Benznidazole treatment safety: the Médecins Sans Frontières experience in a large cohort of Bolivian patients with Chagas’ disease—authors’ response

Benznidazole treatment safety: the Médecins Sans Frontières experience in a large cohort of... Sir, We thank Novaes and Gonçalves1 for their thoughtful comments on our paper.2 We would like to further clarify the characteristics of our study population. We included subjects from rural areas in Bolivia whose serological screening for Chagas’ disease was positive. Therefore, our focus was on patients in the chronic phase of Chagas’ disease; however, as this disease is endemic to rural areas in Bolivia,3 we cannot rule out recent reinfection. Thus, patients positive for Trypanosoma cruzi infection were treated with benznidazole based on the assumption of a possible recent chronic phase, as recommended by a recent consensus.4 We are aware of the results of the BENEFIT trial,5 but we considered that most of our population was not composed of patients in the advanced stages of the cardiac form of the disease as among patients with available ECG data, 73.3% presented a normal ECG.2 However, as we have already published,2 information on ECG changes was limited and we could not properly classify patients with ECG changes into indeterminate or cardiac form and therefore we could not evaluate if the form of Chagas’ disease influenced the likelihood of developing adverse drug reactions (ADRs) during benznidazole treatment. We agree with the authors that the clinical efficacy of benznidazole in chronic cases is still under debate, but unfortunately our study2 did not evaluate the clinical or parasitological efficacy of benznidazole treatment as the study was run in a rural area with a retrospective design. Therefore, we cannot contribute any data on the relationship between ADRs and the clinical or parasitological efficacy of benznidazole treatment. We agree with Novaes and Gonçalves1 that studies on new treatment protocols are welcome, but at this point we cannot recommend protocols with shorter benznidazole treatment duration or using lower or intermittent doses until these new regimens are proved safe and effective in double-blind, randomized, prospective, controlled trials. Furthermore, the dose of benznidazole does not appear to be associated with ADRs causing treatment interruption (P = 0.27, P = 0.780),6,7 and ADRs that require treatment interruption occur mostly in the first 30 days of treatment (P < 0.001).6 Additionally, our recent results suggest that skin disorders were significantly associated with permanent suspension of benznidazole treatment,2 and allergic dermatitis due to benznidazole is not dose related.8 Moreover, skin reactions are the main side effect of benznidazole and begin around the 10th day of treatment.8 These reactions are responsible for benznidazole treatment suspension on average by the 28th day of benznidazole treatment,2 suggesting that a 30 day long protocol would not be enough to avoid benznidazole treatment interruption. On the contrary, the Médecins Sans Frontières protocol described in our paper proved very interesting as up to 89.8% of the patients were able to complete the proposed treatment even though 56% of the patients experienced some kind of ADR.2 We attributed this success to the close follow-up surveillance together with patient counselling and reassurance, which prompted an earlier identification of ADRs and their treatment with a consequent lower abandonment rate. Regarding the authors’ comments on individual resistance to ADRs, we agree that individual characteristics and resistance to ADRs may be an alternative explanatory variable for adherence rates. In fact, we have reported that educational level was able to predict overall ADRs.7 However, in the present study the retrospective design and the unavailability of data regarding educational level precluded some variables from being entered in the analysis, as already discussed in the published paper.2 Transparency declarations None to declare. References 1 Novaes RD, Gonçalves RV. Comment on: Benznidazole treatment safety: the Médecins Sans Frontières experience in a large cohort of Bolivian patients with Chagas’ disease. J Antimicrob Chemother  2018; 73: 1114– 5. 2 Sperandio da Silva GM, Mediano MFF, Hasslocher-Moreno AM et al.   Benznidazole treatment safety: the Médecins Sans Frontières experience in a large cohort of Bolivian patients with Chagas’ disease. J Antimicrob Chemother  2017; 72: 2596– 601. Google Scholar CrossRef Search ADS PubMed  3 Pérez-Molina JA, Molina I. Chagas disease. Lancet  2017; doi:10.1016/S0140-6736(17)31612-4. 4 Dias JCPJr, R Novaes A et al.   2nd Brazilian Consensus on Chagas Disease, 2015. Rev Soc Bras Med Trop  2016; 49 Suppl 1: 3– 60. Google Scholar CrossRef Search ADS   5 Morillo CA, Marin-Neto JA, Avezum A et al.   Randomized trial of benznidazole for chronic Chagas’ cardiomyopathy. N Engl J Med  2015; 373: 1295– 306. Google Scholar CrossRef Search ADS PubMed  6 Hasslocher-Moreno AM, do Brasil PEAA, de Sousa AS et al.   Safety of benznidazole use in the treatment of chronic Chagas’ disease. J Antimicrob Chemother  2012; 67: 1261– 6. Google Scholar CrossRef Search ADS PubMed  7 Sperandio da Silva GM, Mediano MFF, Alvarenga Americano do Brasil PE et al.   A clinical adverse drug reaction prediction model for patients with Chagas disease treated with benznidazole. Antimicrob Agents Chemother  2014; 58: 6371– 7. Google Scholar CrossRef Search ADS PubMed  8 Viotti R, Vigliano C, Lococo B et al.   Side effects of benznidazole as treatment in chronic Chagas disease: fears and realities. Expert Rev Anti Infect Ther  2009; 7: 157– 63. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Benznidazole treatment safety: the Médecins Sans Frontières experience in a large cohort of Bolivian patients with Chagas’ disease—authors’ response

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Oxford University Press
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0305-7453
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1460-2091
D.O.I.
10.1093/jac/dkx505
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Abstract

Sir, We thank Novaes and Gonçalves1 for their thoughtful comments on our paper.2 We would like to further clarify the characteristics of our study population. We included subjects from rural areas in Bolivia whose serological screening for Chagas’ disease was positive. Therefore, our focus was on patients in the chronic phase of Chagas’ disease; however, as this disease is endemic to rural areas in Bolivia,3 we cannot rule out recent reinfection. Thus, patients positive for Trypanosoma cruzi infection were treated with benznidazole based on the assumption of a possible recent chronic phase, as recommended by a recent consensus.4 We are aware of the results of the BENEFIT trial,5 but we considered that most of our population was not composed of patients in the advanced stages of the cardiac form of the disease as among patients with available ECG data, 73.3% presented a normal ECG.2 However, as we have already published,2 information on ECG changes was limited and we could not properly classify patients with ECG changes into indeterminate or cardiac form and therefore we could not evaluate if the form of Chagas’ disease influenced the likelihood of developing adverse drug reactions (ADRs) during benznidazole treatment. We agree with the authors that the clinical efficacy of benznidazole in chronic cases is still under debate, but unfortunately our study2 did not evaluate the clinical or parasitological efficacy of benznidazole treatment as the study was run in a rural area with a retrospective design. Therefore, we cannot contribute any data on the relationship between ADRs and the clinical or parasitological efficacy of benznidazole treatment. We agree with Novaes and Gonçalves1 that studies on new treatment protocols are welcome, but at this point we cannot recommend protocols with shorter benznidazole treatment duration or using lower or intermittent doses until these new regimens are proved safe and effective in double-blind, randomized, prospective, controlled trials. Furthermore, the dose of benznidazole does not appear to be associated with ADRs causing treatment interruption (P = 0.27, P = 0.780),6,7 and ADRs that require treatment interruption occur mostly in the first 30 days of treatment (P < 0.001).6 Additionally, our recent results suggest that skin disorders were significantly associated with permanent suspension of benznidazole treatment,2 and allergic dermatitis due to benznidazole is not dose related.8 Moreover, skin reactions are the main side effect of benznidazole and begin around the 10th day of treatment.8 These reactions are responsible for benznidazole treatment suspension on average by the 28th day of benznidazole treatment,2 suggesting that a 30 day long protocol would not be enough to avoid benznidazole treatment interruption. On the contrary, the Médecins Sans Frontières protocol described in our paper proved very interesting as up to 89.8% of the patients were able to complete the proposed treatment even though 56% of the patients experienced some kind of ADR.2 We attributed this success to the close follow-up surveillance together with patient counselling and reassurance, which prompted an earlier identification of ADRs and their treatment with a consequent lower abandonment rate. Regarding the authors’ comments on individual resistance to ADRs, we agree that individual characteristics and resistance to ADRs may be an alternative explanatory variable for adherence rates. In fact, we have reported that educational level was able to predict overall ADRs.7 However, in the present study the retrospective design and the unavailability of data regarding educational level precluded some variables from being entered in the analysis, as already discussed in the published paper.2 Transparency declarations None to declare. References 1 Novaes RD, Gonçalves RV. Comment on: Benznidazole treatment safety: the Médecins Sans Frontières experience in a large cohort of Bolivian patients with Chagas’ disease. J Antimicrob Chemother  2018; 73: 1114– 5. 2 Sperandio da Silva GM, Mediano MFF, Hasslocher-Moreno AM et al.   Benznidazole treatment safety: the Médecins Sans Frontières experience in a large cohort of Bolivian patients with Chagas’ disease. J Antimicrob Chemother  2017; 72: 2596– 601. Google Scholar CrossRef Search ADS PubMed  3 Pérez-Molina JA, Molina I. Chagas disease. Lancet  2017; doi:10.1016/S0140-6736(17)31612-4. 4 Dias JCPJr, R Novaes A et al.   2nd Brazilian Consensus on Chagas Disease, 2015. Rev Soc Bras Med Trop  2016; 49 Suppl 1: 3– 60. Google Scholar CrossRef Search ADS   5 Morillo CA, Marin-Neto JA, Avezum A et al.   Randomized trial of benznidazole for chronic Chagas’ cardiomyopathy. N Engl J Med  2015; 373: 1295– 306. Google Scholar CrossRef Search ADS PubMed  6 Hasslocher-Moreno AM, do Brasil PEAA, de Sousa AS et al.   Safety of benznidazole use in the treatment of chronic Chagas’ disease. J Antimicrob Chemother  2012; 67: 1261– 6. Google Scholar CrossRef Search ADS PubMed  7 Sperandio da Silva GM, Mediano MFF, Alvarenga Americano do Brasil PE et al.   A clinical adverse drug reaction prediction model for patients with Chagas disease treated with benznidazole. Antimicrob Agents Chemother  2014; 58: 6371– 7. Google Scholar CrossRef Search ADS PubMed  8 Viotti R, Vigliano C, Lococo B et al.   Side effects of benznidazole as treatment in chronic Chagas disease: fears and realities. Expert Rev Anti Infect Ther  2009; 7: 157– 63. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Journal

Journal of Antimicrobial ChemotherapyOxford University Press

Published: Apr 1, 2018

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