1. Cytochrome P450 2B6 (CYP2B6) and constitutive androstane receptor (CAR) polymorphisms are associated with early discontinuation of efavirenz-containing regimens.
- Author
-
Wyen C, Hendra H, Siccardi M, Platten M, Jaeger H, Harrer T, Esser S, Bogner JR, Brockmeyer NH, Bieniek B, Rockstroh J, Hoffmann C, Stoehr A, Michalik C, Dlugay V, Jetter A, Knechten H, Klinker H, Skaletz-Rorowski A, Fätkenheuer G, Egan D, Back DJ, and Owen A
- Subjects
- Adult, Aged, Aged, 80 and over, Alkynes, Alleles, Anti-HIV Agents therapeutic use, Antiretroviral Therapy, Highly Active, Benzoxazines therapeutic use, Cohort Studies, Constitutive Androstane Receptor, Cyclopropanes, Cytochrome P-450 CYP2B6, DNA genetics, Ethnicity, Female, Genotype, Germany, Humans, Logistic Models, Male, Middle Aged, Polymorphism, Single Nucleotide genetics, Prospective Studies, Risk Factors, Sex Characteristics, Smoking, Socioeconomic Factors, Anti-HIV Agents adverse effects, Aryl Hydrocarbon Hydroxylases genetics, Benzoxazines adverse effects, Oxidoreductases, N-Demethylating genetics, Polymorphism, Genetic genetics, Receptors, Cytoplasmic and Nuclear genetics
- Abstract
Objectives: Cytochrome P450 2B6 (CYP2B6) is responsible for the metabolic clearance of efavirenz and single nucleotide polymorphisms (SNPs) in the CYP2B6 gene are associated with efavirenz pharmacokinetics. Since the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) correlate with CYP2B6 in liver, and a CAR polymorphism (rs2307424) and smoking correlate with efavirenz plasma concentrations, we investigated their association with early (<3 months) discontinuation of efavirenz therapy., Methods: Three hundred and seventy-three patients initiating therapy with an efavirenz-based regimen were included (278 white patients and 95 black patients; 293 male). DNA was extracted from whole blood and genotyping for CYP2B6 (516G → T, rs3745274), CAR (540C → T, rs2307424) and PXR (44477T → C, rs1523130; 63396C → T, rs2472677; and 69789A → G, rs763645) was conducted. Binary logistic regression using the backwards method was employed to assess the influence of SNPs and demographics on early discontinuation., Results: Of the 373 patients, 131 withdrew from therapy within the first 3 months. Black ethnicity [odds ratio (OR) = 0.27; P = 0.0001], CYP2B6 516TT (OR = 2.81; P = 0.006), CAR rs2307424 CC (OR = 1.92; P = 0.007) and smoking status (OR = 0.45; P = 0.002) were associated with discontinuation within 3 months., Conclusions: These data indicate that genetic variability in CYP2B6 and CAR contributes to early treatment discontinuation for efavirenz-based antiretroviral regimens. Further studies are now required to define the clinical utility of these associations.
- Published
- 2011
- Full Text
- View/download PDF