Table 1. Summary of the characteristics of the studies included in the systematic review.
| Reference Country | Study Design | Age (years) Gender | Follow-up | Clinical Form | Sample Size | Groups | Primary End Points* | Secondary End Points* | Treatment discontinuation secondary to adverse effects |
|---|---|---|---|---|---|---|---|---|---|
| 1.De Andrade 1996 [38] (Galvao 2003) [39] Brazil |
Randomized, double-blind, placebo-controlled CT | 7–12 years F: 53% |
36 m | CP | 129 | 64: BNZ 7.5 mg/kg/day x 60 d | Negative serology values 37/64 | Negative PCR values 35/58 | 1 case: Morbilliform exanthema |
| 65: PLB | Negative serology values 3/65 | Negative PCR values 19/53 | |||||||
| 2. Coura 1997 [40] Brazil |
Randomized, apparently double-blind placebo-controlled CT | Adults NR |
12 m | CIP | 50 | 26 BNZ 5 mg/kg/day x 30 d | Negative XD 24/26 | Toxicity led to discontinuation in 11.5% of cases. | |
| 24 PLB | Negative XD 1/24 | Toxicity led to discontinuation in 8.3% of cases. | |||||||
| 3. Sosa Estani 1998 [41] Argentina |
Randomized, double-blind placebo-controlled CT | 6–12 years NR |
48 m | CIP | 106 | 55 BNZ 5 mg/kg/day x 60 d | Negative serology values 27/44 | Negative XD 40/42 | 10% of patients had moderate adverse events that disappeared when BNZ was suspended. |
| 51 PLB | Negative serology values 0/44 | Negative XD 21/43 | Not reported | ||||||
| 4. Catalioti 1998 [42] Venezuela |
Prospective Cohort | Mean 35 y Mean 42 y F 61% |
51–68 m | CP | 539 | 74 BNZ 5 mg/kg/day x 60d | Mortality 2/74 | Not reported | |
| 465 not treated | Mortality 8/465 | Not reported | |||||||
| 5. Lauria-Pires 2000 [43] Brazil |
Prospective Cohort | 31–60 years NR |
Mean 10 years | CP | 63 | 17 BNZ 10 mg/kg/day x 60d | Negative PCR values 0/17 | ||
| 46 not treated | Negative PCR values 3/46 | Not recorded | |||||||
| 6. Gallerano 2000 [44] Argentina |
Prospective-retrospective cohort | Mean 33.4 years F 50% |
Mean 5.3 years (80 m BNZ) |
CP | 798 | 130 BNZ 4–8 mg/kg/day 45-60d | Negative serology values 3/130 | 10% of patients discontinued BNZ. | |
| 668 not treated | Negative serology values 0/668 | Not reported | |||||||
| 7. Streiger 2004 [45] Argentina |
Prospective Cohort | 1–14 years F 60% |
BNZ 4–24 years (median 3 years) Not treated 8–24 years |
Early CP | 88 | 64 BNZ 5 mg/kg/day x 30 d | Negative serology values 23/42 | Two patients discontinued BNZ: one due to vomiting and the other due to cutaneous exanthema and edema | |
| 24 not treated | Negative serology values 0/14 | ||||||||
| 8. Viotti 2006 [18] Argentina |
Prospective Cohort | Mean 39 years F 54% |
Mean 9.8 years | CP | 566 | 283 BNZ 5 mg/kg/day x 30 d | Development of heart disease 12/283 Mortality 3/283 Negative serology values 32/218 |
Thirty-seven patients discontinued treatment due to adverse effects: allergic dermatitis (33) and GI intolerance (4). | |
| 283 not treated | Development of heart disease 40/283 Mortality 12/283 Negative serology values 12/212 |
Not reported | |||||||
| 9. De Castro 2006 [46] Brazil |
Observational prospective | Mean 49 years F 57% |
24 m | CP | 40 | 27 BNZ 5 mg/kg/day x 60 d | Negative blood culture values 24/27 | Three patients discontinued BNZ due to adverse reactions. | |
| 13 not treated | Negative blood culture values 6/13 | ||||||||
| 10. Fabbro 2007 [47] Argentina |
Prospective and retrospective observational | 17–46 years F 68% |
BNZ mean 20.6 years. Not treated mean 21.7 years |
CIP | 84 | 27 BNZ 5 mg/kg/day x 30d | Clinical progression 2/27 Negative serology values 9/27 |
Negative XD 27/27 | 6 patients from 9 with adverse effects discontinued treatment |
| 57 not treated | Clinical progression 9/57 Negative serology values 0/57 |
Negative XD 1/57 | |||||||
| 11. Viotti 2011 [48] Argentina |
Prospective Cohort | Mean 42 years F: 60% |
Median 36 m | CP | 142 | 53 BNZ 5 mg/kg/day x 30 d | Clinical progression 0/53 Negative serology values 11/53 |
Not recorded | |
| 89 not treated |
Clinical progression 0/89 Negative serology values 0/89 |
Not recorded | |||||||
| 12. Bertocchi 2013 [49] Argentina |
Prospective Cohort | Not reported for the entire population F:58% |
Not reported for the entire population | Not reported for the entire population | 925 | 545/925 BNZ 5 mg/kg/day x 30 d with a gradually increase of dose of 7 days | Negative serology values 82/545 | Not recorded | |
| 380/925 not treated | Negative serology values 25/380 | Not recorded | |||||||
| 13. Morillo 2015 [21] Argentina (559) Bolivia (357) Brazil (1358) Colombia (502) El Salvador (78) |
Randomized, double-blind, placebo-controlled CT | Mean 55 years F:51% |
2004–2011 (mean of 5.4 years) |
Chronic phase with cardiomyopathy | 2854 | 1431: BNZ 5 mg/kg/day 60 d | Occurrence of primary composite outcome^: 394/1431: | Negative PCR values at 2 years: 517/752 |
342/1429: Adverse Events Leading to Drug Interruption: Cutaneous rash (137/1429), Gastrointestinal symptoms (112/1429), Nervous system symptoms (52/1429), Serious Adverse Events Leading to Drug Interruption (119/1429) |
| 1423: placebo | Occurrence of primary composite outcome^: 414/1423 | Negative PCR values at 2 years: 275/778 |
135/1422: Adverse Events Leading to Drug Interruption: Cutaneous rash (18/1422), Gastrointestinal symptoms (41/1422), Nervous system symptoms: 19/1422 20/1422: Serious Adverse Events Leading to Drug Interruption |
||||||
| 14. Vallejo 2016 [50] Spain (93% Bolivian patients) |
Randomized, open label, CT | Median 35 years F:57% |
18 m | CIP | 14 | 7: BNZ 5 mg/kg/day x 60 d | Negative PCR post treatment after 12 months: 7/7 | 4/7: adverse reactions that lead to treatment discontinuation in BNZ group: | |
| 7: no treatment | Negative PCR after 12 months follow-up: 3/7 | ||||||||
| 15. Morillo 2017 [29] Argentina Chile Guatemala Colombia Mexico Spain |
Randomized- single blinded placebo- controlled CT | Mean 38.6 years F:57% (BNZ) F: 23% (placebo) |
180 days | CIP | 120 | 30: BNZ 5 mg/kg/day x 60 d** | Negative PCR at day 180: 26/30 |
||
| 30: placebo | Negative PCR at day 180: 3/30 |
||||||||
| 16. Torrico 2018 [30] Bolivia |
Randomized, double-blind, placebo-controlled CT | Mean 30 years F:74% |
12 m | CIP | 231 | 45: BNZ 5 mg/kg/day x 60 d | Negative PCR 37/45 | Treatment discontinuation: 4/45 | |
| 47: placebo | Negative PCR: 4/47 | Treatment discontinuation 0/47 | |||||||
| 17. Torrico 2021 [51] Bolivia |
Randomized, double-blind, placebo-controlled CT | 18–50 years Sex not reported |
12 m | CIP | 210 | 60: BZD 300mg/d 4-8w | Negative PCR: 45/52 | Patients with AR that lead to TD: 3 SAE | |
| 30: Placebo | Negative PCR: 1/30 | Patients with AR that lead to TD: 0 |
*The definition of primary and secondary endpoints is based on that established in our systematic review and may not coincide with that assumed as a primary and secondary in each study.
** BNZ 5 mg/kg/day x 60 day until February 2009 and BNZ fixed dose of 300 mg per day and a variable duration of therapy (between 40 and 80 days) on the basis of the patient`s weight since then.
^The primary study outcome in the time-to-event analysis was the first occurrence of death, resuscitated cardiac arrest, insertion of a pacemaker or an implantable cardioverter–defibrillator, sustained ventricular tachycardia, cardiac transplantation, new heart failure, stroke or transient ischemic attack, or a systemic or pulmonary thromboembolic event.
Abbreviations: AR: adverse reactions; BNZ, benznidazole; CIP: Chronic Indeterminate phase; CP: Chronic phase; CT: Clinical Trial; ECG: electrocardiography; F, female; GI, gastrointestinal; m: months; NFT, nifurtimox; NR: not reported; PCR, polymerase chain reaction; PLB, placebo; pt: patient; SAE: Serious adverse event; TD: Treatment discontinuation; w: weeks; XD, xenodiagnoses; y: years