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.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Block H, First Floor, 70 Pembroke Place, Liverpool, L69 3GF, UK. laurad@liverpool.ac.uk.
authors.forename: Laura
authors.initials: L
authors.lastname: Dickinson
authors.affiliation: The Kirby Institute, University of New South Wales Australia, Wallace Wurth Building, High Street, Kensington, Sydney, NSW, 2052, Australia.
authors.forename: Janaki
authors.initials: J
authors.lastname: Amin
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Block H, First Floor, 70 Pembroke Place, Liverpool, L69 3GF, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Else
authors.affiliation: St. Stephen's Centre, Chelsea and Westminster Foundation Trust, London, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Boffito
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Block H, First Floor, 70 Pembroke Place, Liverpool, L69 3GF, UK.
authors.forename: Deirdre
authors.initials: D
authors.lastname: Egan
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Block H, First Floor, 70 Pembroke Place, Liverpool, L69 3GF, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Block H, First Floor, 70 Pembroke Place, Liverpool, L69 3GF, UK.
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Block H, First Floor, 70 Pembroke Place, Liverpool, L69 3GF, UK.
authors.forename: David
authors.initials: D
authors.lastname: Back
authors.affiliation: Desmond Tutu HIV Foundation, Cape Town, South Africa.
authors.forename: Catherine
authors.initials: C
authors.lastname: Orrell
authors.affiliation: HIV-NAT Thai Red Cross AIDS Research Center, Bangkok, Thailand.
authors.forename: Amanda
authors.initials: A
authors.lastname: Clarke
authors.affiliation: Hospital Ramos Mejía, Buenos Aires, Argentina.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Losso
authors.affiliation: HIV-NAT Thai Red Cross AIDS Research Center, Bangkok, Thailand.
authors.forename: Praphan
authors.initials: P
authors.lastname: Phanuphak
authors.affiliation: The Kirby Institute, University of New South Wales Australia, Wallace Wurth Building, High Street, Kensington, Sydney, NSW, 2052, Australia. Dcarey@kirby.unsw.edu.au.
authors.forename: Dianne
authors.initials: D
authors.lastname: Carey
authors.affiliation: The Kirby Institute, University of New South Wales Australia, Wallace Wurth Building, High Street, Kensington, Sydney, NSW, 2052, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Cooper
authors.affiliation: The Kirby Institute, University of New South Wales Australia, Wallace Wurth Building, High Street, Kensington, Sydney, NSW, 2052, Australia.
authors.forename: Sean
authors.initials: S
authors.lastname: Emery
authors.affiliation: The Kirby Institute, University of New South Wales Australia, Wallace Wurth Building, High Street, Kensington, Sydney, NSW, 2052, Australia.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Puls
mesh_terms: D000293:Adolescent; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D048588:Benzoxazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000090702:Constitutive Androstane Receptor; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D012367:RNA, Viral / Q000378:metabolism; D055815:Young Adult
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D000090702:Constitutive Androstane Receptor; D003521:Cyclopropanes; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; C000716327:NR1I3 protein, human; D012367:RNA, Viral; C098320:efavirenz