AZT Trials and Tribulations

With the successful completion of a placebo-controlled trial of zidovudine (AZT) in pregnant women in Thailand--a study designed to determine the safety and efficacy of a short course of AZT in the prevention of maternal-infant HIV transmission--the Centers for Disease Control and Prevention have announced the suspension or modification of all similar trials involving placebos elsewhere in the world. 1 The CDC has claimed victory, asserting that its hotly contested placebo-driven methodology has been vindicated by the study's impressive results. But the critics of this controversial research remain unmoved. For them, the moral of the CDC/Thailand study is a rueful Better late than never. Both sides can agree on one thing, however: they are glad it's over. But our society and research communities in fact have yet to definitively resolve some crucial questions posed by these studies. Are placebo-controlled trials justified in the developing world when a proven treatment already exists in developed countries? Must the same ethical standards be used to judge research conducted at home or abroad, in Rochester or Rwanda? We must try to come to terms with these crucial questions bearing on the ethical conduct of international trials because they will soon recur, either in the form of studies on AIDS vaccines, the effects of breastfeeding on HIV transmission, or any number of other pressing issues on the horizon of biomedical research. The Controversy: Are Placebo-Controlled Trials Justified? While HIV-infected women and their newborns in industrialized nations can look forward to receiving the AIDS Clinical Trials Group (ACTG) 076 study treatment, the largest public health burden associated with perinatal HIV transmission is to be found in the developing world, where the vast majority of the approximately 1, 000 babies born HIV-infected each day reside. Given such grim facts, it is imperative that an alternative safe and effective therapy be established for use in the developing world, where, it has been argued, the intensive 076 protocol could not realistically be implemented. First, the regimen of antenatal, intrapartum, and neonatal AZT requires that women present to the clinic early in their pregnancy for HIV testing and counseling; that they follow the rigorous 076 protocol, which includes five pills per day for at least twelve weeks, and intravenous administration of AZT during delivery; and that the neonates follow a six-week, four-times-per-day, oral AZT regimen, during which time the women are required to abstain from breastfeeding. 2 Unfortunately, however, pregnant women in many developing world settings do not turn up for prenatal care until very late in their pregnancy, if indeed at all; many health care clinics in such locales are not equipped to administer intravenous AZT or, generally, to deliver the fastidious care required by the treatment protocol; and, finally, almost all women in the developing world breastfeed because of the established health benefits for their children and the prohibitive expense of baby formula, thus making adherence to the treatment protocol all but impossible. 3 Second, the 076 regimen has been variously estimated to cost as much as 1, 000 to 1, 500, 4 but certainly no less than 8005 per mother and infant--a sum that makes it unaffordable in most of the developing world. 6 Consequently, U. S. researchers, in cooperation with researchers and public health officials in eleven developing world nations, designed and planned to carry out clinical trials that would compare a shorter, less intensive regimen of AZT to placebo, in the hope of demonstrating that the short course AZT was safe and effective in preventing perinatal HIV transmission in local populations, and that it would be affordable to most developing nations. Though these goals are laudable and endorsed by all, the proposed means to achieve them have engendered fierce criticism, as well as analogies to the infamous Tuskegee syphilis study, from those who believe that the planned means to achieve these results--in particular, the inclusion of a placebo arm in the studies--are unethical. …