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.
Background Higher doses of intravenous rifampicin may improve outcomes in tuberculous meningitis but is impractical in high burden settings. We hypothesized that plasma rifampicin exposures would be similar between oral 35 mg/kg and intravenous 20 mg/kg, which has been proposed for efficacy trials in tuberculous meningitis. Materials and methods We performed a randomized parallel group pharmacokinetic study nested within a clinical trial of intensified antimicrobial therapy for tuberculous meningitis. HIV-positive participants with tuberculous meningitis were recruited from South African hospitals and randomized to one of three rifampicin dosing groups: standard (oral 10 mg/kg), high dose (oral 35 mg/kg), and intravenous (intravenous 20 mg/kg). Intensive pharmacokinetic sampling was done on day 3. Data were described using non-compartmental analysis and exposures compared by geometric mean ratio (GMR). Results Forty-six participants underwent pharmacokinetic sampling (standard dose, n = 17; high dose oral, n= 15; intravenous, n = 14). Median CD4 count was 130 cells/mm3 (IQR 66 - 253). Rifampicin geometric mean AUC0-24 was 42.9 μg·h/mL (95% CI, 24.5 – 75.0) for standard dose; 295.2 μg·h/mL (95% CI, 189.9 – 458.8) for high dose oral; and 206.5 μg·h/mL (95% CI, 154.6 – 275.8) for intravenous administration. Rifampicin AUC0-24 GMR was 1.44 (90% CI, 0.84 - 2.21) and Cmax GMR was 0.89 (90% CI, 0.63 – 1.23) for high dose oral with respect to intravenous dosing. Conclusions Plasma rifampicin AUC0-24 was higher after an oral 35 mg/kg dose compared with intravenous administration at 20 mg/kg dose over the first few days of TB treatment. Findings support oral rifampicin dosing in future tuberculous meningitis trials.
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