Characterization of adverse reactions to benznidazole in patients with Chagas disease in the Federal District, Brazil

Abstract INTRODUCTION: Benznidazole is used for treating Chagas disease (CD). This cross-sectional study aimed to characterize the adverse drug reactions (ADRs) of benznidazole at a public hospital in Brazil's Federal District. METHODS: Medical records were analyzed and ADRs were categorized by type, intensity, seriousness, and causality. RESULTS: Of the 62 patients who started benznidazole treatment for CD, 41 (66%) presented with 105 ADRs; 23 (37%) discontinued the treatment. Most reactions were classified as probable (81%), severe (63%), serious (67%), and dose-dependent (56%). CONCLUSIONS: The high incidence of ADRs because of treatment withdrawal revealed the need for safer alternatives for CD treatment.

Pharmacotherapeutic follow-up of patients with Chagas disease using benznidazole: drug-related problems and pharmaceutical interventions

Abstract INTRODUCTION Benznidazole (BNZ) is a drug available for the etiological treatment of Chagas disease. However, this drug is toxic and has a limited effectiveness on the chronic phase of this disease, often leading to poor treatment adherence. METHODS: This is a descriptive and exploratory study conducted at the Pharmaceutical Care Service for Chagas disease patients of the Federal University of Ceará. Drug-related problems (DRPs) and pharmaceutical interventions (PIs) were classified according to the Second Consensus of Granada. RESULTS: The average age of patients with Chagas disease was 62 years, with the majority residing in the Ceará countryside (86.7%), and having low education levels (63.3% with elementary school education). Regarding family income, most patients belonged to a household that earned ≤1-2 times the minimum wage per month. Approximately 73% of these patients complied with the BNZ treatment, and nearly 7% underwent therapy interruption after medical evaluation. A total of 189 DRPs were identified, of which 51.9% (n=98) were classified as potential, and 48.1% (n=91) as actual. The most frequent DRPs were related to safety (qualitative safety; n=70; 37%), necessity (non-adherence; n=52; 27.5%), and effectiveness (qualitative effectiveness/non-optimal drug selection; n=45; 23.8%). Among the 216 PIs conducted, the majority were related to patient education (n=168; 77.8%) and pharmacological strategy (n=42; 19.4%). CONCLUSIONS: This study indicates the need for pharmacotherapeutic monitoring in patients with Chagas because of the high number of therapeutic interventions, DRPs (approximately 3 DRPs/patient), BNZ adherence, and polypharmacy.

Experiencia terapéutica en un centro para la enfermedad de Chagas / Therapeutic experience in a Chagas disease center

American Trypanosomiasis or Chagas Disease is a major public health problem, endemic in the American continent since prehistoric times. Its natural course is towardschronicity in the immunocompetent host, often leading to severe cardiopathy or bowelinvolvement. Pharmacologic therapy is restricted to two drugs and only one of themis currently available in Chile. Both have poor effectiveness in the chronic stages ofthe disease and cause frequent adverse reactions. Many physicians avoid their use,despite published evidences about the usefulness. We herein report the experienceof our Center in the treatment of Chronic Chagas Disease in adults using the drugnifurtimox, emphasizing its degree of acceptability and its secondary effects.

Estado actual en el tratamiento de la enfermedad de Chagas / Update on the treatment of Chagas' disease

Efficient drugs against Chagas' disease must have an effect on the amastigote forms or intracellular reproduction elements of Trypanosoma cruzi (T. cruzi). Trypomastigote and epimastigote forms derive from the former and their response to medications is less marked. The only drugs used in humans are nifurtimox (NF) and benznidazole (BNZ). Other useful medications are allopurinol and itraconazole. NF acts producing free radicals and BNZ inhibits the synthesis of macromolecules. There is consensus that Chagas' disease must be treated in all its periods, since T.cruzi DNA is detected by polymerase chain reaction in chronic cases, even when microscopy is negative. The pharmacological treatment modifies the natural evolution of the disease. It also helps to solve a public health problem, considering that there is a high number of subjects with Chagas' disease. Subjects with chronic chagasic cardiomyopathy with terminal heart failure are the only cases without indication for treatment. Due to the digestive and skin secondary effects of the drugs, treated patients must be controlled clinically and with complete blood counts and hepatic proiles before, during and after the therapy. Approximately 30 percent of patients will experience secondary effects. Children have a better tolerance to the drugs. Congenital or acquired acute, intermediate and chronic cases should be treated.

Reações adversas em pacientes com doença de Chagas tratados com benzonidazol, no Estado do Ceará / Adverse reactions in Chagas disease patients treated with benznidazole, in the State of Ceará

INTRODUÇÃO: A doença de Chagas, causada pelo Trypanosoma cruzi, é tratada com benzonidazol, tendo o inconveniente de apresentar efetividade parcial e alta toxicidade, que varia desde reações de hipersensibilidade a aplasia medular. O objetivo foi descrever e avaliar a ocorrência de reações adversas em pacientes chagásicos em tratamento com benzonidazol em Fortaleza, Ceará. MÉTODOS: Estudo descritivo prospectivo envolvendo 32 pacientes chagásicos crônicos tratados com benzonidazol entre janeiro de 2005 e abril de 2006. Dados sociodemográficos e clínicos foram coletados de questionários, entrevistas e exames laboratoriais. As amostras de sangue foram coletadas antes, com 30 e 60 dias de tratamento. RESULTADOS: Reações adversas foram relatadas em 28 (87,5 por cento) pacientes tratados, tendo sido as mais frequentes: prurido (50 por cento), formigamento (43,8 por cento), fraqueza muscular (37,5 por cento) e rash cutânea (31,3 por cento). Dos 28 pacientes com reações adversas, oito (28,57 por cento) interromperam o tratamento. Reações adversas que culminaram com a suspensão do tratamento foram formigamento sete (87,5 por cento) ou erupção cutânea cinco (62,5 por cento). Observou-se aumento discreto dos níveis de aminotransferases durante o tratamento em (9,4 por cento) pacientes. CONCLUSÕES: Concluindo, o acompanhamento farmacoterapêutico dos pacientes chagásicos é de grande relevância na prevenção e detecção precoce das reações adversas a medicamentos.

INTRODUCTION: Chagas disease is caused by Trypanosoma cruzi and treated with benznidazole (BNZ). This drug has the troublesome features of presenting partial effectiveness and high toxicity ranging from hypersensitivity reactions to medullary aplasia. The objective here was to describe and evaluate the occurrence of adverse reactions in Chagas disease patients treated with benznidazole in Fortaleza, Ceará. METHODS: This was a prospective descriptive study involving 32 chronic Chagas patients treated with benznidazole between January 2005 and April 2006. Sociodemographic and clinical data were collected through questionnaires, interviews and laboratory tests. Blood samples were collected before treatment and after 30 and 60 days of treatment. RESULTS: Adverse reactions were reported in 28 patients (87.5 percent) patients and the most frequent of these were pruritus (50 percent), prickling (43.8 percent), muscle weakness (37.5 percent) and skin rash (31.3 percent). Out of the 28 patients with adverse reactions, eight (28.57 percent) discontinued their treatment. The adverse reactions that culminated with discontinuation of the treatment were prickling (7; 87.5 percent) or skin eruptions (5; 62.5 percent). There was a slight increase in aminotransferase levels during the treatment in 9.4 percent of the patients. CONCLUSIONS: Following up the drug therapy administered to Chagas patients is of great importance for prevention and early detection of adverse reactions to drugs.

Treatment and seroconversion in a cohort of children suffering from recent chronic Chagas infection in Yoro, Honduras

Between 1999-2002, Médécins Sans Frontières-Spain implemented a project seeking to determine the efficacy and safety of benznidazole in the treatment of recent chronic Chagas disease in a cohort of seropositive children in the Yoro Department, Honduras. A total of 24,471 children were screened for Trypanosoma cruzi IgG antibodies through conventional enzyme-linked immunosorbent assays (ELISA) on filter paper. Recombinant ELISA (0.93 percent seroprevalence) showed 256 initially reactive cases, including 232 confirmed positive cases. Of these, 231 individuals were treated with benznidazole (7.5 mg/kg/day) for 60 days and were followed with a strict weekly medical control and follow-up protocol. At the end of the project, 229 patients were examined by the Honduras Secretariat of Health for post-treatment serological assessments; 88.2 percent seroconverted after 18 months and 93.9 percent seroconverted after three years. No differences were found in the seroconversion rates according to age or sex. Most of the side effects of the treatment were minor. These results support the argument that in areas where T. cruzi I is predominant and in areas affected by T. cruzi II, when vector transmission has been interrupted, Chagas disease diagnosis and treatment are feasible, necessary and ethically indisputable.

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

The efficacy of treatment with nifurtimox and/or benznidazole among adults with chronic Chagas disease with no previous electrocardiographic disturbances was evaluated over a mean follow-up of 21 years, by means of conventional serology, xenodiagnosis, clinical examination, electrocardiograms and chest X-ray. One hundred and eleven patients, between 17 and 46 years old, were studied: 54 underwent treatment (nifurtimox 27, benznidazole 27) and 57 remained untreated (control group). Xenodiagnosis was performed on 65 percent of them: 36/38 of the treated and 9/34 of the untreated patients had previous positive xenodiagnosis. Post-treatment, 133 xenodiagnoses were performed on 41 patients, all resulting negative. In the control group, 29 xenodiagnoses were performed on 14 patients; 2 resulted positive. Sera stored during the follow-up were simultaneously analyzed through conventional serology tests (IHA; DA-2ME; IIF). The serological evolution in the treated group was: a) 37 percent underwent negative seroconversion (nifurtimox 11, benznidazole 9); b) 27.8 percent decreased titers (nifurtimox 9, benznidazole 6), 9 showed inconclusive final serology (nifurtimox 7, benznidazole 2); c) 35.2 percent remained positive with constant titers (nifurtimox 7; benznidazole 12). The control group conserved the initial antibody levels during the follow-up. In the clinical evolution, 2/54 (3.7 percent) of the treated and 9/57 (15.8 percent) of the untreated patients showed electrocardiographic disturbances attributable to Chagas myocardiopathy, with a statistically relevant difference (p<0.05). Treatment caused deparasitation in at least 37 percent of the chronically infected adults and a protective effect on their clinical evolution.

Avaliamos a eficácia do nifurtimox e/ou benznidazol, durante 21 anos em média, em adultos chagásicos crônicos sem alterações eletrocardiográficas iniciais, mediante sorologia convencional, xenodiagnóstico, exames clínicos, eletrocardiográficos e radiografia do tórax. Estudamos 111 pacientes (17 a 46 anos): 54 foram tratados (27 com nifurtimox e 27 com benznidazol) e 57 formaram o grupo controle. Foram submetidos ao xenodiagnóstico 65 por cento dos pacientes estudados: 36/38 tratados e 9/34 do grupo controle com xenodiagnóstico positivo prévio. Após tratamento, foram realizados 133 xenodiagnósticos em 41 pacientes, sendo todos negativos. Foram realizados 29 xenodiagnósticos em 14 pacientes do grupo controle, 2 foram positivos. A sorologia convencional foi realizada em soros estocados durante o seguimento. Evolução sorológica. Grupo tratado: a) 37 por cento negativaram (nifurtimox 11, benznidazol 9); b) 27,8 por cento diminuíram a titulação (nifurtimox 9, benznidazol 6), 9 deles apresentaram sorologia final discordante (nifurtimox 7, benznidazol 2; c) 35,2 por cento permaneceram positivos com titulação constante (nifurtimox 7, benznidazol 12). Grupo controle: conservou os níveis iniciais de anticorpos durante o seguimento. Evolução clínica: 2/54 (3,7 por cento) pacientes tratados e 9/57 não tratados apresentaram alterações eletrocardiográficas atribuíveis a miocardiopatia chagásica. Diferenças estatisticamente significantes (p<0,05). O tratamento produziu efeito de combate ao parasita em pelo menos 37 por cento dos infetados crônicos adultos e efeito protetor na evolução clínica.

Estudo comparativo controlado com emprego de benznidazole, nifurtimox e placebo, na forma crônica da doença de Chagas, em uma área de campo com transmissäo interrompida: I. avaliaçäo preliminar / A controlled comparative study using benznidazole, nifurtimox and placebo in chronic Chaga's disease patients, in a field area with interrupted transmission: I. preliminary evaluation

Foi realizado um estudo controlado para avaliar a eficácia terapêutica e a tolerância do nifurtimox e do benznidazole em pacientes com a doença de Chagas crônica. Todos os pacientes tinham as reaçöes de imunofluorescência e fixaçäo do complemento positivas para anticorpos anti-T. cruzi e pelo menos dois xenodiagnósticos positivos em três realizados, antes do tratamento, e foram submetidos a exames clínicos, eletrocardiográficos do coraçäo e do esôfago. De 77 pacientes estudados, 27 foram tratados com nifurtimox, 26 com benznidazole, ambos na dose de 5mg/kg/dia, durante 30 dias consecutivos, e 24 receberam um placebo em comprimidos semelhantes aos do benznidazole. Dos 77 pacientes, 64 (83,1 por cento) completaram o tratamento: 23 (88,4 por cento) com benznidazole, 19 (70,3 por cento) com niturtimox e 22 (91,6 por cento) com placebo. Os pacientes foram avaliados clinicamente, sorologicamente e parasitologicamente (seis xenodiagnósticos no período de um ano após o tratamento). O grupo do benznidazole mostrou apenas 1,8 por cento de xenodiagnósticos positivos pós-tratamento, o grupo do nifurtimox 9,6 por cento e o do placebo 34,3 por cento. Todas as reaçöes sorológicas continuam positivas e näo houve alteraçöes clínicas, eletrocardiográficas ou radiológicas um ano após o tratamento