title: 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 modestly delayed HIV-1 disease progression in one clinical trial. We investigated the effect of daily suppressive aciclovir on HIV-1 disease progression in Rakai, Uganda.
  
  
  METHODS
  We did a single site, parallel, randomised, controlled trial of HIV-1, HSV-2 dually infected adults with CD4 cell counts of 300-400 cells per μL. We excluded individuals who had an AIDS-defining illness or active genital ulcer disease, and those that were taking antiretroviral therapy. Participants were randomly assigned (1:1) with computer-generated random numbers in blocks of four to receive either aciclovir 400 mg orally twice daily or placebo; participants were followed up for 24 months. All study staff and participants were masked to treatment, except for the two statisticians. The primary outcome was CD4 cell count less than 250 cells per μL or initiation of antiretroviral therapy for WHO stage 4 disease. Our intention-to-treat analysis used Cox proportional hazards models, adjusting for baseline log(10) viral load, CD4 cell count, sex, and age to assess the risk of disease progression. We also investigated the effect of suppressive HSV-2 treatment stratified by baseline HIV viral load with a Cox proportional hazards model. This trial is registered with ClinicalTrials.gov, number NCT00405821.
  
  
  RESULTS
  440 participants were randomly assigned, 220 to each group. 110 participants in the placebo group and 95 participants in the treatment group reached the primary endpoint (adjusted hazard ratio [HR] 0·75, 95% CI 0·58-0·99; p=0·040). 24 participants in the placebo group and 22 in the treatment group were censored, but all contributed data for the final analysis. In a subanalysis stratified by baseline HIV viral load, participants with a baseline viral load of 50,000 copies mL or more in the treatment group had a reduced HIV disease progression compared with those in the placebo group (0·62, 0·43-0·96; p=0·03). No significant difference in HIV disease progression existed between participants in the treatment group and those in the placebo group who had baseline HIV viral loads of less than 50,000 copies per mL (0·90, 0·54-1·5; p=0·688). No safety issues related to aciclovir treatment were identified.
  
  
  CONCLUSIONS
  Aciclovir reduces the rate of disease progression, with the greatest effect in individuals with a high baseline viral load. Suppressive aciclovir might be warranted for individuals dually infected with HSV-2 and HIV-1 with viral loads of 50,000 copies per mL or more before initiation of antiretroviral treatment.
  
  
  BACKGROUND
  National Institute of Allergy and Infectious Diseases, National Cancer Institute (National Institutes of Health, USA).
authors.affiliation: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. sreynol6@jhmi.edu
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Reynolds
authors.forename: Fred
authors.initials: F
authors.lastname: Makumbi
authors.forename: Kevin
authors.initials: K
authors.lastname: Newell
authors.forename: Noah
authors.initials: N
authors.lastname: Kiwanuka
authors.forename: Paschal
authors.initials: P
authors.lastname: Ssebbowa
authors.forename: George
authors.initials: G
authors.lastname: Mondo
authors.forename: Iga
authors.initials: I
authors.lastname: Boaz
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Wawer
authors.forename: Ronald H
authors.initials: RH
authors.lastname: Gray
authors.forename: David
authors.initials: D
authors.lastname: Serwadda
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Quinn
mesh_terms: D000212:Acyclovir / Q000008:administration & dosage / Q000627:therapeutic use*; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D060085:Coinfection; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1; D006561:Herpes Simplex / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D018258:Herpesvirus 2, Human; D006801:Humans; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D014454:Uganda; D019562:Viral Load; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D000212:Acyclovir