What is the treatment for anti-tuberculosis (TB) medicine-induced hepatitis?

Treatment of Anti-Tuberculosis Medicine-Induced Hepatitis

When drug-induced liver injury (DILI) occurs during TB treatment, immediately stop all hepatotoxic drugs (isoniazid, rifampin, and pyrazinamide) and initiate a non-hepatotoxic regimen of streptomycin and ethambutol until liver function normalizes, then sequentially reintroduce drugs starting with isoniazid, followed by rifampin, and lastly pyrazinamide if needed. 1, 2

Immediate Management When Hepatotoxicity Occurs

Stop all hepatotoxic TB drugs immediately when ALT levels are ≥3 times the upper limit of normal with hepatitis symptoms (nausea, vomiting, abdominal pain), or ≥5 times the upper limit of normal without symptoms. 3

• Exclude other causes of liver injury before attributing hepatotoxicity to anti-TB drugs, including viral hepatitis (A, B, C, Epstein-Barr virus, cytomegalovirus), biliary tract disease, alcohol, acetaminophen, lipid-lowering agents, and herbal supplements. 3, 4

• Initiate a non-hepatotoxic holding regimen consisting of streptomycin and ethambutol (15-20 mg/kg daily) to maintain some anti-TB activity while liver function recovers. 1, 2

Sequential Drug Reintroduction Protocol

Once liver function tests normalize, reintroduce drugs one at a time with careful monitoring:

Step 1: Reintroduce Isoniazid First

• Start isoniazid at 50 mg/day for 2-3 days. 1, 2
• If no reaction occurs, increase to 300 mg/day after 2-3 days. 1, 2
• Continue ethambutol and streptomycin throughout. 2

Step 2: Add Rifampin Second

• After 2-3 days of full-dose isoniazid without reaction, start rifampin at 75 mg/day for 2-3 days. 1, 2
• Increase to 300 mg/day for 2-3 days if tolerated. 1, 2
• Further increase to 450 mg (if <50 kg) or **600 mg** (if >50 kg) after another 2-3 days. 1, 2

Step 3: Add Pyrazinamide Last (If Needed)

• Start pyrazinamide at 250 mg/day for 2-3 days. 1
• Increase to 1.0 g after 2-3 days if tolerated. 1
• Further increase to 1.5 g (<50 kg) or **2.0 g** (>50 kg). 1

Important caveat: Pyrazinamide causes more severe and prolonged hepatotoxicity than other drugs, and reintroduction carries higher risk of recurrence with poor prognosis. 5, 6 Consider omitting pyrazinamide entirely if hepatotoxicity was severe. 3, 7

Monitoring During Reintroduction

• Check liver function tests weekly for the first 2 weeks after each drug reintroduction. 1, 2
• Continue monitoring every 2 weeks for the first 2 months. 1, 2
• Educate patients about hepatotoxicity symptoms (nausea, vomiting, abdominal pain, jaundice, dark urine) and instruct them to stop medications immediately and seek medical attention if these occur. 1, 2

Alternative Regimens When Drugs Cannot Be Reintroduced

If Pyrazinamide Cannot Be Tolerated:

• Use isoniazid, rifampin, and ethambutol for 2 months, followed by isoniazid and rifampin for 7 months (total 9 months). 3, 1, 2
• This is the preferred alternative as it retains the two most critical drugs (isoniazid and rifampin). 3

If Isoniazid Cannot Be Tolerated:

• Use rifampin, ethambutol, and a fluoroquinolone (levofloxacin or moxifloxacin) for 12 months. 1, 2
• Some experts recommend adding pyrazinamide if tolerated. 2

If Both Isoniazid and Pyrazinamide Cannot Be Tolerated:

• Use rifampin and ethambutol with a fluoroquinolone for 12-18 months. 4, 2
• Duration depends on disease extent and severity. 4

If All Hepatotoxic Drugs Cannot Be Tolerated:

• Use ethambutol with a fluoroquinolone, cycloserine, and an injectable agent (streptomycin or amikacin) for 18-24 months. 2
• This scenario requires expert consultation. 3

Critical Pitfalls to Avoid

Do not reintroduce pyrazinamide in patients with severe initial hepatotoxicity (marked transaminase elevation, jaundice, or prolonged recovery), as pyrazinamide-induced hepatitis has poor prognosis and high recurrence rates. 5, 6

Rifampin enhances isoniazid hepatotoxicity through enzyme induction, so early hepatotoxicity (within first 15 days) is often rifampin-potentiated isoniazid toxicity with better prognosis, while late hepatotoxicity (>1 month) is typically pyrazinamide-related with worse prognosis. 5

Patients with pre-existing liver disease, chronic alcohol use, hepatitis B/C infection, HIV infection, malnutrition, or advanced age are at higher risk for both initial hepatotoxicity and recurrence, requiring more intensive monitoring. 3, 4, 8

Avoid concurrent hepatotoxic medications (acetaminophen, lipid-lowering agents, certain herbal supplements) during TB treatment and reintroduction. 3, 4

Special Considerations for Extrapulmonary TB

• For TB meningitis or pericarditis, treatment duration may need extension to 9-12 months even with standard regimens. 1
• Corticosteroids should be added for tuberculous pericarditis or meningitis to prevent complications. 1

Key Principle

Rifampin and isoniazid are the most critical drugs for TB treatment efficacy, and every effort should be made to retain them in the regimen, even after hepatotoxicity. 4 The sequential reintroduction protocol allows identification of the specific offending drug while maximizing the chance of successfully resuming effective therapy. 2, 6