Ray Of Hope
UK BBC Documentary
Panorama London, March 1996
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
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.
"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
"He gradually began to lose more and more weight, then he began
to get lots of minor infections."
"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.
"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."
"Trial in about 18 months time..."
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.
"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
"...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.
"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?
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,
"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."
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.
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
"...whether I agree with him or with you about the..."
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.
"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."
"He thought you were saying, approve it now or never. Is that
"I have no idea of what Dr. Brook thought."
"Was that what you were saying?"
"Then what were you saying?"
"That it was much better to approve it now than later, for
everyone. For the company and particularly for the patients."
"So when you said, we would definitely prefer not to continue
and we look at this with great chagrin..."
"...that wasn't in any sense putting pressure on the committee
to approve now."
"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."
"But you were consciously putting pressure on the committee
for a quick approval?"
"Yes, of course."
The drug was approved with only the Chairman voting against. Wellcome
promoted the drug to doctors under its trade name, Retrovir.
"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."
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.
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
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.
"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."
"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."
"What did you feel?"
"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."
"How long did you stay on AZT?"
"I was on it I think just about exactly 18 months."
"And what happened when you stopped?"
"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.
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
"And what did you know about those long term effects at the
moment the drug was approved?"
"We really didn't know anything."
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.
"Did you think that that was a good thing or a bad thing to
"I thought that it was not a good thing to do."
"So why did it happen?"
"Because other people disagreed with me."
"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."
"That was what you hoped and assumed?"
"That's what we believed overall in looking at all the data
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.
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.
"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
"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."
"And so has your company."
"Its no longer my company."
"And so has the company you then worked for."
"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.
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."
"So what did you make of those adjectives?"
"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.
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.
"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."
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
Warrell: "We were worried that the CD4 count might be a
"Why then would the company want to include a CD4 count?"
"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.
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."
De Bock needed to know if it was worth going on with the drug when
he developed what he fears were side effects.
"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."
"And how long did that go on for?"
"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."
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.
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
Peto: "We were very concerned indeed to avoid scaremongering
and statistically that 96 is the same as 76 even though mathematically
"But in fact the result was the wrong way?"
"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.
Warrell: "It did seem to be a surrogate marker of potentially
"But this was one of the markers which the company had relied
on in its own trial of AZT."
"Exactly, so we felt vindicated in our reserve or scepticism
about what one could infer from the CD4 count alone."
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
"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
"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.
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.
"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."
"Why do you call it damage limitation?"
"Well because the share price was falling very rapidly."
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.
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."
"Was it a distortion of your findings?"
"I think you could interpret some of the overheads as a distortion
of the conclusion, the main result, the bottom line of Concorde."
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."
"Did you get a response?"
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.
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
"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.
"Really it was the conclusion, the main conclusion that they
"Why couldn't they swallow it?"
"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
"There was deadlock. The Wellcome representatives continued
to insist on deleting this sentence."
"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."
"The company rehearsed its criticisms again and then late on
in the meeting stated that they felt they couldn't endorse the report."
to ask why, but Dr. Thierry Nebout and Dr. Jane Yeo the two Wellcome
scientists at the meeting have declined to be interviewed.
"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
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
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
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.
"Can you be certain that there is no long term danger in taking
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."
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.
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.
"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?
"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."
"But if we don't know why is the company saying start early?"
"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."
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."
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.