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

Abstract

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.

A Rapid Review on the Efficacy and Safety of Pharmacological Treatments for Chagas Disease

“…We included three RCTs [ 20 , 21 , 22 ] and 10 observational studies [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. The studies were conducted in Latin American countries or in non-endemic countries with Latin American immigrants ( Table 1 ).…”

“…Of the 13 studies included, 11 reported the dosage of BNZ used [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 30 , 31 ], while the remaining two only reported “treated or untreated” based on participant response [ 29 , 32 ]. The most commonly used dosage of BNZ was 5 mg/kg/day orally for 60 days, with two studies using escalating doses (titration), starting at 50 mg on day one and increasing by 50 mg daily until reaching a 300 mg daily dose or in accordance with the participant’s weight ( Table 1 ) .…”

“…The trypanocidal drugs used in the included studies were BNZ, NFX, POS and E1224 (a water-soluble Ravuconazole); three studies [ 25 , 28 , 30 ] compared variations in BNZ dosing. Except for one study that initiated with acute patients, all studies participants were at some stage of indeterminate or chronic Chagas disease.…”

“…The studies reported varying frequency of AEs according to the trypanocidal used. Of the 13 studies, seven presented a thorough reporting [ 20 , 21 , 22 , 23 , 28 , 29 , 30 ], two had incomplete reporting [ 24 , 25 ], and four did not report any AEs [ 26 , 27 , 31 , 32 ]. Three studies did not report AEs because it was not an outcome of interest, and one because AEs were reported in the original study conducted by Morillo et al, 2015 [ 20 ], which is also included in this review.…”

“…Three studies used a variation from the standard BNZ regime. Two of these studies thoroughly reported safety outcomes [ 28 , 30 ], while the third [ 25 ] reported pooled outcomes with the standard dosing regimen; and for this reason the latter was not included in the calculation of overall AEs. Treatment discontinuation in the different dosing regimens was 31%.…”