Ex vivo susceptibility to antimalarial drugs and polymorphisms in drug resistance genes of African Plasmodium falciparum, 2016-2023: a genotype-phenotype association study

Ex vivo susceptibility to antimalarial drugs and polymorphisms in drug resistance genes of African Plasmodium falciparum, 2016-2023: a genotype-phenotype association study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Ex vivo susceptibility to antimalarial drugs and polymorphisms in drug resistance genes of African Plasmodium falciparum , 2016-2023: a genotype-phenotype association study Jason Rosado, Abebe A. Fola, Sandrine Cojean, Véronique Sarrasin, and 18 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4763649/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Given the altered responses to both artemisinins and lumefantrine in Eastern Africa, monitoring antimalarial drug resistance in all African countries is paramount. Methods: We measured the susceptibility to six antimalarials using ex vivo growth inhibition assays (IC 50 ) for a total of 805 Plasmodium falciparum isolates obtained from travelers returning to France (2016-2023), mainly from West and Central Africa. Isolates were sequenced using molecular inversion probes (MIPs) targeting fourteen drug resistance genes across the parasite genome. Findings: Ex vivo susceptibility to several drugs has significantly decreased in 2019-2023 versus 2016-2018 parasite samples: lumefantrine (median IC 50 : 23·0 nM [IQR: 14·4-35·1] in 2019-2023 versus 13·9 nM [8·42-21·7] in 2016-2018, p<0·0001), monodesethylamodiaquine (35·4 [21·2-51·1] versus 20·3 nM [15·4-33·1], p<0·0001), and marginally piperaquine (20·5 [16·5-26·2] versus 18.0 [14·2-22·4] nM, p<0·0001). Only four isolates carried a validated pfkelch13 mutation. Multiple mutations in pfcrt and one in pfmdr1 (N86Y) were significantly associated with altered susceptibility to multiple drugs. The susceptibility to lumefantrine was altered by pfcrt and pfmdr1 mutations in an additive manner, with the wild-type haplotype ( pfcrt K76- pfmdr1 N86) exhibiting the least susceptibility. Interpretation: Our study on P. falciparum isolates from West and Central Africa indicates a low prevalence of molecular markers of artemisinin resistance but a significant decrease in susceptibility to the partner drugs that have been the most widely used since a decade -lumefantrine and amodiaquine. These phenotypic changes likely mark parasite adaptation to sustained drug pressure and call for intensifying the monitoring of antimalarial drug resistance in Africa. Infectious Diseases Antimalarial drug resistance ex-vivo susceptibility IC50 assay genotype Full Text Additional Declarations The authors declare no competing interests. Supplementary Files Suppappendix.zip Supplementary appendix 1 and 2 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4763649","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":328792829,"identity":"8803fe2a-3042-4c4c-b77e-0493daf811c3","order_by":0,"name":"Jason Rosado","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA00lEQVRIiWNgGAWjYBACxoYDIIqZgYG9AUgbWJCihQfEMJAg2jKgFokEEIMILcyNZx8+/FFjLSc/8/nVDT8KJBj427sTCDjsuLExz7F0Y4PbOWU3e4AOkzhzdgMBLcfYpBnYDidukM5Ju8ED1GIgkUtYi+SPf4cT5888k3bzD7FaJHjbDic23GA/dptYW5iNefuAfjmTw3ZbxkCCh6BfDGccY3z44xswxNqPP7v55o+NHH97LyEtB2BMHgMwiVc5CMjzN8CY7A8Iqh4Fo2AUjIKRCQAQpEll+z6sYgAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-4834-2088","institution":"Université Paris Cité, Institut de Recherche pour le Développement, MERIT, F-75006 Paris, France","correspondingAuthor":true,"prefix":"","firstName":"Jason","middleName":"","lastName":"Rosado","suffix":""},{"id":328792830,"identity":"abf82701-3ca8-4e14-b791-3ad2e7f3ca8c","order_by":1,"name":"Abebe A. 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Isolates were sequenced using molecular inversion probes (MIPs) targeting fourteen drug resistance genes across the parasite genome.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFindings:\u003c/strong\u003e \u003cem\u003eEx vivo\u003c/em\u003e susceptibility to several drugs has significantly decreased in 2019-2023 versus 2016-2018 parasite samples: lumefantrine (median IC\u003csub\u003e50\u003c/sub\u003e: 23·0 nM [IQR: 14·4-35·1] in 2019-2023 versus 13·9 nM [8·42-21·7] in 2016-2018, p\u0026lt;0·0001), monodesethylamodiaquine\u0026nbsp; (35·4 [21·2-51·1] versus 20·3 nM [15·4-33·1], p\u0026lt;0·0001), and marginally piperaquine (20·5 [16·5-26·2] versus 18.0 [14·2-22·4] nM, p\u0026lt;0·0001). Only four isolates carried a validated \u003cem\u003epfkelch13 \u003c/em\u003emutation. Multiple mutations in \u003cem\u003epfcrt\u003c/em\u003e and one in \u003cem\u003epfmdr1\u003c/em\u003e (N86Y) were significantly associated with altered susceptibility to multiple drugs. The susceptibility to lumefantrine was altered by \u003cem\u003epfcrt \u003c/em\u003eand \u003cem\u003epfmdr1 \u003c/em\u003emutations in an additive manner, with the wild-type haplotype (\u003cem\u003epfcrt\u003c/em\u003e K76-\u003cem\u003epfmdr1\u003c/em\u003e N86) exhibiting the least susceptibility.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterpretation:\u003c/strong\u003e Our study on \u003cem\u003eP. falciparum\u003c/em\u003e isolates from West and Central Africa indicates a low prevalence of molecular markers of artemisinin resistance but a significant decrease in susceptibility to the partner drugs that have been the most widely used since a decade -lumefantrine and amodiaquine. These phenotypic changes likely mark parasite adaptation to sustained drug pressure and call for intensifying the monitoring of antimalarial drug resistance in Africa.\u003c/p\u003e","manuscriptTitle":"Ex vivo susceptibility to antimalarial drugs and polymorphisms in drug resistance genes of African Plasmodium falciparum, 2016-2023: a genotype-phenotype association study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-19 04:15:41","doi":"10.21203/rs.3.rs-4763649/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"32db6721-f363-4357-b574-62fc958dca1b","owner":[],"postedDate":"July 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":34804214,"name":"Infectious Diseases"}],"tags":[],"updatedAt":"2024-07-19T04:15:42+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-19 04:15:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4763649","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4763649","identity":"rs-4763649","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}