Human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus type 2 (HSV-2) have caused 2 overlapping epidemics that pose major public health problems worldwide. The 2 viruses are involved in a vicious cycle, with HSV-2 enhancing HIV-1 acquisition, replication, and shedding, and HIV, in turn, facilitating acquisition, reactivation, and shedding of HSV-2 [1]. A high proportion of HIV-infected persons—30%–70% of those in Europe and 50%–90% of those in Africa—are also infected with HSV-2 [2, 3]. A meta-analysis of 19 prospective observational studies found that HSV-2 infection increases the risk of acquiring HIV-1 by 2.7 in men and 3.1 in women [4]. More recently, cohort studies in Uganda and Zimbabwe, respectively, found HSV-2–infected persons to be 2.8 and 4.4 times more likely to acquire HIV-1 than persons without HSV-2 infection [5]. Plasma and genital HIV levels are increased during both symptomatic and asymptomatic HSV-2 reactivations [6–8]. That HSV-2 infection enhances both HIV-1 replication and shedding is further supported by studies of HSV-2 suppressive therapy with valacyclovir. Administration of valacyclovir reduces rectal and plasma HIV-1 levels in HIV-positive men who have sex with men by 33% and 53%, respectively [9], and it reduces the quantity of detectable HIV-1 in Peruvian women by 45% [10] and in African women by 0.71 log10 copies/mL [11]. Certain HSV-2 proteins may increase HIV-1 expression and proinflammatory cytokine levels during HSV-2 reactivation, likely increasing HIV-replication [1]

HIV-1 infection increases the odds of HSV-2 acquisition [3]. HSV-2 reactivation and mucosal shedding of HSV-2 are more frequent in HIV-infected persons, and the quantities of HSV-2 and HIV shed by persons coinfected with both viruses are each greater than that shed by persons with HSV-2 or HIV monoinfection [11, 12]. Immune deficiencies impair local HSV-2 control, increase the duration of HSV-2 reactivation episodes, and increase the development and duration of mucocutaneous lesions, including genital ulcers [1, 13]

Given the bidirectional interactions between HIV-1 and HSV-2, it is not surprising that HSV-2 may account for a substantial proportion of HIV infections in populations in which most incident HIV infections are attributable to sexual transmission. A cross-sectional study in 4 different African cities found HSV-2 infection to be highly prevalent and associated with odds ratios of HIV infection ranging from 4.0 to 7.9 [14]. Modeling on the basis of data collected in this same Four Cities Study estimated that the percentage of incident HIV infections attributable to HSV-2 was 35%–48%, with most HIV infections due to recurrent HSV-2 ulcers rather than primary HSV-2 ulcers because of the longer duration over which recurrent ulcerative HSV-2 acts on HIV [15]. Other modeling has resulted in estimates of greater than one quarter of HIV infections attributable directly to HSV-2 in Kisumu, Kenya [16]. Transmission models lead to the conclusion that HSV-2 can more than double the incidence of HIV infection in a population [17]

How does male circumcision fit into the dynamics of HIV and HSV-2 infection? Three randomized controlled trials in Africa have shown that male circumcision reduces the incidence of HIV acquisition among men by ∼60% [18–20]. Given the relationship between HIV and HSV-2, we might expect HSV-2 to be less prevalent in populations in which most men are circumcised, compared with populations in which male circumcision is uncommon. Furthermore, if circumcision reduces the risk of acquiring HSV-2, the protective effect of circumcision against HIV acquisition could be acting indirectly through its protective effect against HSV-2 infection. If circumcision is taken up by large numbers of men in sub-Saharan Africa, will genital herpes become less frequent and, consequently, HIV infection incidence reduced?

The article by Sobngwi-Tambekou et al. [21] in this issue of the Journal provides the first data from a clinical trial that permit an estimation of the fraction of HIV incident cases attributable to HSV-2 infection. Furthermore, this study from Orange Farm, South Africa, examines whether male circumcision in young men reduces the seroincidence of HSV-2. Previously, the only data available concerning circumcision and HSV-2 were from observational studies. A meta-analysis of those studies suggested that circumcision reduces the risk of HSV-2 acquisition but with marginal statistical significance [22]. Preliminary results from the Rakai circumcision trial show statistically significant and strengthened effects [23]. The findings by Sobngwi-Tambekou and colleagues provide crucial insight into the intersection of circumcision, HSV-2, and HIV because they come from a clinical trial that was conducted in an area of low circumcision prevalence, where the HIV epidemic is generalized and the enrolled young men engaged, for the most part, in high HIV risk behaviors (HIV seroincidence among the control subjects, 2.4 cases per 100 person-years)

In the analysis by Sobngwi-Tambekou et al. [21], 34% of HIV seroconversions occurred among men who were HSV-2 seropositive at enrollment or acquired HSV-2 during the study period. After adjustment for sexual behavior and sociodemographic characteristics, 28% of the incident HIV infections in the cohort was estimated to be attributable to prevalent or incident HSV-2 infection. This is remarkable, considering that the HSV-2 prevalence was just 10% in the cohort. Such HSV-2 prevalence is low compared with that in most sub-Saharan African populations [2]. In populations with higher HSV-2 prevalence and incidence, the attributable fraction of HIV-1 infections would be even higher. Primary prevention is not likely to be 100% effective, even in the event of development of an effective vaccine, but the disproportionately higher incidence of HIV infection among HSV-2–infected men indicates that, if just modest decreases in the HSV-2 prevalence and incidence can be achieved, this could result in a substantial reduction in incident HIV infections. Additional data collection that enables analysis of the attributable risk of incident HSV-2 infection for HIV acquisition will permit estimates of how much HIV risk reduction may be possible with various levels of primary prevention of HSV-2 infection

Remarkably, male circumcision was found in this study to reduce HSV-2 seroincidence by ∼55% in multivariate as-treated analysis. This is considerably greater than that found in observational studies [22] and in the Rakai trial [23]. A natural corollary of this finding, if confirmed for other populations, is that, as circumcision interventions are introduced and the prevalence of circumcision in a population increases, the incidence and prevalence of HSV-2 should decrease over time. In turn, as the population prevalence of HSV-2 decreases, the risk of HIV acquisition associated with HSV-2 infection should also decrease. Thus, the protective effects of male circumcision against incident HIV infection should be amplified over time. To our knowledge, no models estimating the long-term impacts of circumcision on the incidence and prevalence of HIV infection have taken these effects into account

Sobngwi-Tambekou et al. [21] report HSV-2 prevalence and incidence on the basis of serological findings only. No clinical signs or symptoms of HSV-2 infection are reported. The importance of including observations of symptomatic genital herpes in analyses of risks for incident HIV infection is highlighted by their finding that the protective effect of circumcision against HIV acquisition was not modified by prevalent or incident HSV-2 infection detected by serological analysis. The authors conclude that the effect of circumcision on HIV acquisition that is attributable to circumcision’s effects on HSV-2 is very limited. However, we know that genital ulcer disease (GUD) increases the odds of HIV infection [24, 25]. If circumcised and uncircumcised men differ in the incidence of HSV-2–induced GUD, then HSV-2 serostatus may appear not to modify the effect of circumcision on HIV acquisition, but in fact it may actually do so through GUD

Additional information is needed on how circumcision affects the clinical course of HSV-2 infection. Limited clinical observations by O’Farrell [26] suggest that recurrence of genital herpes may be reduced in men after circumcision. This is consistent with results from the Kisumu trial, in which the HSV-2 seroincidence did not differ between circumcised and uncircumcised men yet the incidence of GUD was ∼2 times greater in the uncircumcised group (unpublished data), indicating that the clinical manifestations of positive HSV-2 serological findings for circumcised men differ from those for uncircumcised men. The protective effect of circumcision against HIV acquisition may be conferred through reduction of the prevalence of genital herpes lesions, rather than through prevention of HSV-2 acquisition only. This indicates that not only should detection of herpetic lesions be included in studies of circumcision and HIV but also that interventions for HIV prevention might achieve greater efficacy if they include early symptom recognition and avoidance of sex during outbreaks. The logical course is that suppression of symptomatic reactivations of HSV-2 with therapy will offer some protection against HIV acquisition. Unfortunately, a clinical trial of twice daily acyclovir in HIV-negative, HSV-2–seropositive women in Africa and men who have sex with men from sites in Peru and the United States was not effective in reducing HIV-1 acquisition [27], despite reduction of HSV-2–positive genital ulcers by 63% in the acyclovir group. Similarly, a trial of acyclovir undertaken in HIV-negative, HSV-2–seropositive high-risk women in Tanzania found no reduction in HIV acquisition and no reduction in HSV-2 genital ulcers [28]. An additional, multisite clinical trial involving 3400 HIV-discordant couples is investigating acyclovir’s effect on HIV transmission, and the results should be available soon. Because that trial is being conducted in communities where circumcision prevalence varies, it may be possible to do a subanalysis to examine the effect of circumcision on HSV-2 serostatus, GUD, and HIV transmission

HSV-2 as a biological cofactor in HIV acquisition and transmission has likely contributed substantially to the HIV epidemic. Although it remains possible that HSV-2 suppressive therapy will be efficacious in reducing HIV transmission, it is not clear how and whether a twice daily regimen of acyclovir will be manageable and effective at a population level. Research is needed to develop and test a prophylactic vaccine that, even if only partially protective against HSV-2 acquisition, is likely to be effective in both concentrated epidemics and in generalized epidemics in which a large proportion of HIV transmission occurs in stable partnerships [16]. Many questions about the interaction between these 2 organisms remain. Add male circumcision into the mix, and the interactions become even more complex. Male circumcision services are now being introduced in regions with high HIV and low circumcision prevalences—regions where HSV-2 prevalences are also high. As the proportion of circumcised men increases, the interactions between HIV and HSV-2 are likely to change, and the number of HIV infections averted may be different from those currently projected. Quantifying how much and understanding the biological mechanisms by which circumcision’s protective effect against HIV acquisition is modified by HSV-2 infection and herpetic genital ulcers will provide insight into current epidemic dynamics and will assist in designing and evaluating future HSV-2 and HIV interventions

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Potential conflicts of interest: none reported
Financial support: R.C.B. receives funds for research and implementation of male circumcision interventions from the US government and the Bill and Melinda Gates Foundation through Family Health International