Pharmacogenomics of Antiretroviral Drug Metabolism and Transport

Abstract

Antiretroviral therapy has markedly reduced morbidity and mortality for persons living with human immunodeficiency virus (HIV). Individual tailoring of antiretroviral regimens has the potential to further improve the long-term management of HIV through the mitigation of treatment failure and drug-induced toxicities. While the mechanisms underlying anti-HIV drug adverse outcomes are multifactorial, the application of drug-specific pharmacogenomic knowledge is required in order to move toward the personalization of HIV therapy. Thus, detailed understanding of the metabolism and transport of antiretrovirals and the influence of genetics on these pathways is important. To this end, this review provides an up-to-date overview of the metabolism of anti-HIV therapeutics and the impact of genetic variation in drug metabolism and transport on the treatment of HIV. Future perspectives on and current challenges in pursuing personalized HIV treatment are also discussed.

Keywords: HIV medication; drug metabolism; drug-drug interactions; personalized medicine; pharmacogenomics.

Figure 1.

The first-pass metabolism of HIV drugs upon oral administration. After being swallowed, a drug is absorbed via the gut wall and intestine. It then enters the hepatic portal system. An abundance of drug metabolizing enzymes are present in the intestine and liver. Prior to metabolism, the drug is actively transported (OATPs = organic-anion-transporting peptides, OCTs = organic cation transporters, ABCs = ATP-binding cassette transporters, P-gp = P-glycoprotein, a member of ABCs) or passively diffuses into the cell, or both. In the liver, drug metabolism occurs inside hepatocytes where the drug undergoes modifications (e.g., oxidation by P450s) or conjugations (e.g., glucuronidation by UGTs). The resulting metabolites are excreted into the bile canaliculus or re-enter the blood, after which they can be excreted by the kidneys.

Figure 2.

Lifecycle of HIV-1 and action of antiretrovirals in CD4+ cells. The lifecycle is initiated by the binding of viral envelope protein gp120 to the receptors on a CD4+ cell (process targeted by entry inhibitors) (step 1). Once inside the cell, HIV releases and uses reverse transcriptase to convert viral RNA into DNA (process targeted by NRTIs and NNRTIs; NRTIs must be phosphorylated by host kinases inside the cell in order to become pharmacologically active) (step 2). Subsequently, viral integrase catalyzes the incorporation of viral DNA into the host genome (process targeted by integrase inhibitors) (step 3), which allows HIV to hijack host cellular machinery to produce long chains of viral proteins (step 4). Hydrolysis of these long chains of viral proteins by viral protease furnishes each individual component (process targeted by protease inhibitors) (step5) that is assembled into newly formed HIV progeny ready to bud off (step 6).