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
相关论文
共 28 条
  • [11] Allele frequency net: a database and online repository for immune gene frequencies in worldwide populations
    Gonzalez-Galarza, Faviel F.
    Christmas, Stephen
    Middleton, Derek
    Jones, Andrew R.
    [J]. NUCLEIC ACIDS RESEARCH, 2011, 39 : D913 - D919
  • [12] Pharmacogenetics of nevirapine-associated hepatotoxicity: An adult AIDS clinical trials group collaboration
    Haas, David W.
    Bartlett, John A.
    Andersen, Janet W.
    Sanne, Ian
    Wilkinson, Grant R.
    Hinkle, John
    Rousseau, Franck
    Ingram, Christiana D.
    Shaw, Audrey
    Lederman, Michael M.
    Kim, Richard B.
    [J]. CLINICAL INFECTIOUS DISEASES, 2006, 43 (06) : 783 - 786
  • [13] Hoskins JM, 2009, CURR OPIN MOL THER, V11, P226
  • [14] Replication validity of genetic association studies
    Ioannidis, JPA
    Ntzani, EE
    Trikalinos, TA
    Contopoulos-Ioannidis, DG
    [J]. NATURE GENETICS, 2001, 29 (03) : 306 - 309
  • [15] Kappelhoff BS, 2005, ANTIVIR THER, V10, P489
  • [16] Appropriate use of nevirapine for long-term therapy
    Leith, J
    Piliero, P
    Storfer, S
    Mayers, D
    Hinzmann, R
    [J]. JOURNAL OF INFECTIOUS DISEASES, 2005, 192 (03) : 545 - 546
  • [17] HLA-Cw*04 allele associated with nevirapine-induced rash in HIV-infected Thai patients
    Likanonsakul S.
    Rattanatham T.
    Feangvad S.
    Uttayamakul S.
    Prasithsirikul W.
    Tunthanathip P.
    Nakayama E.E.
    Shioda T.
    [J]. AIDS Research and Therapy, 6 (1)
  • [18] HLA-dependent hypersensitivity to nevirapine in Sardinian HIV patients
    Littera, Roberto
    Carcassi, Carlo
    Masala, Alessandro
    Piano, Paola
    Serra, Paolo
    Ortu, Francesco
    Corso, Nicoletta
    Casula, Basilia
    La Nasa, Giorgio
    Contu, Licinio
    Manconi, Paolo Emilio
    [J]. AIDS, 2006, 20 (12) : 1621 - 1626
  • [19] Cytochrome P450 2B6 516G→T is associated with plasma concentrations of nevirapine at both 200 mg twice daily and 400 mg once daily in an ethnically diverse population
    Mahungu, T. W.
    Smith, C. J.
    Turner, F.
    Egan, D.
    Youle, M.
    Johnson, M. A.
    Khoo, S.
    Back, D. J.
    Owen, A.
    [J]. HIV MEDICINE, 2009, 10 (05) : 310 - 317
  • [20] Predisposition to nevirapine hypersensitivity associated with HLA-DRB1*0101 and abrogated by low CD4 T-cell counts
    Martin, AM
    Nolan, D
    James, I
    Cameron, P
    Keller, J
    Moore, C
    Phillips, E
    Christiansen, FT
    Mallal, S
    [J]. AIDS, 2005, 19 (01) : 97 - 99