title: Minority resistant HIV-1 variants and the response to first-line NNRTI therapy.
abstract: BACKGROUND
  The presence of low-frequency HIV-1 variants with mutations making them resistant to non-nucleoside reverse-transcriptase inhibitors (NNRTI) could influence the virological response to first-line NNRTI therapy.
  
  
  OBJECTIVE
  This study was designed to describe the proportions and quantities of NRTI and NNRTI-resistant variants in patients with successful first-line NNRTI therapy.
  
  
  METHODS
  We evaluated the presence of drug-resistance mutations (DRMs) prior to treatment initiation in 131 naive chronically HIV-1-infected patients initiating NNRTI-based first-line therapy. DRMs were detected by ultradeep pyrosequencing (UDPS) on a GS Junior instrument (Roche).
  
  
  RESULTS
  The mean HIV RNA concentration was 4.78 ± 0.74 log copies/mL and the mean CD4 cell count was 368 ± 184 CD4 cells/mm(3). Patients were mainly infected with subtype B (68%) and 96% were treated with efavirenz. The sensitivity threshold for each mutation was 0.13-1.05% for 2000 reads. Major NRTI-resistant or NNRTI-resistant mutations were detected in 40 patients (33.6%). The median frequency of major NRTI-resistant mutations was 1.37% [IQR: 0.39-84.1], i.e.: a median of 556 copies/mL [IQR: 123-37,553]. The median frequency of major NNRTI-resistant DRMs was 0.78% [IQR: 0.67-7.06], i.e.: a median of 715 copies/mL [IQR: 391-3452]. The genotypic susceptibility score (GSS) of 9 (7.3%) patients with mutations to given treatment detected by UDPS was 1.5 or 2.
  
  
  CONCLUSIONS
  First-line NNRTI-based treatment can produce virological success in naïve HIV-1-infected patients harboring low-frequency DRMs representing <1% of the viral quasispecies. Further studies are needed to determine the clinical cut-off of low-frequency resistant variants associated to virological failure.
authors.affiliation: CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, Institut fédératif de biologie de Purpan, F-31300, France. Electronic address: nicot.f@chu-toulouse.fr.
authors.forename: F
authors.initials: F
authors.lastname: Nicot
authors.affiliation: CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, Institut fédératif de biologie de Purpan, F-31300, France; INSERM, U1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse F-31300, France; Université Toulouse III Paul-Sabatier, Faculté de Médecine Toulouse, Toulouse F-31300, France.
authors.forename: K
authors.initials: K
authors.lastname: Sauné
authors.affiliation: CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, Institut fédératif de biologie de Purpan, F-31300, France; INSERM, U1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse F-31300, France; Université Toulouse III Paul-Sabatier, Faculté de Médecine Toulouse, Toulouse F-31300, France.
authors.forename: S
authors.initials: S
authors.lastname: Raymond
authors.affiliation: CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, Institut fédératif de biologie de Purpan, F-31300, France.
authors.forename: N
authors.initials: N
authors.lastname: Jeanne
authors.affiliation: CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, Institut fédératif de biologie de Purpan, F-31300, France.
authors.forename: R
authors.initials: R
authors.lastname: Carcenac
authors.affiliation: CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, Institut fédératif de biologie de Purpan, F-31300, France.
authors.forename: C
authors.initials: C
authors.lastname: Lefebvre
authors.affiliation: CHU Toulouse, Hôpital Purpan, Service des Maladies Infectieuses et Tropicales, Toulouse F-31300, France.
authors.forename: L
authors.initials: L
authors.lastname: Cuzin
authors.affiliation: Université Toulouse III Paul-Sabatier, Faculté de Médecine Toulouse, Toulouse F-31300, France; CHU Toulouse, Hôpital Purpan, Service des Maladies Infectieuses et Tropicales, Toulouse F-31300, France.
authors.forename: B
authors.initials: B
authors.lastname: Marchou
authors.affiliation: INSERM, U1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse F-31300, France; Université Toulouse III Paul-Sabatier, Faculté de Médecine Toulouse, Toulouse F-31300, France; CHU Toulouse, Hôpital Purpan, Service des Maladies Infectieuses et Tropicales, Toulouse F-31300, France.
authors.forename: P
authors.initials: P
authors.lastname: Delobel
authors.affiliation: CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, Institut fédératif de biologie de Purpan, F-31300, France; INSERM, U1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse F-31300, France; Université Toulouse III Paul-Sabatier, Faculté de Médecine Toulouse, Toulouse F-31300, France.
authors.forename: J
authors.initials: J
authors.lastname: Izopet
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D024882:Drug Resistance, Viral; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D017422:Sequence Analysis, DNA; D019562:Viral Load
chemical_list: D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors
keywords: Deep sequencing; Human immunodeficiency virus; Minority variants