A Randomized Controlled Trial of Intravenous N-Acetylcysteine in the Management of Anti-tuberculosis Drug–Induced Liver Injury

Abstract

Background Liver injury is a common complication of first-line anti-tuberculosis therapy. N-acetylcysteine (NAC) is widely used in patients with paracetamol toxicity with limited evidence of benefit in liver injury due to other causes. Methods We conducted a randomized, double-blind, placebo-controlled trial to assess whether intravenous NAC hastens liver recovery in hospitalized adult patients with anti-tuberculosis drug induced liver injury (AT-DILI). The primary endpoint was the time for serum alanine aminotransferase (ALT) to fall below 100 U/L. Secondary endpoints included length of hospital stay, in-hospital mortality and adverse events. Results Fifty-three participants were randomized to NAC and 49 to placebo. Mean age was 38 (SD±10) years, 58 (57%) were female and 89 (87%) were HIV-positive. Median serum ALT and total bilirubin at presentation were 462 U/L (IQR 266-790) and 56 μmol/L (IQR 25-100) respectively. Median time to ALT&100 U/L was 7.5 days (IQR 6 -11) in the NAC arm and 8 days (IQR 5 -13) in the placebo arm. Median time to hospital discharge was shorter in the NAC arm (9 days; IQR 6-15) than in the placebo arm (18 days; IQR 10-25), hazard ratio 1.73 (95% CI 1.13-2.65). Mortality was 14% overall and did not differ by study arm. The study infusion was stopped early due to an adverse reaction in 5 participants receiving NAC [nausea and vomiting (3), anaphylaxis (1), pain at drip site (1)]. Conclusion NAC did not shorten time to ALT&100 U/L in participants with AT-DILI, but significantly reduced length of hospital stay. NAC should be considered in management of AT-DILI.

Drug-Induced Liver Injury: Highlights and Controversies in the Recent Literature

“…There were several reports of the use of NAC to treat DILI published over the last year [186,187]. Notably, we found a randomized controlled trial that evaluated the use of NAC for anti-TB-DILI [186]. Its results showed that although NAC did not shorten the time to ALT < 100 U/L in participants with anti-TB-DILI, it did significantly reduce the length of a hospital stay from 18 days to 9 days compared with placebo.…”

“…Other than treatment with intravenous N-acetylcysteine (NAC), there have been few other options for improving transplant-free survival in non-acetaminophen acute liver failure. There were several reports of the use of NAC to treat DILI published over the last year [186,187]. Notably, we found a randomized controlled trial that evaluated the use of NAC for anti-TB-DILI [186].…”

Pharmacotherapies for Drug-Induced Liver Injury: A Current Literature Review

“…Moosa MS et al conducted a randomized, double-blind, placebo-controlled trial to assess whether intravenous NAC hastens liver recovery in hospitalized adult patients with anti-tuberculosis (Anti-TB) DILI. The results revealed that NAC did not shorten time to ALT<100 U/L in participants with Anti-TB DILI, but significantly reduced length of hospital stay ( Moosa et al, 2020 ). In another study NAC together with prednisolone when used in cases of severe idiosyncratic DILI due to fupirtine (central acting non-opiod analgesic) showed a significant improvement in ALT, AST and INR within 2 weeks compared to those who were not treated with NAC ( Borlak et al, 2018 ).…”

Photoclick Reaction Constructs Glutathione-Responsive Theranostic System for Anti-Tuberculosis

“…Tuberculosis also arises in other organs, including bone and spine, then evolving into one of the most typical forms of extrapulmonary tuberculosis ( Pandey et al, 2009 ; Magnussen et al, 2013 ; Pigrau-Serrallach and Rodríguez-Pardo, 2013 ; Rodriguez-Takeuchi et al, 2019 ). Recently, the surgical intervention accompanied by indispensable anti-tubercular drug therapy is the primary routine treatment ( Mukewar et al, 2012 ; Shrivastava et al, 2019 ; Moosa et al, 2020 ; Phillips et al, 2020 ). Although rifampicin (RIF) and isoniazid have been widely chosen as clinical anti-tubercular drugs due to their excellent effectiveness and reasonable price ( Hakkimane et al, 2018 ; Campbell et al, 2020 ; Sterling et al, 2020 ; Villa et al, 2020 ; Kabir et al, 2021 ), their short plasma life and relatively low concentration in tuberculosis granulomas and the inescapable side effects of chemotherapeutic drugs have drawn growing attention from interdisciplinary and clinical medicine research circles ( Du Toit et al, 2006 ; Dartois, 2014 ; Liao et al, 2020 ).…”