BACKGROUND Male circumcision significantly reduced the incidence of human immunodeficiency virus (HIV) infection among men in three clinical trials. We assessed the efficacy of male circumcision for the prevention of herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) infections and syphilis in HIV-negative adolescent boys and men. METHODS We enrolled 5534 HIV-negative, uncircumcised male subjects between the ages of 15 and 49 years in two trials of male circumcision for the prevention of HIV and other sexually transmitted infections. Of these subjects, 3393 (61.3%) were HSV-2–seronegative at enrollment. Of the seronegative subjects, 1684 had been randomly assigned to undergo immediate circumcision (intervention group) and 1709 to undergo circumcision after 24 months (control group). At baseline and at 6, 12, and 24 months, we tested subjects for HSV-2 and HIV infection and syphilis, along with performing physical examinations and conducting interviews. In addition, we evaluated a subgroup of subjects for HPV infection at baseline and at 24 months. RESULTS At 24 months, the cumulative probability of HSV-2 seroconversion was 7.8% in the intervention group and 10.3% in the control group (adjusted hazard ratio in the intervention group, 0.72; 95% confidence interval [CI], 0.56 to 0.92; P = 0.008). The prevalence of high-risk HPV genotypes was 18.0% in the intervention group and 27.9% in the control group (adjusted risk ratio, 0.65; 95% CI, 0.46 to 0.90; P = 0.009). However, no significant difference between the two study groups was observed in the incidence of syphilis (adjusted hazard ratio, 1.10; 95% CI, 0.75 to 1.65; P = 0.44). CONCLUSIONS In addition to decreasing the incidence of HIV infection, male circumcision significantly reduced the incidence of HSV-2 infection and the prevalence of HPV infection, findings that underscore the potential public health benefits of the procedure.

Uncircumcised HIV-negative men aged 15-49 years were randomized to immediate circumcision (n=441) or delayed circumcision (n=399). HPV was detected by Roche HPV Linear Array at enrollment, 6, 12 and 24 months. Incident HR-HPV was estimated in men who acquired a new HR-HPV genotype. HR-HPV clearance was determined in men with prior genotype-specific HR-HPV infections. Rate ratios (RR) and 95% confidence intervals (95%CI) of HR-HPV acquisition were estimated by Poisson multiple regression Enrollment characteristics were comparable between groups. HR-HPV incidence was 19.7/100 py in the intervention (70/355.8 py) and 29.4/100 py (125/424.8 py) in the control arm (RR=0.67, 95%CI 0.51-0.89, p = 0.006.) The incidence of multiple HR-HPV infections was 6.7/100 py in the intervention and 14.8/100 py in control arm (RR = 0.45, 95%CI 0.28-0.73), but there was no significant effect on single infections (RR=0.89, 95%CI 0.60-1.30). HR-HPV incidence was lower in the intervention arm for all genotypes and demographic/behavioral subgroups. The clearance of pre-existing HR-HPV infections was 215.8/100py (205/95 py) in intervention and 159.1/100py (255/160.25 py) in control arm men (adjRR=1.39, 95%CI 1.17-1.64). Male circumcision reduces the incidence of multiple HR-HPV infections and increases clearance of HR-HPV infections in HIV-uninfected men. The trial was registered with ClinicalTrials.gov numbers NCT00425984

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.

Reports from the United States have demonstrated that elevated markers of microbial translocation from the gut may be found in chronic and advanced HIV-1 infection and are associated with an increase in immune activation. However, this phenomenon's role in HIV-1 disease in Africa is unknown. This study examined the longitudinal relationship between microbial translocation and circulating inflammatory cytokine responses in a cohort of people with varying rates of HIV-1 disease progression in Rakai, Uganda. Multiple markers for microbial translocation (lipopolysaccharide, endotoxin antibody, and sCD14) did not change significantly during HIV-1 disease progression. Moreover, circulating immunoreactive cytokine levels either decreased or remained virtually unchanged throughout disease progression. These data suggest that microbial translocation and its subsequent inflammatory immune response do not have a causal relationship with HIV-1 disease progression in Africa.