Table 1. Studies evaluating benznidazole dosing regimens in adult patients with chronic Chagas disease (n=23).
| Author/Country | Sample size | Treatment regimen of benznidazole | Follow-up period post treatment | Analyzed outcome | Limitations |
|---|---|---|---|---|---|
| Alvarez et al.6 Argentina | Total sample size n=20 qPCR n= 17 | 5 mg/kg/day, divided into two daily doses every 5 days, for a total of 60 days (12 days of intermittent treatment). | 67 days | PCR Adverse effects: severity and suspension rate | The efficacy of treatment as measured by qPCR was limited to a short-term follow-up period. Thecomparison of quantitative PCR (qPCR) occurred before and one week after the end of treatment. . |
| Andrade et al.12 Brazil | Total sample size n=13 BNZ n=13 | 5 mg/kg/day/60 days | 4 years | Serological parameters Cardiac conditions | - |
| Andrade et al.13 Brazil | Total sample size n=30 BNZ n=30 | 5 mg/kg every 8 hours/ 60 days | 6 years | Serological parameters Cardiac conditions | Difficulty to perform the follow-up for a long period of time as the patient's lived in rural areas. |
| Antunes et al. 20 Brazil | Total sample size n=241 BNZ n=43 BNZ ≤ 60 days, n=28 (50 days n = 5; 60 days n = 23) BNZ > 60 days; n=15 (90 days n=4, 100 days n=4, 120 days n=3, 180 days n=1, 200 days n=1,250 days n=1, 700 days n=1) Control group (untreated) n=198 | No dose information BNZ for 50-60 days | Until 700 days | PCR Cardiac conditions | Bias and the absence of information in the study population relating to dosage and the length of time after treatment completion; The adoption of positive ELISA results in the inclusion criteria may have led to the exclusion of serologically cured patients, thereby reducing the ability to detect differences favoring the treatment; The small sample population probably reduced the statistical power to detect differences. |
| Braga et al.21 Brazil | Total sample size n=51 BNZ n=17 BNZ/30 days: n=7 BNZ/60 days: n=10 Untreated group n=17 Control group (non-Chagas individuals) n=17 | 10 mg/Kg/day/30 or 60 days | 10 years | PCR Molecular method | - |
| Coura et al.22 Brazil | Total sample size n=77 Nifurtimox n=27 BNZ n=26 Control group (placebo) n=24 | 5 mg/kg/twice daily/ 30 days | 1 year | Parasitological, serological and clinical parameters (cardiac conditions) | - |
| Fabbro et al.23 Argentina | Total sample size n=111 Nirfutimox n=27 BNZ n=27 Control group (untreated) n=57 | 5 mg/kg/day/30 days with half of the dose in the first week. | 21 years | Parasitological, serological and clinical parameters (cardiac conditions) | There was lack of randomization of the groups, as most infected patients whose xenodiagnosis were positive, received treatment. |
| Fernández et al. 11 Argentina | Total sample size n=6 BNZ n=6 | 2.5-5.5 mg/Kg/60 days (2.50, 2.60, 4.12, 4.55, 4.55, 5.48) | 06 months | PCR | - |
| Lana et al.14 Brazil | Total sample size n=28 BNZ n=28 | 5-10 mg/kg/day for 40-60 consecutive days | 9 years | PCR Parasitological, serological and clinical parameters (cardiac conditions) | There was a low number of available samples. There was no intrinsic control group. |
| Laucella et al. 24 Argentina | Total sample size n=75 BNZ n=43 Control group (untreated) n=32 | 5 mg/kg/day/ 30 days | 3-5 years | Immunological, serological and clinical parameters | - |
| Levi et al.15 Brazil | Total sample size n=49 BNZ n=41 NirfutImox n=8 | 5 mg/kg/day to 8 mg/kg/day/60 days | Ranged from 1 to 20 years (mean: 6 years. 7 months). | Parasitological parameters | - |
| Molina et al.25 Bolivia, Brazil and Paraguay | Total sample size n=78 BNZ n=26 High-dose POS n=26 Low-dose POS n=26 | 150 mg twice daily/ 60 days | 10 months | PCR Adverse effects: suspension rate | PCR results were not used as a measure of efficacy or cure, only as a marker of treatment failure. |
| Morillo et al.26 Argentina, Bolivia, Brazil, Colombia and El Salvador | Total sample size n=2854 BNZ n=1431 Control group (placebo) n=1423 | 300 mg per day with a variable duration of therapy (40 to 80 days) | 5.4 years | PCR Cardiac conditions | The 95% confidence intervals rule out a relative risk reduction of 20%, which is smaller than the difference that the study was designed to detect. |
| Morillo et al.27 Argentina, Chile, Colombia, Guatemala, Mexico and Spain | Total sample size n=120 POS n=30 BNZ+placebo n=30 POS + BNZ n=30 Control group (placebo) n=30 | POS:400 mg twice daily/60 days BNZ+placebo:200 mg daily/60 days POS+BNZ: 400+200 mg twice daily/60 days Placebo:10 mg twice daily/ 60 days | 1 year | PCR | Follow-up was limited to only one year and the effect of trypanocidal treatment on progression to cardiomyopathy is unknown. |
| Oliveira et al.16 Brazil | Total sample size n=45 BNZ n=21 Control group (untreated) n=24 | 5 mg/kg twice daily/60 days | 6 months | Blood culture PCR Cardiac conditions | The small number of treated patients. Most subjects in the chronic phase of the disease did not fulfill the inclusion criteria, limiting the number of patients The effects of BNZ during treatment or for a long time after treatment were not investigated. |
| Pérez-Antón et al. 19 Spain | Total sample size n=50 BNZ n=38 Control group (non-Chagas individuals) n=12 | 5 mg/kg/day/60 days | 4 years | PCR Immunological parameters | - |
| Perez-Mazliah et al.17 Argentina | Total sample size n=50 Allopurinol and BNZ n=15 Untreated subjects n=17 BNZ alone n=9 Control group (non-Chagas individuals) n=9 | Allopurinol: 600 mg/day/90days followed by 30 days of BNZ (5 mg/kg/day) | 3 years | Immunological, Serological and clinical parameters | - |
| Pinazo et al.28 Spain | Total sample size n=54 BNZ n=54 | 5 mg/kg/day/ 60 days | 1 year | Adverse effects Biochemical and hematology testing | The serum concentrations of benznidazole metabolites were not measured and they might play an important role in toxicity. |
| Pinazo et al.29 Spain | Total sample size n=99 BNZ n=56 Control group (non-Chagas individuals) n=43 | 5 mg/kg/day/ 60 days | 3 years | Hemostasis tests PCR Biochemical testing Basic blood testing | A larger sample could have detected differences that would be expected to appear earlier (e.g., before 12 months). The lost to follow-up samples affected the estimates. It is difficult to follow-up individuals with high migratory mobility for long periods. The fact that only 30% of patients had a positive baseline qRT-PCR result was a constraint for assessing the effect of treatment. |
| Torrico et al.30 Bolivia | Total sample size n=560 BNZ n=45 Control group (untreated) n=89 | 5 mg/kg/day/ 60 days | 1 year | PCR Serological parameters | - |
| Vallejo et al.33 Spain | Total sample size n=14 BNZ n=7 Control group (untreated) n=7 | 5 mg/kg twice daily/ 60 days | 18 months | PCR Immune parameters | Small sample size. Problems with the follow-up of some patients that have impaired the analysis of parameters at specific time points. |
| Viotti et al.31 Argentina | Total sample size n=566 BNZ n=283 Control group (untreated) n=283 | 5 mg/kg/day/ 30 days | Median time 9.8 years | Serological parameters Cardiac conditions Disease progression (defined as a change to a more advanced Kuschnir group or death). | Non-random, unblinded treatment assignment was used, and follow-up data were missing for 20% of the patients. Loss to follow-up was more common among patients who were less sick. |
| Viotti et al.32 Argentina | Total sample size n=142 BNZ n=53 Control group (untreated) n=89 | 5 mg/kg/day/ 30 days | 3 years | Serological parameters Cardiac conditions | The non-randomized design. Results should be also extrapolated with caution due to the possibility that diverse T. cruzi lineages may have different susceptibilities to BNZ. |
POS = Posaconazole; qPCR = quantitative polymerase chain reaction; F1+2 = Prothrombin fragment 1+2; ETP = endogenous thrombin potential; PAP = plasmin-antiplasmin complexes