Summary of main results

We included two studies in this update. Coura 1997 compared treatment with nifurtimox or benznidazole with placebo for the clearance of parasitaemia. Infection was assessed using indirect immunofluorescence in a screening assay followed by positive complement fixation as well as confirmatory parasitologic assay (at least two out of the three positive xenodiagnosis results). Twenty‐six participants were randomly assigned to benznidazole 5 mg/kg/day, 27 to nifurtimox 5 mg/kg/day, and 24 to placebo for 30 days. Morillo 2015 included 2854 participants with late‐stage, symptomatic Chagas disease and CCC: 1431 participants were randomly assigned to benznidazole 300 mg/day for 40 to 80 days, and 1423 to placebo. We also identified one ongoing study (NCT03191162).

Benznidazole compared to placebo

Low quality of the evidence from the BENEFIT study trial, Morillo 2015, suggests there may be a benefit of benznidazole when compared to placebo for clearance or reduction of antibody titres at 12 months (RR 1.91, 95% CI 1.64 to 2.21), 2 years (RR 1.44, 95% CI 1.29 to 1.60), and 5 years (RR 1.25, 95% CI 1.14 to 1.37). This shows that the effect of the intervention declines over time as a result of the natural reduction of the antibodies titres as an individual immune response rather than as the effect of the imidazolic treatment.

Due to very limited evidence, we are uncertain about the effects of benznidazole on the clearance of parasitaemia demonstrated by negative xenodiagnosis, blood culture, and/or molecular assays.

Low quality of the evidence suggests that benznidazole may make little to no difference for the risk of heart failure and ventricular tachycardia when compared to placebo.

Moderate quality of the evidence shows that adverse events increase with benznidazole when compared to placebo. 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 pathological demonstration of tissue parasites and quality of life.

Nifurtimox compared to placebo

The only outcome with data available for this comparison was clearance or reduction of antibody titres in Coura 1997, with an RR of 16.89 (95% CI 2.44 to 116.85; P = 0.004; 1 trial; 51 participants). Even though the estimated RR is large in favour of nifurtimox efficacy, we are uncertain about the effect due to very limited evidence to establish the effectiveness of nifurtimox for the treatment of late‐stage, symptomatic Chagas disease and CCC.

Regarding adverse events, Coura 1997 mentioned in a general manner that nifurtimox caused more intense adverse events than benznidazole, without any quantification.

Overall completeness and applicability of evidence

This review included only two randomised clinical trials. The purpose of both studies was to clarify the therapeutic role of the nitrofuran and imidazole drugs in late‐stage, symptomatic Chagas disease and CCC; however, it was not possible to conduct a meta‐analysis due to the small number of trials identified. Furthermore, due to the low level of certainty, especially in relation to the effect of nifurtimox compared to placebo, since only 51 participants were included, only one study was reviewed, and there is a high risk of bias. Consequently, for this outcome, it remains uncertain whether the use of this type of drugs in the chronic phase has no effect once Chagas disease has provoked organ damage, and is pending further corroboration that may come from the currently ongoing study.

Quality of the evidence

It is important to note that there is a gap of almost 20 years between the two RCTs included in this review. This is significant because the burden and costs of the chronic diseases were finally accepted by health authorities in most Latin American countries. With this in mind, the quality of evidence of the first RCT may be questionable, since sources of financing were scarce, and most studies were conducted with limited resources. Consequently, selection bias may have been introduced; random allocation and concealment are not explained; attrition bias regarding adverse events was introduced; and outcome data are incomplete (Coura 1997). The second study is a multicentric RCT with a sample of 2854 participants with late‐stage, symptomatic Chagas disease and CCC, from five endemic countries, with a long follow‐up (up to seven years). Random allocation and concealment were detailed; adverse events were fully informed; and attrition bias may have occurred in relation to the PCR test since only 66% of participants were tested (Morillo 2015). We judged that this study has a low or unclear risk of bias.

Potential biases in the review process

We followed standard Cochrane methodology in order to avoid duplication and publication bias; there were no restrictions regarding the language or date of publication. The review was undertaken by three review authors working independently. We attempted to contact study authors in order to obtain missing data; however, one of the trials was published almost 20 years ago. Since Chagas disease is a neglected tropical disease, with little interest from the authorities, limited studies are conducted in relation to the efficacy of parasitological cure in the late‐stage of the disease (Tarleton 2014).

Agreements and disagreements with other studies or reviews

Human infection with T cruzi induces an immune response in most human hosts, but a chronic indolent infection is common. A proportion of the infected people develop late‐stage, symptomatic Chagas disease with two main clinical patterns: heart disease or dilated gastrointestinal 'mega' syndromes. Chronic chagasic cardiomyopathy may produce a progressive heart disease characterised by rhythm and conduction disorders with or without dilated cardiomyopathy. Both high morbidity and mortality of people with these manifestations of Chagas disease is common.

Interventions to treat Chagas disease were initiated shortly after its description early in the 20th century. However, they were unsuccessful for 50 years. In 1962, the first useful drug treatment was found using animal models – a nitrofuran derivative marketed as Nifurtimox – and was shortly followed by the imidazole drug benznidazole, both of which have become the cornerstone of treatment of American trypanosomiasis. Good results have been found in acute infections, with the absence of parasitaemia in most treated patients and remission of serologic response. These drugs are now used in recently infected children, in cases of laboratory needle stick injuries resulting in acute infection, as well as in iatrogenic infection through contaminated blood products (Rodriguez‐Coura 2002; Stoppani 1999; Urbina 1999).

In questioning the efficacy of nifurtimox and benznidazole in the treatment of late‐stage, symptomatic Chagas disease and CCC, we found only two controlled clinical trials. We did not find strong evidence that standard treatment with either nifurtimox or benznidazole in individuals with late‐stage T cruzi infection is beneficial.

A major problem in conducting trials and interpreting long‐term prognostic studies is the issue of criteria to define cure. For example, some studies have shown a significant reduction of blood antibodies and fewer ECG abnormalities in chronically infected patients treated with benznidazole compared to a placebo group, and interpreted this as an indication of a delay in tissue damage (Moretti 1998; Segura 1994; Viotti 1994). A clinical criteria for cure requires the disappearance of parasitaemia, but this is not easy to demonstrate in chronic cases, with the sensitivity of haemoculture or xenodiagnosis being no more than 50% at best. Inclusion of this criterion is clearly insufficient to determine the efficacy of drug treatment, and, perhaps not surprisingly, most papers have failed to demonstrate any reduction in parasitaemia (Contijo 1999; Urbina 1999).

The diagnosis of Chagas disease has limitations, mainly due to the great complexity of the factors involved in it, as well as the low sensitivity of parasitological techniques and the low specificity of immunological tests, such as those used in the two studies included in this review. Circulating antibodies against T cruzi is a diagnostic hallmark of chronic infection. The disappearance of antibodies has been used as a clinical cure criterion in acute disease, but does not occur in the chronic Chagas disease. The current established criteria to define cure in CCC may be insufficient and outdated. New developments in molecular biology have further challenged the existing clinical cure criteria. Parasite DNA can now be clearly demonstrated in several tissues, thereby reinforcing the notion of parasite persistence (despite apparent clinical cure) and its possible role as an inducer of an immune response. Changes in Trypanosoma cruzi‐specific immune response after treatment with benznidazole have been proven by Laucella and colleagues (Laucella 2009), who found a significant decline of peripheral interferon (IFN) gamma‐producing T cells specific for T cruzi as early as 12 months after benznidazole treatment and which became undetectable in a substantial proportion of treated participants. Finally, further RCTs are needed that consider the application of immunomics, which combines serology with proteomics. This would help to discover genes and molecules related to the susceptibility and immunity of T cruzi infection, allowing the creation of an adequate diagnosis of the disease, elucidating new targets and therapies, and, why not, making possible the creation of a vaccine against Chagas disease (Lopez‐Monteon 2019).

Both nifurtimox and benznidazole are linked to adverse reactions (peripheral neuropathy, skin disorders, and other health problems) in a relatively high proportion of users. This indicates the need for safer and effective drugs for late‐stage, symptomatic Chagas disease and CCC, where treatment is likely to be long term. On balance, the limited findings of this review cast doubt on the efficacy of treatment for CCC with either nifurtimox or benznidazole, but do provide modest evidence of potential harm from adverse effects.

We also identified non‐RCTs as follows.

A study was conducted in Brazil with 17 patients who had completed full treatment with antitrypanosomal drugs (nitrofurans or nitroimidazole 10 mg/kg/day) and were age‐ and sex‐matched with patients from a cohort study of chronic chagasic cardiomyopathy patients, all of whom showed immunological and/or serological assay evidence of T cruzi. The aim was to determine whether serological or immunological cures correlate with molecular methods of diagnosis. Although the study was not randomised, and patients and physicians were not blinded to treatment allocation, the investigators made the useful observation that despite apparent cure through immunological/serological outcome measures, the molecular markers persisted. This indicated that parasites were not eliminated after treatment with nitrofuran derivatives (Braga 2000). A further paper using the same cohort of patients reported the findings of a 10‐year follow‐up of 91 people with chronic chagasic cardiomyopathy and 41 uninfected controls. Using molecular methods of competitive PCR, they found that both treated and untreated patients showed evidence of active infection (Lauria‐Pires 2000).

Dr Viotti and colleagues have been screening patients with Chagas disease in the Chagas disease section at Eva Peron Hospital in Buenos Aires, Argentina since 1984, and have recruited almost 2000 patients during this period. The treatment of Chagas disease has been a major concern, therefore in 1994 a published study aiming to compare the clinical and serological progress of cardiomyopathy in patients treated with benznidazole and untreated individuals was undertaken. Seventy untreated patients and 131 benznidazole‐treated patients (5 mg/kg/day for 30 days) were recruited. The follow‐up period averaged eight years. The proportion of patients who were serologically negative at the end of follow‐up was higher in the treated group than in the untreated group (19.1% versus 6%; P = 0.05). The investigators concluded that treatment with benznidazole decreases antibody titres if treatment is used early in the course of chronic chagasic cardiomyopathy (Viotti 1994).

Due to the chronic implications of Chagas disease, the effectiveness of treatment has been widely studied. In a 2006 study of 566 undetermined patients 30 to 50 years old with three positive serologies and without heart failure, 283 were treated with benznidazole (5 mg/kg/day for 30 days) and the same number remained untreated. The authors concluded that treatment of Chagas disease in the early stage of the illness prevents progression towards cardiac manifestations and increases negative seroconversion (Viotti 2006).

In a further study of patients who became seronegative, either spontaneously or by parasitological treatment, clinical and epidemiological progression features of Chagas disease were analysed. The authors concluded that the parasitological cure is a favourable clinical course (Bertocchi 2013). Although the effectiveness of benznidazole has been widely proven, its adverse reactions have been a major cause of concern. Consequently, developing new drugs and new schemes of treatment is integral.

In 2016, Viotti's research team conducted a pilot study to assess the efficiency of a new treatment scheme with benznidazole for individuals with chronic Chagas disease. Twenty patients were included; however, 17 were tested by PCR. All patients received 5 mg/kg/day in 2 daily doses every 5 days for 60 days. Parasitological cure was achieved in 65% of patients, whilst 50% had adverse reactions, and only one patient suspended treatment. The authors concluded that the low rate of treatment suspension was a major accomplishment of this study. However, further studies are required to confirm these results in longitudinal assessments (Alvarez 2016).

A further study from Argentina followed 198 people drawn from a larger cohort of 492 patients that had suffered attrition due to losses to follow‐up, with the aim of examining the prognosis of chronic Chagasic cardiomyopathy in treated and untreated groups undergoing prolonged follow‐ups. There were three groups: a) 32 patients treated with nifurtimox (5 to 8 mg/kg/day for 60 days); b) 36 patients treated with benznidazole (5 mg/kg/day for 30 days); and c) 130 untreated patients. All patients underwent the following tests at the beginning or during the follow‐up of the cohort study: a) three serological Chagas‐specific tests (Direct agglutination with 2‐mercaptoethanol (DA‐2ME), Indirect Haemoagglutination (IHA), or Indirect Immunofluorescence (IIF)) with titers equal to or higher than 1/32 for at least two out of the three reactions; and b) electrocardiogram and chest X‐ray.

The patients were followed for an average of 14 years (8 to 32 years). At the outset, only 9.6% of the infected patients had cardiomyopathy; however, when comparing treated and untreated patients, the proportion of cardiomyopathy was higher in the former group (7% versus 3.2%) and reflects the use of drug treatment in those with symptomatic disease. The clinical prognosis was worse in the untreated group, with less likelihood of reductions in antibody titres (≤ 1/64 in 86% versus 38% of treated and untreated patients, respectively). These long‐term findings suggest that drug treatment is superior to no treatment (Fabbro 2000).

A further long‐term follow‐up (13 to 21 years) was reported in which the prognosis of acute and chronic Chagas disease was compared, with all patients receiving benznidazole. The cure criteria were established by means of quantitative serological tests that included: to complement fixation, indirect immunofluorescence, indirect haemagglutination, and ELISA. However, given the duration of follow‐up, not all of these tests were used in all of the patients. The cure rate was higher in patients with acute disease (76%) than in those with chronic disease (8% to 9%). It was concluded that the cure criteria should include parasitological as well as immunological criteria, and that new immunological tests have opened a door to a different way of studying the natural history of Chagas disease. It is challenging to make any inferences about the effects of treatment in this study since there was no randomised control group, neither patients nor physicians were blind to the treatment group, and the criteria for cure changed over the follow‐up (Cancado 2002; Schijman 2011).