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 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, 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

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 (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).

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.

Trial registration: ClinicalTrials.gov NCT00124878 NCT00425984.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1. Trial profile.
Figure 1. Trial profile.

References

    1. Auvert B, Taljaard D, Lagarde E, Sobngwi-Tambekou J, Sitta R, et al. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial. PLoS Med. 2005;2:e298. doi: .
    1. Bailey RC, Moses S, Parker CB, Agot K, Maclean I, et al. Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial. Lancet. 2007;369:643–656.
    1. Gray RH, Kigozi G, Serwadda D, Makumbi F, Watya S, et al. Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet. 2007;369:657–666.
    1. Weiss HA, Quigley MA, Hayes RJ. Male circumcision and risk of HIV infection in sub-Saharan Africa: a systematic review and meta-analysis. Aids. 2000;14:2361–2370.
    1. Szabo R, Short RV. How does male circumcision protect against HIV infection? BMJ. 2000;320:1592–1594.
    1. Patterson BK, Landay A, Siegel JN, Flener Z, Pessis D, et al. Susceptibility to human immunodeficiency virus-1 infection of human foreskin and cervical tissue grown in explant culture. Am J Pathol. 2002;161:867–873.
    1. McCoombe SG, Short RV. Potential HIV-1 target cells in the human penis. Aids. 2006;20:1491–1495.
    1. Donoval BA, Landay AL, Moses S, Agot K, Ndinya-Achola JO, et al. HIV-1 target cells in foreskins of African men with varying histories of sexually transmitted infections. Am J Clin Pathol. 2006;125:386–391.
    1. Tobian AA, Serwadda D, Quinn TC, Kigozi G, Gravitt PE, et al. Male circumcision for the prevention of HSV-2 and HPV infections and syphilis. N Engl J Med. 2009;360:1298–1309.
    1. Weiss HA, Thomas SL, Munabi SK, Hayes RJ. Male circumcision and risk of syphilis, chancroid, and genital herpes: a systematic review and meta-analysis. Sex Transm Infect. 2006;82:101–109; discussion 110.
    1. Sobngwi-Tambekou J, Taljaard D, Lissouba P, Zarca K, Puren A, et al. Effect of HSV-2 serostatus on acquisition of HIV by young men: results of a longitudinal study in Orange Farm, South Africa. J Infect Dis. 2009;199:958–964.
    1. Rottingen JA, Cameron DW, Garnett GP. A systematic review of the epidemiologic interactions between classic sexually transmitted diseases and HIV: how much really is known? Sex Transm Dis. 2001;28:579–597.
    1. Wald A, Link K. Risk of human immunodeficiency virus infection in herpes simplex virus type 2-seropositive persons: a meta-analysis. J Infect Dis. 2002;185:45–52.
    1. Corey L. Synergistic copathogens–HIV-1 and HSV-2. N Engl J Med. 2007;356:854–856.
    1. Gamiel JL, Tobian AAR, Laeyendecker OB, Reynolds SJ, Morrow RA, et al. Improved performance of enzyme-linked immunosorbent assays and the effect of human immunodeficiency virus coinfection on the serologic detection of herpes simplex virus type 2 in Rakai, Uganda. Clin Vaccine Immunol. 2008;15:888–890.
    1. Barros AJ, Hirakata VN. Alternatives for logistic regression in cross-sectional studies: an empirical comparison of models that directly estimate the prevalence ratio. BMC Med Res Methodol. 2003;3:21.
    1. Risbud A, Chan-Tack K, Gadkari D, Gangakhedkar RR, Shepherd ME, et al. The etiology of genital ulcer disease by multiplex polymerase chain reaction and relationship to HIV infection among patients attending sexually transmitted disease clinics in Pune, India. Sex Transm Dis. 1999;26:55–62.
    1. Orle KA, Gates CA, Martin DH, Body BA, Weiss JB. Simultaneous PCR detection of Haemophilus ducreyi, Treponema pallidum, and herpes simplex virus types 1 and 2 from genital ulcers. J Clin Microbiol. 1996;34:49–54.
    1. Freedman LS, Graubard BI, Schatzkin A. Statistical validation of intermediate endpoints for chronic diseases. Stat Med. 1992;11:167–178.
    1. Jewell NP. Statistics for epidemiology. Boca Raton (Florida): Chapman & Hall; 2004.
    1. Sobngwi-Tambekou J, Taljaard D, Lissouba P, Zarca K, Puren A, et al. Effect of HSV-2 serostatus on acquisition of HIV by young men: results of a longitudinal study in Orange Farm, South Africa. J Infect Dis. 2009;199:958–964.
    1. Gupta R, Warren T, Wald A. Genital herpes. Lancet. 2009;370:2127–2137.
    1. Zhu J, Hladik F, Woodward A, Klock A, Peng T, et al. Persistence of HIV-1 receptor-positive cells after HSV-2 reactivation is a potential mechanism for increased HIV-1 acquisition. Nat Med. 2009;15:886–892.
    1. Celum C, Wald A, Hughes J, Sanchez J, Reid S, et al. Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial. Lancet. 2008;371:2109–2119.
    1. Watson-Jones D, Weiss HA, Rusizoka M, Changalucha J, Baisley K, et al. Effect of herpes simplex suppression on incidence of HIV among women in Tanzania. N Engl J Med. 2008;358:1560–1571.

Source: PubMed

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