Chapter 43 : Implications of Pharmacogenetics for Antimicrobial Prescribing

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Implications of Pharmacogenetics for Antimicrobial Prescribing, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555819071/9781555819088.ch43-1.gif /docserver/preview/fulltext/10.1128/9781555819071/9781555819088.ch43-2.gif


Antimicrobial efficacy and toxicity are influenced by the interplay of factors related to the human host, the microbe, and the drug (1–3). A number of such factors are represented in Fig. 1 (4). Antimicrobials can be described by characteristic pharmacokinetic (PK) and pharmacodynamic (PD) profiles, which in many cases are influenced by absorption, distribution, elimination, and metabolism (ADME) genes. While some antimicrobials are eliminated largely unchanged in urine (e.g., vancomycin) or stool (e.g., atovaquone), many undergo extensive metabolism by phase I enzymes (e.g., cytochrome P450 isoforms) and/or phase II enzymes (e.g., UDP-glucuronosyltransferases). The resultant metabolites may lack antimicrobial activity, or conversely the active moiety may be generated from an inactive parent compound (i.e., prodrug). Toxic and hypersensitivity reactions may be mediated by parent compounds or their metabolites, depending on the particular drug. Antimicrobial disposition is also affected by membrane transporters in various tissues including liver, intestine, kidney, genital tract, and brain (5–7). Genetic polymorphisms that affect ADME gene expression or protein activity may be associated with interindividual differences in exposure to parent compound and/or metabolites. Some of these genotype-phenotype associations have implications for efficacy and toxicity.

Citation: Aung A, Phillips E, Hulgan T, Haas D. 2016. Implications of Pharmacogenetics for Antimicrobial Prescribing, p 613-633. In Persing D, Tenover F, Hayden R, Ieven M, Miller M, Nolte F, Tang Y, van Belkum A (ed), Molecular Microbiology. ASM Press, Washington, DC. doi: 10.1128/9781555819071.ch43
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of FIGURE 1

Relationships among drug, pathogen, and host factors affecting antimicrobial treatment outcome. CCR5, C-C chemokine receptor type 5; HLA, human leukocyte antigen; PD, pharmacodynamics; PK, pharmacokinetics. Modified with permission from Pavlos and Phillips ( ).

Citation: Aung A, Phillips E, Hulgan T, Haas D. 2016. Implications of Pharmacogenetics for Antimicrobial Prescribing, p 613-633. In Persing D, Tenover F, Hayden R, Ieven M, Miller M, Nolte F, Tang Y, van Belkum A (ed), Molecular Microbiology. ASM Press, Washington, DC. doi: 10.1128/9781555819071.ch43
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Davison DB, Barrett JF . 2003. Antibiotics and pharmacogenomics. Pharmacogenomics 4 : 657 665[CrossRef].[PubMed]
2. McNicholl JM, Downer MV, Udhayakumar V, Alper CA, Swerdlow DL . 2000. Host-pathogen interactions in emerging and re-emerging infectious diseases: a genomic perspective of tuberculosis, malaria, human immunodeficiency virus infection, hepatitis B, and cholera. Annu Rev Public Health 21 : 15 46[CrossRef].[PubMed]
3. Tan SL, Ganji G, Paeper B, Proll S, Katze MG . 2007. Systems biology and the host response to viral infection. Nat Biotechnol 25 : 1383 1389[CrossRef].[PubMed]
4. Pavlos R, Phillips EJ . 2012. Individualization of antiretroviral therapy. Pharm Genomics Pers Med 5 : 1 17.[PubMed]
5. Ho RH, Kim RB . 2005. Transporters and drug therapy: implications for drug disposition and disease. Clin Pharmacol Ther 78 : 260 277[CrossRef].[PubMed]
6. Minuesa G, Huber-Ruano I, Pastor-Anglada M, Koepsell H, Clotet B, Martinez-Picado J . 2011. Drug uptake transporters in antiretroviral therapy. Pharmacol Ther 132 : 268 279[CrossRef].[PubMed]
7. Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, Dahlin A, Evers R, Fischer V, Hillgren KM, Hoffmaster KA, Ishikawa T, Keppler D, Kim RB, Lee CA, Niemi M, Polli JW, Sugiyama Y, Swaan PW, Ware JA, Wright SH, Yee SW, Zamek-Gliszczynski MJ, Zhang L , International Transporter Consortium . 2010. Membrane transporters in drug development. Nat Rev Drug Discov 9 : 215 236[CrossRef].[PubMed]
8. Wedi B . 2010. Definitions and mechanisms of drug hypersensitivity. Expert Rev Clin Pharmacol 3 : 539 551[CrossRef].[PubMed]
9. Johansson SG, Hourihane JO, Bousquet J, Bruijnzeel-Koomen C, Dreborg S, Haahtela T, Kowalski ML, Mygind N, Ring J, van Cauwenberge P, van Hage-Hamsten M, Wüthrich B , EAACI (the European Academy of Allergology and Cinical Immunology) nomenclature task force . 2001. A revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task force. Allergy 56 : 813 824.
10. Pavlos R, Mallal S, Phillips E . 2012. HLA and pharmacogenetics of drug hypersensitivity. Pharmacogenomics 13 : 1285 1306[CrossRef].[PubMed]
11. 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 : 287 300[CrossRef].[PubMed]
12. Riska P, Lamson M, MacGregor T, Sabo J, Hattox S, Pav J, Keirns J . 1999. Disposition and biotransformation of the antiretroviral drug nevirapine in humans. Drug Metab Dispos 27 : 895 901.[PubMed]
13. Bélanger AS, 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 : 1793 1796[CrossRef].[PubMed]
14. Haas DW, Ribaudo HJ, Kim RB, Tierney C, Wilkinson GR, Gulick RM, Clifford DB, Hulgan T, Marzolini C, Acosta EP . 2004. Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS 18 : 2391 2400.[PubMed]
15. Tsuchiya K, Gatanaga H, Tachikawa N, Teruya K, Kikuchi Y, Yoshino M, Kuwahara T, Shirasaka T, Kimura S, Oka S . 2004. Homozygous CYP2B6 *6 (Q172H and K262R) correlates with high plasma efavirenz concentrations in HIV-1 patients treated with standard efavirenz-containing regimens. Biochem Biophys Res Commun 319 : 1322 1326[CrossRef].[PubMed]
16. Rotger M, Colombo S, Furrer H, Bleiber G, Buclin T, Lee BL, Keiser O, Biollaz J, Décosterd L, Telenti A , Swiss HIV Cohort Study . 2005. Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients. Pharmacogenet Genomics 15 : 1 5[CrossRef].[PubMed]
17. Haas DW, Smeaton LM, Shafer RW, Robbins GK, Morse GD, Labbe L, Wilkinson GR, Clifford DB, D'Aquila RT, De Gruttola V, Pollard RB, Merigan TC, Hirsch MS, George AL Jr, Donahue JP, Kim RB . 2005. Pharmacogenetics of long-term responses to antiretroviral regimens containing efavirenz and/or nelfinavir: an Adult AIDS Clinical Trials Group Study. J Infect Dis 192 : 1931 1942[CrossRef].[PubMed]
18. Rodriguez-Novoa S, Barreiro P, Rendón A, Jiménez-Nacher I, González-Lahoz J, Soriano V . 2005. Influence of 516G>T polymorphisms at the gene encoding the CYP450-2B6 isoenzyme on efavirenz plasma concentrations in HIV-infected subjects. Clin Infect Dis 40 : 1358 1361[CrossRef].[PubMed]
19. Holzinger ER, Grady B, Ritchie MD, Ribaudo HJ, Acosta EP, Morse GD, Gulick RM, Robbins GK, Clifford DB, Daar ES, McLaren P, Haas DW . 2012. Genome-wide association study of plasma efavirenz pharmacokinetics in AIDS Clinical Trials Group protocols implicates several CYP2B6 variants. Pharmacogenet Genomics 22 : 858 867[CrossRef].[PubMed]
20. Wyen C, Hendra H, Vogel M, Hoffmann C, Knechten H, Brockmeyer NH, Bogner JR, Rockstroh J, Esser S, Jaeger H, Harrer T, Mauss S, van Lunzen J, Skoetz N, Jetter A, Groneuer C, Fätkenheuer G, Khoo SH, Egan D, Back DJ, Owen A , German Competence Network for HIV/AIDS . 2008. Impact of CYP2B6 983T>C polymorphism on non-nucleoside reverse transcriptase inhibitor plasma concentrations in HIV-infected patients. J Antimicrob Chemother 61 : 914 918[CrossRef].[PubMed]
21. Wang J, Sönnerborg A, Rane A, Josephson F, Lundgren S, Ståhle L, Ingelman-Sundberg M . 2006. Identification of a novel specific CYP2B6 allele in Africans causing impaired metabolism of the HIV drug efavirenz. Pharmacogenet Genomics 16 : 191 198.[PubMed]
22. Ribaudo HJ, Liu H, Schwab M, Schaeffeler E, Eichelbaum M, Motsinger-Reif AA, Ritchie MD, Zanger UM, Acosta EP, Morse GD, Gulick RM, Robbins GK, Clifford D, Haas DW . 2010. Effect of CYP2B6, ABCB1, and CYP3A5 polymorphisms on efavirenz pharmacokinetics and treatment response: an AIDS Clinical Trials Group study. J Infect Dis 202 : 717 722[CrossRef].[PubMed]
23. Kwara A, Lartey M, Sagoe KW, Rzek NL, Court MH . 2009. CYP2B6 (c.516G—>T) and CYP2A6 (*9B and/or *17) polymorphisms are independent predictors of efavirenz plasma concentrations in HIV-infected patients. Br J Clin Pharmacol 67 : 427 436[CrossRef].[PubMed]
24. di Iulio J, Fayet A, Arab-Alameddine M, Rotger M, Lubomirov R, Cavassini M, Furrer H, Günthard HF, Colombo S, Csajka C, Eap CB, Decosterd LA, Telenti A , Swiss HIV Cohort Study . 2009. In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function. Pharmacogenet Genomics 19 : 300 309[CrossRef].[PubMed]
25. Haas DW, Kwara A, Richardson DM, Baker P, Papageorgiou I, Acosta EP, Morse GD, Court MH . 2014. Secondary metabolism pathway polymorphisms and plasma efavirenz concentrations in HIV-infected adults with CYP2B6 slow metabolizer genotypes. J Antimicrob Chemother 69 : 2175 2182[CrossRef].[PubMed]
26. Kwara A, Lartey M, Sagoe KW, Kenu E, Court MH . 2009. CYP2B6, CYP2A6 and UGT2B7 genetic polymorphisms are predictors of efavirenz mid-dose concentration in HIV-infected patients. AIDS 23 : 2101 2106[CrossRef].[PubMed]
27. 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 : 71 75[CrossRef].[PubMed]
28. Gallego L, Barreiro P, del Río R, González de Requena D, Rodríguez-Albariño A, González-Lahoz J, Soriano V . 2004. Analyzing sleep abnormalities in HIV-infected patients treated with Efavirenz. Clin Infect Dis 38 : 430 432[CrossRef].[PubMed]
29. Gutiérrez F, Navarro A, Padilla S, Antón R, Masiá M, Borrás J, Martín-Hidalgo A . 2005. Prediction of neuropsychiatric adverse events associated with long-term efavirenz therapy, using plasma drug level monitoring. Clin Infect Dis 41 : 1648 1653[CrossRef].[PubMed]
30. Clifford DB, Evans S, Yang Y, Acosta EP, Goodkin K, Tashima K, Simpson D, Dorfman D, Ribaudo H, Gulick RM . 2005. Impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals. Ann Intern Med 143 : 714 721[CrossRef].[PubMed]
31. Fumaz CR, Muñoz-Moreno JA, Moltó J, Negredo E, Ferrer MJ, Sirera G, Pérez-Alvarez N, Gómez G, Burger D, Clotet B . 2005. Long-term neuropsychiatric disorders on efavirenz-based approaches: quality of life, psychologic issues, and adherence. J Acquir Immune Defic Syndr 38 : 560 565[CrossRef].[PubMed]
32. Takahashi M, Ibe S, Kudaka Y, Okumura N, Hirano A, Suzuki T, Mamiya N, Hamaguchi M, Kaneda T . 2007. No observable correlation between central nervous system side effects and EFV plasma concentrations in Japanese HIV type 1-infected patients treated with EFV containing HAART. AIDS Res Hum Retroviruses 23 : 983 987[CrossRef].[PubMed]
33. Read TR, Carey D, Mallon P, Mijch A, Goodall R, Hudson F, Wand H, Emery S . 2009. Efavirenz plasma concentrations did not predict cessation of therapy due to neuropsychiatric symptoms in a large randomized trial. AIDS 23 : 2222 2223[CrossRef].[PubMed]
34. Gounden V, van Niekerk C, Snyman T, George JA . 2010. Presence of the CYP2B6 516G> T polymorphism, increased plasma Efavirenz concentrations and early neuropsychiatric side effects in South African HIV-infected patients. AIDS Res Ther 7 : 32[CrossRef].[PubMed]
35. Johnson DH, Gebretsadik T, Shintani A, Mayo G, Acosta EP, Stein CM, Haas DW . 2013. Neuropsychometric correlates of efavirenz pharmacokinetics and pharmacogenetics following a single oral dose. Br J Clin Pharmacol 75 : 997 1006[CrossRef].[PubMed]
36. Gatanaga H, Hayashida T, Tsuchiya K, Yoshino M, Kuwahara T, Tsukada H, Fujimoto K, Sato I, Ueda M, Horiba M, Hamaguchi M, Yamamoto M, Takata N, Kimura A, Koike T, Gejyo F, Matsushita S, Shirasaka T, Kimura S, Oka S . 2007. Successful efavirenz dose reduction in HIV type 1-infected individuals with cytochrome P450 2B6 *6 and *26. Clin Infect Dis 45 : 1230 1237[CrossRef].[PubMed]
37. Haas DW, Severe P, Jean Juste MA, Pape JW, Fitzgerald DW . 2014. Functional CYP2B6 variants and virologic response to an efavirenz-containing regimen in Port-au-Prince, Haiti. J Antimicrob Chemother 69 : 2187 2190[CrossRef].[PubMed]
38. Puls R , ENCORE1 Study Group . 2013. A daily dose of 400mg efavirenz (EFV) is non-inferior to the standard 600mg dose: week 48 data from the ENCORE1 study, a randomised, double-blind, placebo controlled, non-inferiority trial, abst. WELBB01. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 2013.
39. Hicks JK, Crews KR, Flynn P, Haidar CE, Daniels CC, Yang W, Panetta JC, Pei D, Scott JR, Molinelli AR, Broeckel U, Bhojwani D, Evans WE, Relling MV . 2014. Voriconazole plasma concentrations in immunocompromised pediatric patients vary by CYP2C19 diplotypes. Pharmacogenomics 15 : 1065 1078[CrossRef].[PubMed]
40. Mikus G, Schöwel V, Drzewinska M, Rengelshausen J, Ding R, Riedel KD, Burhenne J, Weiss J, Thomsen T, Haefeli WE . 2006. Potent cytochrome P450 2C19 genotype-related interaction between voriconazole and the cytochrome P450 3A4 inhibitor ritonavir. Clin Pharmacol Ther 80 : 126 135[CrossRef].[PubMed]
41. Mikus G, Scholz IM, Weiss J . 2011. Pharmacogenomics of the triazole antifungal agent voriconazole. Pharmacogenomics 12 : 861 872[CrossRef].[PubMed]
42. Suzuki Y, Tokimatsu I, Sato Y, Kawasaki K, Sato Y, Goto T, Hashinaga K, Itoh H, Hiramatsu K, Kadota J . 2013. Association of sustained high plasma trough concentration of voriconazole with the incidence of hepatotoxicity. Clin Chim Acta 424 : 119 122[CrossRef].[PubMed]
43. Levin MD, den Hollander JG, van der Holt B, Rijnders BJ, van Vliet M, Sonneveld P, van Schaik RH . 2007. Hepatotoxicity of oral and intravenous voriconazole in relation to cytochrome P450 polymorphisms. J Antimicrob Chemother 60 : 1104 1107[CrossRef].[PubMed]
44. Matsumoto K, Ikawa K, Abematsu K, Fukunaga N, Nishida K, Fukamizu T, Shimodozono Y, Morikawa N, Takeda Y, Yamada K . 2009. Correlation between voriconazole trough plasma concentration and hepatotoxicity in patients with different CYP2C19 genotypes. Int J Antimicrob Agents 34 : 91 94[CrossRef].[PubMed]
45. Zonios D, Yamazaki H, Murayama N, Natarajan V, Palmore T, Childs R, Skinner J, Bennett JE . 2014. Voriconazole metabolism, toxicity, and the effect of cytochrome P450 2C19 genotype. J Infect Dis 209 : 1941 1948[CrossRef].[PubMed]
46. Hariprasad SM, Mieler WF, Holz ER, Gao H, Kim JE, Chi J, Prince RA . 2004. Determination of vitreous, aqueous, and plasma concentration of orally administered voriconazole in humans. Arch Ophthalmol 122 : 42 47[CrossRef].[PubMed]
47. Laties A, Zrenner E . 2002. Viagra (sildenafil citrate) and ophthalmology. Prog Retin Eye Res 21 : 485 506[CrossRef].[PubMed]
48. Sharma SK, Balamurugan A, Saha PK, Pandey RM, Mehra NK . 2002. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. Am J Respir Crit Care Med 166 : 916 919[CrossRef].[PubMed]
49. Huang YS, Chern HD, Su WJ, Wu JC, Chang SC, Chiang CH, Chang FY, Lee SD . 2003. Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology 37 : 924 930[CrossRef].[PubMed]
50. Vuilleumier N, Rossier MF, Chiappe A, Degoumois F, Dayer P, Mermillod B, Nicod L, Desmeules J, Hochstrasser D . 2006. CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis. Eur J Clin Pharmacol 62 : 423 429[CrossRef].[PubMed]
51. Roy B, Ghosh SK, Sutradhar D, Sikdar N, Mazumder S, Barman S . 2006. Predisposition of antituberculosis drug induced hepatotoxicity by cytochrome P450 2E1 genotype and haplotype in pediatric patients. J Gastroenterol Hepatol 21 : 784 786[CrossRef].[PubMed]
52. Cho HJ, Koh WJ, Ryu YJ, Ki CS, Nam MH, Kim JW, Lee SY . 2007. Genetic polymorphisms of NAT2 and CYP2E1 associated with antituberculosis drug-induced hepatotoxicity in Korean patients with pulmonary tuberculosis. Tuberculosis (Edinb) 87 : 551 556[CrossRef].[PubMed]
53. Huang YS, Su WJ, Huang YH, Chen CY, Chang FY, Lin HC, Lee SD . 2007. Genetic polymorphisms of manganese superoxide dismutase, NAD(P)H:quinone oxidoreductase, glutathione S-transferase M1 and T1, and the susceptibility to drug-induced liver injury. J Hepatol 47 : 128 134[CrossRef].[PubMed]
54. Roy PD, Majumder M, Roy B . 2008. Pharmacogenomics of anti-TB drugs-related hepatotoxicity. Pharmacogenomics 9 : 311 321[CrossRef].[PubMed]
55. Sun F, Chen Y, Xiang Y, Zhan S . 2008. Drug-metabolising enzyme polymorphisms and predisposition to anti-tuberculosis drug-induced liver injury: a meta-analysis. Int J Tuberc Lung Dis 12 : 994 1002.[PubMed]
56. Kim SH, Kim SH, Bahn JW, Kim YK, Chang YS, Shin ES, Kim YS, Park JS, Kim BH, Jang IJ, Song J, Kim SH, Park HS, Min KU, Jee YK . 2009. Genetic polymorphisms of drug-metabolizing enzymes and anti-TB drug-induced hepatitis. Pharmacogenomics 10 : 1767 1779[CrossRef].[PubMed]
57. Yamada S, Tang M, Richardson K, Halaschek-Wiener J, Chan M, Cook VJ, Fitzgerald JM, Elwood RK, Brooks-Wilson A, Marra F . 2009. Genetic variations of NAT2 and CYP2E1 and isoniazid hepatotoxicity in a diverse population. Pharmacogenomics 10 : 1433 1445[CrossRef].[PubMed]
58. Yamada S, Richardson K, Tang M, Halaschek-Wiener J, Cook VJ, Fitzgerald JM, Elwood K, Marra F, Brooks-Wilson A . 2010. Genetic variation in carboxylesterase genes and susceptibility to isoniazid-induced hepatotoxicity. Pharmacogenomics J 10 : 524 536[CrossRef].[PubMed]
59. Ramachandran G, Swaminathan S . 2012. Role of pharmacogenomics in the treatment of tuberculosis: a review. Pharm Genomics Pers Med 5 : 89 98.[PubMed]
60. Cai Y, Yi J, Zhou C, Shen X . 2012. Pharmacogenetic study of drug-metabolising enzyme polymorphisms on the risk of anti-tuberculosis drug-induced liver injury: a meta-analysis. PLoS One 7 : e47769[CrossRef].[PubMed]
61. Monteiro TP, El-Jaick KB, Jeovanio-Silva AL, Brasil PE, Costa MJ, Rolla VC, de Castro L . 2012. The roles of GSTM1 and GSTT1 null genotypes and other predictors in anti-tuberculosis drug-induced liver injury. J Clin Pharm Ther 37 : 712 718[CrossRef].[PubMed]
62. Azuma J, Ohno M, Kubota R, Yokota S, Nagai T, Tsuyuguchi K, Okuda Y, Takashima T, Kamimura S, Fujio Y, Kawase I , Pharmacogenetics-based tuberculosis therapy research group . 2013. NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: a randomized controlled trial for pharmacogenetics-based therapy. Eur J Clin Pharmacol 69 : 1091 1101[CrossRef].[PubMed]
63. Wang PY, Xie SY, Hao Q, Zhang C, Jiang BF . 2012. NAT2 polymorphisms and susceptibility to anti-tuberculosis drug-induced liver injury: a meta-analysis. Int J Tuberc Lung Dis 16 : 589 595.[PubMed]
64. Kim SH, Kim SH, Yoon HJ, Shin DH, Park SS, Kim YS, Park JS, Jee YK . 2012. TNF-α genetic polymorphism -308G/A and antituberculosis drug-induced hepatitis. Liver Int 32 : 809 814[CrossRef].[PubMed]
65. Yimer G, Ueda N, Habtewold A, Amogne W, Suda A, Riedel KD, Burhenne J, Aderaye G, Lindquist L, Makonnen E, Aklillu E . 2011. Pharmacogenetic & pharmacokinetic biomarker for efavirenz based ARV and rifampicin based anti-TB drug induced liver injury in TB-HIV infected patients. PLoS One 6 : e27810[CrossRef].[PubMed]
66. Tang S, Lv X, Zhang Y, Wu S, Yang Z, Xia Y, Tu D, Deng P, Ma Y, Chen D, Zhan S . 2013. Cytochrome P450 2E1 gene polymorphisms/haplotypes and anti-tuberculosis drug-induced hepatitis in a Chinese cohort. PLoS One 8 : e57526[CrossRef].[PubMed]
67. Nebert DW . 1997. Polymorphisms in drug-metabolizing enzymes: what is their clinical relevance and why do they exist? Am J Hum Genet 60 : 265 271.[PubMed]
68. Goel UC, Bajaj S, Gupta OP, Dwivedi NC, Dubey AL . 1992. Isoniazid induced neuropathy in slow versus rapid acetylators: an electrophysiological study. J Assoc Physicians India 40 : 671 672.[PubMed]
69. Yamamoto M, Sobue G, Mukoyama M, Matsuoka Y, Mitsuma T . 1996. Demonstration of slow acetylator genotype of N-acetyltransferase in isoniazid neuropathy using an archival hematoxylin and eosin section of a sural nerve biopsy specimen. J Neurol Sci 135 : 51 54[CrossRef].[PubMed]
70. Jaffe HS, Abrams DI, Ammann AJ, Lewis BJ, Golden JA . 1983. Complications of co-trimoxazole in treatment of AIDS-associated Pneumocystis carinii pneumonia in homosexual men. Lancet 2 : 1109 1111[CrossRef].[PubMed]
71. Leoung GS, Stanford JF, Giordano MF, Stein A, Torres RA, Giffen CA, Wesley M, Sarracco T, Cooper EC, Dratter V, Smith JJ, Frost KR , American Foundation for AIDS Research . (amfAR) Community-Based Clinical Trials Network. 2001. Trimethoprim-sulfamethoxazole (TMP-SMZ) dose escalation versus direct rechallenge for Pneumocystis Carinii pneumonia prophylaxis in human immunodeficiency virus-infected patients with previous adverse reaction to TMP-SMZ. J Infect Dis 184 : 992 997.
72. Lin D, Li WK, Rieder MJ . 2007. Cotrimoxazole for prophylaxis or treatment of opportunistic infections of HIV/AIDS in patients with previous history of hypersensitivity to cotrimoxazole. Cochrane Database Syst Rev 2 : CD005646.[PubMed]
73. Tilles SA . 2001. Practical issues in the management of hypersensitivity reactions: sulfonamides. South Med J 94 : 817 824[CrossRef].[PubMed]
74. Pirmohamed M, Alfirevic A, Vilar J, Stalford A, Wilkins EG, Sim E, Park BK . 2000. Association analysis of drug metabolizing enzyme gene polymorphisms in HIV-positive patients with co-trimoxazole hypersensitivity. Pharmacogenetics 10 : 705 713[CrossRef].[PubMed]
75. Wang D, Para MF, Koletar SL, Sadee W . 2011. Human N-acetyltransferase 1 *10 and *11 alleles increase protein expression through distinct mechanisms and associate with sulfamethoxazole-induced hypersensitivity. Pharmacogenet Genomics 21 : 652 664[CrossRef].[PubMed]
76. Wang D, Curtis A, Papp AC, Koletar SL, Para MF . 2012. Polymorphism in glutamate cysteine ligase catalytic subunit (GCLC) is associated with sulfamethoxazole-induced hypersensitivity in HIV/AIDS patients. BMC Med Genomics 5 : 32[CrossRef].[PubMed]
77. Kerb R, Fux R, Mörike K, Kremsner PG, Gil JP, Gleiter CH, Schwab M . 2009. Pharmacogenetics of antimalarial drugs: effect on metabolism and transport. Lancet Infect Dis 9 : 760 774[CrossRef].[PubMed]
78. Piedade R, Gil JP . 2011. The pharmacogenetics of antimalaria artemisinin combination therapy. Expert Opin Drug Metab Toxicol 7 : 1185 1200[CrossRef].[PubMed]
79. Roederer MW, McLeod H, Juliano JJ . 2011. Can pharmacogenomics improve malaria drug policy? Bull World Health Organ 89 : 838 845[CrossRef].[PubMed]
80. Di YM, Chow VDW, Yang LP, Zhou SF . 2009. Structure, function, regulation and polymorphism of human cytochrome P450 2A6. Curr Drug Metab 10 : 754 780[CrossRef].[PubMed]
81. Zanger UM, Schwab M . 2013. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 138 : 103 141[CrossRef].[PubMed]
82. Noedl H, Socheat D, Satimai W . 2009. Artemisinin-resistant malaria in Asia. N Engl J Med 361 : 540 541[CrossRef].[PubMed]
83. Phompradit P, Muhamad P, Cheoymang A, Na-Bangchang K . 2014. Preliminary investigation of the contribution of CYP2A6, CYP2B6, and UGT1A9 polymorphisms on artesunate-mefloquine treatment response in Burmese patients with Plasmodium falciparum malaria. Am J Trop Med Hyg 91 : 361 366[CrossRef].[PubMed]
84. Staehli Hodel EM, Csajka C, Ariey F, Guidi M, Kabanywanyi AM, Duong S, Decosterd LA, Olliaro P, Beck HP, Genton B . 2013. Effect of single nucleotide polymorphisms in cytochrome P450 isoenzyme and N-acetyltransferase 2 genes on the metabolism of artemisinin-based combination therapies in malaria patients from Cambodia and Tanzania. Antimicrob Agents Chemother 57 : 950 958[CrossRef].[PubMed]
85. Gil JP . 2008. Amodiaquine pharmacogenetics. Pharmacogenomics 9 : 1385 1390[CrossRef].[PubMed]
86. Parikh S, Ouedraogo JB, Goldstein JA, Rosenthal PJ, Kroetz DL . 2007. Amodiaquine metabolism is impaired by common polymorphisms in CYP2C8: implications for malaria treatment in Africa. Clin Pharmacol Ther 82 : 197 203[CrossRef].[PubMed]
87. Adjei GO, Kristensen K, Goka BQ, Hoegberg LC, Alifrangis M, Rodrigues OP, Kurtzhals JA . 2008. Effect of concomitant artesunate administration and cytochrome P4502C8 polymorphisms on the pharmacokinetics of amodiaquine in Ghanaian children with uncomplicated malaria. Antimicrob Agents Chemother 52 : 4400 4406[CrossRef].[PubMed]
88. Cavaco I, Piedade R, Msellem MI, Bjorkman A, Gil JP . 2012. Cytochrome 1A1 and 1B1 gene diversity in the Zanzibar islands. Trop Med Int Health 17 : 854 857[CrossRef].[PubMed]
89. Janha RE, Sisay-Joof F, Hamid-Adiamoh M, Worwui A, Chapman HL, Opara H, Dunyo S, Milligan P, Rockett K, Winstanley P, Pirmohamed M, Miller AK, Conway DJ, Walton RT . 2009. Effects of genetic variation at the CYP2C19/CYP2C9 locus on pharmacokinetics of chlorcycloguanil in adult Gambians. Pharmacogenomics 10 : 1423 1431[CrossRef].[PubMed]
90. Cappellini MD, Fiorelli G . 2008. Glucose-6-phosphate dehydrogenase deficiency. Lancet 371 : 64 74[CrossRef].[PubMed]
91. Toovey S . 2009. Mefloquine neurotoxicity: a literature review. Travel Med Infect Dis 7 : 2 6[CrossRef].[PubMed]
92. Aarnoudse AL, van Schaik RH, Dieleman J, Molokhia M, van Riemsdijk MM, Ligthelm RJ, Overbosch D, van der Heiden IP, Stricker BHC . 2006. MDR1 gene polymorphisms are associated with neuropsychiatric adverse effects of mefloquine. Clin Pharmacol Ther 80 : 367 374[CrossRef].[PubMed]
93. Fellay J, Thompson AJ, Ge D, Gumbs CE, Urban TJ, Shianna KV, Little LD, Qiu P, Bertelsen AH, Watson M, Warner A, Muir AJ, Brass C, Albrecht J, Sulkowski M, McHutchison JG, Goldstein DB . 2010. ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature 464 : 405 408[CrossRef].[PubMed]
94. Thompson AJ, Fellay J, Patel K, Tillmann HL, Naggie S, Ge D, Urban TJ, Shianna KV, Muir AJ, Fried MW . 2010. Variants in the ITPA gene protect against ribavirin-induced hemolytic anemia and decrease the need for ribavirin dose reduction. Gastroenterology 139 : 1181 1189. e1182.
95. Sakamoto N, Tanaka Y, Nakagawa M, Yatsuhashi H, Nishiguchi S, Enomoto N, Azuma S, Nishimura-Sakurai Y, Kakinuma S, Nishida N, Tokunaga K, Honda M, Ito K, Mizokami M, Watanabe M . 2010. ITPA gene variant protects against anemia induced by pegylated interferon-α and ribavirin therapy for Japanese patients with chronic hepatitis C. Hepatol Res 40 : 1063 1071[CrossRef].[PubMed]
96. Hitomi Y, Cirulli ET, Fellay J, McHutchison JG, Thompson AJ, Gumbs CE, Shianna KV, Urban TJ, Goldstein DB . 2011. Inosine triphosphate protects against ribavirin-induced adenosine triphosphate loss by adenylosuccinate synthase function. Gastroenterology 140 : 1314 1321[CrossRef].[PubMed]
97. Clark PJ, Aghemo A, Degasperi E, Galmozzi E, Urban TJ, Vock DM, Patel K, Thompson AJ, Rumi MG, D'Ambrosio R, Muir AJ, Colombo M . 2013. Inosine triphosphatase deficiency helps predict anaemia, anaemia management and response in chronic hepatitis C therapy. J Viral Hepat 20 : 858 866[CrossRef].[PubMed]
98. Rallón NI, Morello J, Labarga P, Benito JM, Rodríguez-Nóvoa S, Vispo E, Barreiro P, Castro , Aguirrebengoa K, Pineda JA, Miralles P, Tellez MJ, Portu J, Miralles C, Ocampo A, Soriano V , Peginterferon Ribavirin Coinfection Team . 2011. Impact of inosine triphosphatase gene variants on the risk of anemia in HIV/hepatitis C virus-coinfected patients treated for chronic hepatitis C. Clin Infect Dis 53 : 1291 1295[CrossRef].[PubMed]
99. Gallant JE, Staszewski S, Pozniak AL, DeJesus E, Suleiman JM, Miller MD, Coakley DF, Lu B, Toole JJ, Cheng AK , 903 Study Group . 2004. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 292 : 191 201.
100. Gallant JE, DeJesus E, Arribas JR, Pozniak AL, Gazzard B, Campo RE, Lu B, McColl D, Chuck S, Enejosa J, Toole JJ, Cheng AK , Study 934 Group . 2006. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 354 : 251 260[CrossRef].[PubMed]
101. Cassetti I, Madruga JV, Suleiman JM, Etzel A, Zhong L, Cheng AK, Enejosa J , Study 903E Team . 2007. The safety and efficacy of tenofovir DF in combination with lamivudine and efavirenz through 6 years in antiretroviral-naïve HIV-1-infected patients. HIV Clin Trials 8 : 164 172.
102. Molina JM, Andrade-Villanueva J, Echevarria J, Chetchotisakd P, Corral J, David N, Moyle G, Mancini M, Percival L, Yang R, Thiry A, McGrath D , CASTLE Study Team . 2008. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet 372 : 646 655[CrossRef].[PubMed]
103. Ortiz R, Dejesus E, Khanlou H, Voronin E, van Lunzen J, Andrade-Villanueva J, Fourie J, De Meyer S, De Pauw M, Lefebvre E, Vangeneugden T, Spinosa-Guzman S . 2008. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS 22 : 1389 1397[CrossRef].[PubMed]
104. Sax PE, Tierney C, Collier AC, Fischl MA, Mollan K, Peeples L, Godfrey C, Jahed NC, Myers L, Katzenstein D, Farajallah A, Rooney JF, Ha B, Woodward WC, Koletar SL, Johnson VA, Geiseler PJ, Daar ES , AIDS Clinical Trials Group Study A5202 Team . 2009. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med 361 : 2230 2240.
105. Lennox JL, DeJesus E, Lazzarin A, Pollard RB, Madruga JV, Berger DS, Zhao J, Xu X, Williams-Diaz A, Rodgers AJ, Barnard RJ, Miller MD, DiNubile MJ, Nguyen BY, Leavitt R, Sklar P , STARTMRK investigators . 2009. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet 374 : 796 806[CrossRef].[PubMed]
106. Post FA, Moyle GJ, Stellbrink HJ, Domingo P, Podzamczer D, Fisher M, Norden AG, Cavassini M, Rieger A, Khuong-Josses MA, Branco T, Pearce HC, Givens N, Vavro C, Lim ML . 2010. Randomized comparison of renal effects, efficacy, and safety with once-daily abacavir/lamivudine versus tenofovir/emtricitabine, administered with efavirenz, in antiretroviral-naive, HIV-1-infected adults: 48-week results from the ASSERT study. J Acquir Immune Defic Syndr 55 : 49 57[CrossRef].[PubMed]
107. Daar ES, Tierney C, Fischl MA, Sax PE, Mollan K, Budhathoki C, Godfrey C, Jahed NC, Myers L, Katzenstein D, Farajallah A, Rooney JF, Pappa KA, Woodward WC, Patterson K, Bolivar H, Benson CA, Collier AC , AIDS Clinical Trials Group Study A5202 Team . 2011. Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1. Ann Intern Med 154 : 445 456.
108. Rockstroh JK, Lennox JL, Dejesus E, Saag MS, Lazzarin A, Wan H, Walker ML, Xu X, Zhao J, Teppler H, Dinubile MJ, Rodgers AJ, Nguyen BY, Leavitt R, Sklar P , STARTMRK Investigators . 2011. Long-term treatment with raltegravir or efavirenz combined with tenofovir/emtricitabine for treatment-naive human immunodeficiency virus-1-infected patients: 156-week results from STARTMRK. Clin Infect Dis 53 : 807 816.
109. Cohen CJ, Molina JM, Cahn P, Clotet B, Fourie J, Grinsztejn B, Wu H, Johnson MA, Saag M, Supparatpinyo K, Crauwels H, Lefebvre E, Rimsky LT, Vanveggel S, Williams P, Boven K , ECHO Study Group, THRIVE Study Group . 2012. Efficacy and safety of rilpivirine (TMC278) versus efavirenz at 48 weeks in treatment-naive HIV-1-infected patients: pooled results from the phase 3 double-blind randomized ECHO and THRIVE Trials. J Acquir Immune Defic Syndr 60 : 33 42[CrossRef].[PubMed]
110. Gérard L, Chazallon C, Taburet AM, Girard PM, Aboulker JP, Piketty C . 2007. Renal function in antiretroviral-experienced patients treated with tenofovir disoproxil fumarate associated with atazanavir/ritonavir. Antivir Ther 12 : 31 39.[PubMed]
111. Goicoechea M, Liu S, Best B, Sun S, Jain S, Kemper C, Witt M, Diamond C, Haubrich R, Louie S , California Collaborative Treatment Group 578 Team . 2008. Greater tenofovir-associated renal function decline with protease inhibitor-based versus nonnucleoside reverse-transcriptase inhibitor-based therapy. J Infect Dis 197 : 102 108[CrossRef].[PubMed]
112. Horberg M, Tang B, Towner W, Silverberg M, Bersoff-Matcha S, Hurley L, Chang J, Blank J, Quesenberry C Jr, Klein D . 2010. Impact of tenofovir on renal function in HIV-infected, antiretroviral-naive patients. J Acquir Immune Defic Syndr 53 : 62 69[CrossRef].[PubMed]
113. Ray AS, Cihlar T, Robinson KL, Tong L, Vela JE, Fuller MD, Wieman LM, Eisenberg EJ, Rhodes GR . 2006. Mechanism of active renal tubular efflux of tenofovir. Antimicrob Agents Chemother 50 : 3297 3304[CrossRef].[PubMed]
114. Izzedine H, Hulot JS, Villard E, Goyenvalle C, Dominguez S, Ghosn J, Valantin MA, Lechat P, Deray AG . 2006. Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy. J Infect Dis 194 : 1481 1491[CrossRef].[PubMed]
115. Nishijima T, Komatsu H, Higasa K, Takano M, Tsuchiya K, Hayashida T, Oka S, Gatanaga H . 2012. Single nucleotide polymorphisms in ABCC2 associate with tenofovir-induced kidney tubular dysfunction in Japanese patients with HIV-1 infection: a pharmacogenetic study. Clin Infect Dis 55 : 1558 1567[CrossRef].[PubMed]
116. Pushpakom SP, Liptrott NJ, Rodríguez-Nóvoa S, Labarga P, Soriano V, Albalater M, Hopper-Borge E, Bonora S, Di Perri G, Back DJ, Khoo S, Pirmohamed M, Owen A . 2011. Genetic variants of ABCC10, a novel tenofovir transporter, are associated with kidney tubular dysfunction. J Infect Dis 204 : 145 153[CrossRef].[PubMed]
117. Lubomirov R, di Iulio J, Fayet A, Colombo S, Martinez R, Marzolini C, Furrer H, Vernazza P, Calmy A, Cavassini M, Ledergerber B, Rentsch K, Descombes P, Buclin T, Decosterd LA, Csajka C, Telenti A , Swiss HIV Cohort Study . 2010. ADME pharmacogenetics: investigation of the pharmacokinetics of the antiretroviral agent lopinavir coformulated with ritonavir. Pharmacogenet Genomics 20 : 217 230.[PubMed]
118. Hartkoorn RC, Kwan WS, Shallcross V, Chaikan A, Liptrott N, Egan D, Sora ES, James CE, Gibbons S, Bray PG, Back DJ, Khoo SH, Owen A . 2010. HIV protease inhibitors are substrates for OATP1A2, OATP1B1 and OATP1B3 and lopinavir plasma concentrations are influenced by SLCO1B1 polymorphisms. Pharmacogenet Genomics 20 : 112 120[CrossRef].[PubMed]
119. Kohlrausch FB, de Cássia Estrela R, Barroso PF, Suarez-Kurtz G . 2010. The impact of SLCO1B1 polymorphisms on the plasma concentration of lopinavir and ritonavir in HIV-infected men. Br J Clin Pharmacol 69 : 95 98[CrossRef].[PubMed]
120. Zhang X, Tierney C, Albrecht M, Demeter LM, Morse G, DiFrancesco R, Dykes C, Jiang H, Haas DW . 2013. Discordant associations between SLCO1B1 521T→C and plasma levels of ritonavir-boosted protease inhibitors in AIDS clinical trials group study A5146. Ther Drug Monit 35 : 209 216[CrossRef].[PubMed]
121. Haas DW, Smeaton LM, Shafer RW, Robbins GK, Morse GD, Labbé L, Wilkinson GR, Clifford DB, D'Aquila RT, De Gruttola V, Pollard RB, Merigan TC, Hirsch MS, George AL Jr, Donahue JP, Kim RB . 2005. Pharmacogenetics of long-term responses to antiretroviral regimens containing efavirenz and/or nelfinavir: an Adult AIDS Clinical Trials Group study. J Infect Dis 192 : 1931 1942[CrossRef].[PubMed]
122. Saitoh A, Capparelli E, Aweeka F, Sarles E, Singh KK, Kovacs A, Burchett SK, Wiznia A, Nachman S, Fenton T, Spector SA . 2010. CYP2C19 genetic variants affect nelfinavir pharmacokinetics and virologic response in HIV-1-infected children receiving highly active antiretroviral therapy. J Acquir Immune Defic Syndr 54 : 285 289[CrossRef].[PubMed]
123. Bertrand J, Treluyer JM, Panhard X, Tran A, Auleley S, Rey E, Salmon-Céron D, Duval X, Mentré F , COPHAR2-ANRS 111 Study Group . 2009. Influence of pharmacogenetics on indinavir disposition and short-term response in HIV patients initiating HAART. Eur J Clin Pharmacol 65 : 667 678[CrossRef].[PubMed]
124. Colombo S, Soranzo N, Rotger M, Sprenger R, Bleiber G, Furrer H, Buclin T, Goldstein D, Décosterd L, Telenti A , Swiss HIV Cohort Study . 2005. Influence of ABCB1, ABCC1, ABCC2, and ABCG2 haplotypes on the cellular exposure of nelfinavir in vivo. Pharmacogenet Genomics 15 : 599 608[CrossRef].[PubMed]
125. Elens L, Yombi JC, Lison D, Wallemacq P, Vandercam B, Haufroid V . 2009. Association between ABCC2 polymorphism and lopinavir accumulation in peripheral blood mononuclear cells of HIV-infected patients. Pharmacogenomics 10 : 1589 1597[CrossRef].[PubMed]
126. Foulkes AS, Wohl DA, Frank I, Puleo E, Restine S, Wolfe ML, Dube MP, Tebas P, Reilly MP . 2006. Associations among race/ethnicity, ApoC-III genotypes, and lipids in HIV-1-infected individuals on antiretroviral therapy. PLoS Med 3 : e52[CrossRef].[PubMed]
127. Arnedo M, Taffé P, Sahli R, Furrer H, Hirschel B, Elzi L, Weber R, Vernazza P, Bernasconi E, Darioli R, Bergmann S, Beckmann JS, Telenti A, Tarr PE , Swiss HIV Cohort Study . 2007. Contribution of 20 single nucleotide polymorphisms of 13 genes to dyslipidemia associated with antiretroviral therapy. Pharmacogenet Genomics 17 : 755 764[CrossRef].[PubMed]