What is the next step for a patient on Anti-Tuberculosis Treatment (ATT) with a Hepatotoxicity profile, specifically HRZE (Isoniazid, Rifampicin, Pyrazinamide, Ethambutol) regimen, who develops elevated liver enzymes, with Aspartate Aminotransferase (AST) levels more than 3 times the Upper Limit of Normal (ULN)?

Management of AST >3x ULN in a Patient on HRZE

Stop all hepatotoxic anti-tuberculosis drugs (isoniazid, rifampicin, and pyrazinamide) immediately and assess the patient's clinical status and bilirubin level to determine the next steps. 1

Immediate Actions

Discontinue Hepatotoxic Drugs

• Stop rifampicin, isoniazid, and pyrazinamide immediately when AST rises to 5 times the upper limit of normal (ULN), or when accompanied by symptoms of hepatitis at any elevation, or when bilirubin rises above normal. 1, 2
• At 3x ULN, the British Thoracic Society recommends close monitoring with weekly liver function tests for two weeks, then biweekly until normalization. 1
• However, given the threshold of >3x ULN in your patient, err on the side of caution and stop hepatotoxic drugs if the patient has any symptoms (fever, malaise, vomiting, jaundice, abdominal pain) or if bilirubin is elevated. 1, 2

Assess Clinical Status and Disease Severity

• Determine if the patient is clinically unwell or has infectious tuberculosis (sputum smear-positive). 1, 2
• Check bilirubin levels immediately, as elevated bilirubin mandates drug cessation regardless of transaminase levels. 1, 2
• Investigate non-drug causes of hepatitis, including viral hepatitis (hepatitis A, B, C). 1, 2

Bridging Therapy While Awaiting Liver Recovery

For Infectious or Clinically Unwell Patients

• Continue treatment with non-hepatotoxic drugs: streptomycin and ethambutol until liver function normalizes. 1, 2
• These drugs should be given with appropriate monitoring (audiometry for streptomycin, visual acuity and color vision for ethambutol). 1
• Fluoroquinolones can also be considered as part of the bridging regimen. 1

For Non-Infectious, Clinically Stable Patients

• No treatment is required until liver function returns to normal. 1, 2
• Continue monitoring liver enzymes and clinical status. 1

Sequential Drug Reintroduction After Liver Recovery

Once liver function normalizes (transaminases return to normal), reintroduce drugs sequentially to identify the offending agent: 1, 2

Step-by-Step Reintroduction Protocol

1. Start with isoniazid at 50 mg/day, monitoring clinical condition and liver function daily. 1, 2

   • Increase to 300 mg/day after 2-3 days if no reaction occurs. 1
   • Continue for another 2-3 days without reaction before proceeding. 1

2. Add rifampicin at 75 mg/day after isoniazid is tolerated. 1, 2

   • Increase to 300 mg after 2-3 days without reaction. 1
   • Then increase to full dose (450 mg if <50 kg, 600 mg if >50 kg) after another 2-3 days. 1
   • Continue for 2-3 days without reaction before proceeding. 1

3. Finally, add pyrazinamide at 250 mg/day. 1, 2

   • Increase to 1.0 g after 2-3 days. 1
   • Then increase to full dose (1.5 g if <50 kg, 2.0 g if >50 kg) after another 2-3 days. 1

If Hepatotoxicity Recurs During Reintroduction

• Stop the offending drug permanently and use an alternative regimen. 1, 2
• If pyrazinamide is the culprit, treat with rifampicin and isoniazid for 9 months total, supplemented with ethambutol for the initial 2 months. 1, 3, 2
• This represents a 3-month extension compared to standard 6-month therapy due to loss of pyrazinamide's sterilizing activity. 3

Critical Pitfalls to Avoid

Do Not Use Combined Drug Preparations During Reintroduction

• Sequential reintroduction requires individual drugs to identify the specific offending agent. 3
• Combined preparations (Rifater, Rifinah) prevent identification of the causative drug. 1

Monitor Throughout the Entire Reintroduction Process

• Daily clinical assessment and liver function monitoring are essential during each step of reintroduction. 1, 2
• Any recurrence of symptoms or transaminase elevation should prompt immediate cessation of the most recently added drug. 1

Consider Risk Factors

• Pyrazinamide is the most hepatotoxic first-line agent and is often the culprit in late-onset hepatotoxicity (>1 month into treatment). 4
• Rifampicin may enhance isoniazid hepatotoxicity through enzyme induction, causing early-onset hepatotoxicity (<15 days). 4
• Patients with underlying liver disease, alcohol use, advanced age, or female sex have higher hepatotoxicity risk. 2, 5