title: Risk of drug resistance among persons acquiring HIV within a randomized clinical trial of single- or dual-agent preexposure prophylaxis.
abstract: BACKGROUND
  Preexposure prophylaxis (PrEP) with emtricitabine plus tenofovir disoproxil fumarate (FTC/TDF) or TDF alone reduces the risk of human immunodeficiency virus (HIV) acquisition. Understanding the risk of antiretroviral resistance selected by PrEP during breakthrough infections is important because of the risk of treatment failure during subsequent antiretroviral use.
  
  
  METHODS
  Within the largest randomized trial of FTC/TDF versus TDF as PrEP, plasma samples were tested for HIV with resistance mutations associated with FTC (K65R and M184IV) and TDF (K65R and K70E), using 454 sequencing.
  
  
  RESULTS
  Of 121 HIV seroconverters, 25 received FTC/TDF, 38 received TDF, and 58 received placebo. Plasma drug levels in 26 individuals indicated PrEP use during or after HIV acquisition, of which 5 had virus with resistance mutations associated with their PrEP regimen. Among those with PrEP drug detected during infection, resistance was more frequent in the FTC/TDF arm (4 of 7 [57%]), compared with the TDF arm (1 of 19 [5.3%]; P = .01), owing to the FTC-associated mutation M184IV. Of these cases, 3 had unrecognized acute infection at PrEP randomization, and 2 were HIV negative at enrollment.
  
  
  CONCLUSIONS
  These results suggest that resistance selected by PrEP is rare but can occur both with PrEP initiation during acute seronegative HIV infection and in PrEP breakthrough infections and that FTC is associated with a greater frequency of resistance mutations than TDF.
authors.affiliation: Division of Human Biology Department of Global Health.
authors.forename: Dara A
authors.initials: DA
authors.lastname: Lehman
authors.affiliation: Department of Global Health Department of Medicine Department of Epidemiology, University of Washington.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Baeten
authors.affiliation: Division of Public Health Sciences.
authors.forename: Connor O
authors.initials: CO
authors.lastname: McCoy
authors.affiliation: Division of Human Biology.
authors.forename: Julie F
authors.initials: JF
authors.lastname: Weis
authors.affiliation: Division of Human Biology.
authors.forename: Dylan
authors.initials: D
authors.lastname: Peterson
authors.affiliation: Division of Human Biology Department of Global Health.
authors.forename: Gerald
authors.initials: G
authors.lastname: Mbara
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center Department of Global Health.
authors.forename: Deborah
authors.initials: D
authors.lastname: Donnell
authors.affiliation: Department of Global Health.
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Thomas
authors.affiliation: Department of Medicine Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Hendrix
authors.affiliation: Department of Medicine Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Marzinke
authors.affiliation: Seattle Children's Research Institute, Seattle, Washington.
authors.forename: Lisa
authors.initials: L
authors.lastname: Frenkel
authors.affiliation: Department of Global Health.
authors.forename: Patrick
authors.initials: P
authors.lastname: Ndase
authors.affiliation: Department of Global Health Kenyatta National Hospital, University of Nairobi, Kenya.
authors.forename: Nelly R
authors.initials: NR
authors.lastname: Mugo
authors.affiliation: Department of Global Health Department of Medicine Department of Epidemiology, University of Washington.
authors.forename: Connie
authors.initials: C
authors.lastname: Celum
authors.affiliation: Division of Human Biology Division of Public Health Sciences.
authors.forename: Julie
authors.initials: J
authors.lastname: Overbaugh
authors.affiliation: Division of Public Health Sciences.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Matsen
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000627:therapeutic use; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004311:Double-Blind Method; D024882:Drug Resistance, Viral / Q000502:physiology*; D000068679:Emtricitabine; D015658:HIV Infections / Q000188:drug therapy*; D006679:HIV Seropositivity / Q000503:physiopathology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D063065:Organophosphonates / Q000627:therapeutic use; D012306:Risk; D000068698:Tenofovir
chemical_list: D019380:Anti-HIV Agents; D044966:Anti-Retroviral Agents; D063065:Organophosphonates; D003841:Deoxycytidine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine
keywords: HIV; HIV prevention; antiretroviral resistance; pre-exposure prophylaxis