Document:AZT Front 2
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New York Native
16 January 1989
In my previous article, "On the AZT Front: Part One", I concluded there is no scientifically credible evidence that AZT has benefits of any kind. Nevertheless, the popular media and medical journals are filled with statements to the effect that AZT has been shown to "extend life". This claim appears to be based on three bodies of "research":
First, there are the Phase II ("Double-Blind, Placebo-Controlled") AZT trials, conducted by the Food and Drug Administration (FDA) (1). In "AZT on Trial", I demonstrated that the FDA-conducted trials of AZT were not merely sloppy, but fraudulent, and that government approval of AZT was therefore improper and illegal.
Second, there are a number of abstracts which were presented at the AIDS conference held in Stockholm last summer. These consist of unpublished data derived from uncontrolled observations of small numbers of patients; for scientific debate, such reports, in the context of a conference where 3,200 abstracts were presented, are no better than anecdotal evidence.
Third, there is a major study of AZT, "Survival Experience Among Patients Wtih AIDS Receiving Zidovudine [AZT]", which has just appeared in the 25 November 1988 issue of the Journal of the American Medical Association (JAMA) (2). The purpose of this article is to show that this is very bad research, on which no credence of any kind should be placed.
The AZT Philosophy
The toxicities of AZT are firmly established. The drug is cytotoxic (i.e., it kills healthy cells); it destroys bone marrow; it causes severe anemia, headaches, nausea, and muscular atrophy; it damages the kidneys, liver, and nerves; and it inhibits DNA synthesis. The consequences of AZT toxicity should not be taken lightly. When DNA synthesis is blocked, new cells are not formed; cells do not develop – the life process in effect comes to a halt. Joseph Sonnabend, a prominent New York City AIDS researcher and physician, expressed it succinctly: "AZT is incompatible with life."
The question then arises: How can physicians justify prescribing this drug, whose benefits are so dubious and whose side effects are so terrible? Physicians are supposed to honor the Oath of Hippocrates, the cardinal principle of which is to act for the good of the patient, doing nothing that is harmful. But AZT is harmful. In the words of molecular biologist Peter Duesberg, "AZT is pure poison."
I suggest that the answer to this paradox can be found in the common belief that AIDS is "invariably fatal", that people with AIDS (PWAs) have only a few months to live. The JAMA article expresses this cornerstone of the AZT philosophy: "AIDS is a terminal disease." (3) Physicians who accept this premise may be able to prescribe AZT in good conscience: since PWAs are considered to be facing imminent death, the cumulative toxicities of AZT can be ignored, and AZT therapy can be rationalized as offering the hope of "extending life" for a few months (though there is no factual basis for even this modest claim).
There are several objections to the AZT philosophy. Most important is the fact that AIDS is not invariably fatal. There are PWAs who have survived for many years, who are leading full and productive lives, and who appear by all rational criteria to be recovering. And why not? What other disease is "invariably fatal"? I imagine that future medical historians, looking back on the present, will regard many or even most of the AIDS fatalities as iatrogenic – caused by medical treatments rather than by AIDS itself (whatever exactly "AIDS" is). It is noteworthy that long-term survivors, almost without exception, have avoided toxic chemotherapy (like AZT) and have opted for strengthening their bodies through a healthy lifestyle: exercise, good nutrition, rest and stress reduction, and avoidance of harmful substances (including cigarettes, alcohol, poppers, and all other "recreational drugs"). PWAs deserve a chance to recover. With AZT there is no chance.
AZT is now being tested on healthy people who merely have antibodies to HIV, which according to Duesberg is a typically harmless retrovirus. Members of the AIDS establishment, like William Haseltine, have advocated giving AZT to seronegative members of "high risk groups" (meaning us, gay men). To do so would be tantamount to genocide.
The poisoning of sick and healthy people alike with AZT is a cruel hoax, inasmuch as there is still no hard scientific evidence to support claims of AZT benefits, least of all in the latest "research" emanating from Burrough-Wellcome.
The JAMA Article
When the Phase II AZT trials were abruptly terminated in September 1986, it was anticipated that government procedures would require about sic months before AZT could be marketed for prescription use. An interim measure was established, whereby AIDS patients who had previously experienced an episode of pneumocystis carinii pneumonia (PCP) could receive a "compassionate plea" basis under a "Treatment Investigational New Drug (IND)" exemption, the rationale being that these patients were "at substantial risk of early death" and AZT would benefit them, presumably by preventing further attacks of PCP. The JAMA article, "Survival Experience Among Patients With AIDS Receiving Zidovudine [AZT]", reports on 4,805 patients who received AZT under this IND program.
Collaborating in the study were the National Institute for Allergy and Infectious Diseases, the National Cancer Institute (NCI), the Food and Drug Administration (FDA), Burroughs-Wellcome (the manufacturer of AZT), and Biospherics Inc. (apparently a private research company located in Beltsville, Maryland). It was hoped that the program wouljd provide "an opportunity to gather data regarding longer-term experience with zidovudine" in a population that was larger and more varied than that in the Phase II trials.
Children were totally, and women almost entirely, excluded from the study. The average age of the 4,805 subjects was 37 years; 97% of them were male, 87% were "homosexual or bisexual", and 79% were "white, not Hispanic". It is stated that "Many patients reported more than one AIDS risk behavior" – in other words, many of the gay men were also intravenous drug users – and yet this overlap has been suppressed in the JAMA article's Table 1 (4). (See Exhibit 1.)
Each patient was initially dosed with 200 mg of AZT every four hours around the clock. However, provision was made to lower the dosage or to discontinue dosage temporarily, in the case of "adverse effects". Approximately 1,500 physicians cooperated in the study by enrolling or following up patients. These doctors were told, when they agreed to participate, that they would be expected to supply information on their patients on a regular basis. Before September 15, 1986, patient information came in automatically, since doctors needed to provide it in order to obtain further supplies of AZT for their patients. After September 16, 1986, data collection became more haphazard, though the investigators tried to continue obtaining data through telephone contact and mailed questionnaires.
Missing: 1,120 Patients
In the interests of fairness, I called Burroughs-Wellcome, to hear their explanations for what appear to be incompetence, dishonesty, and fraud connected with this research. I spoke briefly with Terri Creagh-Krik, MS, the principal author of the JAMA article, and at greater length with David W. Barry, MD, also an author of the article and Burroughs-Wellcome Vice President in charge of research. I'll say this much for Burroughs-Wellcome: at least their people are courteous and willing to talk – in sharp contrast to the NCI and the CDC, where military security measures prevent unauthorized reporters (whether from the Native or the BBC) from talking to the so-called "scientists". I found the explanations of the Burroughs-Wellcome researchers to be completely unacceptable, but at least they have some respect for dialogue. In an atmosphere of intensifying censorship and totalitarianism, this is appreciated.
For some reason, the Burroughs-Wellcome researchers set their sights on reporting 44 week (or 10 month) survival for the AZT recipients. Unfortunately, by this time they had completely lost control of the study. It had bombed. Incredible as it sounds, nearly one out of four subjects (23%) had been lost. The researchers did not know whether 1,120 patients were even dead or alive – and if alive, whether or not they were still taking AZT. (See Table A. Please note that in this article, the lettered tables are my own, whereas the "Exhibit" tables are reproduced from the JAMA article, with my own comments at the bottom.)
|Base:||4,805 = 100%|
|Survival Status After 44 Weeks...|
|Reported alive||2,838 = 59%|
|Reported dead||847 = 18%|
|Unknown (i.e. lost)||1,120 = 23%|
If one looks only at the 1,043 patients who were enrolled in the first four weeks of the IND program, the record of the Burroughs-Wellcome researchers is even more appalling. No fewer than 734 (70%) of these patients had been "lost". (See Table B.)
|Total Patients Enrolled in First 4 Weeks|
|Base:||1,043 = 100%|
|Survival Status After 44 Weeks...|
|Reported alive||309 = 30%|
|Unknown (either dead or lost)||734 = 70%|
Terri Creagh-Kirk explained that they had tried hard to find out what had happened to the 1,120 patients who were lost (letters, telephone calls, etc.). I am not impressed. Professional researchers are expected to anticipate problems before they occur. To lose track of nearly one-quarter of an entire study group is colossal incompetence, for which there can be no excuses. If a professional researcher ever found himself responsible for such a disaster, he would probably be contemplating two courses of action: exile or suicide. But not the intrepid Burroughs-Wellcome researchers – they decided to resort to some statistical hocus-pocus, in order to pretend that the 1,120 patients hadn't really been lost after all.
A Guess is a Guess is a Guess
Of the 4,805 patients, 2,838 (59%) were reported as being alive after 44 weeks – if we assume that all of the "lost" patients had died, then 59% would represent the lowest possible survival estimate. On the other hand, 3,958 patients (82%) were not reported to have died after 44 weeks – if we assume that all of these patientse were indeed alive, then 82% would represent the highest possible survival estimate. The true percent surviving presumably lies somewhere in between 59% and 82%. The Burroughs-Wellcome researchers used some kind of statistical projection technique in order to estimate – or guess, as it were – what the true percent surviving would be if all the data were in and the 1,120 patients had not been lost.
This is an abuse of statistics. Projection techniques are not a form of magic. The fact is that the Burroughs-Wellcome researchers lost control of their study. They failed. And there is no form of statistics that can remedy this, any more than it can put spilt milk back in the bottle or put Humpty Dumpty back together again. Terri Creagh-Kirk said that the Kaplan-Meier Product Limit method had been used to estimate the percent surviving after 44 weeks. However, the Kaplan-Meier Product Limit method is not mentioned in the JAMA article, which refers to a "LIFETEST procedure" and to "standard survival techniques", whatever those might be.
After all the talk about the Kaplan-Meier Product Limit method and/or the LIFETEST procedure, it is something of a letdown to find that the authors may have obtained their 73% estimate by a simpler method. They state that if all the "lost" patients were still alive (and on AZT), "the survival at 44 weeks could be estimated to be as high as 82%". On the other hand, if all of the "lost" patients had "died 15 days after the last report was received [a peculiar assumption, but let it pass]", the "survival could be estimated to be as low as 64%". At this point, they add together the two percents (82% + 64%) and divide by two, thus obtaining – Eureka! – an average of 73%. Having performed elementary school arithmetic, they write: "The true survival falls somewhere between these two points, presumably most closely reflected by the overall point estimate of 73%." (5)
Whatever projection techniques were used, the authors of the report reach the conclusion: "Overall survival at 44 weeks after having started therapy was 73% (± 2.1%) (Fig. 12)". (6) At this point I wish to emphasize two things. First, the use of the word, "was". The authors did not write, "was estimated to be", which would have been honest; they wrote, "was", which is a lie. Unless specified otherwise, a percent is always assumed to be an actual percent. Second, the confidence interval of ± 2.1% is impossibly low, considering that it must reflect not only the error inherent in a projection trying to compensate for the loss of 23% of the total sample, but must reflect sampling variation as well. (See Exhibit 2.)
On the first page of the article it is stated: "A detailed description of data management and tracking procedures is beyond the scope of this article and will be published elsewhere." When I talked to Creagh-Kirk, she said she had just begun to write this "description". I look forward eagerly to reading it, but in the meantime we already know enough to reject and repudiate what the Burroughs-Wellcome researchers have done. They have deliberately and fraudulently presented an estimate as though it were an actual percent (derived by dividing an actual number by an actual total). That these people intended to deceive is evident from the statement in the abstract at the beginning of the JAMA article: "Overall survival at 44 weeks after initiation of therapy was 73% (± 2.1%)." (7) Nowhere in the abstract is there even a hint that the 73% figure is merely an estimate. It goes without saying that an abstract should accurately summarize the main article, since many people never read beyond the abstract.
David Barry claimed that Burroughs-Wellcome had no control over these matters, that they were dictated by the editorial board of JAMA. This is nonsense. It is not for JAMA editors of anyone else to decide that a guess is just as good as an actual statistic. Nor is it for them to decide whether or not tables and charts need to have sufficient annotation that they will be meaningful and truthful.
Since the focus of the study was on survival versus death, it is obviously important to know the causes of death for the 847 patients who are known to have died. The inadequacy of the information obtained reveals once again the incompetence of the researchers. At the very beginning of the study, the physicians ought to have been told that they would be expected to provide complete and accurate information on their patients. Therefore it is disconcerting to learn that the single most frequent cause of death was described as "unspecified" (16.4%). (See Exhibit 3.) And if we add together "unspecified" (16.4%) with "AIDS, not classified" (11.2%), we find that fully 27.6% of the deaths were described in unacceptably vague and meaningless terms. Further, we observe that there are no fewer than three "causes" related to pneumonia, which might or might not be the same thing: "pneumocystis carinii pneumonia" (13.8%), "respiratory arrest" (7.2%), and "pneumonia unspecified" (6.0%); together these three add up to 27% (8). A professional analyst would have "netted" together the three forms of pneumonia – showing the "net" total on the table, with the three specific forms of pneumonia underneath the net. David Barry did not know what "netting" meant, although it is an elementary statistical procedure, and one which is essential to produce meaningful tables.
Even if one accepted the 73% survival at 44 weeks after initiation of AZT therapy, one would still have to ask whether this survival rate is really very good. The authors of this study believe that it is, and state: "The survival estimate for this treated cohort is significantly above that described in previously reported natural history cohorts." They then proceed to make a number of specious comparisons to:
- An old (1981-1985) New York City cohort where the median cumulative survival was estimated to be 10.5 months.
- A fragment of the CDC's AIDS statistics, focussing only on cases diagnosed in the first six months of 1986.
- A study of one year [not 44-week] survival for hemophiliacs [a congenitally sickly population] with AIDS.
- A "prospective" study of a San Francisco cohort showing only 50% surviving beyond 11.2 months [not 44 weeks or 10 months]. This so-called "prospective" study is merely an abstract presented at a June 1987 AIDS conference.
None of these "natural history" studies is at all comparable to the IND study reported on in the JAMA article. Besides which, there are numerous and major problems involved in attempting to make survival comparable: Do AIDS patients who take AZT have the same characteristics as those who do not take AZT? Probably not. Do PWAs on AZT receive the same patient management as PWAs who are not on AZT? Probably not. Are PWAs living longer now than they were a few years ago? They probably are (and this could be because patient management is better, or because PWAs being diagnosed now are not as sick as those being diagnosed several years ago). In addition there is the fact that about 50% of PWAs cannot tolerate AZT and have to be taken off the drug. What this means is that the stronger patients (taking AZT because they can tolerate it) and compared with the weaker patients (who cannot tolerate AZT). Obviously this is a strong bias in favor of AZT.
Speaking with a forked tongue, the authors of the JAMA article say:
The use of historical controls is intended simply to provide a reference point, and no attempt is made to make statistical comparisons between the natural history cohort and this population of zidovudine-treated patients. (9)
This caveat is definitely called for. Any such comparison would be invalid. Nevertheless, the JAMA article had no sooner appeared in print than the Burroughs Wellcome researchers rushed to the media to claim that AZT had extended the lives of the patients in the IND study. An Associated Press dispatch of November 25, 1988 reported that:
Nearly 5,000 people who took the AIDS-fighting drug once known as AZT survived at a much greater rate than those without it, say researchers for the medicine's maker.
According to the AP story, Terri Creagh-Kirk said that "records of people who were diagnosed with AIDS before zidovudine became available show only 50% survived past 11 months". This is a reference to the "prospective" San Francisco cohort study, a completely improper comparison. The disparity between the caveat in the JAMA article, and the subsequent statements made by the authors of the JAMA article to the media, suggests that these people intend to deceive.
It is disgraceful that the editors of JAMA allowed this garbage to be published. It is disgraceful that they permitted a dubious estimate to be palmed off as an actual survival statistic, and that they permitted false and misleading comparisons to be made. In no way does this study show that AZT "extends life" or is even slightly beneficial. The study demonstrates only how farcical are the peer-review standards of even the leading medical journals.
- ↑ Margaret A. Fischl, "The Efficacy of Azidothymidine (AZT) in the Treatment of Patients with AIDS and AIDS-Related Complex", and Douglas D. Richman, "The Toxicity of Azidothymidine (AZT) in the Treatment of Patients with AIDS and AIDS-Related Complex", New England Journal of Medicine, 23 July 1987.
- ↑ 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.
- ↑ Ibid, p. 3014.
- ↑ Ibid, p. 3013.
- ↑ Ibid, p. 3013.
- ↑ Ibid, p. 3012.
- ↑ Ibid, p. 3009.
- ↑ Ibid, p. 3012.
- ↑ Ibid, p. 3015.