What is the management approach for Anti-Tuberculosis Treatment (ATT)-induced Drug-Induced Liver Injury (DILI)?

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

Immediately discontinue all hepatotoxic anti-TB drugs (isoniazid, rifampin, and pyrazinamide) when ALT is ≥3× upper limit of normal (ULN) with hepatitis symptoms (nausea, vomiting, abdominal pain, jaundice) OR when ALT is ≥5× ULN even without symptoms. 1

Initial Recognition and Diagnosis

Biochemical Thresholds for Stopping Treatment

• Stop all hepatotoxic drugs immediately when meeting either criterion: ALT ≥3× ULN with symptoms of hepatitis OR ALT ≥5× ULN without symptoms 1
• Measure ALT, AST, bilirubin, and alkaline phosphatase to assess hepatotoxicity pattern 1
• The most common serious adverse reaction to first-line TB drugs is drug-induced hepatitis, with isoniazid, rifampin, and pyrazinamide all capable of causing DILI 1

Exclude Alternative Causes Before Confirming ATT-DILI

Before attributing liver injury to anti-TB drugs, systematically exclude: 1

• Viral hepatitis (hepatitis A, B, C in all patients; EBV, CMV, HSV in immunosuppressed)
• Biliary tract disease
• Alcohol use
• Other hepatotoxic medications (acetaminophen, statins, other drugs)
• Herbal and dietary supplements

Monitoring During Drug Rechallenge

Sequential Reintroduction Protocol

The safest approach is sequential reintroduction starting with the least hepatotoxic drugs first, with careful monitoring at each step. 2

1. Continue non-hepatotoxic drugs: Maintain ethambutol and streptomycin throughout, as these are minimally hepatotoxic 2

2. Reintroduce rifampin first (after liver enzymes normalize): 2

   • Start rifampin 75 mg/day for 2-3 days
   • If no reaction, increase to 300 mg/day for 2-3 days
   • Then advance to full dose: 450 mg (<50 kg) or 600 mg (≥50 kg)

3. Add isoniazid last (after 2-3 days of full-dose rifampin without reaction): 2

   • Start isoniazid 50 mg/day for 2-3 days
   • If tolerated, increase to 300 mg/day

4. Avoid pyrazinamide rechallenge in most cases due to risk of severe recurrent hepatotoxicity with poor prognosis 3

Monitoring Frequency During Rechallenge

• Check liver function tests weekly for the first 2 weeks after each drug reintroduction 2
• Continue monitoring every 2 weeks for the first 2 months 2, 4
• High-risk patients require monitoring every 2 weeks during the first 2 months of treatment, then monthly 4
• Educate patients to stop medications immediately and seek care if hepatitis symptoms develop 2

Alternative Regimens When Drugs Cannot Be Reintroduced

If Pyrazinamide Cannot Be Tolerated

• Use isoniazid + rifampin + ethambutol for 2 months, followed by isoniazid + rifampin for 7 months (total 9 months) 2

If Isoniazid Cannot Be Tolerated

• Use rifampin + pyrazinamide + ethambutol with or without fluoroquinolone for at least 6 months 2

If Both Isoniazid and Pyrazinamide Cannot Be Tolerated

• Use rifampin + ethambutol + fluoroquinolone for 12-18 months 2

If All Hepatotoxic Drugs Cannot Be Tolerated

• Use ethambutol + fluoroquinolone + cycloserine + injectable agent for 18-24 months 2
• Streptomycin should be dosed at 15 mg/kg 2-3 times weekly long-term to minimize toxicity 2

Management of Recurrent Hepatotoxicity During Rechallenge

• Stop the most recently added hepatotoxic drug if liver enzymes rise during sequential reintroduction 2
• If the patient is not acutely ill and TB is non-infectious, pause treatment until liver function normalizes 2
• For severe hepatocellular injury with jaundice or INR elevation, do not attempt rechallenge 1

Risk Factors Requiring Enhanced Monitoring

Patients at higher risk for ATT-DILI who warrant closer surveillance include: 4, 5, 6

• Age >55 years (21.1% developed ALT/AST ≥3× ULN on standard therapy) 6
• HIV-positive patients (15% experienced peak ALT/AST ≥3× ULN vs 9% HIV-negative) 6
• Asian ethnicity (85.1% of Asians with elevated enzymes were on isoniazid-containing regimens) 6
• Chronic alcohol consumption 5
• Viral hepatitis (hepatitis B or C) or preexisting liver disease 5
• Pregnancy or within 3 months postpartum 5
• Concomitant hepatotoxic medications 5

Timing Patterns of ATT-DILI

Understanding when hepatotoxicity occurs helps identify the causative agent: 3, 6

• Early pattern (within first 15 days): Likely rifampin-enhanced isoniazid hepatotoxicity; generally good prognosis 3
• Late pattern (>1 month): May be related to pyrazinamide; generally poor prognosis 3
• Median time to DILI is 28 days (IQR 14-56 days) 6
• Patients on isoniazid reach peak ALT ≥3× ULN approximately 9.5 days earlier than those without isoniazid 6

Common Pitfalls to Avoid

• Do not automatically discontinue for mild ALT elevations (<3× ULN without symptoms), as this may represent benign adaptation rather than true hepatotoxicity 1
• Never reintroduce pyrazinamide in patients who developed severe hepatotoxicity, as recurrence carries poor prognosis 3
• Do not give pyrazinamide to patients with underlying liver test abnormalities at baseline 3
• Avoid concurrent hepatotoxic drugs during TB treatment whenever possible 4
• Monitoring during the first 2 months of standard therapy detects approximately 75% of patients with significant enzyme elevations 6