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

Comment on: Benznidazole treatment safety: the Médecins Sans Frontières experience in a large... Sir, We read with great interest the paper of Sperandio da Silva et al.,1 recently published in the Journal of Antimicrobial Chemotherapy. The authors bring up an important discussion of the relationship between the occurrence of adverse effects and the rates of adherence to benznidazole-based antitrypanosomal therapy. In their retrospective study of 2075 patients, the authors reported that, in general, benznidazole administration was safe and associated with only 211 cases (10.2%) of treatment suspension, which occurred mainly in women (63%). The rate of adverse effects was high among patients who discontinued treatment (90%). However, although the occurrence of adverse effects in the other patients was also significant (52%), there was no apparent relationship to treatment suspension. Considering the relevance of the results for broadening the understanding of Chagas’ disease chemotherapy, we would like to comment on the study’s findings. Although the relationship between adverse effects and the therapeutic efficacy of benznidazole-based chemotherapy has often been discussed,2–5 this relationship must be contextualized considering that the clinical and parasitological outcomes of chemotherapy are directly influenced by the phase of infection.6 Although the treatment is effective and highly indicated for acute infections,6 the relevance of chemotherapy for the management of chronic infections is still controversial, especially considering that benznidazole seems to be unable to significantly reduce cardiac deterioration (Chagas’ cardiomyopathy) in chronically infected patients.7 Thus, characterization of the phases of infection in relation to the clinical outcomes would be of great value to the study of Sperandio da Silva et al.,1 allowing clarification of the rationale underlying the treatments administered. As long as this aspect remains poorly understood, there is still uncertainty about the extent to which the occurrence of adverse effects may compromise the results of chemotherapy. In this context, it would be prudent to discuss whether chemotherapy protocol adaptations may be necessary for individuals at higher risk of discontinuing treatment. In addition, there is evidence that the dose and period of treatment are related to the rates of adverse effects and benznidazole-based chemotherapy interruption.2 Although a period of treatment between 30 and 60 days is often recommended, the rational basis for this prescription is not clear and, in most cases, is based on clinical experience in different health centres. Thus, treatment protocols for 30 days, guided by negativization of the parasitaemia, control of drug bioaccumulation and fractionated doses,2 as well as intermittent doses, are recommended to minimize the risk of adverse effects.3 Although benznidazole serum level is a controversial predictor of adverse effects,4 fractionated doses (5.0–7.5 mg/kg/day for 30–60 days, divided into two or three doses per day) have been demonstrated to be effective and without toxic effects in adults.5 As the evidence is fragmented in heterogeneous studies reporting different chemotherapy protocols, the relationship between therapeutic efficacy and adverse effects remains uncertain, making it difficult to delimit the ideal characteristics of dosimetry. This aspect raises the consideration that treatment protocols may be more relevant to the occurrence of adverse effects than the intrinsic benznidazole toxicity, which is frequently overestimated. Considering that a relevant group of patients (52%) experienced adverse effects but did not discontinue treatment,1 the clinical significance of the signal and symptoms requires a complementary interpretation. In addition to a direct approach to the relationship between adverse effects and discontinuation of treatment, individual resistance to the adverse effects could be considered as an explanatory variable for adherence rates. Admitting that adherence to chemotherapy is strongly linked to the subjective perception of symptomatology, as well as the potential risks and benefits of treatment, information and early consultation can represent a simple and feasible measure to increase the chances of completing the chemotherapy protocol.2 More than a century after the discovery of Chagas’ disease, no drug more effective than benznidazole (developed more than 40 years ago) is available. Since this disease is closely related to poverty, it represents an unattractive market, far from the pharmaceutical priorities for drug development in relation to investment in research. As there is no vaccine for Chagas’ disease, and no prospects that one will be developed in the near future,8 health services should deal with the serious shortcomings of chemotherapy for this disease. Thus, as long as more effective and safer drugs are unavailable, the management of adverse effects and the identification of groups at greater risk of chemotherapy interruption represents a current challenge for the aetiological treatment of Chagas’ disease. Transparency declarations None to declare. References 1 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  2 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  3 Álvarez MG, Hernández Y, Bertocchi G et al.   New scheme of intermittent benznidazole administration in patients chronically infected with Trypanosoma cruzi: a pilot short-term follow-up study with adult patients. Antimicrob Agents Chemother  2015; 60: 833– 7. Google Scholar CrossRef Search ADS PubMed  4 Pinazo MJ, Guerrero L, Posada E et al.   Benznidazole-related adverse drug reactions and their relationship to serum drug concentrations in patients with chronic Chagas disease. Antimicrob Agents Chemother  2013; 57: 390– 5. Google Scholar CrossRef Search ADS PubMed  5 Soy D, Aldasoro E, Guerrero L et al.   Population pharmacokinetics of benznidazole in adult patients with Chagas disease. Antimicrob Agents Chemother  2015; 59: 3342– 9. Google Scholar CrossRef Search ADS PubMed  6 Cancado JR. Long term evaluation of etiological treatment of Chagas disease with benznidazole. Rev Inst Med Trop Sao Paulo  2002; 44: 29– 37. Google Scholar CrossRef Search ADS PubMed  7 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  8 Avery V. Ask the experts: drug discovery for the treatment of leishmaniasis, African sleeping sickness and Chagas disease. Future Med Chem  2013; 5: 1709– 18. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2017. 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

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

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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/dkx472
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Abstract

Sir, We read with great interest the paper of Sperandio da Silva et al.,1 recently published in the Journal of Antimicrobial Chemotherapy. The authors bring up an important discussion of the relationship between the occurrence of adverse effects and the rates of adherence to benznidazole-based antitrypanosomal therapy. In their retrospective study of 2075 patients, the authors reported that, in general, benznidazole administration was safe and associated with only 211 cases (10.2%) of treatment suspension, which occurred mainly in women (63%). The rate of adverse effects was high among patients who discontinued treatment (90%). However, although the occurrence of adverse effects in the other patients was also significant (52%), there was no apparent relationship to treatment suspension. Considering the relevance of the results for broadening the understanding of Chagas’ disease chemotherapy, we would like to comment on the study’s findings. Although the relationship between adverse effects and the therapeutic efficacy of benznidazole-based chemotherapy has often been discussed,2–5 this relationship must be contextualized considering that the clinical and parasitological outcomes of chemotherapy are directly influenced by the phase of infection.6 Although the treatment is effective and highly indicated for acute infections,6 the relevance of chemotherapy for the management of chronic infections is still controversial, especially considering that benznidazole seems to be unable to significantly reduce cardiac deterioration (Chagas’ cardiomyopathy) in chronically infected patients.7 Thus, characterization of the phases of infection in relation to the clinical outcomes would be of great value to the study of Sperandio da Silva et al.,1 allowing clarification of the rationale underlying the treatments administered. As long as this aspect remains poorly understood, there is still uncertainty about the extent to which the occurrence of adverse effects may compromise the results of chemotherapy. In this context, it would be prudent to discuss whether chemotherapy protocol adaptations may be necessary for individuals at higher risk of discontinuing treatment. In addition, there is evidence that the dose and period of treatment are related to the rates of adverse effects and benznidazole-based chemotherapy interruption.2 Although a period of treatment between 30 and 60 days is often recommended, the rational basis for this prescription is not clear and, in most cases, is based on clinical experience in different health centres. Thus, treatment protocols for 30 days, guided by negativization of the parasitaemia, control of drug bioaccumulation and fractionated doses,2 as well as intermittent doses, are recommended to minimize the risk of adverse effects.3 Although benznidazole serum level is a controversial predictor of adverse effects,4 fractionated doses (5.0–7.5 mg/kg/day for 30–60 days, divided into two or three doses per day) have been demonstrated to be effective and without toxic effects in adults.5 As the evidence is fragmented in heterogeneous studies reporting different chemotherapy protocols, the relationship between therapeutic efficacy and adverse effects remains uncertain, making it difficult to delimit the ideal characteristics of dosimetry. This aspect raises the consideration that treatment protocols may be more relevant to the occurrence of adverse effects than the intrinsic benznidazole toxicity, which is frequently overestimated. Considering that a relevant group of patients (52%) experienced adverse effects but did not discontinue treatment,1 the clinical significance of the signal and symptoms requires a complementary interpretation. In addition to a direct approach to the relationship between adverse effects and discontinuation of treatment, individual resistance to the adverse effects could be considered as an explanatory variable for adherence rates. Admitting that adherence to chemotherapy is strongly linked to the subjective perception of symptomatology, as well as the potential risks and benefits of treatment, information and early consultation can represent a simple and feasible measure to increase the chances of completing the chemotherapy protocol.2 More than a century after the discovery of Chagas’ disease, no drug more effective than benznidazole (developed more than 40 years ago) is available. Since this disease is closely related to poverty, it represents an unattractive market, far from the pharmaceutical priorities for drug development in relation to investment in research. As there is no vaccine for Chagas’ disease, and no prospects that one will be developed in the near future,8 health services should deal with the serious shortcomings of chemotherapy for this disease. Thus, as long as more effective and safer drugs are unavailable, the management of adverse effects and the identification of groups at greater risk of chemotherapy interruption represents a current challenge for the aetiological treatment of Chagas’ disease. Transparency declarations None to declare. References 1 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  2 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  3 Álvarez MG, Hernández Y, Bertocchi G et al.   New scheme of intermittent benznidazole administration in patients chronically infected with Trypanosoma cruzi: a pilot short-term follow-up study with adult patients. Antimicrob Agents Chemother  2015; 60: 833– 7. Google Scholar CrossRef Search ADS PubMed  4 Pinazo MJ, Guerrero L, Posada E et al.   Benznidazole-related adverse drug reactions and their relationship to serum drug concentrations in patients with chronic Chagas disease. Antimicrob Agents Chemother  2013; 57: 390– 5. Google Scholar CrossRef Search ADS PubMed  5 Soy D, Aldasoro E, Guerrero L et al.   Population pharmacokinetics of benznidazole in adult patients with Chagas disease. Antimicrob Agents Chemother  2015; 59: 3342– 9. Google Scholar CrossRef Search ADS PubMed  6 Cancado JR. Long term evaluation of etiological treatment of Chagas disease with benznidazole. Rev Inst Med Trop Sao Paulo  2002; 44: 29– 37. Google Scholar CrossRef Search ADS PubMed  7 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  8 Avery V. Ask the experts: drug discovery for the treatment of leishmaniasis, African sleeping sickness and Chagas disease. Future Med Chem  2013; 5: 1709– 18. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2017. 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.

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Journal of Antimicrobial ChemotherapyOxford University Press

Published: Apr 1, 2018

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