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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Clinical trials registration: NCT01448616.

Keywords: HIV acquisition; HSV-2 transmission; genital herpes; herpes simplex virus-2 (HSV-2); tenofovir; vaginal microbicide.

© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Flow of subjects through the study. aAll enrolled participants performed twice-daily genital swabbing and kept daily diaries for 28 days during the lead-in phase. Only participants completing ≥90% of swabs during the lead-in phase were randomly assigned at a ratio of 2:2:1 to a treatment arm. bPer protocol is defined as use of study drug for a minimum of 33 days and ≥90% adherence to the regimen, as determined by returned pill or applicator counts. Abbreviations: AE, adverse event; HBsAg, hepatitis B virus surface antigen; HIV, human immunodeficiency virus; HSV-1/2, herpes simplex virus 1/2; LTFU, lost to follow-up; TDF, tenofovir disoproxil fumarate; TFV, tenofovir.