title: Integrase inhibitor (INI) genotypic resistance in treatment-naive and raltegravir-experienced patients infected with diverse HIV-1 clades.
abstract: OBJECTIVE
  The aim of this study was to characterize the prevalence and patterns of genotypic integrase inhibitor (INI) resistance in relation to HIV-1 clade.
  
  
  METHODS
  The cohort comprised 533 INI-naive subjects and 255 raltegravir recipients with viraemia who underwent integrase sequencing in routine care across Europe, including 134/533 (25.1%) and 46/255 (18.0%), respectively, with non-B clades (A, C, D, F, G, CRF01, CRF02, other CRFs, complex).
  
  
  RESULTS
  No major INI resistance-associated mutations (RAMs) occurred in INI-naive subjects. Among raltegravir recipients with viraemia (median 3523 HIV-1 RNA copies/mL), 113/255 (44.3%) had one or more major INI RAMs, most commonly N155H (45/255, 17.6%), Q148H/R/K + G140S/A (35/255, 13.7%) and Y143R/C/H (12/255, 4.7%). In addition, four (1.6%) raltegravir recipients showed novel mutations at recognized resistance sites (E92A, S147I, N155D, N155Q) and novel mutations at other integrase positions that were statistically associated with raltegravir exposure (K159Q/R, I161L/M/T/V, E170A/G). Comparing subtype B with non-B clades, Q148H/R/K occurred in 42/209 (20.1%) versus 2/46 (4.3%) subjects (P = 0.009) and G140S/A occurred in 36/209 (17.2%) versus 1/46 (2.2%) subjects (P = 0.005). Intermediate- to high-level cross-resistance to twice-daily dolutegravir was predicted in 40/255 (15.7%) subjects, more commonly in subtype B versus non-B clades (39/209, 18.7% versus 1/46, 2.2%; P = 0.003). A glycine (G) to serine (S) substitution at integrase position 140 required one nucleotide change in subtype B and two nucleotide changes in all non-B clades.
  
  
  CONCLUSIONS
  No major INI resistance mutations occurred in INI-naive subjects. Reduced occurrence of Q148H/R/K + G140S/A was seen in non-B clades versus subtype B, and was explained by the higher genetic barrier to the G140S mutation observed in all non-B clades analysed.
authors: Department of Infectious Diseases, King's College London, London, UK.
authors: Tomas
authors: T
authors: Doyle
authors: MRC Clinical Trial Unit at UCL, London, UK.
authors: David T
authors: DT
authors: Dunn
authors: Faculty of Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy.
authors: Francesca
authors: F
authors: Ceccherini-Silberstein
authors: Research Institute and Hospital Puerta de Hierro, Madrid, Spain.
authors: Carmen
authors: C
authors: De Mendoza
authors: HU San Cecilio, Granada, Spain.
authors: Frederico
authors: F
authors: Garcia
authors: Heart of England NHS Foundation Trust, Birmingham, UK.
authors: Erasmus
authors: E
authors: Smit
authors: MRC Clinical Trial Unit at UCL, London, UK.
authors: Esther
authors: E
authors: Fearnhill
authors: AP-HP, Hôpital Pitié-Salpêtrière, INSERM-Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1136, Paris, France.
authors: Anne-Genevieve
authors: AG
authors: Marcelin
authors: IrsiCaixa, ICREA and UVic-UCC, Barcelona, Spain.
authors: Javier
authors: J
authors: Martinez-Picado
authors: Institute of Virology, University of Cologne, Cologne, Germany.
authors: Rolf
authors: R
authors: Kaiser
authors: Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, UK geretti@liverpool.ac.uk.
authors: Anna Maria
authors: AM
authors: Geretti
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015331:Cohort Studies; D024882:Drug Resistance, Viral; D005060:Europe; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D019429:Integrase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D020125:Mutation, Missense; D000068898:Raltegravir Potassium / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; D019429:Integrase Inhibitors; D000068898:Raltegravir Potassium