Pharmacogenetic effects of single nucleotide polymorphisms commonly associated with antiretroviral therapy metabolism

Abstract

Introduction. Identification of pharmacogenetic effects on antiretroviral therapy (ART) has become an important milestone to reach in the advancement of personalised treatment for HIV-positive patients. The therapy schemes are accompanied by multiple side effects. Therapy effectiveness and adverse reactions can be dictated by individual genetic predisposition factors, which should be taken into account for an optimal prescription. Some genetic markers (HLA-B*57:01 and UGT1A1*28), were already proven to improve discontinuation rates, and efforts are allocated to expand the range of clinically-relevant genetic tests.Objective. In this review, an updated summary of genetic polymorphisms and their effects defining patients’ tolerability to ART is presented. The aim of this research is to assess single nucleotide polymorphisms (SNPs) present in the genes that encode proteins involved in ART metabolism and transport. This review will be used to develop a PCR-based testing methodology for the detection and confirmation of risk alleles in the Caucasian population.Materials and methods. Data from 46 original research papers and reviews was analysed. Allele frequencies of the most relevant polymorphisms were checked against the data for European population.Results. As an outcome of this review, a few most promising SNPs were selected for future research. Firstly, ABCC4 rs1751034 and rs3742106 and ABCC10 rs9349256 and rs2125739 were associated with an increased risk of renal impairment, higher plasma concentration, and toxicity when treated with tenofovir. Parallel analysis of ABCC4 and ABCC10 SNP effects on renal impairment together with CYP24A1 rs2248359 that was recently reported as a potential renal toxicity marker might be more informative. Secondly, CYP2B6 rs3745274 that was associated with an increased efavirenz plasma concentration, and increased risk of liver and CNS toxicity should be evaluated. SNPs in CYP2B6, CYP2A6 (rs28399433), and CYP3A4 (rs4646437) should be evaluated in parallel since possession of all three variants might put patients at a much higher risk.Conclusion. Identified alleles could become new markers used in drug prescription protocols if significant effect in Caucasian population will be found. The most relevant SNPs should be tested in in supporting future studies to evaluate the significance for patients with HIV in Russia.