Evidence map›Paper›PMID 26715213›Full record

Trial reportClinical pharmacokinetics2016

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, Janaki Amin, Laura Else, Marta Boffito, Deirdre Egan, Andrew Owen, Saye Khoo, David Back, Catherine Orrell, Amanda Clarke and 6 more

Open access · hybridAbstract readMulticenter StudyRandomized Controlled Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in Clinical pharmacokinetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
29citing papers in PubMed, 1 pooled it
3.3field-weighted citation impact, top 7% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

29 citing papers in PubMed, 1 synthesis or guideline pooled it, 50 citations in OpenAlex.

  1. Pooled it
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  14. Using mechanistic physiologically-based pharmacokinetic models to assess prenatal drug exposure: Thalidomide versus efavirenz as case studies.European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences · 2019
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  16. Observational
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

16 authors at 5 institutions in 5 countries.

Laura DickinsonDepartment of Molecular and Clinical Pharmacology, University of Liverpool, Block H, First Floor, 70 Pembroke Place, Liverpool, L69 3GF, UK. laurad@liverpool.ac.uk.
Janaki AminThe Kirby Institute, University of New South Wales Australia, Wallace Wurth Building, High Street, Kensington, Sydney, NSW, 2052, Australia.
Laura ElseDepartment of Molecular and Clinical Pharmacology, University of Liverpool, Block H, First Floor, 70 Pembroke Place, Liverpool, L69 3GF, UK.
Marta BoffitoSt. Stephen's Centre, Chelsea and Westminster Foundation Trust, London, UK.
Deirdre EganDepartment of Molecular and Clinical Pharmacology, University of Liverpool, Block H, First Floor, 70 Pembroke Place, Liverpool, L69 3GF, UK.
Andrew OwenDepartment of Molecular and Clinical Pharmacology, University of Liverpool, Block H, First Floor, 70 Pembroke Place, Liverpool, L69 3GF, UK.
Saye KhooDepartment of Molecular and Clinical Pharmacology, University of Liverpool, Block H, First Floor, 70 Pembroke Place, Liverpool, L69 3GF, UK.
David BackDepartment of Molecular and Clinical Pharmacology, University of Liverpool, Block H, First Floor, 70 Pembroke Place, Liverpool, L69 3GF, UK.
Catherine OrrellDesmond Tutu HIV Foundation, Cape Town, South Africa.
Amanda ClarkeHIV-NAT Thai Red Cross AIDS Research Center, Bangkok, Thailand.
Marcelo LossoHospital Ramos Mejía, Buenos Aires, Argentina.
Praphan PhanuphakHIV-NAT Thai Red Cross AIDS Research Center, Bangkok, Thailand.
Dianne CareyThe Kirby Institute, University of New South Wales Australia, Wallace Wurth Building, High Street, Kensington, Sydney, NSW, 2052, Australia. Dcarey@kirby.unsw.edu.au.
David A CooperThe Kirby Institute, University of New South Wales Australia, Wallace Wurth Building, High Street, Kensington, Sydney, NSW, 2052, Australia.
Sean EmeryThe Kirby Institute, University of New South Wales Australia, Wallace Wurth Building, High Street, Kensington, Sydney, NSW, 2052, Australia.
Rebekah PulsThe Kirby Institute, University of New South Wales Australia, Wallace Wurth Building, High Street, Kensington, Sydney, NSW, 2052, Australia.
University of Liverpool · GBUNSW Sydney · AUHIV Netherlands Australia Thailand Research Collaboration · THDesmond Tutu HIV Foundation · ZAHospital Ramos Mejía · AR

Funding

Medical Research Council G0800247Medical Research Council G0901364
6 · The paper itself

Abstract

backgroundENCORE1 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.

methodsRelationships 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.

resultsA 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.

conclusionsA 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.

Indexed as

AdolescentAdultAlkynesAnti-HIV AgentsArea Under CurveBenzoxazinesConstitutive Androstane ReceptorCyclopropanesDose-Response Relationship, DrugDouble-Blind MethodEmtricitabine, Tenofovir Disoproxil Fumarate Drug CombinationFemaleGenotypeHIV InfectionsHumansMaleAlkynesAnti-HIV AgentsBenzoxazinesConstitutive Androstane ReceptorCyclopropanesefavirenzEmtricitabine, Tenofovir Disoproxil Fumarate Drug CombinationNR1I3 protein, humanRNA, Viral

Identifiers

PMID26715213
PMCPMC4916189
OpenAlexW2196612948

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.