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.

HAART-Associated Dyslipidemia Varies by Biogeographical Ancestry in the Multicenter AIDS Cohort Study

“…Previous findings have shown that certain HLA types are associated with adverse HAART drug reactions and that these HLA variants do vary in frequency across racial populations. 53,54 Our study has a number of limitations. The MACS is a multiethnic cohort of men only and thus our analysis and conclusions are not directly applicable to dyslipidemic responses in women on HAART.…”

Selecting patients who can be re-challenged with Nevirapine in case of skin rash with Efavirenz – A Study

“…In some studies skin rash has been shown to be related to a CYP2B6516TT polymorphism. 26,27 Rash with NVP has been documented with an overall incidence of 17-32%, although 13% of these are mild rashes. Generally, NVP rashes are transient with risk being greatest in the first 6 weeks of treatment.…”

“…NVP shows immunecompetence linked toxicity such that patients with a higher CD4 count and a detectable viral load are seen to be more susceptible to risk of symptomatic hepatic adverse events. 27,36,37 Switching from NVP to EFV in cases of hepatotoxicity has seemed safe and effective. As observed by Walubo et al (2006) 38 , NVP induced hepatotoxicity and liver injury has close association with enzyme induction.…”

The Pharmacogenetics of HIV Treatment: A Practical Clinical Approach

“…The mechanism involved in the development of the adverse events related with NVP is not well understood. Cutaneous effects are most likely MHC class I-mediated, influenced by NVP CYP2B6 metabolism, whereas hepatic toxicity is most likely MHC class IImediated and unaffected by such metabolism [23]. studied so far.…”