The efficacy of treatment with nifurtimox and/or benznidazole among adults with chronic Chagas disease with no previous electrocardiographic disturbances was evaluated over a mean follow-up of 21 years, by means of conventional serology, xenodiagnosis, clinical examination, electrocardiograms and chest X-ray. One hundred and eleven patients, between 17 and 46 years old, were studied: 54 underwent treatment (nifurtimox 27, benznidazole 27) and 57 remained untreated (control group). Xenodiagnosis was performed on 65% of them: 36/38 of the treated and 9/34 of the untreated patients had previous positive xenodiagnosis. Post-treatment, 133 xenodiagnoses were performed on 41 patients, all resulting negative. In the control group, 29 xenodiagnoses were performed on 14 patients; 2 resulted positive. Sera stored during the follow-up were simultaneously analyzed through conventional serology tests (IHA; DA-2ME; IIF). The serological evolution in the treated group was: a) 37% underwent negative seroconversion (nifurtimox 11, benznidazole 9); b) 27.8% decreased titers (nifurtimox 9, benznidazole 6), 9 showed inconclusive final serology (nifurtimox 7, benznidazole 2); c) 35.2% remained positive with constant titers (nifurtimox 7; benznidazole 12). The control group conserved the initial antibody levels during the follow-up. In the clinical evolution, 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). Treatment caused deparasitation in at least 37% of the chronically infected adults and a protective effect on their clinical evolution.
BACKGROUND: Benznidazole is effective for treating acute-stage Chagas disease, but its effectiveness for treating indeterminate and chronic stages remains uncertain.
OBJECTIVE: To compare long-term outcomes of patients with nonacute Chagas disease treated with benznidazole versus outcomes of those who did not receive treatment.
DESIGN: Clinical trial with unblinded, nonrandom assignment of patients to intervention or control groups.
SETTING: Chagas disease center in Buenos Aires, Argentina.
PATIENTS: 566 patients 30 to 50 years of age with 3 positive results on serologic tests and without heart failure.
MEASUREMENTS: The primary outcome was disease progression, defined as a change to a more advanced Kuschnir group or death. Secondary outcomes included new abnormalities on electrocardiography and serologic reactivity.
INTERVENTION: Oral benznidazole, 5 mg/kg of body weight per day for 30 days (283 patients), or no treatment (283 patients).
RESULTS: Fewer treated patients had progression of disease (12 of 283 [4%] vs. 40 of 283 [14%]; adjusted hazard ratio, 0.24 [95% CI, 0.10 to 0.59]; P = 0.002) or developed abnormalities on electrocardiography (15 of 283 [5%] vs. 45 of 283 [16%]; adjusted hazard ratio, 0.27 [CI, 0.13 to 0.57]; P = 0.001) compared with untreated patients. Left ventricular ejection fraction (hazard ratio, 0.97 [CI, 0.94 to 0.99]; P < 0.002) and left ventricular diastolic diameter (hazard ratio, 2.45 [CI, 1.53 to 3.95]; P < 0.001) were also associated with disease progression. Conversion to negative results on serologic testing was more frequent in treated patients than in untreated patients (32 of 218 [15%] vs. 12 of 212 [6%]; adjusted hazard ratio, 2.1 [CI, 1.06 to 4.06]; P = 0.034).
LIMITATIONS: Nonrandom, unblinded treatment assignment was used, and follow-up data were missing for 20% of patients. Loss to follow-up was more common among patients who were less sick. Two uncontrolled interim analyses were conducted.
CONCLUSIONS: Compared with no treatment, benznidazole treatment was associated with reduced progression of Chagas disease and increased negative seroconversion for patients presenting with nonacute disease and no heart failure. These observations indicate that a randomized, controlled trial should now be conducted.
The change in parasitemia profile, measured by sequential blood cultures of 27 benznidazole (Bz) treated patients compared with 13 untreated patients, on the chronic phase of chagas disease, is described. All patients were adults (age limits: 23-88) with positive serology (three tests); 23 of them were females. All patients were submitted to six blood cultures, three before and three after Bz treatment. The parasitemia was classified as nondetected (with three negative blood cultures), medium (one positive culture in three), and high (two or three positive cultures). From the eight patients with nondetected parasitemia before Bz, seven still had the same profile and only one switched to medium; from eight with medium parasitemia, seven shifted to nondetected, and one to high parasitemia. From the 11 patients with high parasitemia before Bz, ten converted to nondetected and only one was positive after Bz. Nineteen of the 27 patients changed the parasitemia profile (70.4%), and the rate of therapeutic failure was 11.1% (3/27) during the first 24 months of follow-up after Bz. The shift to nondetected parasitemia profile was from 8/27 to 24/27 patients after Bz treatment for the first 2 years. Only 46.2% (6/13) of the nontreated individuals changed the parasitemia profile. We conclude that there is a strong trypanocide effect of Bz (88.8%) and a rate of therapeutic failure of 11.1% during the first 2 years after trypanocidal treatment.
Clinical and epidemiological results of 95 treated and untreated chronic chagasic children, with an up to 24 years follow-up period are presented. This population studied in the 1/14 age bracket, residing in Santa Fe city, Argentina, was diagnosed through Chagas-specific conventional serologic reactions. Clinical examination was supplemented with electrocardiogram, chest X-rays, and blood and urine tests for evaluating hepatic function. The drugs employed were nifurtimox or benznidazole. In post treatment period xenodiagnosis was made in 33 patients. Regarding Trypanosoma cruzi transmission, the studied individuals presented multi-risk antecedents: vectorial, congenital and/or blood transfusion. Among 24 untreated children 14 were controlled during 8/24 years: all this patients maintained the initial antibody concentration and clinical status. From 71 treated patients 49 were followed-up 4/24 years: 14 remained positive, 6 presented dubious results, and 29 showed final non-reactive results. 9 of this presented sometimes oscilating results. In 1/6 age bracket children, the serology turned negative after 3.5 years (median) once the treatment was finished, while patients treated in the 7/14 age bracket, the median of negativization was 8 years. 3.8% did not tolerate the drug. None of the groups changed their clinical condition. The untreated children did not change the serology. The percentage of treated children presenting negative serological results decrease according to the age when treatment was given: 75% became negative when treated at < or =4 years old and 43% when treated at > or =9 years old.
A randomized ten-year follow-up study involving 91 Chagas patients and 41 uninfected controls was undertaken to determine the effectiveness of nitroderivative therapy. Anti-Trypanosoma cruzi antibodies were consistently lower one year after treatment than 10 years thereafter (P < 0.001). The blood of all treated and 93.7% of untreated Chagas patients yielded polymerase chain reaction (PCR) product from probes annealing to T. cruzi nuclear DNA, indicating active infection. Competitive PCR showed means +/- standard deviations of 20.1+/-22.6 T. cruzi/ml of blood from untreated and 13.8+/-14.9 from treated Chagas patients, but the differences between means were not statistically significant (P > 0.05). Electrocardiograms recorded a gamut of alterations several-fold more frequent in Chagas patients, regardless of treatment, than in uninfected controls (P < 0.001). These results show that nitroderivative therapy for T. cruzi infections is unsatisfactory and cannot be recommended since it fails to eradicate the parasite or change the progression of heart disease in chronic Chagas patients.
In this study is presented the comparative therapeutical experience comparing the Allopurinol, Benznidazol y Nifurtimox, in a prospective following in a long term, considering the responses to the parasitemia, specific serology and evolution of the clinic manifestations and complementaries in the 535 chronic chagasic cases (44.5%), instead of 668 patients who did not get any treatment (1203 chagasic cases followed for more than 5 years average). This study was done between April 1984 and April 1994 in patients with and without cardiopathy, in the Córdoba Hospital and the Salud Estudiantil Direccion, Universidad Nacional de Córdoba (U.N.C.); from them, 309 patients were given Allopurinol, 130 were given Benznidazol, and 96 were given Nifurtimox, with usual doses of Benznidazol and Nifurtimox, but with Allopurinol it was made an study evaluating the answering-doses, with a following time of post-therapeutic average of 55.6 months (D.S. = + -57 m.) The comparative parameters were the starting clinic characteristics, the qualitative and quantitative for Chagas, the pre-treatment xerodiagnostic, the treatment fulfillment, the treatment duration, the adverse effects, the treatment abandon, the time of postreatment longitudinal following till the last clinic-complementary evaluation, the clinic characteristics at the end of the following period; quantitative and qualitative serology for Chagas after the treatment, and post-treatment xerodiagnostic. It was observe a prevalence of Electrocardiographic Changes in the ECG in rest, in the first complementary evaluation in 76 of the 535 "Treated" and in the 225 "No-treated" patients, being Electrocardiographic abnormality proportion much more in the "No-treated" patients (P = 0.000000). After the end of the following period it was thought to have been found Miocardic Damage Progression in 120 patients "No-treated" and in 31 "Treated" patients (17.9% and 5.8% respectively) (P = 0.0000000). The complications in the evolution course were proved in 113 of the "No-treated" and in 19 of the "Treated" patients (16.9% and 3.5%, being this a statistically significant difference (P = 0.0000000). The mortality along the evolution was proved in 37 of the "No-Treated:" patients and in 7 of the "Treated" patients (5.5% and 1.3%), being this a statistically significant difference (P = 0.00019). The most tolerated drug and the one with the least incidence of therapeutic abandons was the Allopurinol. The xerodiagnostic negativization percentages were 72.5% for Allopurinol, 76.4% for Benznidazol and 76.5% for Nifurtimox (non-significant differences). A year and two years after the end of the treatment was made a titled serology with the Inmunofluorescence and Indirect Hemoaglutination Tests, getting significant statistical differences between the three drugs, resulting lower the values obtain after the treatment with Benznidazol and Nifurtimox than with Allopurinol (P = 0.0042 and P = 0.00039), respectively). The biggest proportion of Progression in the Cardiopathies, Complications, General Mortality and Attributed Mortality in "No Treated" (specially in older than 30 years) significant both for infected patient and slight cardiopathy, stabilises the possibility of stopping or reducing the morbid course of the Chronic Chagasic Cardiopathy, specially relevant in the formers, where the pathogenic process seems to be accelerated related to the latters. The negativation of the parasitemia and the parasitemia and the title disminution of the specific serology like effectiveness treatment parameters, and the stopping in the progression or dissemination of the incidence in new cases of Chronic Chagasic Cardiopathies were considered to be the real benefit of the antiparasitaric therapeutic in the Chagas Disease. As a conclusion, it is thought that the further the instauration of the specific antiparasitaric treatment the more the possibilities of effectiveness, as well as the increase in the probabilities of preventing or reducing the incidence of cardiopathy in chronic infected, or to stop its evolution and reduce its morbimortality in patients with already installed cardiopathy.
A double-blind, randomized, clinical field trial was designed to test the efficacy and tolerance of a specific drug treatment in children in the indeterminate phase of infection by Trypanosoma cruzi. Children were treated with benznidazole at a dose of 5 mg/kg/day for 60 days or placebo and followed-up for 48 months. The treated children showed a significant decrease in geometric mean titers of antibodies against T. cruzi measured by indirect hemagglutination, indirect immunofluorescence, and ELISA. After a four year follow-up, 62% of the benznidazole-treated children and no placebo-treated child were seronegative for T. cruzi when tested by an ELISA using a T. cruzi flagellar calcium-binding protein (F29). Xenodiagnosis carried out after 48 months of follow-up was positive in 4.7% of the benznidazole-treated children and in 51.2% of the placebo-treated children. These results show the tolerance to and efficacy of benznidazole against T. cruzi in seropositive children six to 12 years of age. We used an early serologic marker of cure after treatment, consisting of a recombinant antigen implemented in a rapid, conventional serologic procedure.
A controlled clinical trial was carried out to evaluate the therapeutic efficacy and tolerance of nifurtimox and benznidazole in patients with chronic Chagas' disease. All patients had immunofluorescence and complement fixation reactions positives for T. cruzi antibodies and at least two xenodiagnoses positives in three performed before treatment, and they were submitted to clinical examinations, ECG and X-ray of the heart and esophagus. Of 77 patients studied, 27 were treated with nifurtimox and 26 with benznidazole in the dosage of 5 m/kg/day for 30 consecutive days, and 24 received a placebo in tablets similar to benznidazole. From the 77 patients, 64 (83.1%) accomplished the treatment: 23 (88.4%) with benznidazole, 19 (70.3%) with nifurtimox and 22 (91.6%) with placebo. The patients were evaluated, clinically, serologically and parasitologically (six xenodiagnoses within one year after treatment). The benznidazole group showed only 1.8% of positive xenodiagnoses post-treatment, the nifurtimox 9.6% and the placebo 34.3%. All serologic reactions continued positive and there were no clinical, ECG or X-ray changes one year after treatment.
BACKGROUND: Benznidazole, a nitroimidazole derivative, has been recommended for the treatment of acute and congenital Trypanosoma cruzi infection (Chagas' disease). We have examined the safety and efficacy of this drug in the treatment of the early chronic phase of T cruzi infection.
METHODS: Between 1991 and 1995, we carried out a randomised, double-blind, placebo-controlled trial in a rural area of Brazil with endemic Chagas' disease. 82% of 2434 schoolchildren (aged 7-12 years) identified in a census were screened for antibodies to T cruzi by indirect immunofluorescence, indirect haemagglutination, and ELISA. 130 were positive in all tests and were randomly assigned benznidazole (7.5 mg/kg daily for 60 days by mouth) or placebo. The primary endpoint for efficacy was the disappearance of specific antibodies (negative seroconversion) by the end of 3-year follow-up. The secondary endpoint was the reduction of antibody titres on repeated serological tests. One child moved away from the area just after randomisation and was excluded from the analyses. Insecticidal measures were taken throughout the trial to reduce the risk of reinfection.
FINDINGS: Minor side-effects requiring no specific medication were recorded in a small proportion of individuals. On a chemiluminescent ELISA with purified trypomastigote glycoconjugate, serum from all participants was positive at the beginning of the trial. At the end of follow-up, 37 (58%) of the 64 benznidazole-treated participants and 3 (5%) of those who received placebo were negative for T cruzi antibodies. The efficacy of benznidazole treatment estimated by intention to treat was 55.8% (95% CI 40.8-67.0). At the end of follow-up, children who received benznidazole had five-fold lower geometric mean titres by indirect immunofluorescence than placebo-treated children (196[147-256] vs 1068[809-1408], p < 0.00001).
INTERPRETATION: The trial showed that a 60-day course of benznidazole treatment of early chronic T cruzi infection was safe and 55.8% effective in producing negative seroconversion of specific antibodies. The results are very encouraging and justify the recommendation of treatment for seropositive children as public health policy.
The efficacy of treatment with nifurtimox and/or benznidazole among adults with chronic Chagas disease with no previous electrocardiographic disturbances was evaluated over a mean follow-up of 21 years, by means of conventional serology, xenodiagnosis, clinical examination, electrocardiograms and chest X-ray. One hundred and eleven patients, between 17 and 46 years old, were studied: 54 underwent treatment (nifurtimox 27, benznidazole 27) and 57 remained untreated (control group). Xenodiagnosis was performed on 65% of them: 36/38 of the treated and 9/34 of the untreated patients had previous positive xenodiagnosis. Post-treatment, 133 xenodiagnoses were performed on 41 patients, all resulting negative. In the control group, 29 xenodiagnoses were performed on 14 patients; 2 resulted positive. Sera stored during the follow-up were simultaneously analyzed through conventional serology tests (IHA; DA-2ME; IIF). The serological evolution in the treated group was: a) 37% underwent negative seroconversion (nifurtimox 11, benznidazole 9); b) 27.8% decreased titers (nifurtimox 9, benznidazole 6), 9 showed inconclusive final serology (nifurtimox 7, benznidazole 2); c) 35.2% remained positive with constant titers (nifurtimox 7; benznidazole 12). The control group conserved the initial antibody levels during the follow-up. In the clinical evolution, 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). Treatment caused deparasitation in at least 37% of the chronically infected adults and a protective effect on their clinical evolution.
