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Comprehensive Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Evaluation of Once-Daily Efavirenz 400 and 600 mg in Treatment-Naïve HIV-Infected Patients at 96 Weeks: Results of the ENCORE1 Study

BACKGROUND: ENCORE1 demonstrated non-inferiority of daily efavirenz 400 mg (EFV400) versus 600 mg (EFV600) to 96 weeks in treatment-naïve, HIV-infected adults but concerns regarding lower EFV400 concentrations remained. Therefore, relationships between EFV pharmacokinetics (PK) and key genetic polym...

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Autores principales: Dickinson, Laura, Amin, Janaki, Else, Laura, Boffito, Marta, Egan, Deirdre, Owen, Andrew, Khoo, Saye, Back, David, Orrell, Catherine, Clarke, Amanda, Losso, Marcelo, Phanuphak, Praphan, Carey, Dianne, Cooper, David A., Emery, Sean, Puls, Rebekah
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916189/
https://www.ncbi.nlm.nih.gov/pubmed/26715213
http://dx.doi.org/10.1007/s40262-015-0360-5
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author Dickinson, Laura
Amin, Janaki
Else, Laura
Boffito, Marta
Egan, Deirdre
Owen, Andrew
Khoo, Saye
Back, David
Orrell, Catherine
Clarke, Amanda
Losso, Marcelo
Phanuphak, Praphan
Carey, Dianne
Cooper, David A.
Emery, Sean
Puls, Rebekah
author_facet Dickinson, Laura
Amin, Janaki
Else, Laura
Boffito, Marta
Egan, Deirdre
Owen, Andrew
Khoo, Saye
Back, David
Orrell, Catherine
Clarke, Amanda
Losso, Marcelo
Phanuphak, Praphan
Carey, Dianne
Cooper, David A.
Emery, Sean
Puls, Rebekah
author_sort Dickinson, Laura
collection PubMed
description BACKGROUND: ENCORE1 demonstrated non-inferiority of daily efavirenz 400 mg (EFV400) versus 600 mg (EFV600) to 96 weeks in treatment-naïve, HIV-infected adults but concerns regarding lower EFV400 concentrations remained. Therefore, relationships between EFV pharmacokinetics (PK) and key genetic polymorphisms with 96-week efficacy and safety were investigated. METHODS: Relationships between EFV PK parameters and single nucleotide polymorphisms (SNP; CYP2B6,CYP2A6, CYP3A4, NR1I3, NR1I2, ABCB1) with plasma HIV-RNA (pVL) <200 copies/mL and EFV discontinuation and adverse events at 96 weeks were explored. Receiver operating characteristic curve analysis evaluated the predictability of mid-dose interval (C(12)) cutoffs and 96-week pVL. RESULTS: A total of 606 patients (32 % female; 37 % African, 33 % Asian; n = 311 EFV400, n = 295 EFV600) were included. EFV PK parameters, including C(12), were not associated with pVL <200 copies/mL at 96 weeks (odds ratio [OR] 5.25, 95 % confidence interval [CI] 0.41–67.90, p = 0.204). Lower risk of CNS-related adverse events was associated with CYP2B6 983TC/CC (OR 0.35, 95 % CI 0.15–0.81, p = 0.015) and higher risk was associated with CYP2B6 15582CT/TT and ABCB1 3435TT (OR 1.46, 95 % CI 1.02–2.09, p = 0.040; OR 2.31, 95 % CI 1.33–4.02, p = 0.003, respectively). Discontinuation due to adverse events (clinician decision) was independently associated with dose (OR 2.54, 95 % CI 1.19–5.43, p = 0.016). C(12) between 0.47 and 0.76 mg/L provided sensitivity/specificity >90 % (100 %/92.3 to 98.9 %/92.3 %) for achieving pVL <200 copies/mL at 96 weeks. CONCLUSIONS: A higher rate of EFV-related adverse events and discontinuations due to these events for EFV600 were not driven by polymorphisms assessed. Although a single threshold concentration associated with HIV suppression may be clinically useful, it was not viable for ENCORE1. Implementation of EFV400 would improve toxicity management whilst still maintaining good efficacy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40262-015-0360-5) contains supplementary material, which is available to authorized users.
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spelling pubmed-49161892016-07-06 Comprehensive Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Evaluation of Once-Daily Efavirenz 400 and 600 mg in Treatment-Naïve HIV-Infected Patients at 96 Weeks: Results of the ENCORE1 Study Dickinson, Laura Amin, Janaki Else, Laura Boffito, Marta Egan, Deirdre Owen, Andrew Khoo, Saye Back, David Orrell, Catherine Clarke, Amanda Losso, Marcelo Phanuphak, Praphan Carey, Dianne Cooper, David A. Emery, Sean Puls, Rebekah Clin Pharmacokinet Original Research Article BACKGROUND: ENCORE1 demonstrated non-inferiority of daily efavirenz 400 mg (EFV400) versus 600 mg (EFV600) to 96 weeks in treatment-naïve, HIV-infected adults but concerns regarding lower EFV400 concentrations remained. Therefore, relationships between EFV pharmacokinetics (PK) and key genetic polymorphisms with 96-week efficacy and safety were investigated. METHODS: Relationships between EFV PK parameters and single nucleotide polymorphisms (SNP; CYP2B6,CYP2A6, CYP3A4, NR1I3, NR1I2, ABCB1) with plasma HIV-RNA (pVL) <200 copies/mL and EFV discontinuation and adverse events at 96 weeks were explored. Receiver operating characteristic curve analysis evaluated the predictability of mid-dose interval (C(12)) cutoffs and 96-week pVL. RESULTS: A total of 606 patients (32 % female; 37 % African, 33 % Asian; n = 311 EFV400, n = 295 EFV600) were included. EFV PK parameters, including C(12), were not associated with pVL <200 copies/mL at 96 weeks (odds ratio [OR] 5.25, 95 % confidence interval [CI] 0.41–67.90, p = 0.204). Lower risk of CNS-related adverse events was associated with CYP2B6 983TC/CC (OR 0.35, 95 % CI 0.15–0.81, p = 0.015) and higher risk was associated with CYP2B6 15582CT/TT and ABCB1 3435TT (OR 1.46, 95 % CI 1.02–2.09, p = 0.040; OR 2.31, 95 % CI 1.33–4.02, p = 0.003, respectively). Discontinuation due to adverse events (clinician decision) was independently associated with dose (OR 2.54, 95 % CI 1.19–5.43, p = 0.016). C(12) between 0.47 and 0.76 mg/L provided sensitivity/specificity >90 % (100 %/92.3 to 98.9 %/92.3 %) for achieving pVL <200 copies/mL at 96 weeks. CONCLUSIONS: A higher rate of EFV-related adverse events and discontinuations due to these events for EFV600 were not driven by polymorphisms assessed. Although a single threshold concentration associated with HIV suppression may be clinically useful, it was not viable for ENCORE1. Implementation of EFV400 would improve toxicity management whilst still maintaining good efficacy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40262-015-0360-5) contains supplementary material, which is available to authorized users. Springer International Publishing 2015-12-29 2016 /pmc/articles/PMC4916189/ /pubmed/26715213 http://dx.doi.org/10.1007/s40262-015-0360-5 Text en © The Author(s) 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Research Article
Dickinson, Laura
Amin, Janaki
Else, Laura
Boffito, Marta
Egan, Deirdre
Owen, Andrew
Khoo, Saye
Back, David
Orrell, Catherine
Clarke, Amanda
Losso, Marcelo
Phanuphak, Praphan
Carey, Dianne
Cooper, David A.
Emery, Sean
Puls, Rebekah
Comprehensive Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Evaluation of Once-Daily Efavirenz 400 and 600 mg in Treatment-Naïve HIV-Infected Patients at 96 Weeks: Results of the ENCORE1 Study
title Comprehensive Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Evaluation of Once-Daily Efavirenz 400 and 600 mg in Treatment-Naïve HIV-Infected Patients at 96 Weeks: Results of the ENCORE1 Study
title_full Comprehensive Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Evaluation of Once-Daily Efavirenz 400 and 600 mg in Treatment-Naïve HIV-Infected Patients at 96 Weeks: Results of the ENCORE1 Study
title_fullStr Comprehensive Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Evaluation of Once-Daily Efavirenz 400 and 600 mg in Treatment-Naïve HIV-Infected Patients at 96 Weeks: Results of the ENCORE1 Study
title_full_unstemmed Comprehensive Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Evaluation of Once-Daily Efavirenz 400 and 600 mg in Treatment-Naïve HIV-Infected Patients at 96 Weeks: Results of the ENCORE1 Study
title_short Comprehensive Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Evaluation of Once-Daily Efavirenz 400 and 600 mg in Treatment-Naïve HIV-Infected Patients at 96 Weeks: Results of the ENCORE1 Study
title_sort comprehensive pharmacokinetic, pharmacodynamic and pharmacogenetic evaluation of once-daily efavirenz 400 and 600 mg in treatment-naïve hiv-infected patients at 96 weeks: results of the encore1 study
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916189/
https://www.ncbi.nlm.nih.gov/pubmed/26715213
http://dx.doi.org/10.1007/s40262-015-0360-5
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