E. A. Ashley, Spread of artemisinin resistance in Plasmodium falciparum malaria, N. Engl. J. Med, vol.371, pp.411-423, 2014.

M. D. Conrad and P. J. Rosenthal, Antimalarial drug resistance in Africa: the calm before the storm?, Lancet Infect. Dis, vol.19, pp.338-351, 2019.

, Genomic epidemiology of artemisinin resistant malaria, MalariaGEN Plasmodium falciparum Community Project, vol.5, p.8714, 2016.

D. Menard, A worldwide map of Plasmodium falciparum K13-propeller polymorphisms, N. Engl. J. Med, vol.374, pp.2453-2464, 2016.
URL : https://hal.archives-ouvertes.fr/pasteur-01336483

F. Ariey, A molecular marker of artemisinin-resistant Plasmodium falciparum malaria, Nature, vol.505, pp.50-55, 2014.
URL : https://hal.archives-ouvertes.fr/pasteur-00921203

J. Straimer, K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates, Science, vol.347, pp.428-431, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01925134

A. Uwimana, Efficacy of artemether-lumefantrine versus dihydroartemisinin-piperaquine for the treatment of uncomplicated malaria among children in Rwanda: an open-label, randomized controlled trial, Trans. R. Soc. Trop. Med. Hyg, vol.113, pp.312-319, 2019.

, World Health Organization. World Malaria Report, 2019.

N. J. White, Lancet, vol.383, pp.723-735, 2014.

D. Menard and A. Dondorp, Antimalarial drug resistance: a threat to malaria elimination, Cold Spring Harb. Perspect. Med, vol.7, p.25619, 2017.
URL : https://hal.archives-ouvertes.fr/hal-02559309

A. M. Dondorp, Artemisinin resistance in Plasmodium falciparum malaria, N. Engl. J. Med, vol.361, pp.455-467, 2009.
URL : https://hal.archives-ouvertes.fr/hal-02427334

R. Amato, Origins of the current outbreak of multidrug-resistant malaria in Southeast Asia: a retrospective genetic study, Lancet Infect. Dis, vol.18, pp.337-345, 2018.

M. Imwong, The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study, Lancet Infect. Dis, vol.17, pp.491-497, 2017.
URL : https://hal.archives-ouvertes.fr/hal-02559325

R. W. Van-der-pluijm, Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study, Lancet Infect. Dis, vol.19, pp.952-961, 2019.

W. L. Hamilton, Evolution and expansion of multidrug-resistant malaria in Southeast Asia: a genomic epidemiology study, Lancet Infect. Dis, vol.19, pp.943-951, 2019.

B. Blasco, D. Leroy, and D. A. Fidock, Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic, Nat. Med, vol.23, pp.917-928, 2017.

C. J. Murray, Global malaria mortality between 1980 and 2010: a systematic analysis, Lancet, vol.379, pp.413-431, 2012.

Z. Huang and A. J. Tatem, Global malaria connectivity through air travel, Malar. J, vol.12, p.269, 2013.

N. Scott, Implications of population-level immunity for the emergence of artemisinin-resistant malaria: a mathematical model, Malar. J, vol.17, p.279, 2018.

J. Birnbaum, A Kelch13-defined endocytosis pathway mediates artemisinin resistance in malaria parasites, Science, vol.367, pp.51-59, 2020.

T. Yang, Decreased K13 abundance reduces hemoglobin catabolism and proteotoxic stress, underpinning artemisinin resistance, Cell Rep, vol.29, p.2915, 2019.

L. C. Mathieu, Local emergence in Amazonia of Plasmodium falciparum k13 C580Y mutants associated with in vitro artemisinin resistance, vol.9, p.51015, 2020.
URL : https://hal.archives-ouvertes.fr/hal-02862736

O. Miotto, Emergence of artemisinin-resistant Plasmodium falciparum with kelch13 C580Y mutations on the island of New Guinea, 2019.

, Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: a literature review and meta-analysis of individual patient data, BMC Med, vol.13, p.212, 2015.

M. Ocan, K13-propeller gene polymorphisms in Plasmodium falciparum parasite population in malaria affected countries: a systematic review of prevalence and risk factors, Malar. J, vol.18, p.60, 2019.

, Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7_1343700) with parasite clearance rates after artemisinin-based treatments-a WWARN individual patient data meta-analysis, BMC Med, vol.17, p.1, 2019.

O. Miotto, Genetic architecture of artemisinin-resistant Plasmodium falciparum, Nat. Genet, vol.47, pp.226-234, 2015.

B. Witkowski, A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype-genotype association study, Lancet Infect
URL : https://hal.archives-ouvertes.fr/pasteur-01400955

. Dis, , vol.17, pp.174-183, 2017.

R. Amato, Genetic markers associated with dihydroartemisinin-piperaquine failure in Plasmodium falciparum malaria in Cambodia: a genotype-phenotype association study, Lancet Infect. Dis, vol.17, pp.164-173, 2017.

A. B. Sidhu, Decreasing pfmdr1 copy number in Plasmodium falciparum malaria heightens susceptibility to mefloquine, lumefantrine, halofantrine, quinine, and artemisinin, J. Infect. Dis, vol.194, pp.528-535, 2006.

S. K. Dhingra, J. L. Small-saunders, D. Menard, and D. A. Fidock, Plasmodium falciparum resistance to piperaquine driven by PfCRT, Lancet Infect. Dis, vol.19, pp.1168-1169, 2019.
URL : https://hal.archives-ouvertes.fr/hal-02558651

L. S. Ross, Emerging Southeast Asian PfCRT mutations confer Plasmodium falciparum resistance to the first-line antimalarial piperaquine, Nat. Commun, vol.9, p.3314, 2018.
URL : https://hal.archives-ouvertes.fr/hal-02558701

B. Witkowski, Novel phenotypic assays for the detection of artemisinin-resistant Plasmodium falciparum malaria in Cambodia: in vitro and ex vivo drug-response studies, Lancet Infect. Dis, vol.13, pp.1043-1049, 2013.
URL : https://hal.archives-ouvertes.fr/pasteur-00863935

K. O'flaherty, Contribution of functional antimalarial immunity to measures of parasite clearance in therapeutic efficacy studies of artemisinin derivatives, J. Infect. Dis, vol.220, pp.1178-1187, 2019.

N. Mishra, Surveillance of artemisinin resistance in Plasmodium falciparum in India using the kelch13 molecular marker, Antimicrob. Agents Chemother, vol.59, pp.2548-2553, 2015.

X. Wang, Molecular surveillance of PfCRT and k13 propeller polymorphisms of imported Plasmodium falciparum cases to Zhejiang Province, China between, Malar. J, vol.19, p.59, 2016.

G. M. Bwire, B. Ngasala, W. P. Mikomangwa, M. Kilonzi, and A. A. Kamuhabwa, Detection of mutations associated with artemisinin resistance at k13-propeller gene and a near complete return of chloroquine susceptible falciparum malaria in southeast of, Tanzania. Sci. Rep, vol.10, p.3500, 2020.

M. P. Barrett, D. E. Kyle, L. D. Sibley, J. B. Radke, and R. L. Tarleton, Protozoan persister-like cells and drug treatment failure, Nat. Rev. Microbiol, vol.17, pp.607-620, 2019.

H. C. Slater, J. T. Griffin, A. C. Ghani, and L. C. Okell, Assessing the potential impact of artemisinin and partner drug resistance in sub-Saharan Africa, Malar. J, vol.15, p.10, 2016.

, Methods and techniques for clinical trials on antimalarial drug efficacy: Genotyping to identify parasite populations, 2008.

, Status report on artemisinin resistance and ACT efficacy, 2018.

, Children 1-14 years of age presenting with suspected uncomplicated Plasmodium falciparum malaria (temperature ?37.5°C and/ or a history of fever within the past 24h)

, Enrolled patients were randomly assigned to receive a full course of AL (Coartem©, 20 mg artemether and 120 mg lumefantrine per tablet) or DP (Duo-Cotecxin©, 40 mg dihydroarteminisin and 320 mg piperaquine per tablet) according to the manufacturer's dosing schedule. A blood sample was collected prior to the initiation of treatment (day 0) and was spotted onto filter paper for genotyping, vol.35

, The full trial protocol is available from the corresponding authors upon request. Data collection Data were collected from clinical studies, coordinated by the Rwanda National Malaria Program and designed to assess the efficacy of artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) for the treatment of uncomplicated falciparum malaria at Masaka and Ruhuha health facilities in 2013, All manuscripts should comply with the ICMJE guidelines for publication of clinical research and a completed CONSORT checklist must be included with all submissions. Clinical trial registration ISRCTN63145981, pp.2012-2015, 2012.

, Outcomes The primary and secondary outcomes were pre-defined. The primary outcome of the study was the PCR-adjusted clinical response to the designated treatment on day 42. Patients were either classified as cured, or in the case of recurrence, as reinfected (new infection) or recrudescent (true treatment failure) according to the WHO 2009 protocol. The secondary outcome was the day 3 positivity rate (day 3+), defined as the proportion of patients who were still parasitemic on day 3 after initiation of treatment as assessed by microscopic examination of thick blood smears