Research Article: Effects of Genital Ulcer Disease and Herpes Simplex Virus Type 2 on the Efficacy of Male Circumcision for HIV Prevention: Analyses from the Rakai Trials

Date Published: November 24, 2009

Publisher: Public Library of Science

Author(s): Ronald H. Gray, David Serwadda, Aaron A. R. Tobian, Michael Z. Chen, Frederick Makumbi, Tara Suntoke, Godfrey Kigozi, Fred Nalugoda, Boaz Iga, Thomas C. Quinn, Lawrence H. Moulton, Oliver Laeyendecker, Steven J. Reynolds, Xiangrong Kong, Maria J. Wawer, Barbara L. Shacklett

Abstract: Ron Gray and colleagues analyze data from two circumcision trials in Uganda to assess how HSV-2 status and genital ulcer disease affect the procedure’s ability to reduce HIV infection.

Partial Text: 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]. The foreskin is rich in HIV target cells and the inner preputial mucosa is thought to be lightly keratinized and vulnerable to HIV infection [5]–[8]. Thus, it is hypothesized that circumcision may reduce HIV infection by removal of this vulnerable tissue. The Ugandan trial also 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 South African trial reported that circumcision was equally protective against HIV acquisition in HSV-2 seropositive and seronegative men [11]. GUD, particularly due to HSV-2, is thought to be a cofactor for HIV acquisition [12]–[14]. Thus it is possible that circumcision prevents HIV in part by reducing genital ulceration and HSV-2.

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) (Text S3). Details have been published previously [3],[9]. 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 numbers NCT00425984 for NIH trial and NCT00124878 for the Gates Foundation trial. The protocol (see Text S1 and Text S2) 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.

Table 1 shows the distribution of participant characteristics at enrollment. HSV-2 prevalence was 28.3% (782/2,576) in the intervention arm and 27.4% (759/2,775) in the control arm. HSV-2 indeterminate serostatus (Kalon Elisa index values 1.0 to 1.49) was similar in intervention (10.1%, 278/2,756) and control arms (10.8%, 299/2,775), and 61.5% of intervention arm men (1696/2,756) versus 61.7% of control arm men (1,717/2,775) were HSV-seronegative at enrollment. The two study arms were also comparable with respect to sociodemographic and behavioral characteristics (Table 1). However, there were marked differences in the characteristics of men who were HSV-2 seropositive and seronegative at enrollment. Compared to HSV-2 negative men, HSV-2-positive men were significantly older (40+ y, 13.9% versus 2.6%, χ2p<0.0001), more likely to be currently or previously married (77.2% versus 42.5%, χ2p<0.0001), to have a higher number of reported sex partners in the past year (2+ 43.8% versus 31.8%, χ2p<0.0001), and were less likely to consistently use condoms (7.9% versus 16.9%, χ2p<0.0001). MC reduced symptomatic genital ulceration by 41%, and the protection against GUD was similar irrespective of HSV-2 status in this population (Table 2). We estimate that approximately 11.2% of the protection from HIV afforded by circumcision is mediated by the reduction of symptomatic GUD due to circumcision (Table 3). Thus, it is likely that the reduction in symptomatic GUD made only a modest contribution to the overall impact of circumcision on prevention of HIV infection. Source:


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