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

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.

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 (χ 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.

NIH Trial registration

ClinicalTrials.gov NCT00425984

Gates Foundation Trial registration

ClinicalTrials.gov NCT00124878

Please see later in the article for the Editors' Summary

Editors' Summary

Background

Acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people since 1981, and more than 30 million people (22 million in sub-Saharan Africa alone) are now infected with the human immunodeficiency virus (HIV), which causes AIDS. There is no cure for HIV/AIDS. Consequently, prevention of HIV transmission is extremely important. Because HIV is most often spread through unprotected sex with an infected partner, individuals can reduce their risk of becoming infected with HIV by abstaining from sex, by having one or a few partners, and by always using a male or female condom. In addition, three large trials in sub-Saharan Africa (including one in Rakai, Uganda) recently reported that male circumcision—the removal of the foreskin, a loose fold of skin that covers the head of the penis—can halve HIV transmission rates in men. Thus, as part of its HIV prevention strategy, the World Health Organization now recommends that male circumcision programs be scaled up in countries where there is a generalized HIV epidemic and where few men are circumcised.

Why Was This Study Done?

It is still not clear why male circumcision reduces HIV acquisition in men. Certainly, the foreskin contains many cells that HIV can infect and the foreskin's delicate lining is thought to be particularly vulnerable to HIV infection partly because intercourse can cause small tears in it through which HIV can enter the body. But male circumcision also reduces genital ulcer disease—sores on the penis and other genital organs caused by infection with several sexually transmitted organisms including the herpes simplex virus type 2 (HSV-2). Genital ulcer disease, particularly when caused by HSV-2, is thought to increase a person's risk of acquiring HIV, so could male circumcision reduce HIV transmission rates because of its beneficial effects on genital ulcer disease rather than through its removal of foreskin tissue with its rich source of HIV target cells? In this study, the researchers investigate this question by re-analyzing data collected in two Ugandan trials of male circumcision for HIV prevention.

What Did the Researchers Do and Find?

In the Ugandan trials, the researchers randomly assigned about 5,500 HIV-uninfected men to immediate circumcision or to circumcision 24 months later. At enrollment, they asked the men whether they had any symptoms of genital ulcer disease (for example, a painful penile sore or genital itching), examined the men's genital areas, and took blood samples to test for HSV-2 infection. The researchers repeated these examinations and tests at 6 months, 12 months, and 24 months and tested the study participants for HIV infection. The researchers' statistical analysis of these data shows that circumcision approximately halved symptomatic genital ulcer disease in the study participants irrespective of their HSV-2 infection status. Circumcision reduced the risk of HIV acquisition in men without HSV-2 infection by two-thirds but did not affect HIV acquisition among men infected with HSV-2 at enrollment. Among the men who became infected with HSV-2 during the study, circumcision reduced the risk of HIV acquisition but this reduction in risk was not statistically significant. That is, it could have happened by chance. Finally, the researchers calculated that 11.2% of the observed reduction in HIV acquisition associated with circumcision was mediated by reductions in symptomatic genital ulcer disease and 8.6% was mediated by reductions in HSV-2 infections.

What Do These Findings Mean?

The findings of this study are limited by the small number of people in some of the subgroups analyzed and by genital ulcer disease being self-reported. Furthermore, the validity of some of the findings may be compromised because the analysis described here was not specified in the original trial protocol. Nevertheless, these findings suggest that the reduction of genital ulceration following circumcision plays only a minor part in the ability of male circumcision to reduce HIV acquisition in men. They also suggest that circumcision reduces genital ulcer disease primarily by reducing the rate of nonherpetic ulceration, including sores caused by mild trauma during intercourse. Thus, the researchers conclude, most of the reduction in HIV acquisition provided by male circumcision may be attributable to the removal of vulnerable foreskin tissue containing HIV target cells.

Additional Information

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000187.

• Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS

• HIV InSite has comprehensive information on all aspects of HIV/AIDS

• Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on HIV and AIDS in Uganda, and on circumcision and HIV (in English and Spanish)

• More information about male circumcision is available from the Clearinghouse on Male Circumcision

• Information on the Rakai HIV prevention trial is available

• The MedlinePlus Encyclopedia has a page on male genital sores (in English and Spanish)

• The US National Institute of Allergy and Infectious Diseases provides information about genital herpes

• The US Centers for Disease Control and Prevention also provides information on genital herpes (in English and Spanish)