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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 7/2016

Open Access 01-07-2016 | Original Research Article

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

Authors: Laura Dickinson, Janaki Amin, Laura Else, Marta Boffito, Deirdre Egan, Andrew Owen, Saye Khoo, David Back, Catherine Orrell, Amanda Clarke, Marcelo Losso, Praphan Phanuphak, Dianne Carey, David A. Cooper, Sean Emery, Rebekah Puls

Published in: Clinical Pharmacokinetics | Issue 7/2016

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Abstract

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 (C12) 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 C12, 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). C12 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.
Appendix
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Metadata
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
Authors
Laura Dickinson
Janaki Amin
Laura Else
Marta Boffito
Deirdre Egan
Andrew Owen
Saye Khoo
David Back
Catherine Orrell
Amanda Clarke
Marcelo Losso
Praphan Phanuphak
Dianne Carey
David A. Cooper
Sean Emery
Rebekah Puls
Publication date
01-07-2016
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 7/2016
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-015-0360-5

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