Herpes simplex virus type 2: a key role in HIV incidence
Glynn, Judith Ra; Biraro, Samuela,b; Weiss, Helen Aa
aLondon School of Hygiene & Tropical Medicine, UK
bMRC/UVRI Uganda Research Unit on AIDS, Uganda.
Received 12 May, 2009
Accepted 13 May, 2009
Correspondence to Professor Judith Glynn, London School of Hygiene & Tropical Medicine, Keppel St, London WC1E 7HT, UK. Tel: +44 20 7927 2423; e-mail: email@example.com
Many epidemiological studies have found a strong association between HSV-2 infection and HIV infection, including longitudinal studies in which it was known that the HSV-2 infection preceded the HIV infection . However, two recent trials of suppressive therapy of HSV-2 with acyclovir (400 mg b.i.d) showed no reduction in HIV incidence [2,3]. Although this may simply reflect the difficulty of adequately suppressing HSV-2 reactivations with the drug regimen used, the results have led some to challenge the importance of HSV-2 infection as a risk factor for HIV .
In this issue, Tobian et al.  use data from the Rakai male circumcision trial to assess the effect of prevalent and incident HSV-2 infection on HIV incidence. They found that prevalent HSV-2 infection increased HIV incidence three-fold, and that men who acquired HSV-2 during follow-up had a six-fold risk of HIV incidence, in analyses adjusted for sexual behaviour.
These results are very similar to those found in a systematic review . This included cohort and nested case–control studies up to 2004, and identified 18 that were adjusted for age and sexual behaviour. We have re-run the meta-analysis including more recent studies that fit the same criteria (Fig. 1). Six additional studies, as well as that by Tobian et al. , are included: one in men from the circumcision trial in South Africa ; two in women in the general population, in Uganda and Zimbabwe ; two in female sex workers in Kenya  and Tanzania ; and one in men who have sex with men (MSM) in the US . Summary estimates of the relative risk (RR) show a strong and consistent association of prevalent HSV-2 and incident HIV after adjusting for age and measures of sexual behaviour [RRwomen = 3.4, 95% confidence interval (CI) 2.4–4.8; RRmen = 2.8, 2.1–3.7; RRsex workers = 1.5, 0.75–3.0; RRMSM = 1.6, 1.2–2.0). In addition, a cohort study in Uganda found an adjusted rate ratio of 8.7 (1.1–67.2) for men and women combined .
The observational epidemiological evidence is strong, but Tobian et al.  question whether the association between HSV-2 and HIV is causal. Whereas confounding by sexual risk behaviour is likely in these studies, the effect persists after adjusting for sexual behaviour, and in their analysis this adjustment makes very little difference. In fact the association may be underestimated: some studies adjust for genital ulceration, which lies on the causal pathway between HSV-2 and HIV infection; and tests for HSV-2 lack specificity , which would also tend to bias the RR towards one.
The association between recent HSV-2 infection and HIV incidence is generally stronger than the association with prevalent HSV-2 infection [1,6–8,10]. This is biologically plausible as clinical and subclinical reactivations are most common shortly after HSV-2 infection . However, results are difficult to interpret since, unless repeat testing is very frequent, most seroconversions for both infections occur within the same follow-up interval. It is therefore impossible to know which came first and therefore to distinguish HIV-2 infection increasing susceptibility to HIV from coinfections from the same source. In the study by Tobian et al., HSV-2 preceded HIV in three individuals, but the relative timing was unknown in nine. Some studies include all who seroconvert, even when the timing is unknown, which is likely to overestimate the association. Others exclude those for whom the timing is unknown, but this is also biased, since it excludes some who do acquire HIV, and none who do not, so is likely to underestimate the association. In Zimbabwe and Uganda, where the proportion excluded was small, recent HSV-2 infection was associated with a 4–8-fold increase in HIV incidence .
That prior HSV-2 infection increases susceptibility to HIV is thus well supported epidemiologically, and is also biologically plausible. However, the effect of HSV-2 on increasing susceptibility to HIV is only part of the story of their interaction, as genital ulceration and HSV-2 infection also increase HIV plasma load, HIV shedding, and hence transmissibility [14–16], and HIV infection increases the risk of acquisition of HSV-2, and the frequency and severity of reactivations . Randomized controlled trials of HSV suppressive therapy with valacyclovir or high-dose acyclovir (800 mg b.i.d) have shown a significant reduction in genital and plasma HIV-1 RNA levels [17–20], although trials using lower-dose acyclovir (400 mg b.i.d) have tended to find less of an effect [21–23]. Recently announced results from the Partners in Prevention trial, which assessed the effect of suppressive therapy with lower-dose acyclovir on HIV transmission in discordant couples, showed no reduction in transmission .
HSV-2 is a common infection, with an estimated 536 million prevalent infections and 23.6 incident infections in 15–49-year-olds worldwide . It is particularly prevalent in sub-Saharan Africa, reaching 70% in women and 55% in men . If the association between HSV-2 infection and HIV is causal, then the proportion of HIV infections attributable to HSV-2 infection is high, estimated at 25–35% in Africa , and higher further into the epidemic . It may both help explain the variable distribution of HIV in Africa , and provide one of our best hopes in prevention. Whereas to date it has not been possible to suppress HSV-2 adequately to prevent HIV acquisition or transmission, this may be possible with alternative drug regimens, or with a prophylactic HSV-2 vaccine, and such a vaccine could have substantial impact on HIV incidence . The failures of the suppressive therapy trials, far from undermining the hypothesis, make the case for investment in a prophylactic HSV-2 vaccine even stronger.
1. Freeman EE, Weiss HA, Glynn JR, Cross PL, Whitworth JA, Hayes RJ. 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.
2. Watson-Jones D, Weiss HA, Rusizoka M, Changalucha J, Baisley K, Mugeye K, et al
. Effect of herpes simplex suppression on incidence of HIV among women in Tanzania. N Engl J Med 2008; 358:1560–1571.
3. Celum C, Wald A, Hughes J, Sanchez J, Reid S, Delany-Moretlwe S, et al
. Effect of acyclovir 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.
4. Gray RH, Wawer MJ. Reassessing the hypothesis on STI control for HIV prevention. Lancet 2008; 371:2064–2065.
5. Tobian A, Ssempijja V, Kigozi G, Oliver A, Serwadda D, Makumbi F, et al. Incident HIV and Herpes Simplex Virus type 2 infection among men in Rakai, Uganda. AIDS
6. Sobngwi-Tambekou J, Taljaard D, Lissouba P, Zarca K, Puren A, Lagarde E, Auvert B. Effect of HSV-2 serostatus on acquisition of HIV by young men: results of a longitudinal study in Orange Farm, South Africa. J Infect Dis 2009; 199:958–964.
7. Brown JM, Wald A, Hubbard A, Rungruengthanakit K, Chipato T, Rugpao S, et al
. Incident and prevalent herpes simplex virus type 2 infection increases risk of HIV acquisition among women in Uganda and Zimbabwe. AIDS 2007; 21:1515–1523.
8. Baeten JM, Benki S, Chohan V, Lavreys L, McClelland RS, Mandaliya K, et al
. Hormonal contraceptive use, herpes simplex virus infection, and risk of HIV-1 acquisition among Kenyan women. AIDS 2007; 21:1771–1777.
9. Kapiga SH, Sam NE, Bang H, Ni Q, Ao TT, Kiwelu I, 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.
10. Brown EL, Wald A, Hughes JP, Morrow RA, Krantz E, Mayer K, et al
. High risk of human immunodeficiency virus in men who have sex with men with herpes simplex virus type 2 in the EXPLORE study. Am J Epidemiol 2006; 164:733–741.
11. Guwatudde D, Wabwire-Mangen F, Eller LA, Eller M, McCutchan F, Kibuuka H, et al
. Relatively low HIV infection rates in rural Uganda, but with high potential for a rise: a cohort study in Kayunga District, Uganda. PLoS ONE 2009; 4:e4145.
12. 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.
13. Wald A, Zeh J, Selke S, Ashley RL, Corey L. Virologic characteristics of subclinical and symptomatic genital herpes infections. N Engl J Med 1995; 333:770–775.
14. Johnson LF, Lewis DA. The effect of genital tract infections on HIV-1 shedding in the genital tract: a systematic review and meta-analysis. Sex Transm Dis 2008; 35:946–959.
15. Nagot N, Ouedraogo A, Konate I, Weiss HA, Foulongne V, Defer MC, 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.
16. Van de Perre P, Segondy M, Foulongne V, Ouedraogo A, Konate I, Huraux JM, et al
. Herpes simplex virus and HIV-1: deciphering viral synergy. Lancet Infect Dis 2008; 8:490–497.
17. Ouedraogo A, Nagot N, Vergne L, Konate I, Weiss HA, Defer MC, et al
. Impact of suppressive herpes therapy on genital HIV-1 RNA among women taking antiretroviral therapy: a randomized controlled trial. AIDS 2006; 20:2305–2313.
18. Nagot N, Ouedraogo A, Foulongne V, Konate I, Weiss HA, Vergne L, et al
. Reduction of HIV-1 RNA levels with therapy to suppress herpes simplex virus. N Engl J Med 2007; 356:790–799.
19. Baeten JM, Strick LB, Lucchetti A, Whittington WL, Sanchez J, Coombs RW, 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.
20. Dunne EF, Whitehead S, Sternberg M, Thepamnuay S, Leelawiwat W, McNicholl JM, et al
. Suppressive acyclovir therapy reduces HIV cervicovaginal shedding in HIV- and HSV-2-infected women, Chiang Rai, Thailand. J Acquir Immune Defic Syndr 2008; 49:77–83.
21. Delany S, Mlaba N, Clayton T, Akpomiemie G, Capovilla A, Legoff J, et al
. Impact of acyclovir on genital and plasma HIV-1 RNA in HSV-2/HIV-1 co-infected women: a randomized placebo-controlled trial in South Africa. AIDS 2009; 23:461–469.
22. Cowan FM, Pascoe SJ, Barlow KL, Langhaug LF, Jaffar S, Hargrove JW, et al
. A randomised placebo-controlled trial to explore the effect of suppressive therapy with acyclovir on genital shedding of HIV-1 and herpes simplex virus type 2 among Zimbabwean sex workers. Sex Transm Infect 2008; 84:548–553.
23. Tanton C, Watson-Jones D, Rusizoka M, le Goff J, Weiss HA, Changalucha JM, et al. A randomized controlled trial in Tanzania to assess the impact of HSV-2 suppressive therapy on genital HIV viral load among HSV-2 and HIV-1 seropositive women.
Abstract O-099. 17th ISSTDR Meeting – 10th IUSTI World Congress
; Seattle; 2007.
24. Press release. Herpes medication does not reduce risk of HIV transmission from individuals with HIV and genital herpes but demonstrates modest reduction in HIV disease progression and leads to new important insights about HIV transmission, UW-led international study finds
. University of Washington News, 8 May 2009 (http://uwnews.org/article.asp?articleid=49611
, accessed 8 May 2009).
25. Looker KJ, Garnett GP, Schmid GP. An estimate of the global prevalence and incidence of herpes simplex virus type 2 infection. Bull World Health Organ 2008; 86:805–812.
26. Abu-Raddad LJ, Magaret AS, Celum C, Wald A, Longini IM Jr, Self SG, Corey L. 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.
27. Freeman EE, Orroth KK, White RG, Glynn JR, Bakker R, Boily MC, et al
. Proportion of new HIV infections attributable to herpes simplex 2 increases over time: simulations of the changing role of sexually transmitted infections in sub-Saharan African HIV epidemics. Sex Transm Infect 2007; 83(Suppl 1):i17–i24.
28. Freeman EE, White RG, Bakker R, Orroth KK, Weiss HA, Buve A, et al
. Population-level effect of potential HSV2 prophylactic vaccines on HIV incidence in sub-Saharan Africa. Vaccine 2009; 27:940–946.
This article has been cited 8 time(s).
European Journal of Contraception and Reproductive Health CareHormonal contraception and HIV acquisition - What is the evidence? What are the policy and operational implications?European Journal of Contraception and Reproductive Health Care
Tropical Medicine & International HealthEffect of HSV-2 on population-level trends in HIV incidence in Uganda between 1990 and 2007Tropical Medicine & International Health
MbioMale Circumcision Significantly Reduces Prevalence and Load of Genital Anaerobic BacteriaMbio
International Journal of Std & AIDSAssociation between herpes simplex virus type 2 and HIV-1 in a population of married couples from Dakar, SenegalInternational Journal of Std & AIDS
New England Journal of MedicineAcyclovir and Transmission of HIV-1 from Persons Infected with HIV-1 and HSV-2New England Journal of Medicine
New England Journal of Medicine
Acyclovir and Transmission of HIV-1 from Persons Infected with HIV-1 and HSV-2 REPLY
New England Journal of Medicine, 362():
Plos OneHIV-1 Transmission within Marriage in Rural Uganda: A Longitudinal StudyPlos One
Sexually Transmitted DiseasesPopulation Level Impact of an Imperfect Prophylactic Vaccine for Herpes Simplex Virus-2Sexually Transmitted Diseases
herpes simplex virus type 2; HIV; incidence
© 2009 Lippincott Williams & Wilkins, Inc.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.