Background:  Nevirapine (NVP) is a potent non-nucleoside reverse transcriptase inhibitor (NNRTI), but some NVP recipients experience hepatotoxicity. In a prospective, randomized study (Triangle FTC302), 66 (17%) of 385 South African subjects with relatively high CD4 counts developed grade 3 or 4 liver enzyme elevations (hepatotoxicity) after initiating NVP plus 2 nucleosides (stavudine [d4T]/lamivudine [3TC] or d4T/ematricibine [FTC]). NVP is metabolized by hepatic cytochrome P4502B6 (CYP2B6) and CYP3A. A single nucleotide polymorphism (SNP) in CYP2B6 (516G>T) is associated with decreased clearance of the NNRTI efavirenz (EFV). The drug efflux transporter P-glycoprotein, encoded by MDR1, is expressed in liver, and functional SNP have been identified. Adult AIDS Clinical Trials Group (AACTG) study NWCS220 used FTC302 data and specimens to explore associations between genetic variants and NVP-associated hepatotoxicity.

Methods:  For each case with hepatotoxicity on NVP, 2 controls were identified. Cases and controls were matched for gender, baseline HIV-1 RNA and CD4 counts and anonymized. Because of low extracted DNA yields from frozen peripheral blood mononuclear cells (PBMC), OmniPlex® whole genome amplification (Rubicon Genomics) preceded SNP analysis. A total of 7 SNP in MDR1, CYP2B6, 3A4, and 3A5 were characterized. MDR1 and CYP3A5 haplotypes were reconstructed by Bayesian and likelihood methods. Analyses adjusted for 1:2 matching.

Results:  Adequate amplified DNA was available from 161 samples, including up to 53 cases and 108 controls for each SNP. Among all subjects, MDR1 position 3435 genotype was C/C, C/T, and T/T in 72%, 23% and 5%, respectively; Genotypes in cases vs controls were C/C in 83% vs 67%; C/T in 13% vs 28%; T/T in 4% vs 6%, respectively. By univariate matched analysis, MDR1 3435C > T (C/C < C/T < T/T) was associated with decreased hepatotoxicity (p = 0.016, RR = 0.30). There was a trend toward association between CYP3A5 –6986G > A and hepatotoxicity (p = 0.056, RR = 2.1). By multivariate analysis MDR1 3435C > T remained significantly associated with hepatotoxicity, and CYP3A5 was marginally associated. Other MDR1, CYP2B6, and 3A4 SNP, and MDR1 and 3A5 haplotypes were not predictive.

Conclusions:  Among subjects initiating NVP in South Africa, MDR1 3435C > T was associated with decreased hepatotoxicity, whereas a CYP2B6 SNP known to be associated with delayed EFV clearance did not predict risk of hepatotoxicity on NVP. These findings, if confirmed in other populations, may ultimately foster more rational prescribing of NVP.

Keywords: nevirapine; hepatotoxicity; MDR1