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The effect of dose on the antimalarial efficacy of artemether-lumefantrine: A systematic review and pooled analysis of individual patient data

Anstey, Nicholas M., Price, Ric N. and Worldwide Antimalarial Resistance Network (WWARN) AL Dose Impact Study Groups (2015). The effect of dose on the antimalarial efficacy of artemether-lumefantrine: A systematic review and pooled analysis of individual patient data. Lancet Infectious Diseases,15(6):692-702.

Document type: Journal Article
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IRMA ID 75039815xPUB863
Title The effect of dose on the antimalarial efficacy of artemether-lumefantrine: A systematic review and pooled analysis of individual patient data
Author Anstey, Nicholas M.
Price, Ric N.
Worldwide Antimalarial Resistance Network (WWARN) AL Dose Impact Study Groups
Journal Name Lancet Infectious Diseases
Publication Date 2015
Volume Number 15
Issue Number 6
ISSN 1473-3099   (check CDU catalogue open catalogue search in new window)
Scopus ID 2-s2.0-84929505628
Start Page 692
End Page 702
Total Pages 11
Place of Publication United Kingdom
Publisher The Lancet Publishing Group
Field of Research MEDICAL AND HEALTH SCIENCES
HERDC Category C1 - Journal Article (DIISR)
Abstract Background
Artemether–lumefantrine is the most widely used artemisinin-based combination therapy for malaria, although treatment failures occur in some regions. We investigated the effect of dosing strategy on efficacy in a pooled analysis from trials done in a wide range of malaria-endemic settings.

Methods
We searched PubMed for clinical trials that enrolled and treated patients with artemether–lumefantrine and were published from 1960 to December, 2012. We merged individual patient data from these trials by use of standardised methods. The primary endpoint was the PCR-adjusted risk of Plasmodium falciparum recrudescence by day 28. Secondary endpoints consisted of the PCR-adjusted risk of P falciparum recurrence by day 42, PCR-unadjusted risk of P falciparum recurrence by day 42, early parasite clearance, and gametocyte carriage. Risk factors for PCR-adjusted recrudescence were identified using Cox's regression model with frailty shared across the study sites.

Findings
We included 61 studies done between January, 1998, and December, 2012, and included 14 327 patients in our analyses. The PCR-adjusted therapeutic efficacy was 97·6% (95% CI 97·4–97·9) at day 28 and 96·0% (95·6–96·5) at day 42. After controlling for age and parasitaemia, patients prescribed a higher dose of artemether had a lower risk of having parasitaemia on day 1 (adjusted odds ratio [OR] 0·92, 95% CI 0·86–0·99 for every 1 mg/kg increase in daily artemether dose; p=0·024), but not on day 2 (p=0·69) or day 3 (0·087). In Asia, children weighing 10–15 kg who received a total lumefantrine dose less than 60 mg/kg had the lowest PCR-adjusted efficacy (91·7%, 95% CI 86·5–96·9). In Africa, the risk of treatment failure was greatest in malnourished children aged 1–3 years (PCR-adjusted efficacy 94·3%, 95% CI 92·3–96·3). A higher artemether dose was associated with a lower gametocyte presence within 14 days of treatment (adjusted OR 0·92, 95% CI 0·85–0·99; p=0·037 for every 1 mg/kg increase in total artemether dose).

Interpretation
The recommended dose of artemether–lumefantrine provides reliable efficacy in most patients with uncomplicated malaria. However, therapeutic efficacy was lowest in young children from Asia and young underweight children from Africa; a higher dose regimen should be assessed in these groups.

Funding
Bill & Melinda Gates Foundation.
DOI http://dx.doi.org/10.1016/S1473-3099(15)70024-1   (check subscription with CDU E-Gateway service for CDU Staff and Students  check subscription with CDU E-Gateway in new window)
 
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