Background:  Plasma concentrations of efavirenz (EFV) are known for a high degree of inter-individual variability. EFV is mainly metabolized by CYP2B6. We looked for genetic polymorphisms in the CYP2B6 gene in individuals with extremely high EFV plasma levels in order to identify genetic polymorphisms that could explain the extremely elevated drug concentrations.

Methods:  Genomic DNA was obtained from 5 individuals with repeatedly high plasma concentrations in the range of 9165 to 59400 ng/mL (therapeutic range, 1000 to 4000 ng/mL). All presented neuropsychological toxicity that resolved after treatment discontinuation or dose reduction. Promoter region (3051bp) including the phenobarbital-responsive enhancer module (PBREM) and the xenobiotic responsive enhancer module (XREM), and the 9 exons together with the exon-intron boundries (3917bp) of CYP2B6 were screened by direct sequencing.

Results:  All individuals carried 2 copies of known or probable SNP associated with loss of function. Two individuals were CYP2B6*6D (Q172H, K262R) homozygous (one native of Switzerland and the other of Thailand). A third individual (native of Thailand) carried one CYP2B6*6E allele (also characterized by Q172H, K262R) and one *6D copy. The fourth individual (native of Congo) carried the recently reported CYP2B6*18 (I328T) and one *6D copy. The last patient (native from Ivory Coast) carried a possible new allele which would include new exonic nonsynonymous SNP in exon 6 (T306S) and in exon 7 that introduces a stop codon (R378stop) and one *6D copy. Previously reported SNPs were identified in the promoter region; none were localized in the PBREM or in the XREM modules.

Conclusions:  Independently of the diverse ethnicities, these individuals consistently presented 2 copies of CYP2B6 loss-of function alleles. Other predisposing environmental or genetic factors may be needed to explain the extremely high EFV concentration and toxicity in the context of this unfavorable metabolizing profile.