title: The role of genetic polymorphisms in cytochrome P450 and effects of tuberculosis co-treatment on the predictive value of CYP2B6 SNPs and on efavirenz plasma levels in adult HIV patients.
abstract: Efavirenz (EFV) exhibits interindividual pharmacokinetic variability caused by differences in cytochrome P450 (CYP) expression. Most tuberculosis (TB) drugs interact with the CYP metabolizing enzymes, while the clinical validity of genotyping in predicting EFV plasma levels in Rwandan subjects is not known. We investigated in patients co-infected with human immunodeficiency virus (HIV) and TB recruited in Rwanda the effects of 10 SNPs in five drug-metabolizing enzymes on EFV plasma levels and treatment response when patients are treated with EFV-containing therapy alone (n=28) and when combined with rifampicin-based TB treatment (n=62), and the validity of genotyping for CYP2B6 single nucleotide polymorphisms in predicting supra-therapeutic EFV levels. There was a significant difference between CYP1A2 -739T/G and T/T genotypes when patients were treated with EFV-containing therapy combined with rifampicin-based TB treatment, but not when EFV-containing therapy was alone. CYP2B6 516T/T genotype was associated with high EFV levels compared to other CYP2B6 516G>T genotypes in the presence and in the absence of rifampicin-based TB treatment. Predictive factors of EFV plasma levels in the presence of rifampicin-based TB treatment were CYP2A6 1093G>A, CYP2B6 516G>T, and CYP2B6 983T>C accounting for 27%, 43%, and 29% of the total variance in EFV levels, respectively. There was a high positive predictive value (PPV) (100%) for CYP2B6 516T/T and 983T/T genotypes in predicting EFV plasma levels above the therapeutic range, but this PPV decreased in the presence of rifampicin-based TB treatment. Rifampicin-based TB treatment was also shown to affect EFV plasma levels significantly, but did not affect the significant reduction of HIV-RNA copies. These results indicate that genotyping for CYP2B6 SNPs could be used as a tool in predicting supra-therapeutic EFV plasma levels, which could minimize adverse drug events.
authors: Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden. Electronic address: emile.bienvenu@pharm.gu.se.
authors: Emile
authors: E
authors: Bienvenu
authors: Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, South Africa.
authors: Marelize
authors: M
authors: Swart
authors: Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, South Africa.
authors: Collet
authors: C
authors: Dandara
authors: Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden.
authors: Michael
authors: M
authors: Ashton
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000995:Antitubercular Agents / Q000627:therapeutic use*; D048588:Benzoxazines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003521:Cyclopropanes; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry; D020641:Polymorphism, Single Nucleotide; D012432:Rwanda; D014376:Tuberculosis / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D003577:Cytochrome P-450 Enzyme System; C098320:efavirenz
keywords: Efavirenz; HIV; Plasma level; Predictive value; SNP; Tuberculosis