Abstract
Access to potent antiretroviral medications greatly reduces morbidity and mortality due to HIV/AIDS, but drug toxicity limits treatment success in many individuals. The field of pharmacogenomics strives to understand the influence of human genetic variants in response to medications. Investigators have begun to identify associations among human genetic variants, predisposition to HIV drug toxicities, and likelihood of virologic response. These include associations among abacavir hypersensitivity reactions, HLA type, and hsp70-hom genotypes, and among CYP2B6 polymorphisms, efavirenz pharmacokinetics, and central nervous system symptoms. Pharmacogenomics also holds great promise to suggest novel targets for drug development. The discovery that a naturally occurring, nonfunctional variant of the HIV receptor gene CCR5 protected against HIV infection encouraged the development of CCR5 antagonists. Through continued translational and applied research, pharmacogenomics will ultimately benefit persons living with HIV worldwide by identifying new therapeutic targets and through individualized drug prescribing that is informed by human genetic testing.
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References and Recommended Reading
Deng H, Liu R, Ellmeier W, et al.: Identification of a major co-receptor for primary isolates of HIV-1. Nature 1996, 381:661–666.
Dragic T, Litwin V, Allaway GP, et al.: HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CCCKR-5. Nature 1996, 381:667–673.
Dean M, Carrington M, Winkler C, et al.: Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 1996, 273:1856–1862.
Mangeat B, Turelli P, Caron G, et al.: Broad antiretroviral defense by human APOBEC3G through lethal editing of nascent reverse transcripts. Nature 2003, 424:99–103.
Stremlau M, Owens CM, Perron MJ, et al.: The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys. Nature 2004, 427:848–853.
Dong X, Li H, Derdowski A, et al.: AP-3 directs the intracellular trafficking of HIV-1 gag and plays a key role in particle assembly. Cell 2005, 120:663–674.
Haas DW, Wilkinson GR, Kuritzkes DR, et al.: A multiinvestigator/ institutional DNA bank for AIDS-related human genetic studies: AACTG protocol A5128. HIV Clinical Trials 2003, 4/5:287–300.
Peyrieere H, Nicolas J, Siffert M, et al.: Hypersensitivity related to abacavir in two members of a family. Ann Pharmacother 2001, 35:1291–1292.
Symonds W, Cutrell A, Edwards M, et al.: Risk factor analysis of hypersensitivity reactions to abacavir. Clin Ther 2002, 24:565–573.
Mallal S, Nolan D, Witt C, et al.: Association between presence of HLA-B5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002, 359:727–732. This seminal report identified an underlying immunogenetic predisposition to abacavir hypersensitivity.
Hetherington S, Hughes AR, Mosteller M, et al.: Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 2002, 359:1121–1122.
Martin AM, Nolan D, Gaudieri S, et al.: Predisposition to abacavir hypersensitivity conferred by HLA-B5701 and a haplotypic Hsp70-Hom variant. Proc Natl Acad Sci U S A 2004, 101:4180–4185.
Beutler E, Gelbart T, Demina A: Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci U S A 1998, 95:8170–8174.
Zucker SD, Qin X, Rouster SD, et al.: Mechanism of indinavir-induced hyperbilirubinemia. Proc Natl Acad Sci U S A 2001, 98:12671–12676.
O‘Mara E, Randall D, Passarell J, et al.: Population pharmacodynamic assessment of atazanavir exposure, uridine diphosphate-glucuronosyl transferase (UGT) 1A1 genotype and safety in healthy subjects [abstract 3051]. Presented at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL; December 16–19, 2001.
Staszewski S, Morales-Ramirez J, Tashima KT, et al.: Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. New Engl J Med 1999, 341:1865–1873.
Marzolini C, Telenti A, Decosterd LA, et al.: Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS 2001, 15:71–75.
Barrett JS, Joshi AS, Chai M, et al.: Population pharmacokinetic meta-analysis with efavirenz. Int J Clin Pharmacol Ther 2002, 40:507–519.
Pfister M, Labbe L, Hammer SM, et al.: Population pharmacokinetics and pharmacodynamics of efavirenz, nelfinavir, and indinavir: Adult AIDS Clinical Trial Group Study 398. Antimicrob Agents Chemother 2003, 47:130–137.
Ribaudo H, Clifford D, Gulick R, et al.: Relationships between efavirenz pharmacokinetics, side effects, drug discontinuation, virologic response, and race: results from ACTG A5095/A5097s [abstract 132]. Paper presented at 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA; February 8–11, 2004.
Ward BA, Gorski JC, Jones DR, et al.: The cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism: implication for HIV/AIDS therapy and utility of efavirenz as a substrate marker of CYP2B6 catalytic activity. J Pharmacol Exp Ther 2003, 306:287–300.
Lamba V, Lamba J, Yasuda K, et al.: Hepatic CYP2B6 expression: gender and ethnic differences and relationship to CYP2B6 genotype and CAR expression. J Pharmacol Exp Ther 2003, 3:906–922.
Lang T, Klein K, Fischer J, et al.: Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. Pharmacogenetics 2001, 11:399–415.
Kirchheiner J, Klein C, Meineke I, et al.: Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6. Pharmacogenetics 2003, 13:619–626.
Haas DW, Ribaudo HJ, Kim RB, et al.: Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS 2004, 18:2391–2400. This seminal study established that a frequent CYP2B6 polymorphism is associated with increased plasma efavirenz exposure and increased central nervous system side effects. This polymorphism may help to explain previously reported racial differences in plasma efavirenz clearance.
Haas DW, Smeaton LM, Shafer RW, et al.: Pharmacogenetics of long-term responses to antiretroviral regimens containing efavirenz and/or nelfinavir: an Adult AIDS Clinical Trials Group study. J Infect Dis 2005, 192: 1931–1942.
Ribaudo HJ, Haas DW, Tierney C, et al.: Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: an Adult AIDS Clinical Trials Group Study. Clin Infect Dis 2006, 42:401–407.
Mallal SA, John M, Moore CB, et al.: Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection. AIDS 2000, 14:1309–1316.
Bastard JP, Caron M, Vidal H, et al.: Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance. Lancet 2002, 359:1026–1031.
Sethi JK, Hotamisligil GS: The role of TNF alpha in adipocyte metabolism. Semin Cell Dev Biol 1999, 10:19–29.
Maher B, Alfirevic A, Vilar FJ, et al.: TNF-alpha promoter region gene polymorphisms in HIV-positive patients with lipodystrophy. AIDS 2002, 16:2013–2018.
Nolan D, Moore C, Castley A, et al.: Tumor necrosis factoralpha gene -238G/A promoter polymorphism associated with a more rapid onset of lipodystrophy. AIDS 2003, 17:121–123.
Lee CG, Gottesman MM: HIV-1 protease inhibitors and the MDR1 multidrug transporter. J Clin Invest 1998, 101:287–288.
Kim RB, Fromm MF, Wandel C, et al.: The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest 1998, 101:289–294.
Srinivas RV, Middlemas D, Flynn P, Fridland A: Human immunodefiency virus protease inhibitors serve as substrates for multidrug transporter proteins MDR1 and MRP1 but retain antiviral efficy in cell lines expressing these transporters. Antimicrob Agents Chemo 1998, 42:3157–3162.
Polli JW, Jarrett JL, Studenberg SD, et al.: Role of Pglycoprotein on the CNS disposition of amprenavir (141W94), an HIV protease inhibitor. Pharmaceutical Res 1999, 16:1206–1212.
Washington CB, Wiltshire HR, Man M, et al.: The disposition of saquinavir in normal and P-glycoprotein deficient mice, rats, and in cultured cells. Drug Metabol Disp 2000, 28:1058–1062.
Marzolini C, Paus E, Buclin T, Kim RB: Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther 2004, 75:13–33. This excellent review summarized the state of knowledge regarding MDR1 genetic variants and their potential clinical relevance.
Fellay J, Marzolini C, Meaden ER, et al.: Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet 2002, 359:30–36.
Brumme ZL, Dong WW, Chan KJ, et al.: Influence of polymorphisms within the CX3CR1 and MDR-1 genes on initial antiretroviral therapy response. AIDS 2003, 17:201–208.
Nasi M, Borghi V, Pinti M, et al.: MDR1 C3435T genetic polymorphism does not influence the response to antiretroviral therapy in drug-naive HIV-positive patients. AIDS 2003, 17:1696–1698.
Haas DW, Wu H, Li H, et al.: MDR1 gene polymorphisms and phase 1 viral decay during HIV-1 infection: an adult AIDS Clinical Trials Group study. J Acquir Immune Defic Syndr 2003, 34:295–298.
Rotger M, Colombo S, Furrer H, et al.: Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients. Pharmacogenet Genomics 2005, 15:1–5.
Price P, James I, Fernandez S, French MA: Alleles of the gene encoding IL-1alpha may predict control of plasma viraemia in HIV-1 patients on highly active antiretroviral therapy. AIDS 2004, 18:1495–1501.
Haas DW, Bartlett JA, Andersen JA, et al.: Pharmacogenetics of nevirapine (NVP) and hepatotoxicity: an AACTG Collaborative study. Presented at the 12th Conference on Retroviruses and Opportunistic Infections. Boston, MA; February 22–25, 2005.
Ritchie MD, Haas DW, Motsinger AA, et al.: Genetic variation in drug transporter and metabolizing enzyme genes may be associated with non-nucleoside reverse transcriptase inhibitor (NNRTI) hepatotoxicity. Presented at the 12th Conference on Retroviruses and Opportunistic Infections. Boston, MA 2005; February 22–25, 2005.
Hulgan T, Haas DW, Haines JL, et al.: Mitochondrial haplogroups and peripheral neuropathy during antiretroviral therapy: an adult AIDS clinical trials group study. AIDS 2005, 19:1341–1349. This is the first study to suggest that interindividual differences in mitochondrial genetics may predispose to NRTI toxicity.
Martin AM, Nolan D, James I, et al.: Predisposition to nevirapine hypersensitivity associated with HLADRB1 0101 and abrogated by low CD4 T-cell counts. AIDS 2005, 19:97–99.
Tarr PE, Taffe P, Bleiber G, et al.: Modeling the influence of APOC3, APOE, and TNF polymorphisms on the risk of antiretroviral therapy-associated lipid disorders. J Infect Dis 2005, 191:1419–1426. This study, with Foulkes et al. [50], highlights the complexity involved in attempting to discern an underlying genetic predisposition to drug-induced dyslipidemia.
Foulkes AS, Wohl DA, Frank I, et al.: Associations among race/ethnicity, ApoC-III genotypes, and lipids in HIV-1-infected individuals on antiretroviral therapy. PLoS Med 2006, 3-e53:0001–011. This study, with Tarr et al. [49], highlights the complexity involved in attempting to discern an underlying genetic predisposition to drug-induced dyslipidemia.
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Haas, D.W. Human genetic variability and HIV treatment response. Curr HIV/AIDS Rep 3, 53–58 (2006). https://doi.org/10.1007/s11904-006-0018-x
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DOI: https://doi.org/10.1007/s11904-006-0018-x