Herpes Simplex Virus Type 2 Acquisition Research Articles

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.

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.

Tenofovir Gel for Prevention of Herpes Simplex Virus Type 2 Acquisition: Findings From the VOICE Trial.

Genital infection with herpes simplex virus type 2 (HSV-2) is common and increases risk of human immunodeficiency virus (HIV) transmission and acquisition. Pericoital use of tenofovir (TFV) gel provided protection from HSV-2 acquisition in the CAPRISA 004 study. We measured estimate of effect of vaginal TFV 1% gel in preventing HSV-2 acquisition among women in VOICE, randomized, double-blinded, placebo-controlled trial assessing daily use of oral and vaginal TFV for HIV-1 preexposure prophylaxis. The TFV level in plasma at the first quarterly visit was used as a measure of gel use. Of 566 participants at risk for HSV-2 acquisition, 532 (94%) had first-quarter plasma TFV and end-of-study HSV-2 serologic data available. Over a follow-up period of 501 person-years, 92 incident cases of HSV-2 acquisition occurred: 77 were in women with no TFV detected in plasma, and 15 occurred in women with TFV detected in plasma (incidence, 20.6 cases/100 person-years [95% confidence interval [CI], 16.2-25.7] vs 11.9 cases/100 person-years [95% CI, 6.6-19.6], respectively). TFV detection in plasma was associated with a trend toward a reduced risk of HSV-2 seroconversion, with an unadjusted hazard ratio (HR) of 0.59 (95% CI, .34-1.02; P = .060) and a HR adjusted for site, age, having ≥2 male sex partners in the past 3 months, use of hormonal contraception, having anal sex in the past 3 months, and HIV status of 0.60 (95% CI, .33-1.08; P = .086). Detection of TFV in plasma among TFV gel users was associated with a trend toward a reduced risk of HSV-2 acquisition, after controlling for sexual behavior and HIV-1 acquisition.

Herpes Simplex Virus Type 2 Acquisition Among HIV-1-Infected Adults Treated With Tenofovir Disoproxyl Fumarate as Part of Combination Antiretroviral Therapy: Results From the ACTG A5175 PEARLS Study.

Tenofovir disoproxyl fumarate (TDF) disoproxyl fumarate (TDF) has in vitro activity against herpes simplex virus type 2 (HSV-2) and reduced HSV-2 acquisition as preexposure prophylaxis. Whether TDF-containing antiretroviral therapy (ART) reduces HSV-2 acquisition is unknown. Secondary analysis of AIDS Clinical Trials Group A5175, a randomized, open-label study of 3 ART regimens among 1571 participants. HSV-2 serostatus was assessed at baseline, at study exit, and before a change in ART regimen. Of 365 HSV-2-seronegative persons, 68 acquired HSV-2, with 24 receiving TDF-containing ART and 44 receiving ART without TDF (HSV-2 seroconversion incidence, 6.42 and 6.63 cases/100 person-years, respectively; hazard ratio, 0.89; 95% confidence interval, .55-1.44). HSV-2 acquisition was not reduced in HIV-infected, HSV-2-uninfected persons during TDF-containing ART.

Incidence and risk factors for herpes simplex virus type 2 seroconversion among pregnant women in Uganda: A prospective study.

Herpes simplex virus type 2 (HSV-2) acquired during pregnancy is associated with adverse outcomes such as perinatal HSV-2 transmission. HSV-2 seroconversion occurs within four weeks of HSV-2 acquisition. There was neither documented incidence nor risk factors for HSV-2 seroconversion during pregnancy in Uganda. The objective of this study was to determine the incidence and risk factors for HSV-2 seroconversion among pregnant women in Mulago Hospital, Uganda. A prospective study of 200 consenting HSV-2-negative women between 26 and 28 weeks of gestation was done between November 2013 and October 2014. HSV-2 serostatus was determined using HerpeSelect HSV-2 enzyme-linked immunosorbent assay (ELISA). Interviewer-administered questionnaires were used to collect socio-demographic characteristics and sexual history. Human immunodeficiency virus (HIV) serostatus was obtained from antenatal records. A total of 191 women completed follow-up and repeat HSV-2 serology by 38 weeks. Negative binomial regression analysis was used to estimate risk ratios for risk factors for HSV-2 seroconversion. Of 191 women, 15 (7.9%) seroconverted during pregnancy. Having multiple sexual partners, being in polygamous unions, and having HIV-positive serostatus were found to be risk factors for HSV-2 seroconversion. The incidence of HSV-2 seroconversion during pregnancy in Uganda was high. Multiple sexual partners, polygamy, and HIV-positive serostatus were risk factors for HSV-2 seroconversion during pregnancy. Strengthening health education on the avoidance of multiple sexual partners during pregnancy is paramount in prevention of HSV-2 seroconversion.

Genital Herpes Simplex Virus Type 2 Shedding Among Adults With and Without HIV Infection in Uganda.

Despite the high prevalence of herpes simplex virus type 2 (HSV-2) in sub-Saharan Africa, the natural history of infection among Africans is not well characterized. We evaluated the frequency of genital HSV shedding in HIV-seropositive and HIV-seronegative men and women in Uganda. Ninety-three HSV-2-seropositive Ugandan adults collected anogenital swab specimens for HSV DNA quantification by polymerase chain reaction 3 times daily for 6 weeks. HSV-2 was detected from 2484 of 11 283 swab specimens collected (22%), with a median quantity of 4.3 log10 HSV copies/mL (range, 2.2-8.9 log10 HSV copies/mL). Genital lesions were reported on 749 of 3875 days (19%), and subclinical HSV shedding was detected from 1480 of 9113 swab specimens (16%) collected on days without lesions. Men had higher rates of total HSV shedding (relative risk [RR], 2.0 [95% confidence interval {CI}, 1.3-2.9]; P < .001); subclinical shedding (RR, 1.7 [95% CI, 1.1-2.7]; P = .01), and genital lesions (RR, 2.1 [95% CI, 1.2-3.4]; P = .005), compared with women. No differences in shedding rates or lesion frequency were observed based on HIV serostatus. HSV-2 shedding frequency and quantity are high among HSV-2-seropositive adults in sub-Saharan Africa, including persons with and those without HIV infection. Shedding rates were particularly high among men, which may contribute to the high prevalence of HSV-2 and early acquisition among African women.

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.)

Oral and Vaginal Tenofovir for Genital Herpes Simplex Virus Type 2 Shedding in Immunocompetent Women: A Double-Blind, Randomized, Cross-over Trial.

Tenofovir is a potent anti-human immunodeficiency virus (HIV) agent that decreased risk of herpes simplex virus type 2 (HSV-2) acquisition in HIV pre-exposure prophylaxis trials. Whether tenofovir has utility in established HSV-2 disease is unclear. We randomized immunocompetent women with symptomatic HSV-2 infection to oral tenofovir disoproxil fumarate (TDF)/placebo vaginal gel, oral placebo/tenofovir (TFV) vaginal gel, or double placebo (ratio 2:2:1) in a one-way cross-over trial. Women collected genital swabs twice daily for HSV PCR during 4-week lead-in and 5-week treatment phases. The primary intent-to-treat end point was within-person comparison of genital HSV shedding and lesion rates. 64 women completed the lead-in phase and were randomized. Neither TDF nor TFV gel decreased overall shedding or lesion rate in the primary analysis; TFV gel decreased quantity of HSV DNA by -0.50 (-0.86-0.13) log10 copies/mL. In the per-protocol analysis, TDF reduced shedding (relative risk [RR] = 0.74, P = .006) and lesion rates (RR = 0.75, P = .032); quantity of virus shed decreased by 0.41 log10 copies/mL. Oral TDF modestly decreased HSV shedding and lesion rate, and quantity of virus shed when used consistently. Vaginal TFV gel decreased quantity of virus shed by 60%. In contrast to effects on HSV-2 acquisition, tenofovir is unlikely to provide clinically meaningful reductions in the frequency of HSV shedding or genital lesions. NCT01448616.

Daily 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.

Daily oral preexposure prophylaxis (PrEP) using the antiretroviral tenofovir disoproxil fumarate (TDF) alone or in combination with emtricitabine (FTC-TDF) reduces the risk for HIV-1 acquisition. Tenofovir has in vitro activity against herpes simplex virus type 2 (HSV-2). To assess the efficacy of daily oral PrEP with tenofovir and FTC-TDF in the prevention of HSV-2 acquisition. Subgroup analysis of data from a randomized, placebo-controlled trial with concealed allocation. (ClinicalTrials.gov: NCT00557245). Multiple sites in Kenya and Uganda. Heterosexual men and women who were seronegative for HIV-1 and HSV-2 and at high risk for HIV-1 acquisition due to having an HIV-1-infected partner. Once-daily oral tenofovir disoproxil fumarate (TDF), alone or combined with emtricitabine (FTC-TDF), compared with placebo. HSV-2 seroconversion. A total of 131 participants seroconverted to HSV-2 (79 of 1041 assigned to tenofovir or FTC-TDF PrEP [HSV-2 incidence, 5.6 per 100 person-years] and 52 of 481 assigned to placebo [HSV-2 incidence, 7.7 per 100 person-years]). The hazard ratio (HR) for HSV-2 acquisition with daily oral PrEP was 0.70 (95% CI, 0.49 to 0.99; P = 0.047) compared with placebo, and the absolute risk reduction was 2.1 per 100 person-years. Among the 1044 participants with HSV-2-infected partners, the HR for PrEP was 0.67 (CI, 0.46 to 0.98; P = 0.038) compared with placebo, and the absolute risk reduction was 3.1 per 100 person-years. Randomization was not stratified by HSV-2 status, and diagnostic tests to exclude participants with acute HSV-2 at baseline are not available. Daily oral tenofovir-based PrEP significantly reduced the risk for HSV-2 acquisition among heterosexual men and women. Modest protection against HSV-2 is an added benefit of HIV-1 prevention with oral tenofovir-based PrEP. Bill & Melinda Gates Foundation.

Persistence of mucosal T-cell responses to herpes simplex virus type 2 in the female genital tract.

Relatively little is known about the human T cell response to HSV-2 in the female genital tract, a major site of heterosexual HSV-2 acquisition, transmission and reactivation. In order to understand the role of local mucosal immunity in HSV-2 infection, T cell lines were expanded from serial cervical cytobrush samples from 30 HSV-2 infected women and examined for reactivity to HSV-2. Approximately 3% of the CD3+ T cells isolated from the cervix were HSV-2 specific and of these, a median of 91.3% were CD4+ while a median of 3.9% were CD8+. HSV-2 specific CD4+ T cells expanded from the cervix were not only more frequent than CD8+ T cells but also exhibited greater breadth in terms of antigenic reactivity. T cells directed at the same HSV-2 protein were often detected in serial cervical cytobrush samples and in blood. Thus, broad and persistent mucosal T cell responses to HSV-2 were detected in the female genital tract of HSV-2+ women suggesting that these cells are resident at the site of HSV-2 infection. Understanding the role of these T cells at this biologically relevant site will be central to the elucidation of adaptive immune mechanisms involved in controlling HSV-2 disease.

Prevalence, Incidence and Risk Factors for Acquisition of Herpes Simplex Virus Type 2 among Fishermen on the Shores of Lake Victoria in Kisumu County, Kenya

Background: Herpes simplex virus Type 2 (HSV-2) has been associated with HIV infection. More recently, HSV-2 incidence has been linked to HIV acquisition. A few studies have suggested that the fishing communities have a high HSV-2 prevalence but there is limited knowledge on HSV-2 incidence and associated risk factors among fishermen. Methods: Three hundred fishermen were consented, and evaluated for baseline HSV-2 serology status and again after 12 months among those negative at baseline. Sexual behavior and socio-demographic data were collected at enrolment and exit visits using a structured questionnaire. Baseline HIV serology and Human papillomavirus (HPV) DNA genotyping were also performed. Multivariate logistic regression was used to determine independent factors associated with HSV-2 acquisition. Results: Baseline HSV-2 prevalence was 56.3% (95% CI: 50.7 - 62.0). Factors associated with HSV-2 prevalence were, older age (aOR = 1.96; 95% CI: 1.16 - 2.85), history of STI (aOR 2.12; 95% CI: 1.19 - 3.91), infection with HIV (aOR 2.22; 95% CI: 1.17 - 4.22), ever married (aOR = 3.80; 95% CI: 1.42 - 11.90), most recent sexual act with sex worker/casual partner (OR= 3.56; 95% CI: 1.49 - 8.62) and inconsistent condom use with new sexual partner (aOR = 6.34; 95% CI: 2.24 - 13.04). The HSV-2 incidence was 23.6 (95% CI = 15.4 - 31.8)/100 pyr. Infection with persistent high-risk (HR) HPV (aIRR = 3.35; 95% CI: 1.21 - 11.37), multiple (≥2) partners in 12 months prior to study participation (aIRR = 4.77; 95% CI: 1.12 - 11.38), inconsistent condom use with new partner (aIRR =2.53; 95% CI: 1.12 - 7.38) and most recent sexual act with sex worker/casual partner (OR = 3.03; 95% CI: 1.17 - 8.58) were independent risk factors for HSV-2 acquisition. Conclusion: The incidence of HSV-2 is very high among fishermen. It is associated with persistent HR HPV infection and high-risk sexual behavior. Intervention strategies targeting these men with high risk sexual behavior are urgently needed to stop new HSV-2 acquisition and subsequently prevent HIV infection.

Incident Herpes Simplex Virus Type 2 Infection Increases the Risk of Subsequent Episodes of Bacterial Vaginosis

Herpes simplex virus type 2 (HSV-2) infected women have a higher prevalence of bacterial vaginosis (BV) compared to HSV-2-seronegative women. To explore the temporal association between these conditions, we evaluated the frequency of BV episodes before and after HSV-2 acquisition in a prospective study of 406 HSV-2/HIV-1-seronegative Kenyan women, of whom 164 acquired HSV-2. Incident HSV-2 was associated with increased likelihood of BV (adjusted OR, 1.28; 95% CI, 1.05-1.56; P = .01). Our findings strengthen the evidence for a causal link between genital HSV-2 infection and disruption of the vaginal microbiota.

Daily acyclovir to decrease herpes simplex virus type 2 (HSV-2) transmission from HSV-2/HIV-1 coinfected persons: a randomized controlled trial.

Daily suppressive therapy with valacyclovir reduces risk of sexual transmission of herpes simplex virus type 2 (HSV-2) in HSV-2-serodiscordant heterosexual couples by 48%. Whether suppressive therapy reduces HSV-2 transmission from persons coinfected with HSV-2 and human immunodeficiency virus type 1 (HIV-1) is unknown. Within a randomized trial of daily acyclovir 400 mg twice daily in African HIV-1 serodiscordant couples, in which the HIV-1-infected partner was HSV-2 seropositive, we identified partnerships in which HIV-1-susceptible partners were HSV-2 seronegative to estimate the effect of acyclovir on risk of HSV-2 transmission. We randomly assigned 911 HSV-2/HIV-1-serodiscordant couples to daily receipt of acyclovir or placebo. We observed 68 HSV-2 seroconversions, 40 and 28 in acyclovir and placebo groups, respectively (HSV-2 incidence, 5.1 cases per 100 person-years; hazard ratio [HR], 1.35 [95% confidence interval, .83-2.20]; P = .22). Among HSV-2-susceptible women, vaginal drying practices (adjusted HR, 44.35; P = .004) and unprotected sex (adjusted HR, 9.91; P = .002) were significant risk factors for HSV-2 acquisition; having more children was protective (adjusted HR, 0.47 per additional child; P = .012). Among HSV-2-susceptible men, only age ≤30 years was associated with increased risk of HSV-2 acquisition (P = .016). Treatment of African HSV-2/HIV-1-infected persons with daily suppressive acyclovir did not decrease risk of HSV-2 transmission to susceptible partners. More-effective prevention strategies to reduce HSV-2 transmission from HIV-1-infected persons are needed.

Incident HSV-2 Infections Are Common Among HIV-1-discordant Couples

The synergy between herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus type 1 (HIV-1) is well known, but lack of knowledge about the epidemiology of HSV-2 acquisition in HIV-1-discordant couples hampers development of HSV-2 prevention interventions that could reduce HIV-1 transmission. HIV-1-discordant couples were enrolled in Nairobi, Kenya, and followed for up to 2 years. HSV-2 status was determined using HerpeSelect HSV-2 ELISA. Correlates of prevalence and incidence were assessed. RESULTS.: Of 469 HIV-1-discordant couples, at baseline, 353 (75.3%) were affected by HSV-2, of which 189 (53.5%) were concordantly HSV-2 seropositive and 164 (46.5%) were HSV-2-discordant. Prevalence was lowest among HIV-1-uninfected men (39.9%) compared to HIV-1-infected women (64.8%), HIV-1-infected men (66.7%), and HIV-1-uninfected women (68.5%). During follow-up, HSV-2 seroincidence was 14.9 per 100 person-years. Incidence was 1.6-fold higher among females compared to males (95% confidence interval [CI], 1.00-2.48) and 2.5-fold higher in HIV-1-infected compared to uninfected women (95% CI, 1.12-5.74). At least 30% of incident HSV-2 infections originated from an outside partner. The high HSV-2 prevalence and incidence in HIV-1-discordant couples in sub-Saharan Africa suggest HSV-2 treatment and prevention could be an effective targeted strategy to reduce HSV-2 and HIV-1 transmission in this high-risk population.

P3.370 Daily Oral Emtricitabine/Tenofovir Pre-Exposure Prophylaxis and Prevention of HSV-2 Acquisition Among Heterosexual Men and Women

BackgroundDaily oral and pericoital tenofovir-based antiretroviral pre-exposure prophlyaxis (PrEP), reduced risk of HIV-1 acquisition in trials among high risk populations; oral emtricitabine(FTC)/tenofovir (TDF) received a label indication for HIV-1 prevention....

Herpes simplex virus type 2 incidence and associated risk factors among female sex workers in a high HIV-prevalence area of China

Herpes simplex virus type 2 (HSV-2) can contribute to the spread of HIV. From March 2006 to November 2009, female sex workers (FSWs) in Yunnan, China were recruited into an open cohort study to determine incidence and risk factors for HSV-2 acquisition. Participants were interviewed and tested for HSV-2 and other sexually transmitted infections (STIs) every six months. A multivariate Cox proportional hazards regression model with time-dependent variables was used to measure associations with HSV-2 acquisition. In 3.5 years, 83 incident cases of HSV-2 infection were diagnosed, yielding an overall incidence of 21.9 per 100 person years (PY) (95% confidence interval [CI], 17.8-26.3). Working in higher risk commercial sex venues, current Neisseria gonorrhoeae infection, age of sexual debut <18 years and lack of a regular sex partner were independent factors associated with HSV-2 acquisition. The high incidence of HSV-2 suggests that prevention methods for HIV/STI control are urgently needed.

Response to ‘Herpes simplex virus type-2 (HSV-2) assay specificity and male circumcision to reduce HSV-2 acquisition

In response to the letter from Tobian et al.[1], we too were surprised that we did not find a protective effect of medical male circumcision (MMC) against herpes simplex virus type 2 (HSV-2). On the basis of the results from their trial in Uganda [2], the trial South Africa [3], results from meta-analysis [4], and the reduction in genital ulcer disease (GUD) in our own trial, we expected a reduction in HSV-2 for circumcised men compared with uncircumcised men. Tobian et al.[1] suggest that we did not find an association due to poor assay specificity. We investigated this as a possibility, but believe there are other potentially more plausible explanations for this lack of association between MMC and HSV-2 among our participants in Kenya. Although the sensitivity (95%) and specificity (91%) of the Kalon test for detecting HSV-2 in sub-Saharan Africa are high [5], we found a lower sensitivity (92%) and specificity (79%) in a validation study among men aged 18–24 years in Kisumu [6]. This amount of misclassification could obscure a small effect of MMC on HSV-2 acquisition. However, in keeping with the analysis conducted by Tobian et al.[1] and as reported in our article, to assess the effect of misclassification due to imperfect specificity, we varied the optical density cut-off index value (1.5, 2.0, 2.5, 3.0 and 3.5), with higher values corresponding with higher specificity. Here we present the detailed results of that analysis (Table 1); the relative risk remained close to 1, indicating no protective effect of MMC against HSV-2, and that the results were unaffected by increased specificity.Table 1: Herpes simplex virus type 2 incidence among circumcised and uncircumcised men based on Kalon index value.As we noted, the lack of association between MMC and HSV-2 acquisition also could be due to the location of lesions. Unlike HIV, transmission of HSV-2 can result from contact between skin or mucosa throughout the genital region [7] or may be acquired orally [8], and this may render HSV-2 acquisition less dependent upon the presence of foreskin mucosa. Among circumcised men, 37% of clinically detected genital ulcers were detected on the penile shaft. Comparable results on lesion location are not reported for the MMC trials in Rakai and Orange Farm. Citing their own work and that of others, Tobian et al.[1] note that the majority of genital ulcers are caused by HSV-2. By serological testing, we also found that a majority, but barely so, of GUD was associated with HSV-2 (55% at baseline prior to randomization and 55% of GUD over follow-up). A large proportion of GUD was associated with no sexually transmitted infection (STI) cause. In a sample of clinically detected genital ulcers, 38% were not associated with HSV or Treponema pallidum by PCR or serology. In the Rakai trial, 58% of clinically detected GUD did not have an STI-associated pathogen [9] and an ulcerative STI pathogen was not detected in 32% of GUD specimens in female sex partners [10]. The relative reduction in GUD among circumcised men was similar for those who remained HSV-2 seronegative throughout follow-up compared with those who were HSV-2 seropositive, indicating that reductions in GUD were not limited to those caused by HSV-2. As we stated, if MMC provided protection against herpetic GUD, we would expect to see a reduction in genital ulcers for HSV-2 seropositive circumcised men compared with uncircumcised men, with no reduction in GUD among HSV-2 seronegative men who were circumcised. If MMC provided protection against both herpetic and nonherpetic ulcers, then we would expect to observe a stronger protective effect of MMC against GUD in HSV-2 seropositive men, resulting from the protection against herpetic GUD in addition to protection against nonherpetic GUD. Thus, our finding of no difference in the reduction in GUD by HSV-2 serostatus is consistent with our finding of no protective effect of MMC against HSV-2. Our null findings do not negate the reductions in HSV-2 associated with MMC observed in the Ugandan and South African trials. Despite having such consistent results with regards to the primary outcome (HIV incidence) and secondary outcomes (incidence of nonulcerative STIs and GUD), it is possible that the trials can have different findings for other parameters, due to differences in populations studied or other unmeasured variables. While it would be convenient for all three trials to have the same findings for all measures, differences indicate new, potentially productive avenues of research and expanded knowledge – in this case, regarding the cause of GUD and variation in different populations. Acknowledgements Conflicts of interest There are no conflicts of interest.

Herpes simplex virus type-2 assay specificity and male circumcision to reduce herpes simplex virus type-2 acquisition

In addition, both the Ugandan and Kenyan trials showed that MC reduced genital ulcer disease by 47%–48% [1, 9]. Since the majority of genital ulcers in both men and women are due to herpes simplex virus type-2 (HSV-2) [10–12], it was hypothesized that MC also reduces HSV-2 acquisition. The Ugandan and South African trials evaluated this hypothesis and reported that MC reduced HSV-2 incidence by 25%–34% [8, 13]. Interestingly, however, Mehta et al did not find similar efficacy in the Kenyan trial in Kisumu [9]. All three trials utilized an enzyme-linked immunosorbent assay (ELISA) manufactured by Kalon Biological to detect incident HSV-2. However, interpretation of this assay to detect HSV-2 seroconversion can be problematic, since the index value to define a positive result may differ from the manufacturer’s recommended cut off based on European and North American populations and HSV-2 viruses [14]. There are multiple reports of high false positive rates among African samples [14–18]. We and others found that a higher index cutoff value is required for optimal sensitivity and specificity [14, 16, 19]. When used according to manufacturer’s instructions (index cutoff value 1.1), the Kalon ELISA had a sensitivity of 95.1% and a specificity of only 87.6% in Uganda compared to Western blot [14], whereas a Kalon index value cutoff of 1.5 resulted in a sensitivity of 91.7% and a specificity of 92.4% [14]. Specificity increased to 97.6% with an index value of 2.5 and 98.4% with an index value of 3.5 [14]. In a validation study among men enrolled in the MC trial in Kisumu, the Kalon ELISA at the recommend manufacturer’s cutoff had low sensitivity (92%) and specificity (79%) [20]. In their analysis, Mehta et al used the manufacturer’s cutoff to evaluate the efficacy of MC to reduce HSV-2 incidence [9], a cutoff which is likely to have reduced specificity and may have biased their results towards the null. Mehta et al noted that “no differences were found between circumcised and uncircumcised men at other cutoff values of 1.5, 2.0, 2.5 3.0 and 3.5 [9].” However, to determine whether improved specificity affected MC efficacy estimates in the Ugandan trial, we assessed HSV-2 seroconverters classified by higher Kalon ELISA index values which maximize specificity and reduce potential false positives. For HSV-2 seroconversion rate and person time calculations, it was assumed that HSV-2 infection occurred at the mid-time point between the last negative and first positive serological tests. Time from enrollment was accumulated to the 24 month follow-up visit or the last available sample visit, and HSV-2 seroconversions were estimated per 100 person-years. Incidence rate ratios (IRRs) and 95% confidence intervals (95%CI) were estimated using Poisson regression. As HSV-2 assay specificity increased, MC efficacy to prevent HSV-2 infection increased, albeit modestly (Table). Thus, the previously reported 25–34% reduction in HSV-2 from the Ugandan and South African trials likely represent conservative estimates. As Meta et al note in the discussion, the lack of an association between male circumcision and reduced incident HSV-2 in the Kenyan trial may be due to poor test performance. The results of the Ugandan and Kenyan trials showing reduced genital ulceration following MC and the results of the Ugandan and South African MC trials showing reduced HSV-2 acquisition appear consistent. The analysis in Table 1 suggests that higher assay specificity further strengthens the observed associations that MC reduces both HSV-2 incidence and genital ulcer disease. Table 1 HSV-2 incidence among men in the intervention group (circumcised) and control group based on Kalon index value.

Herpes simplex virus and HIV: genital infection synergy and novel approaches to dual prevention

Sexual transmission of HIV-1, in the absence of co-factors, is poorly efficient. Data support that herpes simplex virus type-2 (HSV-2) may increase a woman's susceptibility to HIV-1. Potential mechanisms by which HSV-2 serves as an HIV-1 enhancing co-factor include (1) initiation of a clinical or subclinical mucosal inflammatory response, (2) alteration of innate mucosal immunity and (3) weakening or breaching the protective genital epithelia. No clinical trial has examined prevention of primary HSV-2 infection to eliminate the major morbidities of this recurrent disease and as a strategy to reduce HIV-1 transmission. Topical administration of potent antivirals can achieve local concentrations that are orders of magnitude higher than those obtained with oral administration. This paper reviews major advances in oral and topical pre-exposure prophylaxis of HIV-1 and HSV-2 and, based on these data, hypothesizes that simultaneous prevention of sexual acquisition of HSV-2 and HIV-1 via topical antiretroviral agents will have a synergistic impact on both epidemics.