Two Committees, Two Conclusions
Critiques by the AZT dissidents would continue after the results of the 019 study were announced. But perhaps more noteworthy (though in practice little noted at the time outside of the scientific press) was the lack of consensus in mainstream science about the merits of early intervention with the drug. All mainstream authorities
agreed that AZT should be prescribed to patients with AIDS. But should it be recommended for use by every HIV-infected person with fewer than five hundred T cells (let alone those with more than five hundred T cells)? Here the gap in perception was not between the two coasts of the United States, but rather between the opposite shores of the Atlantic Ocean. While the New England Journal of Medicine had promoted the message that the "time had come" for early intervention, Lancet , the most important British medical journal, suggested that "clinicians should change their prescribing habits with caution." The 019 study, according to Lancet , had simply shown that AZT could prevent a small number of people from progressing to AIDS over a short time period. Could these results be extrapolated to the majority of patients, who would progress more slowly in any case? Did the drug really halve the progression rate, or did it simply delay progression for a period of months until the onset of drug resistance?
According to Anthony Pinching, a British immunologist and AIDS clinical trials investigator, the difference in judgment "was exacerbated by the 8-month delay between the announcement of some preliminary results and publication [of the study]"—a delay that Europeans, including the British, had found irritating. During this time, while the rest of the world was waiting to see the data, the NIH and the FDA had effectively given their blessing to AZT use in asymptomatics. In the United States, hopes had coalesced into certainty; elsewhere, scientists and patients were in limbo. At root, said Pinching in an editorial about "knowledge and uncertainty" in AZT use, the problem was that U.S. authorities had "extrapolated" beyond the limits of the actual data—even if one considered the full data from the published study. They had been led beyond the limits of legitimate scientific deduction by "the widespread desire to see progress achieved and the wish to be seen to have made such progress." To illustrate his point about extrapolation, Pinching listed fifteen questions about AZT use in asymptomatics that still remained to be answered, even after the conclusion of 019.
The issue of what remained to be answered was very much on the minds of researchers throughout Europe, for some of them were smack in the middle of their own study when the media began trumpeting the news about the termination of 019. A consortium of researchers in Britain, Ireland, and France was conducting a trial dubbed "Concorde" that was substantially similar to 019. As in the United States, the European researchers had dealt with the ethics of placebo-controlled
trials; as in the United States, the Europeans had had to justify to community groups why such trials were necessary in studying AZT use in asymptomatics. But now—even after the results from 019 had been reported—the Concorde researchers were intent on continuing the study. As far as they were concerned, a state of equipoise still held: "The results we have seen," said Jean-Pierre Aboulker, the head of the study on the French side, "do not allow us to give a strict recommendation to give AZT." In deference to those who trusted the results of 019, they would modify the protocol to allow participants to begin "open-label" use of AZT, if they chose not to run the risk of being given the placebo. This change would introduce methodological complications into the interpretation of the data. But it would satisfy ethical objections while allowing Concorde to continue.
"Two committees looking at one set of data have come to radically different conclusions about the anti-AIDS drug AZT," was how a reporter for Science characterized the transatlantic dispute. In practice, everyone agreed on which questions they would like to have answered—questions about long-term risks and benefits, about the development of resistance, about whether early use would squander the limited efficacy of the drug against the virus. The different actions taken had to do with different judgments about the implications of what was known and what wasn't. How and when should a particular balance of certainty and uncertainty about a drug inform clinical practice? And what is the feasibility of continuing a placebo-controlled trial, once a specific (but not conclusive) benefit had been shown?
"I think there is generally a greater skepticism in the U.K. about the value of treatments than in the U.S.," commented biostatistician Susan Ellenberg, reflecting a widespread perception in the U.S. biomedical community. "I think there is much more reluctance [in Britain] to treat unless it is absolutely necessary." Such cultural differences were compounded by differences in the sheer magnitude of the epidemic in the two countries, not to mention the more vociferous character of AIDS treatment activism in the United States. Continuing the 019 trial "was not a conceivable possibility when the data were first seen … by those of us who were on the executive committee of the ACTG," researcher Martin Hirsch later recalled. "There was no choice but to stop the study given what the results were. … If we had withheld that kind of information we would have been strung up on trees. And if we had given out the information and said we were going to continue the placebo control trial anyway, we would have been strung up even
quicker." Similarly, the principal investigator for Concorde in Britain, Dr. Ian Weller, suggested to Science that the large numbers of AIDS patients in the United States had generated greater pressures there for the immediate translation of research into results. And once the formal guidelines had been issued, all the remaining uncertainties, though never denied, had in a practical sense been bracketed, largely to be ignored by the media, most practicing physicians, and most patients. Concorde, by contrast, chose to put uncertainty in the foreground. With the goal of obtaining definitive answers about early intervention with AZT, the Concorde trial would keep running all the way to 1993. Ironically, the results of Concorde, when finally available, would provoke more controversy than any AIDS antiviral study ever.