title: The impact of HIV-1 reverse transcriptase polymorphisms on responses to first-line nonnucleoside reverse transcriptase inhibitor-based therapy in HIV-1-infected adults.
abstract: OBJECTIVE
  HIV-1 genetic variability may influence antiretroviral therapy (ART) outcomes. The study aim was to determine the impact of polymorphisms in regions known to harbor major nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations (codons 90-108, 135-138, 179-190, 225-348) on virologic responses to first-line NNRTI-based ART.
  
  
  METHODS
  Reverse transcriptase sequences from ART-naive individuals who commenced efavirenz (EFV) or nevirapine (NVP) with at least two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) without major drug resistance mutations were analyzed. The impact of polymorphisms on week 4 viral load decrease and time to virologic failure was measured over a median 97 weeks.
  
  
  RESULTS
  Among 4528 patients, most were infected with HIV-1 subtype B (67%) and commenced EFV-based ART (84%). Overall, 2598 (57%) had at least one polymorphism, most frequently at codons 90, 98, 101, 103, 106, 135, 138, 179, and 238. Virologic failure rates were increased in patients with two (n = 597) or more than two (n = 72) polymorphisms [adjusted hazard ratio 1.43; 95% confidence interval (CI) 1.07-1.92; P = 0.016]. Polymorphisms associated with virologic failure occurred at codons 90 (mostly V90I), 98 (mostly A98S), and 103 (mostly K103R), with adjusted hazard ratios of 1.78 (1.15-2.73; P = 0.009), 1.55 (1.16-2.08; P = 0.003), and 1.75 (1.00-3.05: P = 0.049), respectively. Polymorphisms at codon 179, especially V179D/E/T, predicted reduced week 4 responses (P = 0.001) but not virologic failure.
  
  
  CONCLUSIONS
  The occurrence of multiple polymorphisms, though uncommon, was associated with a small increase in the risk of NNRTI treatment failure; significant effects were seen with polymorphisms at codon 90, 98, and 103. The mechanisms underlying the slower suppression seen with V179D/E/T deserve further investigation.
authors.affiliation: aDepartment of HIV/GUM, Imperial College Healthcare NHS Trust bMRC Clinical Trials Unit, London cDepartment of Clinical Virology, Manchester Royal Infirmary, Manchester dResearch Department of Infection and Population Health, UCL Medical School, London eInstitute of Infection & Global Health, University of Liverpool, Liverpool, UK.
authors.forename: Nicola E
authors.initials: NE
authors.lastname: Mackie
authors.forename: David T
authors.initials: DT
authors.lastname: Dunn
authors.forename: David
authors.initials: D
authors.lastname: Dolling
authors.forename: Lucy
authors.initials: L
authors.lastname: Garvey
authors.forename: Linda
authors.initials: L
authors.lastname: Harrison
authors.forename: Esther
authors.initials: E
authors.lastname: Fearnhill
authors.forename: Peter
authors.initials: P
authors.lastname: Tilston
authors.forename: Caroline
authors.initials: C
authors.lastname: Sabin
authors.forename: Anna M
authors.initials: AM
authors.lastname: Geretti
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase