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

Pharmacogenet Genomics. 2016 Oct;26(10):473-80. doi: 10.1097/FPC.0000000000000238.

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.

MeSH terms

  • Adult
  • Alkynes
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Benzoxazines / adverse effects*
  • Central Nervous System Diseases / chemically induced*
  • Central Nervous System Diseases / genetics
  • Cyclopropanes
  • Cytochrome P-450 CYP2B6 / genetics*
  • Ethnicity / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Pharmacogenomic Testing / methods
  • Polymorphism, Single Nucleotide*
  • Predictive Value of Tests
  • Reverse Transcriptase Inhibitors / adverse effects*
  • Steroid Hydroxylases / genetics*
  • Withholding Treatment

Substances

  • Alkynes
  • Benzoxazines
  • Cyclopropanes
  • Reverse Transcriptase Inhibitors
  • Steroid Hydroxylases
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2B6
  • steroid hormone 7-alpha-hydroxylase
  • efavirenz