{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T11:45:52Z","timestamp":1793015152633,"version":"4.5.0"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T00:00:00Z","timestamp":1701216000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UK Health Security Agency"},{"DOI":"10.13039\/100014013","name":"UK Research and Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014013","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,2,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Recent cases of clinical failure in malaria patients in the United Kingdom (UK) treated with artemether-lumefantrine have implications for malaria chemotherapy worldwide.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Parasites were isolated from an index case of confirmed Plasmodium falciparum treatment failure after standard treatment, and from comparable travel-acquired UK malaria cases. Drug susceptibility in vitro and genotypes at 6 resistance-associated loci were determined for all parasite isolates and compared with clinical outcomes for each parasite donor.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A traveler, who returned to the UK from Uganda in 2022 with Plasmodium falciparum malaria, twice failed treatment with full courses of artemether-lumefantrine. Parasites from the patient exhibited significantly reduced susceptibility to artemisinin (ring-stage survival, 17.3% [95% confidence interval {CI}, 13.6%\u201321.1%]; P &amp;lt; .0001) and lumefantrine (effective concentration preventing 50% of growth = 259.4\u2005nM [95% CI, 130.6\u2013388.2\u2005nM]; P = .001). Parasite genotyping identified an allele of pfk13 encoding both the A675V variant in the Pfk13 propeller domain and a novel L145V nonpropeller variant. In vitro susceptibility testing of 6 other P. falciparum lines of Ugandan origin identified reduced susceptibility to artemisinin and lumefantrine in 1 additional line, also from a 2022 treatment failure case. These parasites did not harbor a pfk13 propeller domain variant but rather the novel nonpropeller variant T349I. Variant alleles of pfubp1, pfap2mu, and pfcoronin were also identified among the 7 parasite lines.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We confirm, in a documented case of artemether-lumefantrine treatment failure imported from Uganda, the presence of pfk13 mutations encoding L145V and A675V. Parasites with reduced susceptibility to both artemisinin and lumefantrine may be emerging in Uganda.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cid\/ciad724","type":"journal-article","created":{"date-parts":[[2023,11,28]],"date-time":"2023-11-28T14:50:17Z","timestamp":1701183017000},"page":"445-452","source":"Crossref","is-referenced-by-count":48,"title":["Treatment Failure in a UK Malaria Patient Harboring Genetically Variant\n                    <i>Plasmodium falciparum<\/i>\n                    From Uganda With Reduced In Vitro Susceptibility to Artemisinin and Lumefantrine"],"prefix":"10.1093","volume":"78","author":[{"given":"Donelly A","family":"van Schalkwyk","sequence":"first","affiliation":[{"name":"Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sade","family":"Pratt","sequence":"additional","affiliation":[{"name":"Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debbie","family":"Nolder","sequence":"additional","affiliation":[{"name":"UK Health Security Agency Malaria Reference Laboratory, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay B","family":"Stewart","sequence":"additional","affiliation":[{"name":"UK Health Security Agency Malaria Reference Laboratory, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Liddy","sequence":"additional","affiliation":[{"name":"UK Health Security Agency Malaria Reference Laboratory, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Muwanguzi-Karugaba","sequence":"additional","affiliation":[{"name":"Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalid B","family":"Beshir","sequence":"additional","affiliation":[{"name":"Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawn","family":"Britten","sequence":"additional","affiliation":[{"name":"UK Health Security Agency Malaria Reference Laboratory, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Victory","sequence":"additional","affiliation":[{"name":"UK Health Security Agency Malaria Reference Laboratory, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Rogers","sequence":"additional","affiliation":[{"name":"UK Health Security Agency Malaria Reference Laboratory, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Millard","sequence":"additional","affiliation":[{"name":"Hospital for Tropical Diseases, University College London Hospitals NHS Foundation Trust , London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Brown","sequence":"additional","affiliation":[{"name":"Hospital for Tropical Diseases, University College London Hospitals NHS Foundation Trust , London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura E","family":"Nabarro","sequence":"additional","affiliation":[{"name":"Hospital for Tropical Diseases, University College London Hospitals NHS Foundation Trust , London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Taylor","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Oxford University Hospitals NHS Foundation Trust , Oxford , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernadette C","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Oxford University Hospitals NHS Foundation Trust , Oxford , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter L","family":"Chiodini","sequence":"additional","affiliation":[{"name":"UK Health Security Agency Malaria Reference Laboratory, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1592-6407","authenticated-orcid":false,"given":"Colin J","family":"Sutherland","sequence":"additional","affiliation":[{"name":"Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom"},{"name":"UK Health Security Agency Malaria Reference Laboratory, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,11,29]]},"reference":[{"key":"2024021719314451200_ciad724-B1","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1056\/NEJMoa0808859","article-title":"Artemisinin resistance in Plasmodium falciparum malaria","volume":"361","author":"Dondorp","year":"2009","journal-title":"N Engl J Med"},{"key":"2024021719314451200_ciad724-B2","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1056\/NEJMc0805011","article-title":"Evidence of artemisinin-resistant malaria in western Cambodia","volume":"359","author":"Noedl","year":"2008","journal-title":"N Engl J Med"},{"key":"2024021719314451200_ciad724-B3","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nature12876","article-title":"A molecular marker of artemisinin-resistant Plasmodium falciparum malaria","volume":"505","author":"Ariey","year":"2014","journal-title":"Nature"},{"key":"2024021719314451200_ciad724-B4","doi-asserted-by":"crossref","first-page":"2453","DOI":"10.1056\/NEJMoa1513137","article-title":"A worldwide map of Plasmodium falciparum K13-propeller polymorphisms","volume":"374","author":"Menard","year":"2016","journal-title":"N Engl J Med"},{"key":"2024021719314451200_ciad724-B5","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1056\/NEJMoa2101746","article-title":"Evidence of artemisinin-resistant malaria in Africa","volume":"385","author":"Balikagala","year":"2021","journal-title":"N Engl J Med"},{"key":"2024021719314451200_ciad724-B6","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.1038\/s41591-020-1005-2","article-title":"Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda","volume":"26","author":"Uwimana","year":"2020","journal-title":"Nat Med"},{"key":"2024021719314451200_ciad724-B7","doi-asserted-by":"crossref","first-page":"6353","DOI":"10.1038\/s41467-022-33873-x","article-title":"Decreased susceptibility of Plasmodium falciparum to both dihydroartemisinin and lumefantrine in northern Uganda","volume":"13","author":"Tumwebaze","year":"2022","journal-title":"Nat Commun"},{"key":"2024021719314451200_ciad724-B8","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1016\/S1473-3099(21)00142-0","article-title":"Association of Plasmodium falciparum kelch13 R561H genotypes with delayed parasite clearance in Rwanda: an open-label, single-arm, multicentre, therapeutic efficacy study","volume":"21","author":"Uwimana","year":"2021","journal-title":"Lancet Infect Dis"},{"key":"2024021719314451200_ciad724-B9","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1056\/NEJMc1612765","article-title":"Emergence of indigenous artemisinin-resistant Plasmodium falciparum in Africa","volume":"376","author":"Lu","year":"2017","journal-title":"N Engl J Med"},{"key":"2024021719314451200_ciad724-B10","doi-asserted-by":"crossref","first-page":"3405","DOI":"10.1128\/AAC.00024-09","article-title":"Novel pfdhps haplotypes among imported cases of Plasmodium falciparum malaria in the United Kingdom","volume":"53","author":"Sutherland","year":"2009","journal-title":"Antimicrob Agents Chemother"},{"key":"2024021719314451200_ciad724-B11","doi-asserted-by":"crossref","first-page":"e02382-16","DOI":"10.1128\/AAC.02382-16","article-title":"pfk13-independent treatment failure in four imported cases of Plasmodium falciparum malaria treated with artemether-lumefantrine in the United Kingdom","volume":"61","author":"Sutherland","year":"2017","journal-title":"Antimicrob Agents Chemother"},{"key":"2024021719314451200_ciad724-B12","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1093\/cid\/ciw710","article-title":"High rate of treatment failures in nonimmune travelers treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria in Sweden: retrospective comparative analysis of effectiveness and case series","volume":"64","author":"Sonden","year":"2017","journal-title":"Clin Infect Dis"},{"key":"2024021719314451200_ciad724-B13","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1186\/1475-2875-12-320","article-title":"Culture-adapted Plasmodium falciparum isolates from UK travellers: in vitro drug sensitivity, clonality and drug resistance markers","volume":"12","author":"van Schalkwyk","year":"2013","journal-title":"Malar J"},{"key":"2024021719314451200_ciad724-B14","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1126\/science.1260867","article-title":"Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates","volume":"347","author":"Straimer","year":"2015","journal-title":"Science"},{"key":"2024021719314451200_ciad724-B15","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.ijpddr.2019.02.004","article-title":"Plasmodium knowlesi exhibits distinct in vitro drug susceptibility profiles from those of Plasmodium falciparum","volume":"9","author":"van Schalkwyk","year":"2019","journal-title":"Int J Parasitol Drugs Drug Resist"},{"key":"2024021719314451200_ciad724-B16","doi-asserted-by":"crossref","first-page":"3051","DOI":"10.1093\/jac\/dkx279","article-title":"Comparison of the susceptibility of Plasmodium knowlesi and Plasmodium falciparum to antimalarial agents","volume":"72","author":"van Schalkwyk","year":"2017","journal-title":"J Antimicrob Chemother"},{"key":"2024021719314451200_ciad724-B17","doi-asserted-by":"crossref","first-page":"4938","DOI":"10.1128\/AAC.02902-14","article-title":"Flow cytometry-based analysis of artemisinin-resistant Plasmodium falciparum in the ring-stage survival assay","volume":"58","author":"Amaratunga","year":"2014","journal-title":"Antimicrob Agents Chemother"},{"key":"2024021719314451200_ciad724-B18","doi-asserted-by":"crossref","first-page":"5107","DOI":"10.1038\/s41598-019-41438-0","article-title":"Molecular quantification of Plasmodium parasite density from the blood retained in used RDTs","volume":"9","author":"Robinson","year":"2019","journal-title":"Sci Rep"},{"key":"2024021719314451200_ciad724-B19","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1093\/jac\/dkm104","article-title":"Chloroquine-resistant Plasmodium falciparum infections among UK travellers returning with malaria after chloroquine prophylaxis","volume":"59","author":"Sutherland","year":"2007","journal-title":"J Antimicrob Chemother"},{"key":"2024021719314451200_ciad724-B20","doi-asserted-by":"crossref","first-page":"12799","DOI":"10.1073\/pnas.1812317115","article-title":"Mutations in Plasmodium falciparum actin-binding protein coronin confer reduced artemisinin susceptibility","volume":"115","author":"Demas","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2024021719314451200_ciad724-B21","doi-asserted-by":"crossref","first-page":"2001","DOI":"10.1093\/infdis\/jiu358","article-title":"Directional selection at the pfmdr1, pfcrt, pfubp1, and pfap2mu loci of Plasmodium falciparum in Kenyan children treated with ACT","volume":"210","author":"Henriques","year":"2014","journal-title":"J Infect Dis"},{"key":"2024021719314451200_ciad724-B22","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/S1473-3099(13)70252-4","article-title":"Novel phenotypic assays for the detection of artemisinin-resistant Plasmodium falciparum malaria in Cambodia: in-vitro and ex-vivo drug-response studies","volume":"13","author":"Witkowski","year":"2013","journal-title":"Lancet Infect Dis"},{"key":"2024021719314451200_ciad724-B23","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.ijpddr.2018.12.003","article-title":"Transient temperature fluctuations severely decrease P. falciparum susceptibility to artemisinin in vitro","volume":"9","author":"Henrici","year":"2019","journal-title":"Int J Parasitol Drugs Drug Resist"},{"key":"2024021719314451200_ciad724-B24","doi-asserted-by":"crossref","first-page":"2540","DOI":"10.1128\/AAC.04067-14","article-title":"The mu subunit of Plasmodium falciparum clathrin-associated adaptor protein 2 modulates in vitro parasite response to artemisinin and quinine","volume":"59","author":"Henriques","year":"2015","journal-title":"Antimicrob Agents Chemother"},{"key":"2024021719314451200_ciad724-B25","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1186\/s12936-021-03987-6","article-title":"Prevalence of potential mediators of artemisinin resistance in African isolates of Plasmodium falciparum","volume":"20","author":"Owoloye","year":"2021","journal-title":"Malar J"},{"key":"2024021719314451200_ciad724-B26","doi-asserted-by":"crossref","first-page":"e01542-19","DOI":"10.1128\/AAC.01542-19","article-title":"Modification of pfap2mu and pfubp1 markedly reduces ring-stage susceptibility of Plasmodium falciparum to artemisinin in vitro","volume":"64","author":"Henrici","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"2024021719314451200_ciad724-B27","doi-asserted-by":"crossref","first-page":"5408","DOI":"10.1128\/AAC.05102-11","article-title":"Increased pfmdr1 copy number and sequence polymorphisms in Plasmodium falciparum isolates from Sudanese malaria patients treated with artemether-lumefantrine","volume":"55","author":"Gadalla","year":"2011","journal-title":"Antimicrob Agents Chemother"},{"key":"2024021719314451200_ciad724-B28","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1128\/AAC.00875-06","article-title":"Amodiaquine and artemether-lumefantrine select distinct alleles of the Plasmodium falciparum mdr1 gene in Tanzanian children treated for uncomplicated malaria","volume":"51","author":"Humphreys","year":"2007","journal-title":"Antimicrob Agents Chemother"},{"key":"2024021719314451200_ciad724-B29","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1086\/596738","article-title":"In vivo selection of Plasmodium falciparum parasites carrying the chloroquine-susceptible pfcrt K76 allele after treatment with artemether-lumefantrine in Africa","volume":"199","author":"Sisowath","year":"2009","journal-title":"J Infect Dis"},{"key":"2024021719314451200_ciad724-B30","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1086\/427997","article-title":"In vivo selection of Plasmodium falciparum pfmdr1 86N coding alleles by artemether-lumefantrine (Coartem)","volume":"191","author":"Sisowath","year":"2005","journal-title":"J Infect Dis"},{"key":"2024021719314451200_ciad724-B31","doi-asserted-by":"crossref","first-page":"e441","DOI":"10.1016\/S2666-5247(21)00085-9","article-title":"Drug susceptibility of Plasmodium falciparum in eastern Uganda: a longitudinal phenotypic and genotypic study","volume":"2","author":"Tumwebaze","year":"2021","journal-title":"Lancet Microbe"},{"key":"2024021719314451200_ciad724-B32","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1056\/NEJMoa2211803","article-title":"Evolution of partial resistance to artemisinins in malaria parasites in Uganda","volume":"389","author":"Conrad","year":"2023","journal-title":"N Engl J Med"},{"key":"2024021719314451200_ciad724-B33","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1056\/NEJMoa2210956","article-title":"Increasing prevalence of artemisinin-resistant HRP2-negative malaria in Eritrea","volume":"389","author":"Mihreteab","year":"2023","journal-title":"N Engl J Med"},{"key":"2024021719314451200_ciad724-B34","doi-asserted-by":"crossref","first-page":"e000371","DOI":"10.1136\/bmjgh-2017-000371","article-title":"Randomised controlled trial of two sequential artemisinin-based combination therapy regimens to treat uncomplicated falciparum malaria in African children: a protocol to investigate safety, efficacy and adherence","volume":"2","author":"Schallig","year":"2017","journal-title":"BMJ Glob Health"}],"container-title":["Clinical Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/cid\/advance-article-pdf\/doi\/10.1093\/cid\/ciad724\/55018715\/ciad724.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cid\/article-pdf\/78\/2\/445\/56697768\/ciad724.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cid\/article-pdf\/78\/2\/445\/56697768\/ciad724.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,17]],"date-time":"2024-02-17T14:32:29Z","timestamp":1708180349000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cid\/article\/78\/2\/445\/7453729"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,29]]},"references-count":34,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,11,29]]},"published-print":{"date-parts":[[2024,2,17]]}},"URL":"https:\/\/doi.org\/10.1093\/cid\/ciad724","relation":{},"ISSN":["1058-4838","1537-6591"],"issn-type":[{"value":"1058-4838","type":"print"},{"value":"1537-6591","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,2,15]]},"published":{"date-parts":[[2023,11,29]]}}}