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Although therapeutic resistance to piperaquine has been linked to increased copy number in plasmepsin-coding parasite genes (<jats:italic>pfpm<\/jats:italic>), 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 <jats:italic>pfpm3<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/s41467-025-57726-5","type":"journal-article","created":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T18:35:06Z","timestamp":1742322906000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"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":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9489-1315","authenticated-orcid":false,"given":"Mario","family":"Recker","sequence":"additional","affiliation":[]},{"given":"Mamadou","family":"T\u00e9k\u00e9t\u00e9","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6874-9427","authenticated-orcid":false,"given":"Tais N\u00f3brega","family":"de Sousa","sequence":"additional","affiliation":[]},{"given":"Aliou","family":"Traore","sequence":"additional","affiliation":[]},{"given":"Bakary","family":"Fofana","sequence":"additional","affiliation":[]},{"given":"Kassim","family":"Sanogo","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4734-5754","authenticated-orcid":false,"given":"Ulrika","family":"Morris","sequence":"additional","affiliation":[]},{"given":"Juliana","family":"Inoue","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2682-7722","authenticated-orcid":false,"given":"Pedro E.","family":"Ferreira","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0273-588X","authenticated-orcid":false,"given":"Nouhoum","family":"Diallo","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2190-1698","authenticated-orcid":false,"given":"J\u00fcrgen","family":"Burhenne","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8555-9983","authenticated-orcid":false,"given":"Issaka","family":"Sagara","sequence":"additional","affiliation":[]},{"given":"Alassane","family":"Dicko","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2205-8102","authenticated-orcid":false,"given":"Maria I.","family":"Veiga","sequence":"additional","affiliation":[]},{"given":"Walter","family":"Haefeli","sequence":"additional","affiliation":[]},{"given":"Anders","family":"Bj\u00f6rkman","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0062-2283","authenticated-orcid":false,"given":"Abdoulaye A.","family":"Djimde","sequence":"additional","affiliation":[]},{"given":"Steffen","family":"Borrmann","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6107-9379","authenticated-orcid":false,"given":"Jos\u00e9 Pedro","family":"Gil","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,3,18]]},"reference":[{"key":"57726_CR1","unstructured":"World Health Organization. World malaria report 2024: addressing inequity in the global malaria response. (2024)."},{"key":"57726_CR2","doi-asserted-by":"publisher","first-page":"5127","DOI":"10.1128\/AAC.49.12.5127-5128.2005","volume":"49","author":"J Tarning","year":"2005","unstructured":"Tarning, J. et al. Pitfalls in estimating piperaquine elimination. Antimicrob. Agents Chemother. 49, 5127\u20135128 (2005).","journal-title":"Antimicrob. Agents Chemother."},{"key":"57726_CR3","doi-asserted-by":"publisher","first-page":"1378","DOI":"10.1016\/S0140-6736(18)30291-5","volume":"391","author":"I Sagara","year":"2018","unstructured":"Sagara, I. et al. Pyronaridine\u2013artesunate or dihydroartemisinin\u2013piperaquine versus current first-line therapies for repeated treatment of uncomplicated malaria: a randomised, multicentre, open-label, longitudinal, controlled, phase 3b\/4 trial. Lancet 391, 1378\u20131390 (2018).","journal-title":"Lancet"},{"key":"57726_CR4","unstructured":"World Health Organization. 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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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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