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.

Fig. 1

Disposition of study volunteers. AE, adverse events.

Fig. 2

Associations between single-nucleotide polymorphisms and adverse events. Panel (a) is a Manhattan plot of the results for cutaneous adverse events (AEs) compared with controls. Panel (b) shows CYP2B6 SNPs associated with cutaneous AEs. Panel (c) is a Manhattan plot of the results for hepatic AEs compared with controls. In panels (a) and (b), the −log₁₀ P values were plotted against chromosome positions. Lines indicate a Bonferroni corrected P value of 0.05. Panel (a) represents 2336 SNPs. Panel (c) represents 2058 SNPs. The three SNPs labeled are in CYP2B6.

Fig. 3

Associations between HLA alleles and nevirapine-related adverse events. Panel (a) shows cutaneous adverse events (AEs). Panel (b) shows hepatic AEs. Odds ratios (OR) and two-tailed P value were calculated by Fisher's exact test in race groups for all HLA alleles, and by Cochran-Mantel-Haenszel (CMH)test in the total population for HLA-Cw*04. All Thai participants were also included in the Asian group and were excluded from the CMH test. P values were corrected by Bonferroni procedure and corrected P value = Pvalue/n, where n is 22 for HLA-B*35, 13 for HLA-Cw*04, 13 for HLA-DRB1*01, and 286 for HLA-B35-Cw*04. Cases and controls are presented as numbers of participants (n) with the indicated genotypes divided by the numbers of cases or controls. Height of a square is proportional to the sample size. Horizontal lines represent 95% confidence intervals (CIs).

Fig. 4

Association between polymorphisms and related adverse events. Panel (a) shows major association between genetic polymorphisms and nevirapine-related adverse events (AEs). CYP2B6 polymorphisms include rs2054675, rs3786547, and rs3745274. Panel (b) shows associations between CYP2B6 516G→T, HLA-Cw*04, and cutaneous AEs. The lowest risk genotype (CYP2B6 516GG and lacking HLA-Cw*04) was the reference for calculating odds ratios (OR) and two-tailed P values by Fisher's exact test for race groups and by Cochran-Mantel-Haenszel test for total population. A continuity correction was made to calculate OR by adding one to all cells of a contingency table if a cell harbours zero. Cases and controls are presented as numbers of participants with the indicated genotypes divided by the numbers of cases or controls. Height of a square is proportional to sample size. Horizontal lines represent 95% confidence intervals (CIs).