{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T11:20:29Z","timestamp":1774264829500,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1008850","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T00:00:00Z","timestamp":1617667200000}}],"reference-count":30,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2021,3,25]],"date-time":"2021-03-25T00:00:00Z","timestamp":1616630400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100002271","name":"Pasteur Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002271","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Emergence of resistance to artemisinin and partner drugs in the Greater Mekong Subregion has made elimination of malaria from this region a global priority; it also complicates its achievement. Novel drug strategies such as triple artemisinin combination therapies (ACTs) and chemoprophylaxis have been proposed to help limit resistance and accelerate elimination. The objective of this study was to better understand the potential impacts of triple ACTs and chemoprophylaxis, using a mathematical model parameterized using data from Cambodia. We used a simple compartmental model to predict trends in malaria incidence and resistance in Cambodia from 2020\u20132025 assuming no changes in transmission since 2018. We assessed three scenarios: a status quo scenario with artesunate-mefloquine (ASMQ) as treatment; a triple ACT scenario with dihydroartemisinin-piperaquine (DP) plus mefloquine (MQ) as treatment; and a chemoprophylaxis scenario with ASMQ as treatment plus DP as chemoprophylaxis. We predicted MQ resistance to increase under the status quo scenario. Triple ACT treatment reversed the spread of MQ resistance, but had no impact on overall malaria incidence. Joint MQ-PPQ resistance declined under the status quo scenario for the baseline parameter set and most sensitivity analyses. Compared to the status quo, triple ACT treatment limited spread of MQ resistance but also slowed declines in PPQ resistance in some sensitivity analyses. The chemoprophylaxis scenario decreased malaria incidence, but increased the spread of strains resistant to both MQ and PPQ; both effects began to reverse after the intervention was removed. We conclude that triple ACTs may limit spread of MQ resistance in the Cambodia, but would have limited impact on malaria incidence and might slow declines in PPQ resistance. Chemoprophylaxis could have greater impact on incidence but also carries higher risks of resistance. Aggressive strategies to limit transmission the GMS are needed to achieve elimination goals, but any intervention should be accompanied by monitoring for drug resistance.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1008850","type":"journal-article","created":{"date-parts":[[2021,3,25]],"date-time":"2021-03-25T20:35:40Z","timestamp":1616704540000},"page":"e1008850","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["Novel anti-malarial drug strategies to prevent artemisinin partner drug resistance: A model-based analysis"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8376-4713","authenticated-orcid":true,"given":"Amber","family":"Kunkel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7472-4138","authenticated-orcid":true,"given":"Michael","family":"White","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5717-5974","authenticated-orcid":true,"given":"Patrice","family":"Piola","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,3,25]]},"reference":[{"key":"pcbi.1008850.ref001","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/S0140-6736(13)60024-0","article-title":"Malaria","volume":"383","author":"NJ White","year":"2014","journal-title":"Lancet Lond Engl"},{"key":"pcbi.1008850.ref002","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1098\/rstb.1999.0426","article-title":"Antimalarial drug resistance and combination chemotherapy","volume":"354","author":"N White","year":"1999","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"key":"pcbi.1008850.ref003","unstructured":"World Health Organization. Eliminating malaria in the Greater Mekong Subregion: United to end a deadly disease. Geneva: 2016."},{"key":"pcbi.1008850.ref004","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":"RW van der Pluijm","year":"2019","journal-title":"Lancet Infect Dis"},{"key":"pcbi.1008850.ref005","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1186\/1475-2875-13-452","article-title":"Artemisinin resistance\u2014modelling the potential human and economic costs","volume":"13","author":"Y Lubell","year":"2014","journal-title":"Malar J"},{"key":"pcbi.1008850.ref006","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s12936-015-1075-7","article-title":"Assessing the potential impact of artemisinin and partner drug resistance in sub-Saharan Africa","volume":"15","author":"HC Slater","year":"2016","journal-title":"Malar J"},{"key":"pcbi.1008850.ref007","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1475-2875-8-31","article-title":"The last man standing is the most resistant: eliminating artemisinin-resistant malaria in Cambodia","volume":"8","author":"RJ Maude","year":"2009","journal-title":"Malar J"},{"key":"pcbi.1008850.ref008","unstructured":"World Health Organization. Artemisinin resistance and artemisinin-based combination therapy efficacy: Status report. 2018."},{"key":"pcbi.1008850.ref009","first-page":"1345","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":"RW van der Pluijm","journal-title":"Lancet Lond Engl 2020"},{"key":"pcbi.1008850.ref010","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1186\/s12936-020-03197-6","article-title":"Tools to accelerate falciparum malaria elimination in Cambodia: a meeting report","volume":"19","author":"D Lek","year":"2020","journal-title":"Malar J"},{"key":"pcbi.1008850.ref011","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.pt.2019.03.011","article-title":"Novel Approaches to Control Malaria in Forested Areas of Southeast Asia","volume":"35","author":"L von Seidlein","year":"2019","journal-title":"Trends Parasitol"},{"key":"pcbi.1008850.ref012","doi-asserted-by":"crossref","first-page":"14216","DOI":"10.1073\/pnas.0804628105","article-title":"Benefits of using multiple first-line therapies against malaria","volume":"105","author":"MF Boni","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1008850.ref013","doi-asserted-by":"crossref","first-page":"e758","DOI":"10.1016\/S2214-109X(15)00162-X","article-title":"Optimum population-level use of artemisinin combination therapies: a modelling study","volume":"3","author":"TD Nguyen","year":"2015","journal-title":"Lancet Glob Health"},{"key":"pcbi.1008850.ref014","doi-asserted-by":"crossref","first-page":"20140306","DOI":"10.1098\/rstb.2014.0306","article-title":"How could preventive therapy affect the prevalence of drug resistance? Causes and consequences","volume":"370","author":"A Kunkel","year":"2015","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"key":"pcbi.1008850.ref015","doi-asserted-by":"crossref","first-page":"12106","DOI":"10.1073\/pnas.94.22.12106","article-title":"Evaluating treatment protocols to prevent antibiotic resistance","volume":"94","author":"S Bonhoeffer","year":"1997","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1008850.ref016","first-page":"62","article-title":"Investigating the Efficacy of Triple Artemisinin-Based Combination Therapies for Treating Plasmodium falciparum Malaria Patients Using Mathematical Modeling","author":"S Dini","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"key":"pcbi.1008850.ref017","unstructured":"World Health Organization. Q&A on artemisinin resistance 2020. https:\/\/www.who.int\/malaria\/media\/artemisinin_resistance_qa\/en\/ (accessed November 26, 2020)."},{"key":"pcbi.1008850.ref018","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1056\/NEJMp1901233","article-title":"A Temporizing Solution to \u201cArtemisinin Resistance\u201d","volume":"380","author":"J Wang","year":"2019","journal-title":"N Engl J Med"},{"key":"pcbi.1008850.ref019","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1016\/S1473-3099(17)30635-7","article-title":"Emergence of Plasmodium falciparum triple mutant in Cambodia","volume":"17","author":"G Rossi","year":"2017","journal-title":"Lancet Infect Dis"},{"key":"pcbi.1008850.ref020","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1038\/nm1110","article-title":"Modeling epidemics of multidrug-resistant M. tuberculosis of heterogeneous fitness","volume":"10","author":"T Cohen","year":"2004","journal-title":"Nat Med"},{"key":"pcbi.1008850.ref021","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":"LS Ross","year":"2018","journal-title":"Nat Commun"},{"key":"pcbi.1008850.ref022","doi-asserted-by":"crossref","first-page":"39","DOI":"10.4269\/ajtmh.14-0391","article-title":"Quality of antimalarials at the epicenter of antimalarial drug resistance: results from an overt and mystery client survey in Cambodia","volume":"92","author":"S Yeung","year":"2015","journal-title":"Am J Trop Med Hyg"},{"key":"pcbi.1008850.ref023","doi-asserted-by":"crossref","first-page":"e37166","DOI":"10.1371\/journal.pone.0037166","article-title":"Optimising strategies for Plasmodium falciparum malaria elimination in Cambodia: primaquine, mass drug administration and artemisinin resistance","volume":"7","author":"RJ Maude","year":"2012","journal-title":"PloS One"},{"key":"pcbi.1008850.ref024","doi-asserted-by":"crossref","first-page":"19060","DOI":"10.1038\/s41598-019-55437-8","article-title":"Malaria resurgence after significant reduction by mass drug administration on Ngodhe Island, Kenya","volume":"9","author":"W Kagaya","year":"2019","journal-title":"Sci Rep"},{"key":"pcbi.1008850.ref025","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/S1473-3099(16)30378-4","article-title":"Safety, tolerability, and efficacy of repeated doses of dihydroartemisinin-piperaquine for prevention and treatment of malaria: a systematic review and meta-analysis","volume":"17","author":"J Gutman","year":"2017","journal-title":"Lancet Infect Dis"},{"key":"pcbi.1008850.ref026","doi-asserted-by":"crossref","first-page":"e1767","DOI":"10.1371\/journal.pone.0001767","article-title":"Prospects for malaria eradication in sub-Saharan Africa","volume":"3","author":"R Aguas","year":"2008","journal-title":"PloS One"},{"key":"pcbi.1008850.ref027","first-page":"17","article-title":"Implications of population-level immunity for the emergence of artemisinin-resistant malaria: a mathematical model","author":"N Scott","year":"2018","journal-title":"Malar J"},{"key":"pcbi.1008850.ref028","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1128\/AAC.00241-08","article-title":"Plasmodium falciparum pfmdr1 amplification, mefloquine resistance, and parasite fitness","volume":"53","author":"P Preechapornkul","year":"2009","journal-title":"Antimicrob Agents Chemother"},{"key":"pcbi.1008850.ref029","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":"B Witkowski","year":"2017","journal-title":"Lancet Infect Dis"},{"key":"pcbi.1008850.ref030","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1111\/j.1541-0420.2010.01399.x","article-title":"Estimating and Projecting Trends in HIV\/AIDS Generalized Epidemics Using Incremental Mixture Importance Sampling","volume":"66","author":"AE Raftery","year":"2010","journal-title":"Biometrics"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1008850","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T00:00:00Z","timestamp":1617667200000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1008850","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T17:37:41Z","timestamp":1617730661000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1008850"}},"subtitle":[],"editor":[{"given":"Alex","family":"Perkins","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,3,25]]},"references-count":30,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3,25]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1008850","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pcbi.1008850","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,25]]}}}