In a patient receiving standard first‑line tuberculosis therapy (isoniazid, rifampicin, pyrazinamide ± ethambutol) who develops a late drug‑induced liver injury, what immediate steps should be taken and how should the drugs be re‑introduced?

Management of Late Drug-Induced Liver Injury During Tuberculosis Treatment

When late DILI occurs during first-line TB therapy, immediately stop all hepatotoxic drugs (isoniazid, rifampicin, pyrazinamide), initiate streptomycin plus ethambutol as bridge therapy if the patient is infectious or acutely ill, and once liver function normalizes, sequentially reintroduce drugs starting with isoniazid, followed by rifampicin, but avoid reintroducing pyrazinamide due to its poor prognosis when causing late-onset hepatotoxicity. 1, 2

Immediate Management Steps

Stop All Hepatotoxic Drugs

• Discontinue rifampicin, isoniazid, and pyrazinamide immediately when any of the following occur: 3, 1, 4
  • AST/ALT ≥5× upper limit of normal (ULN), regardless of symptoms
  • AST/ALT ≥3× ULN with symptoms (jaundice, nausea, vomiting, right upper quadrant pain)
  • Any elevation in bilirubin ≥2× ULN
  • Clinical jaundice, regardless of transaminase levels

Assess Disease Severity and Initiate Bridge Therapy

• For infectious TB (sputum smear-positive) or acutely ill patients: Start streptomycin plus ethambutol immediately as bridge therapy until liver function normalizes 3, 1, 5

  • Ethambutol: 15-20 mg/kg daily 1
  • Verify renal function before streptomycin use and monitor appropriately 1

• For non-infectious TB in stable patients: No treatment is required until liver function returns to normal 3, 4

Exclude Alternative Causes

• Perform viral hepatitis testing (A, B, C, E) 1, 5
• Assess alcohol consumption history 1, 5
• Review other hepatotoxic medications 1

Critical Distinction: Late vs. Early DILI

Late-onset hepatotoxicity (>1 month after treatment initiation) is likely pyrazinamide-induced and carries a poor prognosis. 2 This is a critical pitfall: pyrazinamide should not be reintroduced in patients with late DILI, even if liver function normalizes. 1, 2

Early hepatotoxicity (<15 days) is typically rifampicin-enhanced isoniazid toxicity and has a better prognosis. 2

Sequential Drug Reintroduction Protocol

Timing

• Begin reintroduction only after transaminases and bilirubin have completely normalized 3, 1, 4

Step-by-Step Reintroduction (with daily monitoring)

Step 1: Isoniazid 3, 1, 5

• Start at 50 mg/day
• Increase to 300 mg/day after 2-3 days if no reaction
• Continue for 2-3 days at full dose before adding next drug

Step 2: Rifampicin 3, 1, 5

• Start at 75 mg/day
• Increase to 300 mg after 2-3 days without reaction
• Further increase to 450 mg (<50 kg) or 600 mg (>50 kg) after another 2-3 days
• Continue for 2-3 days at full dose before considering next drug

Step 3: Pyrazinamide - AVOID in Late DILI 1, 2

• Do not reintroduce pyrazinamide if hepatotoxicity occurred late (>1 month) due to poor prognosis and high recurrence risk 1, 2
• If reintroduction is attempted (only in early DILI with mild initial injury): start at 250 mg/day, increase to 1.0 g after 2-3 days, then to 1.5 g (<50 kg) or 2.0 g (>50 kg) 3, 1

Monitoring During Reintroduction

• Check AST/ALT and bilirubin daily during each drug addition 1, 5
• Assess for symptoms daily: fever, malaise, vomiting, jaundice, abdominal pain 1, 5
• Stop the most recently added drug immediately if transaminases rise again or symptoms develop 1, 4

Alternative Regimens When Drugs Cannot Be Reintroduced

If Pyrazinamide is Excluded (Most Common in Late DILI)

Use isoniazid + rifampicin + ethambutol for 2 months, then isoniazid + rifampicin for 7 additional months (total 9 months) 3, 1, 4

• This is the preferred alternative regimen when pyrazinamide cannot be used 1
• Ethambutol is included for the initial 2 months 3, 4

If Isoniazid Cannot Be Reintroduced

• Use rifampicin + ethambutol + fluoroquinolone (levofloxacin or moxifloxacin) for 12 months 1

If Multiple First-Line Drugs Fail

• Use ethambutol + fluoroquinolone + cycloserine + injectable agent for 18-24 months 1
• Consult a TB specialist for second-line regimens 5

Absolute Contraindications to Rechallenge

Do not attempt rechallenge if: 1

• Patient meets Hy's Law criteria (ALT ≥3× ULN and bilirubin ≥2× ULN)
• Hepatic decompensation present (ascites, encephalopathy)
• Hypersensitivity features (rash, fever, eosinophilia)
• Cirrhosis or advanced liver disease

Common Pitfalls and How to Avoid Them

1. Never continue hepatotoxic drugs while "monitoring closely" once significant DILI develops - this can lead to fulminant hepatic failure 5

2. Do not reintroduce all drugs simultaneously - sequential reintroduction identifies the offending agent 5

3. Do not reintroduce pyrazinamide in late DILI - late-onset pyrazinamide hepatotoxicity has poor prognosis and high recurrence risk 1, 2

4. Do not discontinue therapy prematurely in asymptomatic patients with transaminases <5× ULN - this increases treatment failure and resistance risk 4

5. Avoid concurrent hepatotoxic medications including over-the-counter acetaminophen 5

Enhanced Monitoring for High-Risk Patients

Patients with the following risk factors require weekly LFTs for 2 weeks, then biweekly for 2 months: 1, 4, 5

• Pre-existing liver disease or cirrhosis
• Chronic alcohol use
• Hepatitis B or C co-infection
• Advanced age
• Female sex (particularly Black and Hispanic women)
• Post-partum period