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Cytochrome P450 2B6 (CYP2B6) and constitutive androstane receptor (CAR) polymorphisms are associated with early discontinuation of efavirenz-containing regimens

Wyen, Christoph ; Hendra, Heidy ; Siccardi, Marco ; Platten, Martin ; Jaeger, Hans ; Harrer, Thomas ; Esser, Stefan ; Bogner, Johannes R. ; Brockmeyer, Norbert H. ; Bieniek, Bernhard ; Rockstroh, Juergen ; Hoffmann, Christian ; Stoehr, Albrecht ; Michalik, Claudia ; Dlugay, Verena ; Jetter, Alexander ; Knechten, Heribert ; Klinker, Hartwig ; Skaletz-Rorowski, Adriane ; Fätkenheuer, Gerd ; Egan, Deirdre ; Back, David J. ; Owen, Andrew ; Dupke, Stephan ; Carganico, Andreas ; Baumgarten, Axel ; Koeppe, Siegfried ; Kreckel, Peter ; Lauenroth-Mai, Elke ; Schlote, Frank ; Schuler, Christoph ; Freiwald, Matthias ; Rausch, Michael ; Gölz, Jörg ; Moll, Arend ; Zeitz, Martin ; Brockmeyer, Norbert ; Hower, Martin ; Reuter, Stefan ; Harrer, Thomas ; Esser, Stefan ; Staszewski, Schlomo ; Plettenberg, Andreas ; Fenske, Stefan ; Buhk, Thomas ; Stellbrink, Hans-Jürgen ; Schmidt, Reinhold ; Kuhlmann, Birger ; Mosthaf, Franz ; Rieke, Ansgar ; Scholten, Stefan ; Jaeger, Hans ; Jaegel-Guedes, Eva ; Volkert, Ramona ; Becker, Werner ; Hartl, Helmut ; Mutz, Antonius ; Ulmer, Albrecht ; Frietsch, Bernhard ; Müller, Markus

In: Journal of Antimicrobial Chemotherapy, 2011, vol. 66, no. 9, p. 2092-2098

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    Title
    • Cytochrome P450 2B6 (CYP2B6) and constitutive androstane receptor (CAR) polymorphisms are associated with early discontinuation of efavirenz-containing regimens
    Author
    • Wyen, Christoph. Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Hendra, Heidy. Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Siccardi, Marco. Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
    • Platten, Martin. Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Jaeger, Hans. HIV Research and Clinical Care Centre Munich, Munich, Germany
    • Harrer, Thomas. Department of Internal Medicine 3, University Hospital Erlangen, University of Erlangen-Nuremberg, Germany
    • Esser, Stefan. Department of Dermatology, University of Essen, Essen, Germany
    • Bogner, Johannes R.. Department of Internal Medicine, University of Munich, Munich, Germany
    • Brockmeyer, Norbert H.. Department of Dermatology, Venerology and Allergology, Ruhr-Universität Bochum, Bochum, Germany
    • Bieniek, Bernhard. PraxisCityOst, Berlin, Germany
    • Rockstroh, Juergen. Department of Internal Medicine, University of Bonn, Bonn, Germany
    • Hoffmann, Christian. IPM Study Centre, Hamburg/University of Schleswig Holstein, Kiel, Germany
    • Stoehr, Albrecht. ifi-Institute for Interdisciplinary Medicine, Hamburg, Germany
    • Michalik, Claudia. Clinical Trials Centre Cologne ZKS, University of Cologne, Cologne, Germany
    • Dlugay, Verena. Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany
    • Jetter, Alexander. Department of Clinical Pharmacology and Toxicology and Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland
    • Knechten, Heribert. PZB Blondelstrasse, Aachen, Germany
    • Klinker, Hartwig. Department of Internal Medicine, University of Würzburg, Würzburg, Germany
    • Skaletz-Rorowski, Adriane. Competence Network for HIV/AIDS, Ruhr-Universität Bochum, Bochum, Germany
    • Fätkenheuer, Gerd. Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Egan, Deirdre. Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
    • Back, David J.. Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
    • Owen, Andrew. Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
    • Dupke, Stephan. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Carganico, Andreas. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Baumgarten, Axel. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Koeppe, Siegfried. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Kreckel, Peter. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Lauenroth-Mai, Elke. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Schlote, Frank. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Schuler, Christoph. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Freiwald, Matthias. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Rausch, Michael. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Gölz, Jörg. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Moll, Arend. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Zeitz, Martin. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Brockmeyer, Norbert. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Hower, Martin. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Reuter, Stefan. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Harrer, Thomas. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Esser, Stefan. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Staszewski, Schlomo. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Plettenberg, Andreas. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Fenske, Stefan. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Buhk, Thomas. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Stellbrink, Hans-Jürgen. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Schmidt, Reinhold. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Kuhlmann, Birger. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Mosthaf, Franz. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Rieke, Ansgar. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Scholten, Stefan. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Jaeger, Hans. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Jaegel-Guedes, Eva. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Volkert, Ramona. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Becker, Werner. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Hartl, Helmut. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Mutz, Antonius. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Ulmer, Albrecht. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Frietsch, Bernhard. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    • Müller, Markus. 1Department of Internal Medicine, University of Cologne, Cologne, Germany
    Document Type
    • Postprint
    Language
    • English
    Published in
    • Journal of Antimicrobial Chemotherapy, 2011, vol. 66, no. 9, p. 2092-2098. Oxford University Press
    Other Version
    OAI-PMH Identifier
    • oai:doc.rero.ch:301629
    Summary
    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