PLOS Medicine Associate Editor Linda Nevin discusses the landmark publication, and striking impact, of the first randomized clinical trial of voluntary medical male circumcision, published in PLOS Medicine in 2005.
Image credit: (left) Sgt. Adam Fischman, US Army Africa & (right) Sterling Riber, MFDI for Jhpiego/Tanzania.
Since the 1980s, observational studies have shown that HIV infection rates in African tribal or ethnic groups that practice male circumcision are lower than rates in groups that do not. HIV protection by male circumcision has biologic plausibility; the removal of the foreskin reduces the covered, moist space in which the virus can incubate after sex. However, because ecological studies can never establish causality, the potential benefits of promoting male circumcision in African communities remained unclear past the year 2000. In 2005, Bertran Auvert and colleagues at the Hôpitaux de Paris, Boulogne, France published the first randomized clinical trial (RCT) of circumcision for HIV prevention, conducted in Orange Farm, a semiurban region close to Johannesburg, South Africa. In this trial, about 3,000 young, heterosexual uncircumcised men were randomly allocated to be circumcised upon enrollment, or 21 months later. In a planned interim analysis 17 months after the study was initiated, the authors observed a striking difference in incidence of HIV infection in the uncircumcised group (49 cases of 1582 participants) compared with the newly circumcised men (20 cases of 1546). The difference represented a statistically significant protection of 60% (95% confidence interval 32%–76%). At the request of the trial’s data and safety monitoring board, the trial was immediately stopped and all interested participants were circumcised.
This was broadly considered a landmark study in the field of HIV research. Its publication initiated robust debate about trial controls, blinding, covariates analyzed, and ethics; the paper has been cited in 998 scientific publications, and collected 99,867 page-views to date. At the time of publication, two other trials– in Kenya and Uganda– were underway, and researchers in the field waited on tenterhooks to see if the Orange Farm RCT results would be corroborated. They were. However, questions remained on the pragmatic front. Would a larger roll-out of a male circumcision program be effective across the diverse communities of Eastern and Southern Africa? Would circumcised men engage in risk compensation, the increase in unsafe behavior due to perceived protection?
Based on trial findings, Auvert and colleagues began a community-wide scale-up of voluntary male circumcision in Orange Farm in 2008. Their results from the 2008-2011 study period, published in PLOS Medicine in 2013, were a second landmark achievement. They observed an increased prevalence of circumcision (from 12% to 53%), a roughly 60% reduction in risk of contracting HIV among circumcised compared to uncircumcised men (consistent with the RCT), and no detectable increase in risky sexual behaviors among circumcised men. Using these numbers, the authors estimated that the VMMC scale-up reduced the 2011 prevalence of HIV in the community from a projected ~15% to ~12%.