The role of sexually transmitted infections in male circumcision effectiveness against HIV – insights from clinical trial simulation

Abstract

Background: A landmark randomised trial of male circumcision (MC) in Orange Farm, South Africa recently showed a large and significant reduction in risk of HIV infection, reporting MC effectiveness of 61% (95% CI: 34%-77%). Additionally, two further randomised trials of MC in Kisumu, Kenya and Rakai, Uganda were recently stopped early to report 53% and 48% effectiveness, respectively. Since MC may protect against both HIV and certain sexually transmitted infections (STI), which are themselves cofactors of HIV infection, an important question is the extent to which this estimated effectiveness against HIV is mediated by the protective effect of circumcision against STI. The answer lies in the trial data if the appropriate statistical analyses can be identified to estimate the separate efficacies against HIV and STI, which combine to determine overall effectiveness.

Using Modeling to Explore the Degree to Which a Microbicide's Sexually Transmitted Infection Efficacy May Contribute to the HIV Effectiveness Measured in Phase 3 Microbicide Trials

“…This is mainly due to the higher prevalence of curable STIs observed in some microbicide trial settings, 7 the possibility that the STI protection afforded by microbicides may be bidirectional and the possibility that microbicide trials may observe a smaller decrease in HIV incidence. Compared to Desai et al, 6 the projections of this analysis are comparable but slightly more conservative with respect to the degree to which a product's/circumcision's STI efficacy contributes to the decrease in HIV incidence observed in a trial. However, considering the different models and methods FIGURE 3.…”

Incremental role of male circumcision on a generalised HIV epidemic through its protective effect against other sexually transmitted infections: from efficacy to effectiveness to population-level impact

“…In both scenarios, the male HIV prevalence was 28% at year 15 and declined as the epidemic progressed due to a strong dependence on STI prevalence which declined due to AIDS differential mortality. In scenario A, the overall STI and HIV prevalence, and HIV incidence averaged 22.3%, 29.8%, and 5.9 per 100 person-years over the 20 years following the intervention (introduced at year 15), respectively compared to 3.7%, 16.4% and 1.9 per 100 person-years respectively for scenario B(1–3,12,14–17). …”

“…The population-level impact of MC on HIV prevalence was assessed using a previously validated stochastic compartmental model which simulates transmission of HIV and one STI in the heterosexual population in the Kisumu district of Kenya(12,14). The modelled population was stratified into six sexual activity classes with specific rates of sexual partner acquisition.…”

“…The distribution by sexual activity classes and rates of sexual partner acquisition for scenario B were selected to agree with infection rates in the Kisumu UNIM male circumcision trial population(12,14–17) and the 2003 Kenyan Demographic and Health Survey(15) corresponding to years 15–17 of the simulated epidemic. Remaining parameters for HIV(14,18–23) and STI(27–29) transmission probabilities, duration of the different HIV states(14,18–24–26) and duration of STI infection(27–29) were based on published studies(Table 2). …”

“…To assess the individual-level impact of MC, Desai et al(14) simulated the Kisumu MC trial by recruiting and following-up 2750 initially uncircumcised seronegative men from the overall simulated population and randomly assigning them to the circumcision or control arm. The simulated follow-up was 24 months, HIV incidence rate was 2.5% per year in control subjects, STI prevalence averaged 8.2% in controls over the 2 years, which compares with the overall prevalence of bacterial infections observed in the UNIM trial participants at baseline.…”