ArticlesRandomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection
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.
Section snippets
Methods
The participants were recruited in three small communities in the north of Goiás–Posse (25 295 inhabitants), Simolândia (6242 inhabitants), and Guarani de Goiás (4766 inhabitants)–in central Brazil. These areas have endemic Chagas’ disease with high transmission rates and seroprevalence rates as high as 30% in the past decade.9 Details of the socioeconomic characteristics of the region have been reported elsewhere.10, 11 Demographic characteristics of the schoolchildren attending 60 village
Results
Figure 1 summarises the trial design and screening procedures for recruitment of participants. The two groups had similar age and sex distributions (table). Although all children were clinically free of symptoms, the ECG recorded at the beginning of the study showed abnormalities in 13. Nine children had complete right bundle branch block which indicates premature development of Chagas’ disease cardiomyopathy. The overall frequency of ECG abnormalities did not differ significantly between the
Discussion
Specific treatment of Chagas’ disease has been recommended only for the acute phase of the infection. Clearance of parasitaemia and disappearance of antibodies are taken as cure criteria.4, 22 Most reported trials have recruited adult patients under medical care in a late phase of chronic infection.23, 24 Cure assessment in chronic infection is controversial, mainly because of the lack of sensitive or specific tests to document parasitological cure.22, 23 Experience with benznidazole started
References (30)
- et al.
Effect of specific chemotherapy on the levels of lytic antibodies in Chagas' disease.
Trans R Soc Med Hyg
(1982) - et al.
Microplate enzyme-linked immunosorbent assay for Chagas' disease.
Lancet
(1975) - et al.
Lytic antibody titre as a means of assessing cure after treatment of Chagas disease: a 10 years follow-up study.
Trans R Soc Trop Med Hyg
(1993) - et al.
Physical activity, opportunity for reinfection, and sibling history of heart disease as risk factors for Chagas' cardiopathy.
Am J Trop Med Hyg
(1990) Chagas disease control in Brazil; which strategy after the attack phase?
Ann Soc Belg Méd Trop
(1991)- UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases. Tropical Disease Research:...
- et al.
Therapy of Chagas disease
- et al.
Enfermedad de Chagas congenita en la ciudad de Salta, Argentina.
Rev Inst Med Trop São Paulo
(1993) Control of Chagas disease
WHO Techni Rep Sers no 811
(1991)- et al.
Methods for field trials of interventions against tropical diseases: a ‘toolbox’
(1992)
Inquérito sorológico da prevalência de infecção chagásica no Brasil, 1975/1980.
Rev Inst Med Trop São Paulo
Evaluation of risk factors for house infestation by Triatoma infestans in Brazil.
Am J Trop Med Hyg
Risk factors for Trypanosoma cruzi infection among children in central Brazil: a case-control study in vector control settings.
Am J Trop Med Hyg
Surveillance of Trypanosoma cruzi transmission by serological screening of schoolchildren.
Bull World Health Organ
Serum diagnosis of American trypanosomiasis in blood banks: a highly sensitive and specific carbohydrate-rich trypomastigote antigen and why there are so many inconclusive results.
Mem Inst Oswaldo Cruz
Cited by (440)
Chagas disease
2024, The LancetBenznidazole, itraconazole, and their combination for the treatment of chronic experimental Chagas disease in dogs
2022, Experimental ParasitologyQSAR predictions on antichagas fenarimols
2022, Results in ChemistryAn α-Gal antigenic surrogate as a biomarker of treatment evaluation in Trypanosoma cruzi-infected children. A retrospective cohort study
2024, PLoS Neglected Tropical DiseasesPopulation pharmacokinetics of benznidazole in neonates, infants and children using a new pediatric formulation
2023, PLoS Neglected Tropical Diseases