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

Abstract

Background: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

Keywords: HIV-1; Herpes simplex virus; genital herpes; preexposure prophylaxis; tenofovir.

Figure 1.

Enrollment and flow of women through the study. The most common reason for exclusion from the parent study was prevalent human immunodeficiency virus type 1 (HIV-1) infection (32% of excluded women [2308 of 7291]). Failure to complete screening and enrollment in the required 56-day window resulted in exclusion of 21% of excluded women, and abnormal laboratory results resulted in exclusion of 16%. Conditions related to reproductive outcomes resulted in the exclusion of 9%: 5.9% were pregnant at screening, with the remainder currently breast-feeding or intending to become pregnant in the next 2 years. Twenty-two participants had HIV-1 RNA detected by polymerase chain reaction assay in the enrollment plasma specimen and were excluded on the basis of acute HIV-1 infection. The 566 women assigned to the tenofovir (TFV) gel arm composed the population for this analysis. Of these, 532 had both end-of-study HSV-2 enzyme immunoassay (EIA) results and plasma TFV levels available to determine the primary end point (HSV-2 seroconversion defined by this assay, as related to detection of plasma TFV). Of these 532, 441 fulfilled criteria for inclusion in the secondary end point analysis, namely, HSV-2 seroconversion detected by HSV-2–specific Western blot (WB).