Background:  Efavirenz (EFV) is metabolized by cytochrome P450 (CYP) 2B6. Single nucleotide polymorphisms (SNP) in CYP2B6 delay EFV clearance, whereas ABCB1 SNP have been associated with treatment response. We characterized relationships between SNP, pharmacokinetics, and response to EFV-containing regimens.

Methods:  Associations between EFV pharmacokinetics and 22 SNP in CYP2B6, ABCB1 and CYP3A5 were investigated among individuals with pharmacokinetic data from the AIDS Clinical Trials Group (ACTG) protocol A5097s (pharmacokinetic substudy of A5095) and ACTG 384. Among subjects randomized to EFV in A5095 we assayed CYP2B6 516G>T, 983T>C, and 5 SNP in ABCB1. We defined CYP2B6 516/983 metabolizer genotype as rapid (516GG+983TT); intermediate (516GT or 983TC); slow (516TT, 983CC, or [516GT+983TC]). Stepwise selection models investigated genotype associations with time to:  EFV discontinuation; first central nervous system (CNS) adverse event; and virologic failure. Analyses adjusted for body mass index, and self-reported adherence at week 12 (virologic failure only). Genotyping was by MALDI-TOF (A5097s, ACTG 384) and Taqman (A5095).

Results:  Of 22 SNP assayed in A5097s (n = 123) and ACTG 384 (n = 174), pharmacokinetic associations were dominated by CYP2B6 516G>T and 983T>C. Other alleles were infrequent (<2%) or had little independent association with pharmacokinetics. Of 765 subjects randomized to EFV-containing regimens in A5095, 287 whites, 225 blacks, and 131 Hispanics were genotyped. Among whites, slow metabolizer CYP2B6 genotype (compared to rapid) was associated with an increased hazard of CNS adverse events (HR = 2.40; 95%CI 1.07 to 5.37; p = 0.034) and EFV discontinuation (2.18; 1.03 to 4.63, p = 0.04), but not virologic failure (1.16; 0.27 to 4.94, p = 0.85). Among blacks with slow metabolizer genotype, there was some evidence of a lower hazard of virologic failure (0.34; 0.12 to 1.00, p = 0.050), but not CNS adverse events (1.18; 0.51 to 2.71; p = 0.69) or EFV discontinuation (0.69; 0.38 to 1.26; p = 0.23). Among Hispanics, significant associations with slow metabolizer genotype were not seen for virologic failure (1.0; p = 0.99), CNS adverse events (0.98; 0.37 to 2.62; p = 0.97), or EFV discontinuation (0.90; 0.19 to 4.32; p = 0.89). A previously reported association between ABCB1 3435C>T and decreased hazard of VF was not seen.

Conclusions:  Associations with EFV pharmacokinetics were dominated by CYP2B6 516G>T and 983T>C. Relationships between SNP in CYP2B6 and ABCB1, CNS AEs, EFV discontinuation, and virologic failure were not consistently identified among populations. A unifying model that relates pharmacogenetics to EFV treatment response remains elusive, and may be affected by additional genetic or non-genetic factors.