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The complex interplay between sources of selective pressure\u2014treatment properties, biological factors, transmission intensity, and access to treatment\u2014obscures understanding how, when, and why resistance establishes and spreads across different locations. We developed a disease modelling approach with emulator-based global sensitivity analysis to systematically quantify which of these factors drive establishment and spread of drug resistance. Drug resistance was more likely to evolve in low transmission settings due to the lower levels of (i) immunity and (ii) within-host competition between genotypes. Spread of parasites resistant to artemisinin partner drugs depended on the period of low drug concentration (known as the selection window). Spread of partial artemisinin resistance was slowed with prolonged parasite exposure to artemisinin derivatives and accelerated when the parasite was also resistant to the partner drug. Thus, to slow the spread of partial artemisinin resistance, molecular surveillance should be supported to detect resistance to partner drugs and to change ACTs accordingly. Furthermore, implementing more sustainable artemisinin-based therapies will require extending parasite exposure to artemisinin derivatives, and mitigating the selection windows of partner drugs, which could be achieved by including an additional long-acting drug.\n                  <\/jats:p>","DOI":"10.7554\/elife.77634","type":"journal-article","created":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T05:15:19Z","timestamp":1655961319000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.77634","source":"Crossref","is-referenced-by-count":39,"title":["The influence of biological, epidemiological, and treatment factors on the establishment and spread of drug-resistant Plasmodium falciparum"],"prefix":"10.7554","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2482-463X","authenticated-orcid":true,"given":"Thiery","family":"Masserey","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03adhka07","id-type":"ROR","asserted-by":"publisher"}],"name":"Swiss Tropical and Public Health Institute","place":["Allschwil, Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/02s6k3f65","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Basel","place":["Basel, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6684-3615","authenticated-orcid":true,"given":"Tamsin","family":"Lee","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03adhka07","id-type":"ROR","asserted-by":"publisher"}],"name":"Swiss Tropical and Public Health Institute","place":["Allschwil, Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/02s6k3f65","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Basel","place":["Basel, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Golumbeanu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03adhka07","id-type":"ROR","asserted-by":"publisher"}],"name":"Swiss Tropical and Public Health Institute","place":["Allschwil, Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/02s6k3f65","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Basel","place":["Basel, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J","family":"Shattock","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03adhka07","id-type":"ROR","asserted-by":"publisher"}],"name":"Swiss Tropical and Public Health Institute","place":["Allschwil, Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/02s6k3f65","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Basel","place":["Basel, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherrie L","family":"Kelly","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03adhka07","id-type":"ROR","asserted-by":"publisher"}],"name":"Swiss Tropical and Public Health Institute","place":["Allschwil, Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/02s6k3f65","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Basel","place":["Basel, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1332-742X","authenticated-orcid":true,"given":"Ian M","family":"Hastings","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03svjbs84","id-type":"ROR","asserted-by":"publisher"}],"name":"Liverpool School of Tropical Medicine","place":["Liverpool, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4972-593X","authenticated-orcid":true,"given":"Melissa A","family":"Penny","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03adhka07","id-type":"ROR","asserted-by":"publisher"}],"name":"Swiss Tropical and Public Health Institute","place":["Allschwil, Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/02s6k3f65","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Basel","place":["Basel, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2022,7,7]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1016\/S1473-3099(18)30068-9","article-title":"Origins of the current outbreak of multidrug-resistant malaria in southeast Asia: a retrospective genetic study","volume":"18","author":"Amato","year":"2018","journal-title":"The Lancet Infectious Diseases"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"1705","DOI":"10.1098\/rspb.2010.1907","article-title":"Environmental, pharmacological and genetic influences on the spread of drug-resistant malaria","volume":"278","author":"Antao","year":"2011","journal-title":"Proceedings. 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