Pharmacogenetics of antiretroviral drugs for the treatment of HIV-infected patients: an update

Abstract

Highly active antiretroviral therapy (HAART), a combination of at least three antiretroviral drugs, has dramatically improved the prognosis of HIV/AIDS. However, viral replication under therapy can lead to the selection of drug resistant viruses and subsequent virologic failure. While poor adherence is likely to be the main cause of treatment failure, individual pharmacokinetic variability can also play an important role. Drug-drug interactions, drug-food interactions, sex, age, renal/hepatic function and pregnancy are all sources of pharmacokinetic variability. Recent pharmacogenetic studies of antiretroviral drugs reported the influence of several genetic polymorphisms on antiretroviral drug exposure, toxicity and response to treatment. Initially, a single nucleotide polymorphism (SNP) in exon 26 (C3435T) of the multi-drug transporter gene (MDR1) was reported to be associated with low antiretroviral plasma drug levels but good initial immunological response; however, conflicting results have since been reported. Several studies on efavirenz, a commonly used antiretroviral drug, have reported higher plasma exposure and early side effects with the homozygous variant of the hepatic cytochrome P450 enzyme CYP2B6 G516T polymorphism, which are more frequently found in African-American subjects. However, despite its association with efavirenz exposure this polymorphism was not associated with time to virologic or toxicity-related failure. Genetic analysis has also proven to be a valuable predictor of antiretroviral drug hypersensitivity reactions; genetic screening of patients prior to initiation of specific antiretrovirals has proven to reduce the incidence of drug hypersensitivity in certain settings. The reasons for antiretroviral treatment failure are multi-factorial but as the individualization of HAART increases understanding the influence of specific genotypes on treatment success and toxicity could further optimize these life-saving treatments.