Absence of association between MDR1 genetic polymorphisms, indinavir pharmacokinetics and response to highly active antiretroviral therapy

Objective: The relationship between MDR1 single nucleoticle polymorphisms (SNP) and the pharmacokinetic or pharmacodynamic responses to protease inhibitors has been recently challenged. Aim: The objective of the present study was to determine whether MDRI genetic polymorphisms in exons 21 and 26 (G2677T/A and C3435T) are in association with indinavir (IDV) plasma concentrations and/or therapeutic response to highly active antiretroviral therapy (HAART) in HIV-infected patients treated with unboosted IDV containing regimens. Methods: MDRI genotyping was performed in a population of 139 HIV-1-positive patients followed during 72 weeks, as part of the previous study called ANRS 081 'Trianon'. The primary study was a randomized trial comparing over 72 weeks the efficacy of two antiretroviral drug combinations in a population of adult HIV-1-infected patients : group 1, [lamivudine (3TC) - stavudine (d4T) - lDV (800 mg three times daily)] and group 2, [Nevirapine (NVP) - d4T - IDV (1000 mg three times daily)]. Results: MDR1 SNPs analyzed separately or combined into haplotypes did not show any significant association with lDV pharmacokinetics nor response to HAART. Mean modelled lDV peak and trough concentrations, as well as clearance modelled from pharmacokinetic model, after 8 weeks of therapy were not significantly different between patients carrying the wild-type haplotype GG-CC (at position 2677 and 3435 respectively) and others. Conclusions: Our results do not support an association between MDR1 genetic polymorphisms and modelled IDV clearance or clinical response to HAART. (c) 2005 Lippincott Williams & Wilkins.