BACKGROUND: Chagas disease is caused by infection with Trypanosoma cruzi. In adults, treatment with benznidazole is associated with a high incidence of adverse drug reactions (ADRs). However, in infants and children, treatment with benznidazole seems associated with a lower incidence and decreased severity of ADRs, but these effects have not been clearly characterized. OBJECTIVE: We aimed to describe ADRs observed in infants and children treated with benznidazole. PATIENTS AND METHODS: We conducted a prospective cohort study of infants and children in Argentina with Chagas disease treated with benznidazole. RESULTS: A total of 107 infants and children diagnosed with asymptomatic Chagas disease (mean age: 6.9 years) were enrolled in the study. Sixty-two events (in 44 children) were considered benznidazole related. Mean ADR duration was 8.2 days. ADRs were mild (80.6%), moderate (16%), or severe (3.2%). Most (77.3%) ADRs were in children older than 7 years. Skin was the organ with the highest incidence of ADRs (21%), followed by the central nervous system (9%) and the gastrointestinal tract (8.5%). Also, the ADR rate was lower in infants and toddlers compared with older children (18% vs 53%) (P < .001). CONCLUSIONS: Treatment with benznidazole was well tolerated in children. Most ADRs were mild and did not require treatment suspension. A strong association was observed between ADR incidence and patient age, and most ADRs occurred in children older than 7 years. We believe that anxiety over potential severe ADRs in children with Chagas disease is not justified and should not be an obstacle to using benznidazole.

Nifurtimox is a recommended treatment for Chagas disease, but data from treated children are limited. We investigated the efficacy, safety and tolerability of nifurtimox administered as divisible, dispersible 30 mg and 120 mg tablets in children with Chagas disease. In this blinded, controlled study conducted January 2016–July 2018, 330 patients aged <18 years from 25 medical centres across three South American countries were randomised 2:1 to nifurtimox 10–20 mg/kg/day (aged <12 years) or 8–10 mg/kg/day (aged ≥12 years) for 60 days (n = 219), or for 30 days plus placebo for 30 days (n = 111) (ClinicalTrials.gov NCT02625974). The primary outcome was anti-Trypanosoma cruzi serological response (negative seroconversion or seroreduction ≥20% in mean optical density from baseline determined by two conventional enzyme-linked immunosorbent assays) at 12 months in the 60-day treatment group versus historical placebo controls. Nifurtimox for 60 days achieved negative seroconversion (n = 10) and seroreduction (n = 62) in 72 patients (serological response 32.9%; 95% confidence interval [CI] 26.4%, 39.3%, of all treated patients), confirming superiority relative to the upper 95% CI of 16% for controls. In patients aged <8 months, 10/12 treated for 60 days (83.3%) and 5/7 treated for 30 days (71.4%) achieved negative seroconversion. Overall serological response was lower for 30-day than for 60-day nifurtimox (between-treatment difference 14.0% [95% CI 3.7%, 24.2%]). The frequency of T. cruzi-positive quantitative polymerase chain reactions decreased substantially from baseline levels (60-day regimen 53.4% versus 1.4%; 30-day regimen 51.4% versus 4.5%). Study drug-related treatment-emergent adverse events (TEAEs), which were observed in 62 patients (28.3%) treated for 60 days and 29 patients (26.1%) treated for 30 days, were generally mild or moderate and resolved without sequelae; 4.2% of all TEAEs led to nifurtimox discontinuation. Age- and weight-adjusted nifurtimox for 60 days achieved a serological response at 12 months post-treatment that was superior to historical placebo, was well tolerated and had a favourable safety profile in children with Chagas disease. Although, at 1 year serological follow-up, efficacy of the shorter nifurtimox treatment was not comparable to the 60-day treatment regimen for the overall study population, further long-term follow-up of the patients will provide important information about the progress of serological conversion in children treated with nifurtimox, as well as the potential efficacy difference between the two regimens over time.

BACKGROUND: Nifurtimox (NF) is one of the only two drugs currently available for Chagas disease (ChD) treatment. However, there is scarce data on NF safety, and many physicians defer or refuse NF treatment because of concerns about drug tolerance. METHODS: Retrospective study of adverse drug reactions (ADRs) associated with NF treatment of ChD. Children received NF doses of 10-15 mg/kg/day for 60-90 days, and adults 8-10 mg/kg/day for 30 days. Results: 215 children (median age: 2.6yrs, range 0-17) and 105 adults (median age: 34yrs, range 18-57) were enrolled. Overall, 127/320 (39.7%) patients developed ADRs, with an incidence of 64/105 in adults, and 63/215 in children (OR = 3.7, 95%CI [2.2;6.3]). We observed 215 ADRs, 131 in adults (median: 2 events/patient (IQR_25-75= 1-3) and 84 in children (median: 1 event/patient (IQR_25-75= 1-1.5) (P_Adjusted < 0.001). ADRs were mainly mild and moderate. Severe ADRs were infrequent (1.2% in children and 0.9% in adults). Nutritional, central nervous and digestive systems were the most frequently affected, without differences between both groups. Treatment was discontinued in 31/320 (9.7%) patients without differences between groups. However, ADR-related discontinuations occurred more frequently in adults than in children (OR = 5.5, 95%CI = [1.5;24]). CONCLUSIONS: Our study supports the safety of NF for ChD treatment. Delaying NF treatment due to safety concerns does not seem to be supported by the evidence.

Chagas disease (ChD), caused by Trypanosoma cruzi , has a global prevalence due to patient migration. However, despite its worldwide distribution, long-term follow-up efficacy studies with nifurtimox (NF) are scarce and have been conducted with only small numbers of patients. A retrospective study of a large cohort of ChD treated children and adults with NF.