{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T03:12:46Z","timestamp":1793329966019,"version":"4.5.0"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2021,2,2]],"date-time":"2021-02-02T00:00:00Z","timestamp":1612224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI125579"],"award-info":[{"award-number":["R01AI125579"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Global Emerging Infections Surveillance"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,9,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Newly emerged mutations within the Plasmodium falciparum chloroquine resistance transporter (PfCRT) can confer piperaquine resistance in the absence of amplified plasmepsin II (pfpm2). In this study, we estimated the prevalence of co-circulating piperaquine resistance mutations in P. falciparum isolates collected in northern Cambodia from 2009 to 2017.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>The sequence of pfcrt was determined for 410 P. falciparum isolates using PacBio amplicon sequencing or whole genome sequencing. Quantitative polymerase chain reaction was used to estimate pfpm2 and pfmdr1 copy number.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Newly emerged PfCRT mutations increased in prevalence after the change to dihydroartemisinin-piperaquine in 2010, with &amp;gt;98% of parasites harboring these mutations by 2017. After 2014, the prevalence of PfCRT F145I declined, being outcompeted by parasites with less resistant, but more fit PfCRT alleles. After the change to artesunate-mefloquine, the prevalence of parasites with amplified pfpm2 decreased, with nearly half of piperaquine-resistant PfCRT mutants having single-copy pfpm2.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>The large proportion of PfCRT mutants that lack pfpm2 amplification emphasizes the importance of including PfCRT mutations as part of molecular surveillance for piperaquine resistance in this region. Likewise, it is critical to monitor for amplified pfmdr1 in these PfCRT mutants, as increased mefloquine pressure could lead to mutants resistant to both drugs.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/infdis\/jiab055","type":"journal-article","created":{"date-parts":[[2021,1,26]],"date-time":"2021-01-26T20:10:43Z","timestamp":1611691843000},"page":"1077-1085","source":"Crossref","is-referenced-by-count":20,"title":["Distribution and Temporal Dynamics of <i>Plasmodium falciparum<\/i> Chloroquine Resistance Transporter Mutations Associated With Piperaquine Resistance in Northern Cambodia"],"prefix":"10.1093","volume":"224","author":[{"given":"Biraj","family":"Shrestha","sequence":"first","affiliation":[{"name":"Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zalak","family":"Shah","sequence":"additional","affiliation":[{"name":"Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew P","family":"Morgan","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piyaporn","family":"Saingam","sequence":"additional","affiliation":[{"name":"Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaiyaporn","family":"Chaisatit","sequence":"additional","affiliation":[{"name":"Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suwanna","family":"Chaorattanakawee","sequence":"additional","affiliation":[{"name":"Department of Parasitology and Entomology, Faculty of Public Health, Mahidol University, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantida","family":"Praditpol","sequence":"additional","affiliation":[{"name":"Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nonlawat","family":"Boonyalai","sequence":"additional","affiliation":[{"name":"Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paphavee","family":"Lertsethtakarn","sequence":"additional","affiliation":[{"name":"Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariusz","family":"Wojnarski","sequence":"additional","affiliation":[{"name":"Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6191-930X","authenticated-orcid":false,"given":"Molly","family":"Deutsch-Feldman","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Adams","sequence":"additional","affiliation":[{"name":"Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darapiseth","family":"Sea","sequence":"additional","affiliation":[{"name":"Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soklyda","family":"Chann","sequence":"additional","affiliation":[{"name":"Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart D","family":"Tyner","sequence":"additional","affiliation":[{"name":"Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte A","family":"Lanteri","sequence":"additional","affiliation":[{"name":"Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele D","family":"Spring","sequence":"additional","affiliation":[{"name":"Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L","family":"Saunders","sequence":"additional","affiliation":[{"name":"US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip L","family":"Smith","sequence":"additional","affiliation":[{"name":"Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanthap","family":"Lon","sequence":"additional","affiliation":[{"name":"Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panita","family":"Gosi","sequence":"additional","affiliation":[{"name":"Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Somethy","family":"Sok","sequence":"additional","affiliation":[{"name":"Royal Cambodian Armed Forces, Phnom Penh, Cambodia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prom","family":"Satharath","sequence":"additional","affiliation":[{"name":"Royal Cambodian Armed Forces, Phnom Penh, Cambodia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huy","family":"Rekol","sequence":"additional","affiliation":[{"name":"National Center for Parasitology, Entomology, and Malaria Control, Village Trapangsvay, Sanakat Phnom Penh,Cambodia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dysoley","family":"Lek","sequence":"additional","affiliation":[{"name":"National Center for Parasitology, Entomology, and Malaria Control, Village Trapangsvay, Sanakat Phnom Penh,Cambodia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian A","family":"Vesely","sequence":"additional","affiliation":[{"name":"Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica T","family":"Lin","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norman C","family":"Waters","sequence":"additional","affiliation":[{"name":"Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon","family":"Takala-Harrison","sequence":"additional","affiliation":[{"name":"Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,2,2]]},"reference":[{"key":"2022020206055198400_CIT0001","author":"World Health Organization."},{"key":"2022020206055198400_CIT0002","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1056\/NEJMoa1314981","article-title":"Spread of artemisinin resistance in Plasmodium falciparum malaria","volume":"371","author":"Ashley","year":"2014","journal-title":"N Engl J Med"},{"key":"2022020206055198400_CIT0003","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/S1473-3099(17)30048-8","article-title":"The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study","volume":"17","author":"Imwong","year":"2017","journal-title":"Lancet Infect Dis"},{"key":"2022020206055198400_CIT0004","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1093\/femsre\/fuw037","article-title":"The clinical impact of artemisinin resistance in Southeast Asia and the potential for future spread","volume":"41","author":"Woodrow","year":"2017","journal-title":"FEMS Microbiol Rev"},{"key":"2022020206055198400_CIT0005","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1056\/NEJMc0805011","article-title":"Evidence of artemisinin-resistant malaria in western Cambodia","volume":"359","author":"Noedl","year":"2008","journal-title":"N Engl J Med"},{"key":"2022020206055198400_CIT0006","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1056\/NEJMoa0808859","article-title":"Artemisinin resistance in Plasmodium falciparum malaria","volume":"361","author":"Dondorp","year":"2009","journal-title":"N Engl J Med"},{"key":"2022020206055198400_CIT0007","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/S1473-3099(15)00487-9","article-title":"Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study","volume":"16","author":"Amaratunga","year":"2016","journal-title":"Lancet Infect Dis"},{"key":"2022020206055198400_CIT0008","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/S1473-3099(15)70049-6","article-title":"Dihydroartemisinin-piperaquine failure associated with a triple mutant including kelch13 C580Y in Cambodia: an observational cohort study","volume":"15","author":"Spring","year":"2015","journal-title":"Lancet Infect Dis"},{"key":"2022020206055198400_CIT0009","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1056\/NEJMc1403007","article-title":"Dihydroartemisinin-piperaquine failure in Cambodia","volume":"371","author":"Saunders","year":"2014","journal-title":"N Engl J Med"},{"key":"2022020206055198400_CIT0010","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/S0140-6736(04)16767-6","article-title":"Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number","volume":"364","author":"Price","year":"2004","journal-title":"Lancet"},{"key":"2022020206055198400_CIT0011","author":"World Health Organization."},{"key":"2022020206055198400_CIT0012","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/S1473-3099(16)30415-7","article-title":"A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype-genotype association study","volume":"17","author":"Witkowski","year":"2017","journal-title":"Lancet Infect Dis"},{"key":"2022020206055198400_CIT0013","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/S1473-3099(16)30409-1","article-title":"Genetic markers associated with dihydroartemisinin-piperaquine failure in Plasmodium falciparum malaria in Cambodia: a genotype-phenotype association study","volume":"17","author":"Amato","year":"2017","journal-title":"Lancet Infect Dis"},{"key":"2022020206055198400_CIT0014","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1186\/s12916-015-0539-5","article-title":"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","volume":"13","author":"Duru","year":"2015","journal-title":"BMC Med"},{"key":"2022020206055198400_CIT0015","doi-asserted-by":"crossref","first-page":"468\u2013","DOI":"10.1093\/infdis\/jix334","article-title":"Association of a Novel Mutation in the Plasmodium falciparum Chloroquine Resistance Transporter With Decreased Piperaquine Sensitivity","volume":"216","author":"Agrawal","year":"2017","journal-title":"J Infect Dis"},{"key":"2022020206055198400_CIT0016","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/S1473-3099(19)30392-5","article-title":"Evolution and expansion of multidrug-resistant malaria in southeast Asia: a genomic epidemiology study","volume":"19","author":"Hamilton","year":"2019","journal-title":"Lancet Infect Dis"},{"key":"2022020206055198400_CIT0017","doi-asserted-by":"crossref","first-page":"3314","DOI":"10.1038\/s41467-018-05652-0","article-title":"Emerging Southeast Asian PfCRT mutations confer Plasmodium falciparum resistance to the first-line antimalarial piperaquine","volume":"9","author":"Ross","year":"2018","journal-title":"Nat Commun"},{"key":"2022020206055198400_CIT0018","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1016\/S1473-3099(19)30543-2","article-title":"Plasmodium falciparum resistance to piperaquine driven by PfCRT","volume":"19","author":"Dhingra","year":"2019","journal-title":"Lancet Infect Dis"},{"key":"2022020206055198400_CIT0019","doi-asserted-by":"crossref","first-page":"4631","DOI":"10.1128\/AAC.00366-15","article-title":"Ex Vivo Drug Susceptibility Testing and Molecular Profiling of Clinical Plasmodium falciparum Isolates from Cambodia from 2008 to 2013 Suggest Emerging Piperaquine Resistance","volume":"59","author":"Chaorattanakawee","year":"2015","journal-title":"Antimicrob Agents Chemother"},{"key":"2022020206055198400_CIT0020","doi-asserted-by":"crossref","first-page":"ofz314","DOI":"10.1093\/ofid\/ofz314","article-title":"Atovaquone-Proguanil in Combination With Artesunate to Treat Multidrug-Resistant P. falciparum Malaria in Cambodia: An Open-Label Randomized Trial","volume":"6","author":"Wojnarski","year":"2019","journal-title":"Open Forum Infect Dis"},{"key":"2022020206055198400_CIT0021","author":"Pacific Biosciences.","year":"2018"},{"key":"2022020206055198400_CIT0022","author":"Li","year":"2013"},{"key":"2022020206055198400_CIT0023","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/ng.806","article-title":"A framework for variation discovery and genotyping using next-generation DNA sequencing data","volume":"43","author":"DePristo","year":"2011","journal-title":"Nat Genet"},{"key":"2022020206055198400_CIT0024","first-page":"11 0 1\u20130 33","article-title":"From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline","volume":"11","author":"Van der Auwera","year":"2013","journal-title":"Curr Protoc Bioinformatics"},{"key":"2022020206055198400_CIT0025","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1093\/bioinformatics\/btq033","article-title":"BEDTools: a flexible suite of utilities for comparing genomic features","volume":"26","author":"Quinlan","year":"2010","journal-title":"Bioinformatics"},{"key":"2022020206055198400_CIT0026","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.1923","article-title":"Fast gapped-read alignment with Bowtie 2","volume":"9","author":"Langmead","year":"2012","journal-title":"Nat Methods"},{"key":"2022020206055198400_CIT0027","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1186\/s12936-016-1569-y","article-title":"Ex vivo piperaquine resistance developed rapidly in Plasmodium falciparum isolates in northern Cambodia compared to Thailand","volume":"15","author":"Chaorattanakawee","year":"2016","journal-title":"Malar J"},{"key":"2022020206055198400_CIT0028","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1186\/1475-2875-11-325","article-title":"Optimizing the HRP-2 in vitro malaria drug susceptibility assay using a reference clone to improve comparisons of Plasmodium falciparum field isolates","volume":"11","author":"Rutvisuttinunt","year":"2012","journal-title":"Malar J"},{"key":"2022020206055198400_CIT0029","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1016\/S1473-3099(19)30391-3","article-title":"Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study","volume":"19","author":"Pluijm","year":"2019","journal-title":"Lancet Infect Dis"},{"key":"2022020206055198400_CIT0030","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/s41586-019-1795-x","article-title":"Structure and drug resistance of the Plasmodium falciparum transporter PfCRT","volume":"576","author":"Kim","year":"2019","journal-title":"Nature"},{"key":"2022020206055198400_CIT0031","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1186\/s12936-020-03339-w","article-title":"Piperaquine resistant Cambodian Plasmodium falciparum clinical isolates: in vitro genotypic and phenotypic characterization","volume":"19","author":"Boonyalai","year":"2020","journal-title":"Malar J"},{"key":"2022020206055198400_CIT0032","doi-asserted-by":"crossref","first-page":"3615","DOI":"10.1128\/AAC.06350-11","article-title":"pfmdr1 amplification is related to increased Plasmodium falciparum in vitro sensitivity to the bisquinoline piperaquine","volume":"56","author":"Veiga","year":"2012","journal-title":"Antimicrob Agents Chemother"},{"key":"2022020206055198400_CIT0033","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1016\/S0140-6736(20)30552-3","article-title":"Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial","volume":"395","author":"van der Pluijm","year":"2020","journal-title":"Lancet"}],"container-title":["The Journal of Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jid\/advance-article-pdf\/doi\/10.1093\/infdis\/jiab055\/37559189\/jiab055.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/224\/6\/1077\/40406409\/jiab055.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/224\/6\/1077\/40406409\/jiab055.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,2]],"date-time":"2022-02-02T06:06:29Z","timestamp":1643781989000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jid\/article\/224\/6\/1077\/6126500"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,2]]},"references-count":33,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,2,2]]},"published-print":{"date-parts":[[2021,9,17]]}},"URL":"https:\/\/doi.org\/10.1093\/infdis\/jiab055","relation":{},"ISSN":["0022-1899","1537-6613"],"issn-type":[{"value":"0022-1899","type":"print"},{"value":"1537-6613","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,9,15]]},"published":{"date-parts":[[2021,2,2]]}}}