Herpes Simplex Virus (HSV) Suppression with Valacyclovir Reduces Rectal and Blood Plasma HIV-1 Levels in HIV-1/HSV-2-Seropositive Men: A Randomized, Double-Blind, Placebo-Controlled Crossover Trial

Richard A. Zuckerman 0 1 Aldo Lucchetti 0 2 William L. H. Whittington 0 Jorge Snchez 0 2 Robert W. Coombs 0 Rosario Zuiga 0 2 Amalia S. Magaret 0 Anna Wald 0 3 4 Lawrence Corey 0 3 Connie Celum () 0 4 0 Received 2 April 2007; accepted 27 April 2007; electronically published 31 October 2007. Potential conflicts of interest: C.C. has received research grant support from the National Institutes of Health (NIH), the Bill and Melinda Gates Foundation , and GlaxoSmithKline (GSK) and has served on an advisory board for GSK. J.S. has received grant support from the NIH and GSK. A.W. has received grant support from the NIH, GSK, Antigenics, 3M, Roche, and Vical; she is a consultant for Novartis, PowderMed, and MediGene and is a speaker for Merck Vaccines. The University of Washington Virology Division Laboratories have received grant funding from GSK and Novartis to perform herpes simplex virus serologic assays and polymerase chain reaction assays for studies funded by these companies. L.C. directs these laboratories. He receives no salary support from these grants. The Journal of Infectious Diseases 2007; 196:1500 - 8 2007 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2007/19610-0013$15.00 DOI: 10.1086/522523 1 Section of Infectious Disease and International Health, Dartmouth-Hitchcock Medical Center , Lebanon, New Hampshire ; Departments of 2 Asociacin Civil Impacta Salud y Educacin, Lima, Peru 3 Program in Infectious Diseases, Fred Hutchinson Cancer Research Center , Seattle 4 Epidemiology, University of Washington Background. Herpes simplex virus type 2 (HSV-2) infection is common among human immunodeficiency virus (HIV)-infected persons, and HSV reactivation increases plasma and genital HIV-1 levels. We studied HIV-1 levels during HSV suppression in coinfected persons in a placebo-controlled crossover trial. Methods. Twenty antiretroviral therapy (ART)-naive HIV-1/HSV-2-seropositive men who have sex with men in Lima, Peru, with CD4 cell counts 200 cells/ L were randomized to receive either valacyclovir at 500 mg twice daily or placebo for 8 weeks, after which they underwent a 2-week washout period and then received the alternative regimen for 8 weeks. Specimens included daily anogenital swabs (for HSV DNA polymerase chain reaction [PCR]), thrice weekly rectal mucosal secretions (for HIV-1 RNA and HSV DNA PCR) obtained by anoscopy, and weekly plasma (for HIV-1 RNA PCR). Outcomes were rectal and plasma HIV-1 RNA levels by treatment arm. Results. HIV-1 was detected in 73% of 844 rectal and 99% of 288 plasma specimens. HSV was detected in 29% and 4% of mucocutaneous specimens obtained during placebo and valacyclovir administration, respectively (P .001). Valacyclovir resulted in a 0.16 (95% confidence interval [CI], 0.07- 0.25; P .0008; 33% decrease) log10 copies/mL lower mean within-subject rectal HIV-1 level and a 0.33 (95% CI, 0.23- 0.42; P .0001; 53% decrease) log10 copies/mL lower plasma HIV-1 level, compared with values for placebo. Conclusions. Valacyclovir significantly reduces rectal and plasma HIV-1 levels in HIV-1/HSV-2- coinfected men. HSV suppression may provide clinical benefits to persons not receiving highly active ART as well as public health benefits. Trial registration. ClinicalTrials.gov identifier: NCT00378976. - Most HIV-infected persons are also infected with herpes simplex virus type 2 (HSV-2) [1]. The risk of HIV-1 transmission is higher in HIV-1 serodiscordant couples when the source partner has reported recent genital ulcers [2]. Plasma and genital HIV-1 levels are increased during both symptomatic and asymptomatic HSV reactivations [3 6]. In vitro studies have demonstrated that HSV proteins increase HIV-1 expression [79], HSV coinfection of HIV-infected cells [10], and levels of proinflammatory cytokines during HSV reactivation, which increase HIV-1 replication [11]. These observations support the hypothesis that, by increasing HIV-1 replication, HSV may have clinical consequences for coinfected persons as well as public health consequences. Proof-of-concept studies among HIV/HSV-coinfected persons are needed to assess whether HSV suppression consistently decreases HIV-1 levels in plasma and genital secretions. Daily suppressive therapy for HSV infection is highly effective in reducing both clinical and subclinical HSV reactivation in HIVinfected persons [12, 13]. A randomized trial in Burkina Faso recently showed that suppressive valacyclovir significantly reduced cervical and plasma HIV-1 levels [14]. This observation is consistent with a pooled analysis of 8 studies conducted in the 1990s of high-dose acyclovir in combination with mono- or dual-nucleoside antiretroviral therapy (ART), which indicated a survival benefit among HIV-infected persons who received acyclovir [15]. To evaluate the effect of HSV-2 suppression on anogenital and plasma HIV-1 levels among men, we conducted a randomized, double-blind, placebo-controlled crossover trial of daily valacyclovir among ART-naive HIV-1/HSV-2 coinfected men who have sex with men (MSM) with CD4 cell counts 200 cells/ L in Lima, Peru. Study Characteristics Study design. A randomized, double-blind, placebo-controlled crossover trial of valacyclovir for HSV and HIV-1 suppression was conducted at the Asociacin Civil Impacta Salud y Educacin, a research organization in Lima. Eligible persons were MSM who were 18 years old, were seropositive for HIV-1 and HSV-2, had no history of antiretroviral use, and had a CD4 cell count 200 cells/ L. Exclusion criteria included current or planned therapy with antiretrovirals or herpes antivirals (acyclovir, famciclovir, or valacyclovir), a history of adverse reactions to herpes antivirals, a history of seizures, a serum creatinine level 2.0 mg/dL, and hematocrit 30%. The human experimentation guidelines of the US Department of Health and Human Services and the individual institutions were followed in the conduct of the clinical research. The institutional review boards of the University of Washington and the Asociacin Civil Impacta Salud y Educacin approved the protocol. Participants provided written informed consent and were compensated for travel and related expenses. Men with sexually transmitted infection (STI) syndromes at screening were treated with regimens recommended by the Peruvian Ministry of Health. At the time of the study, antiretrovirals were available in Peru in public clinics only for HIV-infected persons with CD4 cell counts 200 cells/ L or with an AIDS-related condition. Study medication. Valacyclovir (500 mg orally twice daily) and matching placebo were supplied by GlaxoSmithKline. Subjects were randomly assigned 1:1 (valacyclovir to placebo) in blocks of 10. After 8 weeks of the initial treatment, each participant crossed over to the alternative treatment for 8 weeks, separated by a 2-week washout period with daily placebo. Medication was dispensed every 2 weeks, with pill counts performed at each visit. Op (...truncated)