title: Pharmacological Measures of Treatment Adherence and Risk of HIV Infection in the VOICE Study.
abstract: BACKGROUND
  None of the 3 regimens tested in the VOICE study showed protection against human immunodeficiency virus (HIV) infection in intent-to-treat analyses. Plasma tenofovir concentrations demonstrated poor adherence to the study product among study subjects. Statistical analyses to explore the causal treatment effect on the prevention of HIV infection among adherent individuals are needed.
  
  
  METHODS
  We developed an analytical strategy to evaluate whether conventional covariate adjustment removes confounding and thereby reveals a prevention effect among adherent individuals. We applied this strategy to the VOICE study, using 2 dichotomized proxy measures of product use: detection of tenofovir in plasma at least once during follow-up and detection of tenofovir in plasma at the 3-month follow-up visit.
  
  
  RESULTS
  After adjustment for a set of baseline predictors of the risk of HIV transmission, the confounding associated with comparison of adherent individuals in the tenofovir gel arm to placebo recipients was nearly eliminated. The relative risk for a prevention effect among those ever having tenofovir detected was 0.53 (P = .038); the relative risk among those having tenofovir detected at 3 months was 0.40 (P = .045).
  
  
  CONCLUSIONS
  A novel regression approach was proposed for causal as-treated analyses in the VOICE study. While intent-to-treat analyses yield null results, this exploratory approach presented evidence suggesting a prevention effect among gel users.
  
  
  BACKGROUND
  NCT00705679.
authors.affiliation: Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center University of Washington, Seattle.
authors.forename: James Y
authors.initials: JY
authors.lastname: Dai
authors.affiliation: School of Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Hendrix
authors.affiliation: University of Washington, Seattle.
authors.forename: Barbra A
authors.initials: BA
authors.lastname: Richardson
authors.affiliation: Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center.
authors.forename: Cliff
authors.initials: C
authors.lastname: Kelly
authors.affiliation: School of Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Mark
authors.initials: M
authors.lastname: Marzinke
authors.affiliation: University of Zimbabwe-University of California, San Francisco, Research Programme, Harare.
authors.forename: Z Mike
authors.initials: ZM
authors.lastname: Chirenje
authors.affiliation: University of Washington, Seattle.
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Marrazzo
authors.affiliation: Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center University of Washington, Seattle.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Brown
mesh_terms: D000282:Administration, Intravaginal; D000284:Administration, Oral; D000287:Administration, Topical; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000068679:Emtricitabine / Q000008:administration & dosage / Q000494:pharmacology*; D005782:Gels; D015658:HIV Infections / Q000517:prevention & control*; D006801:Humans; D065129:Pre-Exposure Prophylaxis; D012044:Regression Analysis; D012307:Risk Factors; D000068698:Tenofovir / Q000008:administration & dosage / Q000494:pharmacology*; D016903:Drug Monitoring
chemical_list: D019380:Anti-HIV Agents; D005782:Gels; D000068698:Tenofovir; D000068679:Emtricitabine
keywords: HIV prevention; causal inference; preexposure prophylaxis; prevention efficacy; product adherence; tenofovir detection