title: Tenofovir diphosphate concentrations and prophylactic effect in a macaque model of rectal simian HIV transmission.
abstract: OBJECTIVE
  This study evaluated the relationship between intracellular tenofovir diphosphate concentrations in peripheral blood mononuclear cells and prophylactic efficacy in a macaque model for HIV pre-exposure prophylaxis (PrEP).
  
  
  METHODS
  Macaques were challenged with simian HIV (SHIV) via rectal inoculation once weekly for up to 14 weeks. A control group (n=34) received no drug, a second group (n=6) received oral tenofovir disoproxil fumarate/emtricitabine 3 days before each virus challenge and a third group (n=6) received the same dosing plus another dose 2 h after virus challenge. PBMCs were collected just before each weekly virus challenge. The relationship between tenofovir diphosphate in PBMCs and prophylactic efficacy was assessed with a Cox proportional hazards model.
  
  
  RESULTS
  The percentages of animals infected in the control, one-dose and two-dose groups were 97, 83 and 17, respectively. The mean (SD) steady-state tenofovir diphosphate concentration (fmol/10(6) cells) was 15.8 (7.6) in the one-dose group and 30.7 (10.1) in the two-dose group. Each 5 fmol tenofovir diphosphate/10(6) cells was associated with a 40% (95% CI 17%-56%) reduction in risk of SHIV acquisition, P=0.002. The tenofovir diphosphate concentration associated with a 90% reduction in risk (EC90) was 22.6 fmol/10(6) cells (95% CI 13.8-60.8).
  
  
  CONCLUSIONS
  The prophylactic EC90 for tenofovir diphosphate identified in macaques exposed rectally compares well with the EC90 previously identified in men who have sex with men (MSM; 16 fmol/10(6) cells, 95% CI 3-28). These results highlight the relevance of this model to inform human PrEP studies of oral tenofovir disoproxil fumarate/emtricitabine for MSM.
authors.affiliation: The Department of Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd, Aurora, CO 80045, USA peter.anderson@ucdenver.edu.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Anderson
authors.affiliation: The Department of Epidemiology and Biostatistics, University of California San Francisco, 185 Berry St W., San Francisco, CA 94143, USA.
authors.forename: David V
authors.initials: DV
authors.lastname: Glidden
authors.affiliation: The Department of Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd, Aurora, CO 80045, USA.
authors.forename: Lane R
authors.initials: LR
authors.lastname: Bushman
authors.affiliation: The Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control, 1600 Clifton Rd, Atlanta, GA 30329, USA.
authors.forename: Walid
authors.initials: W
authors.lastname: Heneine
authors.affiliation: The Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control, 1600 Clifton Rd, Atlanta, GA 30329, USA.
authors.forename: J Gerardo
authors.initials: JG
authors.lastname: García-Lerma
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000032:analysis / Q000627:therapeutic use; D000818:Animals; D019380:Anti-HIV Agents / Q000032:analysis / Q000627:therapeutic use*; D004195:Disease Models, Animal; D018562:Disease Transmission, Infectious / Q000517:prevention & control*; D015658:HIV Infections / Q000517:prevention & control* / Q000635:transmission*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000737:chemistry*; D008251:Macaca; D008297:Male; D010755:Organophosphates / Q000032:analysis / Q000627:therapeutic use*; D065129:Pre-Exposure Prophylaxis / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D019380:Anti-HIV Agents; D010755:Organophosphates; C583447:tenofovir diphosphate; D000225:Adenine
keywords: HIV pre-exposure prophylaxis; intracellular pharmacology; non-human primate model; nucleoside analogues; pharmacodynamics