title: Drug resistance profiles for the HIV integrase gene in patients failing raltegravir salvage therapy.
abstract: OBJECTIVE
  Recent data showed the selection of mutations in the integrase gene, mainly involving position 148 or 155, in patients displaying virological failure (VF) on raltegravir (RAL) therapy. Here, we describe the development of RAL resistance, in both plasmatic and cellular compartments, in three heavily pretreated HIV-infected patients failing RAL-containing regimens.
  
  
  METHODS
  Three of 17 patients receiving RAL displayed VF. The entire integrase gene, isolated from plasma and peripheral blood mononuclear cells (PBMC), was sequenced. A clonal analysis was performed in one patient at the time of VF.
  
  
  RESULTS
  At the time of VF, RAL-resistance mutations were selected: (i) Q148R in patients 1 and 3; (ii) T66A and E92Q in patient 2. A gradual accumulation of new mutations was observed in all patients, including G140S, Q148H and N155H in patient 1, L74I in patient 2, and G140S in patient 3. Clonal analysis showed the coexistence, in patient 1, of the two common resistance pathways (mutations Q148R/H and N155H) found in distinct quasi-species. In addition, RAL-resistance mutations were detected in HIV DNA in all patients.
  
  
  CONCLUSIONS
  Having rapidly established, resistance to RAL evolves and diversifies, and is likely to impact the efficacy of subsequently used second-generation integrase inhibitors. Moreover, RAL-resistance mutations can be archived early in PBMC.
authors.affiliation: Laboratoire de Virologie, AP-HP, Hôpital Européen Georges Pompidou, Paris, France. charlotte.charpentier@egp.aphp.fr
authors.forename: C
authors.initials: C
authors.lastname: Charpentier
authors.forename: M
authors.initials: M
authors.lastname: Karmochkine
authors.forename: D
authors.initials: D
authors.lastname: Laureillard
authors.forename: P
authors.initials: P
authors.lastname: Tisserand
authors.forename: L
authors.initials: L
authors.lastname: Bélec
authors.forename: L
authors.initials: L
authors.lastname: Weiss
authors.forename: A
authors.initials: A
authors.lastname: Si-Mohamed
authors.forename: C
authors.initials: C
authors.lastname: Piketty
mesh_terms: D018791:CD4 Lymphocyte Count; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics*; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics* / Q000821:virology; D019427:HIV Integrase / Q000187:drug effects / Q000235:genetics*; D019428:HIV Integrase Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation / Q000187:drug effects / Q000235:genetics*; D010297:Paris; D011760:Pyrrolidinones / Q000627:therapeutic use*; D000068898:Raltegravir Potassium; D016879:Salvage Therapy / Q000009:adverse effects; D017423:Sequence Analysis, RNA; D017211:Treatment Failure; D019562:Viral Load
chemical_list: D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D019427:HIV Integrase