waiting until symptoms appear? There are objections which warn
of "wasting" the AZT option by offering it early to asymptomatic
people only to see them become anemic or reach resistance of the
drug, leaving them without an antiviral if symptoms develop.
This objection appears weak from two perspectives. For one, AZT
or other early treatment options will not have been wasted if
they forestall the progression to illness until another genera-
tion of anti-HIV drugs becomes available. Secondly, the option
may be wasted precisely by waiting until symptoms appear, when
drugs of all kinds are more difficult to tolerate and less potent
against the immune deficiency.
If acyclovir or other agents can permit a decrease in the
dosage of AZT, then many more people with HIV may have access to
the only approved HIV treatment. And preliminary results of a
large NIH study indicate that survival rates for patients on a
full dose of AZT were no better than for those taking a low dose,
without acyclovir as a factor. Whether AZT is absolutely more
effective when combined with acyclovir or dipyridamole is not
clear yet, but the originally recommended high dose of AZT
appears to be unnecessary in any case. We have also spoken to
many people who feel their physicians rely too heavily on AZT
because they are unwilling to consider other potential antivirals
such as dextran sulfate or hypericin which have not been approved
for the treatment of HIV and AIDS. When AZT is routinely
prescribed for someone who is not benefiting from it and who may
benefit from another promising, but unapproved, treatment, then
the letter of the law is obstructing the pursuit of the patient's
health. Hopefully, accessibility to various treatments of prom-
ise will increase with growing public political pressure.
The indications which earned AZT an FDA approval were a T4-
helper cell count below 200 or a diagnosis of AIDS. These could
be exactly good predictors of a poor response to AZT, in light of
the study described above and others. Many clinicians are
prescribing AZT earlier than the FDA indications, but many
insurance companies will only reimburse within the FDA parame-
ters. Which means that without an FDA/NIH-backed "standard of
care" which reflects the growing medical consensus, hundreds of
thousands of U. S. citizens known to be HIV+ may not receive AZT
or acyclovir or anything else, unless they can join an NIH drug
trial or until they become ill (and are less able to manage AZT's
toxicity). And for years, people who could not tolerate AZT were
offered no other alternative by the NIH or FDA until the recent
DDI announcement (see related article on DDI in this issue).
There were hundreds of drugs and drug combinations discussed
at the Montreal conference, one or more of which may someday be a
successful treatment for HIV. At present there is no NIH/FDA-
approved treatment plan for everyone with HIV, which leaves
thousands of doctors lacking authoritative leadership and a stan-
dard of care to apply to their HIV+ patients. Innovative physi-
cians have been staying abreast of current treatment options
without the guidance or permission of the national healthcare
bureaucracy, and their patients are lucky for it: they tend to
receive treatment, AZT or otherwise, before the appearance of
opportunistic infections and they find out about other options if
AZT ceases to be one. But people without innovative doctors will
not fare as well, and for them the vacuum of leadership is unfair
and perhaps deadly.
FOR MORE INFORMATION
Project Inform's HIV treatment strategy can be requested by
calling 800/822-7422 from outside of California, 800/334-7422
inside California, and 415/558-9051 from San Francisco or other
countries. Fact sheets are also available which discuss poten-
tial treatments for HIV, both approved and unapproved. The fol-
lowing periodicals, like AIDS TREATMENT NEWS, also report on new
developments in the treatment of AIDS and HIV infection.
*TREATMENT ISSUES discusses new and now-standard therapies
for HIV and related infections. Sent free of charge, but dona-
tion welcome. Write to GMHC, Dept. of Medical Information, 129
West 20th St., N. Y., NY 10011.
*BETA, (BULLETIN OF EXPERIMENTAL TREATMENTS FOR AIDS) offers
thorough coverage of anti-HIV drugs. Published by the San Fran-
cisco AIDS Foundation, three issues have appeared in the last
year. Call 415/863-2437.
* AIDS/HIV EXPERIMENTAL TREATMENT DIRECTORY, published by
the American Foundation for AIDS Research (AmFAR) lists and
describes a wide spectrum of treatments currently in development
or in clinical trials. Call 212/719-0033.
*****
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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