HPTN 052 is now widely known for the headline figure of 96% placed on the benefit of ART in reducing HIV transmission within sero-discordant couples. The same trial simultaneously assessed the benefits of immediate ART initiation (at the CD4 count <550 cells/mm3 required for trial entry) against delayed initiation at <250 cells/mm3. Less well known, however, is the history of ethical complications recounted by M.S. Cohen & J. Sugarman (http://ctj.sagepub.com.libproxy.ucl.ac.uk/content/9/3/340.full ) in a paper that gives a fascinating insight into the challenges that public health policy can pose for a randomized control trial (RCT) such as HPTN 052.
It is worthwhile setting the “ethical odyssey” of Cohen & Sugarman alongside the recommendations of R. Hayes & D.Mabey in a 1997 paper published in this journal (http://sti.bmj.com/content/73/6/432.abstract?sid=2904aa16-b215-42d5-ba37-c2e895c97673). The potential tension between the desire to maximize the scientific value of a trial and the need to optimize medical outcomes for the participants (especially those in the control arm) is recognized by both papers. But the challenges faced by HPTN 052 as described by Cohen & Sugarman run a coach and horses through the recommendations of Hayes & Mabey.
The apparently straightforward principal that “control communities should not be disadvantaged”, and the recommendation against “interim analyses” (Hayes & Mabey), become highly problematic in the context of the swiftly changing ethical challenges to HPTN 052 over its seven year course (2005-). At the inception of the trial, findings of the Rakai study (http://www.nejm.org/doi/full/10.1056/NEJM200003303421303) regarding the relationship of viral load to transmission suggested there might be benefits to be derived from early ART initiation; on the other hand, several Institutional Review Boards cautioned against ART initiation before CD4 counts fell below CD4 200. As the study progressed, the balance of evidence changed, with a series of observational and ecological studies coming out in favour of early ART initiation, and the release, in 2009, of new “Rapid Advise” WHO guidelines recommending ART initiation at <350 (http://www.who.int/hiv/pub/arv/advice/en/index.html).
Cohen & Sugarman paint the picture of an RCT trial constantly undercut by those international recommendations which it is the goal of RCT trial to inform: public health policy, in the view of the authors, is ever on the point of sawing off the scientific branch on which it sits!