A prospective, multicenter, randomized trial was conducted involving 2854 patients with chronic Chagas’ cardiomyopathy in which patients received either benznidazole or placebo for up to 80 days and were followed for a mean of 5.4 years. The primary outcome was time-to-event of any component of the composite outcome of death, resuscitated cardiac arrest, sustained ventricular tachycardia, insertion of pacemaker or implantable cardioverter-defibrillator, cardiac transplantation, new heart failure, stroke, or other thromboembolic event.

The primary outcome occurred in 27.5% of the benznidazole group and in 29.1% of the placebo recipients. Baseline polymerase chain reaction (PCR) assay was performed on blood from 1896 patients, and 61% were positive for Trypanosoma cruzi. Sixty-six percent of the benznidazole-treated patients and 34% of the placebo-treated patients converted to negative by this PCR assay at the end of treatment. However, only 47% and 33% of benznidazole and placebo-treated patients, respectively, remained PCR-negative at 5 years or more.

Geographic variation in treatment response was seen with odds ratio (OR) of PCR conversion in Brazil of 3.03 at 2 years and 1.87 after 5 years. In Columbia and El Salvador, the OR was 1.33 at 2 years and 0.96 at 5 years. In Argentina and Bolivia, the odds ratio was 2.63 at 2 years and 2.79 at 5 years or more. PCR conversion did not correspond to effects on clinical outcomes.

Serious adverse events leading to drug interruption or discontinuation were more common in benznidazole recipients comparet to placebo recipients, with 6.7% of benznidazole vs. 1.1% of placebo recipients requiring permanent treatment discontinuation. Common adverse events included skin rash, gastrointestinal symptoms, and peripheral neuropathy.

COMMENTARY

Chagas’ disease is the third most common parasitic disease in the world (after malaria and schistosomiasis).1 Unfortunately, in humans, acute infection with Chagas’ usually presents as a nonspecific, self-limited febrile illness, which in about one-third of patients results in progressive non-ischemic cardiomyopathy (after a latent period of two or more decades). While acute infection (if recognized) can be cured with trypanocidal drugs, the utility and effectiveness of anti-parasitic therapy in patients with established cardiac disease has been uncertain.

The results of this trial are disappointing in that while some anti-parasitic effect (as assessed by PCR) was seen with benznidazole, this did not translate into any significant clinical benefit. The potential reasons for this lack of clinical efficacy could include factors such as: It may be that treatment is “too little, too late” for benznidazole to reverse established myocardial damage; Perhaps more prolonged courses of treatment would be more effective; Antigen persistence in the myocardium may result in an ongoing immune response, which is not affected by antiparasitic therapy.

In any case, it is imperative that earlier diagnosis of T. cruzi infection be made so that treatment of early acute disease (which is potentially curable) can be done. Awareness and earlier recognition of Chagas’ disease is of increasing importance to North American physicians since endemic transmission of Chagas’ is now clearly occurring in Texas.

REFERENCE

  1. Bern C. Chagas’ disease. N Engl J Med 2015;373:456-466.