What is the recommended treatment regimen for a patient diagnosed with tuberculosis (TB) and hepatitis?

Treatment of Tuberculosis in Patients with Hepatitis

For patients with tuberculosis and hepatitis, rifampin (RIF) and isoniazid (INH) should be retained whenever possible despite their hepatotoxic potential, while pyrazinamide (PZA) should be omitted, using a regimen of INH, RIF, and ethambutol (EMB) for 2 months followed by 7 months of INH and RIF. 1

Initial Assessment and Risk Stratification

Before initiating treatment, all patients should undergo:

• Baseline hepatitis B and C screening if they have a history of injection drug use, birth in Asia or Africa, or HIV infection 1
• Baseline liver function tests including ALT and total bilirubin 1
• Assessment of hepatic reserve to determine severity of underlying liver disease 1

The crucial point is that abnormal baseline aminotransferases alone are an independent risk factor for drug-induced liver injury (DILI), and the likelihood of hepatotoxicity increases with advanced liver disease, liver transplant, or hepatitis C infection 1.

Treatment Algorithm Based on Hepatic Disease Severity

Patients with Mild Hepatic Disease or ALT ≤3x Upper Limit of Normal

Use the standard regimen with PZA omitted:

• INH, RIF, and EMB for 2 months, followed by 7 months of INH and RIF 1
• This approach removes PZA, which has often been implicated in DILI, while retaining the most effective agents 1

Patients with Advanced Liver Disease or ALT >3x Upper Limit of Normal

Consider regimens with fewer hepatotoxic agents:

Option 1 (Preferred if possible): INH, RIF, and EMB for 2 months, followed by 7 months of INH and RIF 1

Option 2 (For severe hepatic impairment): RIF and EMB with a fluoroquinolone, injectable, or cycloserine for 12-18 months, depending on disease extent 1

Option 3 (Alternative): RIF, PZA, and EMB with or without a fluoroquinolone for at least 6 months (retains 6-month duration but includes two hepatotoxic medications) 1

Patients with Isolated Hyperbilirubinemia

Serum bilirubin above normal range is an absolute indication to discontinue rifampin-pyrazinamide combination therapy 2

For these patients:

• Use rifampin, ethambutol, and a fluoroquinolone with weekly liver function monitoring 2
• Avoid pyrazinamide completely as it is the most hepatotoxic first-line agent 2
• Consider a regimen containing only one potentially hepatotoxic drug plus ethambutol and a fluoroquinolone 2

Monitoring Protocol

Intensive Monitoring Phase (First 2 Months)

• Measure serum aminotransferases and bilirubin twice weekly during the first 2 weeks 3
• Then every 2 weeks for the remainder of the first 2 months 3
• Monthly monitoring thereafter 3

For patients with isolated hyperbilirubinemia:

• Weekly monitoring for the first two weeks, then biweekly for the first two months 2

Discontinuation Criteria

Stop all antitubercular therapy immediately if:

• Aminotransferases are >5 times upper limit of normal in asymptomatic patients 2
• Aminotransferases are >3 times upper limit of normal with hepatitis symptoms 3
• Serum bilirubin concentration is above normal range 2

Drug Reintroduction After Hepatotoxicity

After liver function normalizes:

• Reintroduce isoniazid first at a low daily dose, without rifampin 3
• Do NOT reintroduce pyrazinamide due to risk of recurrence and poor prognosis of PZA-induced hepatitis 3
• Streptomycin is an alternative despite nephrotoxicity, for patients with persistent liver abnormalities 3

Critical Pitfalls to Avoid

1. Never assume hepatotoxic drugs cannot be used - The crucial efficacy of INH and particularly RIF warrant their use even with preexisting liver disease 1

2. Do not use pyrazinamide in patients with baseline liver abnormalities - PZA has the highest hepatotoxic potential and poorest prognosis when causing hepatitis 1, 3

3. Recognize two patterns of fulminant liver injury:

   • Early pattern (within 15 days): Likely rifampin-induced isoniazid hepatotoxicity with generally good prognosis 3
   • Late pattern (>1 month): Likely pyrazinamide hepatotoxicity with generally poor prognosis 3

4. Do not confuse hepatic tuberculosis with DILI - Hepatic TB may cause elevated aminotransferases that improve with effective treatment 1

5. Always obtain drug susceptibility testing to fluoroquinolones and injectables if considering their use in modified regimens 1

Expert Consultation

Expert consultation with a tuberculosis specialist is advisable for all patients with advanced liver disease requiring treatment modifications 1. Adjustments during treatment may be necessary based on clinical response and tolerance 1.