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

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.

Figure 1. Study flowchart

WWARN=Worldwide Antimalarial Resistance Network.

Figure 2. Cumulative risk of PCR-confirmed recrudescence by day 28 in children aged 1–5 years

Error bars are 95% CIs.

Figure 3. Risk of recrudescence by day 28 in Africa and Asia

The predicted risk of recrudescence by day 28 for a given enrolment parasitaemia and total lumefantrine dose in Africa and Asia. The risks were estimated using the coefficients for parasitaemia and lumefantrine dose from a Cox’s model containing age, dose, and baseline parasitaemia for Africa. For Asia, the model contained dose and baseline parasitaemia. We assumed zero study effects. The horizontal line represents the 5% treatment failure rate threshold from WHO that should be used to assess if a new drug can be introduced for treatment of uncomplicated malaria. The vertical line is the parasitaemia of 100 000 per μL, a threshold used in the multivariable models for calculating the population-attributable risk estimates.