Pharmacogenetics of efavirenz discontinuation for reported central nervous system symptoms appears to differ by race

Abstract

Background: Efavirenz frequently causes central nervous system (CNS) symptoms. We evaluated genetic associations with efavirenz discontinuation for CNS symptoms within 12 months of treatment initiation.

Methods: Patients had initiated efavirenz-containing regimens at an HIV primary care clinic in the Southeastern United States and had at least 12 months of follow-up data. Polymorphisms in CYP2B6 and CYP2A6 defined efavirenz metabolizer categories. Genome-wide genotyping enabled adjustment for population stratification.

Results: Among 563 evaluable patients, 99 (17.5%) discontinued efavirenz within 12 months, 29 (5.1%) for CNS symptoms. The hazard ratio (HR) for efavirenz discontinuation for CNS symptoms in slow versus extensive metabolizers was 4.9 [95% confidence interval (CI): 1.9-12.4; P=0.001]. This HR in Whites was 6.5 (95% CI: 2.3-18.8; P=0.001) and 2.6 in Blacks (95% CI: 0.5-14.1; P=0.27). Considering only slow metabolizers, the HR in Whites versus Blacks was 3.1 (95% CI: 0.9-11.0; P=0.081). The positive predictive value of slow metabolizer genotypes for efavirenz discontinuation was 27% in Whites and 11% in Blacks.

Conclusion: Slow metabolizer genotypes were associated significantly with efavirenz discontinuation for reported CNS symptoms. This association was considerably stronger in Whites than in Blacks.

Figure 1. Time to discontinuation of efavirenz for CNS side effects, stratified by genotype

Panel A: all participants stratified by CYP2B6 metabolizer genotype; Panel B: White participants stratified by CYP2B6 metabolizer genotype; Panel C: Black participants stratified by CYP2B6 metabolizer genotype; Panel D: Participants with slow metabolizer genotype, stratified by race.

Figure 2. Proportions of patients who discontinued efavirenz within the first 12 months of therapy, stratified by composite CYP2B6/CYP2A6 genotype

Graphs represent subjects who initiated efavirenz 600 mg once daily, had no change in their antiretroviral therapy regimen before week 48, and had HIV-1 RNA data available at both week 0 and week 48. Panel A: Self-identified White participants. Panel B: Self-identified Black participants. The 12 strata are defined by CYP2B6 15582C→T, 516G→T, 983T→C, and CYP2A6 −48T→G as indicated. Plasma efavirenz concentrations were not measured in the present study. Predicted median efavirenz C_min concentrations are from the study by Holzinger et al, in which median plasma efavirenz exposure within each genotype stratum were very similar among Blacks and Whites [15]. Error bars represent 95% confidence intervals by the modified Wald method. ^a Indicates that the CYP2A6 polymorphism is present together with any of the 3 CYP2B6 strata furthest to the right. The top of each indicated relationships between metabolizer groups (extensive, intermediate, and slow) and the 12 genotype categories.