Comparison of the toxicity of two treatment schemes with benznidazole for chronic Chagas disease: a prospective cohort study in two Spanish referral centres.

OBJECTIVES: Chagas disease (CD) treatment is limited to two therapeutic options: benznidazole (generally the first option in Spain) and nifurtimox. Both drugs present high rates of adverse reactions and treatment discontinuation and there is no consensus regarding the most effective administration schedule for benznidazole or how to prevent and manage treatment toxicity. We aim to compare the tolerability and treatment discontinuation rate between two different treatment schemes with benznidazole. METHODS: This was a prospective observational study of adult patients with CD, enrolled from January 2014 to March 2018 in two referral centres in Madrid (Spain). Participants were treated either with benznidazole 5 mg/kg/day (full dose) over 60 days (benznidazole standard dose scheme (BSD)), or with an escalating dose lasting 5 days up to a maximum of 300 mg/day (benznidazole increasing dose scheme (BID)). RESULTS: 471 patients were analysed: 201 in the BSD group and 270 in the BID group. There were no significant differences regarding age (40.4 (SD 8.7) vs 41 (SD 8.2) years), sex (74.1% (149/201) vs 68.5% (185/270) women), weight (69.4 (SD 12.8) vs 68.9 (SD 11) kg) or nationality (97.5% (196/201) vs 96.7% (261/270) Bolivians) between groups. There were also no differences in adverse reactions rate (55.2% (111/201) vs 55.6% (150/270)), number of adverse reactions per patient, adverse reactions type (except for arthralgias and myalgias which occurred more frequently in the BID group (0% (0/111) BSD vs 8% (12/150) BID; p 0.002)) and degree and time to first adverse reactions. There was significantly more treatment discontinuation (49.8% (100/201) vs 33.0% (89/270); p <0.001) in the BSD group, but not during the first 30 days of treatment (32.3% (65/201) vs 25.6% (69/270); p 0.08). CONCLUSION: The use of increasing doses of benznidazole for 5 days and a maximum dose of 300 mg, does not significantly improve drug tolerability. However, while the treatment discontinuation rates were similar during the first 30 days of treatment, it may improve the treatment completion rate at 60 days.

Toxicity of nifurtimox as second-line treatment after benznidazole intolerance in patients with chronic Chagas disease: when available options fail.

OBJECTIVE: To describe the tolerability and rate of nifurtimox discontinuation when administered as a second-line treatment to patients with previous treatment interruptions due to adverse reactions with benznidazole. METHODS: We studied a prospective cohort study of adult patients with chronic Chagas disease in a referral centre in Spain treated from July 2007 to July 2017. We analysed the tolerability profile and treatment interruption rate due to adverse reactions (ARs) to nifurtimox in patients previously incompletely treated (less than 30 days) with benznidazole due to ARs. RESULTS: A total of 472 patients initiated treatment with benznidazole during the study period. Of these, 118 (25%) developed ARs that led to treatment discontinuation before 30 days of therapy. Fifty-three (44.9%) of 118 initiated nifurtimox as second-line treatment; most were women (79.3%), were of Bolivian origin (98.1%) and had a median age of 37.3 years (interquartile range, 29.8-43.2). The most common ARs with nifurtimox were cutaneous hypersensitivity (24.1%), digestive disorders (22.2%), fever (12.9%), neurologic disturbances (11.1%), depression, anxiety or insomnia (9.2%), dyspnoea (7.4%), myalgia (5.5%), and dizziness, asthenia or malaise (7.4%). Twenty-six (49.1%) of 53 patients discontinued nifurtimox due to ARs, all of them before the required minimal therapy duration of 60 days. There were no deaths. CONCLUSIONS: Treatment of chronic Chagas disease relies on two drugs with a poor tolerability profile. In our cohort, 12.3% of the patients who initiated benznidazole and subsequently nifurtimox in case of nontolerance developed ARs that led to permanent treatment discontinuation. Most were women of childbearing age, a group for whom therapy has the added benefit of interrupting vertical transmission.