HSV suppression reduces seminal HIV-1 levels in HIV-1/HSV-2 co-infected men who have sex with men

Abstract

Objectives: Suppressive herpes simplex virus (HSV) therapy can decrease plasma, cervical, and rectal HIV-1 levels in HIV-1/HSV-2 co-infected persons. We evaluated the effect of HSV-2 suppression on seminal HIV-1 levels.

Design: Twenty antiretroviral therapy (ART)-naive HIV-1/HSV-2 men who have sex with men (MSM) in Lima, Peru, with CD4 >200 cells/microl randomly received valacyclovir 500 mg twice daily or placebo for 8 weeks, then the alternative regimen for 8 weeks after a 2-week washout. Peripheral blood and semen specimens were collected weekly. Anogenital swab specimens for HSV DNA were self-collected daily and during clinic visits.

Methods: HIV-1 RNA was quantified in seminal and blood plasma by TaqMan real-time polymerase chain reaction (RT-PCR) or Roche Amplicor Monitor assays. HSV and seminal cytomegalovirus (CMV) were quantified by RT-PCR. Linear mixed models examined differences within participants by treatment arm.

Results: Median CD4 cell count of participants was 424 cells/microl. HIV-1 was detected in 71% of 231 semen specimens. HSV was detected from 29 and 4.4% of swabs on placebo and valacyclovir, respectively (P < 0.001). Valacyclovir significantly reduced the proportion of days with detectable seminal HIV-1 (63% during valacyclovir vs. 78% during placebo; P = 0.04). Seminal HIV-1 quantity was 0.25 log10 copies/ml lower [95% confidence interval (CI) -0.40 to -0.10; P = 0.001] during the valacyclovir arm compared with placebo, a 44% reduction. CD4 cell count (P = 0.32) and seminal cellular CMV quantity (P = 0.68) did not predict seminal plasma HIV-1 level.

Conclusions: Suppressive valacyclovir reduced seminal HIV-1 levels in HIV-1/HSV-2 co-infected MSM not receiving ART. The significance of this finding will be evaluated in a trial with HIV-1 transmission as the outcome.

Trial registration: ClinicalTrials.gov NCT00378976.

Conflict of interest statement

Potential Conflict of Interest Disclosure: Dr. Celum has received research grant support from GlaxoSmithKline and has served on an advisory board for GlaxoSmithKline. Dr. Jorge Sanchez has received grant support from GlaxoSmithKline. Dr. Wald has received grant support from National Institutes of Health, GlaxoSmithKline, Antigenics, and Astellas. She has been a consultant for Novartis, Powdermed, and Medigene and a speaker for Merck Vaccines. The University of Washington Virology Division Laboratories have received grant funding from GlaxoSmithKline and Novartis to perform HSV serologic assays and PCR assays for studies funded by these companies. Dr. Corey directs these laboratories. He receives no salary support from these grants.

Figures

Figure 1

Graph showing the percent of semen samples in each treatment arm stratified by seminal HIV RNA level in a randomized, double-blind placebo-controlled crossover trial in 19 men. Valacyclovir treatment is associated with lower detection rate and lower seminal HIV-1 levels. Each bar represents the percent of samples in each treatment arm stratified by seminal HIV-1 level (placebo, N=113 samples.; and valacyclovir, N=117samples). Undetectable HIV-1 levels were set halfway between zero and the lower limit of detection (LLOD), hence some values are below the LLOD for our assays.