title: Toxicogenomics of nevirapine-associated cutaneous and hepatic adverse events among populations of African, Asian, and European descent.
abstract: 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.
  
  
  METHODS
  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/μl 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.
  
  
  CONCLUSIONS
  Among patients with at least 150 CD4 T cells/μl, 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.
authors.affiliation: Non-Clinical Drug Safety, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut 06877, USA. jing.yuan@boehringer-ingelheim.com
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.forename: Sheng
authors.initials: S
authors.lastname: Guo
authors.forename: David
authors.initials: D
authors.lastname: Hall
authors.forename: Anna M
authors.initials: AM
authors.lastname: Cammett
authors.forename: Supriya
authors.initials: S
authors.lastname: Jayadev
authors.forename: Manuel
authors.initials: M
authors.lastname: Distel
authors.forename: Stephen
authors.initials: S
authors.lastname: Storfer
authors.forename: Zimei
authors.initials: Z
authors.lastname: Huang
authors.forename: Piroon
authors.initials: P
authors.lastname: Mootsikapun
authors.forename: Kiat
authors.initials: K
authors.lastname: Ruxrungtham
authors.forename: Daniel
authors.initials: D
authors.lastname: Podzamczer
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
mesh_terms: D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008107:Liver Diseases / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000009:adverse effects* / Q000276:immunology; D017193:Skin Diseases, Viral / Q000235:genetics* / Q000276:immunology; D043922:Toxicogenetics; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D019829:Nevirapine