title: Pattern and impact of emerging resistance mutations in treatment experienced patients failing darunavir-containing regimen.
abstract: BACKGROUND
  Ritonavir-boosted darunavir (DRV/r) has proven potent efficacy when used in heavily pretreated patients, harboring protease inhibitor-associated resistance mutations. Limited data are available on resistance pattern emerging in patients failing DRV/r and on subsequent remaining protease inhibitor options.
  
  
  METHODS
  Analysis of baseline and failure resistance genotypes were performed in patients experiencing virologic failure (>200 copies/ml) after at least 3 months on a DRV/r (600/100 mg twice daily)-containing regimen.
  
  
  RESULTS
  Twenty-five highly protease inhibitor-experienced patients were included. Baseline median human immunodeficiency virus type 1 RNA was 5 log10 copies/ml and number of total-protease inhibitor, major-protease inhibitor and DRV-associated-resistance mutations was 13, 4 and 3, respectively. Median viral replication duration on DRV/r selective pressure was 34 weeks. Emergence of DRV-associated-resistance mutations was observed in 72% (18/25) of patients, at codons L89I/M/V (32%), V32I (28%), V11I (20%), I47V/A (20%), I54L/M (20%), L33F/I (16%) and I50V (16%). A high risk of DRV resistance was observed in patients with 2 and 3 baseline DRV-associated-resistance mutations and in patients with more than 24 weeks of ongoing viral replication. According to 2007 ANRS algorithm, isolates classified as susceptible to ritonavir-boosted tipranavir decreased from baseline to failure from 76 to 60% and susceptible to DRV/r from 32 to 12%.
  
  
  CONCLUSIONS
  Emerging mutations observed after DRV/r failure were those already described to impact the DRV efficacy. Our study provided recommendations to firstly, reconsider lowering the cutoff number of DRV mutations to two; secondly, avoid keeping patients on a DRV-failing regimen for more than 24 weeks and thirdly, to examine the efficacy of using tipranavir after DRV failure.
authors.affiliation: Virology Department, Saint Louis Hospital-APHP, Paris, France. constance.delaugerre@sls.aphp.fr
authors.forename: Constance
authors.initials: C
authors.lastname: Delaugerre
authors.forename: Juliette
authors.initials: J
authors.lastname: Pavie
authors.forename: Pierre
authors.initials: P
authors.lastname: Palmer
authors.forename: Jade
authors.initials: J
authors.lastname: Ghosn
authors.forename: Stephane
authors.initials: S
authors.lastname: Blanche
authors.forename: Laurent
authors.initials: L
authors.lastname: Roudiere
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dominguez
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mortier
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Molina
authors.forename: Pierre
authors.initials: P
authors.lastname: de Truchis
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D000069454:Darunavir; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D011725:Pyridines / Q000627:therapeutic use; D011753:Pyrones / Q000627:therapeutic use; D013449:Sulfonamides / Q000627:therapeutic use*; D017211:Treatment Failure; D019562:Viral Load
chemical_list: D017320:HIV Protease Inhibitors; D011725:Pyridines; D011753:Pyrones; D013449:Sulfonamides; D000069454:Darunavir; C107201:tipranavir