Virological, intracellular and plasma pharmacological parameters predicting response to lopinavir/ritonavir (KALEPHAR study).
OBJECTIVE
To assess the impact of HIV-1 protease mutations and intracellular and plasma lopinavir minimum concentrations (Cmin) on virological success or failure on lopinavir/ritonavir-containing highly active antiretroviral therapy (HAART).


METHODS
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/microl (133-477); plasma HIV-1-RNA load 5.3 log10 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 Cmin, 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 Cmin were independently associated with virological success or failure. We defined the most discriminating intracellular and plasma lopinavir Cmin efficacy thresholds (8 and 4 microg/ml, respectively) and GIQ thresholds (1 and 3, respectively).


CONCLUSIONS
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.
Breilh
Dominique
D
Department of Pharmacokinetics and Clinical Pharmacy, Bordeaux 2, France. dominique.breilh@chu-bordeaux.fr
Pellegrin
Isabelle
I
Rouzés
Agnés
A
Berthoin
Karine
K
Xuereb
Fabien
F
Budzinski
Hélène
H
Munck
Michèle
M
Fleury
Hervé J A
HJ
Saux
Marie-Claude
MC
Pellegrin
Jean-Luc
JL
D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D016009:Chi-Square Distribution; D002851:Chromatography, High Pressure Liquid; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D016333:HIV Protease / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D011744:Pyrimidinones / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D016896:Treatment Outcome; D019562:Viral Load
D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; D061466:Lopinavir; D054303:HIV Reverse Transcriptase; D016333:HIV Protease