Genetic Polymorphisms Affecting the Pharmacokinetics of Antiretroviral Drugs

• Published in: Clinical pharmacokinetics Vol. 56; no. 4; pp. 355 - 369
• Main Authors: Calcagno, Andrea, Cusato, Jessica, D’Avolio, Antonio, Bonora, Stefano
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.04.2017; Springer Nature B.V
• Subjects: Acquired immune deficiency syndrome; AIDS; Animals; Anti-HIV Agents - pharmacokinetics; Anti-HIV Agents - therapeutic use; Anti-Retroviral Agents - pharmacokinetics; Anti-Retroviral Agents - therapeutic use; Antiretroviral drugs; Cytochrome; Drug Interactions - physiology; Enzymes; Glycoproteins; HIV; HIV Infections - drug therapy; HIV Infections - genetics; HIV Infections - metabolism; Human immunodeficiency virus; Humans; Internal Medicine; Medicine; Medicine & Public Health; Metabolism; Minority & ethnic groups; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Plasma; Polymorphism, Genetic - drug effects; Polymorphism, Genetic - genetics; Review Article; Studies; Tissue Distribution - drug effects; Tissue Distribution - physiology; Tenofovir; Atazanavir; Efavirenz; Raltegravir; Breast Cancer Resistance Protein
• ISSN: 0312-5963; 1179-1926; 1179-1926
• DOI: 10.1007/s40262-016-0456-6

Background Antiretroviral treatment is highly effective in enhancing HIV-positive patients' survival and quality of life. Despite an increased tolerability in recent years, a substantial amount of patients experience side effects. Antiretrovirals' efficacy and tolerability have been associated with plasma concentrations and single nucleotide polymorphisms in selected genes involved in drug disposition. Objective Our aim was to review the current knowledge in genetic polymorphisms affecting plasma, intracellular or compartmental concentrations of antiretrovirals. Methods A search of the PubMed database was conducted to identify relevant articles, using the following terms: ‘pharmacogenetics’ or ‘pharmacogenomics’ or ‘single nucleotide polymorphisms’ or ‘genetic/allelic variants’ and ‘pharmacokinetics’ or ‘concentrations’ and ‘HIV’ or ‘antiretroviral’. Abstracts from the main HIV conferences during 2015 and 2016 were also searched using the same keywords. Abstracts were manually checked and, if relevant, full papers were obtained. Only articles published in English were selected. Results Several genetic polymorphisms in genes coding enzymes involved in drug metabolism (cytochrome P450 isoenzymes and uridine diphosphate glucuronosyltransferases) and transport (P-glycoprotein, anionic and cationic transporters, other transporters), as well as nuclear receptors (pregnane X receptor and the constitutive androstane receptor), have been associated with concentrations of antiretrovirals. The extent of such influence, the conflicting data, and the potential clinical relevance are discussed in the main section of this article. Conclusion Genetic polymorphisms may affect antiretroviral disposition, as well as both efficacy and toxicity. Despite a large amount of data, such precious knowledge has seldom been applied in patients. Studies on the clinical relevance and cost effectiveness of tailoring antiretroviral regimens to patients’ genetic assets are lacking, but their importance may grow with the increasing age and complexity of persons living with HIV/AIDS.