Has Second Thoughts On AZT
By John Lauritsen
The New York Native
4 March 1991
results from a Veterans Administration (VA) study of AZT therapy
were presented on 14 February 1991 in Washington, DC, at a special
meeting of the Antiviral Drugs Advisory Committee of the Food and
Drug Administration (FDA). The findings indicated that early AZT
therapy conferred no benefits in terms of overall survival, and
might well be harmful to black and hispanic patients.
panic and consternation ensued-in the AIDS Establishment, among
"AIDS Activists", and in the stock market. The very next
day, shares of Wellcome Plc (the parent company of Burroughs-Wellcome,
the manufacturer of AZT) fell more than 10 percent, based "on
market worries about FDA approval stemming from an article in the
New York Times." (Reuter, 15 February 1991) A well-orchestrated
campaign of flak began. Immediately the National Gay & Lesbian
Task Force, the National Association of Black and White Men Together,
and the National Minority AIDS Council issued press releases attacking
the validity of the VA study.
a report on the two-day meeting of the Antiviral Drugs Advisory
Committee, which I attended:
The first day
of the meeting, Wednesday 13 February, was devoted to the question
of surrogate markers-various blood tests which might be used to
evaluate the efficacy of experimental drugs, in lieu of more traditional
measures, such as survival or prevention or amelioration of illness.
This concern reflects pressure being put on the FDA to provide a
shortcut for new drug approval-to forego the usual testing procedures
for efficacy and safety. To date, the only federally approved "AIDS"
drug is AZT, which many "AIDS" patients are unable to
take, owing to the drug's toxicities. Other nucleoside analogues,
like DDI and DDC, are waiting in the wings. AIDS organizations and
self-proclaimed "AIDS activists" are now demanding that
the FDA approve these drugs on the basis of what is already known
about them, which is not much. If a magic surrogate marker could
be found, then a drug could be evaluated without performing placebo-controlled
trials, which necessarily take time. In effect, the "activists"
are calling for an end to drug regulation, which would mean a return
to the marketplace anarchy of the 19th century, when
deadly patent medicines and poisonous food additives were sold without
constraints as to advertising, labelling, or anything else.
In brief, various
presentations indicated that the CD4 or T4 test is the only marker
to have any predictive value for a patient's prognosis, and that
it is not all that good. The CD4 test was described in such terms
as "a partial marker". A certain amount of nonsense was
spoken about how AZT's benefits were reflected in temporary rises
in CD4 counts, but that AZT's benefits might somehow went beyond
CD4 counts. All this was pretty nebulous.
The most absurd
moment of the CD4 talks occurred when a slide was shown depicting
a patient's CD4 counts. The line was roughly horizontal until he
was given AZT, at which point- ZINGO! -- the line shot sharply upwards.
And then-ZONGO! -- the line immediately shot right back down again
to where it had been before. It looked like a horizontal line interrupted
by a highly-elongated upside-down V. And this, presumably, was meant
to show the benefits of AZT therapy.
In fact, temporary
rises in CD4 counts following the initiation of AZT therapy may
represent a well-known rebound phenomenon, and may not be good for
the patient at all. The molecular biologists Peter Duesberg and
Bryan Ellison explain it in the following way:
The other reason
for an apparent benefit of AZT lies in the observation that many
patients on this drug experience short-term increases in their immune
system cells. This, however, is a temporary pseudo-benefit; when
the body is initially exposed to any toxin that depletes its blood
cells, a compensatory reaction begins to produce large quantities
of new blood cells to replace the poisoned ones. The temporary increase
in all blood cells, including immune cells, is likely to be the
result of the body's reaction to AZT, which later proves futile
in the continued presence of the drug.(1)
One thing Wednesday's
meeting did was to lay to rest, once and for all, the P-24 antigen
test, which for several years has been used to claim benefits for
AZT. The P-24 antigen test is now regarded as useless, and not a
word was said in its defence. It means nothing at all.
The main focus
of the meeting on Thursday 14 February was Veterans Administration
Cooperative Study 298, whose preliminary findings were presented
by John Hamilton, MD. This study involved 338 HIV-positive individuals
whose T4 cells were in the range between 200 and 500 and who showed
some "symptoms or signs of HIV infection", including thrush,
oral hairy leukoplakia, zoster, unintentional weight loss of 10%
or more, unexplained persistent diarrhea, fever (100.5 degrees Fahrenheit),
night sweats, fatigue, dermatitis, or lymphadenopathy. According
to "risk group" category, 65% were gay men, 15% were intravenous
drug users, and 8% were both gay men and intravenous drug users.
Ethnically, 65% were white and 35% were black or hispanic. Patients
were enrolled into the study as early as January 1987 or as late
as January 1990.
were randomized into two treatment arms: the first (early treatment)
received 1500 mg. of AZT per day; the second (later treatment) received
placebo followed by AZT at the point where their CD4 count fell
below 200 on two successive occasions.
his overall conclusions twice-at the beginning of his talk, and
then again at the very end. His first statement of conclusions is
as follows (verbatim):
delayed progression to AIDS, as compared to later treatment. But
no benefit for either treatment arm was detected for survival or
the combined clinical endpoints of AIDS and death. Early zidovudine
resulted in transitory benefits in whites and neutral or harmful
effects in black and hispanic patients.
At the end
of his talk, Hamilton expanded his conclusions somewhat, as follows
(verbatim): We found that early zidovudine therapy delayed the progression
of AIDS. We also found that survival was comparable in the two treatment
groups. That is, no benefit-no detectable benefit. We found that
early zidovudine resulted in transitory benefits in whites and neutral
or harmful effects in black and hispanic patients. And we conclude
that further studies are mandatory in minority populations.
I made the
two brief transcripts above from listening dozens of times to the
tape I made of Hamilton's talk. They are, word for word, what he
said. I emphasize this because reports on Hamilton's talk have strangely
distorted, or neglected to mention, the conclusions that he himself
presented. For the record, there they are.
the toxicities of AZT treatment, all of which were found more often
in the early treatment group.Comparing early vs. later, more patients
on early zidovudine: were anemic, were neutropenic, had nausea and
vomiting, had diarrhea, had central nervous system abnormalities,
and had headaches. In response to questioning, Hamilton said that
transfusions were given when necessary. (See Table 1 below)
Not only did
AZT not confer any benefit in terms of survival, a slightly higher
proportion of patients died in the early treatment group (14%) than
in the later treatment group (11%). One astounding finding was that
in the early AZT group, 10 patients (6%) died without ever progressing
to CDC-defined "AIDS", whereas none of the patients in
the later AZT group did so. One must ask, then, what these patients
died from, if not from "AIDS"; and the answer is that
they probably died, at least in part, from AZT poisoning. It would
seem a dubious benefit to take a drug that will prevent you from
progressing to "AIDS" by killing you first. (See Table
By far the
most controversial finding was the possibility that AZT treatment
might be more harmful to black and hispanic patients than to whites.
Among the minority patients, the death rate was significantly much
higher in the early treatment group (14%) than in the later treatment
group (2%). One can only speculate as to why there should be ethnic
differences in the response to AZT treatment. But, at least for
the patients in this study, the differences appear to be real.
presentation a number of talks were given by people who are, officially
or unofficially, in the Burroughs-Wellcome camp: Margaret Fischl,
Paul Volberding, Stephen Lagakos, Sandra Nusinoff Lehrman, Terry
Creagh-Kirk, and others. Nothing any of them said was particularly
memorable or relevant. Paul Volberding discussed Protocol 019 in
a desultory way, striving to downplay the toxicity of AZT. Margaret
Fischl dismissed AZT's toxicities by showing slides analyzing various
toxicities in terms of "rate per 100 person years", whatever
exactly that meant-no one asked her to explain. Stephen Lagakos'
talk consisted of meaningless generalities, and he showed slides
with handwritten words on them; one slide, which attempted to explain
why the pro-AZT studies (016 and 019) differed from the VA study,
gave as a possibility, "016/019 data spurious?", which
at least caught my attention. Terri Creagh-Kirk, who was supposed
to talk for half an hour, spoke for only a couple of minutes. Other
Burroughs-Wellcome presenters whizzed through a series of slides
that apparently had something to do with survival.
was faced with the problem of damage control. It was incumbent on
them to say something in response to the findings of the Veterans
Administration. But without any idea what to say, all they could
do was talk. Which they did. More than one person fell asleep.
An open public
hearing followed the presentations. The first speaker was Wayne
Greaves, MD, an infectious disease specialist at Howard University
and a consultant to the panel. He said he was disturbed by the findings
of the Veterans Administration study, which indicated that early
AZT treatment might have no benefits, or might be harmful for minorities.
I was the second
speaker. Since I had only five minutes to make my case, I decided
to pull no punches. The audience of several hundred people listened
intently to what I had to say, though I found out later from a young
man in the FDA that some of his superiors were red in the face from
rage at what I was saying. (See text of speech.)
The third speaker
was Mark Harrington of ActUp New York, who said that for black and
hispanic people, the cry should now be: "Ten years, one billion
dollars, no drug."
a closed session of discussion among the panel members. For the
physicians, the question was posed, whether they would change their
practices regarding AZT for asymptomatic HIV positives, based on
the findings of the VA study. Wayne Greaves said that they "cannot
sweep the issue under the rug." Greaves said, "I will
tell them the data contradict earlier studies, that early AZT therapy
may not be useful and may even be harmful to minority patients."
Greaves questioned the propriety of the current "Living With
HIV" campaign sponsored by Burroughs- Wellcome.
a gay physician from California, said he would not routinely prescribe
AZT for asymptomatic HIV positives, that he would have long discussions
with them first, pointing out the possibilities that AZT might have
no benefits or even be harmful. He said it was his "gut feeling
that AZT may be poison for black people."
a pediatrician at Columbia University College of Physicians and
Surgeons, expressed a key sentiment of the panel members: "These
are very disquieting results. We don't know where we stand."
of the Harvard Medical School said she considered Dr. Greaves concerns
to be important, and she commented on the inappropriateness of the
Burroughs-Wellcome campaign. She discussed the difficulties of conveying
the uncertainties of AZT's benefits to practising physicians, who
typically receive most of their information from "detailmen"
(salespeople for the pharmaceutical companies).
a San Francisco physician, pointed out that the VA study had been
carried through to completion-it had not been prematurely terminated,
as had all of the studies used for the approval of AZT. It was questionable
to prescribe AZT for asymptomatic patients, he maintained, in the
absence of any survival benefits. The findings from Protocol 019,
discussed last year, merely showed the annual progression rate to
AIDS being cut from 4% (without treatment) to 2% (with AZT); either
way, the vast majority of patients did not develop AIDS. He said
patients have a right to know that different results are coming
from studies done by different institutions.
said he would not change his policy with regard to AZT, because
he has never prescribed AZT based only on HIV status and CD4 counts.
David Ho said,
"AZT is not a great drug." In light of the budget crisis,
he advocated developing more and better drugs, rather than doing
any more research on AZT.
impression of the VA study is that, while it is not definitive,
it is good, honest, competent research, which deserves to be taken
seriously. The tables that John Hamilton showed in his presentation
were clear and meaningful, and were acceptable by the standards
of professional research. Hamilton scrupulously indicated the confidence
intervals for his data, and let the audience know when caution in
interpretation was called for.
to the VA study, the research used to claim benefits for AZT has
consistently been bad. In my book, Poison By Prescription: The
AZT Story, I go into a detailed analysis of the Phase II trials(2),
on the basis of which the FDA approved AZT for marketing, and the
major AZT survival study(3). Both studies can fairly be described
as not just sloppy, but fraudulent.
by Paul Volberding and Stephen Lagakos on Protocol 016(4) (AZT treatment
for asymptomatic HIV positives), which was the basis for the FDA
decision to approve AZT for HIV positives with T4 counts below 500,
is unmitigated garbage. The description of methodology is inadequate
and incomprehensible. None of the tables in their report are acceptable;
none of them make sense. None of their tables even show bases-looking
at one, it is impossible to tell either what people or how
many people the table is based on. Nor is this information to
be found elsewhere in their report. In fact, there are really no
hard data at all in the report, just a lot of unjustified generalizations
and meaningless numbers and verbiage.
The press release
issued by the National Gay & Lesbian Task Force (NGLTF), "Government
Study on AZT and People of Color Questioned by NGLTF", is a
disgrace. It attacks the VA study from a standpoint of total ignorance-of
the study itself, of statistics, and of research techniques. I called
the two contacts listed on the press release: Belinda Rochelle and
Robert Bray. Rochelle refused to answer "difficult questions",
and said I should talk to the press officer, Bray. When I said that
someone listed as a "contact" ought to be willing to answer
questions, she responded that she was a "lesbian of color",
and how dare anyone question her qualifications, at which point
she hung up. Bray, on the other hand, was more than willing to talk,
but incapable of giving straightforward answers to questions. After
giving him several opportunities to describe the qualifications
of himself or anyone else at NGLTF to evaluate statistical research,
and instead being subjected to an endless stream of irrelevant rhetoric,
I gave up. Clearly Bray himself knows absolutely nothing about statistics.
Although Bray denied that the press release was pro-AZT, there is
no other way to interpret it. Why has NGLTF chosen to attack the
VA study, when it has never questioned the really bad research that
has been used to claim "benefits" for AZT-the Phase II
AZT trials or Protocol 019, for example? Why should NGLTF strain
at a gnat, and swallow a camel? NGLTF ought to be doing everything
it can to stop the pharmacogenocide of gay men; instead, it is collaborating
in that genocide.
Burroughs-Wellcome Strikes Back
lost no time in trying to counteract unfavorable publicity arising
from the results of the VA study. A "Dear Doctor" letter
was sent out to physicians on 15 February 1991, signed by Sandra
Nusinoff Lehrman, Head of the Department of Infectious Diseases
at Burroughs-Wellcome. Following is the text:
The FDA Antiviral
Drug Products Advisory committee met February 14, 1991, to review
new data on the efficacy and safety of RETROVIR brand zidovudine.
This data [sic] reaffirmed the usefulness of RETROVIR in treating
individuals who are at less advanced states of HIV infection. These
data are described in the attached "Talk Paper" issued
by the FDA following this meeting.
It is possible
that some lay press coverage may cause patients to have questions
about therapy with RETROVIR. For this reason, we have sent you a
copy of the FDA "Talk Paper," which may be of value in
responding to patient inquiries. A copy of the RETROVIR prescribing
information is enclosed for your reference.
The FDA "Talk
Paper", dated 14 February 1991, reads as though it had been
drafted by Burroughs-Wellcome. A more false and distorted version
of the meetings could hardly be imagined. The first sentence claims
that the committee "reaffirmed the drug's usefulness in treating
individuals who are at less advanced stages of infection with the
AIDS virus." Then the "Talk Paper" goes on to summarize
the VA study in such a way as to obliterate the most important finding:
that AZT treatment conferred no benefit in terms of survival. To
fully appreciate the dishonesty of the FDA "Talk Paper",
compare Box A, in which John Hamilton summarizes the results of
the VA study, with Box B, in which the FDA falsifies the same findings
by eliminating most of what is unfavorable to AZT.
It should be
clear that Burroughs-Wellcome is a thoroughly unscrupulous company,
and that collusion between the FDA and Burroughs-Wellcome is as
strong as ever. *
(6% vs. 0%) is significant at the 99.99% confidence level.
Cooperative Study 298
(28% vs. 13%) is significant at the 99% confidence level.
(14% vs. 2%) is significant at the 98% confidence level.
Cooperative Study 298
OF VETERANS ADMINISTRATION COOPERATIVE STUDY 298 AS PRESENTED BY
JOHN HAMILTON WASHINGTON, DC -- 14 FEBRUARY 1991
1. Early zidovudine
therapy delayed the progression of AIDS.
was comparable in the two treatment groups. That is, no benefit-no
detectable benefit [to early zidovudine treatment].
3. Early zidovudine
resulted in transitory benefits in whites and neutral or harmful
effects in black and hispanic patients.
studies are mandatory in minority populations.
OF VA STUDY 298 FDA "TALK PAPER" 14 FEBRUARY 1991
One study presented
to the committee was conducted by the Veteran's Administration.
Preliminary results from this study, in general, confirmed that
earlier use of zidovudine was beneficial for delaying the onset
of AIDS. However, the study when analyzed by various demographic
factors also indicated that zidovudine's effects might vary significantly
among different patient groups. For unknown reasons, among the African-American
and Hispanic patients in the study, those who received zidovudine
at a later stage of their infection may have fared better than those
who received earlier treatment with the drug. The results regarding
the outcome of African-American and Hispanic patients were not conclusive,
however, and thus no definitive changes in practice were deemed
appropriate by the committee.
1. Peter H.
Duesberg and Bryan J. Ellison, "Is the AIDS Virus a Science
Fiction?: Immunosuppressive Behavior, Not HIV, May Be the Cause
of AIDS", Policy Review, Summer 1990.
A. Fischl et al., "The Efficacy of Azidothymidine (AZT) in
the Treatment of Patients with AIDS and AIDS-Related Complex",
New England Journal of Medicine, 23 July 1987.
3. Terri Creagh-Kirk
et al., "Survival Experience Among Patients With AIDS Receiving
Zidovudine [AZT]: Follow-up of Patients in a Compassionate Plea
Program", Journal of the American Medical Association, 25 November
4. Paul A.
Volberding and Stephen W. Lagakos, et al., "Zidovudine in Asymptomatic
Human Immunodeficiency Virus Infection: A Controlled Trial in Persons
with Fewer than 500 CD4-Positive Cells per Cubic Millimeter",
New England Journal of Medicine, 5 April 1990.