Anti-malarial efficacy and resistance monitoring of artemether-lumefantrine and dihydroartemisinin-piperaquine shows inadequate efficacy in children in Burkina Faso, 2017–2018

Abstract

Background The World Health Organization recommends regularly assessing the efficacy of artemisinin-based combination therapy (ACT), which is a critical tool in the fight against malaria. This study evaluated the efficacy of two artemisinin-based combinations recommended to treat uncomplicated Plasmodium falciparum malaria in Burkina Faso in three sites: Niangoloko, Nanoro, and Gourcy. Methods This was a two-arm randomized control trial of the efficacy of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP). Children aged 6–59 months old were monitored for 42 days. The primary outcomes of the study were uncorrected and PCR-corrected efficacies to day 28 for AL and 42 for DP. Molecular markers of resistance to artemisinin derivatives and partner drugs were also analysed. Results Of 720 children enrolled, 672 reached study endpoints at day 28, 333 in the AL arm and 339 in the DP arm. PCR-corrected 28-day per protocol efficacy in the AL arm was 74% (64–83%) in Nanoro, 76% (66–83%) in Gourcy, and 92% (84–96%) in Niangoloko. The PCR-corrected 42-day per protocol efficacy in the DP arm was 84% (75–89%) in Gourcy, 89% (81–94%) in Nanoro, and 97% (92–99%) in Niangoloko. No Pfk13 mutation previously associated with artemisinin-resistance was observed. No statistically significant association was found between treatment outcome and presence of the 86Y mutation in the Pfmdr1 gene. There was also no association observed between treatment outcome and Pfpm2 or Pfmdr1 copy number variation. Conclusion The results of this study indicate evidence of inadequate efficacy of AL at day 28 and DP at day 42 in the same two sites. A change of first-line ACT may be warranted in Burkina Faso. Trial Registry Pan African Clinical Trial Registry Identifier: PACTR201708002499311. Date of registration: 8/3/2017 https://pactr.samrc.ac.za/Search.aspx

Therapeutic efficacy of artemether–lumefantrine and artesunate–amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Mali, 2015–2016

“…However, when accounting for a 95% confidence interval, the 86.0–95.9% PCR-corrected efficacy range of AL indicates that continued frequent efficacy monitoring of this drug is warranted in Mali. These findings are not unlike those from Uganda [ 35 ], Angola [ 36 ], and Burkina Faso [ 37 ], which have also shown AL not performing as well as other artemisinin-based combinations, such as ASAQ and DP. Similar to the AL day 28 uncorrected efficacy of 83.4% in this study, two other studies from Mali examining day 28 uncorrected efficacy reported results of 83.8% and 84.5% [ 33 , 34 ] and the study performed in Burkina Faso by Tinto & al, gave 58.4% for ASAQ and 46.1% for AL [ 32 ].…”

Efficacy of Dihydroartemisinin-piperaquine Versus Artemether-lumefantrine for the Treatment of Uncomplicated Plasmodium Falciparum Malaria Among Children in Africa: a Systematic Review and Meta-analysis of Randomized Control Trials

“…A target dose (range) of 4 (2-10) mg/kg bw per day dihydroartemisinin and 18 (16-27) mg/kg bw per day piperaquine given once a day for 3 days for children weighing ≥ 25 kg. The target doses and ranges for children weighing < 25 kg are 4 (2.5-10) mg/kg bw per day dihydroartemisinin and 24 (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32) mg/kg bw per day piperaquine once a day for 3 days.…”

“…There are a few reports on artemisinin resistance mediated by mutations kelch13 (K13) gene in Greater Mekong Sub-region [19], Sudan [20], higher prevalence (42%) in Myanmar [21], and low frequency of kelch13 (K13) gene mutation in 18 Sub-Saharan African countries [22,23]. In addition, over the past ten years a decline in parasitological response in Nigeria [24], decrease in PCR corrected therapeutic e cacy of ACT below 80% in Burkina Faso [25] have been noticed, Moreover, increase in copy number of plasmepsin genes associated with decrease in effectiveness of piperaquine has been arisen in South East Asia [26][27][28].…”

Efficacy of Artesunate-Amodiaquine and Artemether-Lumefantrine for Uncomplicated Plasmodium Falciparum Malaria in Madagascar, 2018

“…Additionally, AL absorption may have been compromised in this study because it was not administered with fatty food as recommended by the manufacturer [30]; however, drug levels were not collected, making this assertion impossible to ascertain. Evidence of sub-optimal e cacy of AL has been described in some African countries [10,11,31,32]; correct AL administration (i.e., with fatty food) and close monitoring of e cacy for uncomplicated malaria are warranted in Madagascar.…”

“…For AL, however, no recent studies to evaluate therapeutic e cacy have been done in Madagascar. Evidence of reduced AL e cacy has been described in SSA [10][11][12]; given that it is the second-line antimalarial in Madagascar, and has at times been used as the rst-line treatment due to shortages of ASAQ, describing its e cacy in Madagascar is important.…”