Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection

Summary

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% Cl 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.

Introduction

American trypanosomiasis or Chagas’ disease is a chronic disease caused by the parasite Trypanosoma cruzi. The disease is transmitted by a triatomine insect vector and also by blood transfusion and transplacentally. The infection may cause an acute self-limited disease, which evolves to a symptomless period, known as indeterminate phase. Several years after infection about 30% of individuals present clinical evidence of heart disease, and around 8% develop megavisceras. However, geographical variations in the frequency of the different clinical forms and in severity have been reported.¹ Chagas’ heart disease is one of the main causes of disability and death in many Latin American cities. The control activities implemented in the endemic countries are based on elimination of the insect vector from houses, improvements in housing, and promotion of universal blood screening among blood donors. Seroprevalence rates among young children have fallen from 28% to 1% during the past 15 years, but official estimates indicate that more than 15 million people in South America are infected.2, 3

Infection is thought to be life-long, though detection of parasitaemia during the chronic phase is very difficult. Specific chemotherapy with benznidazole or nifurtimox has been recommended for treatment of acute and congenital infection, as shown by the clearance of parasitaemia and the disappearance of antibodies to T cruzi (negative seroconversion).4, 5 The effect of treatment in the chronic phase is controversial and difficult to demonstrate because there are no specific criteria for success during this phase.⁶ Clinical trials with drugs including nifurtimox, allopurinol, and benznidazole did not show any effect of treatment in preventing the development of chronic Chagas’ disease.3, 4, 7 The general assumption, however, is that the earlier the diagnosis is made and the specific treatment initiated, the greater the chance of parasitological cure.⁷

Before treatment of infected children as a public health measure can be recommended, full-scale investigation of drug safety and efficacy in this target group, preferably under field conditions,⁸ is essential. An effective treatment might prevent the progression of infection to disease and its complications. Large-scale treatment might also decrease the pool of infected individuals in the population, thus reducing the risk of transmission.

We report the results of a phase III randomised double-blind placebo-controlled field trial of benznidazole in the early chronic phase of T cruzi infection carried out from 1991 to 1995 in an endemic area in Brazil.