Treating Chronic Chagas Disease

Abstract and Commentary

By Michele Barry MD, FACP

Professor of Medicine, Co-Director, Tropical Medicine and International Travelers' Clinic, Yale University School of Medicine

Dr. Barry is a consultant for the Ford Foundation, and receives funds from Johnson & Johnson.

Synopsis: Benznidazole is effective for treating acute-stage Chagas disease, but its effectiveness for treating indeterminate and chronic stages is unknown. Can the course of chronic Chagas disease be altered by treatment with this agent?

Sources: Viotti R, et al. Long-Term Cardiac Outcomes of Treating Chronic Chagas Disease with Benznidazole versus No Treatment: A Nonrandomized Trial. Ann Intern Med. 2006;144:724-734.

Currently there are somewhere between 18 to 20 million persons infected with the protozoan parasite, T. cruzi. Benznidazole has previously been shown to be effective for treatment of the acute stages of Chagas disease, but its effectiveness for treating indeterminate and chronic stages is unknown. Previous observational studies have indicated that benznidazole treatment for chronic Chagas disease may delay or prevent clinical progression of heart damage, as well as induce a seronegative conversion during chronic and indeterminate stages of the disease. However, no study has standardized benznidazole treatment for chronic disease, nor proven that treatment prevents cardiomyopathy.

This study compared long-term outcomes of patients from ages 30 to 50 with non-acute Chagas disease treated with 5mg/kg of body weight per day for 30 days (283 patients) to no treatment (283 patients). Recruitment of patients occurred from a group of 1968 individuals referred to the Chagas Disease Section at Hospital Eva Peron in Buenos Aires, Argentina, during the years 1984-2001. Diagnosis was made by serologic testing (3 positive tests), and patients were stratified into Kuschnir Group 0, signifying positive results on serological testing, normal cardiogram (EKG), chest radiograph (CXR); Kuschnir Group I signified positive serology, abnormal EKG, normal CXR; Kuschnir Group II signified positive serology, abnormal EKG, and enlarged heart on CXR. No patient could have clinical signs of heart failure. See Table 1 below, which outlines the Kuschnir groupings.

Patients were then placed by alternating non-random assignment into medical treatment or no treatment groups. No placebo control was offered, so treatment was not blinded. After a median follow-up of 9.8 years, 14.1% (40 of 283) of untreated patients and 4.2% (12 of 283) of benznidazole-treated patients showed progression of heart disease, as defined as a change from one Kuschnir group to a more advanced group, or sudden cardiac death (adjusted hazard ratio, 0.24 (95%; CI, 0.10 to 0.59), P = .002). Conversion to seronegativity was more frequent in treated patients than untreated controls (32 of 218 (15%) vs 12 of 212 (6%), hazard ratio 2.1 (95%; CI, 1.06 to 4.06) P = .034). Follow-up data were not available for 20% of the patients (54 treated and 57 non-treated patients). Viotti and colleagues conclude that treatment during the chronic phase of Chagas disease was associated with a reduced risk of progression and increased rate of conversion to seronegativity.

Commentary

Although this study has serious limitations (being non-random, with unblinded assignment, a relatively short follow-up period, and unavailable data for 20% of patients), proof of clinical benefits of benznidazole treatment for Chagas disease has been elusive. As noted in the accompanying editorial, only negative, inconclusive, retrospective, or cohort studies had been previously reported.1 This study represents an advance because of the large number of patients enrolled, the systematic assignment to drug treatment or none, and the standardization of drug dosing during therapy. These results demonstrate new and positive evidence that specific treatment of chronic Chagas disease can ameliorate the most devastating effects of evolution to chronic cardiomyopathy. Several interesting highlights should be noted in this report:

  1. The more favorable clinical course of patients who became seronegative supports a longstanding hypothesis that parasite persistence may play a role in cardiac lesions.
  2. There can be clinical and serological spontaneous cure rates, even without specific treatment.
  3. Electrocardiographic abnormalities were predictive signs of progression to cardiac enlargement in this series.
  4. Side effects of benznidazole treatment consisted mainly of allergic dermatitis in 28% of treated patients, with 13% discontinuing treatment due to the severity of the dermatitis.

Chagas disease has been detected in 18 Latin American areas ranging from Mexico to Patagonia. The control of insect vectors and transfusion transmission are still poor in many regions. Although a 5-year randomized, controlled trial is currently being conducted in Latin America to examine the effects of benznidazole on cardiac outcomes, new and better drugs must be developed for chronic disease, as well as better epidemiologic surveillance and vector control.

Reference

  1. Pinto Dias JC. The Treatment of Chagas Disease (South American Trypanosomiasis). Ann Intern Med. 2006;144:772-774.