Christopher S Tyler,
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We continue to bring up the issue of the Phase II AZT trials, upon which AZT was approved for human use, for good reason. Patient safety and drug efficacy are theoretically the leading reasons for doing drug trials whose veracity must be strictly maintained in order for these goals to be attained. Otherwise claims made by drug companies are worthless at best.We believe AZT was approved based upon a drug trial that is highly dubious.
Peter Flegg wrote: "Any fool can sit at a computer keyboard and pull out hundreds of references to toxicity associated with HIV therapies." Considering the information below, it is also apparent that 'any fool' (or fools) can produce a research trial to get approval for an anti-HIV drug.
information comes from documents released under the Freedom of
Information Act and analyzed by John Lauritsen (New York Native, March
30, 1992) and Peter Duesberg.
The AZT Phase II Trial's dramatic claim was that in the AZT group, only 1 participant died, whereas in the placebo group, 19 individuals died. The trial, which was supposed to be 24 weeks, was cut short for 'ethical' reasons--how could this miraculous drug be kept from the placebo group? At the time of termination only 15 patients (5% of the total) had gone full term, and 23 patients were treated for less than four weeks. The average trial time for all participants was about 17 weeks. The question arises, if this was a double-blind study, how did the researcher know to which groups the deaths belonged before the trial came to full term?
It should be noted that among the 4-month survivors of AZT, 30 could only be kept alive with multiple blood transfusion because their red cells had been depleted by AZT below survivable levels (Fischl et al 1987; Duesberg 1992). Thus, without life-saving transfusion 30 more AZT-recipients would have died from anemia.
Upon examination of the documentation released substantial flaws were found which confound the trumpeted results:
A document written by Ellen Cooper, the FDA Medical Officer who reviewed the New Drug Application for AZT, indicated that many serious violations of the "protocols" of the study had occurred in all of the centers.(1) The Boston center was so bad that an FDA investigator recommended that all data from the this center "be excluded from the analysis of the multicenter trial."(1)
However, a series of FDA meetings were held in order to decide what to do about the numerous violations of protocol, and in particular, about the Boston center. The decision was made to exclude nothing, to throw all of the bad data in with the good.
In October and November 1986 FDA Inspector Patricia Spitzig made a "For Cause Inspection" of the Massachusetts General Hospital clinical center. The inspector's findings are contained in her 76-page "Establishment Inspection Report" (EIR). The principal investigator at this center was Robert Schooley, MD (assisted by Martin Hirsch, MD; Dr. Ho [no first name cited], and Teri Flynn, Research Nurse). The "Monitor" was Ron Beitman, an employee of Burroughs Wellcome.
Spitzig found the following forms of improprieties in the Boston center:
"The current EI revealed numerous deviations... The observations listed on the FD- 483 included: Deaths (two, so far) and adverse reactions have not been reported to the IRB; undocumented Protocol deviations including: concomitant meds, subjects not meeting entrance criteria admitted (two); tests not performed as frequently as required by the Protocol; adverse reactions not reported as such on Case Report Forms ("CRF's"). There were changes made on photocopied CRF's usually with no explanation, date, or initials; significant observations were not addressed on CRF's by clinical investigator; some raw records could not be located and were explained to have been discarded. Accountability of the Study medication is inadequate; 87 bottles/containers shipped cannot be accounted for; Pharmacy kept the inventory and it does not correlate with shipping records; Study medication returned by subjects was not counted, stored properly, or signed off by the clinical investigator.(2)"
It should be explained that the Case Report Forms (CRFs) were the official recording forms for the study. What was written on the CRFs became "data" for the study. However, medical information on patients was also contained in medical records kept by private physicians, hospitals, and the clinical center at Massachusetts General Hospital, as well as in patients' diaries. For virtually every patient in the Boston center, FDA Investigator Spitzig found serious discrepancies between the medical records and what was entered on the CRFs.
INCORRECT LENGTH OF TIME IN STUDY RECORDED
Comparing the CRFs with medical records, FDA investigator Spitzig found that the CRFs often falsely indicated that patients had been in the study longer than they really were:
"Another general issue applying to a number of subjects in the Study is that a cursory review of their Case Report Forms would indicate that they had been on the Study longer than actually happened. Generally this is due to the fact that Study records continued to be generated even when the subject had been dropped from the Study for a period of two weeks to a month.
• Number 1053, [CENSORED] dropped out of the Study for two weeks from June 19th to July 3rd, and he was off the Study again on August 11 for a final time due to decreased white blood cell count. CRF were generated as though he were on the study through 9-8-86.
• Number 1057, [CENSORED] was on the Study for 13 to 14 weeks but the Monitor's Accountability Sheet indicates that he was on the Study for 16 weeks. The Case Report Forms showed that he last came to the Clinic during Week 14 and nothing was returned thereafter.
• Number 1008, [CENSORED] was off the Study for a month even though the Accountability Record indicates that he never left it. He was off the Study during the Week 6 visit. It is unclear if the Week 8th's medication was dispensed. In fact during Week 4 the Case Report Form states that he had pneumonia beginning July 7th and ending August 7th. And during the week four visit he was not dispensed any medication. In fact it appears that he was hospitalized then or soon after although the Case Report Forms do not state that he wa hospitalized. So he was off the Study medication for at least a month, but to view the Record of Dispensing of Medication to him, as an example, D-2 it appears that he was on the Study pretty regularly for 12 weeks.(2)"
CONCEALMENT OF ADVERSE REACTIONS
The rules of the study indicated clearly that all adverse reactions were to be recorded on the CRFs and reported immediately. Schooley et al. often failed to do so, especially if the patient was on AZT. In theory, the investigators were not supposed to know who was on AZT and who was on placebo, but there are many indications in Spitzig's report that they did know. It would have been easy to determine which medication a patient was on by glancing at blood test results: marked blood abnormalities could be found in nearly all of the AZT patients.
Spitzig wrote that the study rules stated, "ANY ADVERSE EXPERIENCE BY A STUDY SUBJECT IS TO BE REPORTED IMMEDIATELY BY TELEPHONE, FOLLOWED BY A WRITTEN REPORT." She added, "The IRB requirement that all adverse reactions be reported was not met. None of them were reported."(2)
From the standpoint of the study's "data", many serious adverse reactions were concealed by not recording them on the CRFs, even though they were mentioned in the patient's medical records.
• Patient #1008, on AZT, was hospitalized during the study, suffering from anemia, headache, dizziness, nausea, shortness of breath, fever, fatigue, abdominal cramps, chills, odynophagia, and severe anemia. None of these were listed as "adverse reactions" on the CRF. This patient later experienced "extreme postural lightheadedness and felt close to syncope" and was then transferred to the Emergency Ward, where he received a blood transfusion. "There was no mention of having received blood in the Case Report forms for this individual."(2)
• Patient #1012, who was on AZT, developed a severe rash. Although nurse Flynn "agreed that it should have been called an adverse reaction", it was not recorded on the CRF.(2)
• Patient #1053, on AZT, experienced high temperature, nausea, marked fatigue, paresthesia in the toes, and severe anemia; he received multiple transfusions; none of these were recorded on the CRF as being "adverse reactions".(2)
• Patient #1055, on AZT, suffered fatigue, nausea, and loss of appetite, and was hospitalized with a fever of 105 degrees; his CRF said he had experienced no adverse reactions.(2)
PATIENT #1009: FROM AZT TO PLACEBO
Before entering the study patient #1009 was suffering from severe anemia and headaches, for which he "was taking Tylenol every four hours without relief of symptoms." He had received a number of transfusions, the last one only a week before being entered in the study AS A PLACEBO patient on 29 May 1986. However, the record for his Week 1 visit on 5 June 1986 states that the patient "was still taking Azidothymidine as of this visit"!
In other words, patient #1009, who was already taking AZT and who was suffering from typical AZT toxicities, was illegally entered into the study. Patient #1009 was then assigned to the placebo group while continuing to take AZT. He dropped out of the study after being in it for less than a month, and died on 20 August 1986, two months after leaving the study. HE WAS THEN COUNTED AS A DEATH IN THE PLACEBO GROUP.(2)
VIOLATIONS OF PROTOCOL
Investigator Spitzig listed numerous violations of protocol for every patient in the Boston center. In general, tests were not performed that should have been, ineligible patients were entered into the study, records were kept badly, and patients took many concomitant medications.
For instance, patients in the study took the following drugs in addition to their test medications: Cefadroxil, Erythromycin, Acyclovir, Wacomil, Ranitidine (Zantac), Hydrocortisone Cream (topical), Benadryl, Dilantin, Stelazine, Xanax, Halcion, Colace, Compazine, Tylenol, Lomotil, Excedrin, Keflex, Streptomycin, INH (isoniazid), Ethambutol, Pyridoxine, and Lithium.
On 30 January 1987 an in-house FDA meeting was held "to consider whether or not to exclude the data from the Boston center, (Robert Schooley, P.I.) from the analysis of the AZT multi-center trial."(21) For some reason Patricia Spitzig was not present at the meeting.
No consensus was reached on whether or not to drop out the Boston center or drop-out individual patients. "It was finally decided that the situation would be presented to Dr. Young [Commissioner of the FDA] for his input. It was also agreed that a second meeting would be scheduled to discuss issues common to all the study centers e.g. prophylactic medication for OIs, dose reductions and discontinuations not recorded on the CRFs, poor screening of patients, etc."(3)
A final note about the AZT trial
mortality of 1/145 for the AZT group could not be maintained in the
follow-up study, which found the 'survival benefits" of AZT rapidly
declining after the original 4 months period. By 21 months, 42% of the
original AZT group had died and 35% of the control group, which by then
had also openly recieved AZT for 12 months on a "compassionate" basis
(Fischl et al 1989).
Peter Flegg states: "Firstly, zidovudine doses were up to three times higher in the late 1980s than are currently used now, and side effects (usually reversible on discontinuation or dose reduction) occurred at far higher frequencies than are seen today."
This is true, doses in the late 80's and early 90's were higher. By the end of the AZT Phase II trials (and extended followup), it was readily apparent that the toxicities were extreme. Why then weren't doses rapidly reduced? A more pressing question is, if AZT isn't triphosphorylating(7) at the higher dosages to sufficient AZTTP levels in order to achieve an antiviral effect, beyond reducing the toxicity profile how does reducing dosages make an ineffective drug more useful?
Currently doses of AZT are 300 to 500mg. A typical prescription flask with 100 capsules of 100mg Retrovir (AZT) instructs the user, "Take 1 capsule 5 times daily". However, the label of a 100mg AZT sample from Sigma Chemical Co., a non-medical supplier, states on its label, "TOXIC: Toxic by inhalation, contact with skin and if swallowed. Target organ(s): Blood, Bone marrow. If you feel unwell, seek medical advice (show the label where possible). Wear suitable protective clothing." A skull and bones are displayed on the label.
Why isn't the same or similar warning on the 500mg a day bottle of AZT for 'medical purposes'? Pregnant women who are presumed to be infected with HIV are put on 500mg of AZT in order to prevent mother to child transmission. Does the skull and bones warning not apply to pregnant women?
It is true that some people recover from toxic 'side-effects'. However, some aren't so lucky. In 1990, Pluda et all found that a 'late' side effect appears in 46% of patients 36 months after initiation of AZT therapy. Even if we consider that today's dosages are 1/2 to 1/3 those of 1990, why would it be considered safe to put people on a drug with such powerful mutagenic capacities? Just because someone tolerates a drug 'at lower levels than those used in the late 1980's' and manifests fewer side effects doesn't mean the drug is not producing damage and is having a beneficial effect.
Is a 35
year old who has been smoking for 10 years damaged by cigarette smoking
even though they may look perfectly fine? Perhaps smoking 4 cigarettes
a day instead of 10 is an ok compromise.
Peter Flegg states: "Remember that HIV therapy is reserved for symptomatic patients (these are by definition more advanced, and therefore more likely to die)."
I might remind Peter Flegg of Dr. David Ho's popular phrase of the mid 90's, "Hit Hard, Hit Early".
Allow me to quote from a recent (2002) ad for Trizivir, from GlaxoSmithKline:
"BLOOD PROBLEMS: Retrovir, one of the medicines in Trizivir, can cause serious blood cell problems. These include reduced numbers of white blood cells (neutropenia) and extremely reduced numbers of red blood cells (anemia). THESE BLOOD CELL PROBLEMS ARE ESPECIALLY LIKELY TO HAPPEN IN PATIENTS WITH ADVANCED HIV DISEASE OR AIDS." (Emphasis mine)
This doesn't sound reassuring for a drug 'reserved for symptomatic patients.'
In practice "HIV therapy' has not been 'reserved for symptomatic patients' but has been pushed on most HIV positive people. In fact it was upon another study (like the Phase II Trials, sponsored by the manufacturer of AZT), ACTG 019, that AZT was approved for 'asymptomatic HIV-postive' people(6). Like the Phase II trials, it was both cut short and became unblinded. How many "asymptomatic HIV-positive' people and their doctors sat down to do cost benefit analysis before going on this drug knowing this information?
It's important to point out that the 1993 AIDS definition doesn't actually require a person to be ill in order to receive an AIDS diagnosis. Beginning in January of 1993, the number of 'AIDS' patients more than doubled, the majority of them not ill. In 1997, the last year for which ill versus non-ill distinctions were recorded, 61% of all new AIDS cases were classified under this non-disease category(4). It's claimed all the time that people are living longer because of these drugs. However, people that weren't sick to begin with (both asymptomatic antibody positive and asymptomatic AIDS cases) are going to live longer than people who were already sick to begin with. Sadly, these healthy people taking HAART don't stay healthy long. They eventually get sick from the drugs and die if they stay on them long enough (5).
I know men who were never sick, yet have been on these 'life saving' drugs and are exhibiting the telltale signs of lipodystrophy. One friend has become very self-conscious about his growing belly. Another, a young man in his late 20's now looks like a man in his late 40's after having been on the meds for several years. His face is caved in, veins protrude from his arms and legs, and he wears a hat low down over his face because he feels ashamed of his appearance.
In 2000, the US Government began a humbling U-turn regarding early treatment of HIV-positive people, that is, the Hit-Hard, Hit-Early policy. An article from the New York Times from 2001 sums up the situation:
"Altering a long-held policy, federal health officials are now recommending that treatment for the AIDS virus be delayed as long as possible for people without symptoms because of increased concerns over toxic effects of the therapies... More recently, concern has grown over nerve damage, weakened bones unusually accumulations of fat in the neck and abdomen, diabetes and a number of other serious side effects of the therapy. Many people have developed dangerously high levels of cholesterol and other lipids in the blood, raising concern that HIV -infected people might face another epidemic of heart disease... Dr. Fauci, who is the co-chairman of the panel, said in an interview, 'We are adopting a significantly more conservative recommendation profile." (New York Times, Altman 2001)
In addition, the FDA began, "ordering drug makers to tone down their upbeat ads for AIDS medications, calling them 'misleading'... because they imply greater efficacy than demonstrated by substantial evidence, or minimize the risks associated with HIV drugs' (Russell 2001).
It must be
pointed out that deaths were beginning to decline by 1992, years before
the PI's and cocktail came out. The drop in deaths also happens to
coincide with the reduction in the amount of AZT being prescribed.
Peter Flegg also states, "Secondly, pointing out that individuals who have died from AIDS are more likely to have had treatment with zidovudine than those who remain healthy is tantamount to saying patients who have died from cancer are more likely to have had chemotherapy than patients who are well enough not to require chemotherapy."
The difference here is that we don't routinely give chemotherapy to individuals we think MIGHT get cancer. Whereas, we DO give chemotherapy (AZT, ddI, etc.) to healthy gay men (among others) on the assumption that they will get sick, that is, to those 'patients who are well enough not to require chemotherapy." Your statement implies that AZT just happens to go down with a sinking ship. I'm saying, in many cases, AZT sunk the ship and then went down with it. Peter Duesberg aptly calls AZT "AIDS by prescription".
The flip side of this coin relates to long-term non-progressors. Anthony Brink points out:
AIDS researcher Dr Jay Levy, Professor of Medicine at the University of
California at San Francisco, stated in the Lancet in 1998 that
“long-term survivors of HIV” have all avoided ‘antiretrovirals’.
Similarly Dr Donald Abrams, Professor of Medicine and director of the
AIDS program at San Francisco General Hospital, noticed in 1996: “I
have a large population of people who have chosen not to take any
antiretrovirals... I’ve been following them since the very beginning...
They’ve watched all of their friends go on the antiviral bandwagon and
die.” In the same year and in the next, two papers in the Journal of
Infectious Diseases took a formal look at the curious relationship
between keeping off ‘antiretroviral therapy’ and staying alive.
Hogervorst et al noted that “None of the LTAs [long term asymptomatics]
received any antiviral drugs during the study; however, 3 [of 6] rapid
progressors…were treated with zidovudine…[and] a rapid progressor was
treated with didanosine during the study.”
Peter Flegg wrote: "Toxicities such as reversible/transfusion dependent anaemia affect only about 5% of recipients of current regimens."
In the same advertisement for Trizivir as quoted above, taken from a section called, "What is the most important information I should know about Trizivir?", dire information is presented regarding serious, life-threatening allergic reactions:
in 20 patients (5%) who take abacavir (as Trizivir or Ziagen) will have
a serious allergic reaction... that may cause death if the drug is not
stopped right away. You may be having this reaction if:
However, 'common side effects' are listed in another section called Other Side Effects.
"Trizivir can cause other side effects. The most common side effects of taking the medicines in Trizivir together are NAUSEA, VOMITING, DIARRHEA, loss of appetite, headache, dizziness, pain or tingling of hand or feat, and muscle and joint pains."
The absurdity here doesn't need much comment on my part.
According to the Houston Ryan White Needs Assessment 2000, "Side Effects" is listed as the 2nd leading cause for stopping medication affecting an average of 45% of those taking the medications.
The same source lists the "Most Common Side Effects" experienced: Diarrhea, 61%; fatigue, 53%; stomach pain, 45%; headaches, 46%; dizziness, 45%; rashes, 32%.
A presentation at the 14th International AIDS Conference in Barcelona by a University of Pittsburgh AIDS researcher reveals the "most common cause of death among HIV positive people is liver failure.˜ Dr. Amy Justice bases her conclusions on a study following nearly 6,000 HIV-positive diagnosed patients at four sites in the United States. AIDS establishment scientists have never claimed that HIV damages the liver.
It goes without saying that death is not a reversible side effect.
Finally, the reference to the AZT destroying the lining of the stomach is based upon the actions of the drug. That is, destroying fast growing cells. I quoted a section from the Perth Group's article on AZT in Current Medical Research and Opinion regarding this point in a previous post:
"This decrease in the triphosphorylated nucleotides in its turn will lead to decreased cellular DNA synthesis. In the presence of such a profound, global reduction in the concentrations of the naturally occuring nucleotides, one would predict untoward effects on many tissues, especially those with the most rapid cellular turnover including the gut and the bone marrow. Indeed, 'a characteristic feature of zidovudine therapy is an elevated MCV [mean corpuscular red cell volume]'"(7)
Indeed, vomiting, nausea, and diarrhea are consequences of this.
Finally, Peter Flegg wrote: "Sick people with AIDS get anaemia – but this is usually multifactorial and seldom due to zidovudine alone."
In fact, we believe AIDS in general is multifactorial, not just anemia.Chris Tyler 1. Ellen Cooper, "Addendum #1 to Medical Officer Review of NDA 19,655", 16 March 1987. 2. Patricia Spitzig, FDA Investigator, For Cause Establishment Inspection Report of Massachusetts General Hospital and Robert Schooley, MD, October and November 1986. 3. Jackie Knight, minutes of meeting of 30 January 1987. 4. Table 12 of Centers for Disease Control and Prevention: U.S. HIV and AIDS cases reported through December 1997; Year-end edition. 9: 1-43. 5. Levy JA : Caution: should we be treating HIV infection early? The Lancet 352: 982-983 6. Paul Volberding et al., 'Zidovudine in Asymptomatic Human Immunodeficiency Virus Infection', New England Journal of Medicine, 5 April 1990. 7. Current Medical Research and Opinion, Vol. 15: Supplement, 1999
A Critical Analysis of the Pharmacology of AZT and its Use in AIDS
Eleni Papadopulos-Eleopulos, Valendar F. Turner, John M. Papadimitriou, David Causer, Helman Alphonso and Todd Miller
Competing interests: None declared