title: HIV-1 resistance patterns to integrase inhibitors in antiretroviral-experienced patients with virological failure on raltegravir-containing regimens.
abstract: BACKGROUND
  Our aim was to study the in vivo viral genetic pathways for resistance to raltegravir, in antiretroviral-experienced patients with virological failure (VF) on raltegravir-containing regimens.
  
  
  METHODS
  We set up a prospective study including antiretroviral-experienced patients receiving raltegravir-based regimens. Integrase (IN) genotypic resistance analysis was performed at baseline. IN was also sequenced at follow-up points in the case of VF, i.e. plasma HIV-1 RNA>400 copies/mL at month 3 and/or >50 copies/mL at month 6. For phenotyping, the IN region was recombined with an IN-deleted HXB2-based HIV-1 backbone. A titrated amount of IN recombinant viruses was used for antiviral testing against raltegravir and elvitegravir.
  
  
  RESULTS
  Among 51 patients, 11 (21.6%) had VF. Four different patterns of IN mutations were observed: (i) emergence of Q148H/R with secondary mutations (n=5 patients); (ii) emergence of N155H, then replaced by a pattern including Y143C/H/R (n=3); (iii) selection of S230N (n=1); and (iv) no evidence of selection of IN mutations (n=2). The median raltegravir and elvitegravir fold changes (FCs) were 244 (154-647) and 793 (339-892), respectively, for the Q148H/R pattern, while the median raltegravir and elvitegravir FCs were 21 (6-52) and 3 (2-3), respectively, with Y143C/H/R. The median plasma raltegravir Cmin was lower in patients with selection of the N155H mutation followed by Y143C/H/R compared with patients with Q148H/R and with patients without emerging mutations or without VF.
  
  
  CONCLUSIONS
  Diverse genetic profiles can be associated with VF on raltegravir-containing regimens, including the dynamics of replacement of mutational profiles. Pharmacokinetic parameters could be involved in this genetic evolution.
authors.affiliation: Laboratoire de Virologie, Bordeaux University Hospital, and EA2968, Université Victor Segalen, Bordeaux, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: da Silva
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Van Wesenbeeck
authors.forename: Dominique
authors.initials: D
authors.lastname: Breilh
authors.forename: Sandrine
authors.initials: S
authors.lastname: Reigadas
authors.forename: Guerric
authors.initials: G
authors.lastname: Anies
authors.forename: Kurt
authors.initials: K
authors.lastname: Van Baelen
authors.forename: Philippe
authors.initials: P
authors.lastname: Morlat
authors.forename: Didier
authors.initials: D
authors.lastname: Neau
authors.forename: Michel
authors.initials: M
authors.lastname: Dupon
authors.forename: Linda
authors.initials: L
authors.lastname: Wittkop
authors.forename: Hervé
authors.initials: H
authors.lastname: Fleury
authors.forename: Bernard
authors.initials: B
authors.lastname: Masquelier
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D024882:Drug Resistance, Viral; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D019427:HIV Integrase / Q000235:genetics*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D008826:Microbial Sensitivity Tests; D020125:Mutation, Missense; D011446:Prospective Studies; D011760:Pyrrolidinones / Q000494:pharmacology / Q000627:therapeutic use*; D015363:Quinolones / Q000494:pharmacology; D012367:RNA, Viral / Q000097:blood; D000068898:Raltegravir Potassium; D017422:Sequence Analysis, DNA; D017211:Treatment Failure; D019562:Viral Load
chemical_list: D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D015363:Quinolones; D012367:RNA, Viral; D000068898:Raltegravir Potassium; C509700:elvitegravir; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1