Herpes Simplex Virus Type 2 Incidence Research Articles

Twenty years of herpes simplex virus type 2 (HSV-2) research in low-income and middle-income countries: systematic evaluation of progress made in addressing WHO prioritiesfor research in HSV-2 epidemiology and diagnostics

IntroductionLow-income and middle-income countries (LMICs) have a high burden of herpes simplex virus type 2 (HSV-2) infection, which has been strongly associated with HIV. In 2001, the WHO hosted a...

Menstrual cups and cash transfer to reduce sexual and reproductive harm and school dropout in adolescent schoolgirls in western Kenya: a cluster randomised controlled trial

High rates of sexual and reproductive health (SRH) harms and interrupted schooling are global challenges for adolescent girls, requiring effective interventions. We assessed the impact of menstrual cups (MCs) or cash transfers conditioned on school attendance (CCTs), or both, on SRH and schooling outcomes in western Kenya. In this cluster-randomised Cups or Cash for Girls (CCG) trial, adolescent girls in Forms two and three at 96secondary schools in Siaya County (western Kenya) were randomised to receive either CCT, MC, combined CCT and MC, or control (1:1:1:1) for an average of 30 months. The CCT intervention comprised 1500KES (US$15 in 2016) via a cash card each school trimester. All four treatment groups received puberty and hygiene training. Assenting girls with parent or guardian consent who were post-menarche, not pregnant, area residents, not boarding, and had no disabilities precluding participation were eligible. Socio-behavioural risk factors and incidence of HIV and herpes simplex virus type 2 (HSV-2) were measured annually. School retainment and adverse events were monitored throughout. The primary outcome comprised a composite of incident HIV, HSV-2 and/or all-cause school dropout by school exit examination. The primary analysis was by intention-to-treat (ITT) using generalised linear mixed models, controlling for a priori selected baseline covariates. The trial is registered with ClinicalTrials.gov, NCT03051789. Between February 28, 2017 and June 30, 2021, 4137 girls (median age 17.1 [interquartile range (IQR): 16.3-18.0]) were enrolled and followed annually until completion of secondary school (median 2.5 years [IQR: 2.4-2.7]); 4106 (99.3%) contributed to the ITT analysis. No differences in the primary composite outcome between intervention and control groups were seen (MC: 18.2%, CCT: 22.1%, combined: 22.1%, control: 19.6%; adjusted risk ratio [aRR]: 0.97, 95% confidence interval 0.76-1.24; 1.14, 0.90-1.45; and 1.13, 0.90-1.43, respectively). Incident HSV-2 occurred in 8.6%, 13.3%, 14.8%, and 12% of the MC, CCT, combined and control groups, respectively (MC: RR: 0.67, 0.47-0.95, p=0.027; aRR: 0.71, 0.50-1.01, p=0.057; CCT: aRR: 1.02, 0.73-1.41, p=0.92; combined aRR: 1.16, 0.85-2.58, p=0.36). Incident HIV was low (MC: 1.2%, CCT: 1.5%, combined: 1.0%, and control: 1.4%; aRR: 0.88, 0.38-2.05, p=0.77, aRR: 1.16, 0.51-2.62, p=0.72, aRR: 0.80, 0.33-1.94, p=0.62, respectively). No intervention decreased school dropout (MC: 11.2%, CCT: 12.4%, combined: 10.9%, control: 10.5%; aRR: 1.16, 0.86-1.57; 1.23, 0.91-1.65; and 1.06, 0.78-1.44, respectively). No related serious adverse events were seen. MCs, CCTs, or both, did not protect schoolgirls against a composite of deleterious harms. MCs appear protective against HSV-2. Studies of longer follow-up duration with objective measures of health impact are needed in this population. Department of Health and Social Care, the Foreign, Commonwealth & Development Office, the Medical Research Council and Wellcome.

Age Patterns of HSV-2 Incidence and Prevalence in Two Ugandan Communities: A Catalytic Incidence Model Applied to Population-Based Seroprevalence Data.

Herpes simplex virus type 2 (HSV-2) is an incurable sexually transmitted infection associated with increased risk of acquiring and transmitting human immunodeficiency virus (HIV). HSV-2 is highly prevalent in sub-Saharan Africa, but population-level estimates of incidence are sparse. We measured HSV-2 prevalence from cross-sectional serological data among adults aged 18-49 years in 2 south-central Uganda communities (fishing, inland). We identified risk factors for seropositivity, then inferred age patterns of HSV-2 with a Bayesian catalytic model. HSV-2 prevalence was 53.6% (n = 975/1819; 95% confidence interval, 51.3%-55.9%). Prevalence increased with age, was higher in the fishing community, and among women, reaching 93.6% (95% credible interval, 90.2%-96.6%) by age 49 years. Factors associated with HSV-2 seropositivity included more lifetime sexual partners, HIV positive status, and lower education. HSV-2 incidence peakied at age 18 years for women and 19-20 years for men. HIV prevalence was up to 10-fold higher in HSV-2-positive individuals. HSV-2 prevalence and incidence were extremely high, with most infections occurring in late adolescence. Interventions against HSV-2, such as future vaccines or therapeutics, must target young populations. Remarkably higher HIV prevalence among HSV-2-positive individuals underscores this population as a priority for HIV prevention.

The population impact of herpes simplex virus type 2 (HSV-2) vaccination on the incidence of HSV-2, HIV and genital ulcer disease in South Africa: a mathematical modelling study

Evidence suggests HSV-2 infection increases HIV acquisition risk and HIV/HSV-2 coinfection increases transmission risk of both infections. We analysed the potential impact of HSV-2 vaccination in South Africa, a high HIV/HSV-2 prevalence setting. We adapted a dynamic HIV transmission model for South Africa to incorporate HSV-2, including synergistic effects with HIV, to evaluate the impact of: (i) cohort vaccination of 9-year-olds with a prophylactic vaccine that reduces HSV-2 susceptibility; (ii) vaccination of symptomatically HSV-2-infected individuals with a therapeutic vaccine that reduces HSV shedding. An 80% efficacious prophylactic vaccine offering lifetime protection with 80% uptake could reduce HSV-2 and HIV incidence by 84.1% (95% Credibility Interval: 81.2-86.0) and 65.4% (56.5-71.6) after 40 years, respectively. This reduces to 57.4% (53.6-60.7) and 42.1% (34.1-48.1) if efficacy is 50%, 56.1% (53.4-58.3) and 41.5% (34.2-46.9) if uptake is 40%, and 29.4% (26.0-31.9) and 24.4% (19.0-28.7) if protection lasts 10 years. An 80% efficacious therapeutic vaccine offering lifetime protection with 40% coverage among symptomatic individuals could reduce HSV-2 and HIV incidence by 29.6% (21.8-40.9) and 26.4% (18.5-23.2) after 40 years, respectively. This reduces to 18.8% (13.7-26.4) and 16.9% (11.7-25.3) if efficacy is 50%, 9.7% (7.0-14.0) and 8.6% (5.8-13.4) if coverage is 20%, and 5.4% (3.8-8.0) and 5.5% (3.7-8.6) if protection lasts 2 years. Prophylactic and therapeutic vaccines offer promising approaches for reducing HSV-2 burden and could have important impact on HIV in South Africa and other high prevalence settings. WHO, NIAID.

Impact of universal testing and treatment on sexual risk behaviour and herpes simplex virus type 2: a prespecified secondary outcomes analysis of the HPTN 071 (PopART) community-randomised trial

Comprehensive HIV prevention strategies have raised concerns that knowledge of interventions to reduce risk of HIV infection might mitigate an individual's perception of risk, resulting in riskier sexual behaviour. We investigated the prespecified secondary outcomes of the HPTN 071 (PopART) trial to determine whether a combination HIV prevention strategy, including universal HIV testing and treatment, changed sexual behaviour; specifically, we investigated whether there was evidence of sexual risk compensation. HPTN 071 (PopART) was a cluster-randomised trial conducted during 2013-18, in which we randomly assigned 21 communities with high HIV prevalence in Zambia and South Africa (total population, approximately 1 million) to combination prevention intervention with universal antiretroviral therapy (ART; arm A), prevention intervention with ART provided according to local guidelines (universal since 2016; arm B), or standard of care (arm C). The trial included a population cohort of approximately 2000 randomly selected adults (aged 18-44 years) in each community (N=38 474 at baseline) who were followed up for 36 months. A prespecified secondary objective was to evaluate the impact of the PopART intervention compared with standard of care on herpes simplex virus type 2 (HSV-2) and sexual behaviour (N=20 422 completed final visit). Secondary endpoints included differences in sexual risk behaviour measures at 36 months and were assessed using a two-stage method for matched cluster-randomised trials. This trial is registered with ClinicalTrials. gov, number NCT01900977. The PopART intervention did not substantially change probability of self-reported multiple sex partners, sexual debut, or pregnancy in women at 36 months. Adjusted for baseline community prevalence, reported condomless sex was significantly lower in arm A versus arm C (adjusted prevalence ratio 0·80 [95% CI 0·64-0·99]; p=0·04) but not in arm B versus arm C (0·94 [0·76-1·17]; p=0·55). 3-year HSV-2 incidence was reduced in arm B versus arm C (adjusted risk ratio 0·76 [95% CI 0·63-0·92]; p=0·010); no significant change was shown between arm A versus arm C (0·89 [0·73-1·08]; p=0·199). We found little evidence of any change in sexual behaviour owing to the PopART interventions, and reassuringly for public health, we saw no evidence of sexual risk compensation. The findings do not help to explain the differences between the two intervention groups of the HPTN 071 (PopART) trial. National Institute of Allergy and Infectious Diseases, the National Institutes of Health, the International Initiative for Impact Evaluation (3ie), the Bill & Melinda Gates Foundation, the US President's Emergency Plan for AIDS Relief, and the Medical Research Council UK.

Effectiveness of Cash Transfer Delivered Along With Combination HIV Prevention Interventions in Reducing the Risky Sexual Behavior of Adolescent Girls and Young Women in Tanzania: Cluster Randomized Controlled Trial.

BackgroundPoverty and social inequality exacerbate HIV risk among adolescent girls and young women (AGYW) in sub-Saharan Africa. Cash transfers can influence the structural determinants of health, thereby reducing HIV risk.ObjectiveThis study assessed the effectiveness of cash transfer delivered along with combination HIV prevention (CHP) interventions in reducing the risky sexual behavior of AGYW in Tanzania. The incidence of herpes simplex virus type 2 (HSV-2) infection was used as a proxy for sexual risk behavior.MethodsA cluster randomized controlled trial was conducted in 15 matched pairs of communities (1:1 intervention to control) across 3 strata (urban, rural high-risk, and rural low-risk populations) of the Shinyanga Region, Tanzania. The target population was out-of-school AGYW aged 15-23 years who had completed 10-hour sessions of social and behavior change communication. Eligible communities were randomly assigned to receive CHP along with cash transfer quarterly (intervention group) or solely CHP interventions (control group) with no masking. Study recruitment and baseline survey were conducted between October 30, 2017 and December 1, 2017. Participants completed an audio computer-assisted self-interview, HIV counselling and testing, and HSV-2 testing at baseline and during follow-up visits at 6, 12, and 18 months after the baseline survey. A Cox proportional hazards model with random effects specified at the level of clusters (shared frailty) adjusted for matching pairs and other baseline imbalances was fitted to assess the effects of cash transfer on the incidence of HSV-2 infection (primary outcome). Secondary outcomes included HIV prevalence at follow-up, self-reported intergenerational sex, and self-reported compensated sex. All secondary outcomes were measured at each study visit.ResultsOf the 3026 AGYW enrolled in the trial (1482 in the intervention and 1544 in the control), 2720 AGYW (1373 in the intervention and 1347 in the control) were included in the final analysis. Overall, HSV-2 incidence was not significantly different at all follow-up points between the study arms in the adjusted analysis (hazard ratio 0.96, 95% CI 0.67-1.38; P=.83). However, HSV-2 incidence was significantly lower in the rural low-risk populations who received the cash transfer intervention (hazard ratio 0.45, 95% CI 0.29-0.71; P=.001), adjusted for potential confounders.ConclusionsAlthough this trial showed no significant impact of the cash transfer intervention on HSV-2 incidence among AGYW overall, the intervention significantly reduced HSV-2 incidence among AGYW in rural low-risk communities. Factors such as lesser poverty and more asset ownership in urban and rural high-risk communities may have undermined the impact of cash transfer.Trial RegistrationClinicalTrials.gov NCT03597243; https://clinicaltrials.gov/show/NCT03597243

The association of exposure to DREAMS on sexually acquiring or transmitting HIV amongst adolescent girls and young women living in rural South Africa.

We investigate how risk of sexually acquiring or transmitting HIV in adolescent girls and young women (AGYW) changed following the real-world implementation of DREAMS (Determined, Resilient, Empowered, AIDS free, Mentored and Safe) HIV prevention programme. A representative population-based prospective cohort study of AGYW living in rural KwaZulu-Natal. Between 2017 and 2019, we interviewed a random sample of AGYW aged 13-22 years annually. We measured exposure to DREAMS as self-reported receipt of an invitation to participate and/or participation in DREAMS activities that were provided by DREAMS implementing organizations. HIV and herpes simplex virus type 2 (HSV-2) statuses were ascertained through blood tests on Dried Blood Spot (DBS). We used multivariable regression analysis to assess the association between exposure to DREAMS and risk of acquiring HIV: measured as incident HSV-2 (a proxy of sexual risk) and incident HIV;and the risk of sexually transmitting HIV: measured as being HIV positive with a detectable HIV viral load (≥50 copie/ml) on the last available DBS. We adjusted for sociodemographic, sexual relationship, and migration. Two thousand one hundred and eighty-four (86.4%) of those eligible agreed to participate and 2016 (92.3%) provided data for at least one follow-up time-point. One thousand and thirty (54%) were exposed to DREAMS;HIV and HSV-2 incidence were 2.2/100 person-years [95% confidence interval (CI) 1.66-2.86] and 17.3/100 person-years (95% CI 15.5-19.4), respectively. There was no evidence that HSV-2 and HIV incidence were lower in those exposed to DREAMS: adjusted rate ratio (aRR) 0.96 (95% CI 0.76-1.23 and 0.83 (95% CI 0.46-1.52), respectively. HIV viral load was detectable for 169 (8.9%) respondents;there was no evidence this was lower in those exposed to DREAMS with an adjusted risk difference, compared with those not exposed to DREAMS, of 0.99% (95% CI-1.52 to 3.82]. Participants who lived in peri-urban/ urban setting were more likely to have incident HIV and transmissible HIV. Both HSV-2 incidence and the transmissible HIV were associated with older age and ever having sex. Findings did not differ substantively by respondent age group. DREAMS exposure was not associated with measurable reductions in risk of sexually acquiring or transmitting HIV amongst a representative cohort of AGYW in rural South Africa.

HIV and Herpes Simplex Virus Type 2 Incidence Among Adolescent Mothers in South Africa: A Longitudinal Analysis of HIV Prevention Trials Network 068 Data.

Adolescent motherhood is common in South Africa and occurs against a backdrop of high HIV risk. While childbearing during adolescence may result in social and economic strain that may negatively impact health, there has been limited study of whether adolescent motherhood increases the risk of HIV or herpes simplex virus type 2 (HSV-2) acquisition or engagement in high-risk sexual partnerships. Data are from HIV Prevention Trials Network 068, a longitudinal conditional cash transfer study of adolescent girls and young women (age, 13-23) in rural South Africa. We used survival analysis to estimate hazard ratios to determine if adolescent motherhood (live birth before 20 years) predicted incident HIV and incident HSV-2 and generalized estimating equations for behavioral risk ratios to determine if adolescent motherhood was associated with transactional sex and age-disparate partnerships. Of 2452 adolescent girls and young women who were HIV negative at baseline, 5% were adolescent mothers; 16% were adolescent mothers by the end of the study period. After controlling for covariates, adolescent motherhood predicted incident HSV-2 acquisition [ adjusted hazard ratios, 1.30; 95% confidence interval (CI): 1.01 to 1.95] but not HIV acquisition ( adjusted hazard ratios, 1.19; 95% CI, 0.76 to 1.86). Adolescent motherhood was also associated with being in an age-disparate partnership (adjusted risk ratio, 1.30; 95% CI: 1.07 to 1.58) but not transactional sex. Adolescent motherhood increased the risk of HSV-2 and engagement in age-disparate partnerships, both known risk factors for HIV infection. Sexually transmitted infection screening and/or tailored combination HIV prevention interventions that account for the context of adolescent motherhood are critical to maximize adolescent mothers' long-term health and to meet UNAIDS 95-95-95 targets by 2030.

Brief Report: Herpes Simplex Virus Type-2 Shedding and Genital Ulcers During Early HIV in Zimbabwean Women.

Herpes simplex virus type-2 (HSV-2) seropositive persons have a 3- to 5-fold higher risk of acquiring HIV, possibly because of HSV-2-induced inflammation and recruitment of susceptible immune cells to exposure sites. We hypothesized that cervical HSV-2 activation (ie, viral DNA shedding and/or ulcers) preceded HIV acquisition in the hormonal contraception and HIV cohort. Zimbabwean women who acquired HIV were matched to HIV-negative women on visit, age, and bacterial sexually transmitted infections. Up to 5 cervical swabs bracketing first polymerase chain reaction detection of HIV DNA (the index visit) were selected (t-6months, t-3months, tindex, t+3months, t+6months). Women with HSV-2 immunoglobulin G+ before tindex were polymerase chain reaction tested for viral shedding. Self-reported and clinician-diagnosed ulcers were documented. Multivariable logistic regression, accounting for matching, estimated adjusted odds ratios (aOR) and 95% confidence intervals (CIs) at each visit. Of 387 HSV-2 seropositive women, most had prevalent as compared with incident HSV-2 (91% vs. 9%, respectively). HSV-2 viral shedding was more common among HIV seroconverters than HIV-negative women (26% vs. 14%, P < 0.01). Shedding occurred around HIV acquisition (t-3months aOR, 2.7; 95% CI, 0.8 to 8.8; tindex aOR, 2.6; 95% CI, 1.1 to 6.5; t+3months aOR, 2.6; 95% CI, 1.0 to 6.6). Genital ulcers were reported more often among HIV seroconverters than HIV-negative women (13% vs. 7%; P = 0.06) and detection was after HIV acquisition (t+6months aOR, 14.5; 95% CI, 1.6 to 133.9). HSV-2 shedding appeared synergistic with HIV acquisition followed by presentation of ulcers. Evaluating all sexually transmitted infections rather than HSV-2 alone may clarify the relationship between inflammation and HIV acquisition.

HIV and other STIs self-testing to reduce risk compensation among men who have sex with men who use oral pre-exposure prophylaxis in China: protocol for a randomised waitlist-controlled trial

IntroductionPre-exposure prophylaxis (PrEP) reduces the risk of HIV infection among men who have sex with men by up to 99%. However, in real-world settings, PrEP users may exhibit risk compensation...

Multilevel Gender-Equitable Norms and Risk of HIV and Herpes Simplex Virus Type 2 Acquisition Among Young South African Women: A Longitudinal Analysis of the HIV Prevention Trials Network 068 Cohort

PurposeAdolescent girls and young women (AGYW) in South Africa experience a disproportionately high burden of HIV acquisition. National HIV prevalence among AGYW increases nearly three-fold during the transition from late teenage years to their early twenties. We investigated whether beliefs about gender equity influence subsequent HIV acquisition among AGYW in South Africa. MethodsWe used data from the HIV Prevention Trials Network 068, a longitudinal conditional cash transfer study of AGYW in Mpumalanga Province, South Africa. Gender-equitable beliefs were measured at the level of the individual and summarized among school peers and adults in the community using the Gender Equitable Men's Scale (GEMS). Generalized estimating equation regression was used to assess the association between individual, peer and community GEMS and HIV incidence, herpes simplex virus type 2 (HSV-2) incidence, and other HIV risk factors while accounting for repeated observations and clustering. ResultsA total of 2,533 AGYW were followed up for up to 5 years. Adjusting for potential confounders, a unit increase in peer GEMS scores (i.e. more equitable) were significantly protective against subsequent HIV acquisition (risk difference = −.019; 95% confidence interval: −.032, −.006) and subsequent HSV-2 acquisition (risk difference = −.020; 95% confidence interval: −.040, −.000). Low individual and community GEMS scores were associated with multiple HIV risk factors but not with HIV or HSV-2 incidence directly. ConclusionSchool-level peer endorsement of gender equity may be protective against HIV and HSV-2 incidence among AGYW. Interventions that increase gender equity at the individual level and at the level of the social environment, particularly among school peers, have the potential for protective effects on the health of AGYW.

Multilevel Measures of Education and Pathways to Incident Herpes Simplex Virus Type 2 in Adolescent Girls and Young Women in South Africa

PurposeSchooling is associated with a lower risk of Herpes simplex virus type 2 (HSV-2) in adolescent girls and young women, but there is little understanding of the pathways underlying this relationship. MethodsWe used data from adolescent girls and young women in South Africa enrolled in the HIV Prevention Trials Network 068 study. We tested a structural equation model where individual household and community education measures were associated directly and indirectly with incident HSV-2 through HIV knowledge, future aspirations, age-disparate partnerships, sex in the last 12 months, and condomless sex. ResultsCommunity, household, and individual measures of schooling were all associated with incident HSV-2 infection through mediated pathways that increased the likelihood of having sex. Low school attendance (<80% of school days) increased the likelihood of having sex through increased age-disparate partnerships and reduced future aspirations. Fewer community years of education increased the likelihood of having sex through increased age-disparate partnerships. Parental education level was indirectly associated with HSV-2 overall, although we could not identify the individual pathways that were responsible for this association. ConclusionsCommunity and individual schooling interventions may reduce the risk of HSV-2 infection by influencing the likelihood of having sex, partner age, and future aspirations.

Review of mathematical models of HSV-2 vaccination: Implications for vaccine development

Development of a vaccine against herpes simplex virus type 2 (HSV-2), a life-long sexually-transmitted infection (STI), would be a major step forward in improving global sexual and reproductive health. In this review, we identified published literature of dynamic mathematical models assessing the impact of either prophylactic or therapeutic HSV-2 vaccination at the population level. We compared each study’s model structure and assumptions as well as predicted vaccination impact. We examined possible causes of heterogeneity across model predictions, key gaps, and the implications of these findings for future modelling efforts. Only eight modelling studies have assessed the potential public health impact of HSV-2 vaccination, with the majority focusing on impact of prophylactic vaccines. The studies showed that even an imperfect prophylactic HSV-2 vaccine could have an important public health impact on HSV-2 incidence, and could also impact HIV indirectly in high HIV prevalence settings. Therapeutic vaccines also may provide public health benefits, though they have been explored less extensively. However, there was substantial variation in predicted population-level impact for both types of vaccine, reflecting differences in assumptions between model scenarios. Importantly, many models did not account for heterogeneity in infection rates such as by age, sex and sexual activity. Future modelling work to inform decisions on HSV vaccine development and implementation should consider cost-effectiveness, account for additional HSV-2 sequelae such as neonatal transmission, and model greater heterogeneity in infection rates between individuals, more realistic vaccine deployment, and more thorough sensitivity and uncertainty analyses.

The effect of school attendance and school dropout on incident HIV and HSV-2 among young women in rural South Africa enrolled in HPTN 068.

To estimate the association between school attendance, school dropout, and risk of incident HIV and herpes simplex virus type 2 (HSV-2) infection among young women. We used longitudinal data from a randomized controlled trial in rural Mpumalanga province, South Africa, to assess the association between school days attended, school dropout, and incident HIV and HSV-2 in young women aged 13-23 years. We examined inverse probability of exposure weighted survival curves and used them to calculate 1.5, 2.5, and 3.5-year risk differences and risk ratios for the effect of school attendance on incident HIV and HSV-2. A marginal structural Cox model was used to estimate hazard ratios for the effect of school attendance and school dropout on incident infection. Risk of infection increased over time as young women aged, and was higher in young women with low school attendance (<80% school days) compared with high (≥80% school days). Young women with low attendance were more likely to acquire HIV [hazard ratio (HR): 2.97; 95% confidence interval (CI): 1.62, 5.45] and HSV-2 (HR: 2.47; 95% CI: 1.46, 4.17) over the follow-up period than young women with high attendance. Similarly, young women who dropped out of school had a higher weighted hazard of both HIV (HR 3.25 95% CI: 1.67, 6.32) and HSV-2 (HR 2.70; 95% CI 1.59, 4.59). Young women who attend more school days and stay in school have a lower risk of incident HIV and HSV-2 infection. Interventions to increase frequency of school attendance and prevent dropout should be promoted to reduce risk of infection.

Effect of HSV-2 infection on subsequent HIV acquisition: an updated systematic review and meta-analysis

SummaryBackgroundHIV and herpes simplex virus type 2 (HSV-2) infections cause a substantial global disease burden and are epidemiologically correlated. Two previous systematic reviews of the association between HSV-2 and HIV found evidence that HSV-2 infection increases the risk of HIV acquisition, but these reviews are now more than a decade old.MethodsFor this systematic review and meta-analysis, we searched PubMed, MEDLINE, and Embase (from Jan 1, 2003, to May 25, 2017) to identify studies investigating the risk of HIV acquisition after exposure to HSV-2 infection, either at baseline (prevalent HSV-2 infection) or during follow-up (incident HSV-2 infection). Studies were included if they were a cohort study, controlled trial, or case-control study (including case-control studies nested within a cohort study or clinical trial); if they assessed the effect of pre-existing HSV-2 infection on HIV acquisition; and if they determined the HSV-2 infection status of study participants with a type-specific assay. We calculated pooled random-effect estimates of the association between prevalent or incident HSV-2 infection and HIV seroconversion. We also extended previous investigations through detailed meta-regression and subgroup analyses. In particular, we investigated the effect of sex and risk group (general population vs higher-risk populations) on the relative risk (RR) of HIV acquisition after prevalent or incident HSV-2 infection. Higher-risk populations included female sex workers and their clients, men who have sex with men, serodiscordant couples, and attendees of sexually transmitted infection clinics.FindingsWe identified 57 longitudinal studies exploring the association between HSV-2 and HIV. HIV acquisition was almost tripled in the presence of prevalent HSV-2 infection among general populations (adjusted RR 2·7, 95% CI 2·2–3·4; number of estimates [Ne]=22) and was roughly doubled among higher-risk populations (1·7, 1·4–2·1; Ne=25). Incident HSV-2 infection in general populations was associated with the highest risk of acquisition of HIV (4·7, 2·2–10·1; Ne=6). Adjustment for confounders at the study level was often incomplete but did not significantly affect the results. We found moderate heterogeneity across study estimates, which was explained by risk group, world region, and HSV-2 exposure type (prevalent vs incident).InterpretationWe 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.FundingWorld Health Organization.

Decline in Herpes Simplex Virus Type 2 Among Non-Injecting Heroin and Cocaine Users in New York City, 2005 to 2014: Prospects for Avoiding a Resurgence of Human Immunodeficiency Virus.

Herpes simplex virus type 2 (HSV-2) infection increases both susceptibility to and transmissibility of human immunodeficiency virus (HIV), and HSV-2 and HIV are often strongly associated in HIV epidemics. We assessed trends in HSV-2 prevalence among non-injecting drug users (NIDUs) when HIV prevalence declined from 16% to 8% among NIDUs in New York City. Subjects were current non-injecting users of heroin and/or cocaine and who had never injected illicit drugs. Three thousand one hundred fifty-seven NIDU subjects were recruited between 2005 and 2014 among persons entering Mount Sinai Beth Israel substance use treatment programs. Structured interviews, HIV, and HSV-2 testing were administered. Change over time was assessed by comparing 2005 to 2010 with 2011 to 2014 periods. Herpes simplex virus type 2 incidence was estimated among persons who participated in multiple years. Herpes simplex virus type 2 prevalence was strongly associated with HIV prevalence (odds ratio, 3.9; 95% confidence interval, 2.9-5.1) from 2005 to 2014. Herpes simplex virus type 2 prevalence declined from 60% to 56% (P = 0.01). The percentage of NIDUs with neither HSV-2 nor HIV infection increased from 37% to 43%, (P < 0.001); the percentage with HSV-2/HIV coinfection declined from 13% to 6% (P < 0.001). Estimated HSV-2 incidence was 1 to 2/100 person-years at risk. There were parallel declines in HIV and HSV-2 among NIDUs in New York City from 2005 to 2014. The increase in the percentage of NIDUs with neither HSV-2 nor HIV infection, the decrease in the percentage with HSV-2/HIV coinfection, and the low to moderate HSV-2 incidence suggest some population-level protection against resurgence of HIV. Prevention efforts should be strengthened to end the combined HIV/HSV-2 epidemic among NIDUs in New York City.

A 15-year study of the impact of community antiretroviral therapy coverage on HIV incidence in Kenyan female sex workers.

To test the hypothesis that increasing community antiretroviral therapy (ART) coverage would be associated with lower HIV incidence in female sex workers (FSWs) in Mombasa District, Kenya. Prospective cohort study. From 1998 to 2012, HIV-negative FSWs were asked to return monthly for an interview regarding risk behavior and testing for sexually transmitted infections including HIV. We evaluated the association between community ART coverage and FSW's risk of becoming HIV infected using Cox proportional hazards models adjusted for potential confounding factors. One thousand, four hundred and four FSWs contributed 4335 woman-years of follow-up, with 145 acquiring HIV infection (incidence 3.35/100 woman-years). The ART rollout began in 2003. By 2012, an estimated 52% of HIV-positive individuals were receiving treatment. Community ART coverage was inversely associated with HIV incidence (adjusted hazard ratio 0.77; 95% confidence interval 0.61-0.98; P = 0.03), suggesting that each 10% increase in coverage was associated with a 23% reduction in FSWs' risk of HIV acquisition. Community ART coverage had no impact on herpes simplex virus type-2 incidence (adjusted hazard ratio 0.97; 95% confidence interval 0.79-1.20; P = 0.8). Increasing general population ART coverage was associated with lower HIV incidence in FSWs. The association with HIV incidence, but not herpes simplex virus type-2 incidence, suggests that the effect of community ART coverage may be specific to HIV. Interventions such as preexposure prophylaxis and antiretroviral-containing microbicides have produced disappointing results in HIV prevention trials with FSWs. These results suggest that FSWs' risk of acquiring HIV infection might be reduced through the indirect approach of increasing ART coverage in the community.

O18.2 Injectable progestin contraception and acquisition of hsv-2 infection among south african women participating in the voice trial

Introduction Observational data suggest HIV-1 acquisition differs between users of two common injectable progestin-only contraceptives (IPC), depot medroxyprogesterone acetate (DMPA) and norethisterone enanthate (NET-EN). Data are limited on the potential impact of both IPC types on herpes simplex virus type 2 (HSV-2) acquisition. Methods We conducted a secondary analysis among IPC users enrolled at South African sites in VOICE, a multi-centre randomised trial of topical and oral HIV-1 chemoprophylaxis. Contraceptive use assessment was conducted monthly. HSV-2 was diagnosed by Focus HerpeSelect EIA at enrollment and repeat EIA at study exit in all participants (seroconversion cutoff value ≥3.5); quarterly EIA was available for a subset to assess seroconversion timing. Using Cox proportional hazards regression, we assessed the association between IPC type and HSV-2 acquisition with adjustment for potential confounders (age, marriage/cohabitation, education, condom use, number of partners, VOICE study arm). Results Among 1776 IPC users who were HSV-2-seronegative at enrollment, 922 (51.9%) used DMPA, 716 (40.3%) used NET-EN, and 138 (7.8%) used both IPC types at different times during follow-up. Among the 1638 IPC users who did not switch IPC type during follow-up, 1506 (91.9%) had baseline and exit HSV-2 serology available. Over 1534.1 person-years (py) of follow-up, 178 incident HSV-2 cases occurred: 107 in DMPA users (crude incidence rate [IR] 11.3/100 py) and 71 in NET-EN users (crude IR 12.1/100 py). Among 640 participants with quarterly HSV-2 serology, 45 cases occurred among DMPA users over 350.4 py and 31 among NET-EN users over 231.1 py (HR = 0.97; 95% CI 0.61–1.53; aHR = 1.02; 95% CI 0.64–1.62). Conclusion HSV-2 risk did not differ by DMPA versus NET-EN use. These results are consistent with our findings that DMPA users in VOICE did not have higher risk of genital tract infection (gonorrhoea, chlamydia or trichomoniasis) compared to NET-EN users, despite having higher risk for HIV-1 infection. Disclosure of interest statement The authors report no conflicts of interest.

Tenofovir Gel for the Prevention of Herpes Simplex Virus Type 2 Infection

BackgroundGlobally, herpes simplex virus type 2 (HSV-2) infection is the most common cause of genital ulcer disease. Effective prevention strategies for HSV-2 infection are needed to achieve the goals of the World Health Organization global strategy for the prevention and control of sexually transmitted infections.MethodsWe assessed the effectiveness of pericoital tenofovir gel, an antiviral microbicide, in preventing HSV-2 acquisition in a subgroup of 422 HSV-2–negative women enrolled in the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 study, a double-blind, randomized, placebo-controlled trial. Incident HSV-2 cases were identified by evidence of seroconversion on an HSV-2 IgG enzyme-linked immunosorbent assay between study enrollment and exit. A confirmatory analysis was performed by Western blot testing.ResultsThe HSV-2 incidence rate was 10.2 cases per 100 person-years (95% confidence interval [CI], 6.8 to 14.7) among 202 women assigned to tenofovir gel, as compared with 21.0 cases per 100 person-years (95% CI, 16.0 to 27.2) among 222 women assigned to placebo gel (incidence rate ratio, 0.49; 95% CI, 0.30 to 0.77; P=0.003). The HSV-2 incidence rate among the 25 women with vaginal tenofovir concentrations of 10,000 ng per milliliter or more was 5.7 cases per 100 person-years, as compared with 15.5 cases per 100 person-years among the 103 women with no detectable vaginal tenofovir (incidence rate ratio, 0.37; 95% CI, 0.04 to 1.51; P=0.14). As confirmed by Western blot testing, there were 16 HSV-2 seroconversions among women assigned to tenofovir gel as compared with 36 among those assigned to the placebo gel (incidence rate ratio, 0.45; 95% CI, 0.23 to 0.82; P=0.005).ConclusionsIn this study in South Africa, pericoital application of tenofovir gel reduced HSV-2 acquisition in women. (Funded by the U.S. Agency for International Development and others; ClinicalTrials.gov number, NCT00441298.)

Risk factors for incident HSV-2 infections among a prospective cohort of HIV-1-discordant couples in China

ObjectivesIdentification of risk factors is essential for developing herpes simplex virus type 2 (HSV-2) prevention interventions that could also reduce HIV-1 transmission, particularly among HIV-1-discordant couples.MethodsA prospective cohort study was...