• Betty Balikagala, Naoyuki Fukuda, Mie Ikeda, Osbert T Katuro, Shin-Ichiro Tachibana, Masato Yamauchi, Walter Opio, Sakurako Emoto, Denis A Anywar, Eisaku Kimura, Nirianne M Q Palacpac, Emmanuel I Odongo-Aginya, Martin Ogwang, Toshihiro Horii, and Toshihiro Mita.
• From the Department of Tropical Medicine and Parasitology, School of Medicine (B.B., N.F., M.I., S.-I.T., M.Y., S.E., T.M.), and the Atopy Research Center, Graduate School of Medicine (B.B.), Juntendo University, Tokyo, the School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki (E.K.), and the Department of Malaria Vaccine Development, Research Institute for Microbial Diseases, Osaka University, Osaka (N.M.Q.P., T.H.) - all in Japan; and Mildmay Uganda, Nazibwa Hill, Kampala (O.T.K.), and St. Mary's Hospital Lacor (W.O., M.O.) and the Faculty of Medicine, Gulu University (D.A.A., E.I.O.-A.), Gulu - all in Uganda.
• N. Engl. J. Med. 2021 Sep 23; 385 (13): 1163-1171.

BackgroundIn the six Southeast Asian countries that make up the Greater Mekong Subregion, Plasmodium falciparum has developed resistance to derivatives of artemisinin, the main component of first-line treatments for malaria. Clinical resistance to artemisinin monotherapy in other global regions, including Africa, would be problematic.MethodsIn this longitudinal study conducted in Northern Uganda, we treated patients who had P. falciparum infection with intravenous artesunate (a water-soluble artemisinin derivative) and estimated the parasite clearance half-life. We evaluated ex vivo susceptibility of the parasite using a ring-stage survival assay and genotyped resistance-related genes.ResultsFrom 2017 through 2019, a total of 14 of 240 patients who received intravenous artesunate had evidence of in vivo artemisinin resistance (parasite clearance half-life, >5 hours). Of these 14 patients, 13 were infected with P. falciparum parasites with mutations in the A675V or C469Y allele in the kelch13 gene. Such mutations were associated with prolonged parasite clearance half-lives (geometric mean, 3.95 hours for A675V and 3.30 hours for C469Y, vs. 1.78 hours for wild-type allele; P<0.001 and P = 0.05, respectively). The ring-stage survival assay showed a higher frequency of parasite survival among organisms with the A675V allele than among those with the wild-type allele. The prevalence of parasites with kelch13 mutations increased significantly, from 3.9% in 2015 to 19.8% in 2019, due primarily to the increased frequency of the A675V and C469Y alleles (P<0.001 and P = 0.004, respectively). Single-nucleotide polymorphisms flanking the A675V mutation in Uganda were substantially different from those in Southeast Asia.ConclusionsThe independent emergence and local spread of clinically artemisinin-resistant P. falciparum has been identified in Africa. The two kelch13 mutations may be markers for detection of these resistant parasites. (Funded by the Japan Society for the Promotion of Science and others.).Copyright © 2021 Massachusetts Medical Society.

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