A fresh look at an old problem
Authors: Thomas M Zydowsky
Journal: The Lancet Infectious Diseases (2017)

The incidence of HIV infection has not changed in a decade. Since 2005, about 2·6 million people have become newly infected with HIV annually.1GBD 2015 HIV CollaboratorsEstimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980–2015: the Global Burden of Disease Study 2015.Lancet HIV. 2016; 3: e361-e387Summary Full Text Full Text PDF PubMed Scopus (432) Google Scholar Young women, particularly adolescent girls, account for a disproportionate number of new HIV infections. Development of successful strategies to prevent HIV acquisition might require more creative approaches to meet the needs of the most susceptible populations, including exploration of the role of sexually transmitted infections, such as herpes simplex virus type 2 (HSV-2), in HIV infection.2Fernández-Romero JA Deal C Herold BC et al.Multipurpose prevention technologies: the future of HIV and STI protection.Trends Microbiol. 2015; 23: 429-436Summary Full Text Full Text PDF PubMed Scopus (59) Google Scholar HSV-2 contributes to the high incidence of HIV; evidence has shown that HSV-2 infection increases the risk of HIV infection.3Wald 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: 45-52Crossref PubMed Scopus (615) Google Scholar, 4Freeman 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: 73-83Crossref PubMed Scopus (987) Google Scholar In The Lancet Infectious Diseases, Katharine Looker and colleagues5Looker KJ Elmes JAR Gottlieb SL et al.Effect of HSV-2 infection on subsequent HIV acquisition: an updated systematic review and meta-analysis.Lancet Infect Dis. 2017; (published online August 23.)http://dx.doi.org/10.1016/S1473-3099(17)30405-XPubMed Google Scholar provide the first systematic review and meta-analysis (to May 2017) in over a decade to assess the effect of HSV-2 infection on subsequent HIV acquisition. They analysed 57 longitudinal studies and derived pooled random-effect estimates of the association between prevalent or incident HSV-2 infection and HIV acquisition. Their findings for prevalent HSV-2 infection were in line with data from previous studies and showed that the risk of HIV acquisition was roughly tripled in general populations and almost doubled in high-risk populations. Their pooled estimates for the effect of incident HSV-2 infection on HIV infection showed that incident HSV-2 infection was associated with a five times increase in the risk of HIV in general populations and a three times increase in the risk of HIV in high-risk populations. Estimates for HSV-2 infection in 2012 underscored the magnitude of the problem, which was particularly serious for women and girls in Africa.6Looker KJ Magaret AS Turner KM Vickerman P Gottlieb SL Newman LM Global estimates of prevalent and incident herpes simplex virus type 2 infections in 2012.PLoS One. 2015; 10: e114989Crossref PubMed Scopus (325) Google Scholar About 417 million people were living with HSV-2 worldwide in 2012, with women accounting for 64% of infected individuals. Although only a quarter of women infected with HSV-2 were aged 15–24 years, two-thirds of new infections came from this age group, suggesting that policy responses must focus on young women and adolescent girls. In 2012, the estimated overall prevalence of HSV-2 infection in African women aged 15–49 years was 38%. About 135 million people in Africa aged 15–49 years were infected with HSV-2; 22·4 million were women aged 15–24 years. Another 6·4 million people in Africa were newly infected with HSV-2; 2·3 million were women aged 15–24 years. These numbers are particularly concerning because women in Africa aged 15–24 years had the highest number of new HIV infections of all age groups in 2015.7UNAIDSPrevention gap report.http://www.unaids.org/sites/default/files/media_asset/2016-prevention-gap-report_en.pdfDate: 2016Google Scholar Strategies to mitigate the risk of HIV in populations with a high HSV-2 prevalence have been explored. One strategy tested whether HSV-2 suppressive therapy with acyclovir (400 mg twice per day) could reduce the risk of HIV. Data from two studies8Celum C Wald A Hughes J et al.for the HPTN 039 Protocol TeamEffect 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: 2109-2119Summary Full Text Full Text PDF PubMed Scopus (367) Google Scholar, 9Watson-Jones D Weiss HA Rusizoka M et al.for the Steering and Data Monitoring CommitteesEffect of herpes simplex suppression on incidence of HIV among women in Tanzania.N Engl J Med. 2008; 358: 1560-1571Crossref PubMed Scopus (304) Google Scholar showed that acyclovir did not decrease the incidence of HIV in HSV-2 infected individuals. Another study10Celum C Wald A Lingappa JR et al.for the Partners in Prevention HSV/HIV Transmission Study TeamAcyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2.N Engl J Med. 2010; 362: 427-439Crossref PubMed Scopus (420) Google Scholar assessed the effect of acyclovir on HIV transmission from a person coinfected with HIV and HSV-2 who was not on antiretrovirals to a partner who was HIV negative and who might or might not have been infected with HSV-2. Despite a decrease in HIV viral loads and frequency of genital ulcers in the coinfected partner, daily acyclovir therapy did not reduce the risk of HIV transmission. A multipurpose prevention technology that provides pre-exposure prophylaxis for HSV-2, HIV, or both is another option. Data from the CAPRISA 004 HIV prevention trial11Abdool Karim SS Abdool Karim Q Kharsany AB et al.for the CAPRISA 004 Trial GroupTenofovir gel for the prevention of herpes simplex virus type 2 infection.N Engl J Med. 2015; 373: 530-539Crossref PubMed Scopus (73) Google Scholar of 889 women in South Africa showed that vaginally applied 1% tenofovir gel reduced HIV infection by 39% and, unexpectedly, HSV-2 infection by 51%. Subsequent phase 3 trials showed that the gel was not effective against HIV acquisition, which might be attributed to low adherence to the study products. Oral emtricitabine-tenofovir (Truvada) is indicated for pre-exposure prophylaxis to reduce the risk of sexually acquired HIV infection in high-risk adults. Although not indicated for HSV-2, Truvada reduced HSV-2 acquisition in heterosexual men who were HIV-1 negative and in women with HIV-1 and HSV-2 coinfected partners by 33%.12Celum C Morrow RA Donnell D et al.for the Partners PrEP Study TeamDaily oral tenofovir and emtricitabine-tenofovir preexposure prophylaxis reduces herpes simplex virus type 2 acquisition among heterosexual HIV-1-uninfected men and women: a subgroup analysis of a randomized trial.Ann Intern Med. 2014; 161: 11-19Crossref PubMed Scopus (46) Google Scholar However, Truvada is not an option for all at-risk (HIV, HSV-2, or HIV and HSV-2) individuals because of its poor availability in sub-Saharan Africa and other low-income regions, user acceptability and adherence issues, and modest efficacy against HSV-2. Therefore, other multipurpose prevention technologies for HSV-2 and HIV are needed to give individuals a broad range of prevention options and to target the lifestyles and preferences of the most susceptible populations, including young women in Africa who have the highest incidence of HIV and HSV-2 worldwide.13Ugaonkar SR Wesenberg A Wilk J et al.A novel intravaginal ring to prevent HIV-1, HSV-2, HPV, and unintended pregnancy.J Control Release. 2015; 213: 57-68Crossref PubMed Scopus (51) Google Scholar I declare no competing interests. Effect of HSV-2 infection on subsequent HIV acquisition: an updated systematic review and meta-analysisWe found evidence that HSV-2 infection increases the risk of HIV acquisition. This finding has important implications for management of individuals diagnosed with HSV-2 infection, particularly for those who are newly infected. Interventions targeting HSV-2, such as new HSV vaccines, have the potential for additional benefit against HIV, which could be particularly powerful in regions with a high incidence of co-infection. Full-Text PDF Open Access