Table A.3.
(continued)
| Author, year | Country | Study design | Follow-up time | Drugs and dosage | Selection criteria | Sample size n | Toxicity outcomes |
|---|---|---|---|---|---|---|---|
| An, 2012 | China | App | 6 months | Daily treatment with INH, RMP, PZA and EMB for 2 months, followed by 4 months treatment with INH and RMP, with drug dosages calculated according to body weight Body weight < 45 kg: RMP 300 mg, INH 200 mg, PZA 1000 mg Body weight of 45–55 kg: RMP 450 mg, INH 300 mg, PZA 1500 mg Body weight > 55 kg: RMP 600 mg, INH 400 mg, PZA 2000 mg | Inclusion criteria:
|
208 | Hepatotoxocity |
| Azuma, 2013 | Japan | RCT | 6 months | All patients were treated with a 6-month regimen comprising INH, RMP, PZA and EMB/SM for the first 2 months, followed by RMP and INH for 4 months. All patients were started on the standard oral dose (~5 mg/kg body weight, once-daily). For pharmacogenetics-treatment patients, dosages were adjusted based on individual NAT2 status within 3 days. Modified daily INH doses were respectively ~7.5, ~5 and ~2.5 mg/kg for rapid, intermediate and slow acetylators. Regarding the other drugs for the standard regimen, standard daily doses of RMP (10 mg/kg, maximum 600 mg/body), PZA (25 mg/kg, 1500 mg/body), EMB (15 mg/kg, 750 mg/body; 20 mg/kg, 1000 mg/body) and SM (15 mg/kg, 750 mg/body) were recommended with the following dose ranges allowed at the discretion of the physician in charge: RMP 8–12 mg/kg; PZA 20–30 mg/kg; EMB 15–20 mg/kg; SM 12–18 mg/kg | The eligible population was identified from a series of patients newly diagnosed with PTB (male and female aged 20–75 years), requiring the 6-month 4-drug standard treatment for the first time Exclusion criteria: abnormal test results for liver and kidney function (serum AST > 45 IU/l, ALT > 50 IU/l, ALP > 444 IU/l, total bilirubin > 1.6 mg/dl and creatinine > 1.4 mg/dl before the study treatments commenced, long-term use of steroids and/or immunosuppressants, inadequate clinical conditions such as hyperglycaemia, diabetes mellitus, acute life-threatening chronic progressive disease, pregnancy or lactation and alcoholism. Patients not expected to complete the study protocol for social reasons were not recruited | 172 |
|
| Bose, 2011 | India | Prospective cohort | Patients were followed up to 8 weeks after they had started with anti-tuberculosis treatment | All patients received anti-tuberculosis treatment (RMP, INH, EMB and PZA) according to body weight. All four drugs were given for 2 months. PZA and EMB were discontinued, while INH and RMP were continued for another 4 months RMP doses as follows:
|
Newly diagnosed patients of PTB. The baseline LFT of the patients was normal when they were started on anti-tuberculosis treatment Exclusion criteria: no history of habitual alcoholism, chronic liver diseases or steatosis | 218 |
|
| Çetintaş, 2008 | Turkey | Prospective cohort | NR | Patients received INH 5 mg/kg (maximum 300 mg/day), RMP 10 mg/kg (maximum 600 mg/day), PZA 25 mg/kg (maximum 2000 mg/day), EMB 15–25 mg/kg (maximum 1500 mg/day) | Patients diagnosed with TB. Only patients with serum levels before initiation of treatment within the following ranges were included in the study: ALT 0–40 U/l, AST 5–45 U/l and total bilirubin 0.2–1.6 mg/dl Exclusion criteria: patients with positive serum hepatitis B surface antigen, hepatitis C antibody or hepatitis A immunoglobulin M antibody, and patients with alcoholic liver disease or any hepatic or systemic disease that could cause liver function disorder | 100 | DIH |
| Chamorro, 2013 | Argentina | Prospective cohort | NR | The patients began a standard anti-tuberculosis treatment protocol for the first 2 months (INH 5 mg/kg/days, maximum 300 mg/day, RMP 10 mg/kg/day maximum 600 mg/day, PZA 20 mg/kg/day, EMB 20 mg/kg/day), followed by INH and RMP for ⩾4 months, depending on the disease severity or the presence ofextra-pulmonary foci | Inclusion criteria: TB patients aged >18 years with stable haemodynamic levels, normal renal function and negative for pregnancy Exclusion criteria: presence of diseases that directly affected the liver (acute hepatitis A, active hepatitis B and C; cirrhosis; encephalopathy and cancer), INH allergy, HIV, autoimmunity, concomitant hepatotoxic medications, a history of TB treatment failures, refusal of blood extraction and refusal to sign the written informed consent | 175 | ATDH |
| Chang, 2012 | Taiwan | Prospective cohort | NR | First-line anti-tuberculosis medications | Patients diagnosed with TB and treated with first-line anti-tuberculosis medications Exclusion criteria: pregnancy, abnormal liver function and history of positive viral hepatitis before starting treatment with first-line anti-tuberculosis drugs | 98 | ATDH |
| Cho, 2007 | Korea | Prospective cohort | Serum AST, ALT and total bilirubin levels were then monitored monthly until the end of treatment | All patients received oral INH (300 mg), RMP (600 mg), PZA (20 mg/kg body weight) and EMB (800 mg) daily for the first 2 months. PZA was then discontinued, while INH, RMP and EMB were continued for another 4 months | Adult patients newly diagnosed with active TB, with evident lesion of TB using simple X-ray or computed tomography or positive results on sputum smear or culture for detection of mycobacteria Exclusion criteria: 1) abnormal serum ALT, AST, or bilirubin levels or symptoms related to abnormal liver function such as jaundice before anti-tuberculosis treatment; 2) alcoholic liver disease or habitual alcohol drinking; 3) any other hepatic or systemic diseases that may cause liver dysfunction | 132 | ATDH |
| Costa, 2012 | Brazil | Prospective cohort | NR | All patients were treated with the first-line anti-tuberculosis drug regimen INH (300 mg/kg/day), RMP (300 mg/kg/day) and PZA (1500 mg/kg/day) for the first 2 months, followed by INH and RMP for a further 4 months | Male or female subjects aged ⩾18 years, with no previously described renal, allergic or hepatic diseases and not pregnant | 129 | ADRs |
| Dhoro, 2013 | Zimbabwe | Case-control | NR | NR | TB patients | Not clear—189 received INH | Peripheral neuropathy |
| Feng, 2014 | China | Case-control | 6 months | Treatment with anti-tuberculosis drug regimens at the usual dosage—300 mg/day INH, 450 mg/day RMP and 1500 mg/day PZA | Selection of cases: cases selected based on liver functions, i.e., all indices of liver function were normal before anti-tuberculosis chemotherapy, and became abnormal indicating hepatic injury after 6 months of chemotherapy. Cases were patients who showed ATDH based on increased serum transaminase values that were three-fold higher than the ULN (40 IU/l ALT) and symptoms compatible with hepatitis Selection of controls: controls underwent the same anti-tuberculosis chemotherapy with selected cases and were not tested for abnormality in liver functions after 6 months of the chemotherapy. The controls selected matched the criteria compared to the cases: 1) sex; 2) age discrepancy of <5 years; 3) living in the same regions; and 4) treatment with anti-tuberculosis drug regimens at the usual dosage, including 300 mg/day INH, 450 mg/day RMP and 1500 mg/day PZA | 346 | ATDH |
| Fredj, 2016 | Tunisia | Prospective cohort | Serum AST, ALT and ALP were monitored monthly until the end of the treatment | The anti-tuberculosis treatment was based on the association of INH (5 mg/kg/day), RMP (10 mg/kg/day), PZA (25 mg/kg/day) and EMB (15 mg/kg/day) for the first 2 months, followed by INH and RMP for 4–7 additional months, depending on TB clinical presentation | Patients diagnosed with PTB and EPTB | 71 | INH-induced-hepatotoxicity |
| Gupta, 2013 (GI: GUPTA) | India | Prospective cohort | The patients were monitored for ALT, AST, andtotal bilirubin levels weekly for 1 month and then monthly until the completion of treatment | Initially patients received a combination regimen including INH 5 mg/kg (max 300 mg daily), RMP 10 mg/kg (max 600 mg daily), PZA 25 mg/kg (max 1500 mg daily) and EMB 15–25 mg/kg (max 2000 mg daily) for a period of 2 months, followed by an additional 4 months with INH and RMP | Inclusion criteria: 1) age > 18 years; 2) smear and/or culture positive for mycobacteria in clinical samples; and 3) normal ALT, AST and total bilirubin levels Exclusion criteria: 1) patients presenting clinically and laboratory-confirmed chronic liver disease such as jaundice; 2) acute and chronic hepatitis B and/or C or HIV; 3) alcoholic liver diseases; 4) a rise of two times the ULN of ALT, AST and total bilirubin levels; 5) medication with anti-tuberculosis drugs before start of treatment and/or other potentially hepatotoxic drugs; and 6) refusal to provide blood sample or signed informed consent form | 215 | ATDH |
| Higuchi, 2007 (GI: HIGUCHI) | Japan | Prospective cohort | NR | Treated with a INH (400 mg/d) and RMP (450 mg/d) containing regimen for 6 or 9 months | Patients with new onset of PTB treated with a INH (400 mg/d) and RMP (450 mg/d) containing regimen for 6 or 9 months Exclusion criteria: patients with liver cirrhosis, chronic and acute hepatitis, alcoholic liver disease and other chronic liver diseases | 100 |
|
| Ho, 2013 | Taiwan | Prospective cohort | 180 days | All patients received oral INH 300 mg, RMP 600 mg (or 450 mg if body weight was <50 kg), PZA 25 mg/kg of body weight (max daily dose 2000 mg) and EMB 15 mg/kg of body weight daily (max daily dose 1600 mg) for the first 2 months. PZA was then discontinued, whereas INH, RMP and EMB were continued for another 4 months | The inclusion criteria included a sputum smear with AFB or culture positive for M. tuberculosis, undergoing anti-tuberculosis treatment, including INH or starting treatment during the recruitment period, hepatitis serology recorded in the medical chart with signed written consent Patients were excluded if they were infected with hepatitis B virus, hepatitis C virus or HIV, had any other hepatic disease, or did not have at least two visits documented in the medical records | 348 | ATDH |
| Huang, 2003 (GI: HUANG) | Taiwan | Prospective cohort | Serum ALT, AST and total bilirubin levels were monitored monthly until the end of treatment or checked whenever patients had symptoms of suspected hepatitis | Their standard daily anti-tuberculosis regimen for the first 2 months included INH (300 mg), RMP (600 mg or 450 mg if body weight <50 kg), PZA (20 mg/kg body weight) and EMB (25 mg/kg body weight). PZA was then discontinued, whereas INH, RMP, and EMB (15 mg/kg body weight) were continued for another 4 months | Patients with incident PTB or EPTB Exclusion criteria: 1) abnormal serum ALT, AST or bilirubin before anti-tuberculosis treatment; and 2) refusal of blood sampling or informed written consent | 318 | ADIH |
| Jung, 2015 | Korea | Prospective cohort | 4 weeks | Standard 4-drug treatment for 6 months: INH (5 mg/kg, usually 300 mg), RMP (450 mg for <50 kg or 600 mg for ⩾50 kg of body weight), EMB (15 mg/kg) and PZA (20–30 mg/kg), daily for 2 months, followed by INH and RMP with or without EMB for 4 months. Doses were adjusted when applying model-based treatment | Eligible participants were patients newly diagnosed with active TB, who underwent standard 4-drug treatment for 6 months Exclusion criteria: patients with abnormal hepatic function on laboratory testing (increased serum AST, ALT or total bilirubin) before anti-tuberculosis treatment and underlying liver disease or systemic illness such as congestive heart failure, acute life-threatening disease, or alcoholism or disease that was resistant to INH at the start of treatment | 206 | ATDH |
| Khalili, 2011 | Iran | Case-control | 2 months | Treated daily with INH (300 mg), RMP (600 mg), PZA (20 mg/kg), EMB (15 mg/kg) for the first 2 months, followed by INH and RMP daily for 4 additional months | Inclusion criteria: newly diagnosed patients (>18 years) with active PTB, who had been planned to be treated daily with anti-tuberculosis treatment (see drugs and dosage) Exclusion criteria: other possibilities of hepatitis, including patients with HIV infection, hepatic insufficiency (ALT or AST > 2× ULN) or clinically signs and symptoms of liver diseases such as jaundice and ascites, chronic hepatitis (B or C) and renal insufficiency (creatinine clearance < 50 ml/min based on Cockcroft-Gault equation) and history or current use of herbal, supplemental and hepatotoxic non-tuberculosis drugs | 100 | Hepatotoxicity |
| Kim, 2009 (GI: KIM) | Korea | Case-control | Assessments performed 2 weeks after onset of treatment and bi-monthly thereafter | All patients with PTB were treated daily with a combination regimen comprising INH (300–400 mg daily), RMP (450–600 mg daily), EMB (600–800 mg daily) and PZA (1000–1500 mg daily) for 2 months and then without PZA for ⩾4 following months. Doses of each drug were adjusted based on body weight of the patient | Newly diagnosed and treated patients with PTB. Exclusion criteria: patients with active or chronic hepatitis, including alcoholic hepatitis, fatty liver disease, liver cirrhosis, carriers of the hepatitis B or C virus, heavy alcohol intake, decreased renal function and severe cardiac diseases requiring several medications | 226 | ATDH |
| Kim, 2011 (GI: KIM) | Korea | Case-control | NR | The treatment comprised an initial phase of 2 months and a subsequent continuation phase of ⩾4 months. During the initial phase, 4 drugs were administered, including INH (300–400 mg daily), RMP (450–600 mg daily), EMB (600–800 mg daily) and PZA (1000–1500 mg daily). Doses of each drug were adjusted based on the body weight of the patient. In the following continuation phase, only PZA was discontinued, while the other three drugs were continued | Patients newly diagnosed with PTB and/or TB pleuritis and treated with first-line anti-tuberculosis medications such as INH, RMP, EMB and PZA Exclusion criteria: 1) patients with skin diseases before treatment, 2) chronic renal failure and chronic liver diseases affecting drug metabolism, 3) chronic alcoholism, 4) other chronic medical conditions requiring medication, and 5) non-adherence to treatment | 221 | ATD-induced MPE |
| Lee, 2010 | Taiwan | Prospective cohort | NR | All patients received oral INH 300 mg, RMP 600 mg (or 450 mg, if body weight was <50 kg), PZA 200 mg/kg of body weight and EMB 800 mg daily for the first 2 months. PZA was then discontinued, while INH, RMP and EMB were continued for another 4 months | Inclusion criteria: adult patients newly diagnosed with active TB, having evident lesions of TB using simple X-ray, computed tomography, sputum smears and cultures positive for mycobacteria Exclusion criteria: 1) positive serum hepatitis B virus surface antigen, antibody to hepatitis C virus; 2) alcoholic liver disease or habitual alcohol drinking; 3) any other hepatic or systemic diseases that may cause liver dysfunction; 4) abnormal serum ALT, AST or bilirubin levels before anti-tuberculosis treatment | 140 | ATDH |
| Leiro-Fernandez, 2011 | Spain | Case-control | Routine follow-up of clinical assessments every 2 weeks during the first month and monthly thereafter untilcompletion of treatment | Treatment with regimens that included INH, RMP and PZA at the usual dosages (INH 5 mg/kg/day to maximum 300 mg/day, RMP10 mg/kg/day to maximum 600 mg/day and PZA 25–30 mg/kg/day to maximum 2500 mg/day | Inclusion criteria: 1) age 15–75 years; 2) microbiological demonstration of active TB; 3) treatment with regimens that included INH, RMP and PZA at the usual dosages (INH 5 mg/kg/day to max 300 mg/day, RMP 10 mg/kg/day to max 600 mg/day and PZA 25–30 mg/kg/day to max 2500 mg/day); and 4) adequate treatment adherence Exclusion criteria: 1) increased baseline serum transaminases (AST and/or ALT; normal values ⩽ 40 IU/l); 2) positive serological testing for HIV, hepatitis B virus or hepatitis C virus; 3) regular alcohol intake or concomitant use of hepatotoxic drugs; 4) history of chronic liver disease; 5) pregnancy; or 6) no or poor adherence to treatment | 117 | ATDH |
| Lv, 2012 | China | Case-control | 6–9 months | All primary/retreatment patients took INH (600 mg), RMP (600 mg or 450 mg if body weight was <50 kg), PZA (2000 mg) and EMB (1250 mg) every other day in the first 2 months and then INH and RMP were continued for another 4/6 months. The retreatment patients received SM (750 mg) every other day in the first 2 months and continued receiving EMB for another 6 months | Inclusion criteria: sputum smear-positive PTB patients who received standard short-course chemotherapy recommended by the WHO Exclusion criteria: 1) positive serum hepatitis B virus surface antigen or other liver disease, 2) potentially hepatotoxic medications that would confound the picture, 3) abnormal serum ALT, AST or total bilirubin levels before anti-tuberculosis treatment | 445 | ATDH |
| Mahmoud, 2012 | Tunisia | Prospective cohort | 3 months | Treated with INH and RMP containing regimen | Inclusion criteria: adult patients (>18 years) newly diagnosed with TB treated with INH- and RMP-containing regimen, LFTs before initiation of treatment showed completely normal findings on serum ALT, AST, total bilirubin, ALP and gGTP Exclusion criteria: 1) patients receiving other potentially hepatotoxic drugs in addition to anti-tuberculosis agents; 2) positive serum hepatitis B surface antigen or hepatitis C antibody; 3) alcoholic liver disease; 4) any other hepatic or systemic diseases that may cause liver dysfunction | 66 | INH hepatotoxicity |
| Ng, 2014 | Cases recruited in the UK; controls were samples from elsewhere | Case-control | NR | All had been prescribed INH with all but one also taking additional anti-tuberculosis drugs. Patients were prescribed 300 mg INH/day in line with UK/WHO guidelines | Cases: patients diagnosed with DILI either in the past or at the time of sample collection. Onlycases assessed as having DILI that was highly probably, probably or possibly relating to anti-tuberculosis drug exposure were enrolled in the study. Other possible causes of liver toxicity, particularly hepatitis A, B, C and CMV infection were excluded. No patients included were HIV-positive or had pre-existing liver disease. None had been treated for TB under directly observed treatment Controls: 52 DNA samples from individuals of European ancestry; inclusion/exclusion criteria not reported | 127 | DILI |
| Ohno, 2000 | Japan | Prospective cohort | 3 months | Initial chemotherapy always included INH (400 mg/day; 8.2 ± 2.0 mg/kg/day) and RMP (450 mg/day; 9.2 ± 2.2 mg/kg/day); the third drug used was EMB or SM. | Inclusion criteria: patients had no history of alcohol abuse and were negative for hepatitis B surface antigen and hepatitis C antibody. At the beginning of treatment, LFTs showed completely normal findings on serum AST, ALT, bilirubin, ALP and gGTP Patients receiving other potentially hepatopathic drugs in addition to anti-tuberculosis agents were excluded from the study | 77 | INH + RMP-induced hepatotoxicity |
| Possuelo, 2008 (GI: POSSUELO) | Brazil | Prospective cohort | NR | Treatment daily with INH, RMP and PZA for the first 2 months followed by INH and RMP daily for 4 additional months. Drug dosages used were calculated according to patient's weight (weight <45 kg: RMP 300 mg, INH 200 mg, PZA 1000 mg; 45–55 kg: RMP 450 mg, INH 300 mg, PZA 1500 mg; >55 kg: RMP 600 mg, INH 400 mg, PZA 2000 mg) | Inclusion criteria: adult patients (>18 years) newly diagnosed with active TB, who had been treated daily with anti-tuberculosis treatment (see drugs and dosage) Exclusion criteria: patients presenting clinically and laboratory-confirmed liver chronic disease, patients using anti-tuberculosis drugs before enrolment in the study, patients presenting results of LFTs before the beginning of treatment higher that were 2× ULN and refusal to participate of the study | 254 | ATDH Gastrointestinal ADRs |
| Rana, 2014 (GI: RANA) | India | Prospective cohort | Patients were monitored every month until the end of treatment or whenever the patients had symptoms or signs of hepatotoxicity | Daily anti-tuberculosis treatment for the first 2 months included INH (300 mg), RMP (600 or 450 mg for body weight/50 kg), PZA (20 mg/kg body weight) and EMB (25 mg/kg body weight). After 2 months, EMB and PZA were discontinued, whereas INH and RMP were continued for an additional 4 months | Inclusion criteria: patients with pulmonary and EPTB Exclusion criteria: patients with history of alcohol abuse and/or any other liver disease; patients who had received other potentially hepatotoxic drugs in addition to anti-tuberculosis drugs; patients who had abnormal serum ALT, AST or bilirubin before starting anti-tuberculosis treatment; patientswho developed viral hepatitis during anti-tuberculosis treatment; patients with renal failure or cancer; and patients who refused blood sampling or providing informed written consent | 300 | Hepatotoxicity |
| Santos, 2013 (GI: SANTOS) | Brazil | Prospective cohort | NR | Treatment with INH, RMP and PZA for the first 2 months, followed by INH and RMP daily for 4 months | Inclusion criteria: patients diagnosed with TB and treated with anti-tuberculosis treatment (see drugs and dosage) Exclusion criteria: patients aged <18 years, those with mental disabilities, chronic liver disease confirmed by clinical and laboratory data, users of anti-tuberculosis drugs before enrolment in the study, and those with liver function results > 2× ULN before beginning treatment | 270 | ATDH |
| Shimizu, 2006 | Japan | Prospective cohort | 3 months | Treatment with INH (300–400 mg) and RMP (300–450 mg) | Individuals with PTB without abnormal serum levels of ALT, AST, direct or total bilirubin, or serum hepatitis B virus surface antigen or antibody to hepatitis C virus at the beginning of the study | 42 | Hepatotoxicity |
| Singla, 2014 | India | Prospective cohort | NR | NR | Inclusion criteria: newly diagnosed patients with TB Exclusion criteria: history of heavy use of alcohol or chronic liver diseases or liver cirrhosis;patients who were settled in the area for a minimum of three generations; people infected with HIV | 408 | ATDH |
| Sotsuka, 2011 | Japan | Prospective cohort | 3 months | INH, RMP and PZA, plus EMB or SM during the first 2 months, followed by administration of INH and RMP plus EMB or SM during the final 4 months | Inclusion criteria: in-patients with active PTB who were treated with the standard Japanese chemotherapy regimen, followed up for >3 months after treatment, and who consented to this study | 144 | Hepatotoxicity |
| Teixeira, 2011 | Brazil | Case-control | NR | Anti-tuberculosis drug regimens that include INH at the usual dosage (400 mg/day) | Inclusion criteria: 1) age > 18 years, 2) diagnosis of active TB, 3) treatment with anti-tuberculosis drug regimens that include INH at the usual dosage (400 mg/day) and 4) normal baseline serum transaminases (ALT and AST) before treatment Exclusion criteria: 1) positive serological test for the HIV, hepatitis B virus or hepatitis C virus, 2) alcohol abuse, 3) history of chronic liver disease and 4) pregnancy | 167 | Hepatitis |
| Vuilleumier, 2006 | Switzerland | Prospective cohort | NR | INH 300 mg daily and vitamin B6 40 mg per day for a period of 6 months | Inclusion criteria: patients having LTBI as defined by the American Thoracic Society with normal plasma AST and ALT levels before the beginning of INH monotherapy Exclusion criteria: 1) a history of alcohol consumption, 2) positive serology for the HAV, HBV or HCV, 3) poor chemotherapy compliance (negative urine INH 3 times during the follow-up), loss during the follow-up, 4) patients had to receive supplementary anti-tuberculosis agents or other potentially hepatotoxic drugs | 89 | INH-induced hepatotoxicity |
| Wang, 2015 (GI: NTUH) | Taiwan | Prospective cohort | 6 months | Daily INH, RMP, EMB and PZA in the first 2 months, and daily INH and RMP for the next 4 months The daily dosage of each drug was calculated by weight | Adult Taiwanese (>16 years) patients with culture-confirmed PTB Subjects were excluded if they were pregnant, had a life expectancy < 6 months, had abnormal baseline LFT or were resistant to INH, RMP or both | 355 in the derivation cohort, 182 in the validation cohort | Hepatotoxicity during anti-tuberculosis treatment |
| Xiang, 2014 | China | Prospective cohort | 2 months | All patients were prescribed INH (600 mg), RMP (600 mg or 450 mg if the body weight was <50 kg), PZA (2000 mg) and EMB (1250 mg) every other day in the first 2 months. After 2 months, INH and RMP were continued for a further 4–6 months. Retreatment patients in addition received SM (750 mg) every other day in the first 2 months and continued receiving EMB for another 6 months | Inclusion criteria: newly diagnosed PTB patients belonging to the Uyghur ethnic group, who were receiving standard short-course chemotherapy recommended by the WHO, who attended for a 2-month assessment, and any patients attending clinic with suspected liver disease after the start of treatment, before the 2-month visit Exclusion criteria: patients who had signs of abnormal liver function when they started treatment (jaundice or elevated ALT, AST or bilirubin levels) or disease associated with liver dysfunction | 2244 | ATLI |
| Yamada, 2009 (GI: YAMADA) | Canada | Prospective cohort | 9 months | INH 300 mg | Subjects who were receiving treatment with INH 300 mg daily self-administered for LTBI.Subjects were included if they were aged ⩾19 years; not concurrently receiving other anti-tuberculosis drugs; non-reactive to hepatitis B surface antigen and antibody to hepatitis C virus; absence of any liver or metabolic diseases; without a HIV-positive test result; not consuming ⩾7 alcoholic beverages per day and undergoing sufficiently frequentAST tests to detect hepatotoxicity | 170 | Hepatotoxicity |
| Yimer, 2011 | Ethiopia | Prospective cohort | followed up for development of DILI for up to 56 weeks | All study participants received RMP based short-course chemotherapy for TB following the national TB treatment guideline. ART was then initiated | Newly diagnosed ART and anti-tuberculosis treatment-naïve adult TB and HIV co-infected patients. The eligibility criteria were age >18 years, CD4 count, 200 cells/Ul, not pregnant and not on other known hepatotoxic drugs concurrently (except cotrimoxazole, 960 mg per day, which was given to all participants before enrolment and during the follow-up period according to the treatment guideline) | 353 | Anti-tubercular and antiretroviral DILI |
| Yuliwulandari, 2016 | Indonesia | Case-control | NR | NR (anti-tuberculosis treatment) | Patients included in the study were male and female aged 15–70 years, suffering from TB according to the WHO standards, and were under monitored treatment with anti-tuberculosis drugs Exclusion criteria: 1) history of liver disease such as: hepatitis A B or C; hepatoma; liver cirrhosis or cholelithiasis positive; 2) abnormal levels of any LFT (ALT, AST or total bilirubin) before anti-tuberculosis treatment | 241 | ATLI |
| Zaverucha-do-Valle, 2014 | Brazil | Retrospective cohort | Follow-up at days 15 and 30 and at least one visit monthly until the end of treatment | 600 mg/day of RMP, 400 mg/day of INH and 2 g/day of PZA for all patients with corporal weight >45 kg or adjusted for corporal weight <45 kg. After 2 months of treatment, PZA was discontinued | Inclusion criteria: signed written consent, sputum smear with AFB or culture positive for M. tuberculosis; ongoing TB treatment and laboratory tests of liver function Exclusion criteria: age <18 years, pregnancy and no >1 visit registered | 131 | ATDH |
INH =isoniazid; RMP =rifampicin; PZA =pyrazinamide; EMB =ethambutol; ALT =alanine aminotransferase; AST =aspartate aminotransferase; RCT =randomised controlled trial; HIV =human immunodeficiency virus; SM =streptomycin; PTB =pulmonary tuberculosis; IU =international unit; ALP =alkaline phosphatase; DILI =drug-induced liver injury; LFT =liver function test; DIH =drug-induced hepatotoxicity; NR =not reported; ATDH =anti-tuberculosis drug-induced hepatotoxicity; GI =group identifier; ADR =adverse drug reaction; ULN =upper limit of normal; EPTB =extra-pulmonary TB; ADIH =anti-tuberculosis drug-induced hepatitis; ATD =anti-tuberculosis drug; MPE =maculopapular eruption; WHO = World Health Organization; gGTP = gamma-glutamyltranspeptidase; CMV = cytomegalovirus ; LTBI = latent tuberculous infection; ART =antiretroviral therapy; ATLI = anti-tuberculosis drug-induced liver injury.