TY - JOUR
T1 - Effects of genital ulcer disease and herpes simplex virus type 2 on the efficacy of male circumcision for HIV prevention
T2 - Analyses from the Rakai trials
AU - Gray, Ronald H.
AU - Serwadda, David
AU - Tobian, Aaron A.R.
AU - Chen, Michael Z.
AU - Makumbi, Frederick
AU - Suntoke, Tara
AU - Kigozi, Godfrey
AU - Nalugoda, Fred
AU - Iga, Boaz
AU - Quinn, Thomas C.
AU - Moulton, Lawrence H.
AU - Laeyendecker, Oliver
AU - Reynolds, Steven J.
AU - Kong, Xiangrong
AU - Wawer, Maria J.
N1 - Funding Information:
We conducted two concurrent randomized trials that enrolled consenting uncircumcised men aged 15–49 y and randomized them to receive immediate circumcision (intervention arm), or circumcision delayed for 24 mo (control arm) (). Details have been published previously ,. Participants provided written informed consent for screening, enrollment, and follow up, and men receiving circumcision also provided written consent for surgery. Participants were followed at 6, 12, and 24 mo and interviewed with regard to sexual risk behaviors and self-reported genital ulceration during the preceding follow-up interval, as well as recent GUD symptoms within 1 wk of the study visit. In addition, a genital exam was performed and swabs taken from any observed penile lesion. One trial supported by the National Institutes of Health (NIH) enrolled HIV-negative men who, as condition for enrollment eligibility, accepted voluntary counseling and testing (VCT) and agreed to learn their HIV results. A second trial, supported by the Bill & Melinda Gates Foundation, enrolled HIV-negative men who accepted pre-test counseling but declined to learn their HIV results, and thus were ineligible for enrollment in the NIH trial. Under Ugandan policy persons may provide blood for testing but decline to learn their test result, and such individuals were not denied access to trial participation. All participants were offered intensive HIV prevention education, access to free HIV VCT, and condoms, provided free of charge, and were strongly encouraged at each study visit to practice safe sex behaviors and to avail themselves of VCT and condoms. The trials are registered with ClinicalTrials.gov numbers NCT00425984 for NIH trial and NCT00124878 for the Gates Foundation trial. The protocol (see and ) was reviewed and approved by the Uganda National Council for Science and Technology, and by three Institutional Review Boards (IRBs): the Science and Ethics Committee of the Uganda Virus Research Institute, Entebbe, Uganda; the Committee for Human Research at Johns Hopkins University, Bloomberg School of Public Health; and the Western Institutional Review Board, Olympia, Washington. The data were analyzed without personal identifiers.
PY - 2009/11
Y1 - 2009/11
N2 - Background: 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. Methods and Findings: 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 (x2 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 21.2 to 77.1). Conclusions: 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.
AB - Background: 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. Methods and Findings: 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 (x2 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 21.2 to 77.1). Conclusions: 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.
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U2 - 10.1371/journal.pmed.1000187
DO - 10.1371/journal.pmed.1000187
M3 - Article
C2 - 19936044
AN - SCOPUS:72949099285
SN - 1549-1277
VL - 6
JO - PLoS medicine
JF - PLoS medicine
IS - 11
M1 - e1000187
ER -