AZT (Azidothymidine a.k.a Zidovudine) was the first drug approved to target HIV. Consequently, it has a very special – and quite controversial – place in the history of HIV/AIDS. It’s for this reason that I’m going to try and provide a brief overview of its development and its early days as the only antiviral drug available.

In Part One I aim to develop a broad timeline of the main clinical trials that influenced how it was used. This will include links to  additional references. In Part Two I will look at the controversies and other issues that surrounded the use of AZT. I don’t claim that either post will be comprehensive, not least because of my limited knowledge of clinical issues. Therefore I heartily welcome comments, criticisms and other input. (Although I won’t accept abusive language, so play nice!)

Full Disclosure

I am not a clinician, so if you’re  expecting a clinical paper then you will be disappointed. But I do have some relevant professional experience. When it was introduced I was working as a social worker in Australia’s largest AIDS unit in St. Vincent’s Hospital in Sydney. So I saw, up close, what AZT was – and wasn’t – doing to people.

But I should add that I have never used AZT myself, as I am HIV negative.  So my experience of the drug is what I’ve seen it do to people using our services, what other people have told me, and what I’ve read about it. So it’s personal inasmuch as it rarely left my consciousness in the 80s and 90s because of my work. But it’s not too personal because AZT was never part of my personal routine.

Setting the Scene

It’s important to understand the context in which AZT appeared. Most particularly, that it had been almost six years between the first AIDS diagnosis and the licensing of the drug. For our community that was six very long years during which we lost lovers, friends, family members and community activists. Six long years during which we were subject to the most hideous forms of  vilification – from the media, politicians and moral entrepreneurs. And six long years during which we wondered if there would ever be an end to the loss and the pain.

It’s no under-statement, then, to say that we were desperate. So it was understandable that there may have been some reluctance to question this drug – this possible magic bullet – too hard. It had to work.

But AZT did come with a number of questions, which I’ll try and identify here. And while I shall do this as a non-clinician, it will still require a little medical knowledge on your part. In particular, you will need to know what CD4 cells are and what the significance of CD4 counts is. This Wikipedia article should help.

The Development of AZT

AZT wasn’t developed specifically for use against HIV. It was actually developed as an anti-cancer drug at the Michigan Cancer Foundation in 1964. But it didn’t work, so it was shelved until 1984 when drug company Burroughs Wellcome (now GlaxoSmithKlein) began testing it, along with a number of other drugs, as a possible anti-HIV drug. In November 1984 Burroughs Wellcome sent samples to the US Food and Drug Administration (FDA) for confirmation that it worked against the virus in test tubes.

The FDA confirmed that AZT worked in test tubes, so the next step was to test in on humans. This occurred in July 1985, when 19 patients were given the drug. (1) The results were deemed to be of sufficient statistical significance to justify a larger trial.

That larger trial began in 1986 (2). 282 people with AIDS were randomly assigned AZT or a placebo. No one – patient or clinician – was supposed to know who had been given what. The trial was supposed to run for 24 months. However, early analysis of the data showed significant differences between the two groups. Consequently, the trial was stopped and all participants were put on AZT. The data was reported to the FDA, who deemed it to be so significant they gave formal approval for the drug to be used on people with AIDS from March 20th 1987. It was also approved for use in the UK and Australia around this time. [Note: The objectivity of the trial was subsequently brought into question. This is covered in Part Two.]

The apparent success of this trial led researchers to explore whether the drug may be of benefit to people who were HIV positive but had yet to develop symptoms of AIDS. In July 1987 the AIDS Clinical Trials Group (ACTG) began a two-part trial of asymptomatic people with HIV. One study (3) involved people with CD4 cell counts of fewer than 500 per cubic millimetre. The other (4) involved people with CD4 counts greater than 500 per cubic millimetre. Both trials came under the heading ‘ACTG Protocol 019’. And both were ‘double-blinded’; that is, neither researchers nor participants knew what they were receiving.

The first arm of the study (people below 500 CD4 cells) involved 1,338 people. 438 were given a placebo; 453 were given 500 mg of AZT a day and 457 received 1500 mg a day. After 55 weeks, 33 members of the placebo group had developed AIDS, as had 11 of the 500 mg group and 15 of the 1500 mg group. When researchers reported their findings in April 1990 they concluded:

“…Zidovudine is safe and effective in persons with asymptomatic HIV infection and fewer than 500 CD4 cells per cubic millimetre. Additional study will be required to determine whether such treatment will ultimately improve survival of persons with HIV.”

The FDA approved the use of AZT in asymptomatic HIV+ people with fewer than 500 CD4 cells in response.

The second arm of the study had 1,637 participants, all with CD4 counts greater than 500. 547 were given the placebo, 549 were given 500 mg a day and 541 received 1500 mg a day. In 1989 the study was modified so that any participants whose CD4 cells dropped below 500 were offered open-label AZT at the dose of 500 mg per day. In 1995 researchers concluded:

“Treatment with AZT slows the decline in CD4 counts but does not significantly prolong either AIDS-free or overall survival.”

These findings echoed those of a similar study of that time. The Concorde Study (5) involved 1,749 participants in the UK, Ireland and France. Participants received either 1,000 mg of AZT a day or a placebo, taken in four daily doses. Like the ACTG 019 trial, participants could switch to open label AZT if their CD4 cells fell below 500.

But when the data were analysed, there was very little difference between the outcomes of the two groups. For example, 92% of those who started AZT immediately survived, compared to 93% of those on the placebo. The most noticeable difference was the slower rate of decline in CD4 count in those who began AZT immediately.

Five years later, a meta-analysis of research on AZT (6) reached a similar conclusion:

“Zidovudine does not increase a person’s chance of AIDS-free survival in the long-term, although it does reduce disease progression in the short-term.”

And so it was that the real effect of AZT was finally, clinically, described. Not really what we had hoped for. But the disappointing news was tempered by a more positive observation. And that was that AZT was significantly more effective when used in conjunction with one of the new antivirals that had been developed. In effect, what this statement was recognising was that we had just turned a significant corner in the treatment of HIV – combination therapy.

1. NIH History, “In Their Own Words”, Audio Transcript, Dr Robert Yarchoan. Excerpt 3.
2. “The efficacy of azidothymidine(AZT) in the treatment of patients with AIDS and AIDS-related complex: a double-blind, placebo controlled trial.” New England Journal of Medicine, 23^rd July 1987.
3. “Zidovudine in asymptomatic human immunodeficiency virus infection. A controlled trial in persons with fewer than 500 CD4 cells per cubic millimeter.” New England Journal of Medicine, April 1990
4. “A comparison of immediate with deferred zidovudine therapy for asymptomatic HIV-infected adults with CD4 cell counts of 500 or more per cubic millimetre”, New England Journal of Medicine, 17^th August 1995
5. “Concorde:MRC/ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection”, The Lancet, Volume 343, Issue 8902, P 871-881, April 09,1994
6. HIV Trialists Collaborative Group, “Zidovudine, didanosine and zalcatabine in the treatment of HIV infection: meta-analyses of the randomised evidence”, National  Centre for Biotechnology Information, US National Library of Medicine, National Institutes of Health.

 

Acknowledgement: My thanks to Rupert Whitaker for taking time out to discuss this issue with me.