Beneficial effects of benznidazole in Chagas disease: NIH SaMi-Trop cohort study

Clareci Silva Cardoso, Antonio Luiz P Ribeiro, Claudia Di Lorenzo Oliveira, Lea Campos Oliveira, Ariela Mota Ferreira, Ana Luiza Bierrenbach, José Luiz Padilha Silva, Enrico Antonio Colosimo, João Eduardo Ferreira, Tzong-Hae Lee, Michael P Busch, Arthur Lawrence Reingold, Ester Cerdeira Sabino, Clareci Silva Cardoso, Antonio Luiz P Ribeiro, Claudia Di Lorenzo Oliveira, Lea Campos Oliveira, Ariela Mota Ferreira, Ana Luiza Bierrenbach, José Luiz Padilha Silva, Enrico Antonio Colosimo, João Eduardo Ferreira, Tzong-Hae Lee, Michael P Busch, Arthur Lawrence Reingold, Ester Cerdeira Sabino

Abstract

Background: The effectiveness of anti-parasite treatment with benznidazole in the chronic Chagas disease (ChD) remains uncertain. We evaluated, using data from the NIH-sponsored SaMi-Trop prospective cohort study, if previous treatment with benznidazole is associated with lower mortality, less advanced cardiac disease and lower parasitemia in patients with chronic ChD.

Methods: The study enrolled 1,959 ChD patients and abnormal electrocardiogram (ECG) from in 21 remote towns in Brazil. A total of 1,813 patients were evaluated at baseline and after two years of follow-up. Those who received at least one course of benznidazole were classified as treated group (TrG = 493) and those who were never treated as control group (CG = 1,320). The primary outcome was death after two-year follow-up; the secondary outcomes were presence at the baseline of major ChD-associated ECG abnormalities, NT-ProBNP levels suggestive of heart failure, and PCR positivity.

Results: Mortality after two years was 6.3%; it was lower in the TrG (2.8%) than the CG (7.6%); adjusted OR: 0.37 (95%CI: 0.21;0.63). The ECG abnormalities typical for ChD and high age-adjusted NT-ProBNP levels suggestive of heart failure were lower in the TrG than the CG, OR: 0.35 [CI: 0.23;0.53]. The TrG had significantly lower rates of PCR positivity, OR: 0.35 [CI: 0.27;0.45].

Conclusion: Patients previously treated with benznidazole had significantly reduced parasitemia, a lower prevalence of markers of severe cardiomyopathy, and lower mortality after two years of follow-up. If used in the early phases, benznidazole treatment may improve clinical and parasitological outcomes in patients with chronic ChD.

Trial registration: ClinicalTrials.gov, Trial registration: NCT02646943.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Study design diagram.
Fig 1. Study design diagram.
Fig 2. Kaplan-Meier survival curves in ChD…
Fig 2. Kaplan-Meier survival curves in ChD by treatment and control group.

References

    1. Nunes MCP, Dones W, Morillo CA, Encina JJ, Ribeiro AL. Chagas disease: An overview of clinical and epidemiological aspects. Journal of the American College of Cardiology. 2013. 10.1016/j.jacc.2013.05.046
    1. Longo DL, Bern C. Chagas’ Disease. N Engl J Med. 2015;375: 456–466. 10.1056/NEJMra1410150
    1. World Health Organization. Chagas disease in Latin America: an epidemiological update based on 2010 estimates. Wkly Epidemiol Rec. 2015;90: 33–44.
    1. Lee BY, Bacon KM, Bottazzi ME, Hotez PJ. Global economic burden of Chagas disease: a computational simulation model. Lancet Infect Dis. 2013;13: 342–348. 10.1016/S1473-3099(13)70002-1
    1. Sabino EC, Ribeiro AL, Salemi VMC, Di Lorenzo Oliveira C, Antunes AP, Menezes MM, et al. Ten-Year incidence of chagas cardiomyopathy among asymptomatic trypanosoma cruzi-seropositive former blood donors. Circulation. 2013;127: 1105–1115. 10.1161/CIRCULATIONAHA.112.123612
    1. Pérez-Molina JA, Molina I. Chagas disease. The Lancet. June 2017. 10.1016/S0140-6736(17)31612-4
    1. Carlos Pinto Dias J, Novaes Ramos A, Dias Gontijo E, Luquetti A, Aparecida Shikanai-Yasuda M, Rodrigues Coura J, et al. II Consenso Brasileiro em Doença de Chagas, 2015. Epidemiol e Serviços Saúde. Coordenação-Geral de Desenvolvimento da Epidemiologia em Serviços / Secretaria de Vigilância em Saúde / Ministério da Saúde; 2016;25: 1–10.
    1. Fragata-Filho AA, França FF, Fragata C da S, Lourenço AM, Faccini CC, Costa CA de J. Evaluation of Parasiticide Treatment with Benznidazol in the Electrocardiographic, Clinical, and Serological Evolution of Chagas Disease. PLoS Negl Trop Dis. 2016;10 10.1371/journal.pntd.0004508
    1. Morillo CA, Marin-Neto JA, Avezum A, Sosa-Estani S, Rassi A, Rosas F, et al. Randomized Trial of Benznidazole for Chronic Chagas’ Cardiomyopathy. N Engl J Med. 2015;373 10.1056/NEJMoa1507574
    1. Villar JC arlos, Perez JG uillermo, Cortes OL ucia, Riarte A, Pepper M, Marin-Neto JA ntonio, et al. Trypanocidal drugs for chronic asymptomatic Trypanosoma cruzi infection. Villar JC, editor. Cochrane database Syst Rev. Chichester, UK: John Wiley & Sons, Ltd; 2014;5: CD003463 10.1002/14651858.CD003463.pub2
    1. Cardoso CS, Sabino EC, Oliveira CDL, Oliveira LC, Ferreira AM, Cunha-Neto E, et al. Longitudinal study of patients with chronic Chagas cardiomyopathy in Brazil (SaMi-Trop project): a cohort profile. BMJ Open. British Medical Journal Publishing Group; 2016;6: e011181 10.1136/bmjopen-2016-011181
    1. Alkmim MB, Minelli Figueira R, Soriano Marcolino M, Silva Cardoso C, Pena de Abreu M, Rodrigues Cunha L, et al. Improving patient access to specialized health care: the Telehealth Network of Minas Gerais, Brazil. Bull World Health Organ. 2012;90: 373–378. 10.2471/BLT.11.099408
    1. Piron M, Fisa R, Casamitjana N, López-Chejade P, Puig L, Vergés M, et al. Development of a real-time PCR assay for Trypanosoma cruzi detection in blood samples. Acta Trop. 2007;103: 195–200. 10.1016/j.actatropica.2007.05.019
    1. Sabino EC, Lee TH, Montalvo L, Nguyen ML, Leiby DA, Carrick DM, et al. Antibody levels correlate with detection of Trypanosoma cruzi DNA by sensitive polymerase chain reaction assays in seropositive blood donors and possible resolution of infection over time. Transfusion. Wiley/Blackwell (10.1111); 2013;53: 1257–1265. 10.1111/j.1537-2995.2012.03902.x
    1. Maisel A, Mueller C, Kirkwood AJ, Anker SD, Aspromonte N, Cleland JGF, et al. State of the art: Using natriuretic peptide levels in clinical practice. Eur J Heart Fail. 2008;10: 824–839. 10.1016/j.ejheart.2008.07.014
    1. Daniels LB, Maisel AS. Natriuretic Peptides [Internet]. Journal of the American College of Cardiology. 2007. pp. 2357–2368. 10.1016/j.jacc.2007.09.021
    1. Palhares DMF, Marcolino MS, Santos TMM, da Silva JLP, Gomes PR, Ribeiro LB, et al. Normal limits of the electrocardiogram derived from a large database of Brazilian primary care patients. BMC Cardiovasc Disord. BioMed Central; 2017;17: 152 10.1186/s12872-017-0572-8
    1. Macfarlane PW, Latif S. Automated serial ECG comparison based on the Minnesota code. Journal of Electrocardiology. 1996. pp. 29–34. 10.1016/S0022-0736(96)80016-1
    1. Sekhon JS. Multivariate and Propensity Score Matching Software with Automated Balance Optimization: The Matching Package for R. JSS J Stat Softw. 2011;42 Available:
    1. Yan J, Valdez EA, Trivedi PK, Zimmer DM, Staudt A, Shemyakin AE, et al. R: A Language and Environment for Statistical Computing. R Found Stat Comput. 2011;1: 409.
    1. Maguire JH. Treatment of Chagas’ Disease—Time Is Running Out. N Engl J Med. 2015;373: 1369–1370. 10.1056/NEJMe1510170
    1. Bern C. A New Epoch in Antitrypanosomal Treatment for Chagas Disease*. J Am Coll Cardiol. 2017;69: 948–950. 10.1016/j.jacc.2016.12.016
    1. Sabino EC, Ribeiro AL, Lee TH, Oliveira CL, Carneiro-Proietti AB, Antunes AP, et al. Detection of Trypanosoma cruzi DNA in blood by PCR is associated with Chagas cardiomyopathy and disease severity. Eur J Heart Fail. 2015;17: 416–423. 10.1002/ejhf.220
    1. Molina I, Gómez i Prat J, Salvador F, Treviño B, Sulleiro E, Serre N, et al. Randomized trial of posaconazole and benznidazole for chronic Chagas’ disease. N Engl J Med. 2014;370: 1899–908. 10.1056/NEJMoa1313122
    1. Morillo CA, Waskin H, Sosa-Estani S, del Carmen Bangher M, Cuneo C, Milesi R, et al. Benznidazole and Posaconazole in Eliminating Parasites in Asymptomatic T. Cruzi Carriers. J Am Coll Cardiol. 2017;69: 939–947. 10.1016/j.jacc.2016.12.023
    1. Torrico F, Gascon J, Ortiz L, Alonso-Vega C, Pinazo MJ, Schijman A, et al. Treatment of adult chronic indeterminate Chagas disease with benznidazole and three E1224 dosing regimens: a proof-of-concept, randomised, placebo-controlled trial. Lancet Infect Dis. Elsevier; 2018;18: 419–430. 10.1016/S1473-3099(17)30538-8
    1. Ribeiro ALP, Marcolino MS, Prineas RJ, Lima-Costa MF. Electrocardiographic Abnormalities in Elderly Chagas Disease Patients: 10-Year Follow-Up of the Bambui Cohort Study of Aging. J Am Heart Assoc. 2014;3: e000632–e000632. 10.1161/JAHA.113.000632
    1. Viotti R, Vigliano C, Lococo B, Bertocchi G, Petti M, Alvarez MG, et al. Long-term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment: a nonrandomized trial. Ann Intern Med. 2006;144: 724–34. Available:
    1. Ribeiro ALP, dos Reis AM, Barros MVL, de Sousa MR, Rocha ALL, Perez AA, et al. Brain natriuretic peptide and left ventricular dysfunction in Chagas’ disease. Lancet. 2002;360: 461–462. 10.1016/S0140-6736(02)09638-1
    1. Lima-Costa MF, Cesar CC, Peixoto S V., Ribeiro ALP. Plasma -Type Natriuretic Peptide As a Predictor of Mortality in Community-Dwelling Older Adults With Chagas Disease: 10-Year Follow-up of the Bambui Cohort Study of Aging. Am J Epidemiol. 2010;172: 190–196. 10.1093/aje/kwq106
    1. Dias JCP. Doença de Chagas: sucessos e desafios. Cad Saude Publica. Escola Nacional de Saúde Pública, Fundação Oswaldo Cruz; 2006;22: 2020–2020. 10.1590/S0102-311X2006001000001
    1. Brasil. Secretaria de Estado da Saúde do Rio Grande do Sul. Manual Do PIT. Posto de Informação de Triatomíneos [Internet].

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner