title: The activity of the integrase inhibitor dolutegravir against HIV-1 variants isolated from raltegravir-treated adults.
abstract: BACKGROUND
  Dolutegravir (DTG, S/GSK1349572) is an integrase inhibitor with low nanomolar potency. Susceptibility to dolutegravir and raltegravir was determined for raltegravir-resistant clinical isolates.
  
  
  METHODS
  Genotypic and phenotypic susceptibility to integrase inhibitors was examined using 39 clinical isolate samples obtained from 18 adults who had exhibited incomplete viral suppression on a raltegravir-based regimen.
  
  
  RESULTS
  Of 39 samples evaluated, 30 had genotypic and phenotypic resistance to raltegravir. All samples lacking raltegravir resistance retained complete susceptibility to dolutegravir. Of the 30 samples with genotypic evidence of raltegravir resistance, the median level of phenotypic resistance to raltegravir was high (median fold change in inhibitory concentration at 50%, >81; range, 3.7 to >87), while the level of resistance to dolutegravir was close to that of wild-type variants (median fold change, 1.5; range, 0.9-19.0). Longitudinal samples from 5 subjects collected during long-term failure of raltegravir revealed time-dependent general decreases in phenotypic susceptibility to raltegravir, with minimal changes in phenotypic susceptibility to dolutegravir. The median fold change to dolutegravir for isolates containing changes at G140S + Q148H, G140S + Q148R, T97A + Y143R, and N155H (thus including raltegravir signature resistance codons) were 3.75, 13.3, 1.05, and 1.37, respectively.
  
  
  CONCLUSIONS
  Dolutegravir retained in vitro activity against clinical isolates obtained from subjects who failed raltegravir-based therapy at near wild-type levels for variants containing the Y143 and N155 resistance mutations. Isolates with Q148 plus additional integrase mutations possessed a broader range of and more reduced susceptibility to dolutegravir.
authors.affiliation: Infectious Diseases Therapy Area Unit, Medicines Discovery & Development, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. mark.r.underwood@gsk.com
authors.forename: Mark R
authors.initials: MR
authors.lastname: Underwood
authors.forename: Brian A
authors.initials: BA
authors.lastname: Johns
authors.forename: Akihiko
authors.initials: A
authors.lastname: Sato
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Martin
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.forename: Tamio
authors.initials: T
authors.lastname: Fujiwara
mesh_terms: D000328:Adult; D024882:Drug Resistance, Viral; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D019428:HIV Integrase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009154:Mutation; D010078:Oxazines; D010641:Phenotype; D010879:Piperazines; D011728:Pyridones; D011760:Pyrrolidinones / Q000627:therapeutic use*; D000068898:Raltegravir Potassium; D000099226:Dolutegravir
chemical_list: D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D000099226:Dolutegravir