Emergence of artemisinin-based combination treatment failure in patients returning from sub-Saharan Africa with P. falciparum malaria

Artemisinin-based combination therapies (ACTs) are recommended as first-line treatment against uncomplicated P. falciparum infection. Emergence of mutations in the PfKelch13 propeller domain has resulted in resistance to artemisinin in Southeast Asia. Mutations in Pfcoronin propeller domain confer reduced artemisinin susceptibility in vitro to an African Plasmodium strain, but their role in clinical resistance has not been established.We conducted a retrospective observational study of Israeli travellers returning from Sub-Saharan Africa with P. falciparum malaria, including patients with artemether-lumefantrine failure. Blood samples from all malaria-positive returning travellers are delivered to the national Parasitology Reference Laboratory along with personal information. Confirmation of malaria, species identification and comparative parasite-load analysis were performed using real-time PCR. DNA extractions from stored leftover samples were analysed for the presence of mutations in the Pfkelch13 (PF3D7_1343700) and Pfcoronin (PF3D7_1251200) genes. Age, weight, initial parasitemia level and Pfcoronin status were compared in patients who failed treatment versus responders.During 2009-2020, 338 patients had P. falciparum malaria acquired in Africa. Of those, 15 (24-69 years old, 14 males) failed treatment with artemether-lumefantrine. Four were still parasitemic at the end of treatment and 11 had malaria recrudescence. Treatment failure rates were 0% during 2009-2012, 9.1% during 2013-2016 and 17.4% during 2017-2020. In all patients the Pfkelch13 propeller domain had wild-type sequence. We did find the P76S mutation in the propeller domain of Pfcoronin in 4/15 (28.6%) of the treatment-failure cases compared to only 3/56 (5.5%) in the successfully treated patients (p = 0.027).The emergence of artemether-lumefantrine treatment failure was not associated with mutations in Pfkelch13. However, P76S mutation in the Pfcoronin gene was more frequently present in the treatment-failure group and merits further investigation. The increase of malaria incidence in Sub-Saharan-Africa partly attributed to the COVID-19 pandemic might also reflect a wider spread of ACT resistance.