A single-nucleotide polymorphism in CYP2B6 leads to >3-fold increases in efavirenz concentrations in plasma and hair among HIV-infected women

Abstract

Background: Efavirenz exhibits marked interindividual variability in plasma levels and toxicities. Prior pharmacogenetic studies usually measure exposure via single plasma levels, examine limited numbers of polymorphisms, and rarely model multiple contributors. We analyzed numerous genetic and nongenetic factors impacting short-term and long-term exposure in a large heterogeneous population of human immunodeficiency virus (HIV)-infected women.

Methods: We performed 24-hour intensive pharmacokinetic studies in 111 women receiving efavirenz under actual-use conditions and calculated the area-under-the-concentration-time curve (AUC) to assess short-term exposure; the efavirenz concentration in hair was measured to estimate long-term exposure. A total of 182 single-nucleotide polymorphisms (SNPs) and 45 haplotypes in 9 genes were analyzed in relationship to exposure by use of multivariate models that included a number of nongenetic factors.

Results: Efavirenz AUCs increased 1.26-fold per doubling of the alanine aminotransferase level and 1.23-fold with orange and/or orange juice consumption. Individuals with the CYP2B6 516TT genotype displayed 3.5-fold increases in AUCs and 3.2-fold increases in hair concentrations, compared with individuals with the TG/GG genotype. Another SNP in CYP2B6 (983TT) and a p-glycoprotein haplotype affected AUCs without substantially altering long-term exposure.

Conclusions: This comprehensive pharmacogenomics study showed that individuals with the CYP2B6 516TT genotype displayed >3-fold increases in both short-term and long-term efavirenz exposure, signifying durable effects. Pharmacogenetic testing combined with monitoring of hair levels may improve efavirenz outcomes and reduce toxicities.

Figures

Figure 1.

Linkage disequilibrium (LD) map of single-nucleotide polymorphisms (SNPs) assessed in CYP2B6 in relationship to efavirenz exposure. An ideogram of CYP2B6 is presented at the top, which represents the physical distance along human chromosome 19 (46 187 595 to 46 230 064; genome build 36.3, contig NT_011109.15). Exons are represented as boxes, with coding regions rendered in gray and untranslated regions rendered in pink; gray lines connecting exons represent introns. Reference sequence (rs) identifiers for each SNP are plotted both in terms of their physical distance (ie, the white bar at the top of the figure) and also equidistantly to render the pairwise LD estimates, which were calculated and visualized with Haploview 4.2. The gene structure for CYP2B6 (ie, reference sequence NM_000767) was rendered with FancyGene 1.4. The correlation statistics (r2 and D’) are provided in the heat map. LD-based haplotype block definition was based on the D’ confidence interval. The haploblock is indicated in a bolded triangle, and its component SNPs are also rendered in bold font, with dashed regions indicating intervening SNPs that are not part of the haploblock. Pairwise D’ values (range, 0–1) were rendered in color, with darker red diamonds representing D’ values approaching 1.0, and progressively lighter red to pink colored diamonds representing progressively smaller D’ values. Grey diamonds represent pairwise D’ values of 1.0 but with log of odds values of <2 (ie, below the significance threshold of 2.0). When the r2 values (range, 0–100) are not equal to 0 or 100, they are provided in a given diamond.