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.

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.

• Authors: Jing Yuan, Sheng Guo, David Hall, Anna M Cammett, Supriya Jayadev, Manuel Distel, Stephen Storfer, Zimei Huang, Piroon Mootsikapun, Kiat Ruxrungtham, Daniel Podzamczer, David W Haas, Nevirapine Toxicogenomics Study Team
• Journal: AIDS (London, England) (AIDS) Vol. 25 Issue 10 Pg. 1271-80 (Jun 19 2011) ISSN: 1473-5571 [Electronic] England
• PMID: 21505298 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Nevirapine

Topics

• Adolescent
• Adult
• Asian People (genetics)
• Black People (genetics)
• CD4-Positive T-Lymphocytes (drug effects, immunology)
• Female
• Genetic Variation (genetics)
• HIV Infections (drug therapy, genetics, immunology)
• Humans
• Liver Diseases (genetics, immunology)
• Male
• Middle Aged
• Nevirapine (adverse effects, immunology)
• Skin Diseases, Viral (genetics, immunology)
• Toxicogenetics
• White People (genetics)
• Young Adult