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High-Dose Valacyclovir Decreases Plasma HIV-1 RNA More Than Standard-Dose Acyclovir in Persons Coinfected with HIV-1 and HSV-2: A Randomized Crossover Trial

Perti, Tara MD*; Saracino, Misty PhD, MPH; Baeten, Jared M. MD, PhD*,‡,§; Johnston, Christine MD, MPH*,‖; Diem, Kurt BS; Ocbamichael, Negusse PA-C; Huang, Meei-Li PhD†,‖; Selke, Stacy MS; Magaret, Amalia PhD†,‖; Corey, Lawrence MD‖,*,†; Wald, Anna MD, MPH*,†,§,‖

JAIDS Journal of Acquired Immune Deficiency Syndromes: June 1st, 2013 - Volume 63 - Issue 2 - p 201–208
doi: 10.1097/QAI.0b013e3182928eea
Clinical Science

Background: Standard doses of herpes simplex virus (HSV) suppressive therapy reduce plasma HIV-1 RNA levels (0.25–0.53 log10 copies per milliliter) among HIV-1/HSV-2 coinfected persons. Postulated mechanisms for this effect include direct inhibition of HIV-1 by acyclovir or indirect reduction by decreasing HSV-associated inflammation. We hypothesized that high-dose valacyclovir would further reduce plasma HIV-1 RNA and that the effect would be mediated by greater suppression of HSV shedding.

Methods: Thirty-four participants with HIV-1 and HSV-2 not on antiretroviral therapy were enrolled into a randomized, open-label crossover trial of valacyclovir 1000 mg twice daily or acyclovir 400 mg twice daily for 12 weeks, followed by a 2-week washout, and then the alternate treatment arm for 12 weeks. HSV DNA was measured from daily self-collected genital swabs for the initial 4 weeks of each arm, and HIV-1 RNA was quantified from weekly plasma samples.

Results: Twenty-eight participants provided plasma samples and genital swabs on both acyclovir and valacyclovir. The genital HSV-2 shedding rate was the same on valacyclovir and acyclovir [7.8% vs. 8.2% of days; relative risk: 0.95; 95% confidence interval (CI): 0.66 to 1.37; P = 0.78]. Plasma HIV-1 RNA was 0.27 log10 copies per milliliter lower on valacyclovir compared with acyclovir (95% CI: −0.41 to −0.14 log10 copies per milliliter; P < 0.001); this was unchanged after adjustment for genital HSV-2 shedding.

Conclusions: High-dose valacyclovir reduces plasma HIV-1 RNA levels more than standard-dose acyclovir in HIV-1/HSV-2–seropositive persons not receiving antiretroviral therapy. The incremental reduction in plasma HIV-1 RNA achieved is not mediated by greater genital HSV-2 suppression.

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Departments of *Medicine,

Laboratory Medicine,

Global Health, and

§Epidemiology, University of Washington, Seattle, WA; and

Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA.

Correspondence to: Tara Perti, MD, Department of Medicine, University of Washington, Virology Research Clinic, Harborview Medical Center, 325 9th Avenue, Box 359928, Seattle, WA 98104 (e-mail:

Supported by a grant to the University of Washington from GlaxoSmithKline. Additional support was provided by the following grants from the National Institutes of Health: P01 AI30731 (A. Wald, L. Corey), K24 AI071113 (A. Wald), and T32 AI07140 (T. Perti).

Presented in part at the 19th Meeting of the International Society for Sexually Transmitted Diseases Research (ISSTDR), July 2011, Quebec City, Canada.

C. J. is a research investigator for AiCuris GmbH. A. M. is a consultant for Immune Design Corp. L. C. is a consultant for AiCuris GmbH, is the head of the scientific advisory board for and holds stock (<1% of company) in Immune Design Corp, and is listed as a co-inventor in several patents describing antigens and epitopes to which T-cell responses to HSV-2 are directed. A. W. is a consultant for AiCuris GmbH and has received research funding from GSK, Agenus, Gilead Sciences, and Genocea Biosciences. The other authors have no conflicts of interest to disclose.

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Received December 13, 2012

Accepted March 05, 2013

© 2013 by Lippincott Williams & Wilkins