title: A randomized trial to assess anti-HIV activity in female genital tract secretions and soluble mucosal immunity following application of 1% tenofovir gel.
abstract: BACKGROUND
  Preclinical and early phase clinical microbicide studies have not consistently predicted the outcome of efficacy trials. To address this gap, candidate biomarkers of microbicide pharmacodynamics and safety were evaluated in a double-blind, placebo-controlled trial of tenofovir gel, the first microbicide to demonstrate significant protection against HIV acquisition.
  
  
  METHODS
  30 women were randomized to apply a single daily dose of tenofovir or placebo gel for 14 consecutive days. Anti-HIV activity was measured in cervicovaginal lavage (CVL) on Days 0, 3, 7, 14 and 21 by luciferase assay as a surrogate marker of pharmacodynamics. Endogenous activity against E. coli and HSV-2 and concentrations of immune mediators were quantified in CVL as candidate biomarkers of safety. Tenofovir levels were measured in CVL and blood.
  
  
  RESULTS
  A significant increase in anti-HIV activity was detected in CVL from women who applied tenofovir gel compared to their endogenous anti-HIV activity in genital tract secretions on Day 0 and compared to activity in CVL from women in the placebo group. The activity correlated significantly with CVL concentration of tenofovir (r = 0.6, p<0.001) and fit a sigmoid E(max) pharmacodynamic model. Anti-HIV activity in CVL from women who applied tenofovir persisted when virus was introduced in semen, whereas endogenous anti-HIV activity decreased. Tenofovir did not trigger an inflammatory response or induce sustained loss in endogenous antimicrobial activity or immune mediators.
  
  
  CONCLUSIONS
  Tenofovir gel had no deleterious impact on soluble mucosal immunity. The increased anti-HIV activity in CVL, which persisted in the presence of semen and correlated with tenofovir concentration, is consistent with the efficacy observed in a recent clinical trial. These results promote quantified CVL anti-HIV activity as a surrogate of tissue pharmacodynamics and as a potential biomarker of adherence to product. This simple, feasible and inexpensive bioassay may promote the development of models more predictive of microbicide efficacy.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00594373.
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, New York, New York, United States of America. marla.keller@einstein.yu.edu
authors.forename: Marla J
authors.initials: MJ
authors.lastname: Keller
authors.forename: Rebecca P
authors.initials: RP
authors.lastname: Madan
authors.forename: N Merna
authors.initials: NM
authors.lastname: Torres
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Fazzari
authors.forename: Sylvia
authors.initials: S
authors.lastname: Cho
authors.forename: Sabah
authors.initials: S
authors.lastname: Kalyoussef
authors.forename: Gail
authors.initials: G
authors.lastname: Shust
authors.forename: Pedro M M
authors.initials: PM
authors.lastname: Mesquita
authors.forename: Nicolette
authors.initials: N
authors.lastname: Louissaint
authors.forename: Jianmeng
authors.initials: J
authors.lastname: Chen
authors.forename: Hillel W
authors.initials: HW
authors.lastname: Cohen
authors.forename: Erin C
authors.initials: EC
authors.lastname: Diament
authors.forename: Anna C
authors.initials: AC
authors.lastname: Lee
authors.forename: Lydia
authors.initials: L
authors.lastname: Soto-Torres
authors.forename: Craig W
authors.initials: CW
authors.lastname: Hendrix
authors.forename: Betsy C
authors.initials: BC
authors.lastname: Herold
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology; D015415:Biomarkers / Q000032:analysis; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005836:Genitalia, Female / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D018928:Immunity, Mucosal / Q000187:drug effects*; D009092:Mucous Membrane / Q000187:drug effects / Q000276:immunology*; D063065:Organophosphonates / Q000008:administration & dosage* / Q000276:immunology / Q000494:pharmacology; D012661:Semen; D000068698:Tenofovir; D044364:Vaginal Douching; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D015415:Biomarkers; D063065:Organophosphonates; D000068698:Tenofovir; D000225:Adenine