AZT: "The Time Has Come"
This notion that HIV disease could soon become a chronic manageable illness received a sharp boost in August 1989 with the release of the latest news about AZT. "The drug AZT can delay the onset of AIDS in people who are infected with the virus but have no symptoms," began a front-page New York Times article. ACTG 019, as the ACTG-sponsored study of AZT use in asymptomatic HIV-infected patients was dubbed, had just been halted upon the discovery by the Data and Safety Monitoring Board that the participants on placebo had been twice as likely to develop AIDS-related symptoms as those taking AZT. Just a few weeks earlier, ACTG 016 had also been ended, with the conclusion that AZT helped prevent HIV-infected people with mild symptoms from progressing to full AIDS. Out of 713 people in that study, 36 taking a placebo had progressed to AIDS, versus only 14 of those on AZT. Dr. Jerome Groopman had called it "the first clear proof that early intervention makes a difference." Now, with the results from 019, the verdict seemed to be in. "Today we are witnessing a turning point in the battle to change AIDS from a fatal disease to a treatable one," said Dr. Louis Sullivan, the Bush administration's secretary of health and human services. It was
indeed a turning point, though 019 would prove to be one of the most-debated studies in the history of AIDS clinical trials.
The 019 study finally made its way into the New England Journal the following April, with Paul Volberding of San Francisco listed as the first author. About 1,500 patients at thirty-two trial sites around the country had participated in the study for an average time of fifty-five weeks. Though none of them had AIDS symptoms upon entry, all of them were immune deficient, with T cell counts below five hundred per cubic millimeter of blood. One third had received fifteen hundred milligrams a day of AZT—by the time the study ended, this was generally believed to be an unnecessarily high dose—and 14 patients in that group had developed an AIDS-defining illness. Another third had received five hundred milligrams a day, with 11 developing AIDS. And of the final third, the patients on placebo, 33 had developed AIDS. AZT did not stop patients, as an aggregate, from developing AIDS, but it appeared to slow the process down, at least over a fifty-five-week period. Furthermore, the subjects receiving AZT (either high or low doses) showed, on average, statistically significant increases in their T-cell counts as well as decreases in their "p24 antigen levels" (p24 is one of the core proteins that make up HIV, so a measure of p24 is a crude measure of how much virus is present in the bloodstream—also called the "viral load"). These markers provided additional evidence that AZT was boosting immune functioning while curtailing viral replication.
What about the rumors of "cheating" by patients seeking to avoid the placebo? Did this skew the study and make the results untrustworthy? "There were lots of stories circulated in the press about people sharing drugs, analyzing drugs," recalled Volberding. But lab tests to detect the presence of AZT in the blood of the placebo patients suggested that drug sharing in fact "was an incredibly small problem." In any event, noncompliance actually strengthened the results of the study, the authors of the study results argued, since it "would tend to give results that underestimate the true effect of zidovudine" (the generic pharmaceutical name for AZT). Noncompliance effectively blurred the differences between the treatment arm and the placebo arm, so the demonstration of a statistically significant difference became all the more impressive.
Volberding and his coauthors included a series of important disclaimers. Since the trial had been ended early, there was still no definitive evidence about the long-term benefits or safety of AZT: "Thus,
it is possible that the eventual risks of disease progression in the three treatment groups could become similar after a longer time period." This might prove true particularly if AZT were to lose its effectiveness after extended use, as the virus mutated to resist the drug. (Such "resistance-conferring mutations" had already been observed in the test tube.) Finally, said the authors, "it is possible that even if zidovudine persistently delays the onset of AIDS, it may not have an ultimate effect on survival." On first glance, this was a surprising and paradoxical notion: how could a drug delay the progression to AIDS without extending the patient's life span? Volberding and his coauthors didn't elaborate, but the implication was that once progression did occur, the downhill course might then be rapid. Such cases were not unknown in cancer treatment research, where a drug might shrink the size of a tumor yet not confer any survival benefit upon the patient.
The accompanying editorial, by Dr. Gerald Friedland, acknowledged these various uncertainties and also spoke of the psychological implications of putting asymptomatic people on AZT: "The decision to start therapy … converts an apparently healthy person into a patient probably committed to lifelong treatment." The initiation of therapy in effect transformed the infected person's identity; this was not an act to be undertaken lightly. Nor was there any hard evidence from 019 about the best time to take such action: Was it when the patient's T-cell count dropped to seven hundred per cubic millimeter? Five hundred? Three hundred? But despite these words of caution, the overall tone of the editorial was upbeat, and the title conveyed the basic message: "Early Treatment for HIV: The Time Has Come." Friedland wrote: "The results of this study strongly support a recommendation to institute zidovudine therapy at a dose of five hundred mg per day [the lower, less toxic dose used in the study] in persons with asymptomatic HIV infection and CD4+ cell counts [T-cell counts] below five hundred per cubic millimeter."
Treatment recommendations in an editorial in the New England Journal carry considerable authority, but in a certain sense these were moot. Everyone had known about the study for eight months. Moreover, in early 1990 the FDA's new Antiviral Advisory Committee (one of more than forty standing committees of experts charged with giving independent scientific advice to the agency) had already recommended changing the labeling for AZT to include all HIV-positive patients with T-cell counts below five hundred. Despite concerns about the development of drug resistance, the vote this time was unanimous.
The FDA's Ellen Cooper had reservations about the recommendation—after all, the vast majority of people in each arm of the study had done well over the course of fifty-five weeks; the percentage of "events" (progression to AIDS) was small. Did it really make sense to begin mass administration of AZT to hundreds of thousands of relatively healthy people in order to prevent a small fraction of them from progressing to AIDS each year? As Cooper would later acknowledge, this was ultimately less a scientific question than "a matter of judgment and generalization." In the end, the FDA adopted the advisory committee's recommendations on March 2, and the NIH issued new guidelines for physicians concerning when to prescribe AZT. Burroughs Wellcome's potential market thereby increased by a factor of more than ten: In the United States alone, there were fifty thousand reported living AIDS patients, but an estimated six hundred thousand HIV-infected people with no AIDS-defining illnesses and with T-cell counts below five hundred. In England, the stock value of parent company Wellcome PLC increased by 1.4 billion pounds.
In practice, the findings of the 019 study, announced only in preliminary form to the media by NIAID, had provided the basis for regulatory policy making before the full results had even appeared in a peer-reviewed journal, where they could be scrutinized by other experts. Project Inform praised NIAID for its "efforts to release important news without waiting the extra 6 months or more needed for acceptance and printing of a completed journal article." For some time, activist groups had been insisting on the rights of people with AIDS to have access to medical data, and they had criticized the tendencies of some medical journals to monopolize control of information by threatening not to publish studies that had been disclosed to the press. But others, both within the AIDS movement and the scientific establishment, would condemn the practice of "science by press release." As far as Fauci was concerned, however, he really didn't have much of a choice, given the widespread interest in the 019 trial and the extensive monitoring of science by the AIDS movement: "Very, very quickly, everyone would have known the study was terminated. … It would have been unacceptable to everyone to make them guess why."