Universität zu Köln

Cummins, Nathan W., Neuhaus, Jacqueline, Chu, Haitao ORCID: 0000-0003-0932-598X, Neaton, James, Wyen, Christoph, Rockstroh, Juergen K., Skiest, Daniel J., Boyd, Mark A., Khoo, Saye, Rotger, Margalida, Telenti, Amalio, Weinshilboum, Richard and Badley, Andrew D. (2015). Investigation of Efavirenz Discontinuation in Multi-ethnic Populations of HIV-positive Individuals by Genetic Analysis. EBioMedicine, 2 (7). S. 706 - 713. AMSTERDAM: ELSEVIER SCIENCE BV. ISSN 2352-3964

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Abstract

Background: Efavirenz (EFV) based antiretroviral therapy is expanding worldwide. However discontinuation of EFV containing regimens is common in some patients, particularly black patients, due most often to neuropsychiatric side effects. These adverse drug effects often result in premature drug discontinuation, as well as considerable morbidity. Methods: We genotyped CYP2A6, CYP2B6 and CYP3A4, which encode enzymes principally involved in EFV metabolism, from patients enrolled in the multinational SMART, FIRST and ESPRIT studies, for whom outcome data of treatment adherence was available. Patients with loss or decrease of function single nucleotide polymorphisms (SNPs) in the above genes were assigned a risk score based upon the number of SNPs present weighted relative to whether CYP2B6 (main metabolism pathway) and/or CYP2A6 and CYP3A4 (accessory pathways) were involved. Cox regression models were used to study the association between high genetic risk and time from initiation to EFV discontinuation. Failure was defined as discontinuation of an antiretroviral regimen other than for virologic failure or protocol determined discontinuation. Findings: Patients with highest pharmacogenetic risk, as defined by cumulative SNPs in CYP2A6, CYP2B6 and CYP3A4, have an increased risk of discontinuation of EFV containing therapy compared to patients with lower genetic risk scores (adjusted HR 1.9, 95% CI 1.2, 3.1, P= 0.009). High genetic risk score was not associated with an increased risk of discontinuing atazanavir or nevirapine. High genetic risk was present more often in blacks compared to non-blacks (Adjusted OR 4.5, 95% CI: 1.9,10.5), and treatment discontinuation was also increased in blacks overall (Adjusted HR 1.4, 95% CI 1.0, 1.9). However, high genetic riskwas more associated with treatment discontinuation than race alone for both blacks (Adjusted OR 1.9, 95% CI 0.8, 4.8) and non-blacks (Adjusted OR 5.3, 95% CI 1.5, 18.0). Interpretation: Premature discontinuation of ART delays the time to effective long term viral suppression, and is associated with significant morbidity. Pharmacogenetic testing may predict those with a high risk of EFV discontinuation, and therefore should be considered in patients in whom initiation of EFV based ART is being considered. Funding: Funded by NIH. (C) 2015 The Authors. Published by Elsevier B. V.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Cummins, Nathan W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Neuhaus, Jacqueline UNSPECIFIED UNSPECIFIED UNSPECIFIED Chu, Haitao UNSPECIFIED orcid.org/0000-0003-0932-598X UNSPECIFIED Neaton, James UNSPECIFIED UNSPECIFIED UNSPECIFIED Wyen, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Rockstroh, Juergen K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Skiest, Daniel J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boyd, Mark A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Khoo, Saye UNSPECIFIED UNSPECIFIED UNSPECIFIED Rotger, Margalida UNSPECIFIED UNSPECIFIED UNSPECIFIED Telenti, Amalio UNSPECIFIED UNSPECIFIED UNSPECIFIED Weinshilboum, Richard UNSPECIFIED UNSPECIFIED UNSPECIFIED Badley, Andrew D. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-400264
DOI:	10.1016/j.ebiom.2015.05.012
Journal or Publication Title:	EBioMedicine
Volume:	2
Number:	7
Page Range:	S. 706 - 713
Date:	2015
Publisher:	ELSEVIER SCIENCE BV
Place of Publication:	AMSTERDAM
ISSN:	2352-3964
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ANTIRETROVIRAL THERAPY; HIV-1-INFECTED INDIVIDUALS; INFECTED PATIENTS; RANDOMIZED-TRIAL; INITIAL THERAPY; CYP2B6; PHARMACOKINETICS; PHARMACOGENETICS; POLYMORPHISMS; ASSOCIATION Multiple languages Medicine, General & Internal; Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/40026