When should anti‑tubercular therapy be discontinued in a patient with possible drug‑induced hepatitis?

When to Stop Anti-Tubercular Therapy in Drug-Induced Hepatitis

Stop rifampicin, isoniazid, and pyrazinamide immediately when AST/ALT rises to ≥5× the upper limit of normal (regardless of symptoms), or ≥3× upper limit of normal with hepatic symptoms (jaundice, nausea, vomiting, right-upper-quadrant pain), or when any elevation in bilirubin occurs. 1

Critical Stopping Thresholds

Asymptomatic patients:

• ≥5× upper limit of normal (ULN) for AST or ALT mandates immediate cessation of all hepatotoxic drugs 2, 1
• Any rise in serum bilirubin, regardless of transaminase levels, requires immediate drug discontinuation 1

Symptomatic patients:

• ≥3× ULN for AST or ALT accompanied by fever, malaise, vomiting, jaundice, or unexplained deterioration requires immediate cessation 2, 1
• Clinical jaundice alone mandates stopping all hepatotoxic agents, even if transaminases are not markedly elevated 1

What NOT to Stop

Continue treatment in mild elevations:

• Asymptomatic patients with transaminases ≤3× ULN should continue the full regimen without modification 1
• Monitor weekly for the first two weeks, then biweekly until values normalize 1
• Do not prematurely discontinue therapy in this range, as it increases risk of treatment failure and drug resistance 1

Bridging Therapy During Drug Interruption

For infectious TB (sputum smear-positive) or acutely ill patients:

• Replace discontinued hepatotoxic drugs with streptomycin plus ethambutol immediately 1, 3
• Verify renal function before streptomycin use; reduce dose to 250-500 mg/day if creatinine clearance <30 mL/min 1
• Monitor streptomycin levels and assess for ototoxicity regularly, especially in patients >59 years 1

For stable, non-infectious TB patients:

• Withhold all anti-TB therapy until liver enzymes and bilirubin normalize 1, 3
• Continue clinical surveillance for disease progression 1

Baseline Assessment Before Stopping

Before interrupting therapy, obtain:

• Viral hepatitis serology (A, B, C, E) if not done at baseline 2, 3
• Detailed alcohol consumption history 2, 1
• Review of all concurrent medications for other hepatotoxins 3
• Assessment for symptoms of hepatic decompensation (ascites, encephalopathy) 1

Sequential Drug Reintroduction Protocol

Only restart after complete normalization of transaminases and bilirubin (or <2× ULN if baseline was already elevated) 1, 3

Step 1: Isoniazid

• Start at 50 mg/day 2, 1, 3
• Increase to 300 mg/day after 2-3 days if no reaction 2, 1, 3
• Continue full dose for 2-3 days before adding next drug 1, 3

Step 2: Rifampicin

• Start at 75 mg/day 2, 1, 3
• Increase to 300 mg after 2-3 days 2, 1, 3
• Further increase to 450 mg (<50 kg) or 600 mg (≥50 kg) after another 2-3 days 2, 1, 3
• Continue full dose for 2-3 days before considering pyrazinamide 1, 3

Step 3: Pyrazinamide (with critical caveat)

• Do NOT reintroduce pyrazinamide if hepatotoxicity occurred >1 month after treatment initiation (late-onset DILI has poor prognosis) 1, 3
• For early-onset DILI (<15 days), may cautiously reintroduce starting at 250 mg/day 1, 3
• Increase to 1.0 g after 2-3 days, then to 1.5 g (<50 kg) or 2.0 g (≥50 kg) 2, 1, 3

Monitoring During Reintroduction

• Check AST/ALT and bilirubin daily after each drug addition 1, 3
• Assess for hepatic symptoms daily (fever, malaise, vomiting, jaundice, abdominal pain) 1, 3
• Immediately stop the most recently added drug if enzymes rise or symptoms appear 2, 1, 3

Alternative Regimens When Drugs Cannot Be Reintroduced

If pyrazinamide cannot be used:

• Isoniazid + rifampicin + ethambutol for 2 months, followed by isoniazid + rifampicin for 7 months (total 9 months) 1, 3, 4
• Ethambutol is included only during the initial 2 months 1, 3

If isoniazid cannot be tolerated:

• Rifampicin + ethambutol + fluoroquinolone for 12 months 3, 4

If rifampicin cannot be used:

• Isoniazid + ethambutol + fluoroquinolone for 18-24 months 1

Absolute Contraindications to Rechallenge

Never attempt reintroduction if:

• Patient meets Hy's Law criteria (ALT ≥3× ULN and bilirubin ≥2× ULN) 1
• Hepatic decompensation present (ascites, encephalopathy) 1
• Hypersensitivity features (rash, fever, eosinophilia, lymphadenopathy) 1
• Cirrhosis or advanced liver disease 1

High-Risk Populations Requiring Enhanced Monitoring

Patients with pre-existing chronic liver disease:

• Weekly liver function tests for first 2 weeks, then biweekly for first 2 months 2, 1
• Obtain baseline viral hepatitis testing (HBsAg, anti-HBc, HCV antibody) 1

Post-partum women:

• Intensified monitoring (weekly for 2 weeks, then biweekly for 2 months) 3
• Black and Hispanic women may have increased risk of fatal hepatitis 5

Patients >35 years:

• Monthly symptom reviews plus periodic hepatic enzyme measurements throughout treatment 5

Common Pitfalls to Avoid

• Do not stop therapy for asymptomatic transaminase elevations <5× ULN; this increases treatment failure risk 1
• Do not ignore modest pre-treatment elevations; they are common in TB patients and do not preclude standard therapy, but warrant closer monitoring 1
• Do not reintroduce pyrazinamide in late-onset hepatotoxicity (>1 month); it has poor prognosis and high recurrence risk 1, 3
• Do not use rifampin-pyrazinamide regimens in patients with prior isoniazid-associated liver injury 3
• Counsel complete alcohol abstinence during treatment; concurrent use significantly increases hepatotoxicity risk 2, 1, 3