Efficacy and safety of artesunate–amodiaquine and artemether–lumefantrine and prevalence of molecular markers associated with resistance, Guinea: an open-label two-arm randomised controlled trial

Abstract

Background: Anti-malarial resistance is a threat to recent gains in malaria control. This study aimed to assess the efficacy and safety of artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) in the management of uncomplicated malaria and to measure the prevalence of molecular markers of resistance of Plasmodium falciparum in sentinel sites in Maferinyah and Labé Health Districts in Guinea in 2016. Methods: This was a two-arm randomised controlled trial of the efficacy of AL and ASAQ among children aged 6-59 months with uncomplicated Plasmodium falciparum malaria in two sites. Children were followed for 28 days to assess clinical and parasitological response. The primary outcome was the Kaplan-Meier estimate of Day 28 (D28) efficacy after correction by microsatellite-genotyping. Pre-treatment (D0) and day of failure samples were assayed for molecular markers of resistance in the pfk13 and pfmdr1 genes. Results: A total of 421 participants were included with 211 participants in the Maferinyah site and 210 in Labé. No early treatment failure was observed in any study arms. However, 22 (5.3%) participants developed a late treatment failure (8 in the ASAQ arm and 14 in the AL arm), which were further classified as 2 recrudescences and 20 reinfections. The Kaplan-Meier estimate of the corrected efficacy at D28 was 100% for both AL and ASAQ in Maferinyah site and 99% (95% Confidence Interval: 97.2-100%) for ASAQ and 99% (97.1-100%) for AL in Labé. The majority of successfully analysed D0 (98%, 380/389) and all day of failure (100%, 22/22) samples were wild type for pfk13. All 9 observed pfk13 mutations were polymorphisms not associated with artemisinin resistance. The NFD haplotype was the predominant haplotype in both D0 (197/362, 54%) and day of failure samples (11/18, 61%) successfully analysed for pfmdr1. Conclusion: This study observed high efficacy and safety of both ASAQ and AL in Guinea, providing evidence for their continued use to treat uncomplicated malaria. Continued monitoring of ACT efficacy and safety and molecular

Nonparametric Binary Classification to Distinguish Closely Related versus Unrelated Plasmodium falciparum Parasites

“…A total of 175 pairs of D0–DOF samples were available from the previously generated microsatellite data 14 – 17 ( Table 1 ). We calculated a total of 10,286 D0–D0 pairwise distances, ranging from 514 to 3,976 per study.…”

Malaria epidemiology and anti-malarial drug efficacy in Guinea: a review of clinical and molecular studies

“…In particular, the three studies described data collected up to 2016 and there is a paucity of in vivo parasite susceptibility from 2017 onwards. The NMCP has begun therapeutic efficacy studies in four sentinel sites to monitor drug efficacy and track early signs of drug resistance [ 29 ].…”

“…Mutation in pfmdr1 allele is associated with increased failure for ACT with lumefantrine as partner drug [ 49 ]. Monitoring mutations in pfmdr1 gene including assessment of copy number elevation is, therefore, critical for the Guinean malaria control since AL has now largely replaced AS + AQ as a front line drug [ 29 ]. One study described mutations in the kelch-13 gene [ 5 ] and reassuringly, all the mutations identified are currently known not be associated with artemisinin resistance.…”

“…ACT was formally adopted as the first-line treatment for uncomplicated malaria by the NMCP in 2005, with artesunate + amodiaquine (AS + AQ) as the preferred regimen [ 27 ]. The efficacy of AS + AQ was initially tested in Dabola (2004) and has been further evaluated in Mafèrinyah (2011–2016) and Labé (2016) in a total of 632 patients (Table 2 ) [ 18 , 28 , 29 ]. Rapid parasitological responses has been observed following this regimen with day 3 parasite positivity rate (PPR) of 1% in Mafèrinyah and 0% in Labé in 2016 (PPRs were not reported in the Dabola study).…”

“…Artemether-lumefantrine (AL) has now largely replaced AS + AQ as the preferred regimen since 2016 [ 29 ]. The efficacy of the AL regimen has been evaluated in a single study in 2016 (209 patients) at two sites (Mafèrinyah and Labé) [ 5 ].…”