In this prospective observational study of 1096 African HIV-1 serodiscordant couples in which the HIV-1 seropositive partner was male, we found a non-statistically significant decreased risk of HIV-1 transmission from circumcised HIV-1 infected men to their female partners, compared to couples with uncircumcised HIV-1 infected men. This finding adds to a limited body of data relating circumcision status in HIV-1 infected men to the risk of male-to-female HIV-1 transmission, data which may be helpful for programs working to scale-up male circumcision for HIV-1 prevention.
Only one previous longitudinal observational study directly assessed the effect of male circumcision on male-to-female HIV-1 transmission risk by measuring incident HIV-1 infections within HIV-1 serodiscordant couples [9
]. Among 223 couples in Rakai, Uganda, HIV-1 seroincidence was 5.2 versus 13.2 per 100 person-years among female partners of circumcised versus uncircumcised HIV-1 seropositive men, respectively (adjusted risk ratio 0.41, 95% confidence interval 0.10-1.14). No transmissions occurred within couples with circumcised men who had plasma viral loads <50,000 copies/mL, compared with an HIV-1 incidence of 9.6 per 100 person-years in couples with uncircumcised men (p=0.02). Like this study, our results suggest an overall decreased HIV-1 risk in partners of circumcised men, compared with partners of uncircumcised men, although our study did not find a statistically significant difference in circumcision effect for men with lower plasma HIV-1 concentrations compared to those with higher concentrations. Two additional prospective cohort studies in women assessed the relationship between male circumcision status and risk of HIV-1 acquisition: one found a statistically significant protective effect [8
] and the other no effect [10
]. An important limitation of these latter two studies was the potential for misclassification, as both relied on women's report of their partners' circumcision status.
Biologic mechanisms by which circumcision could reduce male-to-female HIV-1 risk include reduced risk of STIs, particularly genital ulcer disease, that may serve as co-factors for HIV-1 transmission [11
] or potentially through direct HIV-1 transmission via microtrauma or inflammation of the foreskin. However, we observed no evidence that genital ulcer disease was a substantial factor explaining the difference in HIV-1 transmission risk for circumcised versus uncircumcised men in our population. Social and behavioral factors could in part explain a relationship between circumcision status and HIV-1 transmission risk, although our analyses adjusting for region and for sexual behavior over time argue against a strong confounding effect be these factors.
A recently-completed clinical trial randomized uncircumcised, HIV-1 infected men to immediate versus delayed circumcision and assessed HIV-1 seroincidence for their partners [11
]. The probability of HIV-1 acquisition was not statistically different for women whose partners became circumcised (21.7% at 24 months) compared with those whose partners remained uncircumcised (13.4%, HR 1.49, p=0.37). Notably, a post hoc
analysis found the HIV-1 acquisition rate among partners of men who remained uncircumcised was 7.9% during the first 6 months after enrollment compared with 27.8% for partners of men who were circumcised and then resumed sexual activity prior to documented healing of the surgical wound (p=0.04), a substantially increased risk.
One possible explanation for the difference between the results of the observational studies in HIV-1 serodiscordant couples and the recent clinical trial may be that men in the observational studies were likely circumcised in childhood or adolescence and thus had many years for full wound healing and keratinization of the glans. This raises the possibility that male circumcision may have long-term null or beneficial effects on male-to-female HIV-1 risk, but short-term risk for enhanced HIV-1 transmission during the post-operative period for men who are already HIV-1 infected when they become circumcised. Thus, circumcision earlier in life (e.g., in childhood, prior to initiation of sexual activity) might maximize the potential benefits of circumcision and minimize risks. Problematically, clinical trials to assess the effect of childhood circumcision on future HIV-1 transmission risk would likely be prohibitively long and expensive, as would trials of long-term follow-up (e.g., 5 years or more, to allow for keratinization of the glans) of partners of HIV-1 infected men who undergo circumcision.
Our study had several strengths, including its geographic diversity and enrollment of women at risk for HIV-1 and their partners, which allowed confirmation of circumcision status, adjustment for plasma HIV-1 levels in the male partner, and determination of viral transmission linkage within the partnership. Condom use was very high among this population of HIV-1 serodiscordant couples who received ongoing individual and couples risk-reduction counseling; unprotected sexual activity might be expected to be more common and HIV-1 incidence higher outside of a clinical trial. Sexual behavior risks did not differ between couples with circumcised and uncircumcised HIV-1 infected men in our population.
In spite of the large sample size (almost 1100 HIV-1 serodiscordant couples with HIV-1 seropositive males), our statistical power for adjusted and subgroup analyses was limited, and even larger observational studies might be necessary to detect a statistically significant effect of circumcision on reducing male-to-female HIV-1 transmission risk. Assuming the protective effect of circumcision on HIV-1 incidence we observed in this study held constant if we had enrolled a larger sample size, we would have achieved statistical significance with 76 linked HIV-1 transmission events, which we estimate we would have seen if we had followed 1302 couples. However, others have recently estimated that a randomized controlled trial of up to 10,000 HIV-1 serodiscordant couples might be necessary to definitively evaluate the effect of circumcising HIV-1 infected men on HIV-1 transmission risk to their female partners [21
], for example, if the true magnitude of a protective effect of circumcision on male-to-female HIV-1 transmission risk is less than we observed in this study or if there is a period of increased HIV-1 transmission risk after circumcision.
Additional limitations include that HIV-1 subtype data are not available for this cohort (which might allow assessment of whether subtype modified the relationship between circumcision status and HIV-1 transmission risk) nor were data collected on the age of circumcision for circumcised men. Etiologic testing for STIs was performed only at enrolment and data on bacterial vaginosis are not available; however, STIs were rare in this population and syndromic assessment and treatment occurred quarterly.
Circumcision roll-out programs targeting HIV-1 uninfected men have recently been initiated in several countries. Mathematical modeling studies have demonstrated that male circumcision programs will lead to decreasing HIV-1 prevalence in women, over 10-20 years, by averting infections in men and onward transmission to their partners [22
]. Women will also benefit from male circumcision programs through decreased risk of STIs, including T. vaginalis
, bacterial vaginosis, herpes simplex virus type 2, and human papilloma virus [11
]. Our results suggest that men who acquire HIV-1 in spite of being circumcised pose no greater HIV-1 risk to their female partners than if they were uncircumcised, and may actually pose a reduced risk. For men who are already HIV-1 infected and who desire circumcision, short-term interventions to protect against transmission risk during wound healing could be studied (e.g., a period of antiretroviral therapy or potentially antiretroviral pre-exposure prophylaxis for their female partners). Finally, programs should involve women for informed decision-making about circumcision [23
], including couples HIV-1 counseling and testing and messaging on the risks and benefits of circumcision for HIV-1 seropositive men and their partners.