Breakthrough! Or maybe not ...

This week's success in Aids drug trials is good news. But scientists have reason to be cautious, says Steve Connor

The venue was a room in the Sheraton Hotel at Heathrow Airport. About 20 of the world's leading Aids researchers had gathered to listen to the latest results of a large clinical trial of anti-HIV drugs. As medical protocol demanded, they had until now all been deliberately kept in the dark about data from the ''double blind'' trial, when neither doctor nor patient knows exactly who is taking which drug. It is standard procedure to prevent experimental bias.

When the International Co-ordinating Committee of the Delta trial heard the results of the two-year follow-up of 3,000 patients from eight countries, an unusual silence descended around the table. They needed time to absorb the magnitude of what they were being told, and perhaps check themselves from thinking they had heard it all before. They could even be forgiven for experiencing a feeling of deja vu. It was not the first time that they were being told to stop an Aids drug trial because the results were so good - to continue would be unethical, given that some patients were deliberately being deprived of what had now become the best treatment.

Yet the results were plain to see. The Delta trial showed that two drugs were better than one at preventing death from Aids over two to three years. In fact, death rates had been reduced by almost 40 per cent in the group taking two drugs compared with the group taking one.

The Heathrow meeting happened two weeks ago yesterday. It took the committee several days to agree on a public statement, which they wanted to make as soon as possible to tell patients and doctors of the results. The news emerged earlier this week and made headlines throughout the world. Many newspapers, included this one, heralded it as a breakthrough.

This was indeed the first real hope since 1986, when a previous clinical trial appeared to show that one drug, AZT, was better than none at all. That trial, too, had been stopped for ethical reasons, albeit after only six months.

Yet it must have played on the minds of many of the scientists at the Delta results meeting that, by stopping short this latest trial, they might end up repeating a mistake made with the earlier 1986 "breakthrough''.

That trial, it turned out, was ended prematurely. Six months into the experiment, it was clear that patients using AZT were benefiting. Out of 145 people taking the drug, only one had died, compared with 19 deaths in the placebo group of 137 who took nothing but a sugar pill. About twice as many in the placebo group had also developed Aids. However, after the trial had been stopped, as time went on, the advantages of taking AZT began to become less apparent. It subsequently emerged that AZT at best can only buy a little extra time, perhaps a year, and even then at the risk of some pretty dreadful side-effects.

Most Aids researchers today feel it was a mistake to stop this 1986 trial before the true limitations of AZT could be seen. But 1986 was a time of unprecedented pressure on the medical community to come up with any Aids treatment that worked. ''The simple message then was to get drugs into bodies now,'' says Nick Partridge, chief executive of the Terrence Higgins Trust, an Aids charity. ''There was a very strong demand from the patients themselves for AZT to be made available as soon as possible.''

Gay pressure groups in Britain and the US lobbied hard for AZT, which was the only drug to show any signs of being able to limit the replication of HIV in an infected person. For a short period at the end of the Eighties, it was the only ''lifeline of hope'' offered to people with HIV and Aids, Mr Partridge says.

That was a difficult time for medical scientists who wanted to establish proper clinical trials - when a randomly chosen group of patients taking a new drug are compared against those given placebo. Scientists are particularly interested in ''clinical end points'', which in the case of Aids often means waiting until someone dies. It may seem a brutal form of experimentation, but such double-blind, placebo-controlled trials are the most powerful method of determining whether a drug works in prolonging life.

The problems of testing AZT in clinical trials have been made worse by suggestions that some patients taking part have deliberately tried to circumvent scientific protocols. Some patients involved in earlier trials have deliberately mixed their medication with that of friends to limit the risk of being given a useless placebo.

Despite such difficulties, British and French scientists planned in 1988 what was then the largest clinical trial of AZT in both Aids patients and HIV-infected people without symptoms. The trial, called Concorde, involved 1,749 patients being followed over a three-year period. Preliminary results of the trial, released in a letter to the Lancet in April 1993, showed that AZT was no better than a placebo at preventing death or the onset of Aids in healthy, HIV-positive people.

After three years, 92 per cent of the AZT group were still alive, compared with 93 per cent survival in the placebo group. In both groups, 18 per cent had gone on to develop Aids and side-effects were significantly more common in the AZT group.

Concorde helped to fuel a growing backlash against AZT on both sides of the Atlantic. The Terrence Higgins Trust was picketed by Aids patients for being too closely linked with Wellcome and its AZT, and a vociferous minority of Aids activists began a campaign, alleging it was the drug, rather than HIV, that was the cause of the disease. The disappointment in AZT helped to foster a climate of new age anti-science within sections of the Aids community who felt the answer to the disease rested with alternative therapies rather than synthetic drugs.

Part of the reason why the Concorde trial was a crushing disappointment for the Aids community was to do with how the caveats and uncertainties of scientific research are translated for a wider public. Undoubtedly, the 1986 clinical trial was interpreted as a ''breakthrough'' (which was subsequently shattered) but this is not a term most scientists ever use. Their preferred phrases, such as ''significant step forward'', do not have quite the same impact with a headline-hunting media.

It was unusual, therefore, for journalists to be told not to play down the significance of the Delta trial results earlier this week. Patients taking both AZT in combination with one of two other anti-viral drugs, called ddI (didanosine) and ddC (zalcitabine), were significantly less likely to die during the period of the trial. Reduction in death rates over the course of the trial was 38 per cent for patients who took two drugs compared with those taking AZT alone. The data showed that 17 per cent of participants who took AZT alone died during the trial, compared with 10 per cent of those who took AZT with ddi and 12 per cent of those who took AZT with ddC.

''We were very surprised at the extent of the effect,'' says Brian Gazzard, UK trial co-ordinator and director of the Aids unit at London's Chelsea and Westminster Hospital. ''This is the first study with long-term follow- up in which survival has been changed dramatically. It establishes once and for all that anti-viral drugs can prolong life.''

Tim Peto, consultant in infectious diseases at the John Radcliffe Hospital in Oxford, who was at the hotel room meeting at Heathrow two weeks ago, was equally adamant that the Delta trial represented the most significant research into Aids treatment for nearly 10 years. His optimism is shared by Professor Alasdair Breckendridge of Liverpool University who chairs the UK Co-ordinating Committee for Delta. ''It is important not to underestimate what has been shown,'' he says.

It seems such optimism is unlikely to be displaced. At an international Aids meeting in Copenhagen yesterday, it became clear that an American drugs trial similar to Delta supports the two-drug approach of combination therapy. Professor Tony Pinching of St Bartholomew's Hospital in London, said: "Clinicians are now seriously persuaded by this data, which they weren't earlier in the week. It is good to see doctors on both sides of the Atlantic coming together. The feelings in the corridor are that we now have enough firm data to act on."

The next stage is to see whether three or more drugs are better than two. The Medical Research Council has already set up a trial of four drugs taken in combination to test the idea in yet another clinical trial.

Unfortunately, unanswered questions remain about combination therapy. The Delta trial does not tell scientists when is the best time to start using the drugs and for how long to continue. It also does not make clear whether people already being treated with AZT get any long-term benefit from switching to the two-drug approach. ''While these drug combinations can slow progression to Aids, they do not prevent it, and the increase in life expectancy is probably still quite small,'' Nick Partridge says.

So can the Delta trial, after all, warrant the label of a genuine breakthrough? Yes and no, says Tim Peto. ''It's a breakthrough in the sense that future research will proceed in a logical and sensible way, and so if the finding influences future research, then it's a breakthrough.''

And how many breakthroughs make a cure? ''Well you need a least another three, four or five to get that.''

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