Daily Acyclovir to Decrease Herpes Simplex Virus Type 2 (HSV-2) Transmission from HSV-2/HIV-1 Coinfected Persons: A Randomized Controlled Trial

Andrew Mujugira () 0 6 Amalia S. Magaret 0 4 5 Connie Celum 0 6 10 11 Jared M. Baeten 0 6 10 11 Jairam R. Lingappa 0 6 9 11 Rhoda Ashley Morrow 0 5 Kenneth H. Fife 0 8 Sinead Delany-Moretlwe 0 12 Guy de Bruyn 0 13 Elizabeth A. Bukusi 0 6 7 Etienne Karita 0 2 Saidi Kapiga 0 3 Lawrence Corey 0 4 5 11 Anna Wald 0 4 5 10 11 for the Partners in Prevention HSV/HIV Transmission Study Team 0 1 0 Received 22 January 2013; accepted 8 April 2013; electronically published 30 July 2013 1 Study team members are listed at the end of the text. Presented in part at the 19th International Society for Sexually Transmitted Diseases Research Conference , Quebec City , Canada , 10-13 July 2011. Poster P1-S5.25. University of Washington , Box 359927, 325 Ninth Ave, Seattle, WA 98104 2 Rwanda-Zambia HIV Research Group , Kigali , Rwanda 3 London School of Hygiene and Tropical Medicine , United Kingdom 4 Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center 5 Department of Laboratory Medicine 6 Department of Global Health 7 Center for Microbiology Research, Kenya Medical Research Institute , Nairobi 8 Department of Medicine, Indiana University , Indianapolis 9 Department of Pediatrics, University of Washington , Seattle, Washington 10 Department of Epidemiology 11 Department of Medicine 12 Wits Reproductive Health and HIV Institute, University of the Witwatersrand , Johannesburg , South Africa 13 Sanofi Pasteur , Swiftwater, Pennsylvania Background. 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. Methods. 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 HIV1-susceptible partners were HSV-2 seronegative to estimate the effect of acyclovir on risk of HSV-2 transmission. Results. 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). Conclusions. 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. - Herpes simplex virus type 2 (HSV-2) is highly prevalent among human immunodeficiency virus type 1 (HIV-1)infected persons in sub-Saharan Africa [14]. Epidemiologic studies suggest synergy between HSV-2 and HIV-1 facilitates the spread of both viruses; HSV-2 reactivation increases HIV-1 concentrations in plasma and genital secretions, increasing the risk of HIV-1 transmission and disease progression, while HIV-1 infection increases HSV-2 shedding and reactivation frequency [58]. Thus, coinfection with HIV-1 likely increases the risk of HSV-2 transmission. Daily therapy with valacyclovir reduces HSV-2 transmission in HSV-2serodiscordant, HIV-1seronegative-concordant healthy, immunocompetent, heterosexual couples by 48%, likely by decreasing the frequency and amount of HSV-2 shed in the genital tract by the HSV-2infected partner [9, 10]. HIV-1infected persons tend to reactivate HSV-2 both more frequently and at higher copy number than their immunocompetent counterparts [7, 8]. It is unknown whether treatment of HSV-2/HIV-1infected persons with acyclovir reduces transmission of HSV-2 to their HSV-2/HIV-1susceptible partner. The Partners in Prevention Trial was a double-blind, randomized, controlled trial among HIV-1serodiscordant couples to determine whether treatment of HSV-2 infection would reduce the transmission of HIV-1. As previously reported, HSV-2 suppression provided to the HIV-1infected partners did not reduce the risk of HIV-1 transmission to their initially HIV-1uninfected partners despite a sustained 0.25 log10 copies/mL reduction in the plasma HIV-1 RNA load, a 73% reduction in genital ulcer disease (GUD) incidence, and a 16%19% decrease in HIV-1 disease progression [3]. We conducted an analysis of the effect of daily acyclovir on the risk of HSV-2 transmission in the subset of participants randomly assigned to receive acyclovir or placebo whose partners who were susceptible to HSV-2 and HIV-1. METHODS Population and Procedures We identified 911 HSV-2 serodiscordant couples from the 3408 heterosexual HIV-1 serodiscordant couples enrolled into the Partners in Prevention HSV/HIV Transmission Study (clinical trials registration: NCT00194519). Couples were enrolled at 14 sites in East Africa (Kenya, Rwanda, Tanzania, and Uganda) and Southern Africa (Botswana, South Africa, and Zambia) from 2004 through 2006. For the present study, we assessed whether HSV-2 suppression provided to the HSV-2infected partner reduced the risk of HSV-2 transmission to the susceptible partner. The clinical trial protocol required HIV-1infected partners to be seropositive for both HSV-2 and HIV-1; a history of GUD was not required. At study entry, HSV-2/HIV-1seropositive partners (henceforth referred to as HSV-2infected individuals) had CD4+ T-cell counts of 250 cells/L and were not receiving antiretroviral therapy (ART) according to national ART guidelines, which, at the time, involved initiation of ART at CD4+ T-cell counts of <200250 cells/L. Those who became pregnant or were eligible for initiation of ART during follow-up were referred to local antenatal and HIV-1 clinics. Open-label acyclovir was offered for recurrent genital herpes [3]. HIV-1susceptible partners enrolled in the clinical trial could be either HSV-2 seropositive or seronegative. Only HSV2/HIV-1seronegative partners (henceforth referred to as HSV-2susceptible individuals) were included in the present analyses (Figure 1). Fixed-block randomization stratified by site was used to randomly assign HSV-2infected partners in a 1:1 ratio to receive acyclovir 400 mg twice daily or matching placebo (Ranbaxy Laboratories, Haryana, India), using a pseudo-random number generator. Only the study statistician and 2 data managers were aware of the treatment assignments. Participants were provided with a monthly resupply of study medication and adherence counseling for 12 (...truncated)