What alternative anti-tuberculosis regimen can be used in cases of pyrazinamide-induced hepatitis?

Management of Pyrazinamide-Induced Hepatitis in Tuberculosis Treatment

When pyrazinamide-induced hepatitis occurs during tuberculosis treatment, the recommended alternative regimen is isoniazid, rifampicin, and ethambutol for 12-18 months, or rifampicin, ethambutol, and a fluoroquinolone for 12-18 months. 1

Diagnosis and Initial Management

When hepatotoxicity is suspected:

1. Immediately discontinue all hepatotoxic anti-TB drugs including pyrazinamide, isoniazid, and rifampicin
2. Monitor liver function tests closely:
   • AST/ALT levels
   • Bilirubin levels
   • Prothrombin time/INR
3. Consider hospitalization for patients with severe hepatotoxicity for close monitoring 1

Alternative Treatment Regimens

After pyrazinamide-induced hepatitis is confirmed, select one of these alternative regimens:

Option 1: Isoniazid, Rifampicin, and Ethambutol

• Duration: 12-18 months
• Monitoring: Regular liver function tests every 2-4 weeks
• Advantage: Contains two bactericidal drugs (isoniazid and rifampicin)

Option 2: Rifampicin, Ethambutol, and a Fluoroquinolone

• Duration: 12-18 months
• Monitoring: Regular liver function tests every 2-4 weeks
• Advantage: Avoids both pyrazinamide and isoniazid if patient has sensitivity to both drugs

Option 3: Isoniazid and Rifampicin

• Duration: 9 months (with ethambutol added for initial 2 months)
• Use when: Pyrazinamide is clearly identified as the sole cause of hepatotoxicity 1

Reintroduction Protocol

If reintroduction of drugs is necessary:

1. Wait for liver enzymes to normalize
2. Reintroduce drugs sequentially, starting with the least hepatotoxic:
   • Start with ethambutol (least hepatotoxic)
   • Add rifampicin next (if not contraindicated)
   • Add isoniazid last (if not contraindicated)
   • Do not reintroduce pyrazinamide due to risk of recurrence and poor prognosis 2

Monitoring Recommendations

For patients on alternative regimens:

• First 2 weeks: Weekly liver function tests
• First 2 months: Biweekly liver function tests
• Thereafter: Monthly liver function tests 1
• Stop treatment immediately if:
  • AST/ALT ≥5× upper limit of normal in asymptomatic patients
  • AST/ALT ≥3× upper limit of normal in symptomatic patients
  • Bilirubin rises above normal range 1

Special Considerations

1. Streptomycin may be considered as an alternative agent in patients with liver test abnormalities, though it has nephrotoxic potential 2

2. Drug dosing: Use the lowest effective dosages of hepatotoxic anti-TB drugs to minimize risk of further hepatotoxicity 1

3. Patient education: Advise patients to:

   • Avoid alcohol consumption during treatment
   • Avoid concurrent use of other hepatotoxic medications
   • Report symptoms immediately (anorexia, nausea, vomiting, dark urine, jaundice, fatigue, right upper quadrant discomfort) 1

Pitfalls and Caveats

• Pyrazinamide-induced hepatitis typically occurs later in treatment (after one month) and has a poorer prognosis than early-onset hepatitis 2
• Never reintroduce pyrazinamide after hepatotoxicity, as recurrence risk is high 2
• Rifampicin may enhance the hepatotoxicity of isoniazid through enzyme induction, requiring careful monitoring if both drugs are used 2
• Patients with pre-existing liver disease should not receive pyrazinamide even initially 2