Clinical and pharmacological profile of benznidazole for treatment of Chagas disease

Figures & data

Table 1. Clinical studies to assess efficacy against Trypanosoma cruzi infection in chronic phase. 1971–2018.

Source (first author, year)	Country	Study design and sample size (N)	Age group	Dosage	Length of follow-up (years)	Serological test* (% Negative)	Parasitological/molecular test** (% Positive)
Cerisola 1971	Argentina	Observational N: 33	Adults	4–10 mg/kg/d	0.2–2.7	CS (0.0)	XD (6.1)
Shenone 1981	Chile	Cohort N: 21	Adults	8–15 mg/kg/d for 30 days	6.9 (mean)	CS-IHA- (0.0)	XD (13.0)
Vigliano 1989	Argentina	Cohort N: 131	Adults	5 mg/kg/d for 35 days	7.5 (mean)	CS-IHA, IIF- (16.0)	Not reported
Gallerano 1990	Argentina	Clinical trial N: 51	Adults	5 mg/kg/d for 60 days	7.2	CS-FC- (49.0) CS-HIA- (34.0)	XD (27.0)
de Oliveira, 1990	Brazil	Cohort N: 50	Children and Adults	5–8 mg/kg/d for 60 days	2.0	CS-IHA, IIF- (8.0)	XD (40.0)
Viotti 1994	Argentina	Observational N: 110	Adults (>18 years old)	5 mg/kg/d for 30 days	8.0	CS-IHA, EIA- (35.0)	XD (4.0)
de Andrade 1996	Brazil	Clinical trial N: 64	Children	7.5 mg/kg/d. for 60 days	3.0	CS-IHA, IIF, EIA- (0.0) NCS-EIA AT 24- (57.8)	ND
Maldonado 1995	Paraguay	Cohort N: 20	Children	5–7 mg/kg/d for 60 days	0.5	CS-IHA, IIF, EIA- (0.0)	XD (0.0)
Coura 1997	Brazil	Clinical trial N: 50	Adullts	5 mg/kg/d. for 30 days	1.0	Not reported	XD (7.7)
Sosa-Estani 1998	Argentina	Clinical trial N: 55	Children	5 mg/kg/d for 60 days	4.0	CS-IHA, IIF, EIA- (11.3) NCS-EIA F29- (62.0)	XD (4,7)
Fabbro 2000	Argentina	Observational N: 38	Children and adults	5 mg/kg/d. for 30 days	14.0	CS-IIF- (5.3)	XD (0.0)
Gallerano 2000	Argentina	Cohort N: 130	Adults	4–8 mg/kg/d for 45–60 days	5.3	CS-IHA, IIF- (0.0)	XD (23.5)
Silveira 2000	Brazil	Cohort N: 10	Children	5–7 mg/kg/d for 60 days	8–20.0	CS-IHA- (37.5) CS-IIF, EIA- (12.5)	XD (12.5) PCR (12.5)
Britto 2001	Brazil	Cohort N: 26	Children and Adults	5–6 mg/kg/d for 30–60 days	20.0	Not reported	XD (16.6) PCR (35.4)
Cançado 2002	Brazil	Observational N: 113	9 to 69	5 mg/kg/d. for 60 days	6.0–18.0	CS-IHA, EIA- (7.9)	ND
Sosa-Estani 2002	Argentina	Observational N: 83	1–4 years old	5 mg/kg/d for 60 days	1.6 (n = 75) 5.0 (n = 8)	CS-IHA, EIA- (49.3) CS-IHA, EIA- (87.2)	ND
		N: 91	5–9 years old	5 mg/kg/d for 60 days	1.6 (n = 61) 5.0 (n = 13) 9.0 (n = 17)	CS-IHA, EIA- (33.7) CS-IHA, EIA- (62.9) CS-IHA, EIA- (88.2)
		N: 59	10–14 years old	5 mg/kg/d) for 60 days	1.6 (n = 11) 5.0 (n = 19) 9.0 (n = 29)	CS-IHA, EIA- (0.0) CS-IHA, EIA- (52.6) CS -IHA, EIA- (69.0)	XD (4.3)
Altcheh 2003	Argentina	Observational N: 13	Children	5–8 mg/kg/d. for 60 days	6.2 (mean) (range 2–13)	CS-IHA, EIA- (80.0) NCS-F 2/3 Ag- (100.0)	ND
Schijman 2003	Argentina	Observational N: 30	Children	5–8mg/kg/d. for 60 days	3.0	CS-IHA, EIA- (23.3)	PCR (4.2)
Diniz-Marques 2003	Brazil	Cohort N: 48	Children	5–10 mg/kg/d for 60 days	2.0	CS-IHA, EIA- (18.7)	Not reported
Streiger 2004	Argentina	Observational N: 49 (64 en RS PlosOne)	Children	5mg/kg/d. for 30 days		CS-DA 2ME, IHA, IIF- (59.2)	XD (0.0)
Meira 2004	Brazil	Cohort N: 31	Adults	5 mg/kg/d for 60 days	2.3 (mean)	CS-IHA, IIF, EIA- (0.0) NCS-CoML- (66.6)	PCR (33.3)
Vera de Bilbao 2004	Paraguay	Cohort N: 12	Children	5–7 mg/kg/d for 60 days	2.0	CS-IIF, EIA- (0.0)	XD (0.0)
de Andrade 2004	Brazil	Clinical trial N: 58	Children	7.5 mg/kg/d. for 60 days	6.0	NCS-EIA AT 24- (84.7)	PCR (39.7) [described in Galvao et al. 2003]
Viotti 2006	Argentina	Obaservational N: 153	Adults	5 mg/kg/d for 30 days	6.0	CS-IHA, IIF- (20.9)	XD (4.0)
Lacunza 2006	Argentina	Cohort N: 14	Adults	5 mg/kg/d for 60 days	0.5	CS-IHA, EIA- (0.0)	PCR (14.3)
Flores-Chavez 2006	Bolivia	Cohort N: 35	Children	8 mg/kg/d for 60 days	1.0	CS-EISA- (4.5) NCS-EIA SAPA-(31.8)	PCR (0.0)
de Castro 2006	Brazil	Cohort N: 27	Adults	5 mg/kg/d for 60 days	2.0	Not reported	HC (11.1)
Sanchez-Negrette 2008	Argentina	Observational N: 18	Adults	5 mg/kg/d) for 60 days	3.8 (mean)	CS-IHA- (5.2) NCS-CMA-EIA- (77.7) NCS-RAM-EIA- (0.0) NCS-IRA-EIA-Ag 13- (66.7)	ND
Sosa-Estani 2009	Argentina	Cohort N: 16	Children	5 mg/kg/d for 60 days	14.0	CS-IHA- (62.5) CS-IIF- (43.8) CS-EIA- (87.5) NCS-EIA F29- (87.5)	XD (0.0) PCR (12.5)
Yun 2009	Honduras Guatemala Bolivia	Cohort N: 232 N: 124 N: 2449	Children	5–7.5 mg/kg/d for 60days	1–3 1.5 5.0	CS-EIA- (92.7) CS-EIA- (58.0) CS-EIA- (5.3)
Fernandes 2009	Brazil	Cohort N: 80	Children and adults	5 mg/kg/d for 60 days	3.0	CS-IIF, EIA- (5.0)	PCR (88.7)
de Lana 2009	Brazil	Cohort N: 16	Children and Adults	5–10 mg/kg/d for 40–60 days	9.0	CS-EIA- (0.0) NCS-FC-Alta IgG- (0.0)	PCR (87.2)
Viotti 2009	Argentina	Cohort N: 760	Adults	5 mg/kg/d for 30 days	10.4 (± 7.8)	CS-IHA, IIF, EIA- (8.8)	Not reported
Fabbro 2010	Argentina	Observational N: 55	Adults	5mg/kg/d. for 30 days	23.0	CS-IHA- (37.7) CS-IIF- (45.5) CS-EIA- (45.5)	XD (0.0)
Hasslocher-Moreno, 2010	Brazil	Cohort N: 62	Adults	5 mg/kg/for 30–60 days	12.0	CS-IIF- (4.8)	XD (1.6)
Viotti 2011	Argentina	Cohort N: 53	Adults	BNZ (n = 53): 5 mg/kg/d for 30 days	3.0	CS-IHA, IIF, EIA- (20.8) NCS-Multiplex- (81.2)	Not reported
Pérez Ayala 2011	Spain	Cohort N: 64	Adults	BNZ (n = 64): 5 mg/kg/for 30–60 days	1.0	CS-IIF, EIA- (0.0)	PCR (0.0)
Machado-de-Assis 2012	Brazil	Cohort N: 94	Children and Adults	5–10 mg/kg/d for 40–60 days	16.9 (± 6.8)	CS-IHA, EIA- (11.7) CS-IIF- (24.7)	PCR (44.8)
Fabbro 2013	Argentina	Cohort N: 29	Adults	5–10 mg/kg/d for 40–60 days	23.0	CS-EIA- (44.8) NCS-F29- (89.5)	Not reported
Rumi 2013	Argentina	Cohort N: 22	Children	5 mg/kg/d for 60 days	2.0–5.0	CS-IHA- (0.0) CS-EIA- (9.1)	PCR (4.8)
Molina 2014	Spain	RCT N: 26	Adults	300 mg daily for 60 days	0.8	CS-EIA- (0.0)	Rt-PCR (38.5)
Fabbro 2014	Argentina	Cohort N: 73	Children and Adults	5 mg/kg/d for 30 to 60 days	22.7	CS-IHA, EIA- (43.8)	Not reported
Moscatelli 2015	Argentina	Cohort N: 14	Children and Adults	6.2 mg/kg/d for 30 to 60 days	5.0	CS-IHA, EIA- (6.7)	PCR (0.0)
Fragatta-Filho 2016	Brazil	Cohort N: 263	Adults	5 mg/kg/d for 60 days	19.6	CS-IIF- (37.5)	Not reported
Sartor 2017	Argentina	Cohort N: 66	Children	5 mg/kg/d for 60 days	0.5	Not reported	PCR (1.5)
Torrico 2018	Bolivia	RCT N: 45	Adults	5 mg/kg/d for 60 days	1.0	CS-EIA (0.0)	PCR (18.0)

*CS = conventional serology (EIA, IIF, and IHA); NCS = non-conventional serology. IIF = indirect immunofluorescence; EIA = enzyme-linked immunosorbent assay; IHA = indirect hemagglutination.

**PCR = polymerase chain reaction; XD = xenodiagnoses.

Figure 1. (a). Percentage of patients with non-reactive serological test (cure) after treatment. Children and adult patients with short- and long-term follow-up. (b). Percentage of patients with positive xenodiagnosis or PCR after treatment. Children and adult patients with short- and long-term follow-up.

Table 2. Comparison of studies measuring long-term clinical outcomes after etiological treatment of chronic Chagas disease with benznidazole.

First author	Number of treated/untreated patients	Years of follow-up	% with ECG changes treated vs. untreated patients	% with heart disease progression treated vs. untreated patients
Viotti 1994	131/70	8	4 vs. 30	2 vs. 17
Gallerano 2000	535/668	5	14 vs. 34	6 vs. 18
Viotti 2006	283/283	6	5 vs. 16	4 vs. 14
Fabbro 2007	54/57	21	4 vs. 16	−
Fabbro 2014	71/46	20	1.4 vs. 15	−
Morillo 2015	1431/1423	6	−	28 vs. 29
Fragata-Filho 2016	263/47	20	21 vs. 53	14 vs. 36

Table 3. Global landscape of benznidazole registration, June 2018.

Country	Presentation tablets	BZN registered
Argentina	12.5 mg; 50 mg; 100 mg	ELEA
Bolivia	50 mg; 100 mg	ELEA
Brazil	100 mg	LAFEPE
Chile	50 mg; 100 mg	ELEA
El Salvador	100 mg	ELEA
Guatemala	50 mg; 100 mg	ELEA
Honduras	50 mg; 100 mg	ELEA
Mexico	50 mg; 100 mg	ELEA
Paraguay	50 mg; 100 mg	ELEA
United States	12.5 mg; 100 mg	CHEMO RESEARCH, S.L.

Note: Spain, Italy, Switzerland, Australia, and Canada are also authorized to distribute the drug.

Box 1. Drug summary.

Antiparasitic class	Nitroimidazole derivative
Structural formula
Molecular formula	C12H12N4O3
Molecular weight	260.25 g/mol
Mechanism of action	After activation by trypanosomal nitroreductases, the reactive metabolites formed interact with several biomolecules leading to the killing of parasites
Manufacturers	LAFEPE, ELEA, CHEMO RESEARCH
US FDA approval	August 29, 2017
Indication	Acute and chronic phase with some limitations
Treatment course	60 days
Route of administration	Oral
Dosage form	Tablets – 100, 50, 12.5 mg
Breastfeeding women	Not recommended; however, preliminary research suggests that there is no risk to infants ^1[116]

Garcia-Bournissen F, Moroni S, Marson ME, et al. Limited infant exposure to benznidazole through breast milk during maternal treatment for Chagas disease. Arch Dis Child. 2015;100(1):90–94.

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