title: Dose response for starting and stopping HIV preexposure prophylaxis for men who have sex with men.
abstract: BACKGROUND
  This study estimated the number of daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) doses required to achieve and maintain (after discontinuation) intracellular drug concentrations that protect against human immunodeficiency virus (HIV) infection for men who have sex with men (MSM).
  
  
  METHODS
  Tenofovir diphosphate (TFV-DP) concentrations in peripheral blood mononuclear cells (PBMCs) and rectal mononuclear cells from an intensive pharmacokinetic study ("Cell-PrEP" [preexposure prophylaxis]) of 30 days of daily TDF/FTC followed by 30 days off drug were evaluated. A regression formula for HIV risk reduction derived from PBMCs collected in the preexposure prophylaxis initiative study was used to calculate inferred risk reduction. The time required to reach steady state for TFV-DP in rectal mononuclear cells was also determined.
  
  
  RESULTS
  Twenty-one HIV-uninfected adults participated in Cell-PrEP. The inferred HIV risk reduction, based on PBMC TFV-DP concentration, reached 99% (95% confidence interval [CI], 69%-100%) after 5 daily doses, and remained >90% for 7 days after stopping drug from steady-state conditions. The proportion of participants reaching the 90% effective concentration (EC90) was 77% after 5 doses and 89% after 7 doses. The percentage of steady state for natural log [TFV-DP] in rectal mononuclear cells was 88% (95% CI, 66%-94%) after 5 doses and 94% (95% CI, 78%-98%) after 7 doses.
  
  
  CONCLUSIONS
  High PrEP activity for MSM was achieved by approximately 1 week of daily dosing. Although effective intracellular drug concentrations persist for several days after stopping PrEP, a reasonable recommendation is to continue PrEP dosing for 4 weeks after the last potential HIV exposure, similar to recommendations for postexposure prophylaxis.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora.
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Seifert
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco.
authors.forename: David V
authors.initials: DV
authors.lastname: Glidden
authors.affiliation: Beacon Center for Infectious Disease, Boulder Community Hospital.
authors.forename: Amie L
authors.initials: AL
authors.lastname: Meditz
authors.affiliation: School of Medicine, Division of Infectious Diseases, University of Colorado Denver, Aurora.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Castillo-Mancilla
authors.affiliation: School of Medicine, Division of Infectious Diseases, University of Colorado Denver, Aurora Denver Public Health, Colorado.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Gardner
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Predhomme
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Rower
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora.
authors.forename: Brandon
authors.initials: B
authors.lastname: Klein
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora.
authors.forename: Becky J
authors.initials: BJ
authors.lastname: Kerr
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora.
authors.forename: L Anthony
authors.initials: LA
authors.lastname: Guida
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora.
authors.forename: Jia-Hua
authors.initials: JH
authors.lastname: Zheng
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora.
authors.forename: Lane R
authors.initials: LR
authors.lastname: Bushman
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Anderson
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001774:Blood Chemical Analysis; D018562:Disease Transmission, Infectious / Q000517:prevention & control*; D000068679:Emtricitabine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015658:HIV Infections / Q000517:prevention & control*; D018451:Homosexuality, Male; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000737:chemistry; D008297:Male; D008875:Middle Aged; D065129:Pre-Exposure Prophylaxis / Q000379:methods*; D011446:Prospective Studies; D012007:Rectum / Q000737:chemistry; D000068698:Tenofovir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013997:Time Factors; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D000068698:Tenofovir; D000068679:Emtricitabine
keywords: HIV; MSM; pharmacokinetics; preexposure prophylaxis; tenofovir