DON'T (DON'T, DON'T) BELIEVE THE HYPE

The results of a three-year study on AZT raise serious doubts about its usefulness. Dr. Michael Lange, a leading AIDS and infectious disease specialist, discusses AZT and the new study with Celia Farber.

I'm beginning to almost feel sorry for AZT. The way you feel sorry for a talentless child whose parents keep dressing it up in shiny clothes and trying to make it tap-dance, when in fact it can barely stand on two feet.

In August of 1989, the National Institutes of Health announced that AZT had been found effective not just in treating AIDS but also in preventing it. They pointed to an NIH study which supposedly proved that when AZT was given to people who had antibodies to HIV but had not yet developed AIDS, it slowed the onslaught of the disease "significantly," Despite the fact that the study - which was intended to go on for three years - was stopped after only nine months and that the data was not yet published, it was established that anyone with a T-cell count below 500 should take AZT as a preventive measure against AIDS (that meant approximately 650,000 people in the U.S. alone). The press, having access only to a two-page NIH press release and not the study figures themselves, trumpeted the news without hesitation: "HIV positive patients are twice as likely to get AIDS if they don't take AZT." Posters sponsored by AIDS organizations and Burroughs-Wellcome, the pharmaceutical company that makes AZT, were plastered on bus stops and subways, urging people to get tested for HIV because early intervention with "new treatments" could now "put time on our side."

Although the claim was scientifically premature and unsubstantiated, the rush for AZT was on, and doctors around the country were urged to prescribe a cancer-causing chemotherapeutic drug as a long-term prophylactic for AIDS in healthy HIV positive patients - patients with no symptoms of AIDS, and who according to statistics had an excellent chance of remaining symptomless.

Meanwhile, researchers at the Veterans Administration and the West Coast and in Europe were reaching very different conclusions about AZT in HIV positive people asymptomatic of AIDS [people with HIV who have not developed any of the opportunistic infections of AIDS]. One year ago, V.A. investigators reported on their observations after two years of a three year study designed to resolve the question of long-term treatment with AZT in asymptomatics. Already then they saw "no statistical difference in progression to AIDS," and said that deaths in both the placebo and the AZT groups were "virtually identical."

This year, on February 14, the V.A. confirmed their preliminary findings, adding new and even more dismal facts. "Early zidovudine {the generic name for AZT]," they reported, "resulted in transitory benefits in whites and neutral or harmful effects in black and Hispanic patients.' As reported by the New York Times, the study said that AZT does slow the development of symptoms in some people with HIV, but that "people who took the drug before they had symptoms lived no longer than those who took it after they had symptoms." The study also showed that black and Hispanic patients had a significantly higher death rate in the group that took AZT from the beginning than the group that took AZT only after dipping below 200 T-cells.

Another very chilling fact to emerge was that in the group who started taking AZT early, some died of causes "not related to HIV infection." The causes of death were listed as adenocarcinoma of the lung, large-cell undifferentiated lymphoma, heart failure, suicide, motorcycle accident and murder. Of the ten patients who died without first developing AIDS, the study reported, "all were in the early-treatment group."

"We're fussing and fuming with a therapy that's not very good," one doctor told New York Times reporter Gina Kolata. In the Times article, three leading doctors expressed deep resentment that they had been led to believe that their asymptomatic patients should be on AZT. "I find the information from the V.A. study disturbing," said Dr. Richard J. O'Brien of the Federal Centers for Disease Control in Atlanta. He said that he had been very enthusiastic in recommending AZT for patients without symptoms of AIDS in the past, adding, "Now I won't be."

Meanwhile, the FDA - who, let's not forget, approved AZT for use in asymptomatics based on questionable and incomplete studies - sent out a press release to doctors that can best be described as a masterpiece of doubletalk, claiming that the V.A. study "reaffirmed the drug's usefulness in treating individuals who are at less advanced stages of infection with the AIDS virus," without even mentioning the fact that AZT was shown to have no beneficial effect on survival.

One doctor who has been a scrupulous critic of AZT from the beginning is Dr. Michael Lange, an infectious disease specialist practising at a large teaching hospital in New York City. He was on the panel that the FDA consulted in 1987, when AZT was approved, and he expressed deep concern about the release of the drug in those meetings and in the follow-up meetings in 1988. In 1989, Lange told SPIN, emphasizing that his views on AZT were his personal opinions, "I personally do not prescribe AZT unless a patient insists. I have continued to find that patients survive longer without it."

SPIN: When we last spoke you were very concerned with the widespread use of AZT in asymptomatics. Now studies have confirmed the uselessness of AZT in "delaying" AIDS. Your fears have come true. What is your reaction?

LANGE: I think it is very disturbing, to say the least. The thing I was most concerned about when using AZT in asymptomatic people was that this is a drug with known long-term toxicity. Since we talked in 1989, that's become even more clear. The August 15, 1990, issue of Annals of Internal Medicine substantiated further the fact that people taking AZT for two to three years had a 45 percent incident of developing non-Hodgkin's lymphomas. What , then, is the benefit of AZT? We keep throwing around these terms -- "beneficial," "usefulness," "in general was beneficial." These terms are exceedingly poorly defined in this study. If you take an AIDS patient, particularly an asymptomatic AIDS patient, how do you determine if the drug is beneficial? Take a patient with three hundred fifty T-helper [immune system] cells, and you know that person has a 50 percent chance of remaining healthy for at least the next three years if you do nothing. In order to catch the 50 percent that will go on to develop symptoms, you're going to give all 100 percent AZT? In the 019 study, when it was stopped, the average person had taken AZT for only nine months, which is an insignificant time period based on the projected time. If there was any benefit to be had with AZT it only lasted about six months. After that, CD4 levels (T4-cells, or immune cells) dropped to below the initial point; HIV levels, measured in as p24 antigen, came back up, and we now know that resistant virus [virus strains that are unaffected by AZT] shows up.

SPIN: How do you feel about those posters that advertise AZT for asymptomatics?

LANGE: The posters and advertisements for AZT are highly unethical, because they are advertising something as fact that is not known. The real question is, Who are the people who stop these AZT studies so soon after they've started? It happened both times, for the approval in 1987, and for the use in asymptomatics in 1989. If it was, as they say, "unethical" to continue a study, then why bother even having any scientific review of it? The antiviral advisory committee to the FDA had no input into stopping the AZT studies as these had been stopped months before. Thus, even if they had decided that the studies had been inadequate, there would have been no way to continue them. If 019 had been carried out for the entire three years planned, the outcome between placebo and AZT may have turned out to be just as insignificant as we now find to be the case in the V.A. study.

SPIN: Why is AZT being pushed, rather than simply offered? It's being hyped to the point where people are made to feel guilty - as if they're not participating in their wellness and recovery - if they don't take AZT. The atmosphere is not rational.

LANGE: yes, it is very disturbing. I have been worried that I will be sued for malpractice for not prescribing AZT. But really, most of my patients come to me because they know I'm not a great fan of AZT and they're looking for the other potential answers. The pressure to prescribe AZT has been intense, absolutely. Now it's let off a little bit. From what I hear, during the last years, a lot more doctors in New York are disillusioned. They don't think AZT is as good as they had hoped because it's been around for three years and people are still dying in flocks.

SPIN: Last time I spoke to you, you didn't feel able to go on the record with anything about AZT. Has that fear lifted? Do you still feel there are certain things you'd like to tell me about AZT but you can't? or do you feel you can speak absolutely openly to me about it?

LANGE: About the treatment issues, I can speak perfectly openly. Because a number of people have reviewed this, and the drug clearly has not held up to promise. AZT has been available for investigational studies now for five years. If it was working in stabilizing disease or making it a chronic disease, which is what the AZT advocates are saying, the death curve of people dying with AIDS as predicted in 1986 should have gone down. To my knowledge it has changed somewhat. The AZT advocates, of course, are saying this is due to AZT. Patients are living somewhat longer if they are being taken care of by doctors who understand the disease. But this is just as true for patients taken care of by doctors who in general do not prescribe AZT. Hence the differences may be due to primary care PCP prophylaxis [treatment to prevent pneumonia that is the leading cause of AIDS deaths]. Although the window of opportunity is closed now, what we really would have needed in 1987 was comparison of AZT to PCP prophylaxis.

SPIN: This fiercy commitment to a particular virus, HIV, and a particular drug - AZT- was it a random selection? In other words, why that virus and that drug? And why do scientist and health-care workers have such a strong, visceral reaction when the topics of HIV and AZT are broached?

LANGE: because, as you know, at the NIH overall, medical funding has gone down, and the one thing that has greatly increased is funding for AIDS. The government has not increased its health funding overall; it has taken away from cancer research, cardiology research, and so on, and given the money to AIDS. And hence it has created very, very powerful financial blocks in different medical schools and hospitals. There's no doubt that the way the system works is that you are judged and your power rises in an institution - be it a university or hospital - according to the money that you bring in for research. the institution gets a lot of money, in the form of indirect costs, for the scientists who bring in this money, and so what you are attacking here is the very foundation of all of this power. The foundation is built on HIV and AZT. All the money - I think you wrote it in an earlier article, what is it... three hundred million dollars for the ACTG [AIDS Clinical Trial Groups]? And 80 percent of them have been studies on AZT.

SPIN: the core thesis of the AIDS activist movement is that not enough money is being put into AIDS because the government doesn't care whether "undesirables" - gays and IV drug users - die. But what you said earlier about money being moved from other areas of medicine into AIDS suggest that that thesis is incorrect. I mean, cancer and heart disease still kill a lot more people than AIDS does. Certainly almost all scientists and clinicians bemoan bitterly the fact that money has been shifted into AIDS from diseases that also should be rightfully explored. I think the money given to AIDS research has been very, very generous. Would better work be done if more money was available for AIDS research? I'm not at all convinced. On the other hand, what I would strongly support is a more open discussion. We do not know the pathogenesis [causation] of this disease. And we were very early forced into a very dogmatic view: namely that somehow HIV kills the T-cells after attaching its GP 120 [a viral envelope]. It was very, very simplified. And hence it was hastily concluded that what we needed was an antiviral agent [e.g. AZT] . I think that even the greatest advocates of HIV no longer believe in 1991 that HIV by itself does all that damage to the immune system. There are many cofactors. Not necessarily other infectious agents. The ACTG leadership shows little interest in cofactors, in spite of the fact that both Dr. Robert Gallo and Dr. Luc Montagnier have strongly come out in favour of cofactors, in the form of HHV-6 [another virus] and a newly discovered microplasma agent, respectively. Meanwhile, I think people are shifting away from all this old dogma. Not in treatment, but in pathogenesis and discussion. The ACTG is still stuck in the mire of "we need an antiviral to suppress HIV." And other ideas get very short shrift or are dismissed.

SPIN: Do you think that AZT, in the long run, has done more harm than good? You've said in the past that the marginal positive effect that AZT has had on patients may be due to its anti-inflammatory effect, which a simple drug as acetaminophen or even aspirin might have achieved without the toxicity. Do you still feel that way?

LANGE: Yes, I still feel that way. I think that AZT as a scientific development is not wrong. It's the political brouhaha that was build around the drug that from the very beginning was a mediocre drug, and should have been handled as such. Too much of the decision-making in the ACTG as to the priority of drugs to be tested in clinical trials appears to be made behind closed doors. I was told by people at the NIH, as early as 1986, "Well, this [AZT] is only the beginning, we'll have three or dour more drugs a year from now." But what do we have in 1991? AZT. There are many things that have an anti-HIV effect in the test tube. Why was AZT selected the way it was? Millions invested in testing it when it was considered too toxic even as a chemotherapy agent. Why was it taken from the shelf where it had sat since the 1960s and made the absolute - and pushed as being almost a cure?" and it still is if you look at these subway ads. The interconnection of drug company advertising with the NIH, building this drug into something which it clearly is not, has been very, very harmful. It has delayed the exploration of other ideas when the evidence was already there that they should be looked at. I mean, now people are willing to look at them because they know that AZT isn't worth too much. But they should have been looked at in 1987. We lost, essentially, three and a half valuable years because all the marbles were put on AZT.

SPIN: Do you think people have been killed by AZT?

LANGE: Well, that's a difficult question. People have had very strong toxic reactions, and there are those who may have died a few months earlier due to those toxic reactions. There are certainly a lot of people whose last few months were made more miserable by AZT, particularly at the higher dose. On the other hand, I can't deny that there have been people with very high fevers which disappeared when given AZT and they felt clinically better. This doesn't mean their disease improved, but they felt better. And that's really the one big plus that AZT offers some people. There's no doubt about that. But it doesn't last. The interesting thing is that at last years hearings - the review of 019 and 016 - I sat up on the stage as a consultant to the antiviral committee and Dr. David Barry from Burroughs-Wellcome was in front of the stage, and he said to me that they had never claimed that AZT prolonged life, only that it improved the quality of life. This was after I pointed out that the effect of AZT wears off after six months, and that there is no evidence that it makes people live longer. Clearly, this is in direct contrast to the message in the subway ads.

SPIN: You've taken a lot of heat for your criticisms of AZT. What does that say about the state of the medical establishment today?

LANGE: I think that if you practice medicine and you're a clinician the traditional role is to be the advocate of your patient. You're not a hireling of the hospital, you are not a hireling of the government or a drug company. Even though many people feel it's old fashioned, there is such a thing as the Hippocratic oath and medical ethics. The reason people come to a doctor is that they want a feeling of trust. They entrust their life to the doctor. I think, naturally, in the role of a doctor, there is a build-in role of potential conflict with institutions. Government institutions, hospitals, and universities are essentially businesses. They have to have a bottom line and so on. But as a physician you are the advocate of your patient, trying to get the best for him or her out of the system. I'm an academic doctor, I'm an associate professor at a major medical school. I could never with a clear conscience convince myself - and I have reviewed all the articles on AZT many times - that AZT is a very useful drug. There were certain clinical situations where I would try it and did try it. But as I've said, I think that the beneficial effects - a better sense of well-being and so on - are short lived. The desired aim with AZT was to make AIDS a chronic disease: Will people live longer than two years following their first episode of PCP? There is no data I have evaluated which has proved to satisfactorily that AZT can do so. I have had a big conflict. Having been put in a corner I've thought, Well, am I going to just give in here, to various pressures, and can I live with my own conscience doing so? And I decided no, I can't. I have had some patients who've wanted to take AZT after I've discussed the pros and cons, and in those cases I've prescribed it - it is the patient's life. It is his or her decision. It is the doctor's duty to inform. Your, the doctor, based on how thoroughly you present the information about a treatment, are the one who is making the decision about this particular patient's life and death. Your job as a doctor is to stay on top of the literature, stay well-informed, read it, weigh the pros and cons, weigh the evidence, just like a lawyer, and act to the best of your ability. I did that, and I could not convince myself that the use of AZT in its present indications is justified. *