From a systematic review framework, we analysed the clinical evidence on the effectiveness and safety of monotherapy and combination chemotherapy for Chagas disease (ChD) treatment. The research protocol was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and patient, intervention, comparison and outcome strategy. Only randomized controlled trials (RCT) were retrieved from Embase, Medline, Scopus and Web of Science databases. Diagnostic tools, treatment protocols, seroconversion rates and adverse events were investigated. Fifteen RCT mainly concentrated in endemic countries were identified. ChD diagnosis was mainly based on haemagglutination, immunofluorescence, enzyme-linked immunosorbent assay and polymerase chain reaction. Benznidazole (BNZ), nifurtimox, fosravuconazole, posaconazole, allopurinol and thioctic acid were the identified drugs. The best negative seroconversion results (100, 96, 94 and 91.3%) were, respectively, based on BNZ (5 mg kg day−1, 200 mg day−1, 150 mg day−1 and 2.5 mg kg−1) administration for 60 days. Negative seroconversion was not achieved with allopurinol (300 mg day−1 for 60 days). Adverse reactions ranged from 5 to 73% in patients receiving antiparasitic chemotherapy. Treatment discontinuation (1.5–57%) was mainly associated with gastrointestinal, cutaneous and neurological manifestations. Current RCT-based evidence indicates that BNZ is the most viable option for ChD treatment. However, new protocols need to be developed to mitigate side effects and increase patient adherence to antiparasitic chemotherapy. Therefore, shorter regimens, lower concentrations and treatments combining BNZ with posaconazole, fosravuconazole or ravuconazole may be viable to ensure comparable efficacy to BZN-based monotherapy, contributing to reduce dose- and time-dependent toxicity reactions.
BACKGROUND: People with Chagas disease may develop progressive and lethal heart conditions. Drugs to eliminate the parasite Trypanosoma cruzi (T cruzi) currently carry limited therapeutic value and are used in the early stages of the disease. Extending the use of these drugs to treat chronic chagasic cardiomyopathy (CCC) has also been proposed.
OBJECTIVES: To assess the benefits and harms of nitrofurans and trypanocidal drugs for treating late-stage, symptomatic Chagas disease and CCC in terms of blood parasite reduction or clearance, mortality, adverse effects, and quality of life.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and LILACS databases on 12 November 2019. We also searched two clinical trials registers, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), on 3 December 2019.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) assessing trypanocidal drugs versus placebo or no treatment for late-stage, symptomatic Chagas disease and CCC.
DATA COLLECTION AND ANALYSIS: We conducted the reporting of the review according the standard Cochrane methods. Two review authors independently retrieved articles, performed data extraction, and assessed risk of bias. Any disagreements were resolved by a third review author. We contacted study authors for additional information.
MAIN RESULTS: We included two studies in this review update. One RCT randomly assigned 26 participants to benznidazole 5 mg/kg/day; 27 participants to nifurtimox 5 mg/kg/day; and 24 participants to placebo for 30 days. The second RCT, newly included in this update, randomised 1431 participants to benznidazole 300 mg/day for 40 to 80 days and 1423 participants to placebo. We also identified one ongoing study. Benznidazole compared to placebo At five-year follow-up, low quality of the evidence suggests that there may be a benefit of benznidazole when compared to placebo for clearance or reduction of antibody titres (risk ratio (RR) 1.25, 95% confidence interval (CI) 1.14 to 1.37; 1 trial; 1896 participants). We are uncertain about the effects of benznidazole for the clearance of parasitaemia demonstrated by negative xenodiagnosis, blood culture, and/or molecular assays due to very limited evidence. Low quality of the evidence suggests that when compared to placebo, benznidazole may make little to no difference in the risk of heart failure (RR 0.89, 95% CI 0.69 to 1.14; 1 trial; 2854 participants) and ventricular tachycardia (RR 0.80, 95% CI 0.51 to 1.26; 1 trial; 2854 participants). We found moderate quality of the evidence that adverse events increase with benznidazole when compared to placebo (RR 2.52, 95% CI 2.09 to 3.03; 1 trial; 2854 participants). Adverse effects were observed in 23.9% of patients in the benznidazole group compared to 9.5% in the placebo group. The most frequent adverse effects were: cutaneous rash, gastrointestinal symptoms, and peripheral polyneuropathy. No data were available for the outcomes of pathological demonstration of tissue parasites and quality of life. Nifurtimox compared to placebo Data were only available for this comparison for the outcome clearance or reduction of antibody titres, and we are uncertain about the effect due to very limited evidence. Regarding adverse events, one RCT mentioned in a general manner that nifurtimox caused intense adverse events, without any quantification.
AUTHORS' CONCLUSIONS: There is insufficient evidence to support the efficacy of the trypanocidal drugs benznidazole and nifurtimox for late-stage, symptomatic Chagas disease and CCC.
Background: Most Chagas patients belong to the chronic indeterminate stage, in which pharmacological treatment has an inconclusive outcome. Objective: To evaluate the efficacy of nifurtimox treatment in chronic asymptomatic Trypanosoma cruzi infection. Methods: We performed a systematic review and meta-analysis of electronically published literature, with no language, type of study, age or gender restrictions, until September 2010. Studies of chronic asymptomatic Chagas disease patients treated exclusively with nifurtimox were included in the analysis. Treatment efficacy was evaluated using parasitological or serological parameters. Results: Of 463 identified studies, 7 were finally selected: 6 observational studies and 1 randomized clinical trial; 4 of the studies were in adults, 3 in children < 14 years. In 6 studies, outcomes were defined by serological techniques. Summary estimate (log odds) was 0.37 (CI9 -1.32 - 2.07). Conclusions: The analyzed studies gave discordant results. Those might be explained by differences in the populations studied, follow-up periods, diagnostic techniques, and sample size. More studies are necessary to obtain conclusive results about treatment efficacy of nifurtimox in this clinical phase of T. cruzi infection.
CONTEXT: Because of population migration from endemic areas and newly instituted blood bank screening, US clinicians are likely to see an increasing number of patients with suspected or confirmed chronic Trypanosoma cruzi infection (Chagas disease). OBJECTIVE: To examine the evidence base and provide practical recommendations for evaluation, counseling, and etiologic treatment of patients with chronic T cruzi infection. Evidence Acquisition Literature review conducted based on a systematic MEDLINE search for all available years through 2007; review of additional articles, reports, and book chapters; and input from experts in the field. EVIDENCE SYNTHESIS: The patient newly diagnosed with Chagas disease should undergo a medical history, physical examination, and resting 12-lead electrocardiogram (ECG) with a 30-second lead II rhythm strip. If this evaluation is normal, no further testing is indicated; history, physical examination, and ECG should be repeated annually. If findings suggest Chagas heart disease, a comprehensive cardiac evaluation, including 24-hour ambulatory ECG monitoring, echocardiography, and exercise testing, is recommended. If gastrointestinal tract symptoms are present, barium contrast studies should be performed. Antitrypanosomal treatment is recommended for all cases of acute and congenital Chagas disease, reactivated infection, and chronic T cruzi infection in individuals 18 years or younger. In adults aged 19 to 50 years without advanced heart disease, etiologic treatment may slow development and progression of cardiomyopathy and should generally be offered; treatment is considered optional for those older than 50 years. Individualized treatment decisions for adults should balance the potential benefit, prolonged course, and frequent adverse effects of the drugs. Strong consideration should be given to treatment of previously untreated patients with human immunodeficiency virus infection or those expecting to undergo organ transplantation.
CONCLUSIONS: Chagas disease presents an increasing challenge for clinicians in the United States. Despite gaps in the evidence base, current knowledge is sufficient to make practical recommendations to guide appropriate evaluation, management, and etiologic treatment of Chagas disease.
Comment in
From a systematic review framework, we analysed the clinical evidence on the effectiveness and safety of monotherapy and combination chemotherapy for Chagas disease (ChD) treatment. The research protocol was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and patient, intervention, comparison and outcome strategy. Only randomized controlled trials (RCT) were retrieved from Embase, Medline, Scopus and Web of Science databases. Diagnostic tools, treatment protocols, seroconversion rates and adverse events were investigated. Fifteen RCT mainly concentrated in endemic countries were identified. ChD diagnosis was mainly based on haemagglutination, immunofluorescence, enzyme-linked immunosorbent assay and polymerase chain reaction. Benznidazole (BNZ), nifurtimox, fosravuconazole, posaconazole, allopurinol and thioctic acid were the identified drugs. The best negative seroconversion results (100, 96, 94 and 91.3%) were, respectively, based on BNZ (5 mg kg day−1, 200 mg day−1, 150 mg day−1 and 2.5 mg kg−1) administration for 60 days. Negative seroconversion was not achieved with allopurinol (300 mg day−1 for 60 days). Adverse reactions ranged from 5 to 73% in patients receiving antiparasitic chemotherapy. Treatment discontinuation (1.5–57%) was mainly associated with gastrointestinal, cutaneous and neurological manifestations. Current RCT-based evidence indicates that BNZ is the most viable option for ChD treatment. However, new protocols need to be developed to mitigate side effects and increase patient adherence to antiparasitic chemotherapy. Therefore, shorter regimens, lower concentrations and treatments combining BNZ with posaconazole, fosravuconazole or ravuconazole may be viable to ensure comparable efficacy to BZN-based monotherapy, contributing to reduce dose- and time-dependent toxicity reactions.
