Abstract: We included 13 studies involving 4229 participants (six RCTs, n = 1096, five RCTs of intermediate risk of bias, one RCT of high risk of bias; four non-randomised experiments, n = 1639 and three observational studies, n = 1494). Ten studies tested nitroderivative drugs nifurtimox or benznidazole (three exposed participants to allopurinol, one to itraconazole). Five studies were conducted in Brazil, five in Argentina, one in Bolivia, one in Chile and one in Venezuela. TT was associated with substantial, but heterogeneous reductions on parasite-related outcomes such as positive serology (9 studies, OR 0.21, 95% CI 0.10 to 0.44, I2 = 76%), positive PCR (2 studies, OR 0.50, 95% CI 0.27 to 0.92, I2 = 0%), positive xenodiagnosis after treatment (6 studies, OR 0.35, 95% CI 0.14 to 0.86, I2 = 79%), or reduction on antibody titres (3 studies, SMD -0.56, 95% CI -0.89 to -0.23, I2 = 28%). Efficacy data on patient-related outcomes was largely from non-RCTs. TT with nitroderivatives was associated with potentially important, but imprecise and inconsistent reductions in progression of CCC (4 studies, 106 events, OR 0.74, 95% CI 0.32 to 1.73, I2 = 66%) and mortality after TT (6 studies, 99 events, OR 0.55, 95% CI 0.26 to 1.14, I2 = 48%). The overall median incidence of any severe side effects among 1475 individuals from five studies exposed to TT was 2.7%, and the overall discontinuation of this two-month therapy in RCTs (5 studies, 134 events) was 20.5% (versus 4.3% among controls) and 10.4% in other five studies (125 events). Despite the evidence that TT reduced parasite-related outcomes, the low quality and inconsistency of the data for patient-important outcomes must be treated with caution. More geographically diverse RCTs testing newer forms of TT are warranted in order to 1. estimate efficacy more precisely, 2. explore factors potentially responsible for the heterogeneity of results and 3. increase knowledge on the efficacy/tolerance balance of conventional TT.

Plain-language summary: We searched scientific databases for studies comparing TT versus a placebo (an inactive or pretend treatment) or no treatment in people with Trypanosoma cruzi infection. The search is current to February 2014. We identified 13 studies comparing the outcomes of 4229 people after receiving TT or placebo. Five of these studies were from Argentina, five from Brazil, one from Venezuela, one from Chile and one from Bolivia. Receiving TT was associated with a 50% to 90% smaller chance of having circulating antibodies or parasitic material, as compared with non-treated people. However, the results on progression towards Chagas disease or death indicate smaller benefits. Furthermore, the results were also statistically inconclusive, did not rule out potential harm and had substantial variation across studies conducted in different countries or testing different drugs. About one in five individuals treated abandoned the treatment and one in 40 treated individuals had a severe reaction (needing hospitalisation, additional treatments or interruption of this treatment). We conclude that although TT may reduce the progression of Chagas disease, better quality studies are warranted before its use can be generally recommended for chronically infected individuals. New data should bring more certainty of the efficacy of TT and provide a precise evaluation of the balance between benefits and harms. Because of the variations across studies, these studies should include populations from more regions and test newer drugs. Only 25% of these data came from good-quality studies. Although most studies were published since 2000, all studies tested drugs developed in the 1960s.