Pharmacogenetics in HIV therapy

Administration of standard doses of most antiretroviral drugs results in significant variations in plasma drug concentrations among different individuals, as well as different rates of drug-associated toxicity. The reasons for the large interindividual variability in drug levels are multifactorial, and involve differences in gender metabolism, concomitant medications, drug compliance, underlying diseases, and genetic factors. Pharmacogenetics is the discipline that analyses the genetic basis for the interindividual variation in the body disposition of drugs. One of the main goals is to give grounds to individualized therapy. The majority of pharmacogenetic traits so far have involved drug metabolism. An example of this is the inherited variation in the pharmacokinetics and pharmacodynamics of drugs such as hydralazine or isoniazid. This variation is due to polymorphisms in the N-acetyltransferase-2 (NAT2) gene, which may split the population into three categories: slow, intermediate, and fast metabolizers. Pharmacogenetic studies conducted so far with antiretrovirals have focused on metabolizing enzymes and transporter proteins in the cell membrane. Herein, we review the genetic polymorphisms known to be associated with altered pharmacokinetics of antiretrovirals, which may influence the efficacy and toxicity of these drugs.