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Although therapeutic resistance to piperaquine has been linked to increased copy number in plasmepsin-coding parasite genes (\n                    <jats:italic>pfpm<\/jats:italic>\n                    ), their effect on the duration of the post-treatment prophylactic period remains unclear. Here, we retrospectively analyzed data from a randomized clinical trial, where patients received either DHA-PPQ or artesunate-amodiaquine for recurrent malaria episodes over two years. We observed an increase in the relative risk of re-infection among patients receiving DHA-PPQ compared to artesunate-amodiaquine after the first malaria season. This was driven by shorter average times to reinfection and coincided with an increased frequency of infections comprising\n                    <jats:italic>pfpm3<\/jats:italic>\n                    multi-copy parasites. The decline in post-treatment protection of DHA-PPQ upon repeated use in a high transmission setting raises concerns for its wider use for chemopreventive strategies in Africa.\n                  <\/jats:p>","DOI":"10.1038\/s41467-025-57726-5","type":"journal-article","created":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T14:35:06Z","timestamp":1742308506000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Decreased dihydroartemisinin-piperaquine protection against recurrent malaria associated with Plasmodium falciparum plasmepsin 3 copy number variation in Africa"],"prefix":"10.1038","volume":"16","author":[{"given":"Leyre","family":"Pernaute-Lau","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9489-1315","authenticated-orcid":false,"given":"Mario","family":"Recker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamadou","family":"T\u00e9k\u00e9t\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6874-9427","authenticated-orcid":false,"given":"Tais N\u00f3brega","family":"de Sousa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aliou","family":"Traore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bakary","family":"Fofana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kassim","family":"Sanogo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4734-5754","authenticated-orcid":false,"given":"Ulrika","family":"Morris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2682-7722","authenticated-orcid":false,"given":"Pedro E.","family":"Ferreira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0273-588X","authenticated-orcid":false,"given":"Nouhoum","family":"Diallo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2190-1698","authenticated-orcid":false,"given":"J\u00fcrgen","family":"Burhenne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8555-9983","authenticated-orcid":false,"given":"Issaka","family":"Sagara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alassane","family":"Dicko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2205-8102","authenticated-orcid":false,"given":"Maria I.","family":"Veiga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Haefeli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"Bj\u00f6rkman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0062-2283","authenticated-orcid":false,"given":"Abdoulaye A.","family":"Djimde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Borrmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6107-9379","authenticated-orcid":false,"given":"Jos\u00e9 Pedro","family":"Gil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,18]]},"reference":[{"key":"57726_CR1","unstructured":"World Health Organization. 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Mass Drug Administration for Falciparum Malaria. (2017)."},{"key":"57726_CR5","doi-asserted-by":"publisher","first-page":"4631","DOI":"10.1128\/AAC.00366-15","volume":"59","author":"S Chaorattanakawee","year":"2015","unstructured":"Chaorattanakawee, S. et al. Ex vivo drug susceptibility testing and molecular profiling of clinical Plasmodium falciparum isolates from Cambodia from 2008 to 2013 suggest emerging piperaquine resistance. Antimicrob. Agents Chemother. 59, 4631\u20134643 (2015).","journal-title":"Antimicrob. Agents Chemother."},{"key":"57726_CR6","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01121-21","volume":"65","author":"M Imwong","year":"2021","unstructured":"Imwong, M. et al. Evolution of multidrug resistance in plasmodium falciparum: a Longitudinal study of genetic resistance markers in the greater Mekong subregion. Antimicrob. Agents Chemother. 65, e0112121 (2021).","journal-title":"Antimicrob. 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Lancet 393, 1428\u20131439 (2019).","journal-title":"Lancet"},{"key":"57726_CR14","first-page":"00746","volume":"S1473-3099","author":"A Nuwa","year":"2025","unstructured":"Nuwa, A. et al. Effectiveness of sulfadoxine\u2013pyrimethamine plus amodiaquine and dihydroartemisinin\u2013piperaquine for seasonal malaria chemoprevention in Uganda: a three-arm, open-label, non-inferiority and superiority, cluster-randomised, controlled trial. Lancet Infect. Dis. S1473-3099, 00746\u20131 (2025).","journal-title":"Lancet Infect. Dis."},{"key":"57726_CR15","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1016\/S0140-6736(07)60160-3","volume":"369","author":"A Ratcliff","year":"2007","unstructured":"Ratcliff, A. et al. Two fixed-dose artemisinin combinations for drug-resistant falciparum and vivax malaria in Papua, Indonesia: an open-label randomised comparison. 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Artemether\u2010lumefantrine versus dihydroartemisinin\u2010piperaquine for falciparum Malaria: A longitudinal, randomized trial in young ugandan children. Clin. Infect. Dis. 49, 1629\u20131637 (2009).","journal-title":"Clin. Infect. Dis."},{"key":"57726_CR21","doi-asserted-by":"publisher","first-page":"928","DOI":"10.1056\/NEJMoa1509150","volume":"374","author":"A Kakuru","year":"2016","unstructured":"Kakuru, A. et al. Dihydroartemisinin-piperaquine for the prevention of malaria in pregnancy. N. Engl. J. Med. 374, 928\u2013939 (2016).","journal-title":"N. Engl. J. Med."},{"key":"57726_CR22","doi-asserted-by":"publisher","first-page":"75","DOI":"10.2165\/00003495-200565010-00004","volume":"65","author":"TME Davis","year":"2005","unstructured":"Davis, T. M. E., Hung, T.-Y., Sim, I.-K., Karunajeewa, H. A. & Ilett, K. F. Piperaquine: a resurgent antimalarial drug. Drugs 65, 75\u201387 (2005).","journal-title":"Drugs"},{"key":"57726_CR23","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/S0140-6736(03)15163-X","volume":"363","author":"TH Tran","year":"2004","unstructured":"Tran, T. H. et al. Dihydroartemisinin-piperaquine against multidrug-resistant Plasmodium falciparum malaria in Vietnam: randomised clinical trial. Lancet 363, 18\u201322 (2004).","journal-title":"Lancet"},{"key":"57726_CR24","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-10-263","volume":"10","author":"CA Morris","year":"2011","unstructured":"Morris, C. A. et al. Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration. Malar. J. 10, 263 (2011).","journal-title":"Malar. J."},{"key":"57726_CR25","doi-asserted-by":"crossref","unstructured":"Hagenah, L. M. et al. Improved fitness can result in the loss of piperaquine resistance. (2023).","DOI":"10.1128\/mbio.01832-23"},{"key":"57726_CR26","first-page":"1352","volume":"211","author":"E Kamau","year":"2015","unstructured":"Kamau, E. et al. K13-propeller polymorphisms in Plasmodium falciparum parasites from sub-Saharan Africa. J. Infect. Dis. 211, 1352\u20131355 (2015).","journal-title":"J. Infect. Dis."},{"key":"57726_CR27","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.1016\/S1473-3099(21)00142-0","volume":"21","author":"A Uwimana","year":"2021","unstructured":"Uwimana, A. et al. Association of Plasmodium falciparum kelch13 R561H genotypes with delayed parasite clearance in Rwanda: an open-label, single-arm, multicentre, therapeutic efficacy study. Lancet. Infect. Dis. 21, 1120\u20131128 (2021).","journal-title":"Lancet. Infect. Dis."},{"key":"57726_CR28","doi-asserted-by":"publisher","first-page":"1602","DOI":"10.1038\/s41591-020-1005-2","volume":"26","author":"A Uwimana","year":"2020","unstructured":"Uwimana, A. et al. Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda. Nat. Med. 26, 1602\u20131608 (2020).","journal-title":"Nat. Med."},{"key":"57726_CR29","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1056\/NEJMoa2211803","volume":"389","author":"MD Conrad","year":"2023","unstructured":"Conrad, M. D. et al. Evolution of partial resistance to artemisinins in malaria parasites in Uganda. N. Engl. J. Med. 389, 722\u2013732 (2023).","journal-title":"N. Engl. J. Med."},{"key":"57726_CR30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-019-08297-9","volume":"10","author":"P Chotsiri","year":"2019","unstructured":"Chotsiri, P. et al. Optimal dosing of dihydroartemisinin-piperaquine for seasonal malaria chemoprevention in young children. Nat. Commun. 10, 1\u201312 (2019).","journal-title":"Nat. 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Haefeli were incorrectly listed as \u201cGerman Center for Infection Research (DZIF), T\u00fcbingen, Germany\u201d. The correct affiliation for both authors is \u201cDepartment of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany\u201d. In addition, Mamadou T\u00e9k\u00e9t\u00e9 was correctly associated with the same institution; however, the department name was incomplete. The full and correct affiliation should read \u201cDepartment of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany\u201d. These errors have now been corrected in the HTML and PDF versions of the Article.","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"We declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"2680"}}