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Review ArticleReview Article

The Dual Role of Pharmacogenetics in HIV Treatment: Mutations and Polymorphisms Regulating Antiretroviral Drug Resistance and Disposition

Veronique Michaud, Tamara Bar-Magen, Jacques Turgeon, David Flockhart, Zeruesenay Desta and Mark A. Wainberg
Theresa A. Shapiro, ASSOCIATE EDITOR
Pharmacological Reviews July 2012, 64 (3) 803-833; DOI: https://doi.org/10.1124/pr.111.005553
Veronique Michaud
McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada (V.M., T.B.-M., M.A.W.); Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana (V.M., D.F., Z.D.); Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada (V.M., J.T.); Laboratory of Molecular Biology, Infectious Diseases Department, Hospital Carlos III, Madrid, Spain (T.B.-M.); and Centre de recherche du Centre hospitalier de l'Université de Montréal, Montréal, Québec, Canada (J.T.)
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Tamara Bar-Magen
McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada (V.M., T.B.-M., M.A.W.); Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana (V.M., D.F., Z.D.); Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada (V.M., J.T.); Laboratory of Molecular Biology, Infectious Diseases Department, Hospital Carlos III, Madrid, Spain (T.B.-M.); and Centre de recherche du Centre hospitalier de l'Université de Montréal, Montréal, Québec, Canada (J.T.)
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Jacques Turgeon
McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada (V.M., T.B.-M., M.A.W.); Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana (V.M., D.F., Z.D.); Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada (V.M., J.T.); Laboratory of Molecular Biology, Infectious Diseases Department, Hospital Carlos III, Madrid, Spain (T.B.-M.); and Centre de recherche du Centre hospitalier de l'Université de Montréal, Montréal, Québec, Canada (J.T.)
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David Flockhart
McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada (V.M., T.B.-M., M.A.W.); Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana (V.M., D.F., Z.D.); Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada (V.M., J.T.); Laboratory of Molecular Biology, Infectious Diseases Department, Hospital Carlos III, Madrid, Spain (T.B.-M.); and Centre de recherche du Centre hospitalier de l'Université de Montréal, Montréal, Québec, Canada (J.T.)
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Zeruesenay Desta
McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada (V.M., T.B.-M., M.A.W.); Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana (V.M., D.F., Z.D.); Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada (V.M., J.T.); Laboratory of Molecular Biology, Infectious Diseases Department, Hospital Carlos III, Madrid, Spain (T.B.-M.); and Centre de recherche du Centre hospitalier de l'Université de Montréal, Montréal, Québec, Canada (J.T.)
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Mark A. Wainberg
McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada (V.M., T.B.-M., M.A.W.); Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana (V.M., D.F., Z.D.); Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada (V.M., J.T.); Laboratory of Molecular Biology, Infectious Diseases Department, Hospital Carlos III, Madrid, Spain (T.B.-M.); and Centre de recherche du Centre hospitalier de l'Université de Montréal, Montréal, Québec, Canada (J.T.)
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Theresa A. Shapiro
McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada (V.M., T.B.-M., M.A.W.); Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana (V.M., D.F., Z.D.); Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada (V.M., J.T.); Laboratory of Molecular Biology, Infectious Diseases Department, Hospital Carlos III, Madrid, Spain (T.B.-M.); and Centre de recherche du Centre hospitalier de l'Université de Montréal, Montréal, Québec, Canada (J.T.)
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Abstract

Significant intra- and interindividual variability has been observed in response to use of pharmacological agents in treatment of HIV infection. Treatment of HIV infection is limited by high rates of adverse drug reactions and development of resistance in a significant proportion of patients as a result of suboptimal drug concentrations. The efficacy of antiretroviral therapy is challenged by the emergence of resistant HIV-1 mutants with reduced susceptibility to antiretroviral drugs. Moreover, pharmacotherapy of patients infected with HIV is challenging because a great number of comorbidities increase polypharmacy and the risk for drug-drug interactions. Drug-metabolizing enzymes and drug transporters regulate drug access to the systemic circulation, target cells, and sanctuary sites. These factors, which determine drug exposure, along with the emergence of mutations conferring resistance to HIV medications, could explain variability in efficacy and adverse drug reactions associated with antiretroviral drugs. In this review, the major factors affecting the disposition of antiretroviral drugs, including key drug-metabolizing enzymes and membrane drug transporters, are outlined. Genetic polymorphisms affecting the activity and/or the expression of cytochromes P450 or UGT isozymes and membrane drug transport proteins are highlighted and include such examples as the association of neurotoxicity with efavirenz, nephrotoxicity with tenofovir, hepatotoxicity with nevirapine, and hyperbilirubinemia with indinavir and atazanavir. Mechanisms of drug resistance conferred by specific viral mutations are also reviewed, with particular attention to replicative viral fitness and transmitted HIV drug resistance with the objectives of providing a better understanding of mechanisms involved in HIV drug resistance and helping health care providers to better manage interpatient variability in drug efficacy and toxicity.

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  • This article is available online at http://pharmrev.aspetjournals.org.

    http://dx.doi.org/10.1124/pr.111.005553.

  • © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 64 (3)
Pharmacological Reviews
Vol. 64, Issue 3
1 Jul 2012
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Review ArticleReview Article

A REVIEW OF HOST AND HIV VIRUS GENETIC VARIABILITY

Veronique Michaud, Tamara Bar-Magen, Jacques Turgeon, David Flockhart, Zeruesenay Desta and Mark A. Wainberg
Pharmacological Reviews July 1, 2012, 64 (3) 803-833; DOI: https://doi.org/10.1124/pr.111.005553

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Review ArticleReview Article

A REVIEW OF HOST AND HIV VIRUS GENETIC VARIABILITY

Veronique Michaud, Tamara Bar-Magen, Jacques Turgeon, David Flockhart, Zeruesenay Desta and Mark A. Wainberg
Pharmacological Reviews July 1, 2012, 64 (3) 803-833; DOI: https://doi.org/10.1124/pr.111.005553
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    • I. Introduction
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