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Correspondence

Male Circumcision for the Prevention of HSV-2 and HPV Infections

To the Editor

When Tobian et al. (March 26 issue)1 sampled only the glans for human papillomavirus (HPV), they guaranteed a positive finding because the location of HPV on the penis differs according to circumcision status.2-5 Uncircumcised men with HPV have the virus on the glans 65% of the time, whereas circumcised men with HPV have the virus on the glans 48% of the time.2 Consequently, sampling only the glans will underestimate the risk of HPV among circumcised men by about 35%. If the numbers reported in the study by Tobian and colleagues are adjusted for this sampling bias, the odds ratio becomes 0.83 (95% confidence interval [CI], 0.56 to 1.24), which is no longer statistically significant.

Similarly, the men in the intervention group of the study were instructed to abstain from sex until healing took place, but no adjustment was made for this difference in exposure when the risk of herpes simplex virus (HSV) infection was determined. If the exposure time is adjusted by 6 weeks to allow for healing, the unadjusted risk ratio is no longer significant (risk ratio, 0.81; 95% CI, 0.63 to 1.03). Consequently, the positive findings reported by Tobian et al. can be completely explained by sampling and lead-time bias.

Michelle R. Storms, M.D.
Michigan State University College of Human Medicine, Marquette, MI 49855

  1. 1. Tobian AAR, Serwadda D, Quinn TC, et al. Male circumcision for the prevention of HSV-2 and HPV infections and syphilis. N Engl J Med 2009;360:1298-1309

  2. 2. Weaver BA, Feng Q, Holmes KK, et al. Evaluation of genital sites and sampling techniques for detection of human papillomavirus DNA in men. J Infect Dis 2004;189:677-685

  3. 3. Aynaud O, Piron D, Bijaoui G, Casanova JM. Developmental factors of urethral human papillomavirus lesions: correlation with circumcision. BJU Int 1999;84:57-60

  4. 4. Hernandez BY, Wilkens LR, Zhu X, et al. Circumcision and human papillomavirus infection in men: a site-specific comparison. J Infect Dis 2008;197:787-794

  5. 5. Nielson CM, Schiaffino MK, Dunne EF, Salemi JL, Giuliano AR. Associations between male anogenital human papillomavirus infection and circumcision by anatomic site sampled and lifetime number of female sex partners. J Infect Dis 2009;199:7-13

To the Editor

Tobian et al. present evidence of the protective effects of male circumcision against HSV type 2 (HSV-2) and HPV infections, underscoring its usefulness as a public health intervention. In sub-Saharan Africa, about 30 million men are uncircumcised, and it is not clear how to scale up circumcision where health care providers are scarce. Potential approaches include delegation of the procedure to nonphysician health care providers, the use of high-throughput surgical models, and the use of visiting physicians to supplement local resources. Lacking from this discussion are male-circumcision devices to reduce operation times, complication rates, and time to wound healing. With disposable devices that remain on the penis for several days, sutures for hemostasis and skin closure (which are time-consuming parts of the operation) are unnecessary. Although device removal is required, this approach could save time, allow for higher throughput, and facilitate expansion of services. Male-circumcision devices are used successfully in infants and young boys; several devices are available in adult sizes. Research to assess the reliability, safety, acceptability, and cost-effectiveness of such devices for use in settings where there is a high prevalence of human immunodeficiency virus (HIV) infection should be a priority.

Renee Ridzon, M.D.
Kanwarjit Singh, M.D.
Bill and Melinda Gates Foundation, Seattle, WA 98109

Response

The authors reply: We agree with Storms that circumcised men have less HPV on the glans penis than uncircumcised men. However, we do not agree that this is a sampling bias; rather, we believe it is a biologic effect of removing the foreskin. In the study cited by Storms, Weaver et al. found that the foreskin of uncircumcised men, as compared with other sites, had the highest prevalence of HPV. Thus, removal of the foreskin is likely to result in reduced penile carriage of HPV; this is supported by the finding that clearance of penile HPV is more rapid among circumcised men.1 The trial in South Africa, which used urethral-swab specimens, showed an efficacy of circumcision in reducing HPV2 that was almost identical to that reported in the trial in Rakai, Uganda. In addition, observational studies with the use of pooled samples from multiple penile sites have shown lower HPV carriage in circumcised men than in uncircumcised men3; this finding is supported by several other observational studies that used different sampling procedures. Storms presents an adjusted estimate of the efficacy of circumcision for HPV prevention, assuming differential HPV detection in circumcised and uncircumcised men. However, this adjustment for the biologic effect of circumcision on HPV conflates cause and effect and results in an uninterpretable underestimate of efficacy.

With regard to Storm's argument that adjustment for postsurgical sexual abstinence could have reduced the efficacy of circumcision for the prevention of HSV-2 infection: it is unclear how these estimates were derived. Wound healing was certified in 85.0% of men 4 weeks after surgery and in 95.8% of men 6 weeks after surgery. Men were to refrain from intercourse until certification of wound healing, so adjusting for this period of sexual abstinence, we estimate that the incidence of HSV-2 infection would be 4.2 per 100 person-years (114 of 2714 person-years) in the intervention group and 5.4 per 100 person-years (153 of 2851 person-years) in the control group (P=0.02). These results, in conjunction with the trial in South Africa, which showed a reduction in HSV-2 acquisition,4 indicate that circumcision is efficacious for the prevention of heterosexually acquired HSV-2 infection.

As noted by Ridzon and Singh, the evidence from three male-circumcision trials showing reduced HIV acquisition and from two trials showing reductions in the acquisition of HSV-2 and HPV provides support for the public health benefits of the procedure.

Aaron A.R. Tobian, M.D., Ph.D.
Johns Hopkins University, Baltimore, MD 21205

David Serwadda, M.Med., M.P.H.
Makerere University, Kampala, Uganda

Ronald H. Gray, M.D., M.Sc.
Johns Hopkins University, Baltimore, MD 21205

  1. 1. Lu B, Wu Y, Nielson CM, et al. Factors associated with acquisition and clearance of human papillomavirus infection in a cohort of US men: a prospective study. J Infect Dis 2009;199:362-371

  2. 2. Auvert B, Sobngwi-Tambekou J, Cutler E, et al. Effect of male circumcision on the prevalence of high-risk human papillomavirus in young men: results of a randomized controlled trial conducted in Orange Farm, South Africa. J Infect Dis 2009;199:14-19

  3. 3. Giuliano AR, Lazcano E, Villa LL, et al. Circumcision and sexual behavior: factors independently associated with human papillomavirus detection among men in the HIM study. Int J Cancer 2009;124:1251-1257

  4. 4. Sobngwi-Tambekou J, Taljaard D, Lissouba P, 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

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