Abstract
Randomized trials show that male circumcision (MC) reduces the incidence of HIV and herpes simplex virus type 2 (HSV-2) infections, and symptomatic genital ulcer disease (GUD). We assessed the role of GUD and HSV-2 in the protection against HIV afforded by MC. HIV-uninfected men were randomized to immediate (n = 2,756) or delayed MC (n = 2,775) in two randomized trials in Rakai, Uganda. GUD symptoms, HSV-2 status, and HIV acquisition were determined at enrollment and at 6, 12, and 24 mo of follow up. Ulcer etiology was assessed by PCR. We estimated the prevalence and prevalence risk ratios (PRRs) of GUD in circumcised versus uncircumcised men and assessed the effects of HSV-2 serostatus as a risk-modifying factor for GUD. We estimated the proportion of the effect of MC on HIV acquisition that was mediated by symptomatic GUD, and by HSV-2 infection. Circumcision significantly reduced symptomatic GUD in HSV-2-seronegative men (PRR = 0.51, 95% [confidence interval] CI 0.43-0.74), HSV-2-seropositive men (PRR = 0.66, 95% CI 0.51-0.69), and in HSV-2 seroconverters (PRR = 0.48, 95% CI 0.30-0.79). The proportion of acute ulcers due to HSV-2 detected by PCR was 48.0% in circumcised men and 39.3% in uncircumcised men (chi(2)p = 0.62). Circumcision reduced the risk of HIV acquisition in HSV-2 seronegative men (incidence rate ratio [IRR] = 0.34, 95% CI 0.15-0.81), and potentially in HSV-2 seroconverters (IRR = 0.56, 95% CI 0.19-1.57; not significant), but not in men with prevalent HSV-2 at enrollment (IRR = 0.89, 95% CI 0.49-1.60). The proportion of reduced HIV acquisition in circumcised men mediated by reductions in symptomatic GUD was 11.2% (95% CI 5.0-38.0), and the proportion mediated by reduced HSV-2 incidence was 8.6% (95% CI -1.2 to 77.1). Circumcision reduced GUD irrespective of HSV-2 status, but this reduction played only a modest role in the protective effect of circumcision on HIV acquisition.
Highlights
Three randomized trials in South Africa [1], Kenya [2], and Uganda [3] found that male circumcision (MC) reduces the risk of human immunodeficiency virus (HIV) acquisition in men, a finding supported by prior observational studies [4]
The Ugandan trial found that circumcision decreased the rate of self-reported genital ulcer disease (GUD) [3] and the incidence of herpes simplex virus type 2 (HSV-2) [9]; these findings had previously been suggested by observational studies [10]
The adjusted incidence rate ratios of HIV acquisition based on Poisson multiple regression, were 0.58 for circumcision, and 3.11 for GUD
Summary
Three randomized trials in South Africa [1], Kenya [2], and Uganda [3] found that male circumcision (MC) reduces the risk of HIV acquisition in men, a finding supported by prior observational studies [4]. Randomized trials show that male circumcision (MC) reduces the incidence of HIV and herpes simplex virus type 2 (HSV-2) infections, and symptomatic genital ulcer disease (GUD). Three large trials in sub-Saharan Africa (including one in Rakai, Uganda) recently reported that male circumcision—the removal of the foreskin, a loose fold of skin that covers the head of the penis—can halve HIV transmission rates in men. As part of its HIV prevention strategy, the World Health Organization recommends that male circumcision programs be scaled up in countries where there is a generalized HIV epidemic and where few men are circumcised
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