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

Yuan J, Guo S, Hall D, Cammett AM, Jayadev S, Distel M, Storfer S, Huang Z, Mootsikapun P, Ruxrungtham K, Podzamczer D, Haas DW, Nevirapine Toxicogenomics Study Team
AIDS. 2011 25 (10): 1271-80

PMID: 21505298 · PMCID: PMC3387531 · DOI:10.1097/QAD.0b013e32834779df

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/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.

CONCLUSION - 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.

MeSH Terms (17)

Adolescent Adult African Continental Ancestry Group Asian Continental Ancestry Group CD4-Positive T-Lymphocytes European Continental Ancestry Group Female Genetic Variation HIV Infections Humans Liver Diseases Male Middle Aged Nevirapine Skin Diseases, Viral Toxicogenetics Young Adult

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