title: Models for predicting effective HIV chemoprevention in women.
abstract: OBJECTIVE
  Model systems that rapidly identify tissue drug concentrations protective of HIV infection could streamline the development of chemoprevention strategies. Tissue models are promising, but limited concentration targets exist, and no systematic comparison to cell models or clinical studies has been performed.
  
  
  METHODS
  We explored the efficacy of maraviroc (MVC) and tenofovir (TFV) for HIV prevention by comparing Emax models from TZM-bl cells to vaginal tissue explants and evaluated their predictive capabilities with a dose-challenge clinical study.
  
  
  METHODS
  HIV-1JR-CSF was used for viral challenge. Drug efficacy was assessed using a luciferase reporter assay in TZM-bl cells and real-time PCR to quantify spliced RNA in a tissue explant model. Cell and tissue concentrations of MVC, TFV, and the active metabolite tenofovir diphosphate were measured by liquid chromatography with tandem mass spectrometry and used to create Emax models of efficacy. Efficacy after a single oral dose of 600 mg MVC and 600 mg tenofovir disoproxil fumarate was predicted from cell and tissue models and confirmed in a clinical study with viral biopsy challenge postdose.
  
  
  RESULTS
  TFV was >10-fold and MVC >1000-fold, more potent in TZM-bl cells compared with vaginal explant tissue. In the dose-challenge study, tissues from 3 of 6 women were protected from HIV infection, which was 49% lower than predicted by TZM-bl data and 36% higher than predicted by tissue explant data.
  
  
  CONCLUSIONS
  Comparative effective concentration data were generated for TFV and MVC in 3 HIV chemoprophylaxis models. These results provide a framework for future early investigations of antiretroviral efficacy in HIV prevention to optimize dosing strategies in clinical investigations.
authors.affiliation: *Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC; †Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC; and ‡Departments of Medicine and §Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC (Melanie R. Nicol is now with the Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN).
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Nicol
authors.forename: Cindi W
authors.initials: CW
authors.lastname: Emerson
authors.forename: Heather M A
authors.initials: HM
authors.lastname: Prince
authors.forename: Julie A E
authors.initials: JA
authors.lastname: Nelson
authors.forename: Yuri
authors.initials: Y
authors.lastname: Fedoriw
authors.forename: Craig
authors.initials: C
authors.lastname: Sykes
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Geller
authors.forename: Kristine B
authors.initials: KB
authors.lastname: Patterson
authors.forename: Myron S
authors.initials: MS
authors.lastname: Cohen
authors.forename: Angela D M
authors.initials: AD
authors.lastname: Kashuba
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D018929:Cell Culture Techniques; D002470:Cell Survival; D018890:Chemoprevention / Q000379:methods*; D002853:Chromatography, Liquid; D003510:Cyclohexanes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D018562:Disease Transmission, Infectious / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015658:HIV Infections / Q000517:prevention & control*; D006801:Humans; D000077592:Maraviroc; D008875:Middle Aged; D009924:Organ Culture Techniques; D063065:Organophosphonates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry; D000068698:Tenofovir; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D014621:Vagina / Q000737:chemistry / Q000821:virology; D019562:Viral Load; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D003510:Cyclohexanes; D063065:Organophosphonates; D014230:Triazoles; D000068698:Tenofovir; D000225:Adenine; D000077592:Maraviroc