TABLE 1.
Characteristics of randomized clinical trials included in the systematic review.
| Study, year (country) | Clinical trial design | Age (y) | Patients (Ex/Cn) a | Treatment regimen | Outcomes primary (P) secondary (S) | TD | DILI criteria/severity | Events d (Ex/Cn) | AE (Ex/Cn) | Summary of conclusions |
|---|---|---|---|---|---|---|---|---|---|---|
| DILI prevention | ||||||||||
| Baniasadi et al. (2010) (Iran) | Study type: interventional | ≥60 | 28/32 | Ex: ATT plus NAC 600 mg (b.d) | P: ATT-induced DILI incidence | 2 weeks | DILI criteria (at least one): (i) ALT and/or AST > 5xULN. (ii) TBil > 1.5 mg/dl. (iii) Any increase in ALT and/or AST along with hepatitis symptoms | 0/12 | NA | NAC protects against ATT-induced DILI |
| Randomization: NA | ||||||||||
| Allocation: NA | ||||||||||
| Open-label | Cn: ATT alone | |||||||||
| SSE: 52 | ||||||||||
| ITT: NA | Severity: NA | |||||||||
| Thandassery et al. (2012) (Taiwan) | Study type: interventional simple | NA | 26/25 | Ex: ATT plus NAC 600 mg (b.d) | P: DILI severity (TBil and transaminases), time to normalization of liver profile, oxidative stress parameters | 8 weeks | DILI criteria: NA | 8/8 f | NA | NAC showed no effect on DILI severity, biochemical recovery, and oxidative stress in cases with ATT-induced DILI |
| Randomization-Allocation: NA | Severity: (i) TBil > 5 mg/dl (ii) Transaminases > 10xULN | |||||||||
| Cn: ATT alone | ||||||||||
| Open-label | ||||||||||
| SSE: NA | ||||||||||
| ITT: NA | ||||||||||
| Ahmed and Rao (2020) (Pakistan) | Study type: interventional | 18–60 | 81/81 | Ex: ATT plus NAC 600 mg (b.d) | P: ATT-induced DILI incidence | 2 m | NA | 1/14 | NA | NAC is effective in preventing ATT-induced DILI |
| Simple randomization: NA | ||||||||||
| Allocation: NA | Cn: ATT alone | |||||||||
| Single-blind | ||||||||||
| SSE: 169 | ||||||||||
| ITT: NA | ||||||||||
| DILI Treatment | ||||||||||
| Lee et al. 2009 (United States) | Study type: interventional | ≥18 | 19/26 e | Ex: 5% GCL with NAC (150 mg/kg/h Over 1 h, 12.5 mg/kg/h for 4 h, 6.25 mg/kg/h for 67 h) | P: Overall survival at 3 weeks | 72 h | DILI criteria: NA | 15/17 | 46/NA | NAC improves transplant-free survival in early-stage NAI-ALF |
| block | ||||||||||
| Randomization: yes | Severity: ALF: any degree of encephalopathy and INR ≥ 1.5 due to an illness of < 24 weeks | |||||||||
| Allocation: yes | Cn: 5% GCL | S: Transplant-free survival at 3 weeks, LT | ||||||||
| Double-blind | ||||||||||
| SSE: 170 | ||||||||||
| ITT: Yes | ||||||||||
| Singh et al. 2013 c (United States) | Study type: interventional block | ≥18 | 81/92 | Ex: 5% GCL with NAC (150 mg/kg/h over 1 h, 12.5 mg/kg/h for 4 h, 6.25 mg/kg/h for 67 h) | P: LT and death | 72 h | DILI criteria: NA | NA | NA | Decreased risk of LT/death or LT alone with NAC in early coma grade NAI-ALF patients was reflected in improved ALT and TBil, but not in INR, creatinine, or AST |
| Randomization: yes | ||||||||||
| Allocation: yes | Severity: ALF: any degree of encephalopathy and INR ≥ 1.5 due to an illness of < 24 weeks | |||||||||
| Double-blind | <70 | Cn: 5% GCL | ||||||||
| SSE:173 | ||||||||||
| ITT: NA | ||||||||||
| Stravitz et al. (2013) c (United States) | Study type: interventional Randomization: yes | ≥18 | 39/39 | Ex: 5% GCL with NAC (150 mg/kg over 1 h, 12.5 mg/kg/h for 4 h, 6.25 mg/kg/h for 67 h) | P: TBil and IL-17 levels | 72 h | DILI criteria: NA | NA | NA | NAC may improve transplant-free survival by ameliorating the production of IL-17 in NAI-ALF |
| Allocation: yes | ||||||||||
| Double-blind | Cn: 5% GCL | Severity: ALF: any degree of encephalopathy and INR ≥ 1.5 due to an illness of <24 weeks | ||||||||
| SSE: NA | ||||||||||
| ITT: NA | ||||||||||
| Nabi et al. 2017 (India) | Study type: interventional simple | ≥18 | 10/5 e | Ex: NAC (150 mg/kg over 1 h, 12.5 mg/kg/h for 4 h, 6.25 mg/kg/h for 67 h) | P: Survival rate, duration of hospital stay, AE | 72 h | DILI criteria: NA | 10/5 b | 0/NA | Recommend the use of NAC along with conventional treatments in patients with NAI‑ALF in non‑transplant centers |
| Randomization: yes | ||||||||||
| Allocation: NA | Severity: ALF: INR of ≥ 1.5 and any degree of encephalopathy caused by illness of duration <8 weeks | |||||||||
| Blinding: NA | Cn: 5% GCL for 72 h | |||||||||
| SSE: NA | ||||||||||
| ITT: NA | ||||||||||
| Moosa et al. (2021) (South Africa) | Study type: interventional block | ≥18 | 53/49 | Ex: NAC (150 mg/kg over 1 h, 50 mg/kg over 4 h and 100 mg/kg over 16 h) | P: Time for ALT to fall below 100 U/L | 21 h | DILI criteria: ALT > 3xULN (hepatitis symptoms present) or ALT > 5xULN (without symptoms of hepatitis) | 7.5 days/8 days | 13/3 | NAC did not shorten time of ALT decrease, but reduced length of hospital stay |
| Randomization: yes | ||||||||||
| Allocation: yes | ||||||||||
| Double-blind | Cn: 0.9% NaCl or 5% GCL (if glucose <3.5 mmol/L) | S: Duration of hospital stay, mortality, AE | Severity: ALF: INR > 1.5 and altered mental status | |||||||
| SSE:100 | ||||||||||
| ITT: Yes | ||||||||||
a
Patients included in the final analysis.
b
Number of drug-induced ALF patients who survived.
c
These studies are substudies of Lee et al. (2009).
d
Related to the principal outcome.
e
Number of drug-induced ALF patients.
f
Patients who presented severe DILI.
Abbreviations: AE, adverse events; ALF, acute liver failure; ALT, alanine aminotransferase; AST, aspartate aminotransferase, ATT, antituberculosis treatment; b.d., twice daily; Cn, control group; d, day; DILI, drug-induced liver injury; Ex, experimental group; h, hours; GLC, glucose; IL, interleukin; ITT, intention-to-treat analysis; LT, liver transplantation; m, months; NA, not available; NAC, N-acetylcysteine; NAI-ALF, non-acetaminophen-induced ALF; INR, international normalized ratio; SSE, sample size estimation; TBil, total bilirubin; TD, treatment duration; ULN, upper limit of normal; wk, week; y, years.