Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies : AIDS

Secondary Logo

Journal Logo


Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies

Freeman, Esther Ea; Weiss, Helen Aa; Glynn, Judith Ra; Cross, Pamela La; Whitworth, James Aa,b; Hayes, Richard Ja

Author Information
AIDS 20(1):p 73-83, January 2, 2006. | DOI: 10.1097/01.aids.0000198081.09337.a7
  • Free



To estimate the sex-specific effect of herpes simplex virus type 2 (HSV-2) on the acquisition of HIV infection.


The increased number of longitudinal studies available since the last meta-analysis was published allows for the calculation of age- and sexual behaviour-adjusted relative risks (RR) separately for men and women.


Systematic review and meta-analysis of longitudinal studies.


PubMed, Embase and relevant conference abstracts were systematically searched to identify longitudinal studies in which the relative timing of HSV-2 infection and HIV infection could be established. Where necessary, authors were contacted for separate estimates in men and women, adjusted for age and a measure of sexual behaviour. Summary adjusted RR were calculated using random-effects meta-analyses where appropriate. Studies on recent HSV-2 incidence as a risk factor for HIV acquisition were also collated.


Of 19 eligible studies identified, 18 adjusted for age and at least one measure of sexual behaviour after author contact. Among these, HSV-2 seropositivity was a statistically significant risk factor for HIV acquisition in general population studies of men [summary adjusted RR, 2.7; 95% confidence interval (CI), 1.9–3.9] and women (RR, 3.1; 95% CI, 1.7–5.6), and among men who have sex with men (RR, 1.7; 95% CI, 1.2–2.4). The effect in high-risk women showed significant heterogeneity, with no overall evidence of an association.


Prevalent HSV-2 infection is associated with a three-fold increased risk of HIV acquisition among both men and women in the general population, suggesting that, in areas of high HSV-2 prevalence, a high proportion of HIV is attributable to HSV-2.


Sexually transmitted infections (STI), especially those causing genital ulcer disease, are associated with increased sexual transmission of HIV [1–4]. Recent studies have highlighted the synergy between HIV and herpes simplex virus type 2 (HSV-2), a major cause of genital ulcers [1,5]. Several randomized controlled trials are currently underway to assess the impact of HSV-2 therapy on HIV acquisition and transmission.

The epidemiology of HSV-2 differs between women and men, with a greater probability of transmission from male-to-female than female-to-male [6] and gender-specific differences in the frequency of herpes recurrences [7]. It is, therefore, plausible that the effect of HSV-2 on HIV acquisition may also vary by gender, but there is little published evidence on this.

One previous meta-analysis[1] assessed the effect of HSV-2 infection on HIV acquisition in studies published up until April 1999. Nine longitudinal studies were identified, only one of which was among women. The summary estimate of studies among men showed a positive association between prevalent HSV-2 and HIV acquisition, while the single study among women showed a non-significant negative association [8] but was unadjusted for confounders. Two more recent reviews did not present an updated meta-analysis for either sex [5,9].

The primary objective of this study is systematically to review studies of the gender-specific effect of HSV-2 on HIV acquisition, and to carry out meta-analyses of studies in general populations and in groups at high risk of STI and HIV, adjusted for age and sexual behaviour. The review is limited to longitudinal studies in order to separate the effect of HSV-2 on HIV acquisition from any effect of HIV infection on subsequent acquisition of HSV-2. A secondary objective of the paper is to assess the effect of recently acquired (incident) HSV-2 on HIV acquisition in these populations; a limitation of this secondary objective is that the time sequence of infections is not always as clear.


Inclusion and exclusion criteria

Types of studies

Cohort and nested case–control studies that assessed the relationship between HSV-2 and HIV infection were eligible for inclusion. Studies in which the relative timing of HSV-2 and HIV infection could not be established were excluded.

Exposure and outcome measures

Studies were eligible if HIV and HSV-2 status was measured in all study participants (not just those who were symptomatic) using appropriate serological tests. Appropriate testing for HSV-2 was considered to be an enzyme-linked immunosorbent assay (ELISA) test or immunoblot test using HSV-2 type-specific glycoprotein G, or a Western blot [10,11]. Appropriate testing for HIV was an ELISA test, Western blot or particle agglutination test, confirmed with a second test.


Abstracts and papers in languages other than English were included and were translated by a fluent speaker of the relevant language.

Statistical requirements

Studies providing an estimate of the relative risk (RR) for HIV infection in HSV-2 seropositive compared with seronegative persons were included. Studies were also included if such an estimate could be calculated from the data. Additionally, authors were contacted whenever it appeared that appropriate data were collected but not presented. Where two publications related to the same study, only the more informative was used.

Search strategy

The PubMED and Embase databases were searched to the first week of June 2004.

For the PubMED search, the following thesaurus terms were first combined with the Boolean operator ‘or’: ‘herpesvirus 2,’ ‘herpes genitalis epidemiology,’ and ‘herpes simplex’ (epidemiology, aetiology, prevention and control, and transmission). Four variations of text words for HSV-2 were then added to broaden the search. In order to identify studies that did not specifically mention HSV-2 in their abstracts, but rather referred to general STI, the thesaurus terms on ‘sexually transmitted diseases’ (epidemiology, aetiology, prevention and control, and transmission) were also included. Then, the search was limited to abstracts also containing information on HIV by adding thesaurus terms ‘HIV seropositivity’ or ‘HIV infections/transmission’ or the text phrase ‘HIV seroconverters’ to the previous search with the Boolean operator ‘anD'. The search also required that the abstracts either contained thesaurus terms for ‘cohort studies’, ‘case–control studies’, or ‘prospective studies’, or contained the appropriate text word for this study type. Only journal articles or letters were eligible. A similar Embase search strategy was also undertaken.

In addition, abstracts from the XIV and the XV International AIDS Conference and the 2003 International Society for Sexually Transmitted Diseases ResearchConference were searched on ‘herpes’ and ‘hsv’. Reference lists of included studies were examined for other pertinent studies. In addition, collaborating researchers were asked about any relevant unpublished data.

All identified abstracts were scanned and those clearly meeting exclusion criteria were eliminated at this point. Full-length papers were then retrieved if published or authors were contacted for more information if an abstract was not associated with a full length paper. Two reviewers (E. F. & H. W.) then applied the inclusion and exclusion criteria previously listed to the retrieved studies. Authors were contacted if further information was needed to include the study in this review.

Data extraction

Data were extracted onto standardized forms by the two reviewers. A quality assessment was also performed on each study to assess selection bias, response rates, loss to follow-up, misclassification and adjustment for confounding.

Statistical analysis

Meta-analyses were undertaken using odds ratios for nested case–control studies and rate ratios for cohort studies. Since HIV incidence rates were low in most studies, the odds ratios would approximate the risk ratio. Summary relative risks (RR) values were calculated where appropriate, using random-effects models rather than fixed-effects models [1,12,13]. Evidence for statistical heterogeneity was taken as P ≤ 0.1 [13,14] since the test for statistical heterogeneity lacked power [15].

Age and sexual behaviour were taken to be a-priori confounders of the relationship between HSV-2 seropositivity and subsequent infection with HIV. Measures of sexual behaviour were allowed to vary by study, since different measures were appropriate for different groups such as commercial sex workers or men who have sex with men (MSM). Only RR adjusted for age and at least one measure of sexual behaviour were included in the final meta-analysis.

It had been hypothesized that the effect of HSV-2 on acquisition of HIV might vary between women and men, and that within each sex there might be variation by type of study population. To explore this potential diversity, studies in males were divided into MSM and men in the general population (assumed to be largely heterosexual) since the effect of HSV-2 could vary by mode of HIV transmission. Studies in females were also divided into two groups: women at high risk, consisting of sex workers and bar workers; and women in the general population. High-risk women are more likely to have other STI besides HSV-2 that might enhance HIV acquisition.

Sex-specific Begg funnel plots were used to examine inclusion bias in the systematic review. The most comprehensively adjusted relative risk for each study was used for this investigation. Data management and statistical analyses were undertaken in STATA 8.0 (Stata Corp., College Station, Texas, USA).

A secondary objective of the systematic review was to collate available information on the incident HSV-2 (acquired during the study period) as a risk factor for HIV acquisition in studies retrieved in the review. An a-priori decision was made that results from these studies would not be included in the meta-analysis because of the unclear relative timing of the two infections, but results are presented in a separate table.


Details of selected studies

After removing duplicates, 4426 abstracts were identified through the PubMED and Embase searches. Additionally, 13 abstracts were retrieved from recent international conferences. One further unpublished study and one in press study were identified by collaborating researchers.

Out of a total of 4441 studies, 4361 were excluded as not relevant. Of the 80 full-length papers retrieved or the authors contacted, as appropriate, 37 studies were identified for possible inclusion (Fig. 1). There were 19 studies that met all of the inclusion criteria (Table 1) [8,16–33]; of these 14 were already published in a peer-reviewed journal, two were in press, and three were unpublished (two of which already had abstracts published in conference proceedings). Additional information and data were received from authors of 14 of these included studies. The 18 studies that were excluded failed to meet specific inclusion criteria, had insufficient information provided by the authors or had repetition of data (see Supplementary Table S1, http://www.lshtm.ac.uk/ideu/research/freeman_hsv2.html) [16,34–50].

Fig. 1:
Flowchart of study selection for inclusion in systematic review.
Table 1:
Studies included in the systematic review.
Table 1:

Of the 19 studies included in the review (Table 1), RR values adjusted for both a-priori confounders, age and a marker of sexual behaviour (and in some cases for other factors as well) were obtained for 18. One study of MSM did not take confounding into account in the presentation of RR values and was considered unadjusted; this study was included in the review but not the meta-analysis. In total, there were 10 studies in women – 4 in the general population and 6 among high-risk women – and 14 studies in men – 9 in the general population and 5 among MSM. Fourteen studies were conducted in developing countries.

The methodological quality of included studies was assessed and can be seen in Supplementary Table S2 (http://www.lshtm.ac.uk/ideu/research/freeman_hsv2.html). Selection bias was considered, including selection of cases and controls where appropriate. Reporting of loss to follow-up was inconsistent; some retrospective studies only considered loss of data or serum rather than loss of individuals in the initial cohort. In studies that did report on this criterion, there was a broad range of loss to follow-up, ranging from a loss at first return visit of 5 to 38% in studies with active follow-up. Few studies supplied information on proportion of selected individuals agreeing to participate. A range of HIV and HSV-2 tests was used by the different studies, but in no case were potential problems thought to have influenced the association of HSV-2 and HIV; no studies were excluded on this basis.

Effect of HSV-2 seropositivity on HIV acquisition

The RR of HIV acquisition in HSV-2-seropositive compared with HSV-2-negative individuals, adjusted for age and sexual behaviour, is shown in Fig. 2. Among general population studies, the summary estimate of adjusted RR was similar for women [RR, 3.1; 95% confidence interval (CI), 1.7–5.6] and men (RR, 2.7; 95% CI, 1.9–3.9) (Table 2). There was little evidence of heterogeneity among studies of women in the general population. The studies in men all showed a positive association (RR values ranging from 1.3 to 7.5), but there was significant heterogeneity (P = 0.03). Among high-risk women, RR values ranged widely, from 0.50 to 6.3, with significant heterogeneity (P = 0.02). Hence, the summary estimates for these studies should be interpreted with caution. The effect of HSV-2 on HIV acquisition in MSM (RR, 1.7; 95% CI, 1.2–2.4) was lower than in general population males, and this difference was of borderline statistical significance (P = 0.07).

Fig. 2:
Relative risk of HIV acquisition in subjects positive for herpes simplex virus type 2 (HIV-2) compared with those negative for HIV-2 in specific populations. The odds ratios are all adjusted for age and sexual behaviour. The squares and horizontal lines correspond to the relative risk and 95% confidence intervals, respectively, for each study. The area of the square reflects the weight of each study. The summary relative risks are shown by the diamonds. (a) General population females; (b) high-risk females (commercial sex workers and bar workers); (c) general population males; (d) men who have sex with men.
Table 2:
Summary of random effects estimates of the relative risk of HIV acquisition in subjects positive for herpes simplex virus type 2 from meta-analyses.

Sex-specific Begg funnel plots of included studies (supplementary Fig. S1, http://www.lshtm.ac.uk/ideu/research/freeman_hsv2.html) plot the natural logarithm of the RR from each study against the logarithm of the study's standard error (a marker of study size). There is little evidence of inclusion bias (i.e., there is no evidence that smaller studies were more likely to be included if they detected large effects).

Effect of incident HSV-2 infection on HIV acquisition

Of the studies in the review, eight either presented a relative risk for incident HSV-2 as a risk factor for HIV seroconversion, or presented data allowing for its calculation. These RR values are presented in Table 3. However, with few exceptions, the majority of HSV-2 and HIV seroconversions were recorded during the same follow-up intervals, so it was impossible to determine which infection occurred first, or whether both infections occurred simultaneously. Also, in contrast to our meta-analyses, very few studies adjusted for confounders such as markers of sexual behaviour. In most [19,24,25,27,32], but not all [30,33] studies, recent HSV-2 seroconverters had a higher risk of HIV acquisition than those who had seroconverted to HSV-2 before the study began (comparing Table 3 with Table 1), but these estimates should be interpreted with caution.

Table 3:
Incident herpes simplex virus type 2 seroconversion (during study period) and risk of HIV acquisition.


This systematic literature review and meta-analysis shows for the first time that prevalent HSV-2 infection is a statistically significant risk factor for HIV acquisition in both men and women in the general population, after adjusting for confounding by age and sexual behaviour. In general populations, men and women infected with HSV-2 had approximately three times the risk of acquiring HIV. Although there was evidence of heterogeneity in the effect among men in the general population, all nine studies contributing to this male summary estimate found a positive association (RR values ranging from 1.3 to 7.5). In MSM, the effect appeared slightly lower than in general population males. This may be due to chance or it could reflect true differences owing to the different transmission route.

The relationship between prevalent HSV-2 and HIV acquisition was not consistent in studies among high-risk women, with RR values ranging from 0.5 to 6.3. This variation between studies could be due to different prevalences of other STI, which act as cofactors for HIV transmission, since these would increase the rate of HIV acquisition in HSV-2-negative individuals. Alternatively, the difference may be a result of residual confounding, if adjustment for sexual exposure to HIV was more complete in some studies than others.

In comparison with the previous meta-analysis [1], we located 16 additional longitudinal estimates of RR from 11 additional studies. In heterosexual men, the new estimate of the adjusted relative risk was slightly higher than that found from unadjusted or partially adjusted studies in the previous meta-analysis (RR, 2.2; 95% CI, 1.3–3.8 [1]). In MSM, our summary adjusted RR was slightly lower than that reported for unadjusted and partially adjusted studies previously (RR, 2.1; 95% CI, 1.3–3.4 [1]), and, unlike the previous study, did not demonstrate any evidence of statistical heterogeneity.

By limiting our meta-analysis to studies with known time sequence of HSV-2 infection and HIV infection, we tried to minimize any bias owing to HIV effects on subsequent acquisition of HSV-2. However, a time lag exists between acquisition of infection and a positive test for both infections. For HSV-2, median time to a positive test from culture-documented primary HSV-2 episodes is 21–120 days, dependent upon the type of test used [51]. The time sequence could, therefore, be misclassified in either direction. This is a particular problem for the examination of incident HSV-2 as a risk factor for HIV, where exact timings are even more difficult to establish.

Although our analysis concentrated on the effect of prevalent HSV-2, there would have been variation between studies in the proportion of individuals with recent and with more remote HSV-2 infections. Since recent HSV-2 may have a stronger effect on HIV acquisition than does more long-standing HSV-2 infection, owing to greater frequency and severity [7,52] of clinical HSV-2 episodes, studies including more recent HSV-2 infections might be expected to have higher RR values.

It was not possible to assess the effect of very recent (incident) HSV-2 infections directly. Few studies examined incident HSV-2, and most of these recorded HSV-2 and HIV seroconversions during the same follow-up interval; consequently, the sequence of infections could not be established. While these studies are consistent with the hypothesis that recent HSV-2 infection is a stronger risk factor for HIV acquisition than is prevalent HSV-2 infection, problems with the time lag, small study size, long intervals between testing dates and lack of adjustment for confounding make the evidence inconclusive.

We attempted to minimize confounding by requesting that authors adjust their estimates of relative risk by a-priori confounders of age and sexual behaviour. Only studies adjusting for at least these confounders were included in the meta-analysis of the effect of prevalent HSV-2. However, residual confounding, especially by sexual behaviour, which was controlled for in a wide variety of ways by included studies, is a major concern in a meta-analysis of observational studies. Obtaining accurate information on sexual behaviour is extremely difficult. However, in most studies the RR changed little upon adjustment for a wide range of confounders.

Studies also used a wide range of HIV and HSV-2 tests. The sensitivity and specificity vary between different tests, and between the same test used on different populations [53]. Misclassification of HSV-2 status is likely to be non-differential with respect to HIV status, leading to underestimation of the association between HSV-2 and HIV.

Publication bias is unlikely to have played an important role in our study since only 5 of the 23 RR values used were published in the form in which they appear in this analysis. Many RR values were extracted from papers or requested from authors whose papers had been published with a different purpose. In these cases, publication was probably not determined by the strength of the RR of interest to this meta-analysis. The funnel plots of ‘inclusion’ bias showed little evidence of any bias.

Controlling HSV-2 could potentially have a large impact on HIV incidence in areas of high HSV-2 prevalence. In a recent review, HSV-2 prevalence in Africa in random and population-based samples of individuals of reproductive age was found to be 29–71% in women and 5–53% in men [54]. Despite the limitations of calculating population-attributable fractions for infectious diseases based on observational studies, from this range of prevalence values and the summary RR values calculated in this meta-analysis, our results suggest that, in these general populations, potentially 38–60% of new HIV infections may be attributable to prevalent HSV-2 infection in women and 8–49% in men.

HSV-2 antiviral treatment is available and has been shown to significantly reduce HSV-2 transmission between discordant heterosexual couples [55]. The impact of this treatment on HIV incidence is not yet known [56]. Ultimately, the best way to establish causality and to understand the impact of HSV-2 interventions on HIV is to undertake HSV-2 intervention studies; several are currently underway.


We would like to thank the authors of studies included in the review, and especially researchers contributing information and further data analyses to this review (listed alphabetically by study group/institution): Scott Holmberg (Centers for Disease Control); Nicolas Nagot (Centre Muraz, Burkina Faso); Eduard Sanders, Nicole Dukers (Ethio-Netherlands AIDS Research Project); Ron Gray (Johns Hopkins University Bloomberg School of Public Health); Steven Reynolds, Mary Shepherd, Sanjay Mehendale (Johns Hopkins University–National AIDS Research Institute India Collaboration); Jim Todd (London School of Hygiene and Tropical Medicine); Gabriele Riedner, Michael Hoelscher (Mbeya Medical Research Programme); Gita Ramjee, Eleanor Gouws, Brian Williams (Medical Research Council, South Africa/UNAIDS/WHO); Willi McFarland, Tim Kellogg (San Francisco Department of Public Health); Peter Kilmarx, Sara Whitehead, Philip Mock, Khanchit Limpakarniarnarat (Thailand MOPH–US CDC Collaboration); Lawrence Kingsley (University of Pittsburgh); Rupert Kaul (University of Toronto); Ludo Lavreys, Jared Baeten, Joel Rakwar (University of Washington/University of Nairobi).

Sponsorship: E. E. Freeman was supported by a Marshall Scholarship; H. A. Weiss is funded by the UK Medical Research Council; J. R. Glynn is supported by the UK Department of Health (Public Health Career Scientist Award).


1. 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.
2. Grosskurth H, Mosha F, Todd J, Mwijarubi E, Klokke A, Senkoro K, et al. Impact of improved treatment of sexually transmitted diseases on HIV infection in rural Tanzania: randomised controlled trial. Lancet 1995; 346:530–536.
3. Fleming DT, Wasserheit JN. From epidemiological synergy to public health policy and practice: the contribution of other sexually transmitted diseases to sexual transmission of HIV infection. Sex Transm Infect 1999; 75:3–17.
4. de Vincenzi I. A longitudinal study of human immunodeficiency virus transmission by heterosexual partners. European Study Group on Heterosexual Transmission of HIV. N Engl J Med 1994; 331:341–346.
5. 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.
6. Wald A, Langenberg AG, Link K, Izu AE, Ashley R, Warren T, et al. Effect of condoms on reducing the transmission of herpes simplex virus type 2 from men to women. JAMA 2001; 285:3100–3106.
7. Benedetti J, Corey L, Ashley R. Recurrence rates in genital herpes after symptomatic first-episode infection. Ann Intern Med 1994; 121:847–854.
8. Kilmarx PH, Limpakarnjanarat K, Mastro TD, Saisorn S, Kaewkungwal J, Korattana S, et al. HIV-1 seroconversion in a prospective study of female sex workers in northern Thailand: continued high incidence among brothel-based women. AIDS 1998; 12:1889–1898.
9. Celum C, Levine R, Weaver M, Wald A. Genital herpes and human immunodeficiency virus: double trouble. Bull World Health Organ 2004; 82:447–453.
10. Wald A, Ashley-Morrow R. Serological testing for herpes simplex virus (HSV)-1 and HSV-2 infection. Clin Infect Dis 2002; 35:S173–S182.
11. van Doornum GJ, Slomka MJ, Buimer M, Groen J, van den Hoek JA, Cairo I, et al. Comparison of a monoclonal antibody-blocking enzyme-linked immunoassay and a strip immunoblot assay for identifying type-specific herpes simplex virus type 2 serological responses. Clin Diagn Lab Immunol 2000; 7:641–644.
12. Cochrane Collaboration. Open Learning Material for Reviewers: Diversity and Heterogeneity. Oxford, UK: Cochrane Library; 2002.
13. Engels EA, Schmid CH, Terrin N, Olkin I, Lau J. Heterogeneity and statistical significance in meta-analysis: an empirical study of 125 meta-analyses. Stat Med 2000; 19:1707–1728.
14. Villar J, Mackey ME, Carroli G, Donner A. Meta-analyses in systematic reviews of randomized controlled trials in perinatal medicine: comparison of fixed and random effects models. Stat Med 2001; 20:3635–3647.
15. Takkouche B, Cadarso-Suarez C, Spiegelman D. Evaluation of old and new tests of heterogeneity in epidemiologic meta-analysis. Am J Epidemiol 1999; 150:206–215.
16. Kamali A, Muhangi L, Quigley M, Whitworth J. Association between prevalence and incidence of herpes simplex virus-2, syphilis, and HIV-1 infection in rural Uganda.XIV International Conference on AIDS. Barcelona, July 2002 [abstract MoOrC1011].
17. Nagot N, Ouedraogo A, Ouangre A, Cartoux M, Defer MC, Meda N, et al. Is STI management among sex workers still able to mitigate the spread of HIV infection in West Africa? J Acquir Immune Defic Syndr 2005; 39:454–458.
18. Ouedraogo A, Nagot N, Ouangre A, Defer MC, Meda N, van de Perre P. Is STI management among sex workers still able to mitigate the spread of HIV infection in West Africa?XV International Conference on AIDS. Bangkok, July 2004 [abstract WePeC6191].
19. Ramjee G, Williams B, Gouws E, van Dyck E, de Deken B, Abdool Karim SS. The impact of incident and prevalent HSV-2 infection on the incidence of HIV-1 infection among commercial sex workers in South Africa. J Acquir Immune Defic Syndr 2005; 39:333–339.
20. Gray RH, Li X, Wawer MJ, Serwadda D, Sewankambo NK, Wabwire-Mangen F, et al. Determinants of HIV-1 load in subjects with early and later HIV infections, in a general-population cohort of Rakai, Uganda. J Infect Dis 2004; 189:1209–1215.
21. Serwadda D, Gray RH, Sewankambo NK, Wabwire-Mangen F, Chen MZ, Quinn TC, 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.
22. Kaul R, Kimani J, Nagelkerke NJ, Fonck K, Ngugi EN, Keli F, et al. Monthly antibiotic chemoprophylaxis and incidence of sexually transmitted infections and HIV-1 infection in Kenyan sex workers: a randomized controlled trial. JAMA 2004; 291:2555–2562.
23. Kebede Y, Dorigo-Zetsma W, Mengistu Y, Mekonnen Y, Schaap A, Wolday D, et al. Transmission of herpes simplex virus type 2 among factory workers in Ethiopia. J Infect Dis 2004; 190:365–372.
24. Renzi C, Douglas JM Jr, Foster M, Critchlow CW, Ashley-Morrow R, Buchbinder SP, et al. Herpes simplex virus type 2 infection as a risk factor for human immunodeficiency virus acquisition in men who have sex with men. J Infect Dis 2003; 187:19–25.
25. Reynolds SJ, Risbud AR, Shepherd ME, Zenilman JM, Brookmeyer RS, Paranjape RS, et al. Recent herpes simplex virus type 2 infection and the risk of human immunodeficiency virus type 1 acquisition in India. J Infect Dis 2003; 187:1513–1521.
26. Turner KR, McFarland W, Kellogg TA, Wong E, Page-Shafer K, Louie B, et al. Incidence and prevalence of herpes simplex virus type 2 infection in persons seeking repeat HIV counseling and testing. STD 2003; 30:331–334.
27. McFarland W, Gwanzura L, Bassett MT, Machekano R, Latif AS, Ley C, et al. Prevalence and incidence of herpes simplex virus type 2 infection among male Zimbabwean factory workers. J Infect Dis 1999; 180:1459–1465.
28. Rakwar J, Lavreys L, Thompson ML, Jackson D, Bwayo J, Hassanali S, et al. Cofactors for the acquisition of HIV-1 among heterosexual men: prospective cohort study of trucking company workers in Kenya. AIDS 1999; 13:607–614.
29. Nopkesorn T, Mock PA, Mastro TD, Sangkharomya S, Sweat M, Limpakarnjanarat K, et al. HIV-1 subtype E incidence and sexually transmitted diseases in a cohort of military conscripts in northern Thailand. J Acquir Immune Defic Syndr 1998; 18:372–379.
30. Nelson KE, Eiumtrakul S, Celentano D, Maclean I, Ronald A, Suprasert S, et al. The association of herpes simplex virus type 2 (HSV-2), Haemophilus ducreyi, and syphilis with HIV infection in young men in northern Thailand. J Acquir Immune Defic Syndr 1997; 16:293–300.
31. Kingsley LA, Armstrong J, Rahman A, Ho M, Rinaldo CR Jr. No association between herpes simplex virus type-2 seropositivity or anogenital lesions and HIV seroconversion among homosexual men. J Acquir Immune Defic Syndr 1990; 3:773–779.
32. Holmberg SD, Stewart JA, Gerber AR, Byers RH, Lee FK, O'Malley PM, et al. Prior herpes simplex virus type 2 infection as a risk factor for HIV infection. JAMA 1988; 259:1048–1050.
33. Keet IP, Lee FK, van Griensven GJ, Lange JM, Nahmias A, Coutinho RA. Herpes simplex virus type 2 and other genital ulcerative infections as a risk factor for HIV-1 acquisition. Genitourin Med 1990; 66:330–333.
34. Hanson J, Posner S, Hassig S, Rice J, Farley TA. Assessment of sexually transmitted diseases as risk factors for HIV seroconversion in a New Orleans sexually transmitted disease clinic, 1990–1998. Ann Epidemiol 2005; 15:13–20.
35. Brown JM, Chitsungo S, Chipato T, Morrison C, Padian NS. Prevalence and risk factors for herpes simplex virus type 2 among Zimbabwean women.International Society for Sexually Transmitted Disease Research Congress. Ottawa, July 2003 [abstract 0125].
36. Brown JM, Rungruengthanakit K, Rugpao S, Cornelisse P, Padian NS, Morrison C. Hormonal contraceptive use and incidence of herpes simplex virus type 2 among women in Thailand.XV International Conference on AIDS. Bangkok, July 2004 [abstract ThPeC7385].
37. del Mar Pujades Rodriguez M, Obasi A, Mosha F, Todd J, Brown D, Changalucha J, et al. Herpes simplex virus type 2 infection increases HIV incidence: a prospective study in rural Tanzania. AIDS 2002; 16:451–462.
38. Gray JA, Dore GJ, Li Y, Supawitkul S, Effler P, Kaldor JM. HIV-1 infection among female commercial sex workers in rural Thailand. AIDS 1997; 11:89–94.
39. Gray RH, Wawer MJ, Brookmeyer R, Sewankambo NK, Serwadda D, Wabwire-Mangen F, 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.
40. Lavreys L, Rakwar JP, Thompson ML, Jackson DJ, Mandaliya K, Chohan BH, 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.
41. Moses S, Kaul R, Kimani J, Fonck K, Nagelkerke NJ, Keli F, et al. Prevalent HSV-2 infection and risk for HIV seroconversion in a cohort of Kenyan female sex workers enrolled in a randomized controlled trial of antibiotic chemoprophylaxis to reduce HIV incidence.XV International Conference on AIDS. Bangkok, July 2004 [abstract LbOrC24].
42. Page-Shafer K, Veugelers PJ, Moss AR, Strathdee S, Kaldor JM, van Griensven GJ. Sexual risk behavior and risk factors for HIV-1 seroconversion in homosexual men participating in the Tricontinental Seroconverter Study, 1982–1994. Am J Epidemiol 1997; 146:531–542.
43. Ramjee G, Gouws E, van Dyck E, Williams B, Abdool Karim SS. Incidence of herpes simplex virus-2 and HIV among sex workers in Kwazulu-Natal Durban: a relation in time study.XIV International Conference on AIDS. Barcelona, July 2002 [abstract ThPeC7616].
44. Reynolds SJ, Risbud AR, Shepherd ME, Zenilman JM, Brookmeyer R, Kulkarni SV, et al. Recent herpes simplex virus type 2 infection and the risk of HIV acquisition in Pune, India.XIV International AIDS Conference. 2002. Barcelona, Spain [abstract MoOrC1012].
45. Reynolds SJ, Risbud AR, Godbole SV, Shepherd ME, Joshi SN, Ghate MV, et al. Comparison of risk factors for incident sexually transmitted infections among men attending STI clinics in Pune, India.XV International Conference on AIDS. Bangkok, July 2004 [abstract ThPpC2097].
46. Salata R, Cornelisse P, Chipato T, Mmiro F, Morrison C, Padian NS, et al. Prevalence and incidence of HIV and sexually transmitted infections among young women in Thailand, Uganda, and Zimbabwe participating in the hormonal contraception and risk of HIV acquisition cohort.XIV International Conference on AIDS. Barcelona, July 2002 [abstract ThPeC7413].
47. Salata R, Cornelisse P, Richardson BA, Chipato T, Mmiro F, Mugerwa RD, et al. Interrelationships between sexually transmitted infections and HIV-1 infection among women in Thailand, Uganda, and Zimbabwe participating in the Hormonal Contraception and Risk of HIV-1 Acquisition Study.XV International Conference on AIDS. Bangkok, July 2004.
48. Sturm P, Moodley P, Connolly C, Sturm AW. Risk factors for the acquisition of HIV-1 and HSV-2 in patients presenting with genital ulcer disease.International Society for Sexually Transmitted Disease Research Congress. Ottawa, July 2003 [abstract 0374].
49. Tabet SR, Krone MR, Paradise MA, Corey L, Stamm WE, Celum CL. Incidence of HIV and sexually transmitted diseases (STD) in a cohort of HIV-negative men who have sex with men (MSM). AIDS 1998; 12:2041–2048.
50. Telzak EE, Chiasson MA, Bevier PJ, Stoneburner RL, Castro KG, Jaffe HW. HIV-1 seroconversion in patients with and without genital ulcer disease. A prospective study. Ann Intern Med 1993; 119:1181–1186.
51. Morrow RA, Friedrich D, Krantz E. Performance of the focus and Kalon enzyme-linked immunosorbent assays for antibodies to herpes simplex virus type 2 glycoprotein G in culture-documented cases of genital herpes. J Clin Microbiol 2003; 41:5212–5214.
52. Benedetti JK, Zeh J, Corey L. Clinical reactivation of genital herpes simplex virus infection decreases in frequency over time. Ann Intern Med 1999; 131:14–20.
53. van Dyck E, Buve A, Weiss HA, Glynn JR, Brown DW, de Deken B, et al. Performance of commercially available enzyme immunoassays for detection of antibodies against herpes simplex virus type 2 in African populations. J Clin Microbiol 2004; 42:2961–2965.
54. Smith JS, Robinson NJ. Age-specific prevalence of infection with herpes simplex virus types 2 and 1: a global review. J Infect Dis 2002; 186(Suppl 1):S3–S28.
55. Corey L, Wald A, Patel R, Sacks SL, Tyring SK, Warren T, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med 2004; 350:11–20.
56. Celum CL, Robinson NJ, Cohen MS. Potential effect of HIV type 1 antiretroviral and herpes simplex virus type 2 antiviral therapy on transmission and acquisition of HIV type 1 infection. J Infect Dis 2005; 191(Suppl 1):S107–S114.

systematic review; meta-analysis; HSV-2; HIV; follow-up

© 2006 Lippincott Williams & Wilkins, Inc.