The NIAID-sponsored trials pursued scientifically safer and more predictable strategies. Since AZT had been shown to have efficacy, investigators focused attention on other dideoxynucleosides,
the family of nucleoside analogues to which AZT belongs. Two drugs in particular showed promise: dideoxycytidine (ddC) and dideoxyinosine (ddI). And since AZT's effect had been shown only in advanced cases of AIDS, it made sense to study the drug in less sick patients to see if it was beneficial to begin prescribing the drug earlier in the course of illness. Two large trials were begun: one, labeled "Protocol 016," studied AZT in mildly symptomatic HIV-infected patients; the other, "Protocol 019," focused on AZT use in asymptomatic patients. No one knew how many of such patients, if left untreated, would go on to develop AIDS. But whereas earlier in the epidemic authorities had suggested that perhaps 5, 10, or 20 percent of those infected would eventually develop AIDS, the experts increasingly were predicting that nearly every infected person might eventually do so. "Early intervention"—before the immune system had been severely compromised by the course of HIV infection—seemed therefore to make good intuitive sense. In fact, community-based treatment advocacy organizations like Project Inform had begun to stake their very identity on the notion of intervening early.
Ellen Cooper, the head of the FDA's Antiviral Drug Division, recalled that "there were a lot of people who would say to me at the agency, 'Well why are we even bothering to do studies in asymptomatics? … We know it's an antiviral, we know it works in more advanced patients. [Why not just] open up the indications to early patients?'" And in practice, some doctors had already begun prescribing AZT to HIV-infected patients who did not have AIDS, prompting bitter controversy between advocates and critics of the practice. "I know you don't get better by yourself," commented one Los Angeles doctor with a large AIDS practice, in a pithy expression of the practicing physician's interventionist orientation. Itzak Brook, the FDA advisory committee chair who had voted against approving the drug, was quick to say "I told you so": "This is just what I was afraid of," he commented to the New York Times . Samuel Broder of the NCI suggested that doctors and patients should simply sit back and wait: "The best thing to do now is to let the scientific community work this out." But Mathilde Krim, writing in a public policy journal, put the blame back on the NCI for having helped create the predicament in the first place: as far back as late 1985, NCI researchers had been discussing AZT in hopeful terms on national television, thereby enhancing the public's belief in the drug and raising the expectations of the patient community.
With HIV-infected people clamoring for AZT, the 016 (mildly
symptomatic patients) and 019 (asymptomatic patients) trials became more important than ever. They also became ever more difficult to conduct. Since there was no approved treatment for patients in these categories, AZT still had to be measured against a placebo. But compared to the original Phase II AZT trial with AIDS patients, these were larger and longer studies—necessarily so, since otherwise there would be "too few" deaths in the placebo arm to prove anything, given the relative health of the patients. Fischl's AZT trial had involved only 137 patients on placebos, and they were kept on it for twenty-four weeks at most. By contrast, the 019 study, conducted by Dr. Paul Volberding of the University of California at San Francisco, had 428 people in the placebo arm, and it was expected to run for several years.
Soon articles in the gay press were publicizing the plight of the "sacrificial lambs" in the AZT studies, sentenced by the research establishment to "death by placebo." Experts on clinical trials sought to emphasize the difference between the 016 and 019 studies and the earlier Phase II AZT study conducted with much sicker AIDS patients. That the patient community might find placebos difficult to countenance in trials of those facing "imminent death" was "entirely understandable," said Thomas Chalmers of the Harvard School of Public Health. But, he argued, "it is more difficult to understand that philosophy when one is dealing with asymptomatic patients … who may never develop AIDS and face a chance of being [made] sicker by a toxic and ineffective drug."
However, the trial participants—who had tested positive, who had gleaned from numerous newspaper accounts that they had a "time bomb" ticking away inside of them, and who, in their day-to-day lives, could see the presumed end results reflected in the bodies of the friends and lovers they visited in hospitals, reflected in the obituaries they read, and reflected in the funerals they attended—quite simply drew different conclusions. One subject in the 019 trial who had discovered he was in the placebo arm commented, "Fuck them. I didn't agree to donate my body to science, if that is what they are doing, just sitting back doing nothing with me waiting until I get PCP [Pneumocystis carinii pneumonia] or something." He told a reporter for the gay press that he had covertly begun taking dextran sulfate, an unapproved drug available through the treatment underground. Some community physicians expressed their incredulity on learning that participants in these studies were not permitted to take prophylactic medication to ward off pneumocystis pneumonia. One doctor described an experience
with one of his patients: "I said hello, and he handed me this lab slip from UCSF and started crying. He said they won't let me have aerosol pentamidine.… I looked at it, looked at him, and said, 'I don't believe you. Nobody would do that!' It drove me nuts!"