Toxicogenomics of nevirapine-associated cutaneous and hepatic adverse events among populations of African, Asian, and European descent

被引:111
作者
Yuan, Jing [1 ]
Guo, Sheng [1 ]
Hall, David [2 ]
Cammett, Anna M. [3 ]
Jayadev, Supriya [4 ]
Distel, Manuel [5 ]
Storfer, Stephen [3 ]
Huang, Zimei [1 ]
Mootsikapun, Piroon [6 ]
Ruxrungtham, Kiat [7 ,8 ]
Podzamczer, Daniel [9 ]
Haas, David W. [10 ,11 ,12 ]
机构
[1] Boehringer Ingelheim Pharmaceut Inc, Nonclin Drug Safety, Ridgefield, CT 06877 USA
[2] Boehringer Ingelheim Pharmaceut Inc, Biometr & Data Management, Ridgefield, CT 06877 USA
[3] Boehringer Ingelheim Pharmaceut Inc, Med Affairs Virol, Ridgefield, CT 06877 USA
[4] Boehringer Ingelheim Pharmaceut Inc, Res Operat, Ridgefield, CT 06877 USA
[5] Boehringer Ingelheim GmbH & Co KG, Corp Dept Clin Dev & Med Affairs, Ingelheim, Germany
[6] Khon Kaen Univ, Fac Med, Dept Med, Khon Kaen, Thailand
[7] Chulalongkorn Univ, Fac Med, Thai Red Cross AIDS Res Ctr, HIV NAT, Bangkok 10330, Thailand
[8] Chulalongkorn Univ, Fac Med, Dept Med, Bangkok 10330, Thailand
[9] Hosp Univ Bellvitge, Infect Dis Serv, Barcelona, Spain
[10] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA
[11] Vanderbilt Univ, Sch Med, Dept Microbiol, Nashville, TN 37212 USA
[12] Vanderbilt Univ, Sch Med, Dept Immunol, Nashville, TN 37212 USA
关键词
CYP2B6; HIV; human leukocyte antigen; nevirapine; pharmacogenomics; rash; toxicogenomics; PLASMA-CONCENTRATIONS; HYPERSENSITIVITY; BIOTRANSFORMATION; PHARMACOGENETICS; HEPATOTOXICITY;
D O I
10.1097/QAD.0b013e32834779df
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Objective: Nevirapine is widely prescribed for HIV-1 infection. We characterized relationships between nevirapine-associated cutaneous and hepatic adverse events and genetic variants among HIV-infected adults. Design: We retrospectively identified cases and controls. Cases experienced symptomatic nevirapine-associated severe (grade III/IV) cutaneous and/or hepatic adverse events within 8 weeks of initiating nevirapine. Controls did not experience adverse events during more than 18 weeks of nevirapine therapy. Methods: Cases and controls were matched 1 : 2 on baseline CD4 T-cell count, sex, and race. Individuals with 150 or less CD4 T cells/mu l at baseline were excluded. We characterized 123 human leukocyte antigen (HLA) alleles and 2744 single-nucleotide polymorphisms in major histocompatibility complex (MHC) and drug metabolism and transport genes. Results: We studied 276 evaluable cases (175 cutaneous adverse events, 101 hepatic adverse events) and 587 controls. Cutaneous adverse events were associated with CYP2B6 516G -> T (OR 1.66, all), HLA-Cw*04 (OR 2.51, all), and HLA-B*35 (OR 3.47, Asians; 5.65, Thais). Risk for cutaneous adverse events was particularly high among Blacks with CYP2B6 516TT and HLA-Cw*04 (OR 18.90) and Asians with HLA-B*35 and HLA-Cw*04 (OR 18.34). Hepatic adverse events were associated with HLA-DRB*01 (OR 3.02, Whites), but not CYP2B6 genotypes. Associations differed by population, at least in part reflecting allele frequencies. Conclusion: Among patients with at least 150 CD4 T cells/mu l, polymorphisms in drug metabolism and immune response pathways were associated with greater likelihood of risk for nevirapine-related adverse events. Results suggest fundamentally different mechanisms of adverse events: cutaneous, most likely MHC class I-mediated, influenced by nevirapine CYP2B6 metabolism; hepatic, most likely MHC class II-mediated and unaffected by such metabolism. These risk variants are insensitive for routine clinical screening. (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins
引用
收藏
页码:1271 / 1280
页数:10
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