First-line treatment with artemether-lumefantrine plus amodiaquine was well-tolerated and an effective alternative compared with artemether-lumefantrine alone in patients with uncomplicated Plasmodium falciparum malaria infection, according to results of a study published in Lancet Infectious Diseases.

In the Greater Mekong subregion of Southeast Asia, late treatment failures following treatment with artemisinin-based combination therapies have increased. In this open-label randomized controlled trial conducted 5 hospitals across Cambodia and Vietnam, researchers tested the efficacy of treatment with amodiaquine plus artemether-lumefantrine for P falciparum malaria infection in regions with an increased prevalence of multidrug-resistant parasites (ClinicalTrials.gov, NCT03355664).

Patients aged between 2 and 65 years with uncomplicated P falciparum malaria infection were randomly assigned in a 1:1 fashion into blocks of 8 to 10 patients each and received either artemether-lumefantrine alone, according to World Health Organization (WHO) dosing guidelines, or artemether-lumefantrine plus amodiaquine at a dose of 10 mg/kg/day; All patients received treatment orally at a rate of 6 doses across 3 days. Patients also received a single dose of primaquine 0.25 mg/kg 24 hours after study initiation to limit transmission of the parasite. 


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Artemisinin resistance was determined by genotyping, and the primary outcome was Kaplan-Meier 42-day polymerase chain reaction-corrected efficacy against recrudescence of the original parasite. The secondary outcome was safety.

Overall, 154 and 156 patients received artemether-lumefantrine and artemether-lumefantrine plus amodiaquine, respectively, and a total of 305 parasites were genotyped. Among patients who received either artemether–lumefantrine plus amodiaquine or artemether-lumefantrine alone, treatment efficacy was observed in 97% (95% CI, 92-99) and 95% (95% CI, 89-97), respectively. The hazard ratio (HR) for recrudescence was 0.6 (95% CI, 0.2-1.9; P =.38).

Among a total of 13 instances of recrudescence, 12 occurred in 174 (57%) of the genytyped infections, with C580Y variations of the Pfkelch13 gene as the predominant strain indicating resistance to artemisinin. Of the 174 patients in whom parasites were genotyped, efficacy was observed in 89 (96%) of those who received artemether-lumefantrine plus amodiaquine compared with 73 (90%) of those who received artemether–lumefantrine alone (HR, 0.44; 95% CI, 0.14-1.40; P =.17). Although the addition of amodiaquine to arthemeter-lumefantrine was well-tolerated, the rate of mild and moderate adverse events was increased among patients who received this treatment compared with those who received artemether-lumefantrine alone.

This study was limited by difficulties with recruitment as the incidence of malaria had been declining in the region at the time of enrollment. Further study limitations included potential assessment and self-reporting bias due to the open-label design. In addition, patients were censored upon reinfection with another P falciparum strain or recurrent infection with P vivax, and in vitro sensitivity to lumefantrine was assessed for only 33 isolates.

The researchers concluded, “the mutual protection by the [2] partner drugs could prolong the useful therapeutic lifetime of combinations containing lumefantrine, providing an alternative first-line treatment in areas with artemisinin-resistant [P] falciparum malaria in Southeast Asia, and elsewhere.”

Disclosure: Some authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures. 

Reference

Peto TJ, Tripura R, Callery JJ, et al. Triple therapy with artemether–lumefantrine plus amodiaquine versus artemether–lumefantrine alone for artemisinin-resistant, uncomplicated falciparum malaria: an open-label, randomised, multicentre trial. Lancet Infect Dis. Published online March 8, 2022. doi:10.1016/S1473-3099(21)00692-7