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The impact of extended treatment with artemether-lumefantrine on antimalarial exposure and reinfection risks in Ugandan children with uncomplicated malaria: A randomized controlled trial.

BACKGROUND
Artemether-lumefantrine (AL) is the most widely used artemisinin-based combination therapy (ACT) in sub-Saharan Africa and is threatened by the emergence of artemisinin resistance. Dosing is suboptimal in young children. We hypothesized that extending AL duration will improve exposure and reduce reinfection risks.


METHODS
We conducted a prospective, randomized, open-label pharmacokinetic/pharmacodynamic study of extended duration AL (EXALT) in children with malaria in high transmission rural Uganda. Children received 3-day (standard 6-dose) or 5-day (10-dose) AL with sampling for artemether, dihydroartemisinin (DHA), and lumefantrine over 42-day clinical follow-up. Primary outcomes were 1) comparative pharmacokinetic parameters between regimens, and 2) recurrent parasitemia analyzed as intention-to-treat.


RESULTS
177 children ages 16 months to 16 years were randomized, contributing 227 total episodes. Terminal median lumefantrine concentrations were significantly increased in the 5-day versus 3-day regimen on days 7, 14, and 21 (p-values < 0.001). A pre-defined day 7 lumefantrine threshold of 280 ng/mL was strongly predictive of recurrence risk at 28 and 42 days (p < 0.001). Kaplan-Meier estimated 28-day (51% vs 40%) and 42-day risk (75% vs 68%) did not significantly differ between 3-day and 5-day regimens. No significant toxicity was seen with the extended regimen.


CONCLUSIONS
Extending the duration of AL was safe and significantly enhanced overall drug exposure in young children but did not lead to significant reductions in recurrent parasitemia risk in our high transmission setting. However, day 7 levels were strongly predictive of recurrent parasitemia risk and those in the lowest weight-band were at higher risk of underdosing with the standard 3-day regimen.