FDA HAS SECOND THOUGHTS ON AZT
By John Lauritsen
The New York Native 4 March 1991
Preliminary 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.
Widespread 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
Following is 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
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
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
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 Veterans Administration Study
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.
The patients 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
Hamilton stated 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):
Early zidovudine 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
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.
Hamilton described 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)
Death by Treatment Group
Base: Total Patients
168 = 100%
170 = 100%
19 = 11%
23 = 14%
Died without progressing to "AIDS"
0 = 0%
10 = 6%*
*Difference (6% vs. 0%) is significant at the 99.99% confidence level. Veterans Administration Cooperative Study 298
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 2 below)
Key Endpoints by Treatment Within Ethnic Group
Base: Total Patients
Progressed to "AIDS"
*Difference (28% vs. 13%) is significant at the 99% confidence level.
**Difference (14% vs. 2%) is significant at the 98% confidence level.
Veterans Administration Cooperative Study 298
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.
Non-responses From Burroughs-Wellcome
After Hamilton's 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
Clearly Burroughs-Wellcome 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,
Next followed 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
Neil Schram, 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."
Anne Gershon, 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."
Deborah Cotton 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
Donald Abrams, 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
John Hamilton 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.
My overall 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.
In contrast 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.
The report 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.
Aftermath: Burroughs-Wellcome Strikes Back
Burroughs-Wellcome 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.
Box A: Overall Conclusions of Veterans Aadministration
Cooperative Study 298 as Presented by John Hamilton
Washington, DC - 14 February 1991
1. Early zidovudine therapy delayed the progression of AIDS.
2. Survival 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.
4. Further studies are mandatory in minority populations.
Box B: Distorted Version of VA Study 298 FDA "Talk Paper" 14
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.
2. Margaret 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 1988.
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.