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Annual Review of Pharmacology and Toxicology

Volume 61, 2021

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.

Keyword(s): drug metabolism, drug-drug interactions, HIV medication, personalized medicine, pharmacogenomics
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/content/journals/10.1146/annurev-pharmtox-021320-111248
2021-01-06
2024-04-25
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Literature Cited

  1. 1. 
    Prince PD, Matser A, van Tienen C, Whittle HC, Schim van der Loeff MF 2014. Mortality rates in people dually infected with HIV-1/2 and those infected with either HIV-1 or HIV-2: a systematic review and meta-analysis. AIDS 28:4549–58
     [Google Scholar]
  2. 2. 
    Cock KMD, Adjorlolo G, Ekpini E, Sibailly T, Kouadio J et al. 1993. Epidemiology and transmission of HIV-2: why there is no HIV-2 pandemic. JAMA 270:172083–86
     [Google Scholar]
  3. 3. 
    UNAIDS. 2019. UNAIDS data 2019 Rep., UNAIDS Geneva:
  4. 4. 
    WHO (World Health Organ.). 2017. Consolidated guidelines on HIV prevention, diagnosis, treatment and care for key populations Policy Brief, WHO Geneva:
  5. 5. 
    Eisinger RW, Dieffenbach CW, Fauci AS 2019. HIV viral load and transmissibility of HIV infection: Undetectable equals untransmittable. JAMA 321:5451–52
     [Google Scholar]
  6. 6. 
    Montessori V, Press N, Harris M, Akagi L, Montaner JSG 2004. Adverse effects of antiretroviral therapy for HIV infection. CMAJ 170:2229–38
     [Google Scholar]
  7. 7. 
    Pirmohamed M, Back DJ. 2001. The pharmacogenomics of HIV therapy. Pharmacogenom. J. 1:4243–53
     [Google Scholar]
  8. 8. 
    Lewis DF. 2003. Human cytochromes P450 associated with the phase 1 metabolism of drugs and other xenobiotics: a compilation of substrates and inhibitors of the CYP1, CYP2 and CYP3 families. Curr. Med. Chem. 10:191955–72
     [Google Scholar]
  9. 9. 
    Dutton G. 2019. Glucuronidation of Drugs and Other Compounds Boca Raton, FL: CRC Press
  10. 10. 
    Lin C, Shi J, Moore A, Khetani SR 2016. Prediction of drug clearance and drug-drug interactions in microscale cultures of human hepatocytes. Drug Metab. Dispos. 44:1127–36
     [Google Scholar]
  11. 11. 
    Zimmermann M, Zimmermann-Kogadeeva M, Wegmann R, Goodman AL 2019. Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature 570:7762462–67
     [Google Scholar]
  12. 12. 
    Kirchmair J, Göller AH, Lang D, Kunze J, Testa B et al. 2015. Predicting drug metabolism: experiment and/or computation. ? Nat. Rev. Drug Discov. 14:6387–404
     [Google Scholar]
  13. 13. 
    Niyonsaba E, Easton MW, Feng E, Yu Z, Zhang Z et al. 2019. Differentiation of deprotonated acyl-, N-, and O-glucuronide drug metabolites by using tandem mass spectrometry based on gas-phase ion–molecule reactions followed by collision-activated dissociation. Anal. Chem. 91:1711388–96
     [Google Scholar]
  14. 14. 
    Lee VHL, Sporty JL, Fandy TE 2001. Pharmacogenomics of drug transporters: the next drug delivery challenge. Adv. Drug Deliv. Rev. 50:S33–40
     [Google Scholar]
  15. 15. 
    Garte S, Gaspari L, Alexandrie A-K, Ambrosone C, Autrup H et al. 2001. Metabolic gene polymorphism frequencies in control populations. Cancer Epidemiol. Biomarkers Prev. 10:121239–48
     [Google Scholar]
  16. 16. 
    Dep. Health Hum. Serv. 2018. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV Guid., Dept. Health Hum. Serv Washington, DC:
  17. 17. 
    Esté JA, Telenti A. 2007. HIV entry inhibitors. Lancet 370:958181–88
     [Google Scholar]
  18. 18. 
    Kadow J, Wang HG, Lin PF 2006. Small-molecule HIV-1 gp120 inhibitors to prevent HIV-1 entry: an emerging opportunity for drug development. Curr. Opin. Investig. Drugs 7:8721–26
     [Google Scholar]
  19. 19. 
    Alessandri-Gradt E, Charpentier C, Leoz M, Mourez T, Descamps D, Plantier J-C 2018. Impact of natural polymorphisms of HIV-1 non-group M on genotypic susceptibility to the attachment inhibitor fostemsavir. J. Antimicrob. Chemother. 73:102716–20
     [Google Scholar]
  20. 20. 
    Patel IH, Zhang X, Nieforth K, Salgo M, Buss N 2005. Pharmacokinetics, pharmacodynamics and drug interaction potential of enfuvirtide. Clin. Pharmacokinet. 44:2175–86
     [Google Scholar]
  21. 21. 
    Joly V, Jidar K, Tatay M, Yeni P 2010. Enfuvirtide: from basic investigations to current clinical use. Expert Opin. Pharmacother. 11:162701–13
     [Google Scholar]
  22. 22. 
    Lu Y, Hendrix CW, Bumpus NN 2012. Cytochrome P450 3A5 plays a prominent role in the oxidative metabolism of the anti-human immunodeficiency virus drug maraviroc. Drug Metab. Dispos. 40:122221–30
     [Google Scholar]
  23. 23. 
    Furman PA, Fyfe JA, Clair MHS, Weinhold K, Rideout JL et al. 1986. Phosphorylation of 3′-azido-3′-deoxythymidine and selective interaction of the 5′-triphosphate with human immunodeficiency virus reverse transcriptase. PNAS 83:218333–37
     [Google Scholar]
  24. 24. 
    Kiang TKL, Wilby KJ, Ensom MHH 2016. In vitro reaction phenotyping and drug interaction data. Pharmacokinetic and Pharmacodynamic Drug Interactions Associated with Antiretroviral Drugs TKL Kiang, KJ Wilby, MHH Ensom 27–41 Singapore: Springer
     [Google Scholar]
  25. 25. 
    Lu Y, Fuchs EJ, Hendrix CW, Bumpus NN 2014. CYP3A5 genotype impacts maraviroc concentrations in healthy volunteers. Drug Metab. Dispos. 42:111796–802
     [Google Scholar]
  26. 26. 
    Siedner MJ, Tumarkin E, Bogoch II 2018. HIV post-exposure prophylaxis (PEP). BMJ 363:k4928
     [Google Scholar]
  27. 27. 
    Coelho LE, Torres TS, Veloso VG, Landovitz RJ, Grinsztejn B 2019. Pre-exposure prophylaxis 2.0: new drugs and technologies in the pipeline. Lancet HIV 6:11e788–99
     [Google Scholar]
  28. 28. 
    Piliero PJ. 2004. Pharmacokinetic properties of nucleoside/nucleotide reverse transcriptase inhibitors. J. Acquir. Immune Defic. Syndr. 37:S2–12
     [Google Scholar]
  29. 29. 
    Solas C, Li Y-F, Xie M-Y, Sommadossi J-P, Zhou X-J 1998. Intracellular nucleotides of (−)-2′,3′-deoxy-3′-thiacytidine in peripheral blood mononuclear cells of a patient infected with human immunodeficiency virus. Antimicrob. Agents Chemother. 42:112989–95
     [Google Scholar]
  30. 30. 
    Lade JM, To EE, Hendrix CW, Bumpus NN 2015. Discovery of genetic variants of the kinases that activate tenofovir in a compartment-specific manner. EBioMedicine 2:91145–52
     [Google Scholar]
  31. 31. 
    Hamlin AN, Tillotson J, Bumpus NN 2019. Genetic variation of kinases and activation of nucleotide analog reverse transcriptase inhibitor tenofovir. Pharmacogenomics 20:2105–11
     [Google Scholar]
  32. 32. 
    Chen J, Flexner C, Liberman RG, Skipper PL, Louissaint N et al. 2012. Biphasic elimination of tenofovir diphosphate and nonlinear pharmacokinetics of zidovudine triphosphate in a microdosing study. J. Acquir. Immune Defic. Syndr. 61:5593–99
     [Google Scholar]
  33. 33. 
    Barbier O, Turgeon D, Girard C, Green MD, Tephly TR et al. 2000. 3′-Azido-3′-deoxythimidine (AZT) is glucuronidated by human UDP-glucuronosyltransferase 2B7 (UGT2B7). Drug Metab. Dispos. 28:5497–502
     [Google Scholar]
  34. 34. 
    Acosta EP, Page LM, Fletcher CV 1996. Clinical pharmacokinetics of zidovudine. Clin. Pharmacokinet. 30:4251–62
     [Google Scholar]
  35. 35. 
    Gallicano KD, Sahai J, Shukla VK, Seguin I, Pakuts A et al. 1999. Induction of zidovudine glucuronidation and amination pathways by rifampicin in HIV-infected patients. Br. J. Clin. Pharmacol. 48:2168–79
     [Google Scholar]
  36. 36. 
    Cretton EM, Xie MY, Bevan RJ, Goudgaon NM, Schinazi RF, Sommadossi JP 1991. Catabolism of 3′-azido-3′-deoxythymidine in hepatocytes and liver microsomes, with evidence of formation of 3′-amino-3′-deoxythymidine, a highly toxic catabolite for human bone marrow cells. Mol. Pharmacol. 39:2258–66
     [Google Scholar]
  37. 37. 
    Cretton EM, Sommadossi JP. 1993. Reduction of 3′-azido-2′,3′-dideoxynucleosides to their 3′-amino metabolite is mediated by cytochrome P-450 and NADPH-cytochrome P-450 reductase in rat liver microsomes. Drug Metab. Dispos. 21:5946–50
     [Google Scholar]
  38. 38. 
    Bowman JE, Frischer H, Ajmar F, Carson PE, Gower MK 1967. Population, family and biochemical investigation of human adenylate kinase polymorphism. Nature 214:50931156–58
     [Google Scholar]
  39. 39. 
    Figueroa DB, Tillotson J, Li M, Piwowar-Manning E, Hendrix CW et al. 2018. Discovery of genetic variants of the kinases that activate tenofovir among individuals in the United States, Thailand, and South Africa: HPTN067. PLOS ONE 13:4e0195764
     [Google Scholar]
  40. 40. 
    Kim YK, Choi MJ, Oh TY, Yu K-S, Lee S 2017. A comparative pharmacokinetic and tolerability analysis of the novel orotic acid salt form of tenofovir disoproxil and the fumaric acid salt form in healthy subjects. Drug Des. Dev. Ther. 11:3171–77
     [Google Scholar]
  41. 41. 
    Nekvindová J, Mašek V, Veinlichová A, Anzenbacherová E, Anzenbacher P et al. 2006. Inhibition of human liver microsomal cytochrome P450 activities by adefovir and tenofovir. Xenobiotica 36:121165–77
     [Google Scholar]
  42. 42. 
    Figueroa DB, Madeen EP, Tillotson J, Richardson P, Cottle L et al. 2018. Genetic variation of the kinases that phosphorylate tenofovir and emtricitabine in peripheral blood mononuclear cells. AIDS Res. Hum. Retrovir. 34:5421–29
     [Google Scholar]
  43. 43. 
    To E, Bumpus NN. 2013. Mucosal expression of the cytochromes P450 (CYP) and nucleotide kinases involved in the biotransformation of drugs used in human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP). FASEB J 27:Suppl. 1664.7
     [Google Scholar]
  44. 44. 
    Bousquet L, Pruvost A, Didier N, Farinotti R, Mabondzo A 2008. Emtricitabine: inhibitor and substrate of multidrug resistance associated protein. Eur. J. Pharm. Sci. 35:4247–56
     [Google Scholar]
  45. 45. 
    Schinkmanová M, Votruba I, Holý A 2006. N6-Methyl-AMP aminohydrolase activates N6-substituted purine acyclic nucleoside phosphonates. Biochem. Pharmacol. 71:91370–76
     [Google Scholar]
  46. 46. 
    Barbarino JM, Kroetz DL, Altman RB, Klein TE 2014. PharmGKB summary: abacavir pathway. Pharmacogenet. Genom. 24:5276–82
     [Google Scholar]
  47. 47. 
    Faletto MB, Miller WH, Garvey EP, Clair MHS, Daluge SM, Good SS 1997. Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89. Antimicrob. Agents Chemother. 41:51099–107
     [Google Scholar]
  48. 48. 
    Grilo NM, Antunes AMM, Caixas U, Marinho AT, Charneira C et al. 2013. Monitoring abacavir bioactivation in humans: screening for an aldehyde metabolite. Toxicol. Lett. 219:159–64
     [Google Scholar]
  49. 49. 
    Mallal S, Phillips E, Carosi G, Molina J-M, Workman C et al. 2008. HLA-B*5701 screening for hypersensitivity to abacavir. N. Engl. J. Med. 358:6568–79
     [Google Scholar]
  50. 50. 
    Pruvost A, Negredo E, Benech H, Theodoro F, Puig J et al. 2005. Measurement of intracellular didanosine and tenofovir phosphorylated metabolites and possible interaction of the two drugs in human immunodeficiency virus-infected patients. Antimicrob. Agents Chemother. 49:51907–14
     [Google Scholar]
  51. 51. 
    Ahluwalia G, Cooney DA, Hartman NR, Mitsuya H, Yarchoan R et al. 1993. Anomalous accumulation and decay of 2′,3′-dideoxyadenosine-5′-triphosphate in human T-cell cultures exposed to the anti-HIV drug 2′,3′-dideoxyinosine. Drug Metab. Dispos. 21:2369–76
     [Google Scholar]
  52. 52. 
    Holec AD, Mandal S, Prathipati PK, Destache CJ 2017. Nucleotide reverse transcriptase inhibitors: a thorough review, present status and future perspective as HIV therapeutics. Curr. HIV Res. 15:6411–21
     [Google Scholar]
  53. 53. 
    Makinson A, Pujol J-L, Le Moing V, Peyriere H, Reynes J 2010. Interactions between cytotoxic chemotherapy and antiretroviral treatment in human immunodeficiency virus-infected patients with lung cancer. J. Thor. Oncol. 5:4562–71
     [Google Scholar]
  54. 54. 
    Liou J-Y, Dutschman GE, Lam W, Jiang Z, Cheng Y-C 2002. Characterization of human UMP/CMP kinase and its phosphorylation of d- and l-form deoxycytidine analogue monophosphates. Cancer Res 62:61624–31
     [Google Scholar]
  55. 55. 
    Zhou Z, Rodman JH, Flynn PM, Robbins BL, Wilcox CK, D'Argenio DZ 2006. Model for intracellular lamivudine metabolism in peripheral blood mononuclear cells ex vivo and in human immunodeficiency virus type 1-infected adolescents. Antimicrob. Agents Chemother. 50:82686–94
     [Google Scholar]
  56. 56. 
    Choi M-K, Song I-S. 2012. Genetic variants of organic cation transporter 1 (OCT1) and OCT2 significantly reduce lamivudine uptake. Biopharm. Drug Dispos. 33:3170–78
     [Google Scholar]
  57. 57. 
    Kang H-J, Song I-S, Shin HJ, Kim W-Y, Lee C-H et al. 2007. Identification and functional characterization of genetic variants of human organic cation transporters in a Korean population. Drug Metab. Dispos. 35:4667–75
     [Google Scholar]
  58. 58. 
    Magula N, Dedicoat M. 2015. Low dose versus high dose stavudine for treating people with HIV infection. Cochrane Database Syst. Rev. 1:CD007497
     [Google Scholar]
  59. 59. 
    Moketla MB, Wadley AL, Kamerman P, de Assis Rosa D 2018. Pharmacogenetic variation influences sensory neuropathy occurrence in Southern Africans treated with stavudine-containing antiretroviral therapy. PLOS ONE 13:10e0204111
     [Google Scholar]
  60. 60. 
    Ho HT, Hitchcock MJ. 1989. Cellular pharmacology of 2′,3′-dideoxy-2′,3′-didehydrothymidine, a nucleoside analog active against human immunodeficiency virus. Antimicrob. Agents Chemother. 33:6844–49
     [Google Scholar]
  61. 61. 
    Domingo P, Cabeza MC, Pruvost A, Torres F, Salazar J et al. 2011. Association of thymidylate synthase gene polymorphisms with stavudine triphosphate intracellular levels and lipodystrophy. Antimicrob. Agents Chemother. 55:41428–35
     [Google Scholar]
  62. 62. 
    Sluis-Cremer N, Tachedjian G. 2008. Mechanisms of inhibition of HIV replication by non-nucleoside reverse transcriptase inhibitors. Virus Res 134:1147–56
     [Google Scholar]
  63. 63. 
    Kohlstaedt LA, Wang J, Friedman JM, Rice PA, Steitz TA 1992. Crystal structure at 3.5 Å resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science 256:50651783–90
     [Google Scholar]
  64. 64. 
    Condra JH, Emini EA, Gotlib L, Graham DJ, Schlabach AJ et al. 1992. Identification of the human immunodeficiency virus reverse transcriptase residues that contribute to the activity of diverse nonnucleoside inhibitors. Antimicrob. Agents Chemother. 36:71441–46
     [Google Scholar]
  65. 65. 
    Lallemant M, Jourdain G, Le Coeur S, Mary JY, Ngo-Giang-Huong N et al. 2004. Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand. N. Engl. J. Med. 351:3217–28
     [Google Scholar]
  66. 66. 
    Jao J, Sturdevant M, Martin JDR, Schiano T, Fiel MI, Huprikar S 2010. Nevirapine-induced Stevens Johnson–syndrome and fulminant hepatic failure requiring liver transplantation. Am. J. Transplant. 10:71713–16
     [Google Scholar]
  67. 67. 
    González de Requena D, Núñez M, Jiménez-Nácher I, Soriano V 2002. Liver toxicity caused by nevirapine. AIDS 16:2290–91
     [Google Scholar]
  68. 68. 
    Chen J, Mannargudi BM, Xu L, Uetrecht J 2008. Demonstration of the metabolic pathway responsible for nevirapine-induced skin rash. Chem. Res. Toxicol. 21:91862–70
     [Google Scholar]
  69. 69. 
    Antunes AMM, Godinho ALA, Martins IL, Oliveira MC, Gomes RA et al. 2010. Protein adducts as prospective biomarkers of nevirapine toxicity. Chem. Res. Toxicol. 23:111714–25
     [Google Scholar]
  70. 70. 
    Antunes AMM, Godinho ALA, Martins IL, Justino GC, Beland FA, Marques MM 2010. Amino acid adduct formation by the nevirapine metabolite, 12-hydroxynevirapine—a possible factor in nevirapine toxicity. Chem. Res. Toxicol. 23:5888–99
     [Google Scholar]
  71. 71. 
    Riska P, Lamson M, MacGregor T, Sabo J, Hattox S et al. 1999. Disposition and biotransformation of the antiretroviral drug nevirapine in humans. Drug Metab. Dispos. 27:8895–901
     [Google Scholar]
  72. 72. 
    Erickson DA, Mather G, Trager WF, Levy RH, Keirns JJ 1999. Characterization of the in vitro biotransformation of the HIV-1 reverse transcriptase inhibitor nevirapine by human hepatic cytochromes P-450. Drug Metab. Dispos. 27:121488–95
     [Google Scholar]
  73. 73. 
    Ciccacci C, Borgiani P, Ceffa S, Sirianni E, Marazzi MC et al. 2009. Nevirapine-induced hepatotoxicity and pharmacogenetics: a retrospective study in a population from Mozambique. Pharmacogenomics 11:123–31
     [Google Scholar]
  74. 74. 
    Chou M, Bertrand J, Segeral O, Verstuyft C, Borand L et al. 2010. Population pharmacokinetic-pharmacogenetic study of nevirapine in HIV-infected Cambodian patients. Antimicrob. Agents Chemother. 54:104432–39
     [Google Scholar]
  75. 75. 
    Haas DW, Bartlett JA, Andersen JW, Sanne I, Wilkinson GR et al. 2006. Pharmacogenetics of nevirapine-associated hepatotoxicity: an adult AIDS clinical trials group collaboration. Clin. Infect. Dis. 43:6783–86
     [Google Scholar]
  76. 76. 
    Ward BA, Gorski JC, Jones DR, Hall SD, Flockhart DA, Desta Z 2003. 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. 306:1287–300
     [Google Scholar]
  77. 77. 
    Avery LB, VanAusdall JL, Hendrix CW, Bumpus NN 2013. Compartmentalization and antiviral effect of efavirenz metabolites in blood plasma, seminal plasma, and cerebrospinal fluid. Drug Metab. Dispos. 41:2422–29
     [Google Scholar]
  78. 78. 
    Kappelhoff BS, van Leth F, Robinson PA, MacGregor TR, Baraldi E et al. 2005. Are adverse events of nevirapine and efavirenz related to plasma concentrations. Antivir. Ther. 10:4489–98
     [Google Scholar]
  79. 79. 
    Bumpus NN. 2011. Efavirenz and 8-hydroxyefavirenz induce cell death via a JNK- and BimEL-dependent mechanism in primary human hepatocytes. Toxicol. Appl. Pharmacol. 257:2227–34
     [Google Scholar]
  80. 80. 
    Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T 2001. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS 15:171–75
     [Google Scholar]
  81. 81. 
    Pérez-Molina JA. 2002. Safety and tolerance of efavirenz in different antiretroviral regimens: results from a national multicenter prospective study in 1,033 HIV-infected patients. HIV Clin. Trials 3:4279–86
     [Google Scholar]
  82. 82. 
    Lochet P, Peyrière H, Lotthé A, Mauboussin JM, Delmas B, Reynes J 2003. Long-term assessment of neuropsychiatric adverse reactions associated with efavirenz. HIV Med 4:162–66
     [Google Scholar]
  83. 83. 
    Rihs TA, Begley K, Smith DE, Sarangapany J, Callaghan A et al. 2006. Efavirenz and chronic neuropsychiatric symptoms: a cross-sectional case control study. HIV Med 7:8544–48
     [Google Scholar]
  84. 84. 
    Tovar-y-Romo LB, Bumpus NN, Pomerantz D, Avery LB, Sacktor N et al. 2012. Dendritic spine injury induced by the 8-hydroxy metabolite of efavirenz. J. Pharmacol. Exp. Ther. 343:3696–703
     [Google Scholar]
  85. 85. 
    Bélanger A-S, Caron P, Harvey M, Zimmerman PA, Mehlotra RK, Guillemette C 2009. Glucuronidation of the antiretroviral drug efavirenz by UGT2B7 and an in vitro investigation of drug-drug interaction with zidovudine. Drug Metab. Dispos. 37:91793–96
     [Google Scholar]
  86. 86. 
    Bae SK, Jeong Y-J, Lee C, Liu K-H 2011. Identification of human UGT isoforms responsible for glucuronidation of efavirenz and its three hydroxy metabolites. Xenobiotica 41:6437–44
     [Google Scholar]
  87. 87. 
    di Iulio J, Fayet A, Arab-Alameddine M, Rotger M, Lubomirov R et al. 2009. In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function. Pharmacogenet. Genom. 19:4300–9
     [Google Scholar]
  88. 88. 
    Desta Z, Gammal RS, Gong L, Whirl‐Carrillo M, Gaur AH et al. 2019. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2B6 and efavirenz-containing antiretroviral therapy. Clin. Pharmacol. Ther. 106:4726–33
     [Google Scholar]
  89. 89. 
    Nyakutira C, Röshammar D, Chigutsa E, Chonzi P, Ashton M et al. 2008. High prevalence of the CYP2B6 516G→T(*6) variant and effect on the population pharmacokinetics of efavirenz in HIV/AIDS outpatients in Zimbabwe. Eur. J. Clin. Pharmacol. 64:4357–65
     [Google Scholar]
  90. 90. 
    Richman DD, Havlir D, Corbeil J, Looney D, Ignacio C et al. 1994. Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J. Virol. 68:31660–66
     [Google Scholar]
  91. 91. 
    Bacheler L, Jeffrey S, Hanna G, D'Aquila R, Wallace L et al. 2001. Genotypic correlates of phenotypic resistance to efavirenz in virus isolates from patients failing nonnucleoside reverse transcriptase inhibitor therapy. J. Virol. 75:114999–5008
     [Google Scholar]
  92. 92. 
    Das K, Clark AD, Lewi PJ, Heeres J, de Jonge MR et al. 2004. Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants. J. Med. Chem. 47:102550–60
     [Google Scholar]
  93. 93. 
    Madruga JV, Cahn P, Grinsztejn B, Haubrich R, Lalezari J et al. 2007. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 370:958129–38
     [Google Scholar]
  94. 94. 
    Yanakakis LJ, Bumpus NN. 2012. Biotransformation of the antiretroviral drug etravirine: metabolite identification, reaction phenotyping, and characterization of autoinduction of cytochrome P450-dependent metabolism. Drug Metab. Dispos. 40:4803–14
     [Google Scholar]
  95. 95. 
    Lubomirov R, Arab-Alameddine M, Rotger M, Fayet-Mello A, Martinez R et al. 2013. Pharmacogenetics-based population pharmacokinetic analysis of etravirine in HIV-1 infected individuals. Pharmacogenet. Genom. 23:19–18
     [Google Scholar]
  96. 96. 
    Schöller-Gyüre M, Kakuda TN, Raoof A, De Smedt G, Hoetelmans RMW 2009. Clinical pharmacokinetics and pharmacodynamics of etravirine. Clin. Pharmacokinet. 48:9561–74
     [Google Scholar]
  97. 97. 
    Kakuda TN, Schöller-Gyüre M, Hoetelmans RMW 2011. Pharmacokinetic interactions between etravirine and non-antiretroviral drugs. Clin. Pharmacokinet. 50:125–39
     [Google Scholar]
  98. 98. 
    Lade JM, Avery LB, Bumpus NN 2013. Human biotransformation of the nonnucleoside reverse transcriptase inhibitor rilpivirine and a cross-species metabolism comparison. Antimicrob. Agents Chemother. 57:105067–79
     [Google Scholar]
  99. 99. 
    Aouri M, Barcelo C, Guidi M, Rotger M, Cavassini M et al. 2017. Population pharmacokinetics and pharmacogenetics analysis of rilpivirine in HIV-1-infected individuals. Antimicrob. Agents Chemother. 61:1e00899–16
     [Google Scholar]
  100. 100. 
    Weiss J, Haefeli WE. 2013. Potential of the novel antiretroviral drug rilpivirine to modulate the expression and function of drug transporters and drug-metabolising enzymes in vitro. Int. J. Antimicrob. Agents 41:5484–87
     [Google Scholar]
  101. 101. 
    Colombier M-A, Molina J-M. 2018. Doravirine: a review. Curr. Opin. HIV AIDS 13:4308–14
     [Google Scholar]
  102. 102. 
    Anderson MS, Gilmartin J, Cilissen C, De Lepeleire I, Van Bortel L et al. 2015. Safety, tolerability and pharmacokinetics of doravirine, a novel HIV non-nucleoside reverse transcriptase inhibitor, after single and multiple doses in healthy subjects. Antivir Ther 20:4397–405
     [Google Scholar]
  103. 103. 
    Sanchez RI, Fillgrove KL, Yee KL, Liang Y, Lu B et al. 2019. Characterisation of the absorption, distribution, metabolism, excretion and mass balance of doravirine, a non-nucleoside reverse transcriptase inhibitor in humans. Xenobiotica 49:4422–32
     [Google Scholar]
  104. 104. 
    Anderson MS, Khalilieh S, Yee KL, Liu R, Fan L et al. 2017. A two-way steady-state pharmacokinetic interaction study of doravirine (MK-1439) and dolutegravir. Clin. Pharmacokinet. 56:6661–69
     [Google Scholar]
  105. 105. 
    Khalilieh S, Yee KL, Sanchez RI, Triantafyllou I, Fan L et al. 2017. Results of a doravirine-atorvastatin drug-drug interaction study. Antimicrob. Agents Chemother. 61:2e01364–16
     [Google Scholar]
  106. 106. 
    Pommier Y, Johnson AA, Marchand C 2005. Integrase inhibitors to treat HIV/Aids. Nat. Rev. Drug Discov. 4:3236–48
     [Google Scholar]
  107. 107. 
    Chen X, Tsiang M, Yu F, Hung M, Jones GS et al. 2008. Modeling, analysis, and validation of a novel HIV integrase structure provide insights into the binding modes of potent integrase inhibitors. J. Mol. Biol. 380:3504–19
     [Google Scholar]
  108. 108. 
    WHO (World Health Organ.). 2018. Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV: interim guidelines: supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection Guid., WHO: Geneva
  109. 109. 
    Steigbigel RT, Cooper DA, Kumar PN, Eron JE, Schechter M et al. 2008. Raltegravir with optimized background therapy for resistant HIV-1 infection. N. Engl. J. Med. 359:4339–54
     [Google Scholar]
  110. 110. 
    Kassahun K, McIntosh I, Cui D, Hreniuk D, Merschman S et al. 2007. Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab. Dispos. 35:91657–63
     [Google Scholar]
  111. 111. 
    Belkhir L, Seguin-Devaux C, Elens L, Pauly C, Gengler N et al. 2018. Impact of UGT1A1 polymorphisms on Raltegravir and its glucuronide plasma concentrations in a cohort of HIV-1 infected patients. Sci. Rep. 8:17359
     [Google Scholar]
  112. 112. 
    Ramanathan S, Mathias AA, German P, Kearney BP 2011. Clinical pharmacokinetic and pharmacodynamic profile of the HIV integrase inhibitor elvitegravir. Clin. Pharmacokinet. 50:4229–44
     [Google Scholar]
  113. 113. 
    Mathias AA, German P, Murray BP, Wei L, Jain A et al. 2010. Pharmacokinetics and pharmacodynamics of GS-9350: a novel pharmacokinetic enhancer without anti-HIV activity. Clin. Pharmacol. Ther. 87:3322–29
     [Google Scholar]
  114. 114. 
    Moyle G. 2001. Use of HIV protease inhibitors as pharmacoenhancers. AIDS Read 11:287–98
     [Google Scholar]
  115. 115. 
    Larson KB, Wang K, Delille C, Otofokun I, Acosta EP 2014. Pharmacokinetic enhancers in HIV therapeutics. Clin. Pharmacokinet. 53:10865–72
     [Google Scholar]
  116. 116. 
    Lepist E-I, Phan TK, Roy A, Tong L, MacLennan K et al. 2012. Cobicistat boosts the intestinal absorption of transport substrates, including HIV protease inhibitors and GS-7340, in vitro. Antimicrob. Agents Chemother. 56:105409–13
     [Google Scholar]
  117. 117. 
    Mykietiuk A, Bonvehì P, Temporiti E, Uruena A, Herrera F, Vila A 2001. Clinical ergotism induced by ritonavir. Scand. J. Infect. Dis. 33:10788–89
     [Google Scholar]
  118. 118. 
    Zhou S-F, Xue CC, Yu X-Q, Li C, Wang G 2007. Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther. Drug Monit. 29:6687–710
     [Google Scholar]
  119. 119. 
    Josephson F. 2010. Drug-drug interactions in the treatment of HIV infection: focus on pharmacokinetic enhancement through CYP3A inhibition. J. Intern. Med. 268:6530–39
     [Google Scholar]
  120. 120. 
    Ramanathan S, Shen G, Hinkle J, Enejosa J, Kearney BP 2007. Pharmacokinetics of coadministered ritonavir-boosted elvitegravir and zidovudine, didanosine, stavudine, or abacavir. J. Acquir. Immune Defic. Syndr. 46:2160–66
     [Google Scholar]
  121. 121. 
    Karmon SL, Markowitz M. 2013. Next-generation integrase inhibitors. Drugs 73:3213–28
     [Google Scholar]
  122. 122. 
    Katlama C, Murphy R. 2012. Dolutegravir for the treatment of HIV. Expert Opin. Investig. Drugs 21:4523–30
     [Google Scholar]
  123. 123. 
    Castellino S, Moss L, Wagner D, Borland J, Song I et al. 2013. Metabolism, excretion, and mass balance of the HIV-1 integrase inhibitor dolutegravir in humans. Antimicrob. Agents Chemother. 57:83536–46
     [Google Scholar]
  124. 124. 
    Chen S, St Jean P, Borland J, Song I, Yeo AJ et al. 2013. Evaluation of the effect of UGT1A1 polymorphisms on dolutegravir pharmacokinetics. Pharmacogenomics 15:19–16
     [Google Scholar]
  125. 125. 
    Yagura H, Watanabe D, Kushida H, Tomishima K, Togami H et al. 2017. Impact of UGT1A1 gene polymorphisms on plasma dolutegravir trough concentrations and neuropsychiatric adverse events in Japanese individuals infected with HIV-1. BMC Infect. Dis. 17:1622
     [Google Scholar]
  126. 126. 
    de Boer MGJ, van den Berk GEL, van Holten N, Oryszcyn JE, Dorama W et al. 2016. Intolerance of dolutegravir-containing combination antiretroviral therapy regimens in real-life clinical practice. AIDS 30:182831–34
     [Google Scholar]
  127. 127. 
    Devanathan AS, Anderson DJC, Cottrell ML, Burgunder EM, Saunders AC, Kashuba ADM 2019. Contemporary drug-drug interactions in HIV treatment. Clin. Pharmacol. Ther. 105:61362–77
     [Google Scholar]
  128. 128. 
    Deeks ED. 2018. Bictegravir/emtricitabine/tenofovir alafenamide: a review in HIV-1 infection. Drugs 78:171817–28
     [Google Scholar]
  129. 129. 
    Flexner C. 1998. HIV-protease inhibitors. N. Engl. J. Med. 338:181281–93
     [Google Scholar]
  130. 130. 
    Kick EK, Ellman JA. 1995. Expedient method for the solid-phase synthesis of aspartic acid protease inhibitors directed toward the generation of libraries. J. Med. Chem. 38:91427–30
     [Google Scholar]
  131. 131. 
    Ali A, Bandaranayake RM, Cai Y, King NM, Kolli M et al. 2010. Molecular basis for drug resistance in HIV-1 protease. Viruses 2:112509–35
     [Google Scholar]
  132. 132. 
    Hirani VN, Raucy JL, Lasker JM 2004. Conversion of the HIV protease inhibitor nelfinavir to a bioactive metabolite by human liver CYP2C19. Drug Metab. Dispos. 32:121462–67
     [Google Scholar]
  133. 133. 
    Zhang KE, Wu E, Patick AK, Kerr B, Zorbas M et al. 2001. Circulating metabolites of the human immunodeficiency virus protease inhibitor nelfinavir in humans: structural identification, levels in plasma, and antiviral activities. Antimicrob. Agents Chemother. 45:41086–93
     [Google Scholar]
  134. 134. 
    Hirt D, Mentré F, Tran A, Rey E, Auleley S et al. 2008. Effect of CYP2C19 polymorphism on nelfinavir to M8 biotransformation in HIV patients. Br. J. Clin. Pharmacol. 65:4548–57
     [Google Scholar]
  135. 135. 
    Hughes PJ, Cretton-Scott E, Teague A, Wensel TM 2011. Protease inhibitors for patients with HIV-1 infection. P&T 36:6332–45
     [Google Scholar]
  136. 136. 
    Moyle GJ, Back D. 2001. Principles and practice of HIV-protease inhibitor pharmacoenhancement. HIV Med 2:2105–13
     [Google Scholar]
  137. 137. 
    Tseng A, Hughes CA, Wu J, Seet J, Phillips EJ 2017. Cobicistat versus ritonavir: similar pharmacokinetic enhancers but some important differences. Ann. Pharmacother. 51:111008–22
     [Google Scholar]
  138. 138. 
    Marzolini C, Gibbons S, Khoo S, Back D 2016. Cobicistat versus ritonavir boosting and differences in the drug-drug interaction profiles with co-medications. J. Antimicrob. Chemother. 71:71755–58
     [Google Scholar]
  139. 139. 
    Fichtenbaum CJ, Gerber JG, Rosenkranz SL, Segal Y, Aberg JA et al. 2002. Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG study A5047. AIDS 16:4569–77
     [Google Scholar]
  140. 140. 
    Zucker SD, Qin X, Rouster SD, Yu F, Green RM et al. 2001. Mechanism of indinavir-induced hyperbilirubinemia. PNAS 98:2212671–76
     [Google Scholar]
  141. 141. 
    Gammal RS, Court MH, Haidar CE, Iwuchukwu OF, Gaur AH et al. 2016. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for UGT1A1 and atazanavir prescribing. Clin. Pharmacol. Ther. 99:4363–69
     [Google Scholar]
  142. 142. 
    Lee CGL, Gottesman MM, Cardarelli CO, Ramachandra M, Jeang K-T et al. 1998. HIV-1 protease inhibitors are substrates for the MDR1 multidrug transporter. Biochemistry 37:113594–601
     [Google Scholar]
  143. 143. 
    Hartkoorn RC, San Kwan W, Shallcross V, Chaikan A, Liptrott N et al. 2010. HIV protease inhibitors are substrates for OATP1A2, OATP1B1 and OATP1B3 and lopinavir plasma concentrations are influenced by SLCO1B1 polymorphisms. Pharmacogenet. Genom. 20:2112–20
     [Google Scholar]
  144. 144. 
    Rodríguez-Nóvoa S, Barreiro P, Jiménez-Nácher I, Soriano V 2006. Overview of the pharmacogenetics of HIV therapy. Pharmacogenomics J 6:4234–45
     [Google Scholar]
  145. 145. 
    Jones K, Bray PG, Khoo SH, Davey RA, Meaden ER et al. 2001. P-glycoprotein and transporter MRP1 reduce HIV protease inhibitor uptake in CD4 cells: potential for accelerated viral drug resistance. ? AIDS 15:111353–58
     [Google Scholar]
  146. 146. 
    Choo EF, Leake B, Wandel C, Imamura H, Wood AJJ et al. 2000. Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. Drug Metab. Dispos. 28:6655–60
     [Google Scholar]
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Pharmacogenomics of Antiretroviral Drug Metabolism and Transport
Annual Review of Pharmacology and Toxicology 61, 565 (2021); https://doi.org/10.1146/annurev-pharmtox-021320-111248
/content/journals/10.1146/annurev-pharmtox-021320-111248
/content/journals/10.1146/annurev-pharmtox-021320-111248
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