Journal
AIDS
Volume 25, Issue 10, Pages 1271-1280Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/QAD.0b013e32834779df
Keywords
CYP2B6; HIV; human leukocyte antigen; nevirapine; pharmacogenomics; rash; toxicogenomics
Categories
Funding
- Boehringer Ingelheim Pharmaceuticals, Inc.
- National Institute of Allergy and Infectious Diseases [AI077505, AI54999]
- National Science and Technology Development Agency (NSTDA), Pathumthani, Thailand
- Boehringer Ingelheim GmbH
- Bristol-Myers Squibb
- Boehringer Ingelheim, Merck Co.
- Gilead Sciences
Ask authors/readers for more resources
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
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available