Overview of drug induced liver injury in Brazil: What is the role of public health policy on the evidence?

Table 1 Summary of published Brazilian studies on drug-induced hepatotoxicity data

Ref.	Year	Place	State	Design	n	Class or medication	Use of algorithm	Frequency of DILI
Silva et al[22]	2019	Ho	BA	Cross-cut	306	MTX	No	2.0%
Alves et al[59]	2011	Ho	SC	Cross-cut	71	MTX/LEF	No	11.0%
Carvalho et al[74]	2014	A	RJ	Cross-cut	219	Azathioprine	No	2.7%
de-Medeiros et al[75]	1998	Ho	PR	RCT	37	Tretinoin	No	16.0%
Werner et al[61]	1989	Ho	SP	PC	389	Propylthiouracil	No	1.3%
Santos et al[63]	2013	Ho	RS	RC	185	5-Fluorouracil	No	57.8%
Uehara et al[76]	2005	Ho	SP	RC	12	Amphotericin B	No	30.0%
Magalhães[26]	2015	Ho	BA	Case series	31	Multiple	RUCAM	NA
Prado et al[27]	2019	A	BA	PC	149	Nimesulide, budesonide and valacyclovir	RUCAM	2.0%
Antonello et al[55]	2014	Ho	RS	PC	65	ARV	No	45.0%
Tovo et al[47]	2006	Ho	RS	PC	CI 385 MI 198	ARV	No	CI 57.8% MI 13.0%
Kondo et al[49]	2008	A	PR	RC	157	Nevirapine	No	4.0%
Gil et al[48]	2007	A	SP	Cross-cut	152	Tuberculostatic ARV and sulfonamides	No	19.7%
Tomich et al[77]	2015	Ho	SP	RC	149	Tuberculostatic, ARV among others1	No	22.1%
Santos et al[23]	2019	Ho	RJ	PC	45	Tuberculostatic	No	13.0%
Heinrich[24]	2014	A	MS	PC	100	Tuberculostatic	NARANJO	11.1%
Monteiro et al[25]	2012	A	RJ	PC	177	Tuberculostatic	RUCAM	33.3%
Gusmão Filho et al[43]	2001	Ho	PE	RC	52	RHZ/ RHE/	No	35.6%
Lima Mde et al[65]	2012	Ho	PE	Control case	156	RHZ and RHZE	No	26.9%
Zaverucha-do-Valle et al[41]	2014	A	RJ	RC	131	RHZ	No	26.7%
Coca et al[73]	2010	Ho	MG	Control case	162	RHZ	No	H3 56.2% and H4 10.4%
de Castro et al[44]	2010	A	RJ	PC	154	RHZ	No	19.5%
Nader et al[45]	2010	Ho	RS	RC	534	RHZ	No	8.8%
Vieira et al[78]	2008	A	SP	RC	297	RHZ	No	8.1%
de Souza et al[79]	1996	Ho	MG	PC	1096	RHZ	NI	6.0%
Fernandes et al[68]	2015	Ho	PA	PC	220	RHZ/RH	No	14.1%
Brito et al[64]	2014	A	RS	PC	245	RHZ/RH	No	6.1%
Schultz et al[46]	2014	Ho	RS	RC	69	Rifampicin	No	33.3%
Santos et al[53]	2013	A	PA	PC	270	Isoniazid	No	6.5%
Teixeira et al[52]	2011	A	RJ	Control case	167	Isoniazid	No	16.0%
Szklo et al[67]	2007	A	RJ	RC	40	SEO32/EO92	No	12.5%
Picon et al[66]	2002	A	RS	PC	78	SHE32/HE32/H32	No	1.3%

¹Sulfa drugs, statins, imidazole, anticonvulsant, nonsteroidal.

²Months.

H³ transaminases > 1.25 to 2.5 × upper limits of normality.

H⁴ transaminases > 2.6 to 5 × upper limits of normality. RUCAM: Causality algorithm; ARV: Antiretrovirals; MTX/LEF: Methotrexate/leflunomide; NA: Not applicable; CI: Human immunodeficiency virus and hepatitis C coinfected; PC: Prospective cohort; RC: Retrospective cohort; MI: Monoinfected for human immunodeficiency virus; DILI: Drug-induced liver injury; RCT: Randomized clinical trial; R: Rifampicin; H: Isoniazid; Z: Pyrazinamide; S: Streptomycin; and ethambutol. O: Ofloxacin, Ho: Hospital; A: Ambulatory.

Table 2 Criteria used for the definition of liver injury

Criteria applied for liver injury definition	Ref.	Condition
Elevated ALT	Tovo et al[47], 2006	HIV/HCV
ALT > 2 × ULN	Monteiro et al[25], 2012	TB
ALT > 2.5 × ULN	Zaverucha-do-Valle et al[41], 2014; Kondo et al[49], 2008	TB/smoker; HIV
ALT > 3 × ULN	Fernandes et al[68], 2015; Santos et al[53] 2013;	TB; TB
ALT or AST > 2 × ULN	Alves et al[59], 2011; de Castro et al[44], 2010	AR; TB/HBV
ALT or AST > 3 × ULN	Heinrich[24], 2014; Vieira et al[78], 2008; Uehara et al[76] 2005	TB/ indigenous; TB; IMQ
ALT or AST > 3 × or BT > 1.5 ×	Schultz et al[46], 2014	TB/TX
ALT > 3 × ULN; BT > 2 ×	Brito et al[64], 2014; Nader et al[45], 2010	TB/HCV
ALT or AST > 3 × ULN; BT > 2 ×	Lima Mde et al[65], 2012; Picon et al[66], 2002	TB/HIV; TB
ALT ≥ 5 × LSN ou FA ≥ 2 × LSN ou ALT ≥ 3 × ULN e BT ≥ 2 × LSN	Prado et al[27], 2019	Gastro-hepatology conditions
(1) ALT > 3 × lower limit of normality; (2) ALT > 3 × ULN; (3) ALT > 3 × ULN and BT > 2 × ULN	Coca et al[73], 2010	TB/HIV
ALT or AST: (1) 1.25 a 2.5 × ULN; (2) 2.6 a 5 × ULN; (3) 5.1 a 10 × ULN; (4) > 10 × ULN	Antonello et al[55], 2014	HIV
ALT or AST: (1) 1.25 a 2.5 × ULN; (2) 2.6 a 5 × ULN; (3) 5.1 a 10 × ULN; (4) > 10 × ULN or BT – (1) 1.1 a 1.5 × ULN; (2) 1.6 a 2.5 × ULN; (3) 2.6 a 5.0 × ULN; (4) > 5.0 × ULN	Tomich et al[77], 2015	TB/HIV
Altered ALT or AST (hepatotoxicity) and ALT or AST > 5 × (hepatitis)	Gusmão Filho et al[43], 2001	TB/children
ALT or AST > 3 × ULN and hepatitis syndromes	Teixeira et al[52], 2011	TB
AST > 3 × ULN and hepatitis syndromes	Szklo et al[67], 2007	TB/previous liver injury
Altered ALT, AST, AP or BT	de Souza et al[79], 1996	TB
Increase in liver function tests	de-Medeiros et al[75], 1998	LMA
Histological assessments	Santos[63], 2013	QT/HPTC
AST or ALT: (1) 1.1-4.9 × ULN; (2) 5.0-9.9 × ULN; (3) 10.0-15.0 × ULN; (4) > 15.0 × ULN	Gil et al[48], 2007	HIV/child/adolescent
ALT > 2 times ULN or the ALT/AP ratio ≥ 5 or AP > 2 times ULN ALT/AP ratio ≤ 2 or ALT > 2 times ULN and ALT/AP ratio between 2 and 5	Magalhães[26], 2015	Several
ALT ou AST > 2 × LSN e BT > 1.3 mg/dL	Santos et al[23], 2019	TB
NI	Silva et al[22], 2019; Carvalho et al[74], 2014; Werner et al[61], 1989	IBD; Ulcerative colitis; Grave’s disease

ALT: Alanine methyltransferase; ULN: Upper limits of normality; AST: Aspartate methyltransferase; BT: Total bilirubin; AP: Alkaline phosphatase; NI: Not identified; TB: Tuberculosis; HIV: Human immunodeficiency virus; HCV: Hepatitis C virus; HBV: Hepatitis B virus; IMQ: Immunosuppressed by chemotherapy; TX: Transplantation; QT: Chemotherapy; HPTC: Hepatectomy; IBD: Inflammatory bowel disease.

Table 3 Main outcomes related to drug-induced liver injury in Brazilian studies

Ref.	DILI outcomes	Medications
Santos et al[23], 2019	6 Cases were resolved after the suspension of medications	Tuberculostatic
Magalhães[26], 2015	21 Cases were resolved after the suspension of the substance, but without the use of medications; 9 cases were resolved with the suspension of the substance associated with medications; 1 case with acute hepatic failure, requiring liver transplantation	Isoniazid, valproic acid, amitriptyline, cyclosporine, clozapine, dasatinib, imatinib, ACO, simvastatin, melphalan, and others
Antonello et al[55], 2014	There was no need to suspend or change the treatment	ARV
Kondo et al[49], 2008	7/157 Patients (4.4%) were hospitalized and, after discontinuation of Nevirapine, all presented clinical and laboratory improvement	Nevirapine
Brito et al[64], 2014	Changed therapeutic regimen in all who developed DILI 15/245 (6.1%)	RHZ
Lima Mde et al[65], 2012	Drug maintenance 26/156 (16.6%), temporary interruption 12/156 (7.7%), treatment change 11/156 (7%), suspension of medications TB 7/156 (4.5%)	RHZ, RHZE
Coca et al[73], 2010	Medication suspended in 7/30 (23.3%) HIV and 15/132 (11.4%) non-HIV	RHZ
Vieira et al[79], 2008	There was a need to modify the treatment regimen in 11/24 (45%) of the patients	RHZ
Picon et al[66], 2002	RHZ: 45 cases changed treatment; SHM: 1 case changed treatment	RHZ, SHM
Gusmão Filho et al[43], 2001	3/52 (5.76%) Required replacement of the medication. In 16/52 (30.7%) there was no need for intervention and in other 13/52 (25%) only the doses of Isoniazid and Rifampicin were changed	RHZ, RHE
de-Medeiros et al[75], 1998	Medication was suspended and 1/37 (2%) patient was excluded from the RCT	Tretinoin
Alves et al[59], 2011	Medication doses were temporarily reduced	MTX
Prado et al[27], 2019	The culprit drug was discontinued, and drug therapy was not necessary to resolve the problem in 3 patients	Nimesulide, budesonide, valacyclovir
Werner et al[61], 1989	There was clinical and laboratory Improvement with the suspension of the medication in 4/389 (1%) and 1/389 (0.25%) evolved to chronic hepatitis	Methimazole, Propylthiouracil

DILI: Drug-induced liver injury; R: Rifampicin H: Isoniazid; Z: Pyrazinamide; S: Streptomycin; and E: Ethambutol; RCT: Randomized clinical trial; MTX: Methotrexate; ARV: Antiretroviral; ACO: Oral contraceptives.

Table 4 Summarization of the Brazilian studies according to the drugs evaluated

Ref.	Drugs	Summary of Brazilian researches
Santos et al[23], 2019	Tuberculostatics	Patients with the CYP2E1 variant genotype or Null GSTT1 showed higher risk of presenting DILI. Individuals with both genotypes had no increased risk compared to individuals with one genotype
Prado et al[27], 2019	Nimesulide, budesonide, valacyclovir	The present prospective study allowed reporting new cases of DILI in 2% outpatients. It also allowed estimating the incidence of hepatotoxicity induced by allopathic medicines, which are standardized by public healthcare authorities
Silva et al[22], 2019	MTX	The frequency of drug hepatotoxicity was about 2% of hepatobiliary disorders in inflammatory bowel disease patients
Fernandes et al[68], 2015	RHZ	An association founded between the 516 TT polymorphism and drug-induced hepatotoxicity
Tomich et al[77], 2015	Tuberculostatics ARV, sulfonamide drugs, statins, imidazoles anticonvulsants, non-steroidal anti-inflammatory	In HIV patients admitted to a tertiary hospital, it was found a high incidence (22.1%) of severe DILI. The use of anti-tuberculosis drugs and baseline liver injury were independent factors associated with severe DILI during a hospital stay
Magalhães[26], 2015	Various	Hepatotoxicity caused by a wide variety of medicines, plant supplies, and dietary supplements. Anti-infectives and chemotherapeutics were responsible for most reactions, in 41% and 19% of cases, respectively. There is a shortage of records in information records to evaluate the causality of reactions
Antonello et al[55], 2014	ARV	The coinfected patients are at an increased risk for developing hepatotoxicity, but the clinical and immunological benefits of highly active antiretroviral therapy are higher than the risk of hepatotoxicity and rarely justify discontinuation of therapy
Heinrich[24], 2014	Tuberculostatics	Age over 60 year old, the time after the start of treatment (15 d) and being indigenous (Brazilian native American) are risk factors for the development hepatotoxicity during treatment of TB
Zaverucha-do-Valle et al[41], 2014	RHZ	The anti-TB drugs interactions with smoking on hepatotoxicity, as well as the NAT2 phenotype, may require adjusting therapeutic regimen dosages or alarm in case of adverse event developments
Schultz et al[46], 2014	Rifampin	The use of rifampin at daily doses of 600 mg or higher and lung transplantation founded to be an independent risk factor for liver toxicity in solid organ transplants recipients. Kidney transplantation appeared as a protective factor. Mortality was higher in the patients who had hepatotoxicity (43.5%), compared with those who did not
Brito et al[64], 2014	RHZ	Clinical (HIV, female and extrapulmonary TB) and genetic characteristics (CYP2E1 without any mutations, having NAT2 slow acetylator profile) are at higher risk of developing DILI in this population. Genotyping for glutathione S-transferase GSTM1 and GSTT1 showed no influence on drug response
Santos et al[53], 2013	5-fluorouracil	Patients exposed to chemotherapy have a 2.2-fold increase in the risk of developing hepatic steatosis
Santos et al[63], 2013	Isoniazid	Large-scale screening for NAT2 and CYP2E1 genotypes can prove useful in predicting the risk of adverse effects
Monteiro et al[25], 2012	Tuberculostatics	GSTM1 and GSTT1 null genotypes do not seem to play important roles in DILI in Brazilians. However, there was evidence that GSTM1 polymorphisms were possibly related to the intensity of toxicity. Active HBV and initial high ALT could predict DILI
Lima Mde et al[65], 2012	RHZ, RHZE	The absence of hepatotoxicity was a protective factor against death. Coinfection with the B and C hepatitis virus and a T CD4+ cell count below 200 cells/mm3 were independent risk factors for hepatotoxicity in these patients
Teixeira et al[52], 2011	Isoniazid	Slow acetylators had a higher incidence of hepatitis than intermediate/rapid acetylators. Slow acetylation status was the only independent risk factor for the occurrence of anti-TB drug-induced hepatitis during anti-TB treatment with INH-containing schemes in Brazilian individuals
Alves et al[59], 2011	MTX, Leflunomide	There was no difference between the elevation of aminotransferases in patients treated with MTX alone or with combined therapy
Coca et al[73], 2010	RHZ	Depending on the definition of drug-induced hepatitis, HIV infection may or may not be associated with hepatotoxicity. The impact that minor alterations in the definition had on the results was impressive. The emergence of new symptoms after initiating antituberculosis therapy could not be attributed to hepatotoxicity in over one-third of the cases
Nader et al[45], 2010	RHZ	The anti-HIV drugs and high doses of isoniazid were considered independent risk factors for hepatotoxicity due to RHZ regimen in this study. Though univariate analysis showed that anti-HCV drugs was associated with the outcome, it was not identified as an independent risk factor for hepatotoxicity related to the use of RHZ when the analysis controlled to HIV
de Castro et al[44], 2010	RHZ	Active HBV, indicated by the detection of surface antigen HBV, could predict hepatotoxicity, although with low precision
Vieira et al[78], 2008	RHZ	The frequency of adverse effects related to the treatment of tuberculosis with RHZ was 49.1% in this group of patients. However, in most cases, there was no need to modify the treatment regimen due to adverse effects
Kondo et al[49], 2008	Nevirapine	There was no correlation between high CD4 counts and adverse events when skin and hepatic reactions were analyzed together. However, hepatotoxicity occurred only in pregnant women with a CD4 count of ≥ 250 cells/μL
Szklo et al[67], 2007	SEO3/EO9	In this series of TB patients with serious liver injury, 3SEO/9EO was well tolerated, and it was effective in 85% of patients when used under routine clinical care conditions
Gil et al[48], 2007	tuberculostatics, ARV, sulfonamide drugs	One-fifth of patients experienced mild hepatotoxicity, attributed to antituberculosis agents and sulfonamides. Our results suggest that the ARV was well tolerated
Tovo et al[47], 2006	ARV	There was no difference between the groups concerning the type of ARV used, as well as cases of hepatotoxicity attributed to PI. There was no difference concerning tolerability to PI between the two groups
Picon et al[66], 2002	SHE3/HE3/H3	Streptomycin, isoniazid, and ethambutol regimen may be recommended as an alternative for the treatment of tuberculosis whenever the RHZ regimen cannot be indicated
de Souza et al[79], 1996	RHZ	Liver changes characterized as of small and medium intensity translated as pure cholestasis or hepatocanalicular hepatic reactions. Possibly Rifampicin was important in this evolution, acting as a potentiator of the actions triggered by isoniazid and pyrazinamide
Werner et al[61], 1989	Propylthiouracil	The adverse effects of thionamide drugs were similar in both high- and low-dose regimens. These undesirable effects demand a strict follow-up, as well as the high dose regimen for Graves' disease treatment particularly advised for patients with severe symptoms

TB: Tuberculosis; TBD: Tuberculostatic drugs HIV: Human immunodeficiency virus; DILI: Drug-induced liver injury; NAT2: N-acetyltransferase 2; MTX: Methotrexate; HCV: Hepatitis C virus; RHZ: Rifampicin, isoniazid and pyrazinamide; HBV: Hepatitis B virus; ARV: Antiretroviral; PI: Protease inhibitors; SEO3: Streptomycin, ethambutol and ofloxacin for 3 mo; SO9: Streptomycin and ofloxacin for 9 mo; SHE3: Streptomycin, isoniazid, and ethambutol for 3 mo; HE3: Isoniazid ethambutol for 3 mo; H3: Isoniazid for 3 mo.