Purpose of review: Herpes simplex virus type 2 (HSV-2) and syphilis are associated with HIV infection. The purpose of this review is to summarize the advances in the relationship of HSV-2 and syphilis with HIV, highlighting intervention trials to prevent HIV acquisition and transmission.
Recent findings: HIV acquisition has often been linked to genital ulcers due to HSV-2 and syphilis. The latest pathophysiological studies have continued to elucidate the relationship between HSV-2, syphilis and HIV, establishing that both syphilitic and HSV-2-infected tissue have increased numbers of chemokine receptor 5-expressing T cells, and several models have further emphasized the viral synergy between HSV-2 and HIV. In clinical trials, HSV suppressive therapy decreased HIV RNA levels that might affect transmission, but two trials have failed to prevent HIV acquisition. Male circumcision, however, prevents both HIV and HSV-2 acquisition.
Summary: Genital ulcers from HSV-2 and syphilis are associated with HIV acquisition. The exact role for these HIV cofactors is still unknown and exemplified by the failure of HSV suppressive therapy to decrease HIV acquisition. Male circumcision, however, reduces HSV-2 acquisition. With several HSV suppressive trials to prevent HIV transmission and disease progression currently ongoing, the future promises to provide more critical information for the control of HIV infection.
aDepartment of Pathology, USA
bDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, USA
cDivision of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
Correspondence to Thomas C. Quinn, Rangos Building, Room 530, 855 N. Wolfe Street, Baltimore, MD 21205, USA Tel: +1 410 955 3151; fax: +1 410 614 9775; e-mail: firstname.lastname@example.org
Herpes simplex virus type 2 (HSV-2) and syphilis are common sexually transmitted infections (STIs) [1–4]. HSV-2-seropositive individuals have a lifelong risk of infecting their sexual partners . It is estimated that HSV-2 seroprevalence increased by almost one-third to 21.8% in the United States between 1976 and 1994 . In Uganda, it is estimated that the HSV-2 seroprevalence in women and men is 74 and 57%, respectively . Treponema pallidum infects at least 12 million individuals annually . Genital ulcer disease (GUD) due to both syphilis and HSV-2 is also associated with an increased risk of acquiring HIV. Recent studies have continued to evaluate the pathophysiological relationship between HSV-2, syphilis and HIV and also explored potential interventions that could reduce HIV acquisition and transmission by suppressing HSV-2 infection. This review highlights recent advances in the synergy between HSV-2, syphilis and HIV.
Syphilis is associated with HIV acquisition
Multiple studies [7–9] have shown that syphilis infection is associated with an increased risk of acquiring HIV. The incidence of syphilis among HIV-positive individuals is increasing and disproportionately affects men who have sex with men (MSM) [7,10]. The association between syphilis and HIV acquisition may be partially mediated by the association between symptomatic GUD and HIV acquisition . The pathophysiology behind this association has been further clarified recently by Sheffield et al. [12•] who showed that women with either syphilis, HSV-1 or HSV-2 infection have significantly higher numbers of CD14+ cells that express chemokine receptor 5 (CCR5) within the genital ulcer. These authors also found that CCR5 mRNA expression is higher in syphilitic tissue [12•].
Although syphilis is associated with HIV acquisition, HIV also adversely affects the serologic response to syphilis. It has been recently demonstrated that HIV-infected individuals with CD4+ T-cell counts of less than 200 cells/μl are at higher risk of a lack of a serologic response to syphilis . In addition, administration of highly active antiretroviral therapy (HAART) is also associated with a 60% reduction in the lack of a serologic response to syphilis . Thus, HIV and syphilis are synergistically associated with one another, with syphilis enhancing transmission and acquisition of HIV, and HIV suppressing the serologic detection of syphilitic infection.
Herpes simplex virus type 2 risk factors
Although there have been numerous studies to evaluate HSV-2 prevalence, little is known about incident HSV-2 infection. Knowledge of HSV-2 risk factors is important for prevention of primary HSV-2 infection and potentially for trials of HSV-2 interventions aimed at reducing HIV transmission and progression. Several recent studies [14,15•,16•] evaluated both prevalent and incident risk factors in Peru, Tanzania and Uganda. One study [16•] in Rakai, Uganda demonstrated that HSV-2 incidence increases with alcohol use when combined with sexual intercourse [adjusted incidence rate ratios (adjIRR), 1.92; 95% confidence interval (CI), 1.46–2.53], and decreased with consistent condom use (adjIRR 0.56; 95% CI, 0.36–0.89), and was not significantly affected by enrolment HIV status. Thus, education on modifiable behavioral changes may reduce HSV-2 acquisition. Although the acquisition of HSV-2 is becoming more well defined, there is still limited research on HSV-2 transmission.
Herpes simplex virus type 2 is associated with HIV acquisition
HSV-2 is associated with a three-fold increased risk for acquiring HIV in observational studies [1–3,5]. It has been estimated that there is a 2.6-fold increased risk of HIV acquisition per coital act associated with genital ulceration . As HSV-2 is the main cause of genital ulceration worldwide [1–3], this fact underscores the importance of the association between HSV-2 and HIV. A recent study  in Tanzania found an increased HIV incidence among women with either prevalent HSV-2, incident HSV-2 or active GUD.
The pathophysiology between HSV-2 and HIV has also been further elucidated recently. It was previously accepted that the association between symptomatic GUD and HIV transmission might be related to higher HIV RNA levels in genital ulcers of those individuals with HSV-2 . In addition to the breaches of the mucosal barrier, it has been proposed that the increased risk of HIV acquisition associated with HSV-2 infection may be due to recruitment of CD4+ T cells expressing CCR5 and immature dendritic cells into areas of HSV replication with both clinical and subclinical reactivation of mucosal lesions [20–22]. Individuals coinfected with HIV and HSV-2 also have higher numbers of CD4+ T cells compared with HIV-positive individuals after adjusting for HIV viral load [23•], but HIV-specific CD8+ T-cell responses and systemic inflammation are reduced . Thus, it has been hypothesized that HSV-2 enhances HIV acquisition by creating mucocutaneous lesions that permit HIV entry while simultaneously recruiting HIV-susceptible cells to the mucosa .
Herpes simplex virus type 2 and HIV viral synergy
Powers et al. [26•] recently conducted a meta-analysis of 27 studies that provided heterosexual infectivity estimates to determine transmission cofactors that affect HIV heterosexual infectivity. The authors found that HIV infectivity is significantly greater among uncircumcised men, individuals with GUD and individuals with early-stage or late-stage (compared with mid-stage) HIV infection [26•]. Although there were limited data that prevented meta-regression analyses, the authors also determined that infectivity is higher for individuals with any STI [26•]. The increased infectivity among individuals with STIs and GUD suggests that HSV-2 may play a role in HIV transmission.
Although it is often difficult to fully and accurately incorporate timing of HIV and HSV-2 infections, durations of viral infection stages, viral shedding and other key transmission factors, Abu-Raddad et al. [27•] created a model of HIV and HSV-2 dynamics and interactions to evaluate the synergy between these two viruses compared with other STIs. The authors estimate that in areas of high HSV-2 prevalence (such as Africa), HSV-2 may contribute to more than 25% of incident HIV infections [27•]. It is proposed that HSV-2 makes individuals more at risk for HIV infection or more infectious for those individuals that are coinfected with HIV and HSV-2 [27•]. Consequently, the authors believe that HSV-2 infection is a critical initiator for the global spread of HIV [27•]. Although this model has plausibility and biological factors to support this synergy in transmission, it does not control for the confounding factor of behavior that invariably is linked to acquisition of both infections.
Herpes simplex virus suppressive therapy decreases HIV RNA levels
A study  from Rakai, Uganda previously demonstrated that HSV-2-positive individuals who experience HIV seroconversion have significantly higher HIV viral load set points when compared with HSV-2-seronegative individuals. In addition, three studies [29–31] showed that HSV-2-seropositive individuals have increased levels of genital or plasma HIV-1 RNA levels, whereas several studies [23•,32,33] showed no association. Nagot et al. [34•] extended these finding using multiple longitudinal samples. They found that both genital and plasma HIV-1 viral loads are higher among women with at least one GUD or genital HSV-2 DNA shedding [34•]. Overall, the findings suggest that HSV suppression might decrease HIV shedding.
Due to the association between HSV-2 and genital HIV shedding, several studies evaluated the role for HSV suppressive therapy to decrease genital and plasma HIV RNA levels. Among 140 HSV-2 and HIV coinfected women in Burkina Faso that received either 500 mg valacyclovir twice daily or placebo, those in the intervention group had significantly lower genital (0.29 log10 copies/ml decrease) and plasma (0.53 log10 copies/ml decrease) HIV RNA levels [35••]. In addition, among 20 HSV-2 and HIV-positive MSM in Lima, Peru with CD4 cell counts of more than 200 cells/μl that received either 500 mg valacyclovir twice daily or placebo, those in the intervention group also had significantly lower rectal (0.16 log10 copies/ml decrease) and plasma (0.33 log10 copies/ml decrease) HIV RNA levels [36••]. The same group of researchers also evaluated 20 HSV-2 and HIV-positive women in Lima, Peru who received either 500 mg valacyclovir twice daily or placebo and then the alternative therapy for 8 weeks after a 2-week washout period. Those in the intervention group had significantly lower cervical and plasma HIV RNA levels [37••]. These findings helped to lay the groundwork for several clinical trials to determine whether HSV suppression can decrease HIV acquisition, HIV transmission or HIV disease progression.
Herpes simplex virus suppressive therapy to prevent HIV acquisition
Due to the ability of HSV suppressive therapy to decrease plasma, genital and rectal HIV RNA levels, it had been hypothesized that HSV suppressive therapy may decrease HIV acquisition, transmission or disease progression. Two randomized control trials [38••,39••] were completed in 2008 to evaluate whether HSV-2 suppressive therapy could prevent HIV acquisition among HIV-negative, HSV-2-seropositive individuals (Table 1). Watson-Jones et al. [38••] enrolled female workers at recreational facilities in Tanzania to receive 400 mg acyclovir twice daily (n = 400) or placebo (n = 421). The HIV incidence was 4.1 per 100 person-years in the placebo group and 4.4 per 100 person-years in the acyclovir group. The trial by Celum et al. [39••] evaluated women in Africa and MSM in Peru and USA and assigned participants to twice daily 400 mg acyclovir (n = 1637) or placebo (n = 1640). Although the incidence of genital ulcers decreased by 47% and HSV-2-positive genital ulcers decreased by 63% in the acyclovir group, the HIV incidence was nonsignificantly higher in the acyclovir group (3.9 per 100 person-years) compared with the placebo group (3.3 per 100 person-years) [39••].
It is hypothesized that the failure of these two clinical trials to prevent HIV acquisition with HSV suppression may be due to insufficient drug concentration or that HSV-2 does not increase HIV susceptibility. Acyclovir does not have good absorption and has a short half-life. Thus, the plasma concentrations may be deficient to prevent HIV acquisition. Although a recently published meta-analysis demonstrated that HSV-2-positive status is a significant risk factor for HIV acquisition, this association is not present among high-risk women . Therefore, it is possible that HSV-2 suppression trials failed to prevent HIV acquisition, as risk factors other than HSV-2 seropositivity may play a more important role for HIV acquisition.
Herpes simplex virus suppressive therapy to prevent HIV transmission or disease progression
In addition to the two trials that evaluated whether HSV suppressive therapy prevents HIV acquisition, the Partners in Prevention trial is currently evaluating whether HSV suppressive therapy could reduce HIV transmission from HIV, HSV-2 coinfected individuals to the HIV-negative partner. Due to the evidence demonstrating that HIV and HSV-2 coinfected individuals have a higher HIV viral load set point than singly HIV-infected individuals [28–31,34•], another randomized clinical trial is evaluating whether HSV suppressive therapy can limit HIV disease progression. Results of these two trials on HIV and HSV-2 viral synergy will be available sometime during the next 2 years.
Male circumcision for HIV prevention and associated sexually transmitted infections
Three large randomized controlled trials and multiple observational studies demonstrated that male circumcision significantly decreases HIV acquisition in men [41–43]. Self-reported GUD was decreased in circumcised men in the trial conducted in Rakai, Uganda, suggesting that male circumcision may reduce other STIs . Additionally, two observational studies [44,45] suggested that male circumcision significantly decreases HSV-2 infection, whereas others showed no association between male circumcision and HSV-2 infection [46–52]. Similarly, two observational studies [53,54] reported that male circumcision decreases syphilis infection, whereas others showed no association [51,55]. A meta-analysis of cross-sectional and prospective studies that estimated the decreased risk of HSV-2 and syphilis infection associated with circumcision is of borderline statistical significance with a relative risk of 0.88 (95% CI, 0.77–1.01) and 0.67 (95% CI, 0.54–0.83), respectively .
In a predefined analysis of secondary endpoints of a randomized control trial of uncircumcised men aged 15–49 years that were HIV and HSV-2 antibody negative at enrolment and were randomized to receive immediate circumcision (n = 1684) or circumcision after 24 months (n = 1709), male circumcision significantly reduced HSV-2 acquisition. The cumulative probability of HSV-2 seroconversion over 2 years was 7.8% in the intervention group and 10.3% in the control group (adjusted hazard ratio, 0.72; 95% CI, 0.56–0.92; P = 0.008) [57••]. HSV-2 incidence was lower in the intervention group than the control group in almost all sociodemographic, behavioral and sexually transmitted disease symptom subgroups. However, no significant difference was observed in syphilis acquisition or prevention by study arm (adjusted hazard ratio, 1.10; 95% CI, 0.75–1.65; P = 0.44) [57••].
It is possible that protection against HIV acquisition due to male circumcision could in part be mediated by decreased GUD-associated and HSV-2-associated genital ulcers. Thus, male circumcision prevents HSV-2 acquisition, and consequently the HSV-2 reduction may contribute to the efficacy of circumcision for prevention of HIV infection in men. However, the exact contribution of protection from HIV acquisition that is due to HSV-2 protection remains unknown.
There have been many advances recently in evaluating the association between HSV-2 and syphilis infections with HIV for both transmission and prevention. The mechanisms responsible for the synergistic association of HSV-2 and syphilis have been further elucidated demonstrating that both syphilitic and HSV-2-infected tissue have increased number of CCR5-expressing T cells, theoretically increasing HIV susceptibility in active GUD due to these infections. HSV-2 and HIV coinfections also result in higher HIV viral loads, and conversely HSV-2 suppression decreases plasma and genital viral load. Male circumcision decreases both HSV-2 and HIV acquisition, and models of HIV and HSV-2 dynamics have stressed the importance of HSV-2 infections in the spread of HIV.
The possibility of confounding due to correlated sexual risk behaviors cannot be excluded in most of these studies, and two trials of HSV-2 suppression in HSV-2-positive and HIV-negative men failed to show protection against HIV acquisition. It is still unknown, however, whether HSV suppressive therapy can prevent HSV-2 transmission or HIV disease progression. With these trials currently underway, it is evident that there is significant synergy between these two major STIs and HIV, and additional data on the relative roles of these infections with each other will be forthcoming in the near future.
Thomas Quinn is supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.
There are no potential conflicts of interest for all authors.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 344).
1 Whitley RJ, Roizman B. Herpes simplex virus infections. Lancet 2001; 357:1513–1518.
2 Corey L, Handsfield HH. Genital herpes and public health: addressing a global problem. JAMA 2000; 283:791–794.
3 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; 35:435–445.
4 Fenton KA, Breban R, Vardavas R, et al
. Infectious syphilis in high-income settings in the 21st century. Lancet Infect Dis 2008; 8:244–253.
5 Gupta R, Warren T, Wald A. Genital herpes. Lancet 2007; 370:2127–2137.
6 Malkin JE. Epidemiology of genital herpes simplex virus infection in developed countries. Herpes 2004; 11(Suppl 1):2A–23A.
7 Zhang X, Wang C, Hengwei W, et al
. Risk factors of HIV infection and prevalence of co-infections among men who have sex with men in Beijing, China. AIDS 2007; 21(Suppl 8):S53–S57.
8 Patterson TL, Semple SJ, Staines H, et al
. Prevalence and correlates of HIV infection among female sex workers in 2 Mexico-US border cities. J Infect Dis 2008; 197:728–732.
9 Chen XS, Yin YP, Tucker JD, et al
. Detection of acute and established HIV infections in sexually transmitted disease clinics in Guangxi, China: implications for screening and prevention of HIV infection. J Infect Dis 2007; 196:1654–1661.
10 Zetola NM, Klausner JD. Syphilis and HIV infection: an update. Clin Infect Dis 2007; 44:1222–1228.
11 Stamm WE, Handsfield HH, Rompalo AM, et al
. The association between genital ulcer disease and acquisition of HIV infection in homosexual men. JAMA 1988; 260:1429–1433.
12• Sheffield JS, Wendel GD Jr, McIntire DD, Norgard MV. Effect of genital ulcer disease on HIV-1 coreceptor expression in the female genital tract. J Infect Dis 2007; 196:1509–1516.
13 Ghanem KG, Moore RD, Rompalo AM, et al
. Antiretroviral therapy is associated with reduced serologic failure rates for syphilis among HIV-infected patients. Clin Infect Dis 2008; 47:258–265.
14 Lama JR, Lucchetti A, Suarez L, et al
. Association of herpes simplex virus type 2 infection and syphilis with human immunodeficiency virus infection among men who have sex with men in Peru. J Infect Dis 2006; 194:1459–1466.
15• Tassiopoulos KK, Seage G 3rd, Sam N, et al
. Predictors of herpes simplex virus type 2 prevalence and incidence among bar and hotel workers in Moshi, Tanzania. J Infect Dis 2007; 195:493–501.
16• Tobian AA, Charvat B, Ssempijja V, et al
. Factors associated with the prevalence and incidence of herpes simplex virus type 2 infections among men in Rakai, Uganda. J Infect Dis 2009; 99:945–949. This is the first study to evaluate incident HSV-2 risk factors in the general population in Africa.
17 Gray RH, Wawer MJ, Brookmeyer R, et al
. Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1-discordant couples in Rakai, Uganda. Lancet 2001; 357:1149–1153.
18 Kapiga SH, Sam NE, Bang H, et al
. The role of herpes simplex virus type 2 and other genital infections in the acquisition of HIV-1 among high-risk women in northern Tanzania. J Infect Dis 2007; 195:1260–1269.
19 Schacker T, Ryncarz AJ, Goddard J, et al
. Frequent recovery of HIV-1 from genital herpes simplex virus lesions in HIV-1-infected men. JAMA 1998; 280:61–66.
20 Rebbapragada A, Wachihi C, Pettengell C, et al
. Negative mucosal synergy between herpes simplex type 2 and HIV in the female genital tract. AIDS 2007; 21:589–598.
21 Corey L. Synergistic copathogens: HIV-1 and HSV-2. N Engl J Med 2007; 356:854–856.
22 Holmberg SD, Stewart JA, Gerber AR, et al
. Prior herpes simplex virus type 2 infection as a risk factor for HIV infection. JAMA 1988; 259:1048–1050.
23• Barbour JD, Sauer MM, Sharp ER, et al
. HIV-1/HSV-2 co-infected adults in early HIV-1 infection have elevated CD4+
T cell counts. PLoS ONE 2007; 2:e1080. This study evaluated the influence of HSV-2 infections on HIV clinical course and found that coinfected individuals have elevated numbers of CD4+
24 Sheth PM, Sunderji S, Shin LY, et al
. Coinfection with herpes simplex virus type 2 is associated with reduced HIV-specific T cell responses and systemic immune activation. J Infect Dis 2008; 197:1394–1401.
25 Van de Perre P, Segondy M, Foulongne V, et al
. Herpes simplex virus and HIV-1: deciphering viral synergy. Lancet Infect Dis 2008; 8:490–497.
26• Powers KA, Poole C, Pettifor AE, Cohen MS. Rethinking the heterosexual infectivity of HIV-1: a systematic review and meta-analysis. Lancet Infect Dis 2008; 8:553–563.
27• Abu-Raddad LJ, Magaret AS, Celum C, et al
. Genital herpes has played a more important role than any other sexually transmitted infection in driving HIV prevalence in Africa. PLoS ONE 2008; 3:e2230. A model of HSV-2 and HIV interactions that suggests HSV-2 has a prominent role in HIV spread.
28 Serwadda D, Gray RH, Sewankambo NK, et al
. Human immunodeficiency virus acquisition associated with genital ulcer disease and herpes simplex virus type 2 infection: a nested case-control study in Rakai, Uganda. J Infect Dis 2003; 188:1492–1497.
29 Mbopi-Keou FX, Gresenguet G, Mayaud P, et al
. Interactions between herpes simplex virus type 2 and human immunodeficiency virus type 1 infection in African women: opportunities for intervention. J Infect Dis 2000; 182:1090–1096.
30 McClelland RS, Wang CC, Overbaugh J, et al
. Association between cervical shedding of herpes simplex virus and HIV-1. AIDS 2002; 16:2425–2430.
31 Baeten JM, McClelland RS, Corey L, et al
. Vitamin A supplementation and genital shedding of herpes simplex virus among HIV-1-infected women: a randomized clinical trial. J Infect Dis 2004; 189:1466–1471.
32 Cowan FF, Pascoe SJ, Barlow KL, et al
. Association of genital shedding of herpes simplex virus type 2 and HIV-1 among sex workers in rural Zimbabwe. AIDS 2006; 20:261–267.
33 Cachay ER, Frost SD, Richman DD, et al
. Herpes simplex virus type 2 infection does not influence viral dynamics during early HIV-1 infection. J Infect Dis 2007; 195:1270–1277.
34• Nagot N, Ouedraogo A, Konate I, et al
. Roles of clinical and subclinical reactivated herpes simplex virus type 2 infection and human immunodeficiency virus type 1 (HIV-1)-induced immunosuppression on genital and plasma HIV-1 levels. J Infect Dis 2008; 198:241–249.
35•• Nagot N, Ouedraogo A, Foulongne V, et al
. Reduction of HIV-1 RNA levels with therapy to suppress herpes simplex virus. N Engl J Med 2007; 356:790–799.
36•• Zuckerman RA, Lucchetti A, Whittington WL, et al
. Herpes simplex virus (HSV) suppression with valacyclovir reduces rectal and blood plasma HIV-1 levels in HIV-1/HSV-2-seropositive men: a randomized, double-blind, placebo-controlled crossover trial. J Infect Dis 2007; 196:1500–1508.
37•• Baeten JM, Strick LB, Lucchetti A, et al
. Herpes simplex virus (HSV)-suppressive therapy decreases plasma and genital HIV-1 levels in HSV-2/HIV-1 coinfected women: a randomized, placebo-controlled, cross-over trial. J Infect Dis 2008; 198:1804–1808.
38•• Watson-Jones D, Weiss HA, Rusizoka M, et al
. Effect of herpes simplex suppression on incidence of HIV among women in Tanzania. N Engl J Med 2008; 358:1560–1571. The first randomized control trial of 821 women to demonstrate that acyclovir does not reduce HIV acquisition.
39•• Celum C, Wald A, Hughes J, et al
. Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial. Lancet 2008; 371:2109–2119.
40 Freeman EE, Weiss HA, Glynn JR, et al
. 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.
41 Gray RH, Kigozi G, Serwadda D, et al
. Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet 2007; 369:657–666.
42 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; 369:643–656.
43 Auvert B, Taljaard D, Lagarde E, et al
. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial. PLoS Med 2005; 2:e298.
44 Auvert B, Buve A, Lagarde E, et al
. Male circumcision and HIV infection in four cities in sub-Saharan Africa. AIDS 2001; 15(Suppl 4):S31–S40.
45 Weiss HA, Buve A, Robinson NJ, et al
. The epidemiology of HSV-2 infection and its association with HIV infection in four urban African populations. AIDS 2001; 15(Suppl 4):S97–S108.
46 Xu F, Markowitz LE, Sternberg MR, Aral SO. Prevalence of circumcision and herpes simplex virus type 2 infection in men in the United States: the National Health and Nutrition Examination Survey (NHANES), 1999–2004. Sex Transm Dis 2007; 34:479–484.
47 Gottlieb SL, Douglas JM Jr, Foster M, et al
. Incidence of herpes simplex virus type 2 infection in 5 sexually transmitted disease (STD) clinics and the effect of HIV/STD risk-reduction counseling. J Infect Dis 2004; 190:1059–1067.
48 Kapiga SH, Sam NE, Shao JF, et al
. Herpes simplex virus type 2 infection among bar and hotel workers in northern Tanzania: prevalence and risk factors. Sex Transm Dis 2003; 30:187–192.
49 Lavreys L, Rakwar JP, Thompson ML, et al
. Effect of circumcision on incidence of human immunodeficiency virus type 1 and other sexually transmitted diseases: a prospective cohort study of trucking company employees in Kenya. J Infect Dis 1999; 180:330–336.
50 Reynolds SJ, Shepherd ME, Risbud AR, et al
. Male circumcision and risk of HIV-1 and other sexually transmitted infections in India. Lancet 2004; 363:1039–1040.
51 Gray R, Azire J, Serwadda D, et al
. Male circumcision and the risk of sexually transmitted infections and HIV in Rakai, Uganda. AIDS 2004; 18:2428–2430.
52 Obasi A, Mosha F, Quigley M, et al
. Antibody to herpes simplex virus type 2 as a marker of sexual risk behavior in rural Tanzania. J Infect Dis 1999; 179:16–24.
53 Bwayo J, Plummer F, Omari M, et al
. Human immunodeficiency virus infection in long-distance truck drivers in east Africa. Arch Intern Med 1994; 154:1391–1396.
54 Cook LS, Koutsky LA, Holmes KK. Circumcision and sexually transmitted diseases. Am J Public Health 1994; 84:197–201.
55 Urassa M, Todd J, Boerma JT, et al
. Male circumcision and susceptibility to HIV infection among men in Tanzania. AIDS 1997; 11:73–80.
56 Weiss HA, Thomas SL, Munabi SK, Hayes RJ. Male circumcision and risk of syphilis, chancroid, and genital herpes: a systematic review and meta-analysis. Sex Transm Infect 2006; 82:101–109, discussion 110.
57•• Tobian AAR, Serwadda D, Quinn TC, et al
. Male circumcision for the prevention of HSV-2 and HPV infections and syphilis. N Engl J Med 2009; 360:1298–1309.