HIV This Week

Tobian AAR, Serwadda D, Quinn TC, Kigozi G, Gravitt PE, Laeyendecker O, Charvat B,* Ssempijja V, Riedesel M, Oliver AE, Nowak RG, Moulton LH, Chen MZ, Reynolds SJ, Wawer MJ and Gray RH. Male Circumcision for the Prevention of HSV-2 and HPV Infections and Syphilis. N Engl J Med. 2009;360:1298-309.

Male circumcision significantly reduced the incidence of human immunodeficiency virus (HIV) infection among men in three clinical trials. Tobian and colleagues assessed the efficacy of male circumcision for the prevention of herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) infections and syphilis in HIV-negative adolescent boys and men. They enrolled 5534 HIV-negative, uncircumcised male subjects between the ages of 15 and 49 years in two trials of male circumcision for the prevention of HIV and other sexually transmitted infections. Of these subjects, 3393 (61.3%) were HSV-2– seronegative at enrolment. Of the seronegative subjects, 1684 had been randomly assigned to undergo immediate circumcision (intervention group) and 1709 to undergo circumcision after 24 months (control group). At baseline and at 6, 12, and 24 months, the authors tested subjects for HSV-2 and HIV infection and syphilis, along with performing physical examinations and conducting interviews. In addition, they evaluated a subgroup of subjects for HPV infection at baseline and at 24 months. At 24 months, the cumulative probability of HSV-2 seroconversion was 7.8% in the intervention group and 10.3% in the control group (adjusted hazard ratio in the intervention group, 0.72; 95% confidence interval [CI], 0.56 to 0.92; P = 0.008). The prevalence of high-risk HPV genotypes was 18.0% in the intervention group and 27.9% in the control group (adjusted risk ratio, 0.65; 95% CI, 0.46 to 0.90; P = 0.009). However, no significant difference between the two study groups was observed in the incidence of syphilis (adjusted hazard ratio, 1.10; 95% CI, 0.75 to 1.65; P = 0.44). In addition to decreasing the incidence of HIV infection, male circumcision significantly reduced the incidence of HSV-2 infection and the prevalence of HPV infection, findings that underscore the potential public health benefits of the procedure.

Editors’ note: To date, limited statistical power, confounding by sexual practices correlated with a high risk of transmission, and determination of circumcision status only by self-report have plagued observational studies on male circumcision and sexually transmitted infections. This randomised, controlled trial in rural Uganda demonstrates that male circumcision in adolescent boys and men significantly reduces the incidence of herpes simplex virus-2 (HSV-2) infection and the prevalence of human papilloma virus (HPV) infection. Whether the latter is due to decreased HPV acquisition or increased HPV clearance is unclear but it does explain the lower risk of cervical cancer experienced by women whose partners are circumcised. The adjusted efficacy of male circumcision was 28% for the prevention of HSV-2, an infection thought to be a cofactor in HIV acquisition. This may explain in part the incontrovertible partial protection from HIV afforded by male circumcision.

Delany-Moretlwe S, Lingappa JR and Celum C. New Insights on Interactions Between HIV-1 and HSV-2. Curr Infect Dis Rep. 2009;11(2):135-42.

Herpes simplex type 2 (HSV-2) infection is common and frequently asymptomatic. Concerns exist about the high prevalence of HSV-2, particularly in areas of high HIV prevalence, because of observations that HSV-2 is associated with an increased risk of HIV acquisition, transmission, and disease progression. Several randomized trials have tested or are testing whether HSV-2 treatment can limit the spread of HIV, with mixed results. Although treatment with acyclovir, 400 mg twice daily, does not reduce HIV incidence, suppressive acyclovir and valacyclovir reduce HIV levels in plasma and in the genital tract. Ongoing trials are evaluating whether HSV suppression will reduce HIV transmission and disease progression. Until a protective HSV-2 or HIV vaccine is available, effective interventions that reduce the effect of HSV-2 on HIV transmission are critically needed.

Editors’ note: This excellent summary of what is known about the complex and bidirectional interactions between HIV-1 and herpes simplex virus–2 (HSV-2) was published before the May 8 th release of results from the multi-centre Partners in Prevention Study of 3408 discordant couples conducted in Botswana, Kenya, Rwanda, South Africa, Tanzania, Uganda and Zambia. To test whether HSV-2 daily suppressive therapy would reduce HIV transmission, HIV/HSV-2 co-infected partners were randomised to receive acyclovir 400 mg twice daily or matching placebo for 2 years while the uninfected partner was followed-up for HIV-1 seroconversion. Although acyclovir reduced the frequency of genital ulcers by 73% and HIV viral load by 40%, no significant difference was found in the rate of HIV transmission. A 17% reduction in HIV disease progression produced by low cost acyclovir was an intriguing result worthy of further study. With more than half a billion people infected with HSV-2, including up to 90% of people living with HIV, developing an HSV-2 vaccine continues to be a very high priority.

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