4.4 Article

Virological, intracellular and plasma pharmacological parameters predicting response to lopinavir/ritonavir (KALEPHAR Study)

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AIDS
卷 18, 期 9, 页码 1305-1310

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LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/00002030-200406180-00009

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genotype inhibitory quotient; lopinavir; pharmacokinetic parameters; protease genotypes; reverse transcriptase

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Objectives: To assess the impact of HIV-1 protease mutations and intracellular and plasma lopinavir minimum concentrations (C-min) on virological success or failure on lopinavir/ritonavir-containing highly active antiretroviral therapy (HAART). Design: HIV-1-infected HAART-experienced patients included in an observational study, received lopinavir/ritonavir (400/100 mg twice a day) plus two to three nucleoside reverse transcriptase inhibitors (NRTI) or one NRTI plus one non-NRTI. A viral load less than 50 copies/ml at month 6 defined virological success. Methods: Intracellular and plasma lopinavir concentrations were determined by high-pressure liquid chromatography with mass-spectrometry detection. Reverse transcriptase and protease genes were sequenced at baseline and the time of virological failure. Results: When the 38 patients started the lopinavir/ritonavir-based regimen, baseline median (25-75th percentile) values were: CD4 cell count 218 cells/mul (133-477); plasma HIV-1-RNA load 5.3 log(10) copies/ml (3.8-5.1); number of lopinavir mutations four per protease gene (two to six). Univariate analysis associated virological success or failure at month 6 (21/38 patients) with the number of baseline lopinavir mutations, intracellular and plasma lopinavir C-min, and the genotype inhibitory quotient (GIQ) at months 1 and 6. Multivariate analysis showed that the number of baseline lopinavir mutations and intracellular and plasma lopinavir C-min were independently associated with virological success or failure. We defined the most discriminating intracellular and plasma lopinavir C-min efficacy thresholds (8 and 4 mug/ml, respectively) and GIQ thresholds (1 and 3, respectively). Conclusion: The monitoring of lopinavir/rironavir-based HAART efficacy should include the number of baseline lopinavir/ritonavir mutations, intracellular and plasma lopinavir Cmin and GIQ calculation. (C) (2)004 Lippincott Williams Wilkins.

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