Male circumcision for the prevention of HSV-2 and HPV infections and syphilis

Abstract

Background: Male circumcision significantly reduced the incidence of human immunodeficiency virus (HIV) infection among men in three clinical trials. We 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.

Methods: We 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 enrollment. 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, we tested subjects for HSV-2 and HIV infection and syphilis, along with performing physical examinations and conducting interviews. In addition, we evaluated a subgroup of subjects for HPV infection at baseline and at 24 months.

Results: 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).

Conclusions: 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. (ClinicalTrials.gov numbers, NCT00425984 and NCT00124878.)

Figure 1. Enrollment and Outcomes in the Evaluation of Herpes Simplex Virus Type 2 (HSV-2) Infection

Some subjects were lost to follow-up at 6 months or 12 months but were then evaluated at 12 months or 24 months, so the numbers of subjects who were evaluated at each follow-up period do not necessarily tally with the numbers of subjects who were lost to follow-up for that period. All subjects who were seen during the trial are shown, but samples were not available for testing at month 6 for 13 subjects in the intervention group and 7 in the control group and at year 1 for 13 subjects in the intervention group and 8 in the control group. Not included in the 24-month analyses were 11 subjects in the intervention group and 8 in the control group who had been enrolled in the trial for less than 24 months.

Figure 2. Kaplan–Meier Estimates of the Probability of Detection of Herpes Simplex Virus Type 2 (HSV-2) Infection at 24 Months

During the 24-month study period in the intention-to-treat population, HSV-2 infection was detected in 114 subjects who had undergone circumcision (intervention group) and in 153 subjects who had not undergone the procedure (control group). The cumulative probability of HSV-2 infection during the 24-month period was 7.8% in the intervention group, as compared with 10.3% in the control group, with an unadjusted hazard ratio of 0.75 (95% CI, 0.60 to 0.94; P = 0.02). HSV-2 infection was initially detected at 6 months in 24 subjects in the intervention group and 35 in the control group and at 12 months in 29 subjects in the intervention group and 40 in the control group. At 24 months, HSV-2 infection was initially diagnosed in 61 subjects in the intervention group and 78 in the control group.

Figure 3. Incidence of Herpes Simplex Virus Type 2 (HSV-2) Infection and Incidence-Rate Ratios, According to Sociodemographic and Clinical Characteristics

Condom use, the use of alcohol with sexual intercourse, and transactional sexual intercourse were evaluated only in subjects who were sexually active. The horizontal lines represent 95% confidence intervals, with arrows indicating extensions of the intervals beyond 2.0.