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Randomized Controlled Trial
. 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

Laura Dickinson  1 , Janaki Amin  2 , Laura Else  3 , Marta Boffito  4 , Deirdre Egan  3 , Andrew Owen  3 , Saye Khoo  3 , David Back  3 , Catherine Orrell  5 , Amanda Clarke  6 , Marcelo Losso  7 , Praphan Phanuphak  6 , Dianne Carey  8 , David A Cooper  2 , Sean Emery  2 , Rebekah Puls  2
Affiliations
Randomized Controlled Trial

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

Laura Dickinson et al. Clin Pharmacokinet. 2016 Jul.

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.

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Figures

Fig. 1
Fig. 1
Flow diagram summarising a the data included in the population pharmacokinetic model and b genetic data available for analysis. EFV efavirenz, PK pharmacokinetics, LLQ lower limit of quantification, ITT intention to treat, LC–MS/MS liquid chromatography–tandem mass spectrometry, PCR polymerase chain reaction, WK week
See this image and copyright information in PMC

References

    1. World Health Organisation. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Recommendations for a public health approach. 2013. http://www.who.int/hiv/pub/guidelines/arv2013/download/en/. Accessed 12 Aug 2015. - PubMed
    1. Haas DW, Seekins D, Cooper R, Gallant JE, Tashima K, Hicks C, et al. A phase II, double-blind, placebo-controlled, dose ranging study to assess the antiretroviral activity and safety of efavirenz in combination with open-label zidovudine with lamivudine at 36 weeks [DMP 266-005; abstract no. 22334]. The XII International AIDS Conference; Geneva: 28 Jun–3 Jul 1998.
    1. Puls R, Amin J, Losso M, Phanuphak P, Nwizu C, Orrell C, et al. Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): a randomised, double-blind, placebo-controlled, non-inferiority trial. Lancet. 2014;383(9927):1474–1482. doi: 10.1016/S0140-6736(13)62187-X. - DOI - PubMed
    1. ENCORE1 Study Group Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-controlled, non-inferiority ENCORE1 study. Lancet Infect Dis. 2015;15(7):793–802. doi: 10.1016/S1473-3099(15)70060-5. - DOI - PubMed
    1. Dickinson L, Amin J, Else L, Boffito M, Egan D, Owen A, et al. Pharmacokinetic and pharmacodynamic comparison of once daily efavirenz (400mg versus 600mg) in treatment-naive HIV-infected patients: results of the ENCORE1 study. Clin Pharmacol Ther. 2015;98(4):406–416. doi: 10.1002/cpt.156. - DOI - PMC - PubMed

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