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The Cure That Failed
By Neville Hodgkinson
The Sunday Times (London) 4 April 1993

JODY WELLS has been HIV-positive since 1984. He was diagnosed as having AIDS in 1986. Today, seven years on, he says he feels fine with energy levels that belie his 52 years. He does not take the anti-HIV drug AZT.

Wells, unlike thousands of doctors and patients around the world, was neither surprised nor disappointed last week when the Medical Research Council announced that early treatment with AZT, sold under the brand name Retrovir, is useless. In fact, he welcomed the announcement. Not because he could tell his doctors "I told you so" he has consistently refused entreaties to take the drug but because he believes it is a poison that harms more than it helps, and can even kill, producing symptoms which doctors misinterpret as AIDS.

He feels so strongly about the issue that he works up to 18 hours a day establishing a fledgling charity called Continuum, "an organisation for long-term survivors of HIV and AIDS and people who want to be". Founded late last year, the group already has 600 members.

Continuum emphasises nutritional and lifestyle approaches to combating AIDS, arguing that these factors have been grossly neglected in the 10 years since Dr Robert Gallo declared HIV to be the cause of AIDS.

To most within the "AIDS" community, the MRC's announcement came as an unpleasant shock. It meant that a decade of the most intensive research ever mounted by the medical and scientific community against a single virus, costing $1.5billion a year in the United States alone, had left them empty-handed in therapeutic terms.

AZT, some doctors had declared, was the "gold standard" of AIDS treatment. They believed in it so strongly that many patients have come under heavy pressure to take it, and to join trials liberally funded by Wellcome, the drug's manufacturer. At the last count, more than 50 hospitals across Britain were involved in such studies. It is even being given to HIV-positive children.

Yet as The Sunday Times first reported in 1989, some scientists have argued against the huge concentration of resources on AZT, and the wisdom of giving patients a drug originally developed for cancer patients but considered too toxic to administer.

They have also questioned the rationale of an exclusively anti-viral approach to AIDS, pointing out that science has not yet been able to locate a mechanism through which HIV alone could account for the collapse of the immune system seen in AIDS.

"It is an Alice in Wonderland world," says Wells. "There are so many uncertainties, and yet this extremely toxic drug has been given to thousands of people, many of whom are completely well apart from having antibodies in their blood to HIV. It is outrageous that they should have been put at risk in this way."

Last week Wellcome was trying to limit the damage to AZT's credibility, arguing the trial results were not all they seemed, that several other trials have shown benefit, and anyway, AZT's future lies in being used in combination with other drugs. But the latest trial, called Concorde, is far and away the most scientific mounted. Although it was directed at finding out whether AZT would help symptom-free HIV-positive patients rather than those with full-blown AIDS, it adds to the concerns of scientists who doubt whether the drug has any place in AIDS treatment.

AZT is big business. It earned Wellcome more than Pounds 200m last year and Pounds 131m in the six months to February this year. How could a "useless" drug earn the reputation of being the "gold standard" in AIDS and achieve such heights of success?

IN AN AGE when so much has been achieved by science, both professionals and the public often subscribe to the Spock-like image of the scientist as a cool, calm, dispassionate seeker after truth. This is a myth. Scientists are as prone as any other human beings to having their judgement distorted by their emotions, whether from compassion or greed. Normally, the scientific method seeks to overcome this subjectivity by requiring careful analysis of claims.

In the mid-1980s, American researchers were under huge pressure from a panic-stricken homosexual community to fast-track anti-AIDS drugs on to the market. AIDS conferences became as much political as scientific events, with angry demonstrators chanting "Give us the drugs NOW!".

It was in such a climate that AZT, first designed in the 1960s for the treatment of leukaemia, came on the scene. The drug terminates DNA synthesis, the process underlying cell division, and scientists originally hoped it would prevent cancerous, rapidly multiplying blood cells from replicating. It was abandoned because of its toxicity and ineffectiveness in animals.

After HIV was declared the cause of AIDS by Gallo, Dr Samuel Broder, a colleague at the US National Institutes of Health (NIH) in Bethesda, Washington, instigated laboratory tests showing AZT helped block the virus's replication. He steered the drug through regulatory procedures from test-tube to patients in a record 19 months.

Working at the time as associate director of the National Cancer Institute's clinical oncology programme, Broder spoke in 1986 of the tension he felt as his every move was scrutinised and criticised by AIDS lobbyists. "I've had to recognise that we cannot approach this problem in the usual scholarly way," he said.

Later he spoke for much of the scientific community in declaring: "I view AZT as the battle of El Alamein. It is symbolic that we can do something against the virus that causes AIDS; that we can make progress; that those who preached that it was inherently untreatable were wrong."

AZT was granted its licence by America's Food and Drug Administration (FDA), with licensing authorities around the world soon following suit, on the basis of a single, multi-centre study. It took place in 1986, and involved 281 AIDS patients. They were supposed to be tested for 24 weeks, but the trial was called off prematurely, when only 15 patients had run the full course, because there seemed to be a dramatic improvement in survival in the AZT-treated group. Only one had died, compared with 19 patients receiving a dummy pill.

Later, it became evident that investigators and patients had not been "blind" to who was receiving which pill; there were numerous breaches of protocol designed to ensure comparability between the treated and placebo-only patients, and sicker patients may have been placed in the placebo group; there was an acceleration of deaths in the treated group after the study ended (many had been kept alive by repeated transfusions); many adverse reactions were not reported; and that for 19 patients to die within weeks was a phenomenally high death rate never seen again in any other comparable group, suggesting they were not properly treated.

According to John Lauritsen, a gay movement activist and author of Poison by Prescription: the AZT Story, FDA documents obtained under the Freedom of Information Act show a meeting was convened to decide what to do about the "protocol violations and bad data".

"The decision was made to keep everything," he says. "The researchers excused these inexcusable decisions on two grounds: one, if they didn't use the false data, there would be hardly any patients left in the study. Two, using the false data didn't really change the results very much." The FDA's stamp of approval on AZT set in motion a bandwagon which seemed unstoppable.

A flood of reports started appearing claiming various benefits for AZT. Many of these were "anecdotal" that is, based on individual clinicians' observations of patients, rather than arising from scientifically sound trials. Lauritsen has a scathing description of such reports in his book, published in 1990.

"These doctors," he writes, "many of them rather gullible individuals, have been told that AZT represents the 'best hope'. With this expectation, they begin dosing their patients with AZT, and sooner or later some of them believe that they have 'seen good results'.

"Perhaps a patient, having undergone multiple transfusions and suffered agonising side-effects, dies after 11 months; the doctor can then rationalise that he would have died sooner if it hadn't been for the AZT."

As millions poured into Wellcome's coffers from AZT, the company sponsored an ever-growing number of research projects, as well as AIDS "educational" materials and PR campaigns.

In August 1989, Wellcome achieved a breakthrough that appeared to make the sky the limit as far as its future earnings were concerned. It won "scientific" backing for the idea that all HIV-positive patients, not just those progressing towards AIDS, could benefit from AZT. A trial it had sponsored with the National Institute of Allergy and Infectious Diseases in the US also part of the National Institutes of Health was stopped early, just like the original one, on grounds that the drug had been shown to halve the rate at which a group of HIV-positive patients became ill.

Wellcome's shares rose by 164p, adding Pounds 1.4 billion to the company's stock-market value. And there were calls for a rethink over a multi-million-pound Anglo-French study, known as the Concorde trial, which was tackling the same question that the American study seemed to have answered: of whether AZT could delay the onset of illness in all HIV-positive people. Surely, with AZT now of proven benefit, it was unethical to continue Concorde and deny some of its participants the benefits of AZT?

"DRUG offers lease of life", ran the headline across the front page of The Independent on August 19, 1989, with the sub-heading "AZT could be made widely available in Britain after US research shows it can delay onset of the disease". Similar optimism was expressed elsewhere.

Such reports gave scientists involved with Concorde a tough decision to make. They decided to compromise and keep the trial going, but change the protocol so participants would no longer be left in the dark on whether or not they were taking an active drug, but could, if they wished, be switched to AZT.

There were still unanswered questions. It was possible AZT gave a short-term boost to immunity, but failed to give benefit in the longer term. The Americans' habit of stopping trials early could disguise such a phenomenon.

There was also evidence that the American trial, just like the original one with AZT, had failed at least initially to conceal from doctors or patients who was on the active drug and who was not, allowing bias to enter.

Last week, first results from the four-year Concorde trial were published in The Lancet. They show no clinical benefit from AZT in symptom-free HIV-infected individuals, either in terms of living longer or in delaying progression towards disease. Armed with this exposure of the weakness of previous claims, the licensing authorities must surely now review whether AZT is fit to be prescribed to patients with AIDS as well.

They should do so as a matter of urgency. Last year a four-year trial among 340 HIV-positive patients with preliminary signs of AIDS found that rather than saving lives, AZT resulted in slightly more deaths.

The Concorde trial appears to offer one crumb of comfort for Wellcome. Although more than 100 of the 1750 patients in the trial had to drop out because of severe side-effects, that is considered to be a relatively low frequency, and no unexpected toxicity was seen.

Jody Wells, however, believes the real picture is worse than it appears. The reason, he says, is that most patients know from the changes in their body when they are on AZT, even if supposedly "blinded" to the fact when in a trial. He claims to know several who, not wanting to rock the boat, have quietly taken unilateral action. They have thrown their tablets down the toilet.

AIDS IS not the first illness that doctors, en masse, have taken up as a crusade, at the expense of science. Similar problems arose when the profession, again egged on by drug companies, decided heart disease was caused by raised blood pressure or raised cholesterol and tried to persuade millions to change their eating habits or go on lifelong medication. Numerous studies now show not only a lack of benefit from this approach, but actual harm.

Sometimes crusades do bring benefit, but perhaps the worst feature of the medical and scientific professions' behaviour on AIDS has been the enormous dominance of a single focus HIV for research, prevention, and therapeutic efforts, to the exclusion of other approaches.

Last week The Lancet published a letter from Dr Gordon Stewart, professor emeritus of public health at Glasgow University and a former World Health Organisation adviser on AIDS, pointing out that previous AIDS projections for 1992 were up to 10 times higher than the actual figure, largely because of false assumptions about heterosexual spread.

"I have been trying to put this across for nearly four years," Stewart said. "I have tried numerous journals. The response has either been rejection, or silence."

Stewart's efforts have included letters to several government bodies arguing that the medical establishment had "jumped the gun" in using AZT so widely. "I received no comment whatever in response," he said. "They were all persuaded HIV was the sole cause of AIDS, that an anti-viral drug would destroy viral replication, and thereby delay the onset of AIDS. They wouldn't consider any alternative reasoning."

Perhaps Concorde, like its namesake, will also now break a sound barrier: the misguided consensus on AIDS that has kept people like Stewart from being heard for so long. *


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