Viewpoint www.thelancet.com Vol 378 July 16, 2011 285 Lancet 2011; 378: 285–87 Gertrude H Sergievsky Center, College of Physicians and Surgeons, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA (L Kuhn PhD); Department of Anthropology, Hunter College, and the Graduate Center, City University of New York, and Department of Sociomedical Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA (I Susser PhD); and HIV Center for Clinical and Behavioral Studies, New York State Psychiatric Institute, New York, NY, USA (Prof Z Stein MBChB) Correspondence to: Louise Kuhn, Gertrude H Sergievsky Center, College of Physicians and Surgeons and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA lk24@coloumbia.edu Can further placebo-controlled trials of antiretroviral drugs to prevent sexual transmission of HIV be justified? Louise Kuhn, Ida Susser, Zena Stein The Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial 1 that was reported in July, 2010, assessed the efficacy of a gel containing the antiretroviral drug tenofovir, which can be used intravaginally to reduce the risk of sexual transmission of HIV from men to women. In 889 women at community sites in South Africa, the gel was associated with a 39% reduction in HIV incidence in women. After adjustment for reported adherence the reduction was 54%. The randomised, double-blind, placebo-controlled Prexposure Prophylaxis Initiative (iPrEx) study, 2 which was published soon afterwards, assessed the efficacy of daily oral antiretroviral drugs (tenofovir plus emtricita- bine) in reducing the risk of sexual transmission of HIV between men. In 2499 high-risk men who have sex with men and transgender women at sites in Peru, Brazil, Ecuador, Thailand, South Africa, and the USA, this drug combination was associated with a 44% reduction in HIV incidence. After adjustment for estimated adherence the reduction was 73%. Despite the clear results from these two trials of the efficacy and safety of antiretroviral drugs to prevent sexual transmission of HIV, further placebo- controlled trials in women are planned or underway. 3 On the basis of fundamental concepts of public health, we believe that to undertake more placebo-controlled trials would be short-sighted and surely unethical, and to delay implementation would cost the lives of the very women whom the drugs are intended to benefit. 4 A rationale for further placebo-controlled trials is that they are required by regulatory agencies, such as the US Food and Drug Administration, before antiretroviral drugs are approved for prophylactic use. If this claim is true, these agencies are putting researchers in an untenable position and expecting them to violate clinical equipoise—a principle that is central to the ethical use of a placebo. Researchers in this specialty are deeply committed to making these interventions immediately available to the high-risk populations who need them; therefore, further placebo-controlled trials raise a profound ethical dilemma. To enable high-risk men and women to access these interventions in the long term, researchers might feel compelled to act in a compromised way in the short term. Investigators who undertake further placebo-controlled trials will need to make the case to their study participants, and to the Institutional Review Boards that oversee them, that there is genuine uncertainty about whether antiretroviral prophylaxis will reduce the risk of HIV transmission. However, the positive results of the CAPRISA and iPrEx trials and expansion of the scientific evidence-base make such a case increasingly impossible to make. 5 Our argument against placebo-controlled trials does not mean that further research is not needed. Many important issues do need further research, but they can be best addressed with study designs that do not use placebos. For example, one important question is how best to use antiretroviral drug products. Is oral administration easier and more effective than mucosal administration or vice versa? Is use targeted around anticipated sexual intercourse? And is use of the product before and after intercourse (ie, the original study of tenofavir gel) better or worse than daily consumption (ie, iPrEx and oral contraceptive pills)? Randomised trials comparing different antiretroviral drug strategies are the optimum designs to address these issues, and such comparisons render the use of placebo unnecessary. Safety is another relevant question for which further research is needed. Because the completed trials were large and closely monitored, common and important safety concerns have already been ruled out. The remaining rare and serious side-effects are best addressed through systematic, planned, and transparent data collection with programme roll-out, similar to post- marketing surveillance. Behavioural factors, including short-term and long- term adherence to antiretroviral prophylaxis, are crucial for whether an intervention can be successfully introduced in the communities that are most affected. However, these factors cannot be satisfactorily addressed by a study in which participants do not know whether they have received an effective intervention or an inert placebo. Furthermore, doubt among participants might undermine adherence in ways that cannot be adequately measured or controlled. Another argument for further placebo-controlled trials is to confirm results that could be wrong. In science, initially positive results can, on further investigation, be not so positive. Randomisation does not guarantee the elimination of confounding and, even in the most rigorously undertaken trial, chance might produce spurious associations. However, the likelihood of chance producing consistent results in two disparate populations is extremely low. The reduction reported in the intention-to-treat analyses of the CAPRISA and iPrEx trials was moderate and did not reach the 50% efficacy that would be equivalent to halving the risk of infection. Nevertheless, for costly and potentially life-limiting infections such as HIV, even small reductions can translate into substantial numbers of lives saved and suffering averted. Additionally, the results of both trials indicate that improved adherence would increase this intervention’s efficacy—a result that is consistent with a true biological