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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

Ashley, Elizabeth A., Aweeka, Francesca, Barnes, Karen I., Bassat, Quique, Borrmann, Steffen, Dahal, Prabin, Davis, Timothy M. E., Deloron, Philippe, Denis, Mey B., Djimde, Abdoulaye A., Faucher, Jean-Francois, Genton, Blaise, Guerin, Philippe J., Hamed, , Kamal, Hodel, Eva M., Huang, Liusheng, Jullien, Vincent, Karunajeewa, Harin A., Price, Ric N., WorldWide Antimalarial Resistance Network (WWARN) Lumefantrine PK/PD Study Group and et al. (2015). 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,13(Article No. 227).

Document type: Journal Article
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IRMA ID 11381xPUB171
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 Ashley, Elizabeth A.
Aweeka, Francesca
Barnes, Karen I.
Bassat, Quique
Borrmann, Steffen
Dahal, Prabin
Davis, Timothy M. E.
Deloron, Philippe
Denis, Mey B.
Djimde, Abdoulaye A.
Faucher, Jean-Francois
Genton, Blaise
Guerin, Philippe J.
Hamed, , Kamal
Hodel, Eva M.
Huang, Liusheng
Jullien, Vincent
Karunajeewa, Harin A.
Price, Ric N.
WorldWide Antimalarial Resistance Network (WWARN) Lumefantrine PK/PD Study Group
et al.
Journal Name BMC Medicine
Publication Date 2015
Volume Number 13
Issue Number Article No. 227
ISSN 1741-7015   (check CDU catalogue  open catalogue search in new window)
Total Pages 19
Place of Publication United Kingdom
Publisher BioMed Central Ltd.
HERDC Category C1 - Journal Article (DIISR)
Abstract 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.
Keywords Artemether-lumefantrine
Day 7 lumefantrine concentration
Pharmacokinetic
Pharmacodynamic
Uncomplicated Plasmodium falciparum malaria
Baseline parasitemia
Malnutrition
Early parasitological response
Drug resistance
Meta-analysis
DOI http://dx.doi.org/10.1186/s12916-015-0456-7   (check subscription with CDU E-Gateway service for CDU Staff and Students  check subscription with CDU E-Gateway in new window)
Additional Notes This is an Open Access article distributed under the terms of the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
Description for Link Link to CC Attribution 4.0 License
URL https://creativecommons.org/licenses/by/4.0/au
 
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