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Circumcision Protects against Herpes and Human Papillomavirus in addition to HIV

In recent years, research has shown that adult male circumcision provides significant protection against HIV acquisition among heterosexual men in high-prevalence areas. A South African study reported in 2005 showed that elective circumcision reduced men's HIV infection rate by 61%. In late 2006, the National Institutes of Health halted 2 circumcision trials in Kenya and Uganda after interim analyses found that the procedure was associated with fewer new infections; final data from the studies showed that circumcision reduced the risk of HIV infection by 50%-60%.

Now, a study published in the March 26, 2009 issue of the New England Journal of Medicine has found that circumcision of adolescent and adult men also reduces the risk of acquiring 2 other sexually transmitted infections, herpes simplex virus (HSV-2, the usual cause of genital herpes) and human papillomavirus (HPV, the cause of genital warts and cervical and anal cancers).

Aaron Tobian from Johns Hopkins University's Bloomberg School of Public Health and colleagues assessed the efficacy of circumcision for the prevention of HSV-2, HPV, and syphilis in HIV negative adolescent boys and men in rural Rakai, Uganda (a further analysis of the Uganda study noted above).

The investigators looked at more than 5000 HIV negative, initially uncircumcised heterosexual men between the ages of 15 and 49 enrolled in 2 trials of circumcision for the prevention of HIV and other sexually transmitted infections. The Rakai-1 trial ran from September 2003 through September 2005, while the Raiki-2 trial ran from February 2004 through December 2006.

The participating men all expressed an interest in circumcision. About half were randomly assigned to undergo the procedure immediately, while the rest were put on a waiting list to be circumcised after 24 months. All participants received condoms and HIV prevention counseling.

Among these men, 3393 (61.3%) were HSV-2 seronegative at enrollment. Of the HSV-2 seronegative participants, 1684 were randomly assigned to the immediate circumcision arm and 1709 to the delayed circumcision arm.

At baseline and at 6, 12, and 24 months, the researchers tested the men for HSV-2, HIV, and syphilis. They also performed physical examinations and conducted interviews about risk behavior and other factors. In addition, a subgroup of participants were tested for HPV infection at baseline and at 24 months.

Results

• At 24 months, retention rates were high, 81.9% in the immediate circumcision group and 82.0% in the delayed circumcision group.
• After 24 months, 114 circumcised men and 153 uncircumcised men were infected with HSV-2.
• The cumulative probability of HSV-2 infection was 7.8% in the immediate circumcision group versus 10.3% in the delayed circumcision group.
• After adjusting for other factors including number of sex partners and condom use, circumcision was associated with a 28% reduction in the risk of HSV-2 infection (adjusted hazard ratio 0.72; P=0.008).
• 42 circumcised men and 80 uncircumcised men were found to have high-risk HPV types (e.g., 16, 18).
• The prevalence of high-risk HPV was 18.0% in the immediate circumcision group versus 27.9% in the delayed group.
• After adjusting for other factors, circumcision was associated with a 35% lower prevalence of high-risk HPV (adjusted risk ratio 0.65; P=0.009).
• The prevalence of non-high-risk HPV genotypes at 24 months was also lower in the circumcised group (26.2%) compared with the uncircumcised (39.4%) (risk ratio 0.66; P=0.01).
• At 24 months, 50 men (2.4%) in the immediate circumcision group and 45 (2.1%) in the delayed group had syphilis.
• After adjusting for other factors, the risk of syphilis infection did not differ significantly between the circumcised and uncircumcised groups (adjusted hazard ratio 1.10; P=0.44).

Based on these findings the authors concluded, "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."

Previous studies have shown that having HSV-2 increases the risk of both acquiring and transmitting HIV, so it is possible that circumcision's protective effect against HSV-2 may directly contribute to its efficacy against HIV.

"These findings, in conjunction with those of previous trials, indicate that circumcision should now be accepted as an efficacious intervention for reducing heterosexually acquired infections with HSV-2, HPV, and HIV in adolescent boys and men," the researchers wrote in their discussion. "However, it must be emphasized that protection was only partial, and it is critical to promote the practice of safe sex."

This study did not assess the risk of the men's female partners becoming infected with HSV-2 or HPV, but the researchers plan to do so. Some studies suggest that male circumcision is associated with a lower rate of HPV in female partners, but any benefits could be outweighed if circumcision leads to more high-risk sexual behavior.

Furthermore, the risk reduction observed in heterosexual men in a high HIV prevalence area may not carry over to men who have sex with men in low HIV prevalence countries.

In an accompanying editorial, Matthew Golden and Judith Wasserheit of the University of Washington at Seattle reviewed studies to date of adolescent and adult circumcision and discussed the implications of this research.

Though not studied directly, they suggested that infant circumcision could be expected to have a similar protective effect, and would have the advantage of ensuring that the procedure is done before young men start having sex.

"In areas with a high prevalence of heterosexually transmitted HIV, expanding access to safe circumcision, both for adults and neonates, is well justified, and new data related to HPV and HSV-2 add to already compelling arguments supporting circumcision," Golden and Wasserheit wrote. "In low-income and middle-income countries with a lower prevalence of heterosexually transmitted HIV (particularly those with high rates of cervical cancer and limited infrastructure to perform safe circumcision), decisions should be made after estimating the costs and potential population-level benefits of the procedure."

"These new data should prompt a major reassessment of the role of male circumcision, not only in HIV prevention but also in the prevention of other sexually transmitted infections," they concluded. "Male circumcision will remain a personal decision for patients and parents, and some unanswered questions persist. However, evidence now strongly suggests that circumcision offers an important prevention opportunity and should be widely available."

Departments of Pathology and Medicine, School of Medicine, and the Departments of Epidemiology and Molecular Microbiology and Immunology, Population, Family, and Reproductive Health, and International Health and Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD; Institute of Public Health, Makerere University, Kampala, Uganda; Rakai Health Sciences Program, Entebbe, Uganda; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.

3/31/09

References

AAR Tobian, D Serwadda, TC Quinn, and others. Male Circumcision for the Prevention of HSV-2 and HPV Infections and Syphilis. New England Journal of Medicine 360(13): 1298-1309. March 26, 2009.

MR Golden and JN Wasserheit. Prevention of Viral Sexually Transmitted Infections -- Foreskin at the Forefront. New England Journal of Medicine 360(13): 1349-1351. March 26, 2009.