Multidrug Resistance 1 Polymorphisms and Trough Concentrations of Atazanavir and Lopinavir in Patients with HIV

Abstract

Introduction: HIV-infected patients receiving protease inhibitors may benefit from therapeutic drug monitoring-assisted dose adjustment to achieve target plasma concentrations. However, efflux pumps such as permeability-glycoprotein, which is encoded by the multidrug resistance (MDR)1 gene, may decrease intracellular drug concentrations, thus reducing the amount of drug at the site of action. Plasma concentrations of protease inhibitors and CD4 cell count response have been associated with the T allele at the MDR1 C3435T locus. We examined MDR1 single nucleotide polymorphisms in a cohort of patients in whom therapeutic drug monitoring is ongoing through a research protocol. Methods: In a multicenter study, genotypic analyses at two MDR1 loci, C3435T and G2677T, were performed by a real-time polymerase chain reaction method using DNA from 103 patients categorized as substance users or nonusers on atazanavir or lopinavir as the primary antiretrovirals. Allelic frequencies were determined as a function of racial/ethnic background, substance use status and trough concentrations of atazanavir and lopinavir. Results: The C/T and G/T alleles at the MDR1 C3435T and G2677T loci were equally frequent in the Caucasian population, but the wild-type alleles were more prevalent in the African–American population (59% homozygous [CC] and 32% heterozygous [CT] for C3435T; 80% homozygous [GG] and 16% heterozygous [GT] for G2677T). The frequencies in the Hispanic population were 46% CC and 38% CT for C3435T, and 58% GG and 38% GT for G2677T. No significant differences were seen in allele frequencies for MDR1 polymorphisms in substance user versus nonuser groups. Trough plasma concentrations of atazanavir or lopinavir were not correlated with the variant T allele. Conclusions: These data confirm the higher prevalence of wild-type alleles of the MDR1 gene in African–Americans and the linkage disequilibrium between C3435T and G2677T loci. The T allele at the MDR1 C3435T and G2677T loci was not associated with higher atazanavir or lopinavir trough concentrations.

Keywords: :

• antiretrovirals
• multidrug resistance 1 polymorphisms
• P-glycoprotein
• protease inhibitors

Acknowledgements

The contributions of Raju Sadal, Julie Sarlo, Carol Greisberger, Leslie Thompson, Norma Storer and the clinical research staff at the Montefiore Medical Center AIDS Center, the University of Rochester HIV Program, the University of Miami AIDS Research Unit, the University Hospitals Case Medical Center HIV Program and the patients at each of the participating HIV treatment centers are appreciated. The dedication of the research staff of the Pharmacotherapy Research Center and Core Analytical Laboratory at University at Buffalo to investigating therapeutic drug monitoring is also appreciated. This research was supported by grant DA-015024 from the National Institute on Drug Abuse. B Zingman is supported in part by the Center for AIDS Research at the Albert Einstein College of Medicine and Montefiore Medical Center (AI-51519).

Additional information

Funding

The contributions of Raju Sadal, Julie Sarlo, Carol Greisberger, Leslie Thompson, Norma Storer and the clinical research staff at the Montefiore Medical Center AIDS Center, the University of Rochester HIV Program, the University of Miami AIDS Research Unit, the University Hospitals Case Medical Center HIV Program and the patients at each of the participating HIV treatment centers are appreciated. The dedication of the research staff of the Pharmacotherapy Research Center and Core Analytical Laboratory at University at Buffalo to investigating therapeutic drug monitoring is also appreciated. This research was supported by grant DA-015024 from the National Institute on Drug Abuse. B Zingman is supported in part by the Center for AIDS Research at the Albert Einstein College of Medicine and Montefiore Medical Center (AI-51519).