title: Predicting HIV Pre-exposure Prophylaxis Efficacy for Women using a Preclinical Pharmacokinetic-Pharmacodynamic In Vivo Model.
abstract: The efficacy of HIV pre-exposure prophylaxis (PrEP) relies on adherence and may also depend on the route of HIV acquisition. Clinical studies of systemic tenofovir disoproxil fumarate (TDF) PrEP revealed reduced efficacy in women compared to men with similar degrees of adherence. To select the most effective PrEP strategies, preclinical studies are critically needed to establish correlations between drug concentrations (pharmacokinetics [PK]) and protective efficacy (pharmacodynamics [PD]). We utilized an in vivo preclinical model to perform a PK-PD analysis of systemic TDF PrEP for vaginal HIV acquisition. TDF PrEP prevented vaginal HIV acquisition in a dose-dependent manner. PK-PD modeling of tenofovir (TFV) in plasma, female reproductive tract tissue, cervicovaginal lavage fluid and its intracellular metabolite (TFV diphosphate) revealed that TDF PrEP efficacy was best described by plasma TFV levels. When administered at 50 mg/kg, TDF achieved plasma TFV concentrations (370 ng/ml) that closely mimicked those observed in humans and demonstrated the same risk reduction (70%) previously attained in women with high adherence. This PK-PD model mimics the human condition and can be applied to other PrEP approaches and routes of HIV acquisition, accelerating clinical implementation of the most efficacious PrEP strategies.
authors.affiliation: Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, 27599, United States of America.
authors.forename: Angela
authors.initials: A
authors.lastname: Wahl
authors.affiliation: Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, 27599, United States of America.
authors.forename: Phong T
authors.initials: PT
authors.lastname: Ho
authors.affiliation: Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, 27599, United States of America.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Denton
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, 27599, United States of America.
authors.forename: Katy L
authors.initials: KL
authors.lastname: Garrett
authors.affiliation: Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, 27599, United States of America.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hudgens
authors.affiliation: Advanced Bioscience Laboratories, Rockville, 20850, United States of America.
authors.forename: Glenn
authors.initials: G
authors.lastname: Swartz
authors.affiliation: Advanced Bioscience Laboratories, Rockville, 20850, United States of America.
authors.forename: Cynthia
authors.initials: C
authors.lastname: O'Neill
authors.affiliation: Prevention Sciences Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20852, United States of America.
authors.forename: Fulvia
authors.initials: F
authors.lastname: Veronese
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, 27599, United States of America.
authors.forename: Angela D
authors.initials: AD
authors.lastname: Kashuba
authors.affiliation: Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, 27599, United States of America.
authors.forename: J Victor
authors.initials: JV
authors.lastname: Garcia
mesh_terms: D000818:Animals; D044966:Anti-Retroviral Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D000068679:Emtricitabine / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D015658:HIV Infections / Q000517:prevention & control* / Q000635:transmission / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity; D006207:Half-Life; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D065129:Pre-Exposure Prophylaxis; D016016:Proportional Hazards Models; D012367:RNA, Viral / Q000097:blood; D000068698:Tenofovir / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D044966:Anti-Retroviral Agents; D012367:RNA, Viral; D000068698:Tenofovir; D000068679:Emtricitabine