Background:   Across multiple epidemiologic studies, herpes simplex virus-2 (HSV-2) infection increases HIV susceptibility 2- to 3-fold, after controlling for sexual behavior. We conducted a proof-of-concept, randomized, placebo-controlled trial (HPTN 039) to assess whether HSV-2 suppression with twice-daily ART reduces the risk of HIV acquisition among women in Africa and men who have sex with men (MSM) in the Americas. 

Methods:  We enrolled MSM from the United States and Peru and heterosexual women from Africa. At entry, participants were HIV^– and HSV-2⁺, and reported high-risk sexual behavior. Participants were randomized to oral acyclovir, 400 mg twice daily, or matching placebo, had monthly visits for 12 to 18 months for study drug dispensation and adherence and risk reduction counseling, with quarterly HIV testing.

Results:  We enrolled 3251 participants:  1871 MSM from 3 US and 3 Peruvian sites, and 1380 women from sites in Zimbabwe, Zambia, and South Africa. At entry, clinically recognized genital herpes in 3 months prior to entry were reported by 12% of MSM and 26% of women. Median number of partners in the past 12 months was 10 among MSM and 1 among women; 60% of participants reported a partner of unknown HIV status. Adherence to study drug by self-report and pill count was excellent with 94.3% of dispensed drug taken and <5% having missed 6 or more doses in a row. HIV incidence was 3.9/100 person-years in the acyclovir arm (75 events) and 3.3/100 person-years in the placebo arm (64 events), HR = 1.16 (95%CI 0.83 to 1.62). There were no significant differences by gender (HR = 0.9 for men and HR = 1.5 for women), reported adherence to the drug (HR = 1.6 for <90% adherence, HR = 1.0 for those with ≥90% adherence), or history of genital ulcer disease (GUD) at study entry (HR = 1.4 for those with GUD and HR= 1.1 for those without GUD at entry). Genital ulcers based on self-report and exam findings were reduced by 35% in the acyclovir arm. No serious adverse events due to study drug were observed. Retention was 88% at 18 months. 

Conclusions:  In HPTN 039, with excellent retention and adherence to twice-daily study drug, daily suppressive therapy with standard doses (400 mg twice daily) of acyclovir did not reduce HIV acquisition among HSV-2⁺ women and MSM. However, the incidence of GUD was reduced. Thus, acyclovir (400 mg twice daily) suppresses HSV-2, but does not prevent HIV acquisition. Further research is needed to elucidate the disparity between extensive data on epidemiologic and biologic interactions between HSV-2 and HIV and these trial results.