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Prevention of Viral Sexually Transmitted Infections - Foreskin at the Forefront (male circumcision) EDITORIAL
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"They found that adult male circumcision decreased the prevalence of HPV by 35%, reduced HSV-2 acquisition by 25%, and had no effect on the incidence of syphilis (which probably reflected a limited power to detect an effect). In previous reports from this trial, the Ugandan team reported that male circumcision reduced the occurrence of genital ulcers in men and genital ulcers, bacterial vaginosis, and trichomoniasis in female partners.8,9.....the foreskin may increase susceptibility to microabrasion and allows prolonged contact time between pathogens and nonkeratinized skin. 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......Male circumcision appears to decrease the rate of cervical cancer in female partners.....All the circumcision trials have evaluated adult circumcision in heterosexuals. The procedure may not be protective against sexually transmitted infections in men who have sex with men.....In higher-income nations, such as the United States......widespread access to accurate information about circumcision and to safe procedures should be available. In the United States, rates of circumcision are declining and are lowest among black and Hispanic patients, groups in whom rates of HIV, herpes, and cervical cancer are disproportionately high"
NEJM March 26 2009
Matthew R. Golden, M.D., M.P.H., and Judith N. Wasserheit, M.D., M.P.H.
Three landmark randomized, controlled trials conducted in South Africa, Uganda, and Kenya from 2005 through 2007 demonstrated that adult male circumcision reduced the acquisition of human immunodeficiency virus (HIV) by 50 to 60%.1,2,3 Complications associated with the procedure were rare and almost uniformly minor.4 These findings were largely consistent with those of observational and ecologic studies in which adult male circumcision was associated with a lower HIV risk at both individual and population levels,5 and mathematical models suggest that widespread circumcision could substantially reduce the HIV epidemic in high-prevalence heterosexual populations.6 In 2007, the World Health Organization and the United Nations Programme on HIV/AIDS recommended that circumcision be promoted in areas with a high prevalence of heterosexually transmitted HIV, and donor agencies are now funding male circumcision programs in Africa.
In this issue of the Journal, Tobian et al.7 report findings from the Ugandan trial on the effect of circumcision on the prevalence of human papillomavirus (HPV) infection and the incidence of herpes simplex virus type 2 (HSV-2) infection and syphilis. They found that adult male circumcision decreased the prevalence of HPV by 35%, reduced HSV-2 acquisition by 25%, and had no effect on the incidence of syphilis (which probably reflected a limited power to detect an effect). In previous reports from this trial, the Ugandan team reported that male circumcision reduced the occurrence of genital ulcers in men and genital ulcers, bacterial vaginosis, and trichomoniasis in female partners.8,9 These findings agree with two recent studies from South Africa showing that circumcision reduced the prevalence of high-risk HPV and the incidence of HSV-2 by one third.10,11 The results are also biologically plausible, since the foreskin may increase susceptibility to microabrasion and allows prolonged contact time between pathogens and nonkeratinized skin. 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.
Both HPV and HSV-2 infections are global health problems that far outstrip HIV infection in frequency and result in substantial morbidity and mortality. Roughly three quarters of U.S. adults have had at least one HPV infection. High-risk HPV types cause cervical cancer, the second most common cause of cancer deaths in women globally. In 2002, a total of 273,000 women worldwide died of cervical cancer, including 6500 in North America. Furthermore, approximately 536 million people (16% of the world's population between the ages of 15 and 49 years) and more than 25 million Americans (17% of the adult U.S. population) are infected with HSV-2. In adults, the infection is seldom fatal, but it is associated with substantial morbidity and is costly, generating almost $1 billion annually in direct medical costs in the United States alone. HSV-2 infection is associated with an increase in the risk of HIV infection by a factor of two to four, and up to 2800 neonatal herpes cases occur in the United States annually, often resulting in severe disability or death.
The data from these trials are consistent with the majority of observational studies of male circumcision and HPV infection. A meta-analysis of eight cross-sectional studies conducted from 1999 through 2005 showed a reduced risk of HPV in men who had been circumcised (odds ratio, 0.56; 95% confidence interval [CI], 0.39 to 0.82),12 and three of four studies published subsequently likewise reported that circumcision was protective. What these data do not address is whether circumcision prevents HPV acquisition or decreases the duration of HPV infection or shedding. Three recent cohort studies all showed similar rates of HPV acquisition in circumcised and uncircumcised men, but the two studies that evaluated the issue found that circumcised men cleared HPV more quickly. From a population perspective, a reduction in the rate of either HPV acquisition or shedding in men should reduce women's exposure to the virus and therefore decrease the incidence of cervical cancer. However, the magnitude of the effect of reduced acquisition may differ from that of reduced shedding.
Male circumcision appears to decrease the rate of cervical cancer in female partners. Pooled case-control data for 1913 couples showed that cervical cancer was less than half as common among monogamous women with circumcised, nonmonogamous male sex partners as among women with uncircumcised partners.13 Also, rates of cervical cancer are higher in areas of the world where circumcision is less common.4 Thus, although the preponderance of evidence suggests that circumcision prevents cervical cancer, the magnitude of that protection at a population level is unknown.
Data on circumcision and HSV-2 are more limited but raise analogous questions. A meta-analysis of studies conducted from 1950 through 2004 showed that circumcision was modestly protective against HSV-2 (odds ratio, 0.88; 95% CI, 0.7 to 1.01).14 However, circumcision was not associated with a lower risk of HSV-2 in a nationally representative serosurvey in the United States, and ecologic data are equivocal.4,15 The randomized, controlled studies leave little doubt that circumcision protects against HSV-2 acquisition and reduces symptomatic genital ulcers. Thus, again, circumcision is protective for individuals, but the population-level effect is uncertain.
All the circumcision trials have evaluated adult circumcision in heterosexuals. The procedure may not be protective against sexually transmitted infections in men who have sex with men, and the effect of neonatal circumcision may differ from that of adult circumcision. However, the findings of these studies are consistent with observational data, and there is no biologic reason to anticipate that neonatal circumcision would have a less robust effect than adult circumcision. Moreover, neonatal circumcision would ensure protection before the first coital experience, would minimize the risk of disinhibition, is associated with fewer complications, and is easier to scale up than adult circumcision. The neonatal procedure also confers other childhood health benefits, including a decreased risk of urinary tract infections and phimosis.
So should we promote male circumcision and, if so, where and to whom? 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. 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.
In higher-income nations, such as the United States, the findings from studies of circumcision are a call to action for professional societies and providers. Given the frequency, morbidity, and mortality that characterize the three most important sexually transmitted viral infections, widespread access to accurate information about circumcision and to safe procedures should be available. In the United States, rates of circumcision are declining and are lowest among black and Hispanic patients, groups in whom rates of HIV, herpes, and cervical cancer are disproportionately high.15 Medicaid, which insures many low-income persons in these populations, does not pay for routine neonatal circumcision in 16 states. This policy limits access to the procedure on the basis of economic circumstances, potentially exacerbating existing disparities.
Professional organizations have a leadership role to play in ensuring that medical providers actively educate all parents or guardians of newborn sons about the benefits and risks of circumcision. The American Academy of Pediatrics, which previously concluded that evidence was insufficient to recommend routine neonatal circumcision, is reviewing its position in collaboration with other professional organizations. This process should optimally lead to a multidisciplinary consensus statement involving providers such as obstetricians, midwives, pediatricians, urologists, and family doctors and to the development and dissemination of educational materials for medical professionals and families.
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.
Dr. Golden reports receiving lecture fees from Pfizer and drugs donated by Pfizer and Lupon Pharmaceuticals for research funded by the National Institutes of Health; and Dr. Wasserheit, receiving research support from the Bill and Melinda Gates Foundation. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Center for AIDS and STD (M.R.G.) and the Departments of Global Health and Medicine (J.N.W.), University of Washington; Public Health-Seattle and King County STD Control Program (M.R.G.); and the Fred Hutchinson Cancer Research Center (J.N.W.) - all in Seattle.
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