Background
American Trypanosomiasis, or Chagas disease (Chagas 1909), is caused by a flagellate protozoan parasite, Trypanosoma cruzi. The geographical distribution of the human T.cruzi infection extends from Southern United States and Mexico to the south of Argentina. The disease affects 16 - 18 million people and it is estimated that 100 million i.e. about 25% of the population of Latin America is at risk of acquiring Chagas disease (WHO 1991).
People are infected with Chagas disease by the following routes.
(a) Vectoral transmission: T.cruzi parasites, living in the gut of the Triatomine insects enter the bloodstream through the bite of the insect. Triatomine bugs live in cracks and crevices of poor-quality houses usually in rural areas, emerge at night to bite and extract blood from human hosts. T.cruzi parasites are present in insect faeces deposited during the blood meal and enter the bloodstream through the wound when it is scratched or rubbed.
(b) Transfusion linked transmission - or iatrogenic transmission: Through transfusion with blood infected with T.cruzi or allotransplants is the second important transmission pathway.
(c) Vertical transmission from infected mother to fetus, laboratory accidents and other routes has also been described (Grant 1989; Monteón-Padilla 1999; Nickerson 1989; Pinto 1995, Schmunis 1999).
The clinical course of Chagas disease is characterized by an initial "acute phase", in which parasitemia is easily demonstrated. During this phase clinical symptoms may or may not be apparent, but most people spontaneously improve within six to eight weeks. Demonstration of circulating parasites confirms the clinical diagnosis. After a few weeks of infection an immune response may occur which is life long. Chronic infection may result in an "interdeterminate phase" of Chagas disease which is a long asymptomatic period that can last 30 to 40 years or more. The only proof of infection is a strong immune response with high titer of anti T.cruzi antibodies. Within this phase approximately 30% of chronically infected persons develop irreversible alterations of heart muscle and enlargement of the intestine (Barretti 1990; Schmunis 1994; Tanowitz 1992; WHO 1991). This is called chronic Chagas disease or the chronic symptomatic phase, and most cases will have chronic Chagasic cardiopathy (CCC), a specific cardiomyopathy, characterized by heart failure with bizarre rhythm and/or conduction defects. Unfortunately during the chronic phase it is difficult to demonstrate the presence of parasites either in peripheral blood or tissues. Therefore, immunoserology, and recently immunohistochemistry and biomolecular techniques are used as diagnostic assays.
Control and treatment of Chagas disease
Although treatment is the focus of this review, it is important to put the impact of treatment into the broader context of the international efforts to control transmission. In 1991 the Health Ministries of Argentina, Brazil, Bolivia, Chile, Paraguay and Uruguay, created the South Cone Initiative, with the objective of eliminating the vectoral transmission of Chagas disease by the year 2010 and establishing permanent blood donor screening to avoid transfusion linked transmission. To date, advances have been made. Uruguay was declared free of vectoral transmission in 1998 and in the remaining countries, active transmission rates has fallen from 96% to 75%; and the infection rate in the young population (below 18-year-old) is now between 0.17 to 1% (Cecere 1999; Harry 2000; Oliveira-Filho 1989; Rojas-de-Arias 1999; Schofield 1999).
It is hoped that through initiatives such as "South Cone", transmission of T.cruzi parasites will be significantly reduced or stopped in the near future. Unfortunately, Chagas disease will continue to impose a high social and economical cost (Cecere 1999; Harry 2000; Oliveira-Filho 1989; Rojas-de-Arias 1999; Schofield 1999). This is because of the long latent phase of the disease (10 to 30 years) and the considerable number of infected people that are currently in the chronic (indeterminate) phase of Chagas disease. A high proportion of people currently symptomless will in the future experience symptoms of Chagas disease.
A report describing 10 years of experience in Honduras, Guatelmala, and Bolivia focusing on feasible protocols, safety of drug therapy and treatment effectiveness, concluded that it is possible to implement a Chagas disease diagnosis and treatment program even in limited resources settings. However, treatment effectiveness may be related to differences in patients and parasite populations. New treatments with improved safety profiles, paediatric formulations and more a reliable test of cure are urgently needed (Yun 2009).
Trypanocidal drugs have been used in the treatment of Chagas disease since the 1960s (Brener 1975), when nitrofurans and later imidazolic drugs were introduced after a long history of therapeutic failures lasting 50 years. The trypanocidal drug Nifurtimox (3- methyl-N-`[(5 -nitro-2 furanyl)-methylene]-4-morpholinamine 1,1 dioxide) and Benznidazole (2-nitro-N-[phenylmethyl]-1H-imidazole-1-acetamide) are thought to exert their action by generation of free radicals either in intact cells or Trypanosoma cruzi lysates. However, the mechanisms involved in such reactions are ill defined (Stoppani 1999). Recently Kubata et al, (Kubata 2002 ) studying intracellular trypanosomal arachidonic acid and its metabolism in these parasites, found an enzyme which reduced prostanoid metabolites as well as naphthoquinone and nitro heterocyclic drugs .This reduction results in drug derived quinone intermediates as a source of free radicals which cause damage in organelles of parasitic protozoa. These reactions clarify the mechanism of action for both Nifurtimox and Benznidazole.
Both nitrofurans and imidazole derivatives (Nifurtimox and Benznidazole respectively) have a well recognized clinical activity limited to acute and early chronic trypanosoma infections, achieving a cure rate near to 76% after four weeks of treatment. Some promising results have been reported in the treatment of infected individuals in the chronic (indeterminate) phase of Chagas disease in trials carried out in Argentina and Brazil where reduction of parasitaemia ranges from 58% to 95% (de Andrade 1996; Sosa 1998; Stoppani 1999). In addition a Cochrane systematic review of Trypanocidal drugs for chronic asymptomatic Trypanosoma cruzi infection (Villar 2002) showed that "nitro imidazolic derivatives substantially and significantly modified parasite-related outcomes compared to placebo and that other agents showed borderline or not significant effect." The review concluded that "Trypanocidal therapy, particularly nitro imidazolic derivatives given to children or young adults with positive xenodiagnosis improve parasite-related outcomes" (Villar 2002). But efficacy in later stages of the disease is questionable. People with CCC are usually older than 25 years. Treatment for the late chronic symptomatic phase of Chagas disease is usually limited to managing complications associated with the pathology found in the heart and digestive organs, and avoiding antiparasitics drugs because of potential adverse reactions. However, recent studies have shown that chronically ill patients treated with Benznidazole had a significant reduction of blood antibodies compared with those in a placebo group. There is evidence that even if no cure was possible, fewer electrocardiographic abnormalities were found in the treatment group which may be interpreted as due to the delay in tissue damage (Moretti 1998; Segura 1994; Mady 2008).
However until the development of the ideal drug for the treatment of Chagas disease, Coura et al (Coura 2009) proposed to treat chagasic patients with a combination of currently used drugs such as Nifurtimox and Beznidazole, along with potential drugs like Allopurinol, and first, second and third generation antifungal agents, all of which have different mechanisms of action in order to boost the action of different compounds and avoid the development of parasite resistance.
A double blind placebo-controlled clinical trial in 55 individuals from endemic areas of Central Brazil was conducted, authors concluded that at the used dose (900 mg/d), Allopurinol was not effective to clear T. Cruzi form peripheral blood of infected individuals. (Rassi 2007)
New drugs have been tested like the modified candidate cancer, which have shown picomolar activity against cultured T. cruzi and was efficacious in a mouse model of acute Chagas disease (Kraus 2009)
Further studies need to be conducted, in both the acute and the chronic phases of the disease, in which strict cure criteria are established, specific diagnostic tests are used (e.g. PCR methods) together with long term follow-up and with clinically relevant outcomes.
The potential of trypanocidal therapy to modify CCC remains to be evaluated (Urbina 2009). Therefore, we therefore conducted a systematic review of the effects of treatment with Nitrofuran or imidazolic derivatives on clinically relevant outcomes in people with CCC.
Glossary
Acute phase
This is the phase immediately following infection. Acute symptoms only occur in about 1% of cases. Most people infected do not seek medical attention. The most recognized symptom of acute Chagas infection is the Romaña's sign, or swelling of the eye on one side of the face, usually at the site of the bite, or by direct infection of the conjunctiva. Other symptoms are usually not specific for Chagas infection. These symptoms may include fatigue, fever, enlarged liver or spleen, and swollen lymph glands. Sometimes, a rash, loss of appetite, diarrhoea, and vomiting occur. Infants and very young children with acute Chagas disease can develop meningoencephalitis which can cause death. In general, symptoms last for 4-8 weeks in the acute phase and then disappear even if no treatment is given.
Indeterminate phase
During this stage, people do not have symptoms. These chronically infected individuals become seropositive and remain asymptomatic for the next 10-30 years or for the rest of their lives when, if the electrocardiogram is normal and no evidence of cardiomegaly or digestive mega viscera is observed at X-rays, they are defined as in the indeterminate phase.
Chronic Chagasic cardiopathy (CCC)
A specific cardiomyopathy, characterized by heart failure with bizarre rhythm and/or conduction defects.
Chronic phase
Ten to 30 years after infection, people may develop the most serious symptoms of Chagas disease. Cardiac problems, including an enlarged heart, altered heart conduction or rhythm, heart failure, or cardiac arrest are symptoms of chronic disease. Chagas disease can also lead to enlargement of parts of the digestive tract, which result in severe constipation or problems with swallowing. In persons who are immune compromised, including persons with HIV/AIDS, Chagas disease can be severe. Not everyone will develop the chronic symptoms of Chagas disease.
Parasite
An animal or plant that lives in or upon another organism (technically called its host) and draws its nutriment directly from it.
PCR
Polymerase Chain Reaction. (PCR) is a molecular biological technique for amplifying (creating multiple copies of) DNA without using a living organism, such as E. coli or yeast. PCR is commonly used in medical and biological research labs for a variety of tasks, such as the detection of hereditary diseases, the identification of genetic fingerprints, the diagnosis of infectious diseases, the cloning of genes, and paternity testing.
Parasitemia
The presence of parasites in the blood.
Vector
An agent, often an insect, which transfers a disease caused by parasite or microorganism from one host to another. In Chagas disease the vectors are species of Triatoma bugs, they have many common names e.g. "vinchuca", "barbeiro", "chipo, "the kissing bug" or "assassin bug". Triatominae are insects of the order Hemiptera, family Reduviidae, sub-family Triatominae.
Objectives
To assess the effects (benefits and harms) of trypanocidal drugs for treating late, chronic Chagasic disease including CCC, in terms of blood parasite lowering or clearance, mortality, quality of life and adverse effects.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled clinical trials (RCT), single or double blind, using drugs versus placebo or no treatment with a minimum follow up of 18 months.
Types of participants
Adults with a definite diagnosis of CCC defined clinically as presence of either heart failure with or without specific dilated cardiomyopathy and/or tachyarrhythmia and/or heart block. A long "incubation" period of usually more than 20 years prior to CCC is expected. In addition, serum antibodies to T.cruzi demonstrated by at least two different validated tests (hemagglutination, indirect immunofluorescence, ELISA) (Monteón-Padilla 1995) would need to have confirmed CCC. If available positive xenodiagnosis, positive hemo culture or molecular biology assays, would alos be considered as diagnostic tests, as well as pathological demonstration of tissue parasitism when biopsy or necropsy were done.
Types of interventions
Orally administered licensed nitrofuran or imidazole derivatives versus placebo or versus no treatment in any dose given for at least 30 days.
Types of outcome measures
Primary outcomes
- Clearance of parasitaemia.
- Disappearance or reduction in antibody titer to T.cruzi.
Secondary outcomes
- Clinical improvement defined by disappearance of clinical signs of heart failure, rhythm and conduction defects on ECG.
- Quality of life, maintenance of a functional status such as New York Heart Association class I condition without hospitalisation.
- Able to care by him/herself in daily life activities.
- Return to work.
- Patients who dropped out because of adverse effects, such as severe cutaneous reactions and/or peripheral polyneuropathy;
- Patients who were not followed up.
Search methods for identification of studies
Electronic searches
The following databases were searched: the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (Issue 1, 2010), MEDLINE (OVID) (1985 to March 2010), EMBASE (OVID) (1985 to March 2010), BIREME (1985 to 2004), LILACS (1985 to March 2010), ARTEMISA (1985 to 2004), and SCIELO (1985 to 2004). No language restrictions were applied.
The searches were first run in 2004 (Appendix 1) and the searches of CENTRAL, MEDLINE, EMBASE and LILACS were updated in 2008 (Appendix 2) and on 31 March 2010 (Appendix 3).
Data collection and analysis
Selection of relevant studies
Two reviewers (MV and PR) independently read the citations retrieved from the search of databases and identified the papers relevant to the review: MV a non-expert of the content area with clinical and epidemiological background and PR, an expert of the content area. A list of all those eligible was compared and disagreements were resolved by a third independent reviewer (MS). All papers considered relevant were examined in full text for inclusion or exclusion.
Assessment of study quality
Methods described in the Cochrane Reviewers' Handbook (Higgins 2009) were used.
1. Allocation concealment in each study was graded as adequate (A), unclear (B), inadequate (C).
2. Random allocation of patients to treatment groups was adequate if random-number tables, computer random-number generators, coin tossing, shuffling cards or other procedures that genuinely provide a random number were used.
3. Blinding of investigator to treatment group was considered adequate if the investigator responsible for patient selection was blind to the treatment group of the patients.
4. Patient blinding was considered adequate if the placebo drugs used were identical in appearance and in taste to the treatment drugs.
5. Blinding of outcome assessors was considered adequate if this was done without knowledge of treatment status.
6. Studies with losses to follow up of more than or equal to 20% were excluded.
Data collection
All articles retrieved were reviewed using a check list in which the following information was identified.
1. Method of random allocation of patients to treatment group, and adequacy of concealment.
2. Blinding of patients to treatment group as well as, physicians responsible for the treatment patients.
3. Dose of trypanocidal drug, route of administration, duration of treatment.
4. Duration of follow up after treatment.
5. Number and type of laboratory tests used in the diagnosis of the patients and in the follow up.
6. Cure criteria, clearance or disappearance of parasites and reduction of parasite burden.
7. Clinical data on cardiomyopathy.
8. Sample size.
9. Country in which trial took place.
10. Proportion of loss to follow up either as result of withdrawals or to drop-outs by treatment/placebo groups.
11. Authors names, article title, publication type, source, language, year and journal.
The articles which did not fulfil all the relevant inclusion criteria were eliminated as valid sources of data for the purpose of making inferences about treatment efficacy. Nevertheless, as the evidence base was known to be extremely limited, they were included in the review and their findings described. Independently, MV and PR used a data collection form, which had been previously piloted on three articles. Disagreements were resolved by a third reviewer (MS).
Analysis
Had we identified sufficient studies appropriate for inclusion in this systematic review with outcomes suitable for meta-analysis, we would have analysed them following the Cochrane Reviewers' Handbook (Higgins 2009).
Data from each study would be pooled using a fixed effect model, except where substantial heterogeneity existed according to the I
The following predefined subgroups would be compared in the meta-analyses:
Nifurtimox versus placebo;
Benznidazol versus placebo;
Nifurtimox versus no treatment;
Benznidazol versus no treatment;
Nifurtimox versus Benznidazol.
If interval or boundary P-values were given we would use the upper boundary, e.g. 0.05 if P < 0.05 is reported. When only standard errors, confidence intervals or reference ranges are provided, we would calculate corresponding variances.
Results
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.
The original systematic search of the information available about treatment of chronic Chagasic disease, conducted in 2004, identified 47 articles representing:
- basic science;
- review articles (about chemotherapy, pathophysiology, immunology, etc);
- letters (or short communications or editorials);
- treatment of indeterminate Chagasic disease;
- laboratory test as markers of therapeutic efficacy;
- and treatment of chronic Chagasic disease with different types of drugs.
We found only 6 articles on treatment of chronic Chagasic cardiopathy, of which only one was a randomised controlled trial and therefore only one study is included in this review (Rodriguez-Coura 1997). This trial comprised a total of 77 people in Brazil and compared the effects of treatment with Nifurtimox or Benznidazol with placebo. Infection was assessed using indirect immunofluorescence in screening assay followed by positive complement fixation as well as confirmatory parasitologic assay (at least two out of three positive xenodiagnoses tests) (see Characteristics of included studies). The other five articles on treatment of chronic Chagasic cardiopathy have been excluded (see Characteristics of excluded studies).
An updated search in 2008 resulted in 87 new records, after removal of duplicates. None of these were eligible for inclusion in this review.
In the latest update in 2010, 52 new references were identified, of which 18 were eliminated because they referred to other infectious diseases. Eleven were related to treatment of Chagas disease, and one of these references belongs to the ongoing BENEFIT study (Marin-Neto 2008). The remaining, 23 studies treated other aspects of Chagas diseases. The ongoing study (BENEFIT), is a multicenter, randomised, double-blind, placebo-controlled clinical trial which will include 3,000 patients with Chagas' cardiomyopathy from three Latin American countries (Marin-Neto 2008; Marin-Neto 2009) (see Characteristics of ongoing studies).
Since we only found one randomised, single blind placebo controlled clinical trial and five more studies, we limited ourselves to a narrative description of the single study.
We found several non-randomised studies and we have summarized the results from these as diagnostic criteria, dose and duration of treatment, percentage of patients experiencing side effects, proportion of patients that completed the treatment, duration of follow up, main outcome and authors' conclusion.
Risk of bias in included studies
Study participants were recruited from two places in Minais Gerais, Brazil, all of the had CCC with an independently established diagnosis which included seropositivity, xenodiagnosis, clinical assessment including ECG and oesophagram. We graded the methodologcal quality as B: 77 participants were randomly allocated to three groups - placebo, Benznidazole and Nifurtimox. The method of randomisation was not reported. Patients and physicians were blind to treatment group (see Characteristics of included studies). Sixty-four patients completed the study: 23 received Benznidazol, 19 Nifurtimox and 22 placebo. Participants were evaluated at one, two, three and 12 months after treatment with three xenodiagnostic tests, with 15 days interval. In addition, participants had two serological assays. Of the 77 patients included in the study, 83% completed the full course of treatment. Confounding variables such as sex and age were evenly distributed between the groups. The sample size was too small to provide adequate power to detect clinically important differences in outcome.
Effects of interventions
Trial participants were between 25 and 65 years of age with a definite diagnosis of CCC.
Randomized controlled trials
Parasitologic cure was achieved in patients who received either Benznidazole or Nifurtimox, 98% and 90% respectively. However, people treated with placebo had a 66% parasitologic cure rate. There was no strong evidence of any difference in parasitologic cure between the treated and untreated groups (P > 0.05). Serological reactions did not change over the follow-up and there were no clinical ECG or X-ray changes one year after treatment in any of the groups. Nifurtimox was linked to adverse effects with digestive intolerance and neuropsychiatric manifestations more commonly than Benznidazole, which was associated with cutaneous rashes, peripheral neuropathy and digestive intolerance. However, the placebo group also reported digestive manifestations. The investigators did not provide quantitative data with regard to these adverse effects of treatment. The non-randomised studies found in this search related to the treatment of chronic Chagasic cardiopathy are described next (Rodriguez-Coura 1997).
In the BENEFIT study the primary outcome will be the composite of death; resuscitated cardiac arrest; sustained ventricular tachycardia; insertion of pacemaker or cardiac defibrillator; cardiac transplantation; and development of new heart failure, stroke, or systemic or pulmonary thromboembolic events. The average follow-up time will be five years, and the trial has a 90% power to detect a 25% relative risk reduction. (Marin-Neto 2008; Marin-Neto 2009)
Non-randomized studies
A study was established in Brazil, of 17 patients who had completed full treatment with anti-trypanosoma drugs (nitrofurans or nitroimidazole (10mg/kg/day) and were age and sex matched with patients from a cohort study of chronic Chagasic cardiopathy patients, all of whom by immunological and/or serological assay evidence of T.cruzi. The aim was to determine whether serological or immunological cure correlated 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 on immunological/serological outcome measures, the molecular markers persisted, indicating 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 ten year follow up of 91 people with chronic Chagasic cardiopathy and 41 uninfected controls. Using molecular methods of, competitive PCR, they showed that both treated and untreated patients had evidence of active infection (Lauria-Pires 2000).
An Argentinian study aiming to compare the clinical and serological progress of cardiomyopathy in patients treated with Benznidazole and untreated individuals, recruited 70 untreated patients and 131 Benznidazol treated patients (5mg/kg /day for 30 days). The follow-up period was of an average of 8 years. The proportion of treated patients who were serologically negative at the end of follow up was higher than in the untreated group (19.1% versus 6% respectively P= 0.05). The investigators concluded that treatment with Benznidazole decreased antibody titers if treatment was used early in the course of chronic Chagasic cardiopathy, but that people over 50 years old did not appear to show a serologic response and continued to have cardiac symptoms (Viotti 1994).
The further cohort study from Argentina was found which studied 198 people, drawn from a larger cohort of 492 patients which had suffered attrition due to losses to follow up, with the aim of examining the prognosis of chronic Chagasic cardiopathy in treated and untreated groups undergoing prolonged follow up. There were three groups: a) 32 patients treated with Nifurtimox (5 to 8 mg/kg/day for 60 days), b) 36 treated patients with Benznidazole (5 mg/kg/day for 30 days) and c) 130 untreated patients. All patients underwent, at the beginning or during the follow up of the cohort study, the following tests:
a) 3 serological Chagas-specific tests (DA-2ME, IHA or IIF) with titers equal or higher than 1/32, for at least two out of the three reactions.
b) EKG and chest X-ray.
The patients were followed for an average of 14 years (eight to 32 years). At the outset, only 9.6% of the infected patients had cardiomyopathy, but when comparing treated and untreated patients, the proportion of this cardiopathy was higher in the former group (7% versus 3.2% P < 0.05), reflecting 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 titers (<=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. (Fabro 2000).
A further long-term follow up (13-21 years) was reported in which the prognosis of acute and chronic Chagas disease was compared, with all patients receiving Benznidazole. The criteria for 'cure' was established by means of quantitative serological tests which included: complement fixation, indirect immunofluorescence, indirect hemagglutination and ELISA, but given the duration of follow up, not all these tests were used in all patients. (Cancado 2002). The cure rate was higher in patients with acute disease (76%) than in those with chronic disease (8 to 9%). It was concluded that 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 (Cancado 2002). It is difficult to make any inferences about the effects of treatment in this study as there was no randomised control group, neither patients nor physicians were blind to treatment group, and the criteria for cure changed over the follow-up (Cancado 2002).
Discussion
Human infection with T.cruzi induces an immune response in most human hosts and a chronic indolent infection is common. A proportion of infected people develop chronic symptomatic disease with two main clinical patterns: heart disease or dilated gastro-intestinal "mega" syndromes. CCC may produce a progressive heart disease characterized 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 twentieth century, however,over a period of 50 years, these were unsuccessful. In 1962 the first useful drug treatment was found using animal models - a nitrofuran derivative marketed as Nifurtimox, and shortly followed by an imidazolic drug, Benznidazol, both of which have become the cornerstone for treatment of American Trypanosomosis. Good results have been found in acute infection with absence of parasitaemia in most treated patients and remission of serologic response. These drug 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 Benznidazol in the treatment of CCC, we found one randomised trial and few non-randomised tudies, all of which had low patient numbers. There was no strong evidence to suggest that using standard treatment with either Nifurtimox or Benznidazol in patients with late stage T.cruzi infection was beneficial.
A major problem for conducting trials and interpreting long-term prognostic studies is the issue of defining 'cure'. For example, some studies have shown a significant reduction of blood antibodies and fewer ECG abnormalities in chronically infected patients treated with Benznidazol compared to a placebo group, and this was interpreted as an indication of a delay in tissue damage (Moretti 1998; Segura 1994; Viotti 1994). Clinical criteria for defining 'cure' requires the disappearance of parasitaemia but this is not easy to demonstrate in chronic cases, with the sensitivity of hemo culture or xenodiagnosis being no more than 50% at best. Inclusion of this definition is insufficient to determine the efficacy of drug treatment, and perhaps not surprisingly most papers failed to demonstrate any reduction in parasitaemia (Dias-Contijo 1999; Urbina 1999).
Circulating antibodies against T.cruzi is a diagnostic hallmark for chronic infection. Disappearance of antibodies has been used as a definition as 'cure' in acute disease but does not feature in CCC. The current established criteria to define 'cure' in CCC are currently inadequate. New developments in molecular biology have further challenged the existing definition of 'cure'. Parasite DNA can now be clearly demonstrated in several tissues, reinforcing the notion of parasite persistence (despite apparent clinical cure) and its possible role as an inducer of immune response. Changes in Trypanosoma cruzi-specific immune response after treatment with Beznidazole have been proven by Laucella et al (Laucella 2009). They 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 became undetectable in a substantial proportion of treated subjects. They demonstrated the impact of this treatment in chronically infected people by monitoring the parasite-specific immune response which indicates the efficacy of treatment and cure.
Both Nifurtimox and Benznidazol are linked to adverse reactions (peripheral neuropathy, skin disorders and other health problems) in a relatively high proportion of users, indicating the need for safer and effective drugs for 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 Benznidazol, but do provide modest evidence of potential harm from adverse effects.
Currently a multicenter (BENEFIT), randomised, double-blind, placebo-controlled clinical trial of beznidazole (5 mg/kg per day) of 3,000 chagasic patients is ongoing in 35 centres in Argentina, Brazil and Colombia. It also comprises a sub-study to evaluate the effects of beznidazole on parasite clearance and the impact of the etiological treatment on the left ventricular function (Marin-Neto 2008).
This study will clarify the efficiency of imidazolic drugs in the treatment of chronic chagasic patients, especially when overt heart disease is present. Nitrofuran or imidazolic drugs may be useful and are recommended during acute infection and perhaps early in evolution of indeterminate chronic infected people.
Authors' conclusions
Implications for practice There is no strong evidence to support treatment with either Nifurtimox or Benznidazol in patients with chronic T.cruzi infection and overt heart disease (CCC). There is the potential for adverse drug effects and caution in the use of these drugs in CCC should be exercised. |
Implications for research Further studies with randomised designs are required to test the effects of both established and new drugs. The latter may be derived from molecules designed to modify parasite metabolism but without adverse effects on human physiology, i.e. a sort of " chemical bullet", which would aim to eliminate both blood and tissue parasitism. Better criteria for cure are also needed for use as outcome measures in such trials. The pathogenesis of chronic complications of T.cruzi infection also requires further research because the host contribution through the immune response could be a cornerstone for the development of late stage clinical disease, making anti-parasite treatment of much less relevance as the main therapeutic strategy in advanced disease. Preventive measures such as those applied in Latin-America through the South Cone, Andine and Central America Initiatives may offer the best cost/ benefit approach to sustainably control Chagas disease by reducing acute infection, preventing reinfection and progression to chronic stages with target organ damage. |
Acknowledgements
Dra. G. Faba, Centro Mexicano de Colaboracion Cochrane, for assistance with databases searching and paper retrieval.
Data and analyses
This review has no analyses.
Appendices
Appendix 1. Search strategies 2004
CENTRAL
#1 CHAGAS-DISEASE*:ME
#2 CHAGA*
#3 TRYPANOSOMIA*
#4 ((#1 or #2) or #3)
#5 IMIDAZOLES*:ME
#6 TRYPANOCIDAL-AGENTS*:ME
#7 TRYPANOCIDAL*
#8 IMIDAZOLE*
#9 NITROFURA*
#10 BENZNIDAZOL*
#11 CHEMOTHERAPY
#12 TREATMENT*
#13 (((((((#5 or #6) or #7) or #8) or #9) or #10) or #11) or #12)
#14 (#4 and #13)
Other databases:
Both English and Spanish search terms were used for searching:
English:
Chagas disease (title or abstract word) or trypanosomiasis/trypanosomosis (title or abstract word) AND treatment (title or abstract word) or chemotherapy (title or abstract word) OR Imidazolic drugs (title or abstract word) or trypanocidal drugs (title or abstract word).
Spanish:
Enfermedad de Chagas (title or abstract word) o trypanosomiasis (title or abstract word) AND tratamiento (title or abstract word) o antiparasitarios (title or abstract word) o imidazólicos (title or abstract word).
Appendix 2. Search strategies 2008
CENTRAL
#1 MeSH descriptor Chagas Disease explode all trees
#2 chaga* in All Text
#3 MeSH descriptor Trypanosomiasis this term only
#4 trypanosomiasis in All Text
#5 cardiomyopath* in All Text
#6 (#1 or #2 or #3 or #4 or #5)
#7 nifurtimox in All Text
#8 allopurinol in All Text
#9 benznidazole in All Text
#10 itraconazole in All Text
#11 trypanocid* in All Text
#12 antitrypanosom* in All Text
#13 anti-trypanosom* in All Text
#14 MeSH descriptor trypanocidal agents explode all trees
#15 MeSH descriptor nitrofurans explode all trees
#16 nitrofurans in All Text
#17 bzd in All Text
#18 MeSH descriptor allopurinol this term only
#19 MeSH descriptor itraconazole this term only
#20 bay next 2502 in All Text
#21 (#7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18
or #19 or #20)
#22 (#6 and #21)
MEDLINE
1 exp chagas disease/
2 trypanosomiasis/
3 chaga$.tw.
4 trypanosomiasis.tw.
5 cardiomyopath$.tw.
6 or/1-5
7 nifurtimox.tw.
8 allopurinol.tw.
9 benznidazole.tw.
10 itraconazole.tw.
11 trypanocid$.tw.
12 antitrypanosom$.tw.
13 anti-trypanosom$.tw.
14 exp Trypanocidal Agents/
15 exp Nitrofurans/
16 nitrofurans.tw.
17 bzd.tw.
18 Allopurinol/
19 Itraconazole/
20 trypanocidal.tw.
21 or/7-20
22 6 and 21
23 randomized controlled trial.pt.
24 controlled clinical trial.pt.
25 Randomized controlled trials/
26 random allocation/
27 double blind method/
28 single-blind method/
29 or/23-28
30 exp animal/ not humans/
31 29 not 30
32 clinical trial.pt.
33 exp Clinical Trials as Topic/
34 (clin$ adj25 trial$).ti,ab.
35 ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).ti,ab.
36 placebos/
37 placebo$.ti,ab.
38 random$.ti,ab.
39 research design/
40 or/32-39
41 40 not 30
42 31 or 41
43 22 and 42
44 limit 43 to yr="2004 - 2008"
EMBASE
1 chagas disease/
2 trypanosomiasis/
3 chaga$.tw.
4 trypanosomiasis.tw.
5 cardiomyopath$.tw.
6 or/1-5
7 exp Antitrypanosomal Agent/
8 exp Nitrofuran Derivative/
9 nifurtimox.tw.
10 allopurinol.tw.
11 benznidazole.tw.
12 itraconazole.tw.
13 trypanocid$.tw.
14 antitrypanosom$.tw.
15 anti-trypanosom$.tw.
16 nitrofurans.tw.
17 bzd.tw.
18 Allopurinol/
19 Itraconazole/
20 trypanocidal.tw.
21 or/7-20
22 6 and 21
23 controlled clinical trial/
24 random$.tw.
25 randomized controlled trial/
26 follow-up.tw.
27 double blind procedure/
28 placebo$.tw.
29 placebo/
30 factorial$.ti,ab.
31 (crossover$ or cross-over$).ti,ab.
32 (double$ adj blind$).ti,ab.
33 (singl$ adj blind$).ti,ab.
34 assign$.ti,ab.
35 allocat$.ti,ab.
36 volunteer$.ti,ab.
37 Crossover Procedure/
38 Single Blind Procedure/
39 or/23-38
40 22 and 39
41 limit 40 to yr="2004 - 2008"
LILACS
(random$ or trial$ or clinical stud$ or rct) and (chaga$ or trypanosomiasis or cardiomyopath$) [Words] and antitrypanocidal$ or anti-trypanocidal$ or nitrofurans or nifurtimox or allopurinol or benznidazole or itraconazole or anti-trypanosom$ or antitrypanosom$ [Words] and 2004 or 2005 or 2006 or 2007 or 2008 [Country, year publication]
Appendix 3. Search strategies 2010
CENTRAL
#1 MeSH descriptor Chagas Disease explode all trees
#2 chaga* in All Text
#3 MeSH descriptor Trypanosomiasis this term only
#4 trypanosomiasis in All Text
#5 cardiomyopath* in All Text
#6 (#1 or #2 or #3 or #4 or #5)
#7 nifurtimox in All Text
#8 allopurinol in All Text
#9 benznidazole in All Text
#10 itraconazole in All Text
#11 trypanocid* in All Text
#12 antitrypanosom* in All Text
#13 anti-trypanosom* in All Text
#14 MeSH descriptor trypanocidal agents explode all trees
#15 MeSH descriptor nitrofurans explode all trees
#16 nitrofurans in All Text
#17 bzd in All Text
#18 MeSH descriptor allopurinol this term only
#19 MeSH descriptor itraconazole this term only
#20 bay next 2502 in All Text
#21 (#7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18
or #19 or #20)
#22 (#6 and #21)
MEDLINE (OVID)
1. exp Chagas Disease/
2. Trypanosomiasis/
3. chaga$.tw.
4. trypanosomiasis.tw.
5. cardiomyopath$.tw.
6. or/1-5
7. nifurtimox.tw.
8. allopurinol.tw.
9. benznidazole.tw.
10. itraconazole.tw.
11. trypanocid$.tw.
12. antitrypanosom$.tw.
13. anti-trypanosom$.tw.
14. exp Trypanocidal Agents/
15. exp Nitrofurans/
16. nitrofurans.tw.
17. bzd.tw.
18. Allopurinol/
19. Itraconazole/
20. trypanocidal.tw.
21. or/7-20
22. 6 and 21
23. randomized controlled trial.pt.
24. controlled clinical trial.pt.
25. Randomized Controlled Trials/
26. Random Allocation/
27. Double-Blind Method/
28. Single-Blind Method/
29. or/23-28
30. exp animal/ not humans/
31. 29 not 30
32. clinical trial.pt.
33. exp Clinical Trials as Topic/
34. (clin$ adj25 trial$).ti,ab.
35. ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).ti,ab.
36. Placebos/
37. placebo$.ti,ab.
38. random$.ti,ab.
39. Research Design/
40. or/32-39
41. 40 not 30
42. 31 or 41
43. 22 and 42
44. 43 and (2008$ or 2009$ or 2010$).ed.
EMBASE (OVID)
1. Chagas disease/
2. trypanosomiasis/
3. chaga$.tw.
4. trypanosomiasis.tw.
5. cardiomyopath$.tw.
6. or/1-5
7. exp antitrypanosomal agent/
8. exp nitrofuran derivative/
9. nifurtimox.tw.
10. allopurinol.tw.
11. benznidazole.tw.
12. itraconazole.tw.
13. trypanocid$.tw.
14. antitrypanosom$.tw.
15. anti-trypanosom$.tw.
16. nitrofurans.tw.
17. bzd.tw.
18. allopurinol/
19. itraconazole/
20. trypanocidal.tw.
21. or/7-20
22. 6 and 21
23. controlled clinical trial/
24. random$.tw.
25. randomized controlled trial/
26. follow-up.tw.
27. double blind procedure/
28. placebo$.tw.
29. placebo/
30. factorial$.ti,ab.
31. (crossover$ or cross-over$).ti,ab.
32. (double$ adj blind$).ti,ab.
33. (singl$ adj blind$).ti,ab.
34. assign$.ti,ab.
35. allocat$.ti,ab.
36. volunteer$.ti,ab.
37. crossover procedure/
38. single blind procedure/
39. or/23-38
40. 22 and 39
41. 40 and (2008$ or 2009$ or 2010$).em.
LILACS (in English)
(random$ or trial$ or clinical stud$ or rct) [Words] and (chaga$ or trypanosomiasis or cardiomyopath$) and (antitrypanocidal$ or anti-trypanocidal$ or nitrofurans or nifurtimox or allopurinol or benznidazole or itraconazole or anti-trypanosom$ or antitrypanosom$) [Words] and 2008 or 2009 or 2010 [Country, year publication]
What's new
Last assessed as up-to-date: 12 September 2010.
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History
Protocol first published: Issue 1, 2003
Review first published: Issue 4, 2005
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Contributions of authors
Maite Vallejo - conceived and wrote protocol, undertook retrieval and review of citations
Pedro A. Reyes - conceived and wrote protocol, undertook retrieval and review of citations
Declarations of interest
There is no conflict of interest in this work.
Sources of support
Internal sources
- Insituto Nacional de Cardiologia, Ignacio Chavez, Tlalpan, Mexico.
External sources
- No sources of support supplied
Index terms
Medical Subject Headings (MeSH)
Chagas Cardiomyopathy [drug therapy]; Chagas Disease [*drug therapy]; Chronic Disease; Clinical Trials as Topic; Imidazoles [therapeutic use]; Nifurtimox [therapeutic use]; Nitroimidazoles [therapeutic use]; Trypanocidal Agents [*therapeutic use]
MeSH check words
Humans