Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection. Epidemiology of helminth infections: implications for parasite control programmes, a South African perspective.
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.
                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.
                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).
                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. To determine the epidemiology of helminthic infections and the efficacy of parasite treatment among rural South African primary school children in the province of KwaZulu-Natal. To assess the South African government's parasite control policy.
                The study recruited 268 school children, aged 8 to 10, and randomly allocated them into treatment and placebo groups (treatment consisted of a single dose of albendazole (400 mg) and praziquantel (40 mg/kg)). Anthropometric measurements and the prevalence and intensity of helminth infections were taken at baseline (prior to treatment) and 16 weeks post treatment. Two weeks after treatment prevalence and intensity were again measured for an approximate 50% sub-sample of the children to investigate efficacy of treatment. An analysis of the South African government's policies concerning parasite control is assessed in the light of these epidemiological findings.
                Low levels of both stunting and wasting were observed throughout the study (approximately 10% and 1%, respectively), but did not vary significantly across either treatment group or time period (P >0.50). At baseline the observed prevalences for the three main helminths found in this study among the treated children were Ascaris lumbricoides 29.5%, Trichuris trichiura 51.9% and Schistosoma haematobium 22.3%. These prevalences declined significantly to 4.7% (P <0.0005), 38.0% (P < 0.03), and 3.3% (P < 0.0002), respectively, 16 weeks post treatment. The majority of infections observed at baseline were of light intensity, namely A. lumbricoides (50%), T. trichiura (80%) and S. haematobium (100%), and following treatment these levels were reduced significantly (P <0.0001, P< 0.05 and P < 0.005, respectively). The levels of both prevalence and intensity in the untreated group remained constant. The cure rates over the first two weeks of the study were found to be 94.4% for A. lumbricoides, 40% for T. trichiura and 72.2% for S. haematobium.
                The benefits of targeted, school-based treatment in reducing the prevalence and intensity of infection supports the South African government's focus of using school-based interventions as part of an integrated parasite control programme. These strategies and programmes are consistent with recommendations of the World Health Organization (WHO) and The United Nations Children's Fund (UNICEF).
Despite major public health importance, trypanocidal·therapy for chronic asymptomatic T. cruzi infection has been tested in few, small size RCTs which were designed to assess parasitic-related, but not clinical outcomes. Therefore, the potential of trypanocidal therapy to prevent Chagas' disease among asymptomatic, chronically infected subjects is promising, but remains to be evaluated. Trypanocidal therapy, particularly nitroimidazolic derivatives given to children or adults with positive xenodiagnosis improve parasite-related outcomes. The large contrast between the burden of Chagas disease and the existing evidence on its prevention points the need to test these or newer agents in more and larger RCTs that include clinical endpoints.