Daily Acyclovir Delays HIV-1 Disease Progression Among HIV-1/ HSV-2 Dually-Infected Persons: A Randomized Trial

Abstract

Background—Well-tolerated medications that slow HIV-1 disease progression and delay initiation of antiretroviral therapy (ART) are needed. Most HIV-1-infected persons are dually-infected with herpes simplex virus type 2 (HSV-2). Daily HSV-2 suppression reduces plasma HIV-1 levels, but whether HSV-2 suppression delays HIV-1 disease progression is unknown. Methods—Within a randomized, placebo-controlled trial of HSV-2 suppressive therapy (acyclovir 400 mg orally bid) to decrease HIV-1 transmission, 3381 HSV-2/HIV-1 dually-infected heterosexual Africans who at enrollment had CD4 counts ≥250 cells/mm3 and were not taking ART were followed for up to 24 months. We evaluated the effect of acyclovir on HIV-1 disease progression, defined by a primary composite endpoint of first occurrence of CD4 count <200 cells/mm3, ART initiation, or non-trauma related death. As an exploratory analysis, we evaluated the endpoint of CD4 decline to <350 cells/mm3. Findings—At enrollment, median CD4 was 462 cells/mm3 and median HIV-1 plasma RNA was 4.1 log10 copies/mL. Acyclovir reduced risk of HIV-1 disease progression: 284 participants on acyclovir versus 324 on placebo reached the primary endpoint (hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.71–0.98, p=0.03). Among participants with CD4 counts ≥350 cells/ mm3, acyclovir delayed risk of CD4 decline to <350 cells/mm3 (HR 0.81, 95% CI 0.71–0.93, p=0.002). Interpretation—HSV-2 suppression with acyclovir reduced the risk of HIV-1 disease progression by 16% (95% CI 2–29%). The role of HSV-2 suppression in reducing HIV-1 disease progression prior to ART initiation warrants consideration (ClinicalTrials.gov #NCT00194519