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

Ronald H Gray, David Serwadda, Aaron A Tobian, Michael Z. Chen, Frederick Makumbi, Tara Suntoke, Godfrey Kigozi, Fred Nalugoda, Boaz Iga, Thomas C Quinn, Lawrence Hale Moulton, Oliver B. Laeyendecker, Steven James Reynolds, Xiangrong Kong, Maria J Wawer

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article numbere1000187
JournalPLoS Medicine
Volume6
Issue number11
DOIs
StatePublished - Nov 2009

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Male Circumcision
Human Herpesvirus 2
Ulcer
HIV
Odds Ratio
Incidence
Virus Diseases
Polymerase Chain Reaction
Uganda

ASJC Scopus subject areas

  • Medicine(all)

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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. / Gray, Ronald H; Serwadda, David; Tobian, Aaron A; Chen, Michael Z.; Makumbi, Frederick; Suntoke, Tara; Kigozi, Godfrey; Nalugoda, Fred; Iga, Boaz; Quinn, Thomas C; Moulton, Lawrence Hale; Laeyendecker, Oliver B.; Reynolds, Steven James; Kong, Xiangrong; Wawer, Maria J.

In: PLoS Medicine, Vol. 6, No. 11, e1000187, 11.2009.

Research output: Contribution to journalArticle

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title = "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",
abstract = "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.",
author = "Gray, {Ronald H} and David Serwadda and Tobian, {Aaron A} and Chen, {Michael Z.} and Frederick Makumbi and Tara Suntoke and Godfrey Kigozi and Fred Nalugoda and Boaz Iga and Quinn, {Thomas C} and Moulton, {Lawrence Hale} and Laeyendecker, {Oliver B.} and Reynolds, {Steven James} and Xiangrong Kong and Wawer, {Maria J}",
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T2 - Analyses from the Rakai trials

AU - Gray, Ronald H

AU - Serwadda, David

AU - Tobian, Aaron A

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 Hale

AU - Laeyendecker, Oliver B.

AU - Reynolds, Steven James

AU - Kong, Xiangrong

AU - Wawer, Maria J

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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