Mahiane S-G, Legeai C, Taljaard D, et al. Transmission probabilities of HIV and herpes simplex type 2, effect of male circumcision and interactions: a longitudinal study in a township of South Africa. AIDS 2009;24:377-83.
Observational data have demonstrated an association between herpes simples virus type 2 (HSV-2) and HIV infections,(1,2,3,4) and randomized clinical trials have documented the effect of male circumcision (MC) on reducing HIV acquisition.(5,6,7) Although estimates of the per contact risk of HSV-2 and of HIV transmission in heterosexual couples exist, how each virus affects the risk of transmission of the other is not known and the effect MC has on these transmissions has not been determined. Such information may be useful in developing and prioritizing interventions to reduce rates of HIV transmission.
To estimate the 1) per-sex-act and per-partnership female-to-male transmission probabilities (FtoMTPs) of HSV-2 and HIV; 2) the effect of each virus on the other's FtoMTP; and 3) the effect of male circumcision on FtoMTP of HSV-2 and HIV
Orange Farm township, South Africa
Men enrolled in a randomized trial of MC to reduce rates of HIV acquisition
Relative risks of per-sex-act and per-partnership transmission probabilities of HIV and HSV-2
Between February 2002 and July 2004, uncircumcised men aged 18-24 years were entered into a randomized clinical trial of MC to reduce HIV acquisition. HSV-2 and HIV serologies, MC status, and sexual behavioral data were obtained at baseline and follow-up visits at 3, 12, and 21 months. An additional 590 participants were included in this analysis but not in the MC analysis because laboratory data were not available at the time of MC analysis.
Two mathematical models of HIV and HSV-2 status as functions of time were constructed and used to estimate the FtoMTPs (defined as an uninfected man acquiring infection from a single sex act with an infected woman). The models considered the status of HIV and HSV-2 simultaneously. Model 1 estimated transmission per sex act and model 2 estimated transmissions per partnership. The probabilities of transmission were assumed to be constant as a function of time and were estimated by fitting the predicted HIV status and HSV-2 status using the maximum likelihood method. The models included the effect of three cofactors: 1) the effect of each virus on the transmission probability of the other (two cofactors); 2) the effect of MC on the transmission probability of each virus (two cofactors); and 3) the effect of condom use on each of the transmission probabilities (two cofactors). Sexual partnerships were considered protected if participants reported always using condoms, or the partnership was classified as unprotected.
Seroprevalence of HSV-2 and HIV among female partners was estimated using data obtained in cross-sectional survey of 476 women aged 15-49 years in the Orange Farm township in 2004.1 The data used from this study included the age of the women, HIV and HSV-2 serostatus, (25.8% and 67.7%, respectively and 24% infected with both) and number of partners in the past 12 months (mean 3.4, median 3). For each of the participants in the MC trial, an estimate of the HIV and HSV status of their female partners was made based upon the woman's age and the number of partners she reported.
The effect of the co-factors of interest on the transmission probabilities was expressed as a relative risk (RR). The estimate of the effect of MC and condom use on transmission of HIV and HSV-2 was calculated by dividing the FtoMTP in the presence of each of these co-factors by the FtoMTP in the absence of the co-factors. The effect of HSV-2 on the transmission probability of HIV was considered to be the FtoMTP multiplied by the corresponding RR when one of the partners was infected with HSV-2 and RR2 when both partners were infected. The same method was used to estimate the effect of HIV on transmission of HSV-2.
The FtoMTPs were estimated using the formula Pn,HIV(or HSV-2)=1-(1-P HIV(or HSV-2)n where n is the number of sexual contacts and other co-factors were held constant. PHIV/HSV-2 is the FtoMTP per-sex-act or per-partnership. The bootstrap re-sampling method using 2000 replications was used to calculate the 95% confidence intervals.
The per-sex-act FtoMTPs of HIV and HSV-2, for a male uncircumcised and noncondom user, in the absence of the other virus in both partners, were 0.0047 (95% CI: 0.0014-0.017) and 0.0067 (95% CI: 0.0028-0.014), respectively. The corresponding per-partnership FtoMTPs were 0.017 (95% CI: 0.0065-0.044) and 0.026 (95% CI: 0.014-0.047), respectively. For each virus, the per-partnership FtoMTP was about four times higher than the corresponding per-sex-act FtoMTP.
After adjusting for circumcision and condom use, the per-sex-act RR of HIV infection associated with HSV-2 infection in one of the partners was estimated to be 3.0 (95% CI: 1.01-7.3). Circumcision reduced the risk of HIV (RR 0.24, 95% CI: 11-0.44). Condom use did not significantly affect the risk of HIV transmission. The adjusted per-partnership RR of HIV infection associated with HSV-2 in one of the partners was 3.7 (95% CI: 1.7-6.9) and both circumcision and condom use decreased the risk (RR 0.25, 95% CI: 0.12-0.44 and RR 0.47, 95% CI: 0.17-0.92, respectively).
After adjusting for circumcision and condom use, the per-sex-act RR of HSV-2 infection associated with HIV infection in one of the partners was 2.5 (95% CI: 1.08-6.32). Circumcision reduced the risk of HSV-2 infection (RR 0.59, 95% CI: 0.36-0.91). Condom use did not significantly affect the risk of transmission. The adjusted per-partnership RR of HSV-2 associated with HIV in one of the partners was 3.03 (95% CI: 1.6-5.3) and both circumcision and condom use decreased the risk (RR 0.61, 95% CI: 0.39-0.89 and RR 0.49, 95% CI: 0.26-0.80, respectively).
This study provides additional support for a synergistic relation between HIV and HSV-2, demonstrates a protective effect of MC on HSV-2 acquisition, and provides the first estimate of the per-sex-act FtoMTP of HSV-2.
This is a very good mathematical modeling study. As with all such modeling, it carries limitations. In this analysis, limitations include using an earlier study to estimate the probability of HIV and HSV-2 infections in the female partners. Because the male participants were part of a randomized trial they are unlikely to be representative of the at-risk population. The condom-use data were collected per partnership, not per sex act, which may explain the lack of protective effect of condoms on the per-sex-act FtoMTP. Mathematical modeling exercises such as this one are useful in the absence of strong observational or clinical trial data.
This study provides further evidence of the protective effect of MC on HIV acquisition(1,2,3,4) and also provides evidence of its protective effect against the acquisition of HSV-2. These findings support expanding efforts to provide MC in sub-Saharan Africa.
- Corey L, Wald A, Celum CL, Quinn TC. The effects of herpes simplex virus-2 on HIV-1 acquisition and transmission: a review of two overlapping epidemics. J Acquir Immune Defic Syndr 2004;35:435-45.
- Wald A, Link K. Risk of human immunodeficiency virus infection in herpes simplex virus type 2-seropositive persons: a meta-analysis. J Infect Dis 2002;185:45-52.
- Freeman EE, Weiss HA, Glynn JR, Cross PL, Whitworth JA, Hayes RJ. Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS 2006;20:73-83.
- Brown JM, Wald A, Hubbard A, et al. Incident and prevalent herpes simplex virus type 2 infection increases risk of HIV acquisition among women in Uganda and Zimbabwe. AIDS 2007;21:1515-23.
- Auvert B, Taljaard D, Lagarde E, Sobngwi-Tambekou J, Sitta R, Puren A. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 trial. PLoS Med 2005;2:e298.
- Gray RH, Kigozi G, Serwadda D, et al. Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet 2007;369:657-66.
- Bailey RC, Moses S, Parker CB, et al. Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial. Lancet 2007;369:643-56.