Investigation of Efavirenz Discontinuation in Multi-ethnic Populations of HIV-positive Individuals by Genetic Analysis

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Version: Final published version
Serval ID
serval:BIB_B9EDF7F14C26
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Investigation of Efavirenz Discontinuation in Multi-ethnic Populations of HIV-positive Individuals by Genetic Analysis
Journal
Ebiomedicine
Author(s)
Cummins N.W., Neuhaus J., Chu H., Neaton J., Wyen C., Rockstroh J.K., Skiest D.J., Boyd M.A., Khoo S., Rotger M., Telenti A., Weinshilboum R., Badley A.D.
ISSN
2352-3964 (Electronic)
ISSN-L
2352-3964
Publication state
Published
Issued date
2015
Peer-reviewed
Oui
Volume
2
Number
7
Pages
706-712
Language
english
Notes
Publication types: Original Article ; research-article Identifiant PubMed Central: PMC4534686
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 risk was 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.
Keywords
HIV, Pharmacogenetics, Efavirenz, Premature discontinuation
Pubmed
Web of science
Open Access
Yes
Create date
25/07/2016 8:18
Last modification date
20/08/2019 15:27
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