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

Nathan W Cummins, Jacqueline Neuhaus, Haitao Chu, James Neaton, Christoph Wyen, Jürgen K. Rockstroh, Daniel J. Skiest, Mark A. Boyd, Saye Khoo, Margalida Rotger, Amalio Telenti, Richard M Weinshilboum, Andrew David Badley

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)706-712
Number of pages7
JournalEBioMedicine
Volume2
Issue number7
DOIs
StatePublished - Jul 1 2015

Fingerprint

efavirenz
HIV
Population
Cytochrome P-450 CYP3A
Polymorphism
Single Nucleotide Polymorphism
Nucleotides
Metabolism
Morbidity
Nevirapine

Keywords

  • Efavirenz
  • HIV
  • Pharmacogenetics
  • Premature discontinuation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Investigation of Efavirenz Discontinuation in Multi-ethnic Populations of HIV-positive Individuals by Genetic Analysis. / Cummins, Nathan W; Neuhaus, Jacqueline; Chu, Haitao; Neaton, James; Wyen, Christoph; Rockstroh, Jürgen K.; Skiest, Daniel J.; Boyd, Mark A.; Khoo, Saye; Rotger, Margalida; Telenti, Amalio; Weinshilboum, Richard M; Badley, Andrew David.

In: EBioMedicine, Vol. 2, No. 7, 01.07.2015, p. 706-712.

Research output: Contribution to journalArticle

Cummins, NW, Neuhaus, J, Chu, H, Neaton, J, Wyen, C, Rockstroh, JK, Skiest, DJ, Boyd, MA, Khoo, S, Rotger, M, Telenti, A, Weinshilboum, RM & Badley, AD 2015, 'Investigation of Efavirenz Discontinuation in Multi-ethnic Populations of HIV-positive Individuals by Genetic Analysis', EBioMedicine, vol. 2, no. 7, pp. 706-712. https://doi.org/10.1016/j.ebiom.2015.05.012
Cummins, Nathan W ; Neuhaus, Jacqueline ; Chu, Haitao ; Neaton, James ; Wyen, Christoph ; Rockstroh, Jürgen K. ; Skiest, Daniel J. ; Boyd, Mark A. ; Khoo, Saye ; Rotger, Margalida ; Telenti, Amalio ; Weinshilboum, Richard M ; Badley, Andrew David. / Investigation of Efavirenz Discontinuation in Multi-ethnic Populations of HIV-positive Individuals by Genetic Analysis. In: EBioMedicine. 2015 ; Vol. 2, No. 7. pp. 706-712.
@article{71f281017f924bee85076780deeb2c12,
title = "Investigation of Efavirenz Discontinuation in Multi-ethnic Populations of HIV-positive Individuals by Genetic Analysis",
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 = "Efavirenz, HIV, Pharmacogenetics, Premature discontinuation",
author = "Cummins, {Nathan W} and Jacqueline Neuhaus and Haitao Chu and James Neaton and Christoph Wyen and Rockstroh, {J{\"u}rgen K.} and Skiest, {Daniel J.} and Boyd, {Mark A.} and Saye Khoo and Margalida Rotger and Amalio Telenti and Weinshilboum, {Richard M} and Badley, {Andrew David}",
year = "2015",
month = "7",
day = "1",
doi = "10.1016/j.ebiom.2015.05.012",
language = "English (US)",
volume = "2",
pages = "706--712",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",
number = "7",

}

TY - JOUR

T1 - Investigation of Efavirenz Discontinuation in Multi-ethnic Populations of HIV-positive Individuals by Genetic Analysis

AU - Cummins, Nathan W

AU - Neuhaus, Jacqueline

AU - Chu, Haitao

AU - Neaton, James

AU - Wyen, Christoph

AU - Rockstroh, Jürgen K.

AU - Skiest, Daniel J.

AU - Boyd, Mark A.

AU - Khoo, Saye

AU - Rotger, Margalida

AU - Telenti, Amalio

AU - Weinshilboum, Richard M

AU - Badley, Andrew David

PY - 2015/7/1

Y1 - 2015/7/1

N2 - 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.

AB - 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.

KW - Efavirenz

KW - HIV

KW - Pharmacogenetics

KW - Premature discontinuation

UR - http://www.scopus.com/inward/record.url?scp=84951574162&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84951574162&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2015.05.012

DO - 10.1016/j.ebiom.2015.05.012

M3 - Article

C2 - 26288843

AN - SCOPUS:84951574162

VL - 2

SP - 706

EP - 712

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

IS - 7

ER -