Antiparasitical chemotherapy in Chagas’ disease cardiomyopathy: current evidence

Authors

  • Paulo Marcos Matta Guedes,

    1.  Department of Microbiology and Parasitology, Bioscience Center, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil
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  • Fredy Roberto Salazar Gutierrez,

    1.  School of Medicine, University Antonio Nariño, Bogotá, Colombia
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  • Manuela Sales Lima Nascimento,

    1.  Department of Biochemistry and Immunology, Medicine School at Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
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  • Maria Adelaide Do-Valle-Matta,

    1.  Laboratory of Cellular Ultrastructure, Oswaldo Cruz Institute-FIOCRUZ, Rio De Janeiro, Rio de Janeiro State, Brazil
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  • João Santana Silva

    1.  Department of Biochemistry and Immunology, Medicine School at Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
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Corresponding Author Paulo Marcos Matta Guedes, Department of Microbiology and Parasitology, Federal University of Rio Grande do Norte, Av Salgado Filho SN, Lagoa Nova, 59072-970, Natal, Rio Grande do Norte, Brazil. E-mail: pauloguedes@cb.ufrn.br

Abstract

Chronic chagasic cardiomyopathy affects 20% of Chagas’ disease patients. At present, Chagas’ disease chemotherapy uses nitrofurans, benznidazole (Rochagan®, Rodanil®, Roche) or nifurtimox (Lampit®, Bayer). Treatment during acute and recent chronic phases in childhood effects 71.5% and 57.6%, respectively, of parasitological cure. However, in clinical trials during the late chronic phase, only 5.9% of parasitological cure were achieved. This review focuses on the benefit from aetiological treatment to avoid, stop or revert myocarditis. Divergent data gathered from clinical practice are not convincing to support prescription of aetiological treatment as routine for indeterminate and cardiac chronic patients.

Abstract

La cardiomyopathie chronique chagasique affecte 20% des patients de la maladie de Chagas. A l’heure actuelle la chimiothérapie la maladie de Chagas utilise des nitrofuranes, benznidazole (Rochagan®, Rodanil®, Roche) ou nifurtimox (Lampit®, Bayer). Le traitement des phases aiguës et chroniques récentes chez les enfants atteint respectivement 71,5% et 57,6% de guérison parasitologique. Cependant, dans les essais cliniques sur la phase tardive chronique, seule 5,9% de guérison parasitologique a été atteinte. Cette revue se concentre sur l’avantage d’un traitement étiologique pour éviter, arrêter ou reverser une myocardite. Le traitement étiologique de durée indéterminée et les patients cardiaques chroniques ont des résultats divergents, ce qui justifie l’utilisation régulière d’un traitement étiologique chez ces groupes.

Abstract

La cardiomiopatía chagásica crónica afecta a un 20% de los pacientes con enfermedad de Chagas. Actualmente en la quimioterapia para la enfermedad de Chagas se utilizan los nitrofuranos, Benznidazol (Rochagan®, Rodanil®, Roche) o Nifurtimox (Lampit®, Bayer). El tratamiento durante las fases aguda y crónica reciente en la niñez tiene conlleva en un 71.5% y 57.6% respectivamente, a la cura parasitológica. Sin embargo, en ensayos clínicos, durante la fase crónica tardía solo se alcanzó un 5.9% de cura parasitológica. Esta revisión se centra en los beneficios del tratamiento etiológico para evitar, parar o revertir la miocarditis. El tratamiento etiológico de pacientes indeterminados y cardiacos crónicos tienen resultados divergentes, justificando el uso regular del tratamiento etiológico en estos grupos.

Introduction

Trypanosoma cruzi (T. cruzi) is a flagellate protozoan that causes Chagas’ disease, endemic in Latin America, where 7.7 million people are infected and 28 million people are at risk of acquiring the disease (OPAS 2007; Salvatella 2007). Chagas’ disease has distinct manifestations. Clinical signs are absent from most patients suffering from chronic disease, leading to a condition characteristic of the indeterminate form. 10% of infections evolve into digestive (megacolon and megaesophagus) forms; 20% of patients present the cardiac form (chronic chagasic cardiomyopathy, CCC). Mixed forms also occur (Tafuri 1987; Pinto Dias 1995; Rassi et al. 2010). Histopathology of cardiac damage evinces a slow and gradual proliferation of intra-fascicular inflammatory focuses over time. This event triggers myocarditis with a significant lymphomononuclear infiltrate along with interstitial fibrosis and cardiomyocyte hypertrophy. This myocarditis can lead to dilated cardiomyopathy, end-stage heart failure and death (Higuchi et al. 2003). The beginning and persistence of the pathogenic process imply that parasites are present (Jones et al. 1993; Higuchi 1995; Bellotti et al. 1996; Anez et al. 1999); moreover, the autoimmune events associated with the genetic background of the parasite and host seem to amplify the cardiac injury (Leon et al. 2003). This could explain the gap observed between the inflammation and the parasite burden in the lesion (Jones et al. 1993; Higuchi 1995; Bellotti et al. 1996; Anez et al. 1999). Considering that the immunopathological changes progress along with the chronic disease, and that the parasite is pivotal for the myocardial damage in human CCC (Barbosa et al. 1986; Higuchi et al. 1993; Higuchi 1995), an aetiological treatment that promotes parasite clearance to avoid cardiac injury is urgently needed. Effective anti-T. cruzi agents could hold out the possibility to lead a normal life to 8 million chronic patients, which is also important to establish a process less onerous to health systems of developing and underdeveloped countries affected by this neglected disease.

Aetiological treatment of Chagas’ disease

Specific chemotherapy of Chagas’ disease has been developed over three decades ago, but it remains very unsatisfactory. Chemotherapy is based on nitrofurans, benznidazole/Bz (Rochagan®, Rodanil®, Roche) or nifurtimox/Nfx (Lampit®, Bayer) (Docampo 1990). Nfx tablets contain 150 mg of active substance, in children as well as in adults during acute phase, a dose of 15 mg/kg/day is recommended; in adults during the chronic phase, the recommendation is 8–10 mg/kg/day divided into three daily doses for 60 days. Side effects include anorexia, vomiting, peripheral polyneuropathy, weight loss and allergic dermopathy, probably as a consequence of reductive and/or oxidative damage in the host tissue (Docampo et al. 1981; Docampo 1990). Bz tablets contain 100 mg of active substance; the consensus is 5–10 mg/kg/day of Bz recommended for 60 days for the treatment of acute, recent chronic phases and congenital cases and divided in two daily doses, preferably after meals. The maximum daily dose is 300 mg (three tablets) divided into 2–3 doses; for adults weighing over 60 kg, the total dose has to be calculated, and the treatment time extended to complete the dosage, not exceeding 80 days.

There are very few pharmacokinetic studies of Bz and Nfx, especially in humans, for Chagas’ disease treatment. The treatment is recommended based mainly on the clinical phase or forms of disease (Table 1). Dosages and frequency of taking medication (1, 2 or 3 times a day) should be adjusted for different ages. Side effects have been more commonly reported in adults, and severity seems to be much more significant. Severe adverse reactions reported in adults include generalized allergic dermopathy, fever, adenopathy, peripheral neuropathy, leucopenia and agranulocytosis (rare). In these cases, treatment must be discontinued. None of these severe reactions have been observed in children in significant numbers (Altcheh et al. 2011; de Andrade et al. 1996). In a study performed with 107 children with asymptomatic Chagas’ disease, the incidence of side effects was strongly associated with the age of the patient: occurring in children over the age of 7 and very rarely in infants or toddlers, suggesting that children older than 7 years should be monitored more carefully. The evaluation of gastrointestinal adverse reactions is problematic because other factors associated with drug administration, such as formulation and tablet size, could be involved in intolerance. The absence of appropriate paediatric formulations complicates matters further, as tablets are not easily (or willingly) swallowed by small children, which sometimes leads to vomiting and other problems that may not be specifically related to the active drug (Altcheh et al. 2011). However, recently, the LAFEPE laboratory in Brazil (the world’s sole producer of Bz) began producing infant tablets (http://portalsaude.saude.gov.br/portalsaude/noticia/3549/162/medicamento-para-chagas-sera-entregue-a-cinco-paises.html). Liquid preparations are formulations of choice for the paediatric population.

Table 1.   Indication of benznidazol for American antitrypanosomal therapy based on the I Latin American Guidelines on Treatment of chagasic cardiopathy (Data obtained from Andrade et al. 2011)
PatientTherapeutical scheduleIndication for treatmentSpecific comments
Children and acute cases (congenital transmission included)10 mg/kg/day 60 days divided into two dosesYesTreatment should be carried out in all cases as soon as possible
Adult chronic chagasic patients with the indeterminate form5 mg/kg/day 60 days divided into two dosesControversialIndication for etiological treatment is controversial despite the benefit on maintenance of patients symptom-free. This indication deserves further investigation
Adult chronic chagasic patients with different degrees of cardiopathy5 mg/kg/day 60 days divided into two dosesControversialThe benefit from treating this group of patients has been evaluated by an international multicentre, randomized, double-blinded and placebo-controlled study in patients with CCC treated with Benznidazole, called BENEFIT, being in course a six-year follow-up study for evaluation of the clinical outcome. Some experimental and clinical studies indicate that treatment is advantageous considering the occurrence of few severe side effects compared with the potential benefit on the treatment of short duration
Laboratory accidents7–10 mg/kg/day 10–30 days divided into two dosesYesContamination events with cutting/piercing instruments, mucous contact with parasite cultures, infected vectors and laboratory animals, samples from patients and necropsy materials use Benznidazole (7–10 mg/kg/day) for at least 10 days; once proved the occurrence of high parasitism in the contaminant material, use the drug for at least 30 days
Reactivation7–10 mg/kg/day 60–80 days divided into two dosesYesPharmacologically immunossupressed- and HIV-infected patients
Pregnant women, patients with kidney and liver failureContraindicatedTeratogenic effect in experimental model and drug toxicity

Treatment is also indicated for patients who have reactivation of the disease because of immunosuppression, such as patients with haematologic malignancies, those co-infected with human immunodeficiency virus, and patients treated with immunosuppressive drugs such as transplant recipients (Brazilian Consensus 2005). In case of accidental infections, comprised of laboratory accidents, treatment must begin immediately with 7–10 mg/kg/day of Bz for 10–30 days. However, no effective treatment exists for the chronic form of the disease. The efficacy of aetiological treatment of chagasic patients with the standardized drugs Nfx or Bz in inducing parasitological cure or preventing the development of chronic Chagas’ disease is frequently controversial. Chagas’ disease therapy schedules are summarized in Table 1.

Bz treatment throughout acute (Shikanai-Yasuda et al. 1990; Andrade et al. 1992; Bahia-Oliveira et al. 2000; Cancado 2002) and recent chronic phases (young people aged 2–16 years) (Andrade & Magalhaes 1996; Sosa Estani et al. 1998; Sosa Estani & Segura 1999; Silveira 2000; Andrade et al. 2004; Streiger et al. 2004; Escriba et al. 2009) in childhood effects parasitological cure rates of 71.5% and 57.6% of cure, respectively. However, clinical trials in the late chronic phase (Ferreira Hde 1990; Viotti et al. 1994a; Braga et al. 2000; Fabbro De Suasnabar et al. 2000a; Lauria-Pires et al. 2000; Ferreira et al. 2002; Fernandes et al. 2009; Lana et al. 2009) only achieved 5.9% parasitological cure (Figure 1).

Figure 1.

 Cure rate obtained during aetiological treatment of Chagas’ disease. Mean cure rate obtained with the aetiological treatment carried out during acute- (treatment started with 0–2 months of age), recent chronic- (children with 1–14 years of age) and late chronic (treatment started after 15 years of age) phases of the disease.

Infants with congenital Chagas’ disease are treated with Bz 2.5–15 mg/kg/day for 60 consecutive days and achieve cure rates of 93.8% to 100% when treatment is administered within the first 6 months of life (Russomando et al. 1998; Blanco et al. 2000; Schijman et al. 2003; Burgos et al. 2009). For treatments applied between 7 months and 2 years after infection, cure rates range from 66.7% to 90.1% (Schijman et al. 2003; Chippaux et al. 2010); and for treatments administered 3–15 years after birth, cure rates drop dramatically to 12.5% (Schijman et al. 2003). Patients were followed up from 7 months to 4 years, and the criterion of cure was based mostly on polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence (IIF) and indirect hemagglutination (IHA).

In postnatal infection, we can divide patients into three groups: acute, recent chronic (young people aged 2–16 years) and late chronic phases. Using the treatment with Bz, the results of clinical screenings performed during the acute phase of infection show parasitological cure rates ranging between 66.7% and 76.2% (Shikanai-Yasuda et al. 1990; Andrade et al. 1992; Bahia-Oliveira et al. 2000; Cancado 2002). Treatment of patients in the recent chronic phase of T. cruzi infection led, in most of the cases, to cure rates ranging from 59% to 93.9%. However, a study of 12 individuals aged 7–12 years cured only 8.3% with a dose of 5 mg/kg/day of Bz for 60 days. Patients were followed up for 8–20 years, and parasitological cure was determined by ELISA, IIF, IHA, PCR and xenodiagnosis (Andrade & Magalhaes 1996; Sosa Estani et al. 1998; Sosa Estani & Segura 1999; Silveira 2000; Andrade et al. 2004; Streiger et al. 2004; Escriba et al. 2009). Of these 12 patients, only one showed a positive PCR after treatment, although the antibodies of conventional serology remained positive, a fact that can occur many years after a successful aetiological treatment, because of the immunological memory.

During the late chronic phase, in which the majority of chagasic patients are found, Bz and Nfx treatments are unsatisfactory and should be given more cautiously because of its ineffectiveness and many collateral effects. At this stage of infection, Bz and Nfx treatments provide cure rates from 0% to 19.1%, but in many clinical trials, no patient treated was considered cured (Ferreira Hde 1990; Viotti et al. 1994a; Braga et al. 2000; Fabbro De Suasnabar et al. 2000a; Lauria-Pires et al. 2000; Ferreira et al. 2002; Fernandes et al. 2009; Lana et al. 2009). The data consider dissociated patients as cured; such patients show negative results of hemoculture, xenodiagnosis, PCR, lysis mediated by complement (LMCo) and positive titres of conventional serology (conventional serology: ELISA and hemagglutination). The major goal in the chemotherapy of Chagas’ disease is the discovery of a new and effective drug for the chronic infection phase. We lack an adequate methodological approach for the definition of parasitological cure of patients Nfx/Bz-treated during the chronic infection phase. To evaluate the response to specific chemotherapy in Chagas’ disease, two kinds of tests are available: parasitological and serological methods. Parasitological methods are based on demonstration of the parasite by molecular test (PCR), xenodiagnosis and hemoculture. Conventional serological methods evaluate the presence of specific antibodies (conventional serology antibodies-CSA) by enzyme-linked immunosorbent assay (ELISA), indirect hemagglutination (IH), indirect immunofluorescence (IIF) and complement-mediated lysis or flow cytometry-detected lytic antibodies (Krettli & Brener 1982; Guedes et al. 2011). While conventional serological antibodies can remain positive for a long tome after effective treatment, lytic antibodies gradually disappear after successful chemotherapy. The effective cure of the infection requires negative results by clinical, serological and parasitological tests after a long period of monitoring (Krettli & Brener 1982; Guedes et al. 2011).

Thus, the necessity of better drugs to treat Chagas’ disease patients remains urgent. Compounds must act against the most clinically relevant mammalian stages of T. cruzi (intracellular amastigotes or trypomastigotes) and preferably work in an animal model. Activity against several T. cruzi strains is wanted to ensure the potential for applicability in different disease endemic regions. Low potential for toxicity (less than that of Bz and Nfx) is fundamental. This should include low potential for genotoxicity and teratogenicity, given the need to treat young people, as well as low risk of cardiotoxicity, such as prolonged QT interval because the heart is the primary organ affected in Chagas’ disease. Low risk for interactions with hepatic cytochrome P450s (CYPs) is important to avoid drug–drug interactions, particularly because many patients may be taking antiarrhythmic drugs, anticoagulants and other medications. The drug that will be used in the field will need to be orally administered, so oral bioavailability is a very important characteristic. Finally, a stable compound with low cost is critical to ensure that a future compound is available in the areas where it is most needed (Urbina 2002). Progress is slow, but recent advancements in both drug development and advocacy for research on neglected diseases are encouraging. Drug development efforts are almost exclusively occurring as preclinical research. Among others, we cite ergosterol synthesis inhibitors, cysteine protease inhibitors and aromatic diamidines. Sterol biosynthesis inhibitors intersect sterol synthesis causing impairment in ergosterol synthesis. T. cruzi has a strict requirement for specific endogenous sterols for cell viability and growth, being extremely susceptible to this class of inhibitors in vivo and in vitro (Urbina 2002). Furthermore, enzymes involved in postprocessing steps of lanosterol, a common intermediate in sterol synthesis in mammals, fungi and T. cruzi, do not have counterparts in mammals, as cholesterol synthesis in human hosts is not affected by these drugs. The major cysteine protease of T. cruzi is Cruzain, which accounts for the proteolytic activity in all the life stages of T. cruzi (Apt 2010). Cysteine protease inhibitors block the development of cruzain and its transport by lysosomes. The lack of redundancy of this enzyme makes the parasites vulnerable to cruzain inhibition (Chen et al. 2010). Designed, synthetic heterocyclic diamidines have excellent activity against eukaryotic parasites as T. cruzi. The compounds enter parasite cells rapidly and appear first in the kinetoplast that contains the mitochondrial DNA of the parasite. Active compounds appear to selectively target extended AT sequences present in the structure of kinetoplast DNA minicircles and induce changes in these DNA minicircles that cause a synergistic destruction of the catenated kinetoplast DNA network and cell death (Wilson et al. 2008). Moreover, phase II studies for the antifungal drug, posaconazole and a prodrug of ravuconazole are being planned (Buckner & Navabi 2010).

Reversibility of cardiac damage in preclinical chemotherapy

The evidence burgeoning from experimental protocols reveals interchangeability between the pathological conditions of cardiac inflammation and fibrosis after effective therapy. Bz chemotherapy was administered to mice infected with 21SF and Y T. cruzi strains and the therapeutic intervention proceeded with Bz all along the chronic phase. A process of cure after a dropping off in fibrotic changes of the interstitial matrix seemed to have occurred in the animals, pointing to the advantage of parasite clearance in reducing structural injuries (Andrade et al. 1991). Conversely, Bz treatment of animals infected with Colombian T. cruzi strain was not effective; the infection persisted and the animals evinced myocarditis and fibrosis through persistent T. cruzi provoking heart injury (Andrade et al. 1989). By contrast, treatment of mice during the chronic phase of Chagas’ disease showed less parasitism and myocarditis in the hearts of Bz-treated animals than in the hearts of untreated chagasic mice. Both groups of T. cruzi-infected mice had significant alterations in their electrocardiograms compared with healthy mice. However, untreated mice had significantly higher cardiac conduction disturbances than Bz-treated mice, including intraventricular conduction disturbances, atrioventricular blocks and extrasystoles. These results demonstrate that treatment with Bz in the chronic phase of infection prevents the development of severe chronic cardiomyopathy, despite the lack of complete parasite eradication (Garcia et al. 2005).

Our group’s study involved mice infection with Y strain and a chemotherapic schedule where Bz was administered in concert with an NO donor. We obtained a promising outcome: animals displaying lack of myocarditis with associated cytokine production normalized (Guedes et al. 2010). In this same line of evidence, even animals that were not cured had less myocarditis than infected and untreated control animals. However, infecting dogs with AAS and VL10-Bz-resistant T. cruzi stocks revealed the inefficiency of specific treatment in reducing the intensity of cardiac inflammation in animals considered not cured (Caldas et al. 2008).

A comparative experimental study with Bz and posaconazole in a murine model of Chagas’ disease showed that although both drugs were effective in reducing parasitism and inflammation in the heart, posaconazole-treated animals had plasma activity of creatine kinase isoform MB, correlated to cardiac lesion, indistinguishable from those of uninfected mice, while for Bz the enzyme levels were significantly higher than those of uninfected controls 31 days after the start of treatment (Olivieri et al. 2010).

Benefit of antiparasitical treatment to prevent Chagasic chronic cardiomyopathy

Aetiological treatment designed to avoid, stop or revert myocarditis in both the indeterminate and cardiac chronic patients gave poor and even conflicting results, rendering regular use of aetiological treatment in these groups hard to justify. Few randomized clinical trials have been published assessing chemotherapy with Nfx and Bz in chronic asymptomatic or cardiac chronic patients. It is therefore difficult to assess their efficacy and tolerance. And yet, there are a few among them that examine the benefit of treatment with a view to improving or stabilizing the patient’s prognosis (Braga et al. 2000; Lauria-Pires et al. 2000).

In a randomized 10-year follow-up study involving 91 Chagas, patients and 41 uninfected controls patients were aged 31–60 years and were treated with a therapeutic scheme using 10 mg/kg/day of Bz or Nfx during 20–60 days. Ten years after specific therapy, no patient was considered cured, supported by PCR assay-based criterion as control of parasitological cure. ECG recordings showed that ventricular premature contractions, single or combined bundle branch blocks, intraventricular conducting disturbances and changes of ventricular repolarization were present in significantly higher proportions of Chagas’ patients, regardless of treatment, than in uninfected control subjects. This study demonstrates that nitro-derivative (Bz and Nfx) therapy did not prevent the progression of heart disease in chronic Chagas patients (Lauria-Pires et al. 2000).

Bz or Nfx chemotherapy administered to chronic chagasic patients reduced clinical and electrocardiographic evolution towards cardiomyopathy. Viotti et al. (2006) demonstrated, in a 10-year follow-up, unblinded non-randomized study, in which intervention consisted of oral Bz, 5 mg/kg of body weight per day for 30 consecutive days (283 patients), or no treatment (283 patients) that only fewer treated patients had disease progression (12 of 283 [4%] Bz-treated patients vs. 40 of 283 [14%] untreated patients) or developed abnormalities on electrocardiography (15 of 283 [5%] Bz-treated patients vs. 45 of 283 [16%] untreated patients) as compared with the control group (no treatment). Left ventricular ejection fraction and left ventricular diastolic diameter were also associated with disease progression. In another study, these authors showed that after 8 years of follow-up, there was less deterioration in clinical condition (2.1% in the treated patients vs. 17% in untreated patients) (Viotti et al. 1994b).

Of 63 chronic chagasic patients aged 13–52 years, who were treated with Bz (5 mg/kg/day by 30 days) or Nfx (5–8 mg/kg/day by 60 days), only 4.8% (3/63) were parasitologically cured (Fabbro De Suasnabar et al. 2000). A longitudinal study from a low endemic area (Santa Fe city, Argentina) was performed during an average period of 14 years. Analyses with clinical exams, ECG and X-chest ray were accomplished to compare the evolution of chronic chagasic untreated patients with that of Bz- or Nfx-treated patients. At the beginning, 19/198 infected patients showed chagasic cardiomyopathy while 179 were asymptomatic. Within the chagasic cardiomyopathy group, 2/5 treated showed aggravated myopathy, whereas this happened in 9/14 of untreated patients. Comparing the clinical evolution of all patients, 5.9% of treated patients and 13% of untreated patients had unfavourable evolution. In this study, no differences regarding the clinical and serological evolution between the patients treated with Nfx or Bz were observed (Fabbro De Suasnabar et al. 2000). The follow-up of most of these patients showed that for 21 years, 2/54 (3.7%) of the treated and 9/57 (15.8%) of the untreated patients showed electrocardiographic disturbances attributable to Chagas myocardiopathy, with a statistically relevant difference (P < 0.05) (Fabbro et al. 2007).

In another study, 28 Chagas’ disease patients (aged 6–37 years), of whom 22 had the indeterminate clinical form and six the cardiac or digestive form, were treated with 5–10 mg/kg/day Bz for 40–60 days, but no patient was considered cured (analysed by PCR, ELISA and IHA). These data demonstrate that 82.1% of chagasic patients (23/28) remained clinically stable, and 95.4% of the indeterminate (21/22) and 33.3% of the cardiac/digestive (2/6) patients showed unaltered physical and laboratorial examinations. The clinical evolution rate was 2%/year and was especially low in indeterminate patients (0.5%/year) relative to cardiac or digestive patients (7.4%/year). Although a control group of untreated Chagas’ patients was not included in this study, the data analysis indicates that indeterminate patients present a clinical evolution rate of only 0.5%/year (Lana et al. 2009). This is lower than what has been observed by other authors in epidemiological and clinical studies of untreated patients that showed the indeterminate form of the disease in Brazil, from which rates ranging from 2% to 4%/year were recorded (Prata 2001; Dias 2006). These findings are also lower than what was observed by Lana et al. (2009), who demonstrated an incidence of 1.5%/year (three times higher than that observed in this study) for Chagas’ disease cardiomyopathy among untreated indeterminate patients in a 10-year follow-up study performed in Berilo-MG, Brazil, the same region (Lana et al. 2009).

The results of clinical trials generally show a beneficial effect of treatment with Bz or Nfx, compared with placebo or untreated group in the chronic phase. However, the role of aetiological treatment (Bz or Nfx) in preventing the progress of lesions, reducing the morbidity and mortality associated with Chagas’ disease during chronic phase, must be better studied in chronic Chagas’ cardiomyopathy patients displaying variable degrees of chronic Chagas’ myocarditis as well as those patients with the indeterminate form of the disease (Figure 2). Treatment of patients with mild and/or moderate heart Chagas’ disease is currently under scrutiny by the BENEFIT trial (BENEFIT: Bz Evaluation for Interrupting Trypanosomiasis) (Marin-Neto et al. 2008) that aims to compare Bz with placebo in 3000 patients (aged 18–75 years) from several centres in Latin America. Clinical improvement in Bz-treated patients depends on cardiac parasitism reduction after decrease of the immunopathogenic mechanism. However, parasite susceptibility to Bz correlates with different genetic patterns of T. cruzi strains (Tc-I, II, III, IV, V e VI) (Zingales et al. 2009). Molecular characterization of T. cruzi strains reisolated from patients treated during BENEFIT protocol would be another important aspect that could be used for treatment recommendation or not.

Figure 2.

 Benefit of aetiological treatment of indeterminate and cardiac chronic patients remains uncertain. Trypanosoma cruzi multiplication in cardiomyocyte starts cardiac damage, in which participates specific immune response against the parasite but also involves the release of cell components leading to bystander activation, whereby immune responses are generated against host cellular components. This bystander activation and molecular mimicry between parasite and host antigens generate autoantibodies and autoreactive T cells. The autoantibodies can generate lesions mediating complement activity and opsonizing tissue for macrophage activation. Autoreactive CD8+ T cells recognize self-antigens and destroy cardiac tissue. Cytolytic T lymphocytes not only destroy infected cells but also contribute to the destruction of adjacent cells. Tissue injury leads to TNF-α production, resulting in nitric oxide production (Gutierrez et al. 2009). Benznidazole/Bz treatment can reduce the cardiac parasitism and consequently cardiac damage. However, patients infected with Bz-resistant Trypanosoma cruzi strains can have a higher antigen release or amastigotes in the heart tissue, leading to the enhancement of myocarditis and immunopathogenic mechanisms. (a) Myocardial schedule represents indeterminate- and mild cardiomyopathy, patients with cardiac segmental form can display sinus node dysfunction, right bundle branch block and left anterior fascicular block, ventricular premature beats, non-sustained ventricular tachycardia and ventricular fibrillation (Rassi et al. 2010), (b) Chagas chronic heart disease remains affecting the patients independent of Bz treatment, (c) indeterminate- and mild cardiomyopathy patients treated with Bz remain asymptomatic and with few alterations, (d) the Bz treatment worsens cardiac disease, and the patients can display cardiac global dilated form with tricuspid and mitral regurgitation.

Authors’ opinions converge in that there is an urgent need concerning the adoption of an efficacious therapeutic conduct to be applied to individuals affected by chronic symptomatic or indeterminate Chagas’ disease. Nowadays, evidences assembled from clinical practice are not strong enough to support treatment prescription as routine for those patients. This is the result of a negligible arsenal of anti-parasitic therapies for the prevention of the disease’s progression. At the other end of Chagas’ disease pathology, where indeterminate and cardiac chronic patients require treatment, Bz seems to accumulate evidence favouring its therapeutic use.

Conclusion

Preclinical studies using Bz indicate that aetiological treatment is beneficial in reducing cardiac lesions in animals infected with T. cruzi. The action of Bz in reducing or reversing CCC is still being evaluated. The BENEFIT trial will be important to determine the role of treatment with Bz in chronic patients with different degrees of Chagas’ heart disease. However, the gain of treatment in patients with the indeterminate form needs further investigation to determine whether it can be recommended or not. Therapy using Bz must be deployed with caution and tight follow-up because of its side effects and low efficacy in the chronic stage.

Acknowledgements

The authors gratefully acknowledge Dr. Maria Luiza do Valle Matta for useful discussions.

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