Background We estimated the 72-month efficacy of medical male circumcision (MMC) against HSV-2 seroincidence among men in the randomised trial of MMC in Kisumu, Kenya.

Methods From 2002–2005, 2,784 men aged 18–24 were randomised 1:1 to immediate circumcision or control. At trial end in December 2006, control men were offered free circumcision. Follow-up continued through September 2010. Cox proportional hazards regression incorporating stabilised inverse probability of treatment and censoring weights generated through marginal structural modelling was used to account for potential time-varying confounding and censoring to estimate the efficacy of MMC on HSV-2 risk. Conventional Cox regression identified multivariable risks for HSV-2 acquisition.

Results Among 2,044 men who were HSV-2 seronegative at baseline, the cumulative 72-month HSV-2 seroincidence was 33.1%: 32.7% among circumcised men, 33.5% among uncircumcised men. In weight-adjusted Cox regression, the HR was 0.88 [95% CI: 0.77 – 1.10]. In conventional multivariable analyses, risks (p < 0.05) for HSV-2 included: HIV infection [aHR = 3.75], GUD [aHR = 4.75], penile epithelial trauma [aHR = 1.47], ≥ 2 recent sex partners [aHR = 1.54], and being married/cohabiting [aHR = 1.66]. Of men with seroincident HSV-2, 21% experienced GUD and 80% reported penile epithelial trauma. Conversely, 45% of men with GUD and 80% of men reporting penile epithelial trauma did not acquire HSV-2. GUD preceded HSV-2 in 59% of men with both conditions, with median time to HSV-2 of 12 months. Penile epithelial trauma preceded HSV-2 in 92% of men with both conditions, with median time to HSV-2 of 24 months.

Conclusion MMC had no effect on HSV-2 acquisition at 72 months. The temporal sequence and limited correlation between HSV-2, GUD, and penile epithelial trauma indicate these are distinct phenomena, rather than misclassification of HSV-2 symptoms. Determining the aetiology of non-STI GUD and penile epithelial trauma is necessary as both are risks for HIV acquisition, and are common in populations in sub-Saharan Africa.