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.
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.
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.
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).
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
-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
-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.