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  • Title: Virological response to darunavir/ritonavir-based regimens in antiretroviral-experienced patients (PREDIZISTA study).
    Author: Pellegrin I, Wittkop L, Joubert LM, Neau D, Bollens D, Bonarek M, Girard PM, Fleury H, Winters B, Saux MC, Pellegrin JL, Thiébaut R, Breilh D, ANRS Co3 Aquitaine Cohort.
    Journal: Antivir Ther; 2008; 13(2):271-9. PubMed ID: 18505178.
    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. CONCLUSION: 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.
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