Open-label, randomized, non-inferiority clinical trial of artesunate-amodiaquine versus artemether-lumefantrine fixed-dose combinations in children and adults with uncomplicated falciparum malaria in Côte d'Ivoire

Abstract

BackgroundEmergence of artemisinin resistance has raised concerns that the most potent anti-malarial drug may be under threat. Artesunate-amodiaquine (AS-AQ) and artemether-lumefantrine (AL) are, respectively, the first- and second-line treatments for uncomplicated falciparum malaria in Côte d’Ivoire. Constant monitoring by National Malaria Control Programme (NMCP) of drug efficacy is an important tool in establishing rational anti-malarial drug policies in Côte d’Ivoire.MethodsIn an open label, randomized controlled clinical trial, children and adults were randomized to receive AS-AQ or AL. Both drug regimens were given for three days, and follow-up was for 42 days. The primary endpoint was the 42-day cure rate and was defined as proportion of patients with PCR-corrected cure rate after 42 days of follow-up.ResultsA total of 383 patients who were attending the Anonkoua-koute (Abidjan), Petit Paris (Korhogo) and Libreville (Man) hospitals and presenting with symptomatic acute uncomplicated falciparum malaria were randomized to receive AS-AQ (188) and AL (195). The intention-to-treat analysis showed effectiveness rates of 94.7% and 96.4% for AS-AQ and AL, respectively on day 42. After adjustment for PCR, these rates were 96.8% and 99%, respectively. At day 42, in per-protocol analysis, Adequate clinical and parasitological response (ACPR) PCR uncorrected was 97.8% and 97.4% for AS-AQ and AL, respectively. The PCR adjusted ACPR was 100% for each combination and both regimens were well tolerated.ConclusionsThis study has shown the high efficacy of AS-AQ in patients of all ages with acute uncomplicated falciparum malaria and AS-AQ was non-inferior to AL. Continuous efficacy monitoring is recommended.

Malaria parasite clearance from patients following artemisinin-based combination therapy in Côte d’Ivoire

“…Results from these studies demonstrated an estimated PCT of 48 hours for both AS + AQ and AL. 18 , 19 , 26 However, these estimations of PCT have some limitations. Determination of PCT based on daily sampling lacks precision since the exact time of parasite count is not recorded.…”

“…P. falciparum is the predominant malaria parasite, accounting for more than 95% of malaria infections. 18 Bouake region was the epicenter of the country’s military crisis in 2002. During this period, the NMCP’s guidelines for malaria treatment were not followed by physicians.…”

“…A number of clinical trials have already been conducted in different parts of Côte d’Ivoire on artesunate + amodiaquine (AS + AQ) and artemether + lumefantrine (AL) efficacy and safety from 2005 to 2016 in Malaria Control Program sentinel sites. 18 – 20 Results from these studies have provided evidence that the two ACTs remain efficacious in the treatment of Plasmodium falciparum uncomplicated malaria. Polymerase chain reaction (PCR)-corrected 28-day adequate clinical and parasitological response (ACPR) for each ACT was more than 95% with and no early clinical failures.…”

A randomized trial of dihydroartemisinin–piperaquine versus artemether–lumefantrine for treatment of uncomplicated Plasmodium falciparum malaria in Mali

“…Since 2006, two ACT formulations, artemether–lumefantrine (AL) and artesunate–amodiaquine (ASAQ), were chosen by the National Malaria Control Programme to treat uncomplicated malaria in Mali. Many studies showed that AL and ASAQ remained efficacious against uncomplicated falciparum malaria in Africa [ 1 – 3 ] and data on clinical efficacy, safety and tolerability of AL and ASAQ exists in Mali [ 4 , 5 ]. Dihydroartemisinin–piperaquine (DHA–PQ) is also recommended by the WHO for uncomplicated malaria in Africa but, few data are available on its clinical efficacy and safety [ 6 , 7 ] but little is know on DHA–PQ combination.…”

Molecular Epidemiology of Malaria in Cameroon and Côte d'Ivoire. XXXI. Kelch 13 Propeller Sequences in Plasmodium falciparum Isolates before and after Implementation of Artemisinin-Based Combination Therapy

“…These two ACTs have been shown to be highly effective against acute uncomplicated falciparum malaria in these two countries. 2,3 Elsewhere in sub-Saharan Africa, high cure rates, often attaining > 95% after polymerase chain reaction (PCR) correction to exclude reinfections, have been reported with nearly all ACTs. 4 Artemisinin-resistant Plasmodium falciparum was first reported from Cambodia in 2008.…”