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 allowed 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% C.I. 1.9 to 12.4; p = 0.001). This HR in Whites was 6.5 (95% CI: 2.3 to 18.8; p = 0.001), and in Blacks was 2.6 (95% C.I. 0.5 to 14.1; p = 0.27). Considering only slow metabolizers, the HR in Whites versus Blacks was 3.1 (95% CI: 0.9 to 11.0; p = 0.081). The positive predictive value of slow metabolizer genotypes for efavirenz discontinuation was 27% in Whites and 11% in Blacks. Conclusions Slow metabolizer genotypes were significantly associated with efavirenz discontinuation for reported CNS symptoms. This association was considerably stronger in Whites than in Blacks.

Cytochrome 2B6 polymorphism and efavirenz‐induced central nervous system symptoms : a substudy of the ANRS ALIZE trial

“…Indeed, studies have shown that individuals with higher genetic risk scores for slow EFV metabolization, including cumulative CYP2B6 , CYP2A6 and CYP3A4 variant alleles, had a significantly higher risk of EFV discontinuation for reported CNS symptoms than individuals with lower genetic risk scores . In the aggregate AIDS Clinical Trials Group (ACTG) clinical trials data which demonstrated an excess of suicidality (i.e.…”

“…However, the long‐term efficacy of EFV‐containing regimens , the low cost of EFV, which is a determining factor for its use in developing countries, and the recent demonstration that a reduced dose of 400 mg is noninferior to the standard dose of 600 mg in combination with tenofovir and emtricitabine as initial HIV therapy, with fewer EFV‐related adverse events , suggest that it will continue to be used world‐wide. In addition, EFV‐induced CNS symptoms, which occur, usually, early in therapy but frequently resolve after several weeks , may be associated with genetic variability in EFV metabolism .…”

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and Efavirenz‐Containing Antiretroviral Therapy

“…For these patients, there is a “moderate” recommendation to consider initiating efavirenz with a decreased dose of 400 mg/day. CYP2B6 PMs are at greatest risk for higher dose‐adjusted trough concentrations compared with NMs and IMs, and greater overall plasma efavirenz exposure, which puts these patients up to a 4.8‐fold increased risk for adverse effects and treatment discontinuation . For these patients, there is a “moderate” recommendation to consider initiating efavirenz with a decreased dose of either 400 or 200 mg/day.…”

“…CYP2B6 PMs are at greatest risk for higher dose-adjusted trough concentrations compared with NMs and IMs, and greater overall plasma efavirenz exposure, which puts these patients up to a 4.8-fold increased risk for adverse effects and treatment discontinuation. [20][21][22][23][24][25][26][27][28][29][30][31] For these patients, there is a "moderate" recommendation to consider initiating efavirenz with a decreased dose of either 400 or 200 mg/day. This "moderate" rather than "strong" recommendation reflects the fact that most CYP2B6 PMs do not discontinue efavirenz 600 mg/day for adverse effects.…”

Race/ethnicity difference in the pharmacogenetics of bilirubin-related atazanavir discontinuation

“…Stored DNA from a total of 837 patients who had initiated either atazanavir-containing regimens (including patients in the present association analysis) or efavirenz-containing regimens (from a previous analysis 21 ) was genotyped for 535 543 single nucleotide polymorphisms, including rs887829 C→T, by Illumina HumanCore Exome assay (San Diego, California, USA). Genotype call rates exceeded 99% for 807 samples, including 349 individuals for the current analysis.…”