The Impact of Extended Treatment With Artemether-lumefantrine on Antimalarial Exposure and Reinfection Risks in Ugandan Children With Uncomplicated Malaria: A Randomized Controlled Trial

Abstract

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.

Persistent and multiclonal malaria parasite dynamics despite extended artemether-lumefantrine treatment in children

“…Studies of asymptomatic individuals with consecutive daily sampling noted complex fluctuations in daily parasite clones and densities, reinforcing our understanding that any given sample represents only a fraction of the total parasite population 52 – 54 . Consistent with studies showing that size polymorphism-based genotyping typically underestimates MOI, we previously reported a pre-treatment median of 3 clones using only msp2 in this same cohort of HIV-uninfected children 42 , 55 – 58 .…”

“…We previously showed that extending AL from a 3 day to a 5 day regimen significantly improved artemether and lumefantrine drug exposure in children 42 . Despite this improved exposure, extending the duration (and number of doses) of AL was unable to significantly reduce the risk of recurrent parasitemia as defined by microscopy.…”

“…Although this did not appear to impact clinical outcomes, parasites are only exposed to declining levels of partner drug throughout this time. Previous msp1 , msp2 , and microsatellite genotyping demonstrated that the overwhelming majority of microscopically recurrent parasitemia consisted of new infections, not recrudescence 42 . This suggests that the enormous burden of post-treatment parasitemia seen in our study is reflective of a high rate of new infections rather than treatment failures—and of the overall continued efficacy of AL.…”

“…In high transmission settings such as ours, differentiating between persistent and recurrent parasitemia in the first few weeks following treatment is challenging 42 . We were able to sequence 25 samples in 21 children on day 7 and day 14, which allowed us to explore clonal dynamics during this early post-treatment period.…”

“…This study uses samples collected as part of EXALT: a prospective, randomized, open-label pharmacokinetic/pharmacodynamic study of 3 day (6-dose) versus 5 day (10 dose) AL for the treatment of uncomplicated malaria in HIV-infected and HIV-uninfected children aged 0.5–18 years (Fig. S5 ) 42 . Enrollment and sample collection was performed between August 2018 and January 2020 at Masafu General Hospital in Busia, a high transmission region in Eastern Uganda 65 , 66 .…”