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Emergence and spread of resistant parasite in eastern-India poses a threat to national malaria control programs. Therefore, the objective of our study is to evaluate the artesunate-sulfadoxine-pyrimethamine efficacy in Central India. 180 monoclonal <jats:italic>P. falciparum<\/jats:italic>-infected patients received standard ASSP therapy during August 2015\u2013January 2017, soon after diagnosis and monitored over next 42-days. Artemisinin-resistance was assessed through in-vivo parasite clearance half-life (PC<jats:sub>1\/2<\/jats:sub>), ex-vivo ring-stage survivability (RSA), and genome analysis of <jats:italic>kelch13<\/jats:italic> and other candidate gene (<jats:italic>pfcrt, pfmdr1, pfatpase 6, pfdhfr<\/jats:italic> and <jats:italic>pfdhps<\/jats:italic>). Of 180 <jats:italic>P. falciparum<\/jats:italic> positive patients, 9.5% showed increased PC<jats:sub>1\/2<\/jats:sub> (&gt;\u20095.5\u00a0h), among them eleven isolates (6.1%) showed reduced sensitivity to RSA. In 4.4% of cases, parasites were not cleared by 72\u00a0h and showed prolonged PC<jats:sub>1\/2<\/jats:sub>(5.6\u00a0h) (P\u2009&lt;\u20090.005) along with significantly higher RSA (2.2%) than cured patients (0.4%). None of day-3 positive isolates contained the <jats:italic>pfkelch13<\/jats:italic> mutation implicated in artemisinin resistance. Parasite recrudescence was observed in 5.6% patients, which was associated with triple <jats:italic>dhfr<\/jats:italic>\u2013<jats:italic>dhps<\/jats:italic> (A<jats:sub>16<\/jats:sub><jats:underline>I<\/jats:underline><jats:sub>51<\/jats:sub><jats:underline>R<\/jats:underline><jats:sub>59<\/jats:sub><jats:underline>N<\/jats:underline><jats:sub>108<\/jats:sub>I<jats:sub>164<\/jats:sub>\u2013S<jats:sub>436<\/jats:sub><jats:underline>G<\/jats:underline><jats:sub>437<\/jats:sub>K<jats:sub>540<\/jats:sub><jats:underline>G<\/jats:underline><jats:sub><jats:underline>581<\/jats:underline><\/jats:sub><jats:underline>T<\/jats:underline><jats:sub><jats:underline>613<\/jats:underline><\/jats:sub>) combination mutation. Emergence of reduced sensitivity to artesunate-sulfadoxine-pyrimethamine, in central India highlighted the risk toward spread of resistant parasite across different parts of India. Day-3 positive parasite, featuring the phenotype of artemisinin-resistance without <jats:italic>pfkelch13<\/jats:italic> mutation, suggested <jats:italic>kelch13<\/jats:italic>-independent artemisinin-resistance.<\/jats:p>","DOI":"10.1038\/s41598-021-89295-0","type":"journal-article","created":{"date-parts":[[2021,5,11]],"date-time":"2021-05-11T10:09:20Z","timestamp":1620727760000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Artemisinin combination therapy fails even in the absence of Plasmodium falciparum kelch13 gene polymorphism in Central India"],"prefix":"10.1038","volume":"11","author":[{"given":"Sabyasachi","family":"Das","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amrita","family":"Kar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subhankar","family":"Manna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samaresh","family":"Mandal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayantani","family":"Mandal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subhasis","family":"Das","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhaskar","family":"Saha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amiya Kumar","family":"Hati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,11]]},"reference":[{"key":"89295_CR1","unstructured":"World malaria report 2017 by World Health Organization (WHO). https:\/\/www.who.int\/malaria\/publications\/world-malaria-report-2017\/en\/. 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