Safety Profile of Benznidazole in the Treatment of Chronic Chagas Disease: Experience of a Referral Centre and Systematic Literature Review with Meta-Analysis
- 116 Downloads
Benznidazole is the preferred drug for treatment of Chagas disease. However, it is toxic and of limited value in chronic infection.
We aimed to estimate the rates of and factors related to adverse reactions (ARs) to benznidazole and treatment discontinuations (TDs).
A meta-analysis was performed using an electronic search of the published literature with no language restrictions until June 2017. Prospective studies were included of chronically infected patients in which at least one treatment arm included benznidazole. Data were added from a prospective cohort of patients with Chagas disease at our centre (January 2007–June 2017). Weighted rates of ARs and TDs were estimated, and potentially related factors were analysed.
Some 413 studies were found, from which we chose 42 (nine clinical trials and 33 observational studies, including ours), comprising data for 7822 patients. The weighted rate of ARs to benznidazole was 44.1% (95% confidence interval [CI] 37.2–51.2). ARs were more frequent in adults than in children (51.6 vs. 24.5%), with the most common being skin reactions (34%), gastrointestinal complaints (12.6%) and neurological symptoms (11.5%). Grade 4 ARs were recorded in 3% of cases. The weighted rate of TDs was 11.4% (95% CI 8.5–14.5); TDs were more frequent in adults than in children (14.2 vs. 3.8%). In our cohort, only female sex was related to an increased rate of ARs but not to TDs.
Benznidazole had a poor tolerability profile, with a high incidence of TDs, especially in adult patients and women. Optimised dosing schedules and/or new drugs are urgently needed.
Compliance with Ethical Standards
Funding was provided by ISCIII (Instituto de Salud Carlos III), project “RD16/0027/0020 and RD16/0027/0002” Red de Enfermedades Tropicales, Subprograma RETICS del Plan Estatal de I + D + I 2013–2016 and by FEDER (Fondo Europeo de Desarrollo Regional).
Conflict of interest
Clara Crespillo-Andújar, Emmanuele Venanzi-Rullo, Rogelio López-Vélez, Begoña Monge-Maillo, Francesca Norman, Ana López-Polín and José A. Pérez-Molina declare that they have no conflict of interest.
- 1.World Health Organization. Chagas disease in Latin America: an epidemiological update based on 2010 estimates. Wkly Epidemiol Rec. 2015;90:33–43.Google Scholar
- 2.World Health Organization. Control of Chagas disease: second report of the WHO Expert Committee. WHO technical report series, vol. 905. Geneva: World Health Organization; 2002.Google Scholar
- 21.Fabbro DL, Streiger ML, Arias ED, Bizai ML, del Barco M, Amicone NA. Trypanocide treatment among adults with chronic Chagas disease living in Santa Fe city (Argentina), over a mean follow-up of 21 years: parasitological, serological and clinical evolution. Rev Soc Bras Med Trop. 2007;40:1–10.CrossRefPubMedGoogle Scholar
- 25.Coura JR, de Abreu LL, Willcox HP, Petana W. Comparative controlled study on the use of benznidazole, nifurtimox and placebo, in the chronic form of Chagas’ disease, in a field area with interrupted transmission. I. Preliminary evaluation [in Portuguese]. Rev Soc Bras Med Trop. 1997;30:139–44.CrossRefPubMedGoogle Scholar
- 33.Cancer Therapy Evaluation Program. Common toxicity criteria (CTC). Version 5.0. 2017. Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50. Accessed 12 Feb 2018.
- 34.Barclay CA, Cerisola JA, Lugones H, et al. Aspectos farmacológicos y resultados terapéuticos del benznidazol en el tratamiento de la infección chagásica. Prensa Med Argent. 1978;65:239–44.Google Scholar
- 44.Torrico F, Gascon J, Ortiz L, Alonso-Vega C, Pinazo M-J, 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. 2018;18(4):419–30.CrossRefPubMedGoogle Scholar
- 61.Raaflaub J. Multiple-dose kinetics of the trypanosomicide benznidazole in man. Arzneimittel-Forschung. 1980;30(12):2191–4.Google Scholar
- 63.World Health Organization. The WHO adverse reaction terminology—WHO-ART. Uppsala: WHO Collaborating Centre for International Drug Monitoring; 2009.Google Scholar
- 65.Carpintero DJ. Use of thioctic acid for prevention of the adverse effects induced by benznidazole in patients with chronic Chagas’ infection [in Spanish]. Medicina (B Aires). 1983;43:285–90.Google Scholar
- 70.de Arruda J. Tolerance to benzonidazole during the etiological treatment of Chagas’ disease. Arquivos brasileiros de cardiologia. 1987;48(6):395–7.Google Scholar
- 74.Anselmi M, Angheben A, Degani M, Tais S. Imported Chagas disease in Italy: the tip of the iceberg. Description of the first 10 cases treated at the Centre for Tropical Diseases [abstract]. Trop Med Int Health. 2009;14(Suppl 2):240.Google Scholar
- 78.Moreira CH. Benznidazole-related adverse drug reactions in Brazilian patients with Chagas disease [abstract]. Am J Trop Med Hyg. 2015;93(4 Suppl):336.Google Scholar
- 80.Diniz Marques R, da Silva Marques R, Marques RD, et al. Efficacy of benznidazole in the treatment of young people in the indeterminate phase of Chagas disease. Rev Bras Med. 2003;60(10):755–64.Google Scholar