Clinical and serological evolution in chronic Chagas disease patients in a 4-year pharmacotherapy follow-up : a preliminary study

Introduction: The role of trypanocidal therapy in the chronic phase of Chagas disease remains controversial. Methods: A total of 13 patients with chronic Chagas disease were treated with benznidazole (5mg/kg/day/60 days) and surveyed via antibody measurement and conventional electrocardiogram over the course of 4 years. Results: The antibody titers were signifi cantly reduced after 4 years (p<0.05). Most of the patients showed maintenance of the initial clinical picture (electrocardiographic), with the exception of 4 cases. Conclusions: Although trypanocidal therapy in the chronic phase of Chagas disease was of limited effectiveness, we believe that it is benefi cial in treating these patients.

One hundred years after its discovery, Chagas disease (CD) remains a public health problem in Latin America 1 .In Brazil, it is estimated that two to three million people are infected by vectorial transmission or through blood transfusion.The prevalence of the disease is less than 0.2%.The oral transmission route has also become relevant 2,3 .
One of the main manifestations of CD is cardiac involvement 4 , which occurs most frequently in people between 20 and 59 years of age and represents the leading cause of disability and mortality associated with the disease 5 .The only drug available for the treatment of Chagas disease in Brazil is benznidazole (Bz) 6 .
There is no doubt that the use of Bz during the acute phase of CD is benefi cial; however, there are no convincing data in the medical literature that indicate that this specifi c treatment is effective in preventing the progression of chronic CD (except for the BENEFIT project, currently in progress) 7 .
Given these facts and due to the scarcity of publications on this topic, we evaluated cardiac and serological parameters in patients with chronic CD treated with Bz in a 4-year pharmacotherapy follow-up.The study included 13 patients with chronic CD, aged 27-60 years, living in different municipalities of the State of Ceará, Brazil, with prescriptions for Bz (5 mg/kg per day for 60 days).The patients underwent clinical and laboratory assessments in the cardiology outpatient clinic at the Hospital Universitário Walter Cantídio (HUWC), Ceará, Brazil, and in the Chagas Disease Research Laboratory.After providing informed written consent, the patients were followed for 4 years (2006-2009).In one patient (patient 2), the treatment was interrupted 50 days after the fi rst dose due to an episode of paresthesia (Table 1).
The fi rst serum sample collection was performed prior to the beginning of therapy in 2006, and the subsequent three collections were performed at 1-year intervals.The samples were stored at -20°C until use.Semi-quantitative analyses of the anti-Trypanosoma cruzi immunoglobulin G (IgG) in the serum samples were performed using an enzyme immunoassay (Biomérieux, Brazil).The results were expressed in optical density (OD) units (minus blank).In the serological follow-up, the titer was considered to be: unchanged when the OD from the last collected sample increased or decreased by less than 1.5-fold compared to the OD at the fi rst analysis; progressive when the OD increased by ≥1.5-fold compared to the fi rst analysis; and regressive when the OD decreased by ≥1.5-fold compared to the fi rst analysis, as proposed by Zauza et al. 8 .A conventional electrocardiogram was also performed before (2006) and after treatment (2009).Holter monitoring was used as necessary to clarify obscure cases.
A paired t test was used to compare the geometric means of the anti-T.cruzi IgG titers over time.The level of statistical signifi cance was 0.05.Antibody titers remained unchanged in 9 (69.2%)patients, regressive in 3 (23.1%)patients, and progressive in 1 (7.7%) patient.Antibody titers signifi cantly decreased (p<0.05) between the baseline ( 2006) and at the 4-year follow-up (2009) (paired t test), as shown in Figure 1.
In general, the majority of patients tended to maintain the initial clinical picture, with a normal electrocardiogram (EKG) before and after treatment or the same or similar electrocardiographic fi ndings before and after treatment (Table 1).However, 4 cases merit further comment.Patient 2 required a pacemaker implantation due to an increase in breaks, as detected by Holter monitoring.Before treatment, patient 3 had an ejection fraction (EF) of 56, which showed improvement (EF=72) shortly after the use of Bz.Patient 8 evolved RBBB (right bundle branch block) even after the use of Bz.Patient 10 required a dual-chamber implantable cardioverter defi brillator in 2010 (after the end of the study period).These results reinforce the need for a longer follow-up period of investigation because 4 years of follow-up was shown to be insufficient to evaluate cardiac outcomes in chronic chagasic patients.
The trypanocidal treatment of the chronic phase of CD remains controversial because there are few longitudinal experimental or clinical studies regarding this disease phase 9 .Experts indicate that the time required to achieve seronegative status varies and depends on the disease phase -for instance, 5 to 10 years for a recent chronic phase and over 20 years for a chronic phase of long duration 10 .Fabbro et al. 11 , in a 21-year follow-up study, investigated chronic chagasic patients treated with benznidazole or nifurtimox (n=54) and untreated patients (n=57) aged 17 to 46 years.Of the patients who were treated with benznidazole or nifurtimox, 37% became seronegative, while the untreated patients remained seropositive.A 10year follow-up study conducted with 140 untreated chronic chagasic patients aged 10 to 70 years demonstrated that 57.9% remained serologically unchanged, 37.1% exhibited serological progression, and only 5% exhibited decreases in antibody titers 8 .Our fi ndings revealed a signifi cant reduction of antibody titer in patients treated with benznidazole over 4 years of follow-up.
Perez-Molina et al. 12 performed a systematic review and meta-analysis of benznidazole use in CD.These authors verifi ed that benznidazole use was associated with an 18-fold increase in the probability of a good response to therapy.According to their review, although the data suggest a benefi cial effect of drug treatment, the effi cacy of this therapy in the late chronic phase remains controversial.This uncertainty is largely due both to differences in the studied populations, endpoints, and followup periods and to the fact that almost all information about treatment in the late chronic phase came from non-randomized studies.Our results indicate that treatment of the chronic phase of CD may be benefi cial for the patients; decreased anti-T.cruzi IgG titers and maintenance of the initial clinical picture were observed in most of the patients.Therefore, we believe that an extended follow-up study with a greater number of patients will be important to confi rm our results.
Andrade MC et al -Clinical and serological evolution in chronic Chagas patients

TABLE 1 -
Epidemiological, serological, and electrocardiographic fi ndings in chronic chagasic patients over 4 years of follow-up.