title: Virological response to darunavir/ritonavir-based regimens in antiretroviral-experienced patients (PREDIZISTA study).
abstract: BACKGROUND
  We assessed the association of baseline HIV-1 mutations, phenotypic sensitivity and pharmacokinetics with virological failure (VF) at week 12 (W12) after onset of a darunavir/ritonavir (DRV/r)-based regimen in a cohort of 67 antiretroviral-experienced HIV-patients failing on highly active antiretroviral therapy (HAART).
  
  
  METHODS
  VF was defined as HIV RNA >2.3 log10copies/ml at W12. HIV reverse transcriptase and protease sequencing was performed at WO; mutations with a P-value <0.25 in univariable analyses were used for a backward selection to find the best mutation set for VF prediction. Genotypic and phenotypic sensitivity scores were calculated and virtual phenotype predicted fold change (FC) assessed. DRV Cmin, Cmax, AUC(0-->12 h) and genotypic inhibitory quotient (GIQ) were determined.
  
  
  RESULTS
  Patients had a median of 15 previous treatments for 10 years. Median W0 values included a T-cell count of 129 cells/microl, 4.7 log10 HIV RNA copies/ml, four major protease and six nucleoside reverse transcriptase inhibitor resistance mutations. At W12, median HIV RNA decrease was -2.1 log10 copies/ml with a gain of +67 CD4+ T-cells/microl; 40% of patients failed. We determined the genotypic score I13V+V32I+L33F/I/V+E35D+ M361/L/V+I47V+F53L+I62V. According to <4, 4-5 and >5 mutations, failure occurred in 11%, 48% and 100% of patients. Failure was associated with CDC stage, baseline CD4+ T-cell count, number of major protease inhibitor resistance mutations, FC and DRV/r score. Pharmacokinetics were not associated with failure, but GIQ was.
  
  
  CONCLUSIONS
  At W12, 60% of heavily pretreated patients responded on DRV/r-based HAART. Genotypic and phenotypic information constituted the main virological response determinant in patients with optimal drug concentrations.
authors.affiliation: Department of Virology, Bordeaux University Hospital, Bordeaux, France. isabelle.pellegrin@chu-bordeaux.fr
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pellegrin
authors.forename: Linda
authors.initials: L
authors.lastname: Wittkop
authors.forename: Laurence Morand
authors.initials: LM
authors.lastname: Joubert
authors.forename: Didier
authors.initials: D
authors.lastname: Neau
authors.forename: Diane
authors.initials: D
authors.lastname: Bollens
authors.forename: Mojgan
authors.initials: M
authors.lastname: Bonarek
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Girard
authors.forename: Hervé
authors.initials: H
authors.lastname: Fleury
authors.forename: Bart
authors.initials: B
authors.lastname: Winters
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Saux
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Pellegrin
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Thiébaut
authors.forename: Dominique
authors.initials: D
authors.lastname: Breilh
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D015331:Cohort Studies; D000069454:Darunavir; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D016333:HIV Protease / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D019438:Ritonavir / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D017422:Sequence Analysis, DNA; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D017320:HIV Protease Inhibitors; D013449:Sulfonamides; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D016333:HIV Protease; D019438:Ritonavir; D000069454:Darunavir