Academic Commons

Articles

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

Alemayehu, Bereket H.; Worldwide Antimalarial Resistance Network (WWARN) AL Dose Impact Study Group

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.

Geographic Areas

Files

  • thumnail for WWARN_AL_Dose_Impact_Study_Group._Lancet_Infect_Dis._2015_June_15_6___692-702.pdf WWARN_AL_Dose_Impact_Study_Group._Lancet_Infect_Dis._2015_June_15_6___692-702.pdf application/pdf 1.14 MB Download File

Also Published In

Title
The Lancet Infectious Diseases
DOI
https://doi.org/10.1016/S1473-3099(15)70024-1

More About This Work

Academic Units
International Center for AIDS Care and Treatment Programs
Published Here
March 8, 2017
Academic Commons provides global access to research and scholarship produced at Columbia University, Barnard College, Teachers College, Union Theological Seminary and Jewish Theological Seminary. Academic Commons is managed by the Columbia University Libraries.