Background Randomized trials show that medical male circumcision (MC) reduces high-risk human papillomavirus (HR-HPV) infection in men. We assessed the efficacy of MC to reduce HR-HPV in female partners. Methods HIV-negative men were randomized to immediate MC (intervention) or MC delayed for 24 months (control). HIV-uninfected female partners of married men (648 intervention and 597 control arm) were simultaneously enrolled and provided interview information and self-collected vaginal swabs at baseline, 12 and 24 months. Female HPV infection was a secondary trial end point. Vaginal swabs were evaluated for HR-HPV by Roche HPV Linear Array. An intention-to-treat analysis estimated prevalence risk and incident rate ratios (PRR and IRR) and 95% confidence intervals (95%CI) of HR-HPV by Poisson multiple regression. In women with pre-existing HR-HPV, we estimated the risk ratio (RR) of cleared infection (i.e., loss of detection). The trials were registered with ClinicalTrials.gov, NCT00425984 and NCT00124878.) Findings Female characteristics and HPV prevalence were similar between arms at enrollment. Two year retention rates were 84.7% (549/648) in intervention arm and 84.1% (502/597) in control arm spouses. Year 2 female HR-HPV prevalence was 27.8% (151/544) in the intervention and 38.7% (189/488) in the control arm (PRR=0.72, 95%CI 0.60–0.85, p=0.001). HR-HPV incidence was 20.7/100py in the intervention arm and 26.9/100py in the control arm wives (IRR=0.77, 95%CI 0.63-0.93, p=0.008). HR-HPV incidence was lower in intervention than control arm wives for 13 of 14 (92.9%) HR-HPV genotypes and in most demographic/behavioral subgroups. Genotype specific HR-HPV clearance was higher in the wives of men in the intervention arm (66.2%, 376/568) than the control arm (59.2%, 339/573, RR=1.12, 95%CI 1.02-1.22). Interpretation MC reduces the prevalence and incidence and increases clearance of HR-HPV infections in female partners. Funding Bill & Melinda Gates Foundation with additional laboratory and training support from National Institutes of Health and Fogarty International Center.

Background The efficacy of male circumcision (MC) for HIV prevention over two years has been demonstrated in three randomized trials, but the longer-term effectiveness of MC is unknown. Methods We conducted a randomized trial of MC in 4996 HIV-negative men aged 15-49 in Rakai Uganda. Following trial closure we offered MC to uncircumcised control arm participants maintained surveillance for up to 4.79 years. HIV incidence per 100 person-years (py) was assessed in an as-treated analysis, and the effectiveness of MC was estimated using Cox regression models, adjusted for sociodemographic and time-dependent sexual behaviors. For men uncircumcised at trial closure, sexual risk behaviors at the last trial and first post-trial visits were assessed by subsequent circumcision acceptance to detect behavioral risk compensation. Results By Dec 15, 2010, 78.4% of uncircumcised trial participants accepted MC following trial closure. Retention during post-trial surveillance was was 74%.In control arm participants, post-trial HIV incidence was 0.54/100 py in circumcised and 1.71/100 py in uncircumcised control arm men (adjusted effectiveness 67% (95%CI 38-83%). There were no significant differences in sociodemographic characteristics and sexual behaviors between controls accepting MC and those remaining uncircumcised. Conclusions High effectiveness of MC for HIV prevention was maintained for almost 5 years following trial closure. There was no evidence of self-selection or of behavioral risk compensation associated with post-trial MC acceptance.

Design We assessed foreskin inflammation associated with HIV and herpes simplex virus type 2 (HSV-2) in circumcised men. Methods Foreskin tissues were assessed in 97 HIV-infected and 135 HIV-uninfected men enrolled in randomized trials of circumcision in Rakai, Uganda. Inflammation was quantified using an ordinal score evaluating extent, intensity, and cellular composition of infiltrates in the epithelium and stroma. Prevalence rate ratios of inflammation were estimated by multivariate Poisson regression. Results Foreskin inflammation was primarily focal. Epithelial inflammation was present in 4.2% of men with neither HIV nor HSV-2 infection; 7.8% of men with only HSV-2; 19.0% with HIV alone (P=0.04); and 31.6% in HIV/HSV-2 coinfected men [prevalence rate ratio (PRR) 7.5, 95% confidence interval (CI) 2.3-23.8, P<0.001]. Stromal inflammation was present in 14.1% of HIV/HSV-2 uninfected men, compared with 29.7% in men with HSV-2 alone (P=0.03), 33.3% in men with HIV alone (P=0.04), and 61.0% in men with HIV/HSV-2 coinfection (PRR 4.3, 95% CI 2.3-7.9, P<0.001). In HIV-infected men, epithelial inflammation was associated with higher HIV viral load. Epithelial inflammation was more frequent among men reporting recent genital ulceration. Both epithelial and stromal inflammation were more common among men with smegma on physical examination. Conclusion Foreskin inflammation is increased with HIV and HSV-2 infections, higher HIV viral load and presence of smegma. Foreskin inflammation may have implications for HIV transmission and acquisition in uncircumcised men.