Daily acyclovir for HIV-1 disease progression in people dually infected with HIV-1 and herpes simplex virus type 2: a randomised placebo-controlled trial

Abstract

Background: Most people infected with HIV-1 are dually infected with herpes simplex virus type 2. Daily suppression of this herpes virus reduces plasma HIV-1 concentrations, but whether it delays HIV-1 disease progression is unknown. We investigated the effect of acyclovir on HIV-1 progression.

Methods: In a trial with 14 sites in southern Africa and east Africa, 3381 heterosexual people who were dually infected with herpes simplex virus type 2 and HIV-1 were randomly assigned in a 1:1 ratio to acyclovir 400 mg orally twice daily or placebo, and were followed up for up to 24 months. Eligible participants had CD4 cell counts of 250 cells per mL or higher and were not taking antiretroviral therapy. We used block randomisation, and patients and investigators were masked to treatment allocation. Effect of acyclovir on HIV-1 disease progression was defined by a primary composite endpoint of first occurrence of CD4 cell counts of fewer than 200 cells per microL, antiretroviral therapy initiation, or non-trauma related death. As an exploratory analysis, we assessed the endpoint of CD4 falling to <350 cells per microL. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00194519.

Findings: At enrollment, the median CD4 cell count was 462 cells per microL and median HIV-1 plasma RNA was 4.1 log(10) copies per microL. Acyclovir reduced risk of HIV-1 disease progression by 16%; 284 participants assigned acyclovir versus 324 assigned placebo reached the primary endpoint (hazard ratio [HR] 0.84, 95% CI 0.71-0.98, p=0.03). In those with CD4 counts >or=350 cells per microL, aciclovir delayed risk of CD4 cell counts falling to <350 cells per microL by 19% (0.81, 0.71-0.93, p=0.002)

Interpretation: The role of suppression of herpes simplex virus type 2 in reduction of HIV-1 disease progression before initiation of antiretroviral therapy warrants consideration.

Funding: Bill & Melinda Gates Foundation.

Conflict of interest statement

Potential Conflicts of Interest: CC has received research grant support from GlaxoSmithKline (GSK), which did not include salary support, and has served on an advisory board for GSK. AW has received grant support from Astellas, GSK, and Antigenics; she has been a consultant for Astellas and Aicuris. KF has received research grant funding from Astellas Pharma USA and GSK. RWC is on an advisory board for Merck. RM has served on an advisory board for Abbott Molecular, Biokit USA and Roche Diagnostics. MJM has served on an advisory board for the AIDS Vaccine Research Subcommittee. LC is a consultant for AiCuris and GenPhar. He is the head of the Scientific Advisory Board of Immune Design and receives financial remuneration for this, including equity shares that are <1% ownership. 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; LC directs these laboratories, but receives no salary support from these grants.

Copyright 2010 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Trial Profile *HSV-2 seropositivity at enrollment determined by Focus HerpeSelect-2 EIA at site laboratory; inclusion in primary analysis based on HSV-2 Western blot at University of Washington, as described in the Methods. ** Numerator includes attended visits only. Denominator includes all expected visits and reflects staged site close-out. During follow-up, 3 subjects were dispensed a drug kit for the incorrect randomization arm; follow-up time has been censored at the visit when that occurred.

Figure 2

Cumulative probability of select HIV-1 disease progression endpoints (Kaplan-Meier estimates) by treatment arm. a) Primary composite endpoint, defined as first occurrence of CD4 decline to 3, non-PMTCT ART initiation, or non-trauma death. Hazard ratio 0.83, 95% confidence interval 0.71–0.96, p=0.03. b) First occurrence of CD4 decline to 3 among participants with CD4 counts ≥350 cells/mm3 at study enrollment. Hazard ratio 0.81, 95% confidence interval 0.71–0.93, p=0.002.