Observational studies have suggested an association between HIV and herpes simplex virus type 2 (HSV-2) [1–4]. However, our knowledge is limited regarding their interaction. Determining the transmission probabilities of HSV-2 and HIV, the cofactor effect of each virus on the transmission probability of the other and the cofactor effect of male circumcision status on these transmission probabilities will help understand the dynamics of the HSV-2 and HIV epidemics in Africa and develop targeted interventions.
Published values of female-to-male HSV-2 transmission probability per-sex-act were obtained from studies investigating discordant couples, mostly from developed countries. The value of 0.00015 was found by a study conducted in the United States . Another study conducted in 96 sites from the United States, Canada, Europe, Latin America and Australia found a value of 0.00035 .
Epidemiological studies have also estimated the probability of female-to-male HIV-1 transmission per-sex-act. A study conducted in Rakai (Uganda) estimated this probability to be 0.0011 [95% confidence interval (CI): 0.0008–0.0015] . However, studies in Kenya and Thailand, investigating sexual encounters with prostitutes, evaluated per-contact HIV-1 transmission probabilities to be around 30–80 times higher than the Ugandan study [8,9]. In the context of multiple partnerships, a Kenyan prospective cohort study estimated the overall probability of female-to-male HIV-1 transmission per-sex-act at 0.0063 (95% CI: 0.0035–0.0091) . Recently, a systematic review estimated that the crude female-to-male transmission probability per-sex-act for developing countries was 0.0030 (95% CI: 0.0009–0.010) .
A synergy between HIV and HSV-2 has been observed. Epidemiological studies have demonstrated that prevalent HSV-2 is associated with a two-fold to four-fold increased risk of HIV-1 acquisition [1–4,12]. Several mechanisms can explain this association. The presence of other sexually transmitted infections (STIs) could enhance HIV susceptibility by breaching the epithelial barrier, recruiting HIV target cells to the genital tract or generating a proinflammatory local immune milieu . This has been confirmed by one study that estimated the effect of genital ulceration associated with HSV-2 infection on HIV transmission probability among HIV-1 serodiscordant couples. This study found that genital ulceration in the previous 10 months was a risk factor for HIV transmission, with per-contact risk increasing five-fold (0.0062 versus 0.0012) .
In terms of coinfections, both clinical and sub-clinical reactivations of HSV-2 are associated with the influx of activated CD4+ T cells into the genital mucosa and skin, and conversely, several HSV-2 proteins are capable of reactivating a latent HIV infection . These interactions appear to account for the higher titers of HIV-1 in the plasma of coinfected patients: HIV-1 is shed from genital ulcers caused by HSV-2, and viral variants of HIV-1 that arise from these ulcers can appear and persist in plasma . Frequent sub-clinical episodes of HSV-2 reactivation are associated with both a higher frequency and a higher amount of HIV-1 in genital secretions . Hence, as genital coinfections increase HIV levels in the genital secretions, they may be an important factor in secondary sexual transmission .
HIV infection is also thought to facilitate HSV-2 transmission. Outbreaks of HSV-2 are generally more severe, extensive, persistent and invasive for those with more advanced HIV disease [15,17]. In fact, persistent HSV-2 infection was one of the original opportunistic infections that resulted in the identification of AIDS .
Three randomized controlled trials demonstrated that male circumcision reduces the female-to-male sexual acquisition of HIV by about 60% [19–21]. A meta-analysis of observational data showed that the risk reduction of HSV-2 infection by male circumcision was of borderline statistical significance (RR = 0.88, 95% CI: 0.77–1.01) . Preliminary results of the effect of male circumcision on male HSV-2 acquisition that were observed in the Rakai and Orange Farm (South Africa) male circumcision trials were presented in international AIDS conferences [23,24].
The study's first objective was to estimate the per-sex-act and per-partnership female-to-male transmission probabilities (FtoMTPs) of HSV-2 and HIV. The second objective was to assess the effect of each virus on the FtoMTP of the other. The last objective was to assess the effect of male circumcision on these FtoMTPs. This analysis was conducted using a specific mathematical modeling applied to the longitudinal data of the male circumcision trial conducted in Orange Farm among men aged 18–24 . Orange Farm is a township located close to Johannesburg in Gauteng province, an area with a high HIV prevalence . Samples collected during this trial were specifically tested for HSV-2. The results of a cross-sectional study conducted in the same township  were used to estimate the HIV and HSV-2 statuses of each female partner of the males having participated in the male circumcision trial.
Collection of data
The technical details of the trial have been published elsewhere , and only a summary will be presented in this article. Between February 2002 and July 2004, 3274 uncircumcised males, aged 18–24, were recruited, randomized into two groups and followed up. At baseline, HSV-2 and HIV serological statuses were ascertained, and male circumcision was offered to the intervention group. During each of the follow-up visits at 3, 12 and 21 months, male circumcision status was assessed by a nurse through genital examination, and a blood sample was taken and tested for HIV and HSV-2. Information about sexual behavior was collected, including number of partners as a function of time, number of sexual contacts with each partner, reported condom use with each partner and age of each partner. The data set used in this study included 590 additional 21-month follow-up visits (20.0% of the total number of 21-month visits) that were not included when the analysis of the effect of male circumcision on HIV acquisition was published because corresponding laboratory data were not available at that time.
Details of the HIV testing methods have been described in the main publication of the trial . Plasma samples were tested using an HSV type 2 specific IgG assay to detect HSV-2 antibodies (Kalon HSV-2 gG2 assay; Kalon Biologicals Ltd., Aldershot, UK), according to the manufacturer's recommendations.
We constructed two mathematical models of HIV and HSV-2 statuses as functions of time. These models were used to estimate the FtoMTPs of HIV and HSV-2. In this study, FtoMTP is defined as the probability that a susceptible male becomes infected following a sex act or partnership with an infected female. These mathematical models considered HIV and HSV-2 statuses simultaneously. Model 1 estimated the per-sex-act FtoMTPs of HIV and HSV-2, and model 2 their per-partnership FtoMTPs. These FtoMTPs were supposed to be constant as a function of time and were estimated by fitting the HIV and HSV-2 statuses predicted by the models on the observed data using the maximum likelihood method. Each of these models took into account three types of dichotomous cofactors: the effect of each virus on the FtoMTP of the other (two cofactors), the effect of male circumcision on the FtoMTP of each virus (two cofactors) and the effect of reported condom use on each of these FtoMTPs (two cofactors).
Condom use was dichotomized as follows: a given partnership was considered protected when condom use was reported as ‘always’ used for the partnership. Otherwise, the partnership was considered not protected. All sexual contacts of a protected partnership were considered as protected, otherwise they were considered as not protected.
The model estimated the HIV and HSV-2 statuses of each female partner of the males. For this estimation, we used data from a representative sample of 476 women aged 15–49. These data had been collected during a cross-sectional survey conducted in the same community in the year 2004 . They included age, HIV serostatus and HSV-2 serostatus, obtained with the same HSV-2 assay, and reported number of sexual partners in the past 12 months. HIV and HSV-2 prevalences were 25.8 and 67.7%, respectively. Twenty-four percent of women were coinfected by the two viruses. The mean (median) number of lifetime partners was 3.4 (3). For each female partner of each male of the male circumcision trial, we estimated the probability of being infected with HIV or HSV-2 or both. This estimation was done using the age of these partners and the distribution of the HIV and HSV-2 statuses of women as a function of age and of their reported number of sexual partners. In this manner, the more sexual partners a female had had in the past 12 months, the more likely she was to be a partner of males (see Annex 1).
The effect of each cofactor was expressed by its RR. The RR of any cofactor was obtained by dividing the FtoMTP in the presence of the cofactor by the FtoMTP in the absence of the cofactor. This method was applied to estimate the effect of male circumcision and the effect of reported condom use on the FtoMTPs of HIV and HSV-2. To estimate the effect of HSV-2 infection on the FtoMTP of HIV, we considered that this FtoMTP was multiplied by the corresponding RR when only one of the partners was infected by HSV-2, and that it was multiplied by RR2 when both partners were infected. The same method was applied to estimate the effect of HIV on the FtoMTP of HSV-2. We assumed that the effects of the cofactors were constant as a function of time.
Details of the model are given in Annex 1. Regarding the FtoMTP of HIV per sex act, when all the cofactors were constant (reported condom use, male circumcision status and HSV-2 status of partners), the model assumed that the FtoMTP of HIV after n sexual contacts (Pn,HIV) was given by the following formula:
In this formula, PHIV is the FtoMTP of HIV per sex act. The formulas for HSV-2 and for the FtoMTPs per partnership are similar. The FtoMTPs of HIV and HSV-2 as well as the six RRs were estimated in a unique simulation of model 1 for the per-sex-act FtoMTPs, and of model 2 for the per-partnership FtoMTPs.
A first complementary set of analyses was performed to estimate the FtoMTPs of HIV and HSV-2 with only male circumcision status as cofactor. It generated the FtoMTP of each infection averaged on reported condom use and on the other infection. A second complementary set of analyses was conducted to allow the comparison of the results obtained by this modeling approach with those obtained by a published survival analysis performed on the same dataset . For this, we estimated the intention-to-treat (ITT) RR of male circumcision on the FtoMTP of HIV by replacing circumcision status by the randomization group in the model's equations with only male circumcision as cofactor. These analyses were then repeated with HSV-2 in order to obtain the ITT RR of male circumcision on the FtoMTP of HSV-2.
To estimate the 95% CI of the FtoMTPs and RRs, we used the bootstrap re-sampling method with 2000 replications . For each bootstrap simulation, new samples of 3274 men and 476 women were randomly selected from the male circumcision trial data for men and from the cross-sectional survey data for women. The 95% CI was estimated by the interval between the 2.5th and 97.5th percentiles of the bootstrapped simulations. The RRs were statistically compared with 1 by estimating a corresponding two-tailed P value. This P value was determined using the percentile (r) corresponding to a RR of 1 by P = 2r/100 when r is 50 or less, and by P = 2 (100 − r)/100 when r is at least 50. When the value 1 was out of the range given by the re-sampling method, we used P < 0.001 (2 × 1/2000).
Simulations and estimations were performed using the R programming language (version 2.6.1) . R scripts can be provided upon request to the corresponding author.
The HSV-2 and HIV prevalences at enrolment were 5.9% (194/3274) and 4.4% (145/3274), respectively. Table 1 presents the number of new HSV-2 infections, new HIV infections and new HSV-2/HIV coinfections observed at the end of each follow-up visit.
The per-sex-act FtoMTPs of HIV and HSV-2, for an uncircumcised and noncondom user male, 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.
Table 2 gives the multivariate RRs of the FtoMTPs of HIV per sex act and per partnership. The effects of male circumcision and of an HSV-2 infection in either partner were similar in both cases: male circumcision significantly reduced the FtoMTPs of HIV, whereas HSV-2 infection in either partner significantly increased the FtoMTPs of HIV. Reported condom use significantly reduced the per-partnership FtoMTP of HIV, and the CI of the effect of reported condom use on the per-sex-act FtoMTP was large. Table 3 gives the multivariate RRs of the FtoMTPs of HSV-2 per sex act and per partnership. The results obtained were qualitatively similar to the results obtained with HIV, but quantitatively weaker.
In this longitudinal study, 50.5% of men were circumcised at the beginning of the follow-up. Table 4 presents the FtoMTPs of HIV and HSV-2 per sex act and per partnership as functions of male circumcision status, and averaged on the other cofactors. The univariate protective effect of male circumcision status is significant for HIV and HSV-2. The protective effect on HIV is about twice the protective effect on HSV-2. The per-sex-act and per-partnership FtoMTPs of HIV, averaged on male circumcision, reported condom use and HSV-2 status, were 0.0088 (95% CI: 0.0061–0.013) and 0.032 (95% CI: 0.022–0.045), respectively. The corresponding values for HSV-2 were close: 0.0099 (95% CI: 0.0074–0.013) and 0.037 (95% CI: 0.028–0.048), respectively.
In the univariate ITT analysis, the effects of male circumcision on per-sex-act and per-partnership FtoMTPs of HIV were 0.37 (95% CI: 0.19–0.71, P = 0.004) and 0.40 (95% CI: 0.21–0.73, P = 0.004), respectively. The corresponding values for HSV-2 showed a nonsignificant protective effect with RR values of 0.79 (95% CI: 0.50–1.2, P = 0.32) and 0.83 (95% CI: 0.54–1.2, P = 0.39), respectively.
Using a mathematical modeling approach, this study estimated the per-sex-act and per-partnership FtoMTPs of HIV and HSV-2 among a cohort of young men in South Africa. It suggested that HSV-2 infection enhanced HIV acquisition, and conversely that HIV infection could enhance HSV-2 acquisition. Furthermore, this study provided evidence of a protective effect of male circumcision on HSV-2 acquisition by young men.
This study has some limitations: we used data obtained among men aged 18–24, recruited for a male circumcision trial, and thus not representative of the general male population; condom use was collected by partnership. Thus, condom use per sex act was not directly available and had to be extrapolated; we cannot exclude some bias as the HIV and HSV-2 serostatuses of the female partners of each male were not directly assessed but estimated. Nevertheless, in estimating the males' exposure to these two viruses for each of their sexual partnerships, we were careful to take into account the age of their female partners and the sexual behavior by age of the females of the same community; we also cannot exclude bias due to misreporting of sexual behavior of men and women. However, this limitation is inherent to all studies of this type.
Our estimation of HIV FtoMTP per sex act is consistent with recent values obtained by a meta-analysis of transmission studies conducted in developing countries . In particular, it is consistent with the results of a recent HIV-1 per-sex-act FtoMTP estimation conducted in a Kenyan prospective cohort study in the context of multiple partnerships . In contrast, our estimation of HSV-2 FtoMTP per sex act is higher than the comparable published values obtained in two studies conducted among discordant couples, mostly in developed countries [5,6]. Several factors may explain this difference [5,29]. Using discordant couples can create a selection bias for two reasons: couples having a low average FtoMTP are more likely to be discordant and people engaged in long-term relationships have a lower FtoMTP because HSV-2 transmission decreases as a function of the duration of the partnership .
This study was conducted among young men who are for the most part unmarried or not living as married. The short duration of their partnerships and the low number of sexual contacts [19,30] may explain why per-partnership FtoMTPs were only about four times higher than the corresponding per-sex-act FtoMTPs for HIV and HSV-2.
In this study, which used a mathematical modeling approach, the ITT and as-treated protective effect of male circumcision on the per-sex-act and per-partnership FtoMTPs of HIV were almost identical to the reducing effect of male circumcision on HIV incidence estimated using a statistical approach and the same dataset .
In both ITT and as-treated analyses, we observed a reducing effect of male circumcision on HSV-2 acquisition by men, which was significant for the as-treated analysis. This effect was estimated by ensuring that the effect of male circumcision on HIV and of HIV on HSV-2 were taken into account. The difference between ITT and AT analyses may be partly due to the diluting effect of crossovers. This reducing effect of male circumcision on HSV-2 acquisition is consistent with the conclusions of a meta-analysis  and the results of the Rakai male circumcision trial . It provides additional evidence supporting the promotion of male circumcision in Africa as a method to reduce the spread of STIs such as HIV and HSV-2. This effect should be further investigated by pooling the results of the three circumcision randomized trials.
We found a significant reducing effect of reported condom use on the per-partnership FtoMTPs of HIV and HSV-2. The fact that condom use per sex act was extrapolated in addition to its possible misreporting may have contributed to the large CIs found for the effect of reported condom use on the per-sex-act FtoMTPs of HIV and HSV-2.
The significant enhancing effect of male or female HSV-2 positive status on the FtoMTP of HIV, as shown in this study and in many others, is now well accepted [1–4,12]. This study showed a significant enhancing effect of HIV status on the FtoMTP of HSV-2. Such an effect could be due to transient immunosuppression during the acute stage of HIV infection that may increase either HSV-2 acquisition or HSV-2 infectiousness or both, among HIV-infected females. It should be further investigated.
The findings of this study confirm and reinforce the interpretation of a multisite study that found that sexual behavior and prevalence levels of male circumcision and HSV-2 were key factors in understanding the heterogeneity of the HIV epidemic in Africa [31,32]. It appears that the interactions between HIV, HSV-2, sexual behavior and male circumcision should all be taken into account to understand the heterogeneity of the HIV and HSV-2 epidemics in Africa.
Studying the FtoMTPs of both HIV and HSV-2, we found that cofactors such as male circumcision and the presence of the other virus had a strong effect on these FtoMTPs. Hence, it is important for transmission studies to carefully take into account these cofactors, in order to obtain comparable results independent of the prevalence of these cofactors in the study population.
The results of this study are consistent with our current knowledge of the epidemiology of HSV-2 in Africa and the synergy between the HIV and HSV-2 epidemics in this part of the world. The fact that HSV-2 treatment (acyclovir 400 mg twice daily) does not prevent HIV acquisition , most likely because the current HSV-2 treatment does not eradicate HSV-2, does not disprove the facilitating effect of HSV-2 on HIV acquisition. In addition to the reducing effect of male circumcision on HIV acquisition by men, the effect of male circumcision on HSV-2 is another argument in favor of the roll-out of male circumcision in African countries in which most men are uncircumcised . Modeling studies are needed to better understand the interactions between HIV, HSV-2, male circumcision, sexual behavior including condom use, not only in the short term, as studied by randomized controlled trials, but also in the long term.
S.G.M. and B.A. contributed equally to this work. D.T. and A.P. collected the data. A.P., S.G.M., J.B., E.P.N.N., E.G. and B.A. analyzed the data. A.L., J.B., C.L. and P.L. wrote some parts of the paper and edited the entire manuscript.
The financial support was provided by: ANRS grant 1265 (France), Gates Foundation (USA) grant 33759, NICD (South Africa), INSERM (France), SACEMA (South Africa) and SCAC (France Embassy, Cameroon).
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