{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T11:38:03Z","timestamp":1789472283247,"version":"build-2803163510"},"reference-count":134,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,12,15]],"date-time":"2023-12-15T00:00:00Z","timestamp":1702598400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>Chagas disease (CD) is caused by the flagellate protozoan <jats:italic>Trypanosoma cruzi<\/jats:italic>. It is endemic in Latin America. Nowadays around 6 million people are affected worldwide, and 75 million are still at risk. CD has two evolutive phases, acute and chronic. The acute phase is mostly asymptomatic, or presenting unspecific symptoms which makes it hard to diagnose. At the chronic phase, patients can stay in the indeterminate form or develop cardiac and\/or digestive manifestations. The two trypanocide drugs available for the treatment of CD are benznidazole (BZ) and nifurtimox (NFX), introduced in the clinic more than five decades ago. WHO recommends treatment for patients at the acute phase, at risk of congenital infection, for immunosuppressed patients and children with chronic infection. A high cure rate is seen at the CD acute phase but better treatment schemes still need to be investigated for the chronic phase. There are some limitations within the use of the trypanocide drugs, with side effects occurring in about 40% of the patients, that can lead patients to interrupt treatment. In addition, patients with advanced heart problems should not be treated with BZ. This is a neglected disease, discovered 114\u2009years ago that still has no drug effective for their chronic phase. Multiple social economic and cultural barriers influence CD research. The high cost of the development of new drugs, in addition to the low economical return, results in the lack of investment. More economic support is required from governments and pharmaceutical companies on the development of more research for CD treatment. Two approaches stand out: repositioning and combination of drugs, witch drastically decrease the cost of this process, when compared to the development of a new drug. Here we discuss the progress of the clinical trials for the etiological and pathophysiological treatment for CD. In summary, more studies are needed to propose a new drug for CD. Therefore, BZ is still the best option for CD. The trials in course should clarify more about new treatment regimens, but it is already possible to indicate that dosage and time of treatment need to be adjusted.<\/jats:p>","DOI":"10.3389\/fmicb.2023.1295017","type":"journal-article","created":{"date-parts":[[2023,12,15]],"date-time":"2023-12-15T10:58:50Z","timestamp":1702637930000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Clinical trials for Chagas disease: etiological and pathophysiological treatment"],"prefix":"10.3389","volume":"14","author":[{"given":"Beatriz Matheus de Souza","family":"Gonzaga","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto Rodrigues","family":"Ferreira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura Lacerda","family":"Coelho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Cristina C.","family":"Carvalho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana Ribeiro","family":"Garzoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania C.","family":"Araujo-Jorge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,12,15]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1006\/jaut.2001.0523","article-title":"Chronic Chagas\u2019 disease cardiomyopathy patients display an increased IFN-gamma response to Trypanosoma cruzi infection","volume":"17","author":"Abel","year":"2001","journal-title":"J. Autoimmun."},{"key":"ref9001","doi-asserted-by":"publisher","first-page":"1396","DOI":"10.1128\/JCM.02248-16","article-title":"Towards a new strategy for diagnosis of congenital trypanosoma cruzi infection","volume":"55","author":"Abras","year":"2017","journal-title":"J Clin Microbiol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"e0015221","DOI":"10.1128\/cmr.00152-21","article-title":"Worldwide control and management of Chagas disease in a new era of globalization: a close look at congenital Trypanosoma cruzi infection","volume":"35","author":"Abras","year":"2022","journal-title":"Clin. Microbiol. Rev."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"2375","DOI":"10.1016\/j.ijcard.2013.01.262","article-title":"Chagas' cardiomyopathy: the economic burden of an expensive and neglected disease","volume":"168","author":"Abuhab","year":"2013","journal-title":"Int. J. Cardiol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"e052897","DOI":"10.1136\/bmjopen-2021-052897","article-title":"New chemotherapy regimens and biomarkers for Chagas disease: the rationale and design of the TESEO study, an open-label, randomised, prospective, phase-2 clinical trial in the Plurinational state of Bolivia","volume":"11","author":"Alonso-Vega","year":"2021","journal-title":"BMJ Open"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"e0008912","DOI":"10.1371\/journal.pntd.0008912","article-title":"Prospective, historically controlled study to evaluate the efficacy and safety of a new paediatric formulation of nifurtimox in children aged 0 to 17 years with Chagas disease one year after treatment (CHICO)","volume":"15","author":"Altcheh","year":"2021","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"e0010850","DOI":"10.1371\/journal.pntd.0010850","article-title":"Population pharmacokinetics of benznidazole in neonates, infants and children using a new pediatric formulation","volume":"17","author":"Altcheh","year":"2023","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"e2907","DOI":"10.1371\/journal.pntd.0002907","article-title":"Population pharmacokinetic study of benznidazole in pediatric Chagas disease suggests efficacy despite lower plasma concentrations than in adults","volume":"8","author":"Altcheh","year":"2014","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"e3010","DOI":"10.1371\/journal.pntd.0003010","article-title":"Acute Chagas disease: new global challenges for an old neglected disease","volume":"8","author":"Andrade","year":"2014","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1590\/s0066-782x2011000600002","article-title":"I Latin American guidelines for the diagnosis and treatment of Chagas' heart disease: executive summary","volume":"96","author":"Andrade","year":"2011","journal-title":"Arq. Bras. Cardiol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1407","DOI":"10.1016\/s0140-6736(96)04128-1","article-title":"Randomized trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection","volume":"348","author":"Andrade","year":"1996","journal-title":"Lancet"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1590\/0037-8682-0165-2016","article-title":"Benznidazole therapy for Chagas disease in asymptomatic Trypanosoma cruzi-seropositive former blood donors: evaluation of the efficacy of different treatment regimens","volume":"49","author":"Antunes","year":"2016","journal-title":"Rev. Soc. Bras. Med. Trop."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"111","DOI":"10.3895\/rbect.v11n2.8431","article-title":"Interdisciplinary network engagement in a non-formal education process to study foodborne Chagas disease puzzle in Brazilian Amazon","volume":"11","author":"Araujo-Jorge","year":"2018","journal-title":"R. Bras. Ens. Ci. Tecnol."},{"key":"ref13","article-title":"Chapter \u201cChagas disease - from cellular and molecular aspects of Trypanosoma cruzi-host interactions to the clinical intervention\u201d","volume-title":"The Saga of Selenium Treatment Investigation in Chagas Disease Cardiopathy: Translational Research in a Neglected Tropical Disease in Brazil","author":"Araujo-Jorge","year":""},{"key":"ref14","doi-asserted-by":"publisher","first-page":"e220001","DOI":"10.1590\/0074-02760220001","article-title":"Translational research in Chagas disease: perspectives in nutritional therapy emerging from selenium supplementation studies as a complementary treatment","volume":"117","author":"Araujo-Jorge","year":"2022","journal-title":"Mem. Inst. Oswaldo Cruz"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"349","DOI":"10.3390\/biom12030349","article-title":"Selenium, TGF-beta and infectious endemic cardiopathy: lessons from benchwork to clinical application in Chagas disease","volume":"12","author":"Araujo-Jorge","year":"","journal-title":"Biomol. Ther."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"e1870","DOI":"10.1371\/journal.pntd.0001870","article-title":"Fexinidazole: a potential new drug candidate for Chagas disease","volume":"6","author":"Bahia","year":"2012","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"643\u2013651, 692","DOI":"10.1590\/S0066-782X2009001200021","article-title":"Anti-inflammatory effect of physical training in heart failure: role of TNF-alpha and IL-10","volume":"93","author":"Batista","year":"2009","journal-title":"Arq. Bras. Cardiol."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1833","DOI":"10.1016\/s0003-4975(01)02587-5","article-title":"The paradox of survival results after heart transplantation for cardiomyopathy caused by Trypanosoma cruzi. First guidelines Group for Heart Transplantation of the Brazilian Society of Cardiology","volume":"71","author":"Bocchi","year":"2001","journal-title":"Ann. Thorac. Surg."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"510","DOI":"10.2174\/156652408785748004","article-title":"Chagas heart disease pathogenesis: one mechanism or many?","volume":"8","author":"Bonney","year":"2008","journal-title":"Curr. Mol. Med."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"544.e1","DOI":"10.1016\/j.ahj.2006.12.017","article-title":"A randomized trial of carvedilol after renin-angiotensin system inhibition in chronic Chagas cardiomyopathy","volume":"153","author":"Botoni","year":"2007","journal-title":"Am. Heart J."},{"key":"ref21","year":"2021"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1146\/annurev.mi.27.100173.002023","article-title":"Biology of Trypanosoma cruzi","volume":"27","author":"Brener","year":"1973","journal-title":"Annu. Rev. Microbiol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1046\/j.1462-5822.2002.00226.x","article-title":"Cell signalling and Trypanosoma cruzi invasion","volume":"4","author":"Burleigh","year":"2002","journal-title":"Cell. Microbiol."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1186\/s12978-020-00972-1","article-title":"Short-course Benznidazole treatment to reduce Trypanosoma cruzi parasitic load in women of reproductive age (BETTY): a non-inferiority randomized controlled trial study protocol","volume":"17","author":"Cafferata","year":"2020","journal-title":"Reprod. Health"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1590\/S0036-46652002000100006","article-title":"Long term evaluation of etiological treatment of Chagas disease with benznidazole","volume":"44","author":"Can\u00e7ado","year":"2002","journal-title":"Rev. Inst. Med. Trop. S\u00e3o Paulo"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"e0006814","DOI":"10.1371\/journal.pntd.0006814","article-title":"Beneficial effects of benznidazole in Chagas disease: NIH SaMi-trop cohort study","volume":"12","author":"Cardoso","year":"2018","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1590\/S0074-02761909000200008","article-title":"Nova tripanozomiaze humana. Estudos sobre a morfologia e o ciclo evolutivo do Schizotrypanum cruzi n. gen., n. sp., ajenteetiolojico de nova entidade morbida do homem","volume":"1","author":"Chagas","year":"1909","journal-title":"Mem Int Oswaldo Cruz."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.csbj.2016.12.002","article-title":"Chagas disease research and development: is there light at the end of the tunnel?","volume":"15","author":"Chatelain","year":"2016","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"2791","DOI":"10.3389\/fimmu.2018.02791","article-title":"Disease tolerance and pathogen resistance genes may underlie Trypanosoma cruzi persistence and differential progression to Chagas disease cardiomyopathy","volume":"9","author":"Chevillard","year":"2018","journal-title":"Front. Immunol."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1111\/j.1365-3156.2009.02431.x","article-title":"Antibody drop in newborns congenitally infected by Trypanosoma cruzi treated with benznidazole","volume":"15","author":"Chippaux","year":"2010","journal-title":"Tropical Med. Int. Health"},{"key":"ref31","year":"2018"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"165758","DOI":"10.1016\/j.bbadis.2020.165758","article-title":"State-of-the-art in host-derived biomarkers of Chagas disease prognosis and early evaluation of anti-Trypanosoma cruzi treatment response","volume":"1866","author":"Cortes-Serra","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. basis Dis."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1590\/s0074-02762009000400002","article-title":"Present situation and new strategies for Chagas disease chemotherapy: a proposal","volume":"104","author":"Coura","year":"2009","journal-title":"Mem. Inst. Oswaldo Cruz"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.actatropica.2010.03.008","article-title":"Chagas disease: 100 years after its discovery. A systemic review","volume":"115","author":"Coura","year":"2010","journal-title":"Acta Trop."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1590\/s0037-86822012000300002","article-title":"Chagas disease. What is known and what should be improved: a systemic review","volume":"45","author":"Coura","year":"2012","journal-title":"Rev. Soc. Bras. Med. Trop."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1590\/s0074-02762002000100001","article-title":"A critical review on Chagas disease chemotherapy","volume":"97","author":"Coura","year":"2002","journal-title":"Mem. Inst. Oswaldo Cruz"},{"key":"ref9002","doi-asserted-by":"publisher","first-page":"1344.e1","DOI":"10.1016\/j.cmi.2018.06.006","article-title":"Toxicity of nifurtimox as second-line treatment after benznidazole intolerance in patients with chronic Chagas disease: when available options fail","volume":"24","author":"Crespillo-And\u00fajar","year":"2018","journal-title":"Clin Microbiol Infect."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"798054","DOI":"10.3389\/fcell.2021.798054","article-title":"Extracellular vesicles: potential role in remote signaling and inflammation in Trypanosoma cruzi-triggered disease","volume":"9","author":"Dantas-Pereira","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1590\/0037-8682-0269-2015","article-title":"Chagas disease: still a challenge around the world","volume":"48","author":"Dias","year":"2015","journal-title":"Rev. Soc. Bras. Med. Trop."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"7","DOI":"10.5123\/S1679-49742016000500002","article-title":"II Consenso Brasileiro em Doen\u00e7a de Chagas, 2015 [Brazilian Consensus on Chagas Disease, 2015]","volume":"25","author":"Dias","year":"2016","journal-title":"Epidemiol Serv Saude"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1007\/BF01941187","article-title":"Interaction of benznidazole reactive metabolites with nuclear and kinetoplastic DNA, proteins and lipids from Trypanosoma cruzi","volume":"44","author":"Diaz de Toranzo","year":"1988","journal-title":"Experientia"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"e00401-18","DOI":"10.1128\/AAC.00401-18","article-title":"Outcome of E1224-Benznidazole combination treatment for infection with a multidrug-resistant Trypanosoma cruzi strain in mice","volume":"62","author":"Diniz","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref42","year":"2019"},{"key":"ref43","year":"2021"},{"key":"ref44","year":"2023"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1093\/clinids\/6.2.223","article-title":"Free radical metabolites in the mode of action of chemotherapeutic agent and phagocytic cells on Trypanosoma cruzi","volume":"6","author":"Do campo","year":"1984","journal-title":"Rev Infect Dis"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/0003-9861(79)90251-0","article-title":"Generation of superoxide anio and hydrogen peroxide induced by nifurtimos in Trypanossoma cruzi","volume":"197","author":"Do Campo","year":"1979","journal-title":"Arch. Biochem. Biophys."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"100507","DOI":"10.1016\/j.cpcardiol.2019.100507","article-title":"Chagas disease: chronic Chagas cardiomyopathy","volume":"46","author":"Echavarr\u00eda","year":"2021","journal-title":"Curr. Probl. Cardiol."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.idc.2018.10.015","article-title":"American trypanosomiasis (Chagas disease)","volume":"33","author":"Echeverria","year":"2019","journal-title":"Infect. Dis. Clin. N. Am."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1016\/j.cardfail.2012.06.419","article-title":"Effect of colchicine on myocardial injury induced by Trypanosoma cruzi in experimental Chagas disease","volume":"18","author":"Fernandes","year":"2012","journal-title":"J. Card. Fail."},{"key":"ref9004","doi-asserted-by":"publisher","first-page":"1056","DOI":"10.1093\/cid\/ciw477","article-title":"Safety profile of Nifurtimox for treatment of Chagas disease in the United States","volume":"63","author":"Forsyth","year":"2016","journal-title":"Clin Infect Dis."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"e12996","DOI":"10.1111\/tid.12996","article-title":"Reactivation of Chagas disease among heart transplant recipients in the United States, 2012-2016","volume":"20","author":"Gray","year":"2018","journal-title":"Transpl. Infect. Dis."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1111\/j.1365-3024.2009.01108.x","article-title":"The role of parasite persistence in pathogenesis of Chagas heart disease","volume":"31","author":"Gutierrez","year":"2009","journal-title":"Parasite Immunol."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1016\/S0146-2806(06)80002-2","article-title":"Chagas' heart disease","volume":"20","author":"Hagar","year":"1995","journal-title":"Curr. Probl. Cardiol."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1093\/jac\/dks027","article-title":"Safety of benznidazole use in the treatment of chronic Chagas\u2019 disease","volume":"67","author":"Hasslocher-Moreno","year":"2012","journal-title":"J Antimicrob Chemoth"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"100694","DOI":"10.1016\/j.eclinm.2020.100694","article-title":"Benznidazole decreases the risk of chronic Chagas disease progression and cardiovascular events: a long-term follow up study","volume":"31","author":"Hasslocher-Moreno","year":"2021","journal-title":"Eclinical Med."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"101105","DOI":"10.1016\/j.eclinm.2021.101105","article-title":"Effects of selenium treatment on cardiac function in Chagas heart disease: results from the STCC randomized trial","volume":"28","author":"Holanda","year":"2021","journal-title":"EClinicalMedicine"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1186\/1471-2334-13-85","article-title":"Serological and parasitological response in chronic Chagas patients 3 years after nifurtimox treatment","volume":"13","author":"Jackson","year":"2013","journal-title":"BMC Infect. Dis."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.pt.2010.12.002","article-title":"Would selenium supplementation aid in therapy for Chagas disease?","volume":"27","author":"Jelicks","year":"2011","journal-title":"Trends Parasitol."},{"key":"ref58","doi-asserted-by":"publisher","first-page":"105107","DOI":"10.1016\/j.actatropica.2019.105107","article-title":"Drug discovery for chagas disease: a viewpoint","volume":"198","author":"Kratz","year":"2019","journal-title":"Acta Trop."},{"key":"ref59","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1080\/17512433.2018.1509704","article-title":"Clinical and pharmacological profile of benznidazole for treatment of Chagas disease","volume":"11","author":"Kratz","year":"2018","journal-title":"Expert. Rev. Clin. Pharmacol."},{"key":"ref60","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/j.ijpharm.2005.10.004","article-title":"Development of parenteral formulations and evaluation of the biological activity of the trypanocide drug benznidazole","volume":"307","author":"Lamas","year":"2006","journal-title":"Int. J. Pharm."},{"key":"ref61","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1021\/acs.chemrestox.3c00096","article-title":"Correction to \u201cstructural and mechanistic investigation of the unusual metabolism of Nifurtimox\u201d","volume":"36","author":"Lang","year":"2023","journal-title":"Chem. Res. Toxicol."},{"key":"ref9005","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.ijpharm.2008.09.036","article-title":"Development of novel formulations for Chagas\u2019 disease: Optimization of benznidazole chitosan microparticles based on artificial neural networks","volume":"367","author":"Leonardi","year":"2009","journal-title":"Int J Pharm."},{"key":"ref62","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1016\/S1473-3099(13)70002-1","article-title":"Global economic burden of Chagas disease: a computational simulation model","volume":"13","author":"Lee","year":"2013","journal-title":"Lancet Infect. Dis."},{"key":"ref63","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1111\/j.1550-7408.1980.tb04228.x","article-title":"A newly revised classification of the Protozoa","volume":"27","author":"Levine","year":"1980","journal-title":"J. Protozool."},{"key":"ref64","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1023\/a:1007773901631","article-title":"A cost-minimization of heart failure therapy with bisoprolol in the French setting: an analysis from CIBIS trial data. Cardiac insufficiency Bisoprolol study","volume":"12","author":"Levy","year":"1998","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref65","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1016\/j.pt.2016.08.009","article-title":"Putting infection dynamics at the heart of chagas disease","volume":"32","author":"Lewis","year":"2016","journal-title":"Trends Parasitol."},{"key":"ref66","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1038\/nri2156","article-title":"Getting to the site of inflammation: the leukocyte adhesion cascade updated","volume":"7","author":"Ley","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref67","doi-asserted-by":"publisher","first-page":"3098","DOI":"10.1161\/01.cir.90.6.3098","article-title":"Survival and predictors of survival in patients with congestive heart failure due to Chagas' cardiomyopathy","volume":"90","author":"Mady","year":"1994","journal-title":"Circulation"},{"key":"ref68","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1016\/j.healun.2003.09.027","article-title":"Using polymerase chain reaction in early diagnosis of re-activated Trypanosoma cruzi infection after heart transplantation","volume":"23","author":"Maldonado","year":"2004","journal-title":"J. Heart Lung Transplant."},{"key":"ref69","doi-asserted-by":"publisher","first-page":"1022","DOI":"10.3390\/antiox10071022","article-title":"The use of antioxidants as potential co-adjuvants to treat chronic Chagas disease","volume":"10","author":"Maldonado","year":"2021","journal-title":"Antioxidants (Basel)"},{"key":"ref70","doi-asserted-by":"publisher","first-page":"976","DOI":"10.1016\/j.ahj.2013.08.027","article-title":"CHronic use of amiodarone aGAinSt implantable cardioverter-defibrillator therapy for primary prevention of death in patients with Chagas cardiomyopathy study: rationale and design of a randomized clinical trial","volume":"166","author":"Martinelli","year":"2013","journal-title":"Am. Heart J."},{"key":"ref71","doi-asserted-by":"publisher","first-page":"103","DOI":"10.2471\/BLT.15.152363","article-title":"Mortality from neglected tropical diseases in Brazil, 2000-2011","volume":"94","author":"Martins-Melo","year":"2016","journal-title":"Bull. World Health Organ."},{"key":"ref9007","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1590\/0037-8682-0083-2016","article-title":"Cardiac rehabilitation program in patients with Chagas heart failure: a single-arm pilot study","volume":"3","author":"Mediano","year":"2016","journal-title":"Rev Soc Bras Med Trop."},{"key":"ref9006","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1186\/s13063-016-1553-4","volume":"17","author":"Mendes","year":"2016","journal-title":"Effect of physical exercise training in patients with Chagas heart disease: study protocol for a randomized controlled trial (PEACH study)."},{"key":"ref72","doi-asserted-by":"publisher","first-page":"1262","DOI":"10.1016\/j.amjmed.2020.05.022","article-title":"Chagas disease: epidemiology and barriers to treatment","volume":"133","author":"Mills","year":"2020","journal-title":"Am. J. Med."},{"key":"ref73","doi-asserted-by":"publisher","first-page":"1899","DOI":"10.1056\/NEJMoa1313122","article-title":"Randomized trial of posaconazole and benznidazole for chronic Chagas' disease","volume":"370","author":"Molina","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref74","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1128\/AAC.44.1.150-155.2000","article-title":"Activities of the triazole derivative SCH 56592 (posaconazole) against drug-resistant strains of the protozoan parasite Trypanosoma (Schizotrypanum) cruzi in immunocompetent and immunosuppressed murine hosts","volume":"44","author":"Molina","year":"2000","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref75","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1097\/QCO.0000000000000192","article-title":"The use of posaconazole against Chagas disease","volume":"28","author":"Molina","year":"2015","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref76","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1186\/s13063-020-4226-2","article-title":"Efficacy and safety assessment of different dosage of benznidazol for the treatment of Chagas disease in chronic phase in adults (MULTIBENZ study): study protocol for a multicenter randomized phase II non-inferiority clinical trial","volume":"21","author":"Molina-Morant","year":"2020","journal-title":"Trials"},{"key":"ref77","doi-asserted-by":"publisher","first-page":"106","DOI":"10.3390\/tropicalmed5030106","article-title":"Chagas disease infection reactivation after heart transplant","volume":"5","author":"Moreira","year":"2020","journal-title":"Trop Med Infect Dis."},{"key":"ref78","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1056\/NEJMoa1507574","article-title":"BENEFIT investigators. Randomized trial of Benznidazole for chronic Chagas' cardiomyopathy","volume":"373","author":"Morillo","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref79","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1016\/j.jacc.2016.12.023","article-title":"Benznidazole and Posaconazole in eliminating parasites in Asymptomatic T. cruzi carriers: the STOP-CHAGAS trial","volume":"69","author":"Morillo","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref80","doi-asserted-by":"publisher","first-page":"e0007647","DOI":"10.1371\/journal.pntd.0007647","article-title":"Negligible exposure to nifurtimox through breast milk during maternal treatment for Chagas disease","volume":"13","author":"Moroni","year":"2019","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref81","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1016\/j.jbspin.2006.03.006","article-title":"Colchicine today","volume":"73","author":"Niel","year":"2006","journal-title":"Joint Bone Spine"},{"key":"ref82","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1007\/s11739-011-0671-y","article-title":"Effects of supplementation with polyunsaturated fatty acids in patients with heart failure","volume":"6","author":"Nodari","year":"2011","journal-title":"Intern. Emerg. Med."},{"key":"ref83","year":"2018"},{"key":"ref84","year":"2023"},{"key":"ref85","doi-asserted-by":"publisher","first-page":"3154","DOI":"10.2174\/0929867323999160625124424","article-title":"Challenges in chagas disease drug discovery: a review","volume":"23","author":"Paucar","year":"2016","journal-title":"Current Med Chem"},{"key":"ref86","doi-asserted-by":"publisher","first-page":"1486","DOI":"10.1016\/S0140-6736(19)30288-0","article-title":"Guidelines for the diagnosis and treatment of Chagas disease","volume":"393","author":"Pereiro","year":"2019","journal-title":"Lancet"},{"key":"ref87","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/S0140-6736(17)31612-4","article-title":"Chagas disease","volume":"391","author":"P\u00e9rez-Molina","year":"2018","journal-title":"Lancet"},{"key":"ref88","doi-asserted-by":"publisher","first-page":"1086","DOI":"10.4269\/ajtmh.20-0005","article-title":"Congenital Chagas disease in the United States: the effect of commercially priced Benznidazole on costs and benefits of maternal screening","volume":"102","author":"Perez-Zetune","year":"2020","journal-title":"Am J Trop Med Hyg."},{"key":"ref9008","doi-asserted-by":"crossref","first-page":"4009","DOI":"10.1016\/S0021-9258(18)50687-6","article-title":"Oxygen-sensitive and - insensitive nitroreduction by Escherichia coli and rat hepatic microsomes","volume":"254","author":"Peterson","year":"1979","journal-title":"J Biol Chem"},{"key":"ref89","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1128\/AAC.01401-12","article-title":"Benznidazole-related adverse drug reactions and their relationship to serum drug concentrations in patients with chronic Chagas disease","volume":"57","author":"Pinazo","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref90","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.trre.2010.12.002","article-title":"Recommendations for management of Chagas disease in organ and hematopoietic tissue transplantation programs in nonendemic areas","volume":"25","author":"Pinazo","year":"2011","journal-title":"Transplant. Rev. (Orlando)"},{"key":"ref91","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1080\/00034983.1978.11719278","article-title":"Mode of action of 2-nitroimidazole derivative benznidazol","volume":"72","author":"Polak","year":"1978","journal-title":"Ann. Trop. Med. Parasitol."},{"key":"ref92","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/S1473-3099(01)00065-2","article-title":"Clinical and epidemiological aspects of Chagas disease","volume":"1","author":"Prata","year":"2001","journal-title":"Lancet Infect. Dis."},{"key":"ref93","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1186\/1745-6215-7-21","article-title":"CHARITY: Chagas cardiomyopathy bisoprolol intervention study: a randomized double-blind placebo force-titration controlled study with Bisoprolol in patients with chronic heart failure secondary to Chagas cardiomyopathy [NCT00323973]","volume":"7","author":"Quiros","year":"2006","journal-title":"Trials"},{"key":"ref94","first-page":"377","article-title":"Ventricular arrhythmia in Chagas disease","volume":"65","author":"Rassi","year":"1995","journal-title":"Diagnostic, prognostic, and therapeutic features Arq Bras Cardiol."},{"key":"ref95","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1590\/0074-02760160334","article-title":"Chronic Chagas cardiomyopathy: a review of the main pathogenic mechanisms and the efficacy of aetiological treatment following the BENznidazole evaluation for interrupting trypanosomiasis (BENEFIT) trial","volume":"112","author":"Rassi","year":"2017","journal-title":"Mem. Inst. Oswaldo Cruz"},{"key":"ref96","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/j.idc.2012.03.002","article-title":"American trypanosomiasis (Chagas disease)","volume":"26","author":"Rassi","year":"2012","journal-title":"Infect. Dis. Clin. N. Am."},{"key":"ref97","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1590\/s0066-782x2001000100008","article-title":"Sudden death in Chagas' disease","volume":"76","author":"Rassi","year":"2001","journal-title":"Arq. Bras. Cardiol."},{"key":"ref98","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1161\/CIRCULATIONAHA.106.627265","article-title":"Predictors of mortality in chronic Chagas disease: a systematic review of observational studies","volume":"115","author":"Rassi","year":"2007","journal-title":"Circulation"},{"key":"ref99","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1046\/j.1365-3024.2000.00260.x","article-title":"Chagasic patients develop a type 1 immune response to Trypanosoma cruzi trans-sialidase","volume":"22","author":"Ribeir\u00e3o","year":"2000","journal-title":"Parasite Immunol."},{"key":"ref100","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.ijpddr.2019.11.004","article-title":"Current trends in the pharmacological management of Chagas disease","volume":"12","author":"Ribeiro","year":"2020","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"ref101","doi-asserted-by":"publisher","first-page":"706","DOI":"10.4269\/ajtmh.2002.66.706","article-title":"Progressive Chagas' cardiomyopathy is associated with low selenium levels","volume":"66","author":"Rivera","year":"2002","journal-title":"Am J Trop Med Hyg"},{"key":"ref102","doi-asserted-by":"publisher","first-page":"e674","DOI":"10.1371\/journal.pntd.0000674","article-title":"Coronary microvascular disease in chronic Chagas cardiomyopathy including an overview on history, pathology, and other proposed pathogenic mechanisms","volume":"4","author":"Rossi","year":"2010","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref103","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1177\/1742395320920700","article-title":"A randomized controlled trial of high-intensity interval training and inspiratory muscle training for chronic heart failure patients with inspiratory muscle weakness","volume":"18","author":"Sadek","year":"2022","journal-title":"Chronic Illn."},{"key":"ref104","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.4269\/ajtmh.16-0761","article-title":"Experimental and clinical treatment of Chagas disease: a review","volume":"97","author":"Sales Junior","year":"2017","journal-title":"Am J Trop Med Hyg."},{"key":"ref105","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1007\/s10286-020-00721-1","article-title":"Effect of exercise training on cardiovascular autonomic and muscular function in subclinical Chagas cardiomyopathy: a randomized controlled trial","volume":"31","author":"Sarmento","year":"2021","journal-title":"Clin. Auton. Res."},{"key":"ref106","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1590\/S0066-782X2002001900001","article-title":"Guidelines for the evaluation and treatment of patients with cardiac arrhythmias","volume":"79","author":"Scanavacca","year":"2002","journal-title":"Arq. Bras. Cardiol."},{"key":"ref107","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1016\/j.ejmech.2018.06.040","article-title":"Current advances in drug discovery for Chagas disease","volume":"155","author":"Scarim","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref108","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1093\/cid\/cir956","article-title":"Oral transmission of Chagas disease","volume":"54","author":"Shikanai-Yasuda","year":"2012","journal-title":"Clin. Infect. Dis."},{"key":"ref109","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/s12937-017-0259-0","article-title":"Omega-3 supplementation on inflammatory markers in patients with chronic Chagas cardiomyopathy: a randomized clinical study","volume":"16","author":"Silva","year":"2017","journal-title":"Nutr. J."},{"key":"ref110","doi-asserted-by":"publisher","first-page":"119\u2013121, 131","DOI":"10.1590\/s0066-782x2007001400010","article-title":"Characterization of the apical aneurysm of chronic Chagas' heart disease by scintigraphic image co-registration","volume":"89","author":"Sim\u00f5es","year":"2007","journal-title":"Arq. Bras. Cardiol."},{"key":"ref111","doi-asserted-by":"publisher","first-page":"3342","DOI":"10.1128\/AAC.05018-14","article-title":"Population pharmacokinetics of benznidazole in adult patients with Chagas disease","volume":"59","author":"Soy","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref9009","doi-asserted-by":"publisher","first-page":"105940","DOI":"10.1016\/j.ejps.2021.105940","article-title":"Clinical investigation of the biopharmaceutical characteristics of nifurtimox tablets - Implications for quality control and application","volume":"166","author":"Stass","year":"2021","journal-title":"Eur J Pharm Sci."},{"key":"ref112","doi-asserted-by":"publisher","first-page":"100","DOI":"10.3201\/eid0701.700100","article-title":"Emerging Chagas disease: trophic network and cycle of transmission of Trypanosoma cruzi from palm trees in the Amazon","volume":"7","author":"Teixeira","year":"2001","journal-title":"Emerg. Infect. Dis."},{"key":"ref113","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.ijcard.2007.11.057","article-title":"Predictors of all-cause mortality in chronic Chagas' heart disease in the current era of heart failure therapy","volume":"128","author":"Theodoropoulos","year":"2008","journal-title":"Int. J. Cardiol."},{"key":"ref114","doi-asserted-by":"publisher","first-page":"e923","DOI":"10.1371\/journal.pntd.0000923","article-title":"Fexinidazole \u2013 a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness","volume":"4","author":"Torreele","year":"2010","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref115","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1016\/S1473-3099(20)30844-6","article-title":"BENDITA study group. New regimens of benznidazole monotherapy and in combination with fosravuconazole for treatment of Chagas disease (BENDITA): a phase 2, double-blind, randomised trial","volume":"21","author":"Torrico","year":"2021","journal-title":"Lancet Infect. Dis."},{"key":"ref116","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1016\/S1473-3099(17)30538-8","article-title":"Treatment of adult chronic indeterminate Chagas disease with benznidazole and three E1224 dosing regimens: a proof-of-concept, randomised, placebo-controlled trial","volume":"18","author":"Torrico","year":"2018","journal-title":"Lancet Infect. Dis."},{"key":"ref117","doi-asserted-by":"publisher","first-page":"e1186","DOI":"10.1093\/cid\/ciac579","article-title":"A phase 2, randomized, multicenter, placebo-controlled, proof-of-concept trial of oral Fexinidazole in adults with chronic indeterminate Chagas disease","volume":"76","author":"Torrico","year":"2023","journal-title":"Clin. Infect. Dis."},{"key":"ref118","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.actatropica.2009.10.023","article-title":"Specific chemotherapy of Chagas disease: relevance, current limitations and new approaches","volume":"115","author":"Urbina","year":"2010","journal-title":"Acta Trop."},{"key":"ref119","doi-asserted-by":"publisher","first-page":"1771","DOI":"10.1128\/AAC.42.7.1771","article-title":"Antiproliferative effects and mechanism of action of SCH 56592 against Trypanosoma (Schizotrypanum) cruzi: in vitro and in vivo studies","volume":"42","author":"Urbina","year":"1998","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref120","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/s0924-8579(02)00273-x","article-title":"In vitro and in vivo activities of ravuconazole on Trypanosoma cruzi, the causative agent of Chagas disease","volume":"21","author":"Urbina","year":"2003","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref121","doi-asserted-by":"publisher","first-page":"1228","DOI":"10.1002\/ejhf.580","article-title":"Prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure (PARADIGM-HF) investigators. Efficacy of sacubitril\/valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction: the PARADIGM-HF trial","volume":"18","author":"Vardeny","year":"2016","journal-title":"Eur. J. Heart Fail."},{"key":"ref122","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1186\/s13063-019-3423-3","article-title":"Nifurtimox versus benznidazole or placebo for asymptomatic Trypanosoma cruzi infection (equivalence of usual interventions for trypanosomiasis - EQUITY): study protocol for a randomised controlled trial","volume":"20","author":"Villar","year":"2019","journal-title":"Trials"},{"key":"ref123","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1586\/14787210.7.2.157","article-title":"Side effects of benznidazole as treatment in chronic Chagas disease: fears and realities","volume":"7","author":"Viotti","year":"2009","journal-title":"Expert Rev. Anti-Infect. Ther."},{"key":"ref124","doi-asserted-by":"publisher","first-page":"724","DOI":"10.7326\/0003-4819-144-10-200605160-00006","article-title":"Long-term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment: a nonrandomized trial","volume":"144","author":"Viotti","year":"2006","journal-title":"Ann. Intern. Med."},{"key":"ref125","year":"2023"},{"key":"ref126","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.actatropica.2017.09.017","article-title":"Trypanosoma cruzi genetic diversity: something new for something known about Chagas disease manifestations, serodiagnosis and drug sensitivity","volume":"184","author":"Zingales","year":"2018","journal-title":"Acta Trop."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2023.1295017\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,15]],"date-time":"2023-12-15T10:58:56Z","timestamp":1702637936000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2023.1295017\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,15]]},"references-count":134,"alternative-id":["10.3389\/fmicb.2023.1295017"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2023.1295017","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,15]]},"article-number":"1295017"}}