VIRUSMYTH HOMEPAGE

A RAY OF HOPE

Transcript UK BBC Documentary

Panorama London, March 1996

Retrovir, the drug better known as AZT, is a billion pound success for a British drug company. But can it do more harm than good? Tonight, Panorama reports on the controversial drug sold as a ray of hope.

In 1985 Bob Threakall was told he had HIV - he was one of 1200 British haemophiliacs infected by contaminated blood. Like most others he continued to feel well, and expected to live for many years before developing AIDS.

In 1989 his doctor put him on AZT even though he'd had no symptom of AIDS. An American study had been published encouraging patients not to wait, but to start taking the drug early in the hope of prolonging life.

But Bob Threakall found that after he took AZT his health started to decline.

Bob Threakall: "I am very glad that Sue's here because there isn't a lot I can actually do without making myself breathless and that sort of thing."

Sue Threakall: "He gradually began to lose more and more weight, then he began to get lots of minor infections."

Bob Threakall: "I was actually diagnosed HIV positive in the sense that..."

Within 18 months of starting AZT Bob Threakall was dead. His widow maintains it was the drug that killed him, and she's suing the manufacturer.

Sue Threakall: "I'm totally convinced that the things he was suffering from were the side effects of AZT... If you look at the known documented side effects of AZT there is a similarity between those, a very strong similarity between those and the symptoms of full blown AIDS."

Graham Ross: "Trial in about 18 months time..."

The lawyer bringing the case will rely on Bob Treakall's medical records to support the claim that it was the drug that killed him not his disease.

Graham Ross: "There was never a diagnosis of AIDS at any stage. The form of pneumonia that is on the death certificate is not AIDS associated pneumonia. It was bronchopneumonia. The basis of our claim is that it was AZT that caused that damage, that is going to the whole issue."

Fears of side effects of AZT have led many patients to oppose its use. Some activists maintain that its to toxic it can kill. And yet the same drug was recently hailed as the centre of a breakthrough against the AIDS virus.

Newsman: "...the biggest ever study into AIDS treatment..."

At an international scientific conference in Denmark it was announced that cocktails of drugs each based on AZT could attack HIV and prolong life. And AZT's manufacturer is recommending to patients that once again they should not wait, but start taking the drugs early while they're still well in the hope of delaying the onset of AIDS.

Dr. Palmer: "I think the answer is very simple and that is, treat as early as possible in patients who have been diagnosed as being HIV positive... hit it early, hit it hard."

But is it really so simple? The recent history of AZT might suggest greater caution. Over the past decade clinical trials have tested the drug's long term effects and there have been clashes between the manufacturer, Wellcome, based here, and independent medical researchers over what the results show. Is AZT as good as Wellcome claims? Or as dangerous as its critics feared?

Panorama has investigated how the company dealtwith some uncomfortable evidence - its story which reveals a potential collision course between the pursuit of profit and the search for truth. AZT was first tested where panic met affluence - in the United States a decade ago. Among gay men in San Francisco and other cities the sudden presence of mass death set of a desperate search for treatments. Scientists at Wellcome's US laboratories found that a failed cancer chemotherapy agent inhibited replication of the AIDS virus. It was azidothymidine, AZT.

Dr. Barry: "Our senior laboratory technician that we had worked with for a long time came to my office and said, David I think we have it. And she showed me her laboratory results which showed that the virus had been completely inhibited."

Wellcome patented this breakthrough. In 1986 the company set the first controlled clinical trail of AIDS patients in eight American cities. Half were given AZT, half got an identical looking blank or placebo. The plan was to study them for six months but there were dramatic results only after four months and the trial was stopped early. Among patients taking the placebo there had been 19 deaths. In the matching group taking the real drug there was only one death. AZT worked at least short term, but as for the long-term an important minority had doubts.

Dr. A. Abrams: "We do know that AZT's benefit is short lived, and that if the study had gone too much longer then maybe that benefit that was seen at that point in time could have disappeared. So to say that taking the drug prolongs survival compared to taking the placebo I think was premature, because the study was too short."

And yet officials waived the usual requirement for a second clinical trial. The company worked at record speed with the Food & Drug Administration to prepare data for an approval hearing on Wellcome's application to sell AZT for AIDS patients. But this fast track was little too fast for the Hearing's Chairman.

Dr. Itzhak Brook: "I had serious doubts whether we had all the information we need upon toxicity, about the dose, about even how effective it was and I felt we needed a few more months to get answers from the company."

Dr. Barry: "...whether I agree with him or with you about the..."

The transcript of the Hearing released to Panorama shows that Dr. Barry said Wellcome viewed any delay with great chagrin. We have invested more that 80 million dollars in the program so far. It has been a tremendous burden to us, he said. We would definitely prefer not to continue that program as it is for any significant period of time.

Dr. Brook: "Well it was harsh reality type of approach. Here we were asking for science to protect the public and the answer was you have to consider our financial situation. If you don't approve it today. I'm not sure we can sustain the research of this drug, that was the implication. It was like telling us approve it now or never."

Reporter: "He thought you were saying, approve it now or never. Is that right?"

Dr. Barry: "I have no idea of what Dr. Brook thought."

Reporter: "Was that what you were saying?"

Dr. Barry: "No"

Reporter: "Then what were you saying?"

Dr. Barry: "That it was much better to approve it now than later, for everyone. For the company and particularly for the patients."

Reporter: "So when you said, we would definitely prefer not to continue and we look at this with great chagrin..."

Dr. Barry: "Yes..."

Reporter: "...that wasn't in any sense putting pressure on the committee to approve now."

Dr. Barry: "Of course I wanted pressure on the committee to approve now, that was not a threat, when I said we definitely prefer not to continue the program if the FDA and its committee had said, well though Dr. Barry you'll have to do it, we'd have done it."

Reporter: "But you were consciously putting pressure on the committee for a quick approval?"

Dr. Barry: "Yes, of course."

It worked. The drug was approved with only the Chairman voting against. Wellcome promoted the drug to doctors under its trade name, Retrovir.

Woman Promoter: "Retrovir is a major step forward. Our first weapon against this deathly virus. However, its only the beginning - a ray of hope for us all."

The company says it was hurrying to get help to patients. Wellcome set the initial cost of a year's supply of its ray of hope at ten thousand dollars. Its shares were already rising - after the approval hearing their price more than doubled.

Once Wellcome could sell AZT in 1987 its potential market across the United States and worldwide was perhaps a hundred thousand people living with AIDS. But just over the horizon was a much bigger prospect - millions of people infected with the virus but with no symptoms. If they could take AZT, it could become one of the great pharmaceutical jackpots - an expensive drug sold year after year to people who aren't ill.

People infected with HIV could expect to live for years before developing AIDS illnesses. So for them fears of AZT's long term dangers were important - they might take the drug for years. And some patients in the early trials of AZT found its side effects appalling.

Keith Kroebbel: "I think that AIDS drugs are not like what we're accustomed to thinking of as medicine. We think of antibiotics. AIDS drugs are chemotherapy, nasty nasty stuff, it really hurts your constitution, you've got your bone marrow cause the anaemia."

Randy Vielbig: "I also received two transfusions, two of the AZT, I have AZT related anaemia to this day even though I'm on a low dose of AZT at this time."

Reporter: "What did you feel?"

Kroebbel: "As if I had been poisoned. Very very seasick, it wasn't a throwing up kind of nausea, it was a seasickness that was in my bones. And headaches, inability to concentrate or respond."

Reporter: "How long did you stay on AZT?"

Kroebbel: "I was on it I think just about exactly 18 months."

Reporter: "And what happened when you stopped?"

Kroebbel: "I felt great. I felt so much better, that's when I stopped because I was going on vacation."

For the American government scientific adviser on AZT the drug's long term toxic effects were of major concern.

Dr. Ellen Cooper: "If the efficacy of the drug wanes or lessens over time and there are toxicities that aren't apparent at the beginning, most subtle toxicities that accumulate over time, there may come a point where there's more, the drug does less good than it does damage."

Reporter: "And what did you know about those long term effects at the moment the drug was approved?"

Dr. Cooper: "We really didn't know anything."

Dr. Cooper has told Panorama that she wanted a long term study of the drug among patients with no symptoms. But there was no long term study, The company and a team of researchers set up a trial notionally to last three years, but designed so that it might stop early if it found even a modest short term benefit.

Reporter: "Did you think that that was a good thing or a bad thing to do?"

Dr. Cooper: "I thought that it was not a good thing to do."

Reporter: "So why did it happen?"

Dr.Cooper: "Because other people disagreed with me."

Dr. Barry: "We surmised that if it delayed the onset of symptoms by say a year eventually it would delay their death by approximately that same period, say a year."

Reporter: "That was what you hoped and assumed?"

Dr. Barry: "That's what we believed overall in looking at all the data we had."

And as Dr. Barry anticipated this trial, codename 019, was stopped early, after studying patients for just over a year. Eight in a hundred on placebos had developed the first symptoms of AIDS. But among those taking AZT only four in a hundred had these symptoms. The US government, which had sponsored the trial, acted as cheerleader.

Louis W. Sullivan: "This finding underlines anew the need for people to voluntarily undergo HIV testing and counselling. We are indeed entering the period when AIDS may become a treatable disease."

But while taking AZT early was found to delay the onset of some AIDS symptoms, it was still not known if it could ultimately prolong life. The study stopped too soon to tell.

Dr. Cooper: "Its tempting to stop trials early, there's no question, certainly on the part of the manufacturers, you know we know they want their trials to be seen as successful positive trials, and investigators and sponsors, whether they're pharmaceutical companies or you know in many cases the government want that, want that as well, its good publicity, and of course its good business for the pharmaceutical companies."

Dr. Barry: "I don't think taking cynical views really is going to progress medical practice. What we were looking at is what is the best way to provide the most benefit to the most nations for the longest period of time, that's how we acted, I'm proud of it and I think we did it ethically, I think we did it right, and I think hundreds of thousands, maybe millions of patients have benefited because of that approach."

Reporter: "And so has your company."

Dr. Barry: "Its no longer my company."

Reporter: "And so has the company you then worked for."

Dr. Barry: "Yes, the company did, but we had many other drugs, I mean this was not our most prominent drug."

But AZT was Wellcome's second biggest selling drug. After the publicity for trial 019 shares boomed as a potential global market seemed within reach up to an estimated ten million people living with HIV. The company began to promote early use of AZT - one of its handouts said, this could bring tremendous benefits and have dramatic effects.

Dr. Donald Abrams: "I interpreted that drama and tremendous in a different way and saw that really we were preventing four out of every hundred people from progressing and I didn't feel that that was really worth the potential toxicities and costs."

Reporter: "So what did you make of those adjectives?"

Dr. Abrams: "Well I thought they might have been slightly inflated."

But how did Wellcome present AZT's already known side effects? A company hand out to patients said that the most common side effects, nausea, affected only a very small minority. But Wellcome's technical manual showed that in study 019 this very small minority was in fact 22 or 27% depending on dose. We wanted to ask Wellcome's then Chief Executive John Robb to answer these doubts about the company's promotion of AZT. He declined to be interviewed for this programme.

As sales of AZT grew in the early 90s so did public protests by AIDS activists fearing the drug had hidden dangers. The American trails of AZT left unresolved its long term risks and benefits. But the study designed to run for many years was already under way. But not in the United States. From its base in Oxford a team of British and French doctors had set up a prolonged trial codename 'Concorde' in 1988. The British side came from the specialist AIDS team of the Medical Research Council. For the first time they told Panorama the story of their clash with the company over the trial. They are the team's Chairman, Professor David Warrell. Scientific Secretary Dr. Tim Peto, and the principal investigator of the Concorde trail, Professor Ian Weller.

In 1989 they had to assess the value of the highly publicised results of trial 019 in America, and what they found left them unconvinced.

Prof. Ian Weller: "What we were looking at was a very small effect in terms of delay of progression of disease produced by AZT, very small. And the study, the average follow up or length of treatment was only just over a year, and we know that 50% of people remain well for ten years, so just over a year is rather a short time in the life of somebody who's well with HIV. So the real question for me was, does this degree of benefits persist?"

Like most studies the Concorde trial depended on the company for free supplies of the drug. In return two Wellcome scientists joined the Concorde team. But there was a basic difference over what should count as proof of the drug's effectiveness. The Medical Research Council wanted to concentrate on prolonging life or health.

Prof. Weller: "It was important therefore to at least run a trial for several years to get handle on whether it actually did any good in the long term in people that were well."

The company in line with some other experts also wanted to rely on a more immediate measure. AZT's effect on patients' blood. In particular their number of CD4 blood cells thought vital to the strength of the immune system. The study's British Chairman rejected this, believing AZT might artificially raise this blood count, without bringing any real health benefit.

Prof. David Warrell: "We were worried that the CD4 count might be a cosmetic measure."

Reporter: "Why then would the company want to include a CD4 count?"

Prof. Warrell: "Well a CD4 count had the great advantage that the changes were seen early on. Clearly the longer the study the more expensive, the more delayed the results."

But only a long term expensive study could settle the question troubling patients with no symptoms like Pascal De Bock. He started AZT in 1990 as soon as he found he was HIV positive.

Pascal the Bock: "The doctor who saw me I asked him is there any treatment, and he told me yes we have got this treatment, we still don't know exactly what it does but this is the only thing and I was desperate to sort of cling on to anything that would bring me life or that would somehow sustain my life."

But Pascal De Bock needed to know if it was worth going on with the drug when he developed what he fears were side effects.

de Bock: "It became almost like a headache every day, as soon as I was opening my eyes the headaches were there and they were not shifted by any type of medication. And that was literally me going up to bed and going to sleep with a headache and as soon as I was opening my eyes in the morning the headache was still there."

Reporter: "And how long did that go on for?"

de Bock: "Oh it went on for well for two years. And I couldn't make up my mind whether that drug or that treatment was doing me any good or any harm."

The Concorde team studied more than 1700 HIV patients at hospitals in Britain, Ireland and France. Half were given AZT early while they were still well. The other half got it only if they began to develop AIDS. Because of the known short term benefits of the drug, the study had been designed not to stop early. Only after more than four years were the Concorde team able to meet by the River Thames in Runnymede to hear the first news of their results. It was the longest and by far the most comprehensive trial of AZT. The French team, the British doctors and the company waited eagerly for the answer to their question - did taking AZT early bring any significant clinical benefit? They found none long term. Taking the drug before the onset of symptoms did not produce any significant difference in survival.

Prof. Ian Weller: "We showed no important clinical difference between the two policies of starting treatment early or later. So the first thing was one of depression but on the other hand that was a very important finding. Because we felt that we had shown that the benefit, the early benefit that had been demonstrated previously wore off.."

In fact it looked worse. The figures showed that more patients died among those who took AZT early. 96 died taking it early, 76 taking it late. But the investigators were cautious and anxious to avoid causing alarm. They calculated that given the size of their samples of patients the difference in death rates could be due to chance. It was not statistically significant.

Dr. Tim Peto: "We were very concerned indeed to avoid scaremongering and statistically that 96 is the same as 76 even though mathematically they're different."

Reporter: "But in fact the result was the wrong way?"

Dr. Peto: "The result were certainly the wrong way mathematically yes."

There was also a paradox. While it did not improve survival, taking AZT early did raise the level of patients' CD4 blood cells. So it should in theory give them longer life. But it didn't.

Prof. David Warrell: "It did seem to be a surrogate marker of potentially misleading index."

Reporter: "But this was one of the markers which the company had relied on in its own trial of AZT."

Prof. Warrell: "Exactly, so we felt vindicated in our reserve or scepticism about what one could infer from the CD4 count alone."

The Concorde doctors had agreed to publish a quick summary of their initial findings. But as Wellcome still maintained the value of CD4 counts this led to further disagreement still maintained the value of CD4 counts this led to further disagreement. The Committee Chairman tried to agree a form of words with the company to go as a letter in The Lancet.

Prof. Warrell: "The company representatives wanted to tone down the wording of the letter. As the publication data approached the telephone communication was more and more frequent and more and more frenzied, and it really almost degenerated into a matter of considering individual adjectives. We wanted to say the results casts serious doubt on the value of using changes in CD4 counts. A serious doubt. The company were very keen that we should delete 'serious', so we deleted 'serious' under pressure from the company."

A week after the first Concorde results the letter appeared in The Lancet in April 1993.

Newsman: "British drug company Wellcome has made millions selling AZT and today its shares fell over 15 pence or 7% of the company's value."

AZT came under attack from patients in Britain whose hopes had been dashed.

Pascal de Bock: "Initially I took the whole box of my tablets and put them in the bin and I mean well all the side effects disappeared. Somehow I wanted to make the wider public know that there was something, a very darker side into that marvellous treatment to help those people who suffer so much. Then suddenly the Concorde trial results just appeared and I felt really ecstatic. It was absolutely marvellous for me to realise that what the decision that I had made without somehow any medical advice had been the right one to make."

But the Wellcome Foundation seemed less ecstatic. Four days after the Concorde results at its London headquarters the company briefed the press and city analysts like Peter Cartwright about the trial's findings.

Peter Cartwright: "It wasn't the sort of meeting where maybe its been laid on for months in advance and its well scripted and well rehearsed and comes across as a very slick and very professional affair. This one was damage limitation and called at short notice and the company were on the back foot a little bit."

Reporter: "Why do you call it damage limitation?"

Cartwright: "Well because the share price was falling very rapidly."

The company told the press that an adequate analysis of Concorde would show it to fit their own shorter term studies suggesting that early treatment can improve survival. But this was the exact opposite of what Concorde had found. One of the company's overhead slides shown to the press contradicted another Concorde finding, saying survival appears to be correlated with CD4 response.

Prof. Ian Weller: "If anything Concorde showed that there wasn't a correlation between CD4 and survival, so the whole exercise and its a personal view, was one of damage limitation."

Reporter: "Was it a distortion of your findings?"

Prof. Weller: "I think you could interpret some of the overheads as a distortion of the conclusion, the main result, the bottom line of Concorde."

Prof. David Warrell: "Both the Chairmen of the co-ordinating committee were outraged by this behaviour of the Wellcome Foundation. I composed a letter and sent it to the Wellcome protesting the misleading information provided at the city meeting."

Reporter: "Did you get a response?"

Prof. Warrell: "We didn't."

Panorama wanted to ask Wellcome staff about their comments to analysts and the press. Dr. Trevor Jones, then Director of Research, and Dr. Paul Fiddian a member of the Concorde team - they both declined to be interviewed.

Later that year, in December 1993, the whole Concorde team met in a hotel at Paris Airport to approve the wording of their full report. There were disagreements on points of scientifical detail, and one overriding problem.

Prof. Weller: "Although there were lots of discussions about small points and indeed we did accommodate some of the suggestions, trying to work together on it, the real thing was the last sentence of the paper, and that was the result of this study do not encourage the early use of AZT."

In a compromise with the company this conclusion had been left out of the first letter in The Lancet. Now Wellcome wanted to delete it from the full report too.

Prof. Warrell: "Really it was the conclusion, the main conclusion that they couldn't swallow."

Reporter: "Why couldn't they swallow it?"

Prof. Warrel: "Well why means why scientifically or why commercially, I mean why commercially because this would decrease the market of one of their best selling drugs. Why scientifically we could never really understand."

Reporter: "There was deadlock. The Wellcome representatives continued to insist on deleting this sentence."

Prof. Warrell: "I must say we were a great deal more obstinate this time than we were over the letter because of our experience of the letter. There was no certainty at all that had we compromised the company would not have reneged again after publication."

Prof. Weller: "The company rehearsed its criticisms again and then late on in the meeting stated that they felt they couldn't endorse the report."

Panorama wanted to ask why, but Dr. Thierry Nebout and Dr. Jane Yeo the two Wellcome scientists at the meeting have declined to be interviewed.

Prof. Warrell: "What we learned I suppose was, and we shouldn't have been surprised, is that when the wrong results is produced for a famous and flourishing company on which a great deal of financial expectation rests, the company representatives are going to be under a great deal of pressure, and that the interpretation of those results is going to be stressed, there's going to be an attempt perhaps to blunt the message, to modify it, to make amore mellow conclusion from results which seem to be inescapable in their implications."

Late last year the full five year results of the Concorde study were announced at the AIDS Conference in Copenhagen. The same team have now made an independent analysis codenamed 'Opal' of the company trials of early AZT, and combined the results with Concorde to give greater statistical power.

Dr. Janet Darbyshire: "We put this together and this was the purpose of undertaking this joint follow up of the trials you can see that there is actually no difference between the two policies in terms of survival."

Worse, in the combined survival results after more than five years there are still more deaths among patients taking AZT early. The difference is still not statistically significant, but the numbers are 411 who took AZT early, 387 in the group who waited until they began to develop AIDS.

Worse still, in the only fully independent data, the five year Concorde result taken alone, the difference now is statistically significant. 240 deaths in the early AZT patients, against 199 deaths.

Reporter: "Can you be certain that there is no long term danger in taking AZT early?"

Dr. Tim Peto: "No we certainly can't say that. There could easily be a long term danger which the trials aren't large enough to reliably detect but that certainly is possible."

But alongside this bad news about AZT there was the good news reported late last year. In a separate trial also run by the Medical Research Council, and codenamed 'Delta', there were better results if AZT was taken in combination with other drugs. And about this the company, now merged with Glaxo, was prepared to take an interview.

Dr. James Palmer: "What it showed was that you could improve by about 25 to 30%, in other words delay both the onset of AIDS and also show prolongation of life in patients with HIV, and that was very exciting because it was a real ray of hope."

And with this second ray of hope in a decade the company again advises HIV patients to start treatment as early as possible. James Quinlan had no symptoms of AIDS when he joined the Delta trial in the summer of 1992. Encouraged by the study's results he's now experimenting with more extensive cocktails of drugs.

James Quinlan: "The AZT and the 3TC are the antivirals, and the DDI, and I take hydroxia which is an anti-cancer drug, and the encyclovir specifically fights herpes, the septrin is an anti-PCP for pneumonia. They offered me a position on the trial, it was a sort of a white mouse syndrome and I felt quite happy to be the white mouse. I believed on the basis of you know if you take the paracetamol the moment you think you're going to get a headache rather than you know when you've got a blinding headache and leave it, so I was more convinced on the basis of that I would quite happily take it earlier even though I didn't have any symptoms."

The Delta results shows patients like James that a cocktail of drugs is better than AZT alone. But Delta was not designed to answer the vital question of when to start taking a cocktail. If patients again have their hopes raised of extra benefit from starting treatment early then its possible that their hopes may again be dashed by later research. Is there a danger of going round that whole cycle again?

Dr. Palmer: "The simple answer to that question is yes, there's always the potential danger, but the answer is at the moment we don't know. The data that we have with combination therapy suggest that they have significant benefits over what was available previously, so i.e. better than no treatment or AZT monotherapy."

Reporter: "But if we don't know why is the company saying start early?"

Dr. Palmer: "Well its the typical dilemma that faces physicians who are treating AIDS patients, and it really is an ethical dilemma because it would be very hard not to treat a patient with a combination therapy when you see for instance the results of the Delta study."

Dr. Tim Peto: "We do not know when to start combination treatment, and se exactly the same issues which we had back in 1987 are with us today. We don't know whether its worthwhile taking combinations early when you're still well or whether in fact you can afford to wait until you're ill."

Patients and their doctors can only know when to start treatment with an AZT cocktail from another long term study like Concorde. But now it may prove harder fro researchers to display their independence from the pharmaceutical industry. There's a squeeze on budgets and the medical research is now the responsibility of the Department of trade and Industry. In future more projects will be jointly financed and therefore controlled by drug companies. Which can only increase the risk that commercial pressures will compromise scientific enquiry. *

VIRUSMYTH HOMEPAGE