{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T20:51:08Z","timestamp":1793393468042,"version":"4.5.0"},"reference-count":58,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T00:00:00Z","timestamp":1668729600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T00:00:00Z","timestamp":1668729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Global Emerging Infectious Surveillance (GEIS) Section","award":["P0209_15_KY"],"award-info":[{"award-number":["P0209_15_KY"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Med"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Dihydroartemisinin-piperaquine (DHA-PPQ) is an alternative first-line antimalarial to artemether-lumefantrine in Kenya. However, recent reports on the emergence of PPQ resistance in Southeast Asia threaten its continued use in Kenya and Africa. In line with the policy on continued deployment of DHA-PPQ, it is imperative to monitor the susceptibility of Kenyan parasites to PPQ and other antimalarials.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Parasite isolates collected between 2008 and 2021 from individuals with naturally acquired <jats:italic>P. falciparum<\/jats:italic> infections presenting with uncomplicated malaria were tested for in vitro susceptibility to piperaquine, dihydroartemisinin, lumefantrine, artemether, and chloroquine using the malaria SYBR Green I method. A subset of the 2019\u20132021 samples was further tested for ex vivo susceptibility to PPQ using piperaquine survival assay (PSA). Each isolate was also characterized for mutations associated with antimalarial resistance in <jats:italic>Pfcrt<\/jats:italic>, <jats:italic>Pfmdr1<\/jats:italic>, <jats:italic>Pfpm2\/3<\/jats:italic>, <jats:italic>Pfdhfr<\/jats:italic>, and <jats:italic>Pfdhps<\/jats:italic> genes using real-time PCR and Agena MassARRAY platform. Associations between phenotype and genotype were also determined.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The PPQ median IC<jats:sub>50<\/jats:sub> interquartile range (IQR) remained stable during the study period, 32.70 nM (IQR 20.2\u201345.6) in 2008 and 27.30 nM (IQR 6.9\u201352.8) in 2021 (<jats:italic>P<\/jats:italic>=0.1615). The median ex vivo piperaquine survival rate (IQR) was 0% (0\u20135.27) at 95% CI. Five isolates had a PSA survival rate of \u226510%, consistent with the range of PPQ-resistant parasites, though they lacked polymorphisms in <jats:italic>Pfmdr1<\/jats:italic> and <jats:italic>Plasmepsin<\/jats:italic> genes. Lumefantrine and artemether median IC<jats:sub>50<\/jats:sub>s rose significantly to 62.40 nM (IQR 26.9\u2013100.8) (<jats:italic>P<\/jats:italic> = 0.0201); 7.00 nM (IQR 2.4\u201313.4) (<jats:italic>P<\/jats:italic> = 0.0021) in 2021 from 26.30 nM (IQR 5.1\u201364.3); and 2.70 nM (IQR 1.3\u201310.4) in 2008, respectively. Conversely, chloroquine median IC<jats:sub>50<\/jats:sub>s decreased significantly to 10.30 nM (IQR 7.2\u201320.9) in 2021 from 15.30 nM (IQR 7.6\u201330.4) in 2008, coinciding with a decline in the prevalence of <jats:italic>Pfcrt<\/jats:italic> 76T allele over time (<jats:italic>P<\/jats:italic> = 0.0357). The proportions of piperaquine-resistant markers including <jats:italic>Pfpm2\/3<\/jats:italic> and <jats:italic>Pfmdr1<\/jats:italic> did not vary significantly. A significant association was observed between PPQ IC<jats:sub>50<\/jats:sub> and <jats:italic>Pfcrt<\/jats:italic> K76T allele (<jats:italic>P<\/jats:italic>=0.0026).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Circulating Kenyan parasites have remained sensitive to PPQ and other antimalarials, though the response to artemether (ART) and lumefantrine (LM) is declining. This study forms a baseline for continued surveillance of current antimalarials for timely detection of resistance.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12916-022-02652-2","type":"journal-article","created":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T01:02:50Z","timestamp":1668733370000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Impact of parasite genomic dynamics on the sensitivity of Plasmodium falciparum isolates to piperaquine and other antimalarial drugs"],"prefix":"10.1186","volume":"20","author":[{"given":"Dancan M.","family":"Wakoli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bartholomew N.","family":"Ondigo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas O.","family":"Ochora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph G.","family":"Amwoma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winnie","family":"Okore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin W.","family":"Mwakio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gladys","family":"Chemwor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jackeline","family":"Juma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael","family":"Okoth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Okudo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Redemptah","family":"Yeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin H.","family":"Opot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnes C.","family":"Cheruiyot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Juma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Roth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benhards R.","family":"Ogutu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Boudreaux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Andagalu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoseah M.","family":"Akala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,11,18]]},"reference":[{"key":"2652_CR1","doi-asserted-by":"publisher","DOI":"10.30875\/6c551ba0-en","volume-title":"World malaria report 2021","author":"World Health Organization","year":"2021","unstructured":"World Health Organization. World malaria report 2021, vol. 2021. Geneva: WHO; 2021."},{"key":"2652_CR2","doi-asserted-by":"crossref","unstructured":"Group AC, Musuva A, Ejersa W, Kiptui R, Memusi D, Abwao E. The malaria testing and treatment landscape in Kenya: results from a nationally representative survey among the public and private sector in 2016. Malar J.\u00a02017;16(1):1\u201313.","DOI":"10.1186\/s12936-017-2089-0"},{"key":"2652_CR3","unstructured":"Kenya Malaria Indicator Survey 2020 - Kenya National Bureau of Statistics. https:\/\/www.knbs.or.ke\/kenya-malaria-indicator-survey-2020\/. Accessed Sept\u00a02021."},{"key":"2652_CR4","unstructured":"WHO. World malaria report 2019. Geneva: World Health Organization; 2019."},{"key":"2652_CR5","doi-asserted-by":"publisher","unstructured":"Ebohon O, Irabor F, Ebohon LO, Omoregie ES. Therapeutic failure after regimen with artemether-lumefantrine combination therapy: A report of three cases in Benin city, Nigeria. Rev Soc Bras Med Trop. 2019. https:\/\/doi.org\/10.1590\/0037-8682-0163-2019.","DOI":"10.1590\/0037-8682-0163-2019"},{"issue":"1","key":"2652_CR6","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.coph.2018.07.010","volume":"4","author":"RE Martin","year":"2018","unstructured":"Martin RE, Shafik S, Richards SN. Mechanisms of resistance to the partner drugs of artemisinin in the malaria parasite. Curr Opin Pharmacol. 2018;4(1):26. https:\/\/doi.org\/10.1016\/j.coph.2018.07.010.","journal-title":"Curr Opin Pharmacol"},{"issue":"8","key":"2652_CR7","doi-asserted-by":"publisher","first-page":"1591","DOI":"10.3201\/eid2408.180370","volume":"24","author":"J Inoue","year":"2018","unstructured":"Inoue J, Silva M, Fofana B, Sanogo K, M\u00e5rtensson A, Sagara I, et al. Plasmodium falciparum plasmepsin 2 duplications, West Africa. Emerg Infect Dis. 2018;24(8):1591\u20133.","journal-title":"Emerg Infect Dis"},{"key":"2652_CR8","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1186\/s12936-019-2724-z","volume":"18","author":"EG Tse","year":"2019","unstructured":"Tse EG, Korsik M, Todd MH. The past, present and future of anti-malarial medicines. Malar J. 2019;18:93. https:\/\/doi.org\/10.1186\/s12936-019-2724-z.","journal-title":"Malar J"},{"issue":"2","key":"2652_CR9","doi-asserted-by":"publisher","first-page":"e01949","DOI":"10.1128\/AAC.01949-20","volume":"65","author":"PR Dimbu","year":"2021","unstructured":"Dimbu PR, Horth R, C\u00e2ndido ALM, Ferreira CM, Caquece F, Garcia LEA, et al. Continued low efficacy of artemether-lumefantrine in Angola in 2019. Antimicrob Agents Chemother. 2021;65(2):e01949\u201320.","journal-title":"Antimicrob Agents Chemother"},{"key":"2652_CR10","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1007\/s40265-018-0911-9","volume":"78","author":"EA Ashley","year":"2018","unstructured":"Ashley EA, Phyo AP. Drugs in Development for Malaria. Drugs. 2018;78:861\u201379. https:\/\/doi.org\/10.1007\/s40265-018-0911-9.","journal-title":"Drugs."},{"key":"2652_CR11","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1056\/NEJMoa2101746","volume":"385","author":"B Balikagala","year":"2021","unstructured":"Balikagala B, Fukuda N, Ikeda M, Katuro OT, Tachibana S, Yamauchi M, et al. Evidence of artemis-inin-resistant malaria in Africa. N Engl J Med. 2021;385:1163\u201371.","journal-title":"N Engl J Med"},{"key":"2652_CR12","doi-asserted-by":"publisher","unstructured":"Uwimana A, Umulisa N, Venkatesan M, Svigel SS, Zhou Z, Munyaneza T, 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. 2021. https:\/\/doi.org\/10.1016\/S1473-3099(21)00142-0.","DOI":"10.1016\/S1473-3099(21)00142-0"},{"issue":"1","key":"2652_CR13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12936-021-04021-5","volume":"20","author":"C Ebong","year":"2021","unstructured":"Ebong C, Sserwanga A, Namuganga JF, Kapisi J, Mpimbaza A, Gonahasa S, et al. Efficacy and safety of artemether-lumefantrine and dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria and prevalence of molecular markers associated with artemisinin and partner drug resistance in Uganda. Malar J. 2021;20(1):1\u201312.","journal-title":"Malar J"},{"issue":"1","key":"2652_CR14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1475-2875-13-33","volume":"13","author":"BR Ogutu","year":"2014","unstructured":"Ogutu BR, Onyango KO, Koskei N, Omondi EK, Ongecha JM, Otieno GA, et al. Efficacy and safety of artemether-lumefantrine and dihydroartemisinin-piperaquine in the treatment of uncomplicated Plasmodium falciparum malaria in Kenyan children aged less than five years: results of an open-label, randomized, single-centre study. Malar J. 2014;13(1):1\u201310.","journal-title":"Malar J"},{"key":"2652_CR15","doi-asserted-by":"publisher","unstructured":"White NJ. Intermittent presumptive treatment for malaria. PLoS Med. 2005;2(1). https:\/\/doi.org\/10.1371\/journal.pmed.0020003.","DOI":"10.1371\/journal.pmed.0020003"},{"key":"2652_CR16","doi-asserted-by":"publisher","first-page":"1391","DOI":"10.1128\/AAC.47.4.1391-1394.2003","volume":"47","author":"LK Basco","year":"2003","unstructured":"Basco LK, Ringwald P. In vitro activities of piperaquine and other 4-aminoquinolines against clinical isolates of Plasmodium falciparum in Cameroon. Antimicrob Agents Chemother. 2003;47:1391\u20134.","journal-title":"Antimicrob Agents Chemother"},{"key":"2652_CR17","doi-asserted-by":"publisher","unstructured":"Duru V, Khim N, Leang R, Kim S, Domergue A, Kloeung N, et al. Plasmodium falciparum dihydroartemisinin-piperaquine failures in Cambodia are associated with mutant K13 parasites presenting high survival rates in novel piperaquine in vitro assays: Retrospective and prospective investigations. BMC Medicine.\u00a02015;13(1):1\u201311. https:\/\/doi.org\/10.1186\/s12916-015-0539-5.","DOI":"10.1186\/s12916-015-0539-5"},{"issue":"5","key":"2652_CR18","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/S1473-3099(17):30048-8","volume":"17","author":"M Imwong","year":"2017","unstructured":"Imwong M, Suwannasin K, Kunasol C, Sutawong K, Mayxay M, Rekol H, et al. The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study. Lancet Infect Dis. 2017;17(5):491\u20137. https:\/\/doi.org\/10.1016\/S1473-3099(17):30048-8.","journal-title":"Lancet Infect Dis"},{"key":"2652_CR19","doi-asserted-by":"crossref","unstructured":"Amato R, Lim P, Miotto O, Amaratunga C, Dek D, Pearson RD, et al.\nGenetic markers associated with dihydroartemisinin\u2013piperaquine failure\nin Plasmodium falciparum malaria in Cambodia: a genotype\u2013phenotype\nassociation study. Lancet\u00a0Infect Dis.\u00a02017;17(2):164\u201373.","DOI":"10.1016\/S1473-3099(16)30409-1"},{"issue":"37","key":"2652_CR20","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.pt.2020.09.011","volume":"1","author":"RW van der Pluijm","year":"2021","unstructured":"van der Pluijm RW, Amaratunga C, Dhorda M, Dondorp AM. Triple Artemisinin-Based Combination Therapies for Malaria \u2013 A New Paradigm? Trends Parasitol. 2021;1(37):15\u201324. https:\/\/doi.org\/10.1016\/j.pt.2020.09.011.","journal-title":"Trends Parasitol"},{"key":"2652_CR21","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/j.parint.2009.04.004","volume":"58","author":"T Mita","year":"2009","unstructured":"Mita T, Tanabe K, Kita K. Spread and evolution of Plasmodium falciparum drug resistance. Parasitol Int. 2009;58:201\u20139. https:\/\/doi.org\/10.1016\/j.parint.2009.04.004.","journal-title":"Parasitol Int"},{"issue":"1","key":"2652_CR22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12936-019-2986-5","volume":"18","author":"SA Diakit\u00e9","year":"2019","unstructured":"Diakit\u00e9 SA, Traor\u00e9 K, Sanogo I, Clark TG, Campino S, Sangar\u00e9 M, et al. A comprehensive analysis of drug resistance molecular markers and Plasmodium falciparum genetic diversity in two malaria endemic sites in Mali. Malar J. 2019;18(1):1\u20139.","journal-title":"Malar J"},{"key":"2652_CR23","doi-asserted-by":"publisher","unstructured":"Ansbro MR, Jacob CG, Amato R, Kekre M, Amaratunga C, Sreng S, et al. Development of copy number assays for detection and surveillance of piperaquine resistance associated plasmepsin 2\/3 copy number variation in Plasmodium falciparum. Malar J. 2020;19(1):1\u201310. https:\/\/doi.org\/10.1186\/s12936-020-03249-x.","DOI":"10.1186\/s12936-020-03249-x"},{"key":"2652_CR24","doi-asserted-by":"publisher","unstructured":"Akala HM, Watson OJ, Mitei KK, Juma DW, Verity R, Ingasia LA, et al. Plasmodium interspecies interactions during a period of increasing prevalence of Plasmodium ovale in symptomatic individuals seeking treatment: an observational study. Lancet Microbe. 2021. https:\/\/doi.org\/10.1016\/S2666-5247(21)00009-4.","DOI":"10.1016\/S2666-5247(21)00009-4"},{"issue":"1","key":"2652_CR25","doi-asserted-by":"publisher","first-page":"34","DOI":"10.4269\/ajtmh.2011.10-0674","volume":"85","author":"HM Akala","year":"2011","unstructured":"Akala HM, Eyase FL, Cheruiyot AC, Omondi AA, Ogutu BR, Waters NC, et al. Antimalarial drug sensitivity profile of western Kenya Plasmodium falciparum field isolates determined by a SYBR green I in vitro assay and molecular analysis. Am J Trop Med Hyg. 2011;85(1):34\u201341.","journal-title":"Am J Trop Med Hyg"},{"key":"2652_CR26","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1186\/1475-2875-9-375","volume":"9","author":"C Lourens","year":"2010","unstructured":"Lourens C, Watkins WM, Barnes KI, et al. Implementation of a reference standard and proficiency testing programme by the World Wide Antimalarial Resistance Network (WWARN). Malar J. 2010;9:375. https:\/\/doi.org\/10.1186\/1475-2875-9-375.","journal-title":"Malar J"},{"issue":"1","key":"2652_CR27","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1186\/s12936-020-03339-w","volume":"19","author":"N Boonyalai","year":"2020","unstructured":"Boonyalai N, Vesely BA, Thamnurak C, Praditpol C, Fagnark W, Kirativanich K, et al. Piperaquine resistant Cambodian Plasmodium falciparum clinical isolates: In vitro genotypic and phenotypic characterization. Malar J. 2020;19(1):269. https:\/\/doi.org\/10.1186\/s12936-020-03339-w.","journal-title":"Malar J"},{"issue":"4","key":"2652_CR28","doi-asserted-by":"publisher","first-page":"1723","DOI":"10.1128\/AAC.02306-12","volume":"57","author":"M Hao","year":"2013","unstructured":"Hao M, Jia D, Li Q, He Y, Yuan L, Xu S, et al. In vitro sensitivities of Plasmodium falciparum isolates from the China-Myanmar border to piperaquine and association with polymorphisms in candidate genes. Antimicrob Agents Chemother. 2013;57(4):1723\u20139. https:\/\/doi.org\/10.1128\/AAC.02306-12.","journal-title":"Antimicrob Agents Chemother"},{"key":"2652_CR29","doi-asserted-by":"publisher","unstructured":"Eyase FL, Akala HM, Ingasia L, Cheruiyot A, Omondi A, Okudo C, et al. The Role of Pfmdr1 and Pfcrt in Changing Chloroquine, Amodiaquine, Mefloquine and Lumefantrine Susceptibility in Western-Kenya P. falciparum Samples during 2008\u20132011. PLoS One. 2013;8(5). https:\/\/doi.org\/10.1371\/journal.pone.0064299.","DOI":"10.1371\/journal.pone.0064299"},{"key":"2652_CR30","unstructured":"Akala HM, Lee P and Johnson DJ. In vitro Module, WWARN 2011. P. falciparum drug sensitivity assay using SYBR\u00ae Green I Assay Technique WWARN Procedure 2012. http:\/\/www.wwarn.org\/learning\/procedures\/INV08. Accessed Feb\u00a02012."},{"issue":"4","key":"2652_CR31","doi-asserted-by":"publisher","first-page":"2417","DOI":"10.1128\/AAC.00527-15","volume":"60","author":"AC Cheruiyot","year":"2016","unstructured":"Cheruiyot AC, Auschwitz JM, Lee PJ, Yeda RA, Okello CO, Leed SE, et al. Assessment of the Worldwide antimalarial resistance network standardized procedure for in vitro malaria drug sensitivity testing using SYBR green assay for field samples with various initial parasitemia levels. Antimicrob Agents Chemother. 2016;60(4):2417\u201324. https:\/\/doi.org\/10.1128\/AAC.00527-15.","journal-title":"Antimicrob Agents Chemother"},{"key":"2652_CR32","doi-asserted-by":"publisher","unstructured":"Ngalah BS, Ingasia LA, Cheruiyot AC, Chebon LJ, Juma DW, Muiruri P, et al. Analysis of Major Genome Loci Underlying Artemisinin Resistance and pfmdr1 Copy Number in pre- and post-ACTs in Western Kenya. Sci Rep. 2015;5. https:\/\/doi.org\/10.1038\/srep08308.","DOI":"10.1038\/srep08308"},{"key":"2652_CR33","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1186\/1475-2875-12-377","volume":"12","author":"NO Duah","year":"2013","unstructured":"Duah NO, Matrevi SA, De Souza DK, Binnah DD, Tamakloe MM, Opoku VS, et al. Increased pfmdr1 gene copy number and the decline in pfcrt and pfmdr1 resistance alleles in Ghanaian Plasmodium falciparum isolates after the change of anti-malarial drug treatment policy. Malar J. 2013;12:377. https:\/\/doi.org\/10.1186\/1475-2875-12-377.","journal-title":"Malar J"},{"key":"2652_CR34","doi-asserted-by":"publisher","unstructured":"Chebore W, Zhou Z, Westercamp N, Otieno K, Shi YP, Sergent SB, et al.\u00a0Assessment of molecular markers of anti-malarial drug resistance among children participating in a therapeutic efficacy study in western Kenya. Malaria J. 2020;19(1):1\u201312.\u00a0https:\/\/doi.org\/10.1186\/s12936-020-03358-7.","DOI":"10.1186\/s12936-020-03358-7"},{"issue":"10","key":"2652_CR35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0240174","volume":"15","author":"H Gupta","year":"2020","unstructured":"Gupta H, Galatas B, Chidimatembue A, Huijben S, Cister\u00f3 P, Matambisso G, et al. Effect of mass dihydroartemisinin\u2013piperaquine administration in southern Mozambique on the carriage of molecular markers of antimalarial resistance. PLoS One. 2020;15(10):e0240174. https:\/\/doi.org\/10.1371\/journal.pone.0240174.","journal-title":"PLoS One"},{"issue":"3","key":"2652_CR36","doi-asserted-by":"publisher","first-page":"346","DOI":"10.3390\/pathogens10030346","volume":"10","author":"J Chawla","year":"2021","unstructured":"Chawla J, Oberstaller J, Adams JH. Targeting Gametocytes of the Malaria Parasite Plasmodium falciparum in a Functional Genomics Era: Next Steps. Pathogens. 2021;10(3):346. https:\/\/doi.org\/10.3390\/pathogens10030346 PMID: 33809464; PMCID: PMC7999360.","journal-title":"Pathogens."},{"issue":"1","key":"2652_CR37","doi-asserted-by":"publisher","first-page":"75. 17:75","DOI":"10.1186\/s12936-018-2185-9","volume":"17","author":"C Nsanzabana","year":"2018","unstructured":"Nsanzabana C, Djalle D, Gu\u00e9rin PJ, M\u00e9nard D, Gonz\u00e1lez IJ. Tools for surveillance of anti-malarial drug resistance: An assessment of the current landscape. Malar J. 2018;17(1):75. 17:75. https:\/\/doi.org\/10.1186\/s12936-018-2185-9.","journal-title":"Malar J"},{"issue":"7","key":"2652_CR38","doi-asserted-by":"publisher","first-page":"e02655","DOI":"10.1128\/AAC.02655-16","volume":"61","author":"SM Chenet","year":"2017","unstructured":"Chenet SM, Okoth SA, Kelley J, Lucchi N, Huber CS, Vreden S, et al. Molecular profile of malaria drug resistance markers of Plasmodium falciparum in Suriname. Antimicrob Agents Chemother. 2017;61(7):e02655\u201316. https:\/\/doi.org\/10.1128\/AAC.02655-16.","journal-title":"Antimicrob Agents Chemother"},{"key":"2652_CR39","doi-asserted-by":"publisher","unstructured":"Traor\u00e9 K, Diakit\u00e9 SA, Bah S, Konat\u00e9 DS, Dabitao D, Sanogo I, et al. Susceptibility of Plasmodium falciparum isolates to antimalarial drugs in a highly seasonal malaria endemic village in Mali. Researchsquare. 2019. https:\/\/doi.org\/10.21203\/rs.2.17605\/v1.","DOI":"10.21203\/rs.2.17605\/v1"},{"key":"2652_CR40","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1186\/1475-2875-12-431","volume":"12","author":"A Pascual","year":"2013","unstructured":"Pascual A, Madamet M, Bertaux L, Amalvict R, Benoit N, Travers D, et al. In vitro piperaquine susceptibility is not associated with the Plasmodium falciparum chloroquine resistance transporter gene. Malar J. 2013;12:431. https:\/\/doi.org\/10.1186\/1475-2875-12-431.","journal-title":"Malar J"},{"issue":"12","key":"2652_CR41","doi-asserted-by":"publisher","first-page":"e01516","DOI":"10.1128\/AAC.01516-17","volume":"61","author":"SA Rasmussen","year":"2017","unstructured":"Rasmussen SA, Ceja FG, Conrad MD, Tumwebaze PK, Byaruhanga O, Katairo T, et al. Changing antimalarial drug sensitivities in Uganda. Antimicrob Agents Chemother. 2017;61(12):e01516\u20137. https:\/\/doi.org\/10.1128\/AAC.01516-17.","journal-title":"Antimicrob Agents Chemother"},{"key":"2652_CR42","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1016\/j.actatropica.2018.06.016","volume":"185","author":"SJ Smith","year":"2018","unstructured":"Smith SJ, Kamara ARY, Sahr F, Samai M, Swaray AS, Menard D, et al. Efficacy of artemisinin-based combination therapies and prevalence of molecular markers associated with artemisinin, piperaquine and sulfadoxine\u2013pyrimethamine resistance in Sierra Leone. Acta Trop. 2018;185:363\u201370.","journal-title":"Acta Trop"},{"issue":"11","key":"2652_CR43","doi-asserted-by":"publisher","first-page":"e00374","DOI":"10.1128\/AAC.00374-18","volume":"62","author":"MG Robert","year":"2018","unstructured":"Robert MG, Foguim TF, Gendrot M, Mosnier J, Amalvict R, Benoit N, et al. Absence of a High Level of Duplication of the Plasmepsin II Gene in Africa. Antimicrob Agents Chemother. 2018;62(11):e00374\u201318. https:\/\/doi.org\/10.1128\/AAC.00374-18.","journal-title":"Antimicrob Agents Chemother"},{"key":"2652_CR44","doi-asserted-by":"publisher","unstructured":"Tumwebaze PK, Katairo T, Okitwi M, Byaruhanga O, Orena S, Asua V, et al. Drug susceptibility of Plasmodium falciparum in eastern Uganda: a longitudinal phenotypic and genotypic study. Lancet Microbe. 2021. https:\/\/doi.org\/10.1016\/s2666-5247(21)00085-9.","DOI":"10.1016\/s2666-5247(21)00085-9"},{"issue":"12","key":"2652_CR45","doi-asserted-by":"publisher","first-page":"5069","DOI":"10.1128\/AAC.00638-09","volume":"53","author":"L Mwai","year":"2009","unstructured":"Mwai L, Kiara SM, Abdirahman A, Pole L, Rippert A, Diriye A, et al. In vitro activities of piperaquine, lumefantrine, and dihydroartemisinin in Kenyan plasmodium falciparum isolates and polymorphisms in pfcrt and pfmdr1. Antimicrob Agents Chemother. 2009;53(12):5069\u201373. https:\/\/doi.org\/10.1128\/AAC.00638-09.","journal-title":"Antimicrob Agents Chemother"},{"issue":"3","key":"2652_CR46","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.ijpddr.2014.07.003","volume":"4","author":"O John","year":"2014","unstructured":"John O, Alice K, Kevin M, Colin JS, Lynette IO. Temporal trends in prevalence of Plasmodium falciparum drug resistance alleles over two decades of changing antimalarial policy in coastal Kenya. Int J Parasitol Drugs Drug Resist. 2014;4(3):152\u201363.","journal-title":"Int J Parasitol Drugs Drug Resist"},{"issue":"7","key":"2652_CR47","doi-asserted-by":"publisher","first-page":"978","DOI":"10.1086\/500951","volume":"193","author":"D Francis","year":"2006","unstructured":"Francis D, Nsobya SL, Talisuna A, Yeka A, Kamya MR, Machekano R, et al. Geographic differences in antimalarial drug efficacy in Uganda are explained by differences in endemicity and not by known molecular markers of drug resistance. J Infect Dis. 2006;193(7):978\u201386.","journal-title":"J Infect Dis"},{"issue":"3","key":"2652_CR48","doi-asserted-by":"publisher","first-page":"624","DOI":"10.4269\/ajtmh.16-0668","volume":"96","author":"M Mungthin","year":"2017","unstructured":"Mungthin M, Watanatanasup E, Sitthichot N, Suwandittakul N, Khositnithikul R, Ward SA. Influence of the pfmdr1 gene on in vitro sensitivities of piperaquine in Thai isolates of plasmodium falciparum. Am J Trop Med Hyg. 2017;96(3):624\u20139. https:\/\/doi.org\/10.4269\/ajtmh.16-0668.","journal-title":"Am J Trop Med Hyg"},{"issue":"12","key":"2652_CR49","doi-asserted-by":"publisher","first-page":"1800","DOI":"10.1111\/j.1365-3156.2006.01739.x","volume":"11","author":"MB Denis","year":"2006","unstructured":"Denis MB, Tsuyuoka R, Lim P, Lindegardh N, Yi P, Top SN, et al. Efficacy of artemether\u2013lumefantrine for the treatment of uncomplicated falciparum malaria in northwest Cambodia. Trop Med Int Health. 2006;11(12):1800\u20137.","journal-title":"Trop Med Int Health"},{"issue":"1","key":"2652_CR50","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40249-019-0577-x","volume":"8","author":"A Sowunmi","year":"2019","unstructured":"Sowunmi A, Ntadom G, Akano K, Ibironke FO, Ayede AI, Agomo C, et al. Declining responsiveness of childhood Plasmodium falciparum infections to artemisinin-based combination treatments ten years following deployment as first-line antimalarials in Nigeria. Infect Dis Poverty. 2019;8(1):1\u201318.","journal-title":"Infect Dis Poverty"},{"issue":"1","key":"2652_CR51","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1475-2875-10-231","volume":"10","author":"J Song","year":"2011","unstructured":"Song J, Socheat D, Tan B, Seila S, Xu Y, Ou F, et al. Randomized trials of artemisinin-piperaquine, dihydroartemisinin-piperaquine phosphate and artemether-lumefantrine for the treatment of multi-drug resistant falciparum malaria in Cambodia-Thailand border area. Malar J. 2011;10(1):1\u20138.","journal-title":"Malar J"},{"issue":"1","key":"2652_CR52","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12936-020-03157-0","volume":"19","author":"B Balikagala","year":"2020","unstructured":"Balikagala B, Sakurai-Yatsushiro M, Tachibana SI, Ikeda M, Yamauchi M, Katuro OT, et al. Recovery and stable persistence of chloroquine sensitivity in Plasmodium falciparum parasites after its discontinued use in Northern Uganda. Malar J. 2020;19(1):1\u201312.","journal-title":"Malar J"},{"issue":"1","key":"2652_CR53","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13071-017-2298-y","volume":"10","author":"F Lu","year":"2017","unstructured":"Lu F, Zhang M, Culleton RL, Xu S, Tang J, Zhou H, et al. Return of chloroquine sensitivity to Africa? Surveillance of African Plasmodium falciparum chloroquine resistance through malaria imported to China. Parasit Vectors. 2017;10(1):1\u20139.","journal-title":"Parasit Vectors"},{"key":"2652_CR54","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1186\/s12936-015","volume":"14","author":"T Koleala","year":"2015","unstructured":"Koleala T, Karl S, Laman M, et al. Temporal changes in Plasmodium falciparum anti-malarial drug sensitivity in vitro and resistance-associated genetic mutations in isolates from Papua New Guinea. Malar J. 2015;14:37. https:\/\/doi.org\/10.1186\/s12936-015.","journal-title":"Malar J"},{"issue":"1","key":"2652_CR55","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1186\/s12936-019-2756-4","volume":"18","author":"D Leroy","year":"2019","unstructured":"Leroy D, Macintyre F, Adoke Y, Ouoba S, Barry A, Mombo-Ngoma G, et al. African isolates show a high proportion of multiple copies of the Plasmodium falciparum plasmepsin-2 gene, a piperaquine resistance marker. Malar J. 2019;18(1):126. https:\/\/doi.org\/10.1186\/s12936-019-2756-4.","journal-title":"Malar J"},{"key":"2652_CR56","doi-asserted-by":"publisher","first-page":"340","DOI":"10.21203\/rs.3.rs-721164\/v1","volume":"20","author":"DG Assefa","year":"2021","unstructured":"Assefa DG, Yesmaw G, Makonnen E. Efficacy of Dihydroartemisinin-piperaquine Versus Artemether-lumefantrine for the Treatment of Uncomplicated Plasmodium falciparum Malaria Among Children in Africa: a Systematic Review and Meta-analysis of Randomized Control Trials. Res Square. 2021;20:340. https:\/\/doi.org\/10.21203\/rs.3.rs-721164\/v1.","journal-title":"Res Square"},{"key":"2652_CR57","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.b2763","volume":"339","author":"J Achan","year":"2009","unstructured":"Achan J, Tibenderana JK, Kyabayinze D, Mangen FW, Kamya MR, Dorsey G, et al. Effectiveness of quinine versus artemether-lumefantrine for treating uncomplicated falciparum malaria in Ugandan children: randomised trial. Bmj. 2009;339:b2763. https:\/\/doi.org\/10.1136\/bmj.b2763.","journal-title":"Bmj."},{"issue":"3","key":"2652_CR58","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.ijpddr.2015.05.005","volume":"5","author":"AO Achieng","year":"2015","unstructured":"Achieng AO, Muiruri P, Ingasia LA, Opot BH, Juma DW, Yeda R, et al. Temporal trends in prevalence of Plasmodium falciparum molecular markers selected for by artemether\u2013lumefantrine treatment in pre-ACT and post-ACT parasites in western Kenya. Int J Parasitol Drugs Drug Resist. 2015;5(3):92\u20139.","journal-title":"Int J Parasitol Drugs Drug Resist"}],"container-title":["BMC Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12916-022-02652-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12916-022-02652-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12916-022-02652-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T01:04:25Z","timestamp":1668733465000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcmedicine.biomedcentral.com\/articles\/10.1186\/s12916-022-02652-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,18]]},"references-count":58,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["2652"],"URL":"https:\/\/doi.org\/10.1186\/s12916-022-02652-2","relation":{},"ISSN":["1741-7015"],"issn-type":[{"value":"1741-7015","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,18]]},"assertion":[{"value":"18 February 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 November 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 November 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the Kenya Medical Research Institute (KEMRI) Scientific and Ethics Review Unit and the Walter Reed Army Institute of Research (WRAIR) institutional review boards. Archived (2008-2017) and freshly collected (2018-2021) samples were collected under protocol numbers: KEMRI #1330 and #3628, WRAIR #1384, and #2454.A written informed consent was obtained from every participant. Parents\/guardians provided written assent for children less than 18 years.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"A written informed consent was obtained from enrolled patients for publication. A copy of the written informed consent is available for review by the journal Editor.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that there are no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"448"}}