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Background: The nono-nucleoside reverse transcriptase inhibitors (NNRTI) nevirapine (NVP) and efavirenz (EFV) cause liver injury in some patients, but predictors of NNRTI toxicity risk are uncertain.  NVP and EFV are metabolized primarily by hepatic cytochrome P4502B6 (CYP2B6); A CYP2B6 516G > T single nucleotide polymorphism (SNP) has been associated with increased plasma EFV concentrations. P-glycoprotein, encoded by MDR1, affects hepatic transport of many compounds. To explore the possibility that SNP in drug-metabolizing enzyme and drug transporter genes affect risk of NNRTI hepatotoxicity, we characterized associations between candidate gene SNP and hepatotoxicity in patients receiving EFV or NVP.

Methods:  We performed a nested case-control study among a cohort of 445 HIV⁺ adults who initiated their first NNRTI-containing regimen after enrollment in the Comprehensive Care Center; 30 (6.7%) developed hepatotoxicity (ALT or AST > 5x upper limit of normal or bilirubin > 3.5 mg/dL). Of these, 20 had DNA available for testing. Controls who did not develop hepatotoxicity were selected from the cohort, and matched with cases according to NNRTI, age (± 5 years), race, and hepatitis C status. A total of 4 SNP in 3 candidate genes were characterized (CYP2B6 516G > T and 1459C > T, CYP3A4 –392A > G, and MDR1 3435C > T). Univariate analyses were performed using Fisher’s exact test and simple logistic regression. Gene–gene interactions were explored using multifactor dimensionality reduction.

Results:  There were 20 cases (11 NVP and 9 EFV) and 50 matched controls. The sample consisted of 23% women, 77% men, 19% African Americans, and 81% Caucasians. Mean age was 39 years. Based on single locus analysis, the T allele at MDR1 3435C > T was associated with decreased hepatotoxicity risk (OR = 0.46 [95% CI 0.20 to 1.0]; Fisher’s exact p = 0.03). By multifactor dimensionality reduction, a 2-locus interaction between MDR1 and CYP2B6 was detected which predicted hepatotoxicity with approximately 70% accuracy (p < 0.001).

Conclusions:  A common genetic variant in MDR1 may be associated with hepatotoxicity risk among HIV-infected adults prescribed NNRTI. Considering multiple SNP by multifactor dimensionality reduction may improve predictive accuracy. These associations are unlikely to reflect imbalance based on age, race, or hepatitis C status since cases and controls were matched on these factors. Further study of functional mechanisms and confirmation of this association in other cohorts are warranted.

Keywords: pharmacogenetics; hepatotoxicity; MDR1