title: HIV-1 drug resistance in the iPrEx preexposure prophylaxis trial.
abstract: BACKGROUND
  The iPrEx study demonstrated that combination oral emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) as preexposure prophylaxis (PrEP) protects against HIV acquisition in men who have sex with men and transgender women. Selection for drug resistance could offset PrEP benefits.
  
  
  METHODS
  Phenotypic and genotypic clinical resistance assays characterized major drug resistant mutations. Minor variants with FTC/TDF mutations K65R, K70E, M184V/I were measured using 454 deep sequencing and a novel allele-specific polymerase chain reaction (AS-PCR) diagnostic tolerant to sequence heterogeneity.
  
  
  RESULTS
  Control of primer-binding site heterogeneity resulted in improved accuracy of minor variant measurements by AS-PCR. Of the 48 on-study infections randomized to FTC/TDF, none showed FTC/TDF mutations by clinical assays despite detectable drug levels in 8 participants. Two randomized to FTC/TDF had minor variant M184I detected at 0.53% by AS-PCR or 0.75% by deep sequencing, only 1 of which had low but detectable drug levels. Among those with acute infection at randomization to FTC/TDF, M184V or I mutations that were predominant at seroconversion waned to background levels within 24 weeks after discontinuing drug.
  
  
  CONCLUSIONS
  Drug resistance was rare in iPrEx on-study FTC/TDF-randomized seroconverters, and only as low-frequency minor variants. FTC resistance among those initiating PrEP with acute infection waned rapidly after drug discontinuation. Clinical Trials Registration.NCT00458393.
authors.affiliation: Department of Medicine, University of California AIDS Research Institute, University of California.
authors.forename: Teri
authors.initials: T
authors.lastname: Liegler
authors.affiliation: Department of Medicine, University of California.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abdel-Mohsen
authors.affiliation: J. David Gladstone Institutes.
authors.forename: L Gordon
authors.initials: LG
authors.lastname: Bentley
authors.affiliation: J. David Gladstone Institutes.
authors.forename: Robert
authors.initials: R
authors.lastname: Atchison
authors.affiliation: AIDS Research Institute, University of California.
authors.forename: Timothy
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: AIDS Research Institute, University of California.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Javier
authors.affiliation: J. David Gladstone Institutes.
authors.forename: Megha
authors.initials: M
authors.lastname: Mehrotra
authors.affiliation: J. David Gladstone Institutes.
authors.forename: Christopher
authors.initials: C
authors.lastname: Eden
authors.affiliation: Department of Epidemiology, University of California, San Francisco.
authors.forename: David V
authors.initials: DV
authors.lastname: Glidden
authors.affiliation: J. David Gladstone Institutes.
authors.forename: Vanessa
authors.initials: V
authors.lastname: McMahan
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Anderson
authors.affiliation: Veterans Affairs Medical Center, San Francisco.
authors.forename: Peilin
authors.initials: P
authors.lastname: Li
authors.affiliation: Veterans Affairs Medical Center, San Francisco.
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Wong
authors.affiliation: Bridge HIV, San Francisco Department of Public Health, California.
authors.forename: Susan
authors.initials: S
authors.lastname: Buchbinder
authors.affiliation: Asociación Civil Impacta Salud y Educación, Lima, Peru.
authors.forename: Juan V
authors.initials: JV
authors.lastname: Guanira
authors.affiliation: Department of Medicine, University of California J. David Gladstone Institutes.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Grant
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D000068679:Emtricitabine; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000517:prevention & control* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D018451:Homosexuality, Male; D006801:Humans; D008297:Male; D009154:Mutation; D063065:Organophosphonates / Q000008:administration & dosage / Q000627:therapeutic use; D012367:RNA, Viral / Q000235:genetics; D000068698:Tenofovir; D063106:Transgender Persons; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D063065:Organophosphonates; D012367:RNA, Viral; D003841:Deoxycytidine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine
keywords: 454 deep sequencing; AS-PCR; FTC/TDF; HIV-1; PrEP; drug resistance; minor variant; preexposure prophylaxis
references.citation: N Engl J Med. 2012 Aug 2;367(5):423-34
references.pmid: 22784038
references.citation: J Acquir Immune Defic Syndr. 2007 Feb 1;44(2):148-53
references.pmid: 17117145
references.citation: J Infect Dis. 2009 Oct 15;200(8):1202-6
references.pmid: 19764886
references.citation: J Acquir Immune Defic Syndr. 2006 Aug 15;42(5):610-3
references.pmid: 16773030
references.citation: J Infect Dis. 2005 Jul 1;192(1):24-9
references.pmid: 15942890
references.citation: Sci Transl Med. 2012 Sep 12;4(151):151ra125
references.pmid: 22972843
references.citation: Clin Infect Dis. 2011 Dec;53(12):1265-70
references.pmid: 21976467
references.citation: J Virol Methods. 2010 Mar;164(1-2):122-6
references.pmid: 19948190
references.citation: Clin Infect Dis. 2005 Nov 15;41(10):1507-13
references.pmid: 16231265
references.citation: Nucleic Acids Res. 1989 Apr 11;17(7):2503-16
references.pmid: 2785681
references.citation: J Infect Dis. 1999 Jan;179(1):92-100
references.pmid: 9841827
references.citation: Curr Opin Infect Dis. 2010 Dec;23(6):621-7
references.pmid: 20847692
references.citation: AIDS. 2004 Aug 20;18(12):1683-9
references.pmid: 15280779
references.citation: J Acquir Immune Defic Syndr. 2009 Oct 1;52(2):209-21
references.pmid: 19644384
references.citation: N Engl J Med. 2012 Aug 2;367(5):411-22
references.pmid: 22784040
references.citation: N Engl J Med. 2010 Dec 30;363(27):2587-99
references.pmid: 21091279
references.citation: J Infect Dis. 2003 Oct 1;188(7):992-1000
references.pmid: 14513419
references.citation: Antimicrob Agents Chemother. 2002 Nov;46(11):3437-46
references.pmid: 12384348
references.citation: PLoS Med. 2008 Feb;5(2):e28
references.pmid: 18254653
references.citation: J Acquir Immune Defic Syndr. 2004 Apr 15;35(5):519-25
references.pmid: 15021317
references.citation: J Infect Dis. 2011 Apr 15;203(8):1174-81
references.pmid: 21451005
references.citation: Bioinformatics. 2009 May 1;25(9):1197-8
references.pmid: 19304876
references.citation: N Engl J Med. 2013 Nov 7;369(19):1828-35
references.pmid: 24152233
references.citation: Drugs. 2012 Jun 18;72(9):e1-25
references.pmid: 22686620
references.citation: AIDS. 2007 Mar 30;21(6):665-75
references.pmid: 17413687
references.citation: PLoS One. 2012;7(3):e33948
references.pmid: 22479485
references.citation: J Infect Dis. 2005 Jul 1;192(1):16-23
references.pmid: 15942889
references.citation: PLoS One. 2009;4(3):e4724
references.pmid: 19266092
references.citation: AIDS. 2001 Oct 19;15(15):1951-7
references.pmid: 11600822
references.citation: J Virol. 2009 Feb;83(4):2029-33
references.pmid: 19073730
references.citation: Curr Opin Infect Dis. 2012 Feb;25(1):51-7
references.pmid: 22156901
references.citation: AIDS. 2008 Nov 30;22(18):2501-8
references.pmid: 19005273
references.citation: Clin Infect Dis. 2010 May 15;50(10):1405-14
references.pmid: 20384494
references.citation: J Antimicrob Chemother. 2011 Feb;66(2):240-50
references.pmid: 21118913
references.citation: PLoS One. 2010 Jun 07;5(6):e10992
references.pmid: 20539818
references.citation: Lancet. 2013 Jun 15;381(9883):2083-90
references.pmid: 23769234
references.citation: JAMA. 2011 Apr 6;305(13):1327-35
references.pmid: 21467286
references.citation: AIDS. 2005 Dec 2;19(18):2167-9
references.pmid: 16284468
references.citation: N Engl J Med. 2012 Aug 2;367(5):399-410
references.pmid: 22784037
references.citation: AIDS. 1996 Dec;10 Suppl 5:S27-31
references.pmid: 9030393
references.citation: AIDS. 2007 Jan 11;21(2):215-23
references.pmid: 17197813
references.citation: Science. 2010 Sep 3;329(5996):1168-74
references.pmid: 20643915
references.citation: Proc Natl Acad Sci U S A. 2006 May 2;103(18):7094-9
references.pmid: 16641095
references.citation: Annu Rev Med. 2013;64:219-32
references.pmid: 23020883
references.citation: Int J Epidemiol. 2007 Oct;36(5):1009-21
references.pmid: 17533166
references.citation: Cold Spring Harb Perspect Med. 2012 Apr;2(4):a007161
references.pmid: 22474613
references.citation: J Clin Microbiol. 2004 Apr;42(4):1511-8
references.pmid: 15070997