Table 1.
Characteristics of studies included in a systematic review of age-related risk of hepatotoxicity in the treatment of LTBI and Active Tuberculosis.
| Studies assessing hepatotoxicity reference, country, year | Study period | Study design | Study population number of subjects | Definition of hepatotoxicity | Drugs administered and length of treatment | LTBI/Active TB disease | Transplant/Dialysis |
|---|---|---|---|---|---|---|---|
| Baghaei et al., Iran, 2010 | 2006–2008 | Prospective | Patients treated for pulmonary tuberculosis, regardless of age N = 662 | Elevated AST/ALT; clinically evident hepatotoxicity | Standard 6 month regimen | Active TB | No |
| Bartacek et al., Multinational, 2009 | 2003–2004 | Open label RCT | Patients aged >15 years who were AFB positive and no hx of drug-induced hepatitis N = 1142 | Elevated SGOT, as defined by guidelines; evidence of clinical hepatitis | HRZE 75/150/400/275 mg per tablet daily for 2 months followed by H/R 75/150 mg daily for 4 months | Active TB | No |
| Byrd et al., US, 1979 | Not reported | Prospective | Patients with an intermediate PPD reaction given INH chemoprophylaxis, regardless of age N = 1000 | SGOT >5× normal level with or without symptoms | Standard INH regimen for 9 months | LTBI | No |
| Chien et al., Taiwan, 2010 | 2004–2008 | Retrospective | Patients of all ages with active TB disease with normal AST/ ALT levels of <40 IU/I at baseline N = 295 | Increase in ALT and/or AST >3× ULN with symptoms, or 5× without symptoms | INH (5 mg/kg), RMP (10 mg/kg), EMB (15 mg/kg), PZA (20 mg/kg) for 2 months, followed by 4 months of INH, RMP, EMB | Active TB | No |
| Chong, Brunei, 2008 | 1995–2005 | Retrospective | Patients with clinically diagnosed hepatobilliary TB, regardless of age N = 14 | ALT >2–3× ULN | STP (15 mg/kg daily), RIF (10 mg/kg daily), INH (5 mg/kg daily), PZA (30 mg/kg daily) before 1997 and RIF, INH, PZA, and EMB (20 mg/kg day) after 1997, length of treatment-unknown | Active TB | No |
| Chou et al., Taiwan, 2004 | 1989–2003 | Retrospective | Patients undergoing IST following HTx, with AFB confirmed TB, regardless of age N=5 | Clinical hepatitis as defined by guidelines | Standard WHO regimen, adjusted for concentration interactions with transplant drugs. Twenty-four months for extrapulmonry, and at least twelve months for pulmonary TB | Active TB | Yes |
| Cook et al., US, 2006 | 2000–2006 | Prospective | Patients, of all ages, treated for LTBI N = 291 | 2–5× normal ALT/AST levels | PZA (15 mg/kg daily), RIF (10 mg/kg daily); PZA (50 mg/kg), RIF (10 mg/kg) two times/week for 2 months; RIF (10 mg/kg daily) for 4 months (6 months for children <15 years old); INH (5 mg/kg daily) for adults, INH (10 mg/kg daily) for children | LTBI | No |
| Ekochin et al., US, 2009 | 2001–2008 | Retrospective | Patients, of all ages, treated for LTBI with concommittant MTX treatment N = 40 | LFT elevation >3× ULN | INH (5 mg/kg per day for adults, and 10 mg/ kg per day for children [maximum, 300 mg per day]) length of treatment-unknown | LTBI | No |
| Haley et al., US, 2008 | 2000–2004 | Retrospective | Patients >18 years of age treated for LTBI, with no previous treatment history N = 749 | Serum ALT ≥ 120 U/l with GI symptoms or ≥200 regardless of symptoms | RMP (10 mg/kg daily) for 4 months | LTBI | No |
| Jahng et al., US, 2007 | 2003–2006 | Prospective | Patients with end-stage liver disease > 18 years of age treated for LTBI N = 14 | 2× baseline LFT; clinical presentation of Hepatoxicity | INH (600 mg daily) for 4 months; RIF (300 mg daily) for 9 months | LTBI | Yes |
| Khan et al., Malaysia, 2010 | 2006–2008 | Retrospective cohort | Patients of all ages with active TB disease with normal AST/ ALT levels of <40 IU/I at baseline N = 1542 | Increase to 5× the ULN ALT/AST; Bilirubin >2 mg/dl; clinical jaundice | INH (5 mg/kg), RMP (10 mg/kg), EMB (15 mg/kg), PZA (25 mg/kg), STP (15 mg/kg) daily until end of treatment | Active TB | No |
| Kwon et al., South Korea, 2007 | 1994–2005 | Case-control | Patients of all ages with newly diagnosed active TB disease with normal AST/ALT levels of <40 IU/I at baseline, positive for HCV antibody and negative for hepatitis B surface antigen N = 151 | AST/ALT > 120IU/L AST/ ALT < 200 IU/L, defined as mild AST/ALT ≥ 200–500 IU/L defined as moderate hepatotoxicity AST/ALT levels ≥ 500 IU/L defined as severe hepatotoxicity | RIF (450–600 mgdaily), INH (300 mg daily), PZA (1500 mg daily), EMB(800 to 1200 mg daily) for 2 months followed by 4 months of INH, RIF, EMB | Active TB | No |
| Lee et al., South Korea, 2005 | 1994–2000 | Prospective | Patients of all ages with active Pulmonary TB disease N = 232 | AST/ALT increase >3 times ULN; any elevation of transaminase above basal levels in the presence of icteric hepatitis | INH (300–400 mg daily), RIF (450–600 mg daily), EMB (600–800 mg daily), PZA (1000 –1500 mg daily) for at least 6 months | Active TB | No |
| Lorent et al., Rawanda, 2011 | 2008–2010 | Prospective | Patients aged ≥21 years, both inpatient and outpatient – with newly diagnosed active TB N = 245 | Elevated liver enzymes and/or serum creatinin per guidelines | RIF (450–600 mg daily), INH (300 mg daily), PZA (1500 mg daily), EMB (800–1200 mg daily) for 6 months followed by 4 months of INH, RMP, EMB | Active TB | No |
| Menzies et al., Canada, Brazil, and Saudi Arabia, 2008 | 2004–2007 | Open label RCT | Patients >18 years of age treated for LTBI N = 847 | ALT 3–10 or 5–10× ULN w/ symptoms met criteria for grade 3 hepatotoxicity ALT >10× ULN met criteria for grade 4 toxicity | RIF (600 mg daily for 4 months) INH (300 mg daily for 9 months) | LTBI | No |
| Meyers et al., US, 2000 | 1988–1996 | Retrospective | Patients undergoing therapy for active TB following OLTx, regardless of age N = 8 | Elevation in AST/ALT per guidelines; histological features consistent with toxicity | RIF (450–600 mg daily), INH (300 mg daily), PZA (1500 mg daily), EMB (15 mg/kg/day) for 6 months, followed by 6–12 months of INH, RIF or OFL (800 mg daily) and EMB (15 mg/kg/day) | Active TB | Yes |
| Nader et al., Brazil, 2010 | 1998–2006 | Retrospective | Patients ≥18 years of age treated for active TB infection N = 534 | Increase in ALT >3× ULN; total bilirubin >2× ULN | Patients 20–40 kg: RMP (300 mg), INH (200 mg), PZA (1000 mg); Patients 40 –60 kg: RMP (450 mg), INH (300), PZA (1500 mg); Patients > 60 kg: RMP (600 mg), INH (400 mg), PZA (2000 mg); Standard RHZ length of treatment | Active TB | No |
| Nolan et al., US, 1999 | 1989–1995 | Prospective | Patients, of all ages, treated for LTBI N = 11,141 | AST 5× ULN without symptoms, clinical symptoms of hepatitis; resolution of signs and symptoms after withdrawl of INH | INH preventative therapy, length of treatment-6–12 months | LTBI | No |
| Ormerod et al., UK, 1996 | 1978–1992 | Retrospective cohort | Patients, of all ages, treated for active TB disease N = 1317 | Jaundice and/or elevation of ALT 5× pretreatment level | Adults: INH (300 mg), RMP (450–600 mg), PZA (1500–2000 mg), EMB (15 mg/kg), STM (1.0 gm 6 d/w) Children: INH (10 mg/kg), RMP (10 mg/kg), PZA (30 mg/kg), 2–4 months of RMP, INH, EMB, with continuation of INH/EMB for up to 15 mos/ RMP/INH for up to 12 months | Active TB | No |
| Possuelo et al., Brazil, 2008 | 2005–2007 | Prospective | Patient ≥ 18 years of age with newly diagnosed active TB disease N = 253 | AST/ALT > 3× ULN; and/or total bilirubin >2.0 mg/dL | <45 kg: RIF (300 mg), INH (200 mg), PZA (1000 mg); 45–55 kg: RIF (450 mg), INH (300 mg), PZA (1500 mg); >55 kg: RIF (600 mg), INH (400 mg), PZA (2000 mg); 2 months of daily INH, RIF, PZA, EMB followed by 4 months INH, RMP daily | Active TB | No |
| Quantrill et al., UK, 2003 | 1986–1999 | Retrospective | Patients of all ages with active TB disease and CRF N = 24 | Clinical Hepatitis as defined by BTS guidelines | Standard combination and doses of RMP, INH and PZA, per the BTS Guidelines for 6 –18 months | Active TB | Yes |
| Samandari et al., Botswana, 2011 | 2004–2006 | RCT | Patient ≥18 years of age or older with HIV infection and no symptoms or previous treatment of active TB N = 1995 | AST/ALT > 5× ULN, irrespective of symptoms | INH (300 mg per day) for individuals weighing 30–49 kg; INH (400 mg per day) for those weighing ≥50 kg; 6 months vs 36 months INH prophylaxis | LTBI | No |
| Schaberg et al., Germany, 1996 | 1990–1994 | Retrospective | Patients of all ages with active TB disease N = 519 | AST/ALT 3× the ULM; SGOT>54 U/L; SGPT>60 U/L | INH (5 m/kg daily), RIF (10 mg/kg daily), and PZA (25–30 mg/kg daily), with or without EMB and/or STP; length of treatment not reported | Active TB | No |
| Schluger et al., US, 1996 | 1988–1995 | Retrospective | Patients undergoing therapy for LTBI or active TB following OLTx, regardless of age N = 13 | Abnormal LFTs; exclusion of other causes of hepatitis | INH (300 mg daily); INH (300 mg daily), RIF (600 mg daily), EMB (15 mg/kg daily), PZA (20 mg/kg daily) or HRZE + OFL (800 mg daily) for up to 1 year | Both | Yes |
| Sen et al., Turkey, 2008 | 2002–2007 | Retrospective | Patients of all ages undergoing treatment for active TB with ESRD N = 18 | Elevated AST/ALT; jaundice | INH (300 mg daily), RMP (600 mg daily), MPZ (35–40 mg/kg 3d/w), EMB (20 mg/kg 3 d/w) for 2 months followed by INH and RMP for 4–6 months | Active TB | Yes |
| Shang et al., China, 2011 | 2007–2008 | Prospective | Patients of all ages undergoing treatment for active TB N = 4304 | ALT/AST > three times ULN; >2× ULN, when other causes were excluded | HRZE 75/150/400/275 mg per tablet daily for 2 months followed by H/R 75/150 mg daily for 4 months with or without STP | Active TB | No |
| Sharifzadeh et al., Iran, 2005 | 1999–2002 | Prospective | Patients of all ages undergoing treatment for active TB N = 112 | AST/ALT > three times ULN with any clinical signs/ symptoms or AST/ALT > five times ULN with no symptoms | RIF (10 mg/kg daily), INH (5 mg/kg daily), PZA (25 mg/kg daily), EMB (15 mg/kg daily) for standard treatment length | Active TB | No |
| Sistanizad et al., Iran, 2011 | 2006–2008 | Prospective | Patients of all ages undergoing treatment for newly diagnosed active TB disease N = 50 | ALT or AST > 2–3× ULN; clinical symptoms of liver disease i.e., jaundice and ascites | INH (5 mg/kg), RIF (10 mg/kg), PZA (25 –30 mg/kg), EMB (15 mg/kg daily) for 2 months, followed by 4 months of INH, RIF | Active TB | No |
| Smith et al., Canada, 2011 | 1998–2003 | Cross-sectional | Patients of all ages undergoing treatment for LTBI = 9145 | Toxic hepatitis as defined by guidelines | INH (5 mg/kg daily) for 6 months; RIF (10 mg/kg daily) for 4 months | LTBI | No |
| Sotsuka et al., Japan, 2011 | Not reported | Prospective | Patients of all ages undergoing treatment for active TB = 144 | AST/ALT > 5× ULN, irrespective of symptoms; AST/ALT > 3× ULN in the presence of symptoms; Bilirubin >3 mg/dL | INH (5 mg/kg), RIF (10 mg/kg), PZA (25 –30 mg/kg), EMB (15 mg/kg daily) for 2 months, followed by 4 months of INH, RIF; HER or HRZ were alternative regimens | Active TB | No |
| Stout et al., US, 2003 | 1999–2002 | Retrospective | Patients of all ages undergoing treatment for LTBI N = 119 | AST/ALT >5× ULN with one or more accompanying clinical symptoms/signs (nausea, vomiting, abdominal pain, or jaundice) | 60 doses of daily RIF (10 mg/kg, maximum daily dose of 600 mg) plus PZA (20 mg/kg, maximum daily dose of 2000 mg) or 16 doses of twice-weekly RIF (10 mg/kg, maximum dose of 600 mg) plus PZA (50 mg/kg, maximum dose of 4000 mg) for two months | LTBI | No |
| Sun et al., Taiwan, 2009 | 2000–2001 | Prospective | Patients of all ages undergoing treatment for active TB N = 261 | AST/ALT > 5× ULN, irrespective of symptoms; AST/ALT > 3× ULN in the presence of symptoms; Bilirubin >3 mg/dL | HERZ; HRZ; Combinations of: RIF (mg/kg/ day) INH (mg/kg/day) EMB (mg/kg/day) PZA (mg/kg/day) | Active TB | No |
| Tariq et al., Pakistan, 2009 | Not reported | Descriptive | Patients of all ages undergoing treatment for active TB N = 500 | ALT > 5× ULN; clinically evident hepatitis | Standard first-line regimen of HRZE | Active TB | No |
| Teleman et al., Singapore, 2002 | 1998 | Retrospective | Patients >16 years of age undergoing treatment for active TB disease N = 1036 | ALT/AST > 3× ULN; Bilirubin > ULN and ALT and/or AST >2 × ULN | INH, RMP, PZA with or without EMB or STP for 6 months; RMP, EMB, INH for 9 months | Active TB | No |
| van den Brande et al., Belgium, 1995 | 1980–1985 | Retrospective | Patients of all ages undergoing treatment for active TB N = 131 | ALT > 5× ULN with or without symptoms | RIF (10 mg/kg daily), INH (5 mg/kg daily), EMB (25 mg/kg for 6 wk and 15 mg/kg thereafter) for 9 months | Active TB | No |
| Wang et al., Taiwan, 2011 | 2007–2008 | Prospective | Patients >16 years of age undergoing treatment for active TB disease N = 360 | AST/ALT > 5× ULN, irrespective of symptoms; AST/ALT > 3× ULN in the presence of symptoms | Standard daily INH, RMP, EMB, PZA for 2 months followed by daily INH and RMP | Active TB | No |
| Young et al., US, 2009 | 2003–2007 | Retrospective | Patients > 18 years of age treated for LTBI N = 777 | ALT > 2.5–5× ULN with or without symptoms | INH (5 mg/kg daily) for 9 months; RIF (10 mg/kg daily) for 4 months | LTBI | No |
| Zabana et al., Spain, 2008 | 2003–2006 | Retrospective | Patients of all ages with LTBI and concomitant anti-TNF therapy N = 83 | AST/ALT elevation by standard definition | INH (5 mg/kg daily) for 6 months; INH (15 mg/kg 2× weekly) for 6 months; INH (5 mg/kg daily) for 9 months; INH (15 mg/ kg 2× weekly) for 9 months; INH (5 mg/kg daily) for 12 months; RMP (15 mg/kg daily), INH (10 mg/kg daily) for 6 months | LTBI | No |