Efficacy of Male Circumcision Against HIV Acquisition
Efficacy of Male Circumcision Against HIV Acquisition
In this analysis which accounted for differences in who becomes circumcised and differences in who is lost to follow-up, the protective effect of MMC was maintained at 58% over 6 years of observation, virtually the same as the 58% protective effect observed under trial conditions. Our results show that the protective efficacy does not wane at up to 6 years. Programmatic implementation and scale-up of voluntary MMC services in sub-Saharan Africa is relatively recent, beginning largely in 2008. Because long-term follow-up of circumcised men with an appropriate comparison group of uncircumcised men is generally not feasible in programmatic implementation, surveillance of programmatic effectiveness over time will need to rely on regular cross-sectional surveillance of men's circumcision status and HIV status. Thus, assessment of the long-term effectiveness of MMC is currently limited to data collected through posttrial surveillance. Our results showing long-term protective efficacy of MMC against HIV support the assumptions of studies modeling the population impact of MMC on HIV, and the recommendations for scale-up that are based in part on these model assumptions.
In posttrial surveillance of men initially enrolled in the control arm of the Ugandan MMC trial, the protective effect of circumcision against HIV was 67%, somewhat stronger than the 57% protective effect of MMC against HIV seroconversion observed in the intention-to-treat analysis under their trial conditions. Although Gray et al. found no differences in sociodemographic or behavioral risks between control arm men who chose circumcision and those who did not, comparisons were restricted to the last visit under randomization, and the authors acknowledge that there may have been unmeasured higher risk among men who chose to remain uncircumcised. Their multivariable analysis adjusted for confounders as time-varying covariates, but did not account for the potential of time-varying confounding associated with choosing circumcision or being lost to follow-up.
In posttrial follow-up, circumcision uptake was approximately 50% among men initially randomized to control in our trial, which may indicate significant selection bias, and is significantly less than the 78% circumcision uptake among Rakai trial participants. Reasons for the disparity in uptake in MMC between the two trial populations may have been due to differences in age (men enrolled in the Rakai trial were aged 15–49 years), factors affecting decision to become circumcised, messages, or delivery of promotion of MMC following the trial. Men opting for MMC may be a mixture of potentially lower risk and higher risk men. We found that control men with potentially lower risk for HIV (at baseline used condoms, were married or cohabiting, were not sexually active) were more likely to choose circumcision during posttrial follow-up, although men with more sex partners over follow-up were more likely to become circumcised. Unsurprisingly, greater endorsement of circumcision over follow-up was associated with greater likelihood of becoming circumcised. The WHO/UNAIDS implementation guidance for rapid MMC scale-up recommends that voluntary MMC programs understand reasons for seeking circumcision (situational analysis) and assessment of behavior and practices related to HIV (monitoring and evaluation), so that additional services may be incorporated as needed. Results of our analyses determined specific sexual risk behaviors were associated with choosing circumcision. This highlights the importance of routine HIV testing, counseling to promote protective behaviors, reinforcing that MMC does not reduce HIV risk completely, and syndromic STI screening and treatment, as essential components of voluntary MMC programmatic scale-up. Moreover, while Kenya is over 50% of the way toward reaching the 80% male circumcision target needed to achieve desired population level reductions in HIV prevalence, these results provide insight for advocacy and education that could lead to greater circumcision endorsement to increase service uptake.
In our conventional multivariable Cox regression model, risks for HIV seroconversion were primarily STIs (HSV-2 infection, GUD, and urogenital gonococcal infection), highlighting the need for screening and treatment. Similar to results of our 24-month analysis, both HSV-2 infection (aHR = 2.26) and GUD (aHR = 3.59) were strong, independent risks for HIV seroconversion, suggesting HSV-2 and GUD have different mechanisms of increased HIV risk. Approximately, 60% of clinically detected GUD in our trial was not associated with HSV-2, chancroid, or syphilis by PCR and serology. Rather, pyrosequencing of clinically detected genital ulcers demonstrated that such non-STI GUD was associated with specific anaerobic bacteria that have cytotoxic and tissue destructive properties. The extent to which increased risk of HIV acquisition is a function of dermal compromise and/or inflammation may differ between HSV-2 infection and GUD. The increased risk of HIV acquisition associated with HSV-2 may also reflect differential infectivity of the two viruses when exposed to a co-infected partner, and studies involving discordant couples could assess this. Additionally, controlling for HSV-2 serostatus and GUD, self-reported penile epithelial trauma nearly doubled the risk of HIV seroconversion. From our previous analysis, uncircumcised men are more likely to have epithelial disruptions of the penile skin, which are likely to be mechanical in origin. We previously hypothesized this could represent misclassification of HSV-2 or GUD, but results of this analysis and our previous analyses suggest otherwise. Further study characterizing this potential dermal compromise and mechanisms of increased HIV risk are needed, as genital mucosal trauma was commonly reported among men in our cohort, and in other populations in sub-Saharan Africa.
One of the assumptions of marginal structural models, exchangeability – or the assumption of no measured confounding – cannot be empirically verified. To address this assumption, we attempted to model a sufficient number of joint predictors of becoming circumcised and HIV seroconversion, while balancing this against introduction of too many predictors, which may result in nonpositivity. As reported by Cole and Hernán, estimated weights that are not mean centered or have wide range are indicative of nonpositivity or misspecification. Our weights were mean centered with a narrow range of minimums and maximums for both censoring and treatment. To the extent possible, our models were developed to minimize unmeasured confounding, nonpositivity, and misspecification. The application of marginal structural modeling provides confidence in the causal interpretation of the data.
Posttrial retention among men consenting to extended follow-up was high, and although we accounted for the effect of differential circumcision and loss to follow-up, this still affects the generalizability of our findings. Moreover, this analysis reflects men enrolled in a long-term cohort, with counseling on sexual behavioral risk reduction and testing and treatment of STIs every 6 months.
The efficacy of MMC was sustained at 58% at 6 years of follow-up, similar to findings of the three trials under conditions of randomization at 24 months of follow-up. These findings provide an estimate of the long-term efficacy of MMC against HIV acquisition.
Discussion
In this analysis which accounted for differences in who becomes circumcised and differences in who is lost to follow-up, the protective effect of MMC was maintained at 58% over 6 years of observation, virtually the same as the 58% protective effect observed under trial conditions. Our results show that the protective efficacy does not wane at up to 6 years. Programmatic implementation and scale-up of voluntary MMC services in sub-Saharan Africa is relatively recent, beginning largely in 2008. Because long-term follow-up of circumcised men with an appropriate comparison group of uncircumcised men is generally not feasible in programmatic implementation, surveillance of programmatic effectiveness over time will need to rely on regular cross-sectional surveillance of men's circumcision status and HIV status. Thus, assessment of the long-term effectiveness of MMC is currently limited to data collected through posttrial surveillance. Our results showing long-term protective efficacy of MMC against HIV support the assumptions of studies modeling the population impact of MMC on HIV, and the recommendations for scale-up that are based in part on these model assumptions.
In posttrial surveillance of men initially enrolled in the control arm of the Ugandan MMC trial, the protective effect of circumcision against HIV was 67%, somewhat stronger than the 57% protective effect of MMC against HIV seroconversion observed in the intention-to-treat analysis under their trial conditions. Although Gray et al. found no differences in sociodemographic or behavioral risks between control arm men who chose circumcision and those who did not, comparisons were restricted to the last visit under randomization, and the authors acknowledge that there may have been unmeasured higher risk among men who chose to remain uncircumcised. Their multivariable analysis adjusted for confounders as time-varying covariates, but did not account for the potential of time-varying confounding associated with choosing circumcision or being lost to follow-up.
In posttrial follow-up, circumcision uptake was approximately 50% among men initially randomized to control in our trial, which may indicate significant selection bias, and is significantly less than the 78% circumcision uptake among Rakai trial participants. Reasons for the disparity in uptake in MMC between the two trial populations may have been due to differences in age (men enrolled in the Rakai trial were aged 15–49 years), factors affecting decision to become circumcised, messages, or delivery of promotion of MMC following the trial. Men opting for MMC may be a mixture of potentially lower risk and higher risk men. We found that control men with potentially lower risk for HIV (at baseline used condoms, were married or cohabiting, were not sexually active) were more likely to choose circumcision during posttrial follow-up, although men with more sex partners over follow-up were more likely to become circumcised. Unsurprisingly, greater endorsement of circumcision over follow-up was associated with greater likelihood of becoming circumcised. The WHO/UNAIDS implementation guidance for rapid MMC scale-up recommends that voluntary MMC programs understand reasons for seeking circumcision (situational analysis) and assessment of behavior and practices related to HIV (monitoring and evaluation), so that additional services may be incorporated as needed. Results of our analyses determined specific sexual risk behaviors were associated with choosing circumcision. This highlights the importance of routine HIV testing, counseling to promote protective behaviors, reinforcing that MMC does not reduce HIV risk completely, and syndromic STI screening and treatment, as essential components of voluntary MMC programmatic scale-up. Moreover, while Kenya is over 50% of the way toward reaching the 80% male circumcision target needed to achieve desired population level reductions in HIV prevalence, these results provide insight for advocacy and education that could lead to greater circumcision endorsement to increase service uptake.
In our conventional multivariable Cox regression model, risks for HIV seroconversion were primarily STIs (HSV-2 infection, GUD, and urogenital gonococcal infection), highlighting the need for screening and treatment. Similar to results of our 24-month analysis, both HSV-2 infection (aHR = 2.26) and GUD (aHR = 3.59) were strong, independent risks for HIV seroconversion, suggesting HSV-2 and GUD have different mechanisms of increased HIV risk. Approximately, 60% of clinically detected GUD in our trial was not associated with HSV-2, chancroid, or syphilis by PCR and serology. Rather, pyrosequencing of clinically detected genital ulcers demonstrated that such non-STI GUD was associated with specific anaerobic bacteria that have cytotoxic and tissue destructive properties. The extent to which increased risk of HIV acquisition is a function of dermal compromise and/or inflammation may differ between HSV-2 infection and GUD. The increased risk of HIV acquisition associated with HSV-2 may also reflect differential infectivity of the two viruses when exposed to a co-infected partner, and studies involving discordant couples could assess this. Additionally, controlling for HSV-2 serostatus and GUD, self-reported penile epithelial trauma nearly doubled the risk of HIV seroconversion. From our previous analysis, uncircumcised men are more likely to have epithelial disruptions of the penile skin, which are likely to be mechanical in origin. We previously hypothesized this could represent misclassification of HSV-2 or GUD, but results of this analysis and our previous analyses suggest otherwise. Further study characterizing this potential dermal compromise and mechanisms of increased HIV risk are needed, as genital mucosal trauma was commonly reported among men in our cohort, and in other populations in sub-Saharan Africa.
Limitations
One of the assumptions of marginal structural models, exchangeability – or the assumption of no measured confounding – cannot be empirically verified. To address this assumption, we attempted to model a sufficient number of joint predictors of becoming circumcised and HIV seroconversion, while balancing this against introduction of too many predictors, which may result in nonpositivity. As reported by Cole and Hernán, estimated weights that are not mean centered or have wide range are indicative of nonpositivity or misspecification. Our weights were mean centered with a narrow range of minimums and maximums for both censoring and treatment. To the extent possible, our models were developed to minimize unmeasured confounding, nonpositivity, and misspecification. The application of marginal structural modeling provides confidence in the causal interpretation of the data.
Posttrial retention among men consenting to extended follow-up was high, and although we accounted for the effect of differential circumcision and loss to follow-up, this still affects the generalizability of our findings. Moreover, this analysis reflects men enrolled in a long-term cohort, with counseling on sexual behavioral risk reduction and testing and treatment of STIs every 6 months.
Conclusion
The efficacy of MMC was sustained at 58% at 6 years of follow-up, similar to findings of the three trials under conditions of randomization at 24 months of follow-up. These findings provide an estimate of the long-term efficacy of MMC against HIV acquisition.
Source...