Virological response to darunavir/ritonavir-based regimens in antiretroviral-experienced patients (PREDIZISTA Study)

• Published in: Antiviral therapy 2008-01, Vol.13 (2), p.271-279
• Main Authors: PELLEGRIN, Isabelle, WITTKOP, Linda, PELLEGRIN, Jean-Luc, THIDBAUT, Rodolphe, BREILH, Dominique, MORAND JOUBERT, Laurence, NEAU, Didier, BOLLENS, Diane, BONAREK, Mojgan, GIRARD, Pierre-Marie, FLEURY, Hervé, WINTERS, Bart, SAUX, Marie-Claude
• Format: Article
• Language: English
• Subjects: Adult; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiretroviral Therapy, Highly Active; Antiviral agents; Biological and medical sciences; Cohort Studies; Darunavir; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; HIV Infections - drug therapy; HIV Infections - immunology; HIV Infections - virology; HIV Protease - genetics; HIV Protease Inhibitors - pharmacokinetics; HIV Protease Inhibitors - pharmacology; HIV Protease Inhibitors - therapeutic use; HIV Reverse Transcriptase - genetics; HIV-1 - drug effects; HIV-1 - enzymology; HIV-1 - genetics; Human immunodeficiency virus 1; Human viral diseases; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infectious diseases; Male; Medical sciences; Microbial Sensitivity Tests; Middle Aged; Mutation; Pharmacology. Drug treatments; Phenotype; Ritonavir - pharmacokinetics; Ritonavir - pharmacology; Ritonavir - therapeutic use; Sequence Analysis, DNA; Sulfonamides - pharmacokinetics; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Treatment Outcome; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids
• ISSN: 1359-6535; 2040-2058
• DOI: 10.1177/135965350801300214

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). 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 12 h) and genotypic inhibitory quotient (GIQ) were determined. 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 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. 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.