Effect of daily aciclovir on HIV disease progression in individuals in Rakai, Uganda, co-infected with HIV-1 and herpes simplex virus type 2: a randomised, double-blind placebo-controlled trial

Abstract

Background Daily suppression of herpes simplex virus type 2 (HSV-2) reduces plasma HIV-1 concentrations and has been shown to delay HIV-1 disease progression modestly in one clinical trial. We investigated the impact of daily suppressive acyclovir on HIV-1 disease progression in Rakai, Uganda Methods In a single site trial, 440 HIV-1, HSV-2 dually infected consenting adults with CD4+ T-cell counts 300-400 cells/μL and not on antiretroviral therapy were randomized 1:1 to receive either acyclovir 400 mg orally twice daily or placebo; participants were followed for 24 months. The primary outcome was CD4 <250 or ART initiation for WHO stage IV disease. Intent-to-treat analysis used Cox proportional hazards (CPH) models, adjusting for baseline log10 viral load (VL), CD4 cell count, gender and age to assess the risk of disease progression. The impact of suppressive HSV-2 treatment by baseline VL was also investigated in a CPH model. This trial is registered with clinicaltrials.gov, number NCT00405821. Findings Overall, 110 participants in the placebo arm and 95 participants in the treatment arm reached the primary endpoint (Adj HR 0.75, 95% CI 0.58-0.99; p=0.040). In a sub-analysis stratified by baseline VL quintile, participants with a baseline VL >= 50,000 copies/ml experienced a 38% reduction in HIV disease progression in the treatment compared to placebo arm (Adj HR 0.62, 95% CI 0.43-0.96;p=0.03). Interpretation Acyclovir reduced the rate of disease progression by 25%, with the greatest impact occurring among individuals with high baseline VL. Suppressive acyclovir may be warranted among HSV-2/HIV-1 dually infected individuals with viral loads >= 50,000 copies/ml prior to antiretroviral treatment.

Impact of Asymptomatic Herpes Simplex Virus Type 2 Infection on Mucosal Homing and Immune Cell Subsets in the Blood and Female Genital Tract

“…In addition to DC-SIGN, several DC receptors may be capable of enhancing HIV transmission via a similar "Trojan horse" mechanism (16,17), including langerin (CD207) (18,19) and mannose receptor (MR/CD206) (20,21). Furthermore, the association of HSV-2 infection with increased HIV disease progression in HIV-infected individuals (22,23) suggests that this coinfection may also alter systemic immunology.…”

Prevalencia de herpes labial recurrente en población de 18 a 30 años de edad en Bogotá, Colombia / Prevalence of Recurrent Herpes Labialis in Population of 18-30 Years of Age in Bogota, Colombia

“…Adicionalmente, se considera que la infección por VHS, ya sea de tipo 1 o 2, es un factor para controlar en pacientes VIH positivos, ya que puede contribuir al aumento de los conteos de cargas virales y empeorar el curso de la inmunosupresión (21 La fiebre y el estrés siguen siendo los desencadenantes más frecuentemente asociados a los episodios de recurrencia. El estrés es una reacción inespecífica y su relación con las enfermedades infecciosas y la respuesta inmune ha sido ampliamente estudiada.…”

Decreased monocyte activation with daily acyclovir use in HIV-1/HSV-2 coinfected women

“…The recruitment, randomisation and detailed trial design were previously published 3. Briefly, HIV-1/HSV-2 coinfected individuals from the Rakai Health Sciences Program, Uganda, with a CD4+ cell count from 300–400 cells/µL were enrolled in a double-blind, individually randomised placebo-controlled trial of HSV-2 suppression to assess HIV disease progression.…”

“…Acyclovir treatment, which effectively blocks HSV replication, was shown to also significantly reduce HIV VL, as well as decrease the rate of disease progression in two separate randomised controlled trials 3–5. This effect was most prominent in individuals with high HIV VLs 3. It is unclear if the protective effect of acyclovir use in HIV disease progression is due to its direct effect of decreasing HIV replication or a secondary effect caused by decreased immune activation associated with less herpetic reactivation 6–9…”