[This article is published in Science and Public Affairs, journal of the British Association for the Advancement of Science 1996; winter, 54-57.]
The violation of research ethics and the inability of doctors to admit uncertainty cause trouble in AIDS research and treatment, argues Udo Schüklenk.
'I hesitate taking them because I do not know if they do me any good, and I wonder if they may hurt me. ... I go for a while and take the medicine and then go for a while and not take it'.
This is how one AIDS patient describes how he deals with the prescribed drugs in a research clinical trial. Many people with AIDS (PWA) have lost trust and confidence in the integrity of mainstream AIDS research. What this patient describes is a consequence of a problem that has grown over time and is threatening the viability of clinical research.
Patients see themselves as the scapegoats of a research industry which all too rarely has their survival interests at heart. One patient who participated in an AIDS research clinical trial ---wrote, for example: 'I hate to say it but ... we are no more than lab rats to these people. ... As time passed by my CD4/CD8 counts eventually dropped to almost their original level and I gracefully bowed out of the study ... thank you Mr Lab Rat.'
This lack of trust in AIDS researchers and carers extends to physicians, too. US bioethicist Miriam E Cameron interviewed PWA about their views regarding the conduct of their physicians. Their general attitude was that they would not trust their physician or principal investigator because they believe 'that those AIDS researchers do not tell the truth because of money'.
Patients see themselves as the scapegoats of a research industry which all too rarely has their survival interests at heart.
The problem is, unfortunately, that patients have good reason to be sceptical about the design of quite a number of research clinical AIDS trials. Their survival interests and the interests of researchers trying to generate knowledge in order to help future patient generations do not necessarily coincide. Anthony Fauci, Chief of the US National Institute of Allergy and Infectious Diseases, admitted that the randomized clinical trial routinely asks physicians to sacrifice the interests of their particular patients for the sake of the study. Patients are aware of this situation and have begun in ever -growing numbers to lie and cheat in order to gain access to an experimental agent through their participation in a clinical trial. AIDS researchers in the USA have frankly admitted that many trials have been extended over enough time so as to cross clear lines of new standard care for one or more opportunistic illnesse. There may have even been examples where patients were not advised about appropriate changes to their care. Greg Dubbs, an AIDS sufferer and programme director of clinical trials has pointed out that under such circumstances 'All you are doing is finding out who can who can lie well. They never study how many people he to get into their studies.' It is not unusual today that noncompliance and/or drop-out rates in AIDS research clinical trials reach levels of 50-80%. The predictive value of such research is naturally very limited.
Altruists or hypocrites?
PWA have noticed that very many people in the AIDS research and service industry owe their careers to the illness they are dying from. Even the United Nations (UN) has set up its own agency dealing with AIDS, paying the usual obscene UN salaries to those with connections good enough to score a job in Geneva. At the same time PWA in many developing countries have not even access to basic and cheap AIDS drugs. A small portion of the money going into UN AIDS salaries could help pay for basic pneumocystis carinii pneumonia (PCP) prophylactics. It cannot surprise that very many PWA are bitter about the large number of people making a good living from AIDS while they are dying of it.
In my own field, biomedical ethics, it can clearly be demonstrated that quite a number of US bioethicists owe a professorial position to the occurrence of AIDS: AIDS-related research projects have been invented ad nauseam by social scientists, psychologists and, of course, bioethicists simply because there was research funding available due to the public and media interest in AIDS. Without this funding they would have done something else. Research interests, specializations and even competence often materialize out of nowhere after funding has been made available. AIDS was, and to some lesser degree still is, a career booster. There can be no doubt about this. To assume that all this has gone unnoticed by PWA is naive.
AZT monotherapy
Scepticism in regard to individual researcher's motives for doing the work they do is insufficient to explain why so mainy PWA have only cynicism left for scientists and other researchers working in this field. Why have so many patients developed doubts about the professional conduct of AIDS researchers and specialists', The obvious question: are there widely publicized incidents in the history of AIDS research that have led to a situation where patients changed their attitude towards researchers and physicians?
The failure of AZT monotherapy is to a large extent part of the answer to the question of why so many PWA have lost confidence in their doctors and in AIDS researchers. It is not only the 'AIDS dissidents' such as Peter Duesberg but also very many PWA and AIDS activists who agree that HIV is the cause of AIDS who argue that AZT monotherapy should never have been approved. They argue that there has never been any evidence for the claim that it increases survival. Some surrogate markers such as CD4 counts have improved but when the drug was approved it was unclear whether this would translate into a real survival benefit.
Researchers and physicians were in the uncomfortable positions of knowing on the one hand that the research hadn't been done to justify the approval of this drug for AIDS therapy. At the same time, however, they were subjected to extraordinary emotional stress. Patients aggressively requested a drug. They wanted to do something instead of going down without a fight. It is all too human that researchers put forward a drug for approval by drug regulatory agencies that had not been proven to increase survival or improve the quality of life of PWA.
Physicians subjected to the same pressure gave in to these demands and prescribed AZT. As Bruce Nussbaum reported in his book Good Intentions, 'Gay community activists were putting tremendous pressure on (US) Congress to get something, anything, out to treat their disease. The White House was pushing hard to show that America, and not France, was in the forefront of fighting AIDS. The AZT trial itself had been cut short. AIDS was the most politicized disease (New York City-based Associated Professor of Medicine) Lange had ever seen. Another scientist, deeply involved in AIDS research, would call what happened (in regard to the approval of AZT) evidence that 'science really is nothing but a soap opera'.'
The study in question was undertaken by principal investigators Margaret Fischl, Douglas Richman and their associates. It enrolled 282 patients in 12 participating centres in the USA. AZT was given to 145 while 137 received a placebo. Originally the study was scheduled to last 2 years but it was terminated after 120 days because 19 patients died in the placebo arm compared to only one AZT recipient. The study, which led to the approval of AZT for AIDS, therapy violated basic principles of the 1964 Declaration of Helsinki which requires that every patient including, those of a control group, if any - should be assured of the best proven diagnostic and therapeutic method. The protocol of this research clinical trial explicitly excluded basic standards of care such as antimicrobial prophylactics for the prevention of opportunistic infections. AZT was compared -with nothing. Eight out of the ninteent placebo arm deaths occurred because of PCP for which efficient prophylactics did exist but wasn't approved for political reasons. The principal investigator of this study undertook another study where Bactrim (a PCP prophylactic known to be effective from cancer research) was compared with a placebo, despite protests from community doctors who knew from their own experience that Bactrim worked. The result was that another 28 people (all in the placebo arm) died in order to prove what was known already.
Donald Abrams, a professor of clinical medicine in California, pointed out that the average patient (in San Francisco) with AIDS, but who was not receiving AZT, was expected to live at least several months longer than the duration of the placebo controlled study. Clearly it is unethical to subject patients with terminal illnesses in clinical trials knowingly to sub-standard treatments. It should also be pointed out, however, that such trials don't provide useful information for the real world where patients are using drugs. such as antimicrobial agents, which were withheld from the patients in this trial.
AZT was subsequently propagated to the interested public as a drug that increases survival time. The manufacturer orchestrated an advertising campaign (relying heavily on internationally renowned medical AIDS researchers) in news media read by those at high risk of AIDS, namely gay men. At the same time there was no evidence that AZT monotherapy improves survival.
Nevertheless, lacking alternatives and trusting their doctor's advice most PWA tried the new drug. The side-effects of this chemotherapeutic were devastating to many, as Greg Gonsalves, an AIDS sufferer pointed out in one poster on an AIDS related internet newsgroup. In many other cases, 'beneficial' changes associated with the drug such as viral load do not necessarily correlate well with clinical outcome. Similarly, some chemotherapeutic cancer regimens can shrink the tumour but kill the patients faster than those who are not. Also, in heart disease, some drugs can lower cholesterol or reduce arrhythmias but provide no survival benefit or actually reduce survival compared to a placebo. Patients reasonably expected that physicians would have informed them about uncertainties such as this, but by and large they were not told. AZT was prescribed in most Western countries as a matter of course. Physicians don't like to admit uncertainty for a number of reasons which I will discuss in a moment.
AIDS researchers raised high expectations when they announced the arrival of AZT but ultimately the drug failed to live up to these expectations. The intemet and other sophisticated telecommunications technology allowed patients in Western countries to communicate with each other and analyse their experiences while on AZT. Patients reported to each other the horrific effects they suffered from AZT. One Australian patient wrote the following in a community newsletter:
'I was on AZT for six months. Although the dose was only 600 mg a day, I suffered horrendous migraines, loss of appetite and blueflashes before kicking it and going alternative. Then I felt like I wanted to die - now I feel 100%.
The drugs manufacturer concedes in information for THE PHYSICIAN'S DESK REFTRENCE: 'It was often difficult to distinguish adverse events possibly associated ivith the administration of Retrovir from underlying signs of HIV disease or intercurrent illness.'
It cannot surprise that Duesberg and his 'AIDS dissident' allies use information such as this and the long list of possible side effects to claim that AZT causes AIDS, because AZT has indeed been shown to be capable of causing illnesses that are mentioned in the definition of the acquired immunodeficiency syndrome. The unjustified hyping of AZT monotherapy by AIDS researchers, physicians, the drugs manufacturer and AIDS service organizations helped in the end the very same 'AIDS dissidents' Robin Weiss criticized in his Autumn 1996 article in this magazine (to some degree justifiably) as irresponsible.
Going alternative
Many PWA dropped out of mainstream AIDS treatments altogether and went 'alternatives, just as the Australian patient I have just quoted. Of course, there is no evidence that any of the alternative strategies are any better than what is available in mainstream AIDS treatments. The real problem is that when treatments are available that actually are scientifically proven to increase survival or improve the quality of life of PWA there will be a large number of people who could benefit from these drugs but who won't make use of them because of their mistrust of AIDS researchers. The rejection of survival increasing PCP prophylactics by many of those who have 'gone alternative' is a case in point. For instance, the founder of London - based Continuum magazine died of PCP. The main reason for this irrational behaviour is the belief that 'the establishment lies anyway' and that 'drugs are the causes of AIDS'.
The second reason has been thoroughly and convincingly put to rest by scientists such as Robin Weiss. Psychologists might find it worthwhile to research why people still keep on repeating what has been falsified empirically time and again. The first reason, I believe, is a direct consequence of an attitude endemic among physicians - their inability to admit uncertainty to their patients. This attitude has much to do with the outdated identity of many physicians which forces them to be paternalist and to make decisions on behalf of patients. It is inconceivable for professionals working in such ideological frameworks to admit uncertainty to their patients because it would undermine their status which is that of an quasi-omnipotent 'demi-god in white'.
Biomedical ethicists have long criticised this paternalistic attitude and suggested that doctors take patient autonomy more serious. If this advice had been heeded in the case of AIDS, physicians and patients could have developed a partnership instead of the still too common father-son relationship. In a partnership it would have been possible for the physician to admit uncertainty about the quality and long-term effects of, for instance, AZT. This would have prevented the development of the mistrust that is so widespread today among people with AIDS.
A genuine partnership
Robin Weiss criticism of 'AIDS dissidents' misses the target. The success that alternative views of AIDS have achieved in terms of attracting followers among PWA is not so much due to the quality of some of these views but an indication that patients have lost trust in an establishment that has promised too much and hasn't been able to live up to the expectations it has created. PWA have come to realize that the emperor really is naked. The problem is that the Emperor has recently begun to find her first pieces of clothing. It is possible to keep PWA alive longer with a better quality of life.
Unfortunately, too many patients don't bother to listen anymore. 1 would advise AIDS researchers and physicians to follow the lead of Robin Weiss and admit uncertainty to their patients and admit that many questions about HIV, AIDS and the ideal course of therapy remain open. Perhaps not coincidentally this would also satisfy ethical requirements about physician respect for patient autonomy. It would help to establish an atmosphere of trust between physician and patient and it would assist in building a genuine partnership between patient and doctor. Under such circumstances there would still be patients left who turn for one reason or another to quacks, but I predict that the number of patients going this path will drop because they feel they can trust their GP.
Further reading
Fleming TR (1994) Surrogate Markers in AIDS and Cancer Trials. Statistics in Medicine 13: 1423-35
Fleming TR, DeMets DL (1996) Surrogate end points in clinical trials: are we being misled? Annals of Internal Medicine 125: 605-13
Hellman S (1995) The patient and the public good. Nature Medicine 1: 400-2
Nussbaum B (1990) Good Intentions: How Big Business and the Medical Establishment are Corrupting the Fight Against AIDS, Alzheimer's, Cancer and More. Penguin, New York
Rodwin MA (1993) Medicine, Money and Morals. Oxford University Press, New York
Schüklenk U, Hogan C (1996) Patient access to experimental
drugs and AIDS clinical trial designs: ethical issues. Cambridge
Quarterly of Healthcare Ethics 5: 400-9