{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T06:50:40Z","timestamp":1793429440835,"version":"4.5.0"},"reference-count":47,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T00:00:00Z","timestamp":1743379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/501100008212","name":"Bassir-Thomas Biomedical Foundation","doi-asserted-by":"publisher","award":["TB\/22\/005"],"award-info":[{"award-number":["TB\/22\/005"]}],"id":[{"id":"10.13039\/501100008212","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006761","name":"Bureau of Educational and Cultural Affairs","doi-asserted-by":"publisher","award":["PS00316179"],"award-info":[{"award-number":["PS00316179"]}],"id":[{"id":"10.13039\/100006761","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\n                    Emergence of artemisinin resistance in East Africa has greatly necessitated surveillance of artemisinin resistance in other African countries with great malaria burden. Specific mutations within the \u03b2-propeller and BTB\/Poz domains of\n                    <jats:italic>Pf<\/jats:italic>\n                    kelch13 gene are validated markers of artemisinin resistance. Sparse information exists on mutations outside these domains that may also contribute to artemisinin resistance. This study evaluated the occurrence and frequency of mutations in all domains of\n                    <jats:italic>Pf<\/jats:italic>\n                    kelch13 gene, and their impact on treatment outcome in Ibadan pre- and post-adoption of Artemisinin-based Combination Therapies (ACTs) in Nigeria. Dry blood spots prepared from blood samples obtained from\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    -infected patients during retrospective (2000\u20132005) and prospective (2021) studies were analysed. Treatment outcomes with dihydroartemisinin-piperaquine were evaluated in a cohort of patients from the prospective study during a 42-day follow-up. Nested amplifications of\n                    <jats:italic>Pf<\/jats:italic>\n                    kelch13 gene fragments were done and subjected to Sanger dideoxy sequencing. Mutations were identified by sequence alignment and correlated with treatment outcome parameters including parasite clearance time (PCT) and day 2 parasite reduction ratio (PRRD\n                    <jats:sub>2<\/jats:sub>\n                    ) among others. Mean PCT was 2.1\u2009\u00b1\u20090.6 days (95%CI: 1.97\u20132.24) while PRRD\n                    <jats:sub>2<\/jats:sub>\n                    was 4815 with 100% adequate clinical and parasitological response. Altogether, 64 (11 retrospective\/53 prospective) samples were successfully sequenced. None of the \u03b2-propeller domain mutations validated as artemisinin resistance markers were found within the analysed samples. However, four distinct mutations, K189T (64.2%), K189N (1.9%), R255K (3.8%), and N217H (1.9%) were identified within the N-terminal domain of the prospective samples while the K189T mutation was identified in a retrospective sample obtained in 2003. The K189T and R255K mutations correlated significantly with longer parasite clearance time in treated patients (P\u2009&lt;\u20090.002). There was no evidence of validated molecular marker of artemisinin resistance within the \u00df-propeller domain of\n                    <jats:italic>Pf<\/jats:italic>\n                    kelch13. However, frequency of K189T mutation and its significant correlation with longer PCT may suggest possibilities of geographical variations in genetic drivers of artemisinin resistance.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0316479","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T15:22:14Z","timestamp":1743434534000},"page":"e0316479","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Polymorphisms in Pfkelch13 domains before and after the introduction of artemisinin-based combination therapy in Southwest Nigeria"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1897-6701","authenticated-orcid":true,"given":"Abiodun","family":"Amusan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olugbenga","family":"Akinola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazeem","family":"Akano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Hern\u00e1ndez-Casta\u00f1eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2553-7536","authenticated-orcid":true,"given":"Jenna K.","family":"Dick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akintunde","family":"Sowunmi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey","family":"Hart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"Gbotosho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,3,31]]},"reference":[{"key":"pone.0316479.ref001","doi-asserted-by":"crossref","first-page":"107697","DOI":"10.1016\/j.pharmthera.2020.107697","article-title":"Advances in the research on the targets of anti-malaria actions of artemisinin","volume":"216","author":"J Yang","year":"2020","journal-title":"Pharmacol Ther"},{"key":"pone.0316479.ref002","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1146\/annurev-pathmechdis-012419-032640","article-title":"New insights into malaria pathogenesis","volume":"15","author":"CA Moxon","year":"2020","journal-title":"Annu Rev Pathol"},{"key":"pone.0316479.ref003","author":"World Health Organization","year":"2023"},{"key":"pone.0316479.ref004","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1051\/parasite\/2018021","article-title":"Plasmodium falciparum resistance to artemisinin-based combination therapies: A sword of Damocles in the path toward malaria elimination","volume":"25","author":"M Ouji","year":"2018","journal-title":"Parasite"},{"issue":"1","key":"pone.0316479.ref005","doi-asserted-by":"crossref","first-page":"14392","DOI":"10.1038\/s41598-022-18782-9","article-title":"Relationships between transmission of malaria in Africa and climate factors","volume":"12","author":"BJ Mafwele","year":"2022","journal-title":"Sci Rep"},{"issue":"4","key":"pone.0316479.ref006","first-page":"taz030","article-title":"Geographic expansion of artemisinin resistance","volume":"26","author":"O M\u00fcller","year":"2019","journal-title":"J Travel Med"},{"issue":"1","key":"pone.0316479.ref007","doi-asserted-by":"crossref","first-page":"e01320","DOI":"10.1128\/AAC.01320-21","article-title":"Mutation in the Plasmodium falciparum BTB\/POZ domain of K13 protein confers artemisinin resistance","volume":"66","author":"L Paloque","year":"2022","journal-title":"Antimicrob Agents Chemother"},{"issue":"12","key":"pone.0316479.ref008","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/j.medj.2021.11.005","article-title":"Artemisinin resistance in Africa: How urgent is the threat?","volume":"2","author":"DA Fidock","year":"2021","journal-title":"Med"},{"key":"pone.0316479.ref009","author":"World Health Organization","year":"2022"},{"key":"pone.0316479.ref010","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.ijpddr.2020.11.006","article-title":"Artemisinin-based combination therapy (ACT) and drug resistance molecular markers: A systematic review of clinical studies from two malaria endemic regions \u2013 India and sub-Saharan Africa","volume":"15","author":"A Arya","year":"2021","journal-title":"Int J Parasitol Drugs Drug Resist"},{"key":"pone.0316479.ref011","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.ijpddr.2021.06.001","article-title":"A review of the frequencies of Plasmodium falciparum Kelch 13 artemisinin resistance mutations in Africa","volume":"16","author":"L Ndwiga","year":"2021","journal-title":"Int J Parasitol Drugs Drug Resist"},{"issue":"7481","key":"pone.0316479.ref012","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":"F Ariey","year":"2014","journal-title":"Nature"},{"issue":"5","key":"pone.0316479.ref013","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1056\/NEJMoa1314981","article-title":"Spread of artemisinin resistance in Plasmodium falciparum malaria","volume":"371","author":"EA Ashley","year":"2014","journal-title":"N Engl J Med"},{"issue":"10","key":"pone.0316479.ref014","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1016\/S1473-3099(17)30524-8","article-title":"Spread of a single multidrug resistant malaria parasite lineage (PfPailin) to Vietnam","volume":"17","author":"M Imwong","year":"2017","journal-title":"Lancet Infect Dis"},{"issue":"25","key":"pone.0316479.ref015","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":"D M\u00e9nard","year":"2016","journal-title":"N Engl J Med"},{"key":"pone.0316479.ref016","author":"WHO","year":"2022"},{"issue":"1","key":"pone.0316479.ref017","doi-asserted-by":"crossref","first-page":"3500","DOI":"10.1038\/s41598-020-60549-7","article-title":"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","volume":"10","author":"GM Bwire","year":"2020","journal-title":"Sci Rep"},{"issue":"13","key":"pone.0316479.ref018","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1056\/NEJMoa2101746","article-title":"Evidence of artemisinin-resistant malaria in Africa","volume":"385","author":"B Balikagala","year":"2021","journal-title":"N Engl J Med"},{"issue":"10","key":"pone.0316479.ref019","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":"A Uwimana","year":"2020","journal-title":"Nat Med"},{"key":"pone.0316479.ref020","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s12936-015-1075-7","article-title":"Assessing the potential impact of artemisinin and partner drug resistance in sub-Saharan Africa","volume":"15","author":"HC Slater","year":"2016","journal-title":"Malar J"},{"key":"pone.0316479.ref021","doi-asserted-by":"crossref","first-page":"3318","DOI":"10.1038\/srep03318","article-title":"Genome-wide screen identifies new candidate genes associated with artemisinin susceptibility in Plasmodium falciparum in Kenya","volume":"3","author":"S Borrmann","year":"2013","journal-title":"Sci Rep"},{"issue":"12","key":"pone.0316479.ref022","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":"G Henriques","year":"2014","journal-title":"J Infect Dis"},{"issue":"1","key":"pone.0316479.ref023","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s40249-019-0577-x","article-title":"Declining responsiveness of childhood Plasmodium falciparum infections to artemisinin-based combination treatments ten years following deployment as first-line antimalarials in Nigeria","volume":"8","author":"A Sowunmi","year":"2019","journal-title":"Infect Dis Poverty"},{"key":"pone.0316479.ref024","doi-asserted-by":"crossref","first-page":"e20190163","DOI":"10.1590\/0037-8682-0163-2019","article-title":"Therapeutic failure after regimen with artemether-lumefantrine combination therapy: a report of three cases in Benin City, Nigeria","volume":"52","author":"O Ebohon","year":"2019","journal-title":"Rev Soc Bras Med Trop"},{"issue":"2","key":"pone.0316479.ref025","doi-asserted-by":"crossref","first-page":"217","DOI":"10.4314\/ajcem.v24i2.12","article-title":"Malaria treatment failure after artemisinin-based combination therapy: a case series of children managed at a private tertiary hospital in southwest Nigeria","volume":"24","author":"O Fatunla","year":"2023","journal-title":"Afr J Clin Exper Microbiol"},{"issue":"8","key":"pone.0316479.ref026","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1111\/tmi.13273","article-title":"Kelch 13 propeller gene polymorphism among Plasmodium falciparum isolates in Lagos, Nigeria: molecular epidemiologic study","volume":"24","author":"U Igbasi","year":"2019","journal-title":"Trop Med Int Health"},{"issue":"2","key":"pone.0316479.ref027","doi-asserted-by":"crossref","first-page":"85","DOI":"10.3390\/tropicalmed5020085","article-title":"Identification of mutations in antimalarial resistance gene Kelch13 from Plasmodium falciparum isolates in Kano, Nigeria","volume":"5","author":"UF Abubakar","year":"2020","journal-title":"Trop Med Infect Dis"},{"issue":"2","key":"pone.0316479.ref028","doi-asserted-by":"crossref","first-page":"e0264548","DOI":"10.1371\/journal.pone.0264548","article-title":"Molecular profiling of the artemisinin resistance Kelch 13 gene in Plasmodium falciparum from Nigeria","volume":"17","author":"FV Ajogbasile","year":"2022","journal-title":"PLoS One"},{"issue":"1","key":"pone.0316479.ref029","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s12639-022-01538-7","article-title":"Pfmdr 1 and kelch 13 genes distribution among children that are 5 years and below in Akure, Nigeria","volume":"47","author":"OJ Afolabi","year":"2023","journal-title":"J Parasit Dis"},{"issue":"1","key":"pone.0316479.ref030","doi-asserted-by":"crossref","first-page":"10675","DOI":"10.1038\/s41598-019-47034-6","article-title":"Comparative structural and evolutionary analyses predict functional sites in the artemisinin resistance malaria protein K13","volume":"9","author":"R Copp\u00e9e","year":"2019","journal-title":"Sci Rep"},{"issue":"2","key":"pone.0316479.ref031","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/0035-9203(92)90533-I","article-title":"Innate resistance to new antimalarial drugs in Plasmodium falciparum from Nigeria","volume":"86","author":"AM Oduola","year":"1992","journal-title":"Trans R Soc Trop Med Hyg"},{"key":"pone.0316479.ref032","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1186\/s12936-015-0672-9","article-title":"Prevalence of K13-propeller polymorphisms in Plasmodium falciparum from China-Myanmar border in 2007\u20132012","volume":"14","author":"Z Wang","year":"2015","journal-title":"Malar J"},{"issue":"1","key":"pone.0316479.ref033","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12936-021-03715-0","article-title":"Molecular surveillance of drug resistance: Plasmodium falciparum artemisinin resistance single nucleotide polymorphisms in Kelch protein propeller (K13) domain from Southern Pakistan","volume":"20","author":"NK Ghanchi","year":"2021","journal-title":"Malar J"},{"issue":"10","key":"pone.0316479.ref034","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1038\/s41564-023-01461-4","article-title":"Plasmodium falciparum resistant to artemisinin and diagnostics have emerged in Ethiopia","volume":"8","author":"AA Fola","year":"2023","journal-title":"Nat Microbiol"},{"issue":"9","key":"pone.0316479.ref035","doi-asserted-by":"crossref","first-page":"2651","DOI":"10.15419\/bmrat.v5i9.474","article-title":"Evaluation of Plasmodium falciparum K13 gene polymorphism and susceptibility to dihydroartemisinin in an endemic area","volume":"5","author":"TM Dokunmu","year":"2018","journal-title":"Biomed Res Ther"},{"key":"pone.0316479.ref036","first-page":"2305062","article-title":"Status of artemisinin resistance in malaria parasite Plasmodium falciparum from molecular analyses of the Kelch13 gene in Southwestern Nigeria","author":"MA Oboh","year":"2018","journal-title":"Biomed Res Int"},{"issue":"9","key":"pone.0316479.ref037","doi-asserted-by":"crossref","first-page":"e0221895","DOI":"10.1371\/journal.pone.0221895","article-title":"K-13 propeller gene polymorphisms isolated between 2014 and 2017 from Cameroonian Plasmodium falciparum malaria patients","volume":"14","author":"CE Eboumbou Moukoko","year":"2019","journal-title":"PLoS One"},{"issue":"1","key":"pone.0316479.ref038","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1186\/s12936-020-03193-w","article-title":"Amplicon deep sequencing of kelch13 in Plasmodium falciparum isolates from Senegal","volume":"19","author":"A Gaye","year":"2020","journal-title":"Malar J"},{"issue":"1","key":"pone.0316479.ref039","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1186\/s12936-019-2947-z","article-title":"Rare mutations in Pfmdr1 gene of Plasmodium falciparum detected in clinical isolates from patients treated with anti-malarial drug in Nigeria","volume":"18","author":"AO Idowu","year":"2019","journal-title":"Malar J"},{"issue":"3","key":"pone.0316479.ref040","doi-asserted-by":"crossref","first-page":"e0041322","DOI":"10.1128\/spectrum.00413-22","article-title":"Molecular surveillance of artemisinin-based combination therapies resistance in Plasmodium falciparum parasites from Bioko Island, Equatorial Guinea","volume":"10","author":"Y Liu","year":"2022","journal-title":"Microbiol Spectr"},{"issue":"3","key":"pone.0316479.ref041","doi-asserted-by":"crossref","first-page":"e02116","DOI":"10.1128\/AAC.02116-16","article-title":"Molecular epidemiology of Plasmodium falciparum kelch13 mutations in senegal determined by using targeted amplicon deep sequencing","volume":"61","author":"E Talundzic","year":"2017","journal-title":"Antimicrob Agents Chemother"},{"issue":"1","key":"pone.0316479.ref042","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s12936-019-2701-6","article-title":"K13-propeller gene polymorphisms in Plasmodium falciparum parasite population in malaria affected countries: a systematic review of prevalence and risk factors","volume":"18","author":"M Ocan","year":"2019","journal-title":"Malar J"},{"issue":"5","key":"pone.0316479.ref043","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1093\/infdis\/jiu491","article-title":"Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia","volume":"211","author":"S Takala-Harrison","year":"2015","journal-title":"J Infect Dis"},{"issue":"1","key":"pone.0316479.ref044","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12916-018-1207-3","article-title":"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","volume":"17","author":"WWARN K13 Genotype-Phenotype Study Group","year":"2019","journal-title":"BMC Med"},{"issue":"1","key":"pone.0316479.ref045","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1186\/s12936-023-04588-1","article-title":"Ex vivo RSA and pfkelch13 targeted-amplicon deep sequencing reveal parasites susceptibility to artemisinin in Senegal, 2017","volume":"22","author":"MS Yade","year":"2023","journal-title":"Malar J"},{"issue":"11","key":"pone.0316479.ref046","doi-asserted-by":"crossref","first-page":"2854","DOI":"10.1093\/jac\/dkab264","article-title":"Kelch13 mutations in Plasmodium falciparum and risk of spreading in Amazon basin countries","volume":"76","author":"LC Mathieu","year":"2021","journal-title":"J Antimicrob Chemother"},{"key":"pone.0316479.ref047","doi-asserted-by":"crossref","first-page":"701750","DOI":"10.3389\/fgene.2021.701750","article-title":"First detection in west africa of a mutation that may contribute to artemisinin resistance Plasmodium falciparum","volume":"12","author":"H Zhao","year":"2021","journal-title":"Front Genet"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0316479","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T15:23:56Z","timestamp":1743434636000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0316479"}},"subtitle":[],"editor":[{"given":"Enoch","family":"Aninagyei","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,3,31]]},"references-count":47,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,3,31]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0316479","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,31]]}}}