How to proceed with anti-tuberculosis treatment (ATT) in a patient with drug-induced liver injury (DILI) and improved liver function tests (LFTs) after initial adjustment, currently on ethambutol (800 mg od), streptomycin (750 mg im once a day), and Liv.52 (500 mg od)?

Management of Anti-Tuberculosis Treatment After Drug-Induced Liver Injury (DILI)

For a patient with improved liver function tests after DILI, the recommended approach is to reintroduce anti-TB drugs sequentially, starting with ethambutol and streptomycin, then adding rifampicin followed by isoniazid, with careful monitoring of liver function. 1

Current Situation Assessment

• The patient experienced DILI while on standard anti-TB treatment and was switched to a less hepatotoxic regimen (ethambutol 800 mg daily, streptomycin 750 mg daily, and Liv.52 500 mg daily) 1
• After 3 days on this modified regimen, liver function tests have improved, indicating resolution of acute hepatotoxicity 1
• The patient now requires reintroduction of effective anti-TB therapy to ensure adequate treatment of tuberculosis 1

Recommended Reintroduction Protocol

Step 1: Continue Current Non-hepatotoxic Drugs

• Continue ethambutol 800 mg daily and streptomycin 750 mg daily as these are less hepatotoxic and well-tolerated by the patient 1
• Continue Liv.52 500 mg daily as supportive therapy 1

Step 2: Sequential Reintroduction of First-line Drugs

• Begin with rifampicin at 75 mg/day for 2-3 days 1
• If no reaction occurs, increase rifampicin to 300 mg/day for 2-3 days 1
• Further increase rifampicin to 450 mg (<50 kg) or 600 mg (>50 kg) according to patient's weight and continue 1
• After 2-3 days of full-dose rifampicin without reaction, add isoniazid at 50 mg/day 1
• If no reaction occurs, increase isoniazid to 300 mg/day after 2-3 days 1

Step 3: Consider Pyrazinamide Reintroduction

• If rifampicin and isoniazid are tolerated, consider adding pyrazinamide at 250 mg/day 1
• Increase to 1.0 g after 2-3 days, then to 1.5 g (<50 kg) or 2.0 g (>50 kg) based on weight 1
• If pyrazinamide is not tolerated, continue treatment with rifampicin and isoniazid for a total of 9 months, supplemented with ethambutol for the initial 2 months 1

Monitoring Protocol

• Monitor liver function tests weekly for the first 2 weeks after each drug reintroduction 1
• Continue monitoring liver function tests every 2 weeks for the first 2 months 1
• Educate patient about symptoms of hepatotoxicity (fever, malaise, vomiting, jaundice) and instruct to stop medication and seek medical attention if these occur 1, 2

Management of Recurrent Hepatotoxicity

• If ALT/AST rises to 5 times the upper limit of normal or if bilirubin rises, stop the most recently added hepatotoxic drug 1
• If the patient is not acutely ill and TB is non-infectious, pause treatment until liver function normalizes 1
• For patients who are ill or have infectious TB, continue ethambutol and streptomycin while awaiting liver function normalization 1

Alternative Regimens if Standard Drugs Cannot be Reintroduced

1. If pyrazinamide cannot be tolerated:

   • Use isoniazid, rifampicin, and ethambutol for 2 months, followed by isoniazid and rifampicin for 7 months (total 9 months) 1

2. If isoniazid cannot be tolerated:

   • Use rifampicin, pyrazinamide, and ethambutol with or without a fluoroquinolone for at least 6 months 1

3. If both isoniazid and pyrazinamide cannot be tolerated:

   • Use rifampicin and ethambutol with a fluoroquinolone for 12-18 months 1

4. If all hepatotoxic drugs cannot be tolerated:

   • Use ethambutol with a fluoroquinolone, cycloserine, and injectable agent (streptomycin) for 18-24 months 1

Important Considerations

• The risk of DILI is highest during the first 3 months of therapy 3
• Liver enzyme values often return to normal despite continued treatment, suggesting adaptation to liver injury 3
• Patients with pre-existing liver disease are at higher risk for DILI and require more careful monitoring 1, 2
• Streptomycin should be administered as 15 mg/kg 2-3 times weekly (not daily) in the long term to minimize toxicity 1, 4
• Ethambutol should be dosed at 15 mg/kg daily for standard treatment 5

By following this sequential reintroduction protocol with careful monitoring, you can safely restart effective anti-TB therapy while minimizing the risk of recurrent hepatotoxicity.