{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T03:06:17Z","timestamp":1784862377377,"version":"3.55.0"},"posted":{"date-parts":[[2025,6,23]]},"group-title":"Infectious Diseases (except HIV\/AIDS)","reference-count":57,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T00:00:00Z","timestamp":1750636800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The rise of antimalarial drug-resistant\n                  <jats:italic>Plasmodium falciparum<\/jats:italic>\n                  poses a major threat to malaria treatment, control, and elimination efforts. Mutations in the\n                  <jats:italic>kelch13<\/jats:italic>\n                  (\n                  <jats:italic>k13<\/jats:italic>\n                  ) gene confer artemisinin partial resistance (ART-R), compromising the efficacy of combination therapies. In the Horn of Africa, the validated mutation\n                  <jats:italic>k13<\/jats:italic>\n                  R622I has rapidly emerged in parallel with other mutations elsewhere in Eastern Africa. To monitor and inform control efforts, we conducted in-depth sampling where R622I was first detected, using molecular inversion probe (MIP) targeted sequencing of key resistance mutations and informative SNPs across the genome. Samples were collected for a year within two districts, Gondar Zuria and Tach Armachiho, representing different ecological zones in northwest Ethiopia. Among 903 people with\n                  <jats:italic>P. falciparum<\/jats:italic>\n                  malaria, we observed a markedly higher prevalence of R622I (44.3%) compared to earlier reports, with significantly higher prevalence in Gondar Zuria (52%) than in Tach Armachiho (40%; p&lt;0.001). Alarmingly, the prevalence of histidine rich protein 2 (HRP2) based rapid diagnostic test (RDT) negativity was higher in R622I mutants compared to wild types (48.3% vs 30.7%; p&lt;0.001). Furthermore, 98.2% of R622I samples carried the multidrug resistance protein 1 NFD haplotype associated with reduced susceptibility to lumefantrine. We also detected the\n                  <jats:italic>k13<\/jats:italic>\n                  C580Y mutation in two patients (0.4%) from Gondar Zuria, the first report in the Horn of Africa. Identity-by-descent (IBD) analysis showed C580Y mutant parasites were likely clonal (IBD=1). Whole-genome sequencing confirmed their clonal nature and revealed flanking haplotypes distinct from those seen in Southeast Asia where the mutation was first observed, suggesting a local, de novo emergence. These findings highlight increasing prevalence and types of ART-R mutations and the concerning association now with RDT negativity that will further challenge malaria control and elimination efforts.\n                <\/jats:p>","DOI":"10.1101\/2025.06.23.25330019","type":"posted-content","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:00:13Z","timestamp":1750723213000},"source":"Crossref","is-referenced-by-count":5,"title":["Artemisinin resistant\n                  <i>kelch13<\/i>\n                  R622I and RDT negativity approaching predominance in northern Ethiopia and emerging C580Y of African origin threaten falciparum malaria control"],"prefix":"10.64898","author":[{"given":"Ayalew Jejaw","family":"Zeleke","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abebe A.","family":"Fola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George A.","family":"Tollefson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karamako","family":"Niar\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alec","family":"Leonetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Om","family":"Taropawala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Marglous","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Crudale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bokretsion G.","family":"Brhane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashenafi","family":"Assefa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patience","family":"Kiyuka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan B.","family":"Parr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asrat","family":"Hailu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mulugeta","family":"Aemero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A.","family":"Bailey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"issue":"1","key":"2025062501450520000_2025.06.23.25330019v1.1","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1186\/s12936-021-03745-8","article-title":"Efficacy and Safety of Artemether-Lumefantrine for Treatment of Uncomplicated Plasmodium Falciparum Malaria in Ethiopia: A Systematic Review and Meta-Analysis","volume":"20","year":"2021","journal-title":"Malaria Journal"},{"issue":"6","key":"2025062501450520000_2025.06.23.25330019v1.2","doi-asserted-by":"crossref","first-page":"ofaf279","DOI":"10.1093\/ofid\/ofaf279","article-title":"Expansion of the Plasmodium Falciparum Kelch13 R622I Mutation in Northwest Ethiopia","volume":"12","year":"2025","journal-title":"Open Forum Infectious Diseases"},{"key":"2025062501450520000_2025.06.23.25330019v1.3","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.molbev.a026247"},{"issue":"1","key":"2025062501450520000_2025.06.23.25330019v1.4","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1186\/1475-2875-8-222","article-title":"Seasonal Distribution of Anti-Malarial Drug Resistance Alleles on the Island of Sumba, Indonesia","volume":"8","year":"2009","journal-title":"Malaria Journal"},{"key":"2025062501450520000_2025.06.23.25330019v1.5","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiy223"},{"key":"2025062501450520000_2025.06.23.25330019v1.6","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.15-0477"},{"key":"2025062501450520000_2025.06.23.25330019v1.7","doi-asserted-by":"crossref","unstructured":"Bosman, Andrea , and Kamini N. 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