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Both of these treatment goals face disease-specific and general challenges. In this review, we summarize the current state of knowledge in mechanisms of clinical and parasitological treatment failure in the context of Chagas disease, a neglected tropical disease causing cardiac and gastrointestinal symptoms. Parasite drug resistance and persistence, drug pharmacokinetics and dynamics, as well as persistently altered host immune responses and tissue damage are the most common reasons for Chagas disease treatment failure. We discuss the therapeutics that failed before regulatory approval, limitations of current therapeutic options and new treatment strategies to overcome persistent parasites, inflammatory responses, and metabolic alterations. Large-scale omics analyses were critical in generating these insights and will continue to play a prominent role in addressing the challenges still facing Chagas disease drug treatment.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/msystems.00038-24","type":"journal-article","created":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T14:00:34Z","timestamp":1736258434000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":4,"title":["System-based insights into parasitological and clinical treatment failure in Chagas disease"],"prefix":"10.1128","volume":"10","author":[{"given":"Luis","family":"Ernst","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry, San Diego State University","place":["San Diego, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovana C.","family":"Macedo","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, San Diego State University","place":["San Diego, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1243-8953","authenticated-orcid":true,"given":"Laura-Isobel","family":"McCall","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, San Diego State University","place":["San Diego, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09221"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/652769"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.actatropica.2006.05.006"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.actatropica.2015.06.004"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0020-7519(01)00153-9"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)60061-X"},{"key":"e_1_3_2_8_2","volume-title":"Chagas disease, StatPearls","author":"Nguyen T","year":"2024","unstructured":"Nguyen T, Waseem M. 2024. 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