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Clin Pharmacokinet. 2016 Jul;55(7):861-873. doi: 10.1007/s40262-015-0360-5.

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.

Author information

1
Department of Molecular and Clinical Pharmacology, University of Liverpool, Block H, First Floor, 70 Pembroke Place, Liverpool, L69 3GF, UK. laurad@liverpool.ac.uk.
2
The Kirby Institute, University of New South Wales Australia, Wallace Wurth Building, High Street, Kensington, Sydney, NSW, 2052, Australia.
3
Department of Molecular and Clinical Pharmacology, University of Liverpool, Block H, First Floor, 70 Pembroke Place, Liverpool, L69 3GF, UK.
4
St. Stephen's Centre, Chelsea and Westminster Foundation Trust, London, UK.
5
Desmond Tutu HIV Foundation, Cape Town, South Africa.
6
HIV-NAT Thai Red Cross AIDS Research Center, Bangkok, Thailand.
7
Hospital Ramos Mejía, Buenos Aires, Argentina.
8
The Kirby Institute, University of New South Wales Australia, Wallace Wurth Building, High Street, Kensington, Sydney, NSW, 2052, Australia. Dcarey@kirby.unsw.edu.au.

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.

PMID:
26715213
PMCID:
PMC4916189
DOI:
10.1007/s40262-015-0360-5
[Indexed for MEDLINE]
Free PMC Article

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