Publication:
Artemether-lumefantrine treatment of uncomplicated Plasmodium falciparum malaria: A systematic review and meta-analysis of day 7 lumefantrine concentrations and therapeutic response using individual patient data

Issued Date

2015-09-18

Resource Type

Article

ISSN

17417015

DOI

10.1186/s12916-015-0456-7

Other identifier(s)

2-s2.0-84942087456

Rights

Mahidol University

Rights Holder(s)

SCOPUS

Bibliographic Citation

BMC Medicine. Vol.13, No.1 (2015)

Suggested Citation

Elizabeth A. Ashley, Francesca Aweeka, Karen I. Barnes, Quique Bassat, Steffen Borrmann, Prabin Dahal, Timothy M.E. Davis, Mey Bouth Denis, Abdoulaye A. Djimde, Jean François Faucher, Blaise Genton, Philippe J. Guérin, Kamal Hamed, Eva Maria Hodel, Liusheng Huang, Vincent Jullien, Harin A. Karunajeewa, Jean René Kiechel, Poul Erik Kofoed, Gilbert Lefèvre, Niklas Lindegardh Lindegardh, Andreas Mårtensson, Mayfong Mayxay, Rose Mcgready, Clarissa Moreira, Paul N. Newton, Billy E. Ngasala, Francois Nosten, Christian Nsanzabana, Sunil Parikh, Patrice Piola, Ric N. Price, Pascal Ringwald, Lars Rombo, Birgit Schramm, Carol Hopkins Sibley, Kasia Stepniewska, Joel Tarning, Johan Ursing, Michele Van Vugt, Nicholas J. White, Lesley J. Workman, Philippe Deloron, Kevin Marsh Artemether-lumefantrine treatment of uncomplicated Plasmodium falciparum malaria: A systematic review and meta-analysis of day 7 lumefantrine concentrations and therapeutic response using individual patient data. BMC Medicine. Vol.13, No.1 (2015). doi:10.1186/s12916-015-0456-7 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/36324

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Title

Artemether-lumefantrine treatment of uncomplicated Plasmodium falciparum malaria: A systematic review and meta-analysis of day 7 lumefantrine concentrations and therapeutic response using individual patient data

Author(s)

Elizabeth A. Ashley
 Francesca Aweeka
 Karen I. Barnes
 Quique Bassat
 Steffen Borrmann
 Prabin Dahal
 Timothy M.E. Davis
 Mey Bouth Denis
 Abdoulaye A. Djimde
 Jean François Faucher
 Blaise Genton
 Philippe J. Guérin
 Kamal Hamed
 Eva Maria Hodel
 Liusheng Huang
 Vincent Jullien
 Harin A. Karunajeewa
 Jean René Kiechel
 Poul Erik Kofoed
 Gilbert Lefèvre
 Niklas Lindegardh Lindegardh
 Andreas Mårtensson
 Mayfong Mayxay
 Rose Mcgready
 Clarissa Moreira
 Paul N. Newton
 Billy E. Ngasala
 Francois Nosten
 Christian Nsanzabana
 Sunil Parikh
 Patrice Piola
 Ric N. Price
 Pascal Ringwald
 Lars Rombo
 Birgit Schramm
 Carol Hopkins Sibley
 Kasia Stepniewska
 Joel Tarning
 Johan Ursing
 Michele Van Vugt
 Nicholas J. White
 Lesley J. Workman
 Philippe Deloron
 Kevin Marsh

Other Contributor(s)

Shoklo Malaria Research Unit
 Mahidol University
 University of California, San Francisco
 WorldWide Antimalarial Resistance Network (WWARN)
 University of Cape Town
 Instituto de Salud Global de Barcelona
 Centro de Investigação em Saúde de Manhiça (CISM)
 Wellcome Trust Research Laboratories Nairobi
 Universitat Tubingen
 Nuffield Department of Clinical Medicine
 University of Western Australia
 IRD Institut de Recherche pour le Developpement
 Universite Paris Descartes
 National Center for Parasitology
 Organisation Mondiale de la Sante
 University of Bamako Faculty of Medicine, Pharmacy and Odonto-Stomatology
 Hopital Jean Minjoz
 Swiss Tropical and Public Health Institute (Swiss TPH)
 Centre Hospitalier Universitaire Vaudois
 Novartis Pharmaceuticals Corporation
 Liverpool School of Tropical Medicine
 Drugs for Neglected Diseases Initiative
 Syddansk Universitet
 Kolding Sygehus
 Novartis International AG
 Kenya Medical Research Institute
 Karolinska Institutet
 Wellcome Trust
 Muhimbili University of Health and Allied Sciences
 Yale Schools of Public Health and Medicine
 Department of Clinical Pharmacology
 Institut Pasteur de Madagascar
 Menzies School of Health Research
 Uppsala Universitet
 Epicentre
 University of Washington, Seattle
 University of Amsterdam

Abstract

© 2015 WorldWide Antimalarial Resistance Network (WWARN) Lumefantrine PK/PD Study Group. Background: Achieving adequate antimalarial drug exposure is essential for curing malaria. Day 7 blood or plasma lumefantrine concentrations provide a simple measure of drug exposure that correlates well with artemether-lumefantrine efficacy. However, the 'therapeutic' day 7 lumefantrine concentration threshold needs to be defined better, particularly for important patient and parasite sub-populations. Methods: The WorldWide Antimalarial Resistance Network (WWARN) conducted a large pooled analysis of individual pharmacokinetic-pharmacodynamic data from patients treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria, to define therapeutic day 7 lumefantrine concentrations and identify patient factors that substantially alter these concentrations. A systematic review of PubMed, Embase, Google Scholar, ClinicalTrials.gov and conference proceedings identified all relevant studies. Risk of bias in individual studies was evaluated based on study design, methodology and missing data. Results: Of 31 studies identified through a systematic review, 26 studies were shared with WWARN and 21 studies with 2,787 patients were included. Recrudescence was associated with low day 7 lumefantrine concentrations (HR 1.59 (95 % CI 1.36 to 1.85) per halving of day 7 concentrations) and high baseline parasitemia (HR 1.87 (95 % CI 1.22 to 2.87) per 10-fold increase). Adjusted for mg/kg dose, day 7 concentrations were lowest in very young children (<3 years), among whom underweight-for-age children had 23 % (95 % CI -1 to 41 %) lower concentrations than adequately nourished children of the same age and 53 % (95 % CI 37 to 65 %) lower concentrations than adults. Day 7 lumefantrine concentrations were 44 % (95 % CI 38 to 49 %) lower following unsupervised treatment. The highest risk of recrudescence was observed in areas of emerging artemisinin resistance and very low transmission intensity. For all other populations studied, day 7 concentrations ≥200 ng/ml were associated with >98 % cure rates (if parasitemia <135,000/μL). Conclusions: Current artemether-lumefantrine dosing recommendations achieve day 7 lumefantrine concentrations ≥200 ng/ml and high cure rates in most uncomplicated malaria patients. Three groups are at increased risk of treatment failure: very young children (particularly those underweight-for-age); patients with high parasitemias; and patients in very low transmission intensity areas with emerging parasite resistance. In these groups, adherence and treatment response should be monitored closely. Higher, more frequent, or prolonged dosage regimens should now be evaluated in very young children, particularly if malnourished, and in patients with hyperparasitemia.

Keyword(s)

Medicine

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https://repository.li.mahidol.ac.th/handle/20.500.14594/36324

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Scopus 2011-2015