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

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.