What are the primary liver toxic anti-tuberculosis treatment (ATT) drugs and how to manage drug-induced hepatitis?

Management of Liver Toxic Anti-Tuberculosis Drugs and Drug-Induced Hepatitis

The primary liver toxic anti-tuberculosis drugs are isoniazid, rifampicin, and pyrazinamide, and management of drug-induced hepatitis requires immediate cessation of these medications when AST/ALT levels rise to five times normal or when bilirubin rises above normal range. 1

Primary Hepatotoxic ATT Drugs

Hepatotoxic Potential

• Isoniazid (INH): Major hepatotoxin; risk increases with age 2, 3
• Pyrazinamide (PZA): Major hepatotoxin; associated with poor prognosis when causing late-onset hepatitis 3
• Rifampicin (RIF): Less hepatotoxic alone but may enhance isoniazid hepatotoxicity 3
• Ethambutol: Rarely hepatotoxic 3

Patterns of Hepatotoxicity

1. Early-onset hepatotoxicity: Usually within first 15 days, often due to rifampicin-enhanced isoniazid toxicity; generally has good prognosis 3
2. Late-onset hepatotoxicity: Occurs after 1 month, often related to pyrazinamide; generally has poorer prognosis 3

Monitoring Recommendations

Pre-treatment Assessment

• Check baseline liver function for all patients 2, 1
• Screen for risk factors: pre-existing liver disease, alcohol consumption, HIV infection, hepatitis B/C 2, 1

During Treatment Monitoring

• For patients with normal baseline liver function and no risk factors:

  • No routine monitoring required
  • Test if symptoms develop (fever, malaise, vomiting, jaundice) 2

• For patients with pre-existing liver disease or risk factors:

  • Weekly monitoring for first 2 weeks
  • Biweekly for first 2 months
  • Monthly thereafter 1

Management of Drug-Induced Hepatitis

When to Stop Hepatotoxic Drugs

Stop isoniazid, rifampicin, and pyrazinamide when:

• 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
• Patient develops jaundice 1

Management Algorithm

1. For non-infectious TB and clinically stable patients:

   • Stop all hepatotoxic drugs (INH, RIF, PZA)
   • Wait for liver function to normalize 2, 1

2. For infectious TB or clinically unstable patients:

   • Stop hepatotoxic drugs
   • Continue treatment with non-hepatotoxic drugs (ethambutol and streptomycin)
   • Consider hospitalization for close monitoring 2, 1

3. After liver function normalizes, reintroduce drugs sequentially:

   • Start with isoniazid at 50 mg/day, increasing to 300 mg/day after 2-3 days if no reaction
   • Add rifampicin after 2-3 more days if no reaction
   • Consider adding pyrazinamide last or omitting it completely 2, 1

Alternative Regimens When Specific Drugs Cannot Be Reintroduced

• If pyrazinamide is the cause: Continue INH and RIF for 9 months with ethambutol for initial 2 months 1
• If isoniazid cannot be used: RIF, ethambutol, and a fluoroquinolone for 12-18 months 2, 1
• If rifampicin cannot be used: Extend treatment to 18 months with alternative drugs 2

Special Considerations

Pre-existing Liver Disease

• Avoid pyrazinamide in patients with underlying liver disease 3
• Use lowest effective dosages of hepatotoxic drugs 1
• Consider regimens with fewer hepatotoxic agents 2

HIV Co-infection

• Avoid once-weekly isoniazid-rifapentine in continuation phase
• Avoid twice-weekly isoniazid-rifampin/rifabutin in patients with CD4+ counts <100/mm³ 2
• Be aware of potential drug interactions between rifamycins and antiretroviral medications 2

Patient Education and Prevention

• Educate patients about symptoms requiring immediate medical attention:

  • Unexplained anorexia, nausea, vomiting
  • Dark urine, jaundice
  • Persistent fatigue, weakness
  • Abdominal tenderness, especially right upper quadrant 1

• Advise patients to:

  • Avoid alcohol during treatment
  • Avoid concurrent use of other hepatotoxic medications
  • Report symptoms promptly 1

Common Pitfalls and Caveats

• Transient elevations of liver enzymes during early weeks of treatment are common and do not necessarily indicate serious toxicity 4
• Never add a single drug to a failing regimen as this may lead to acquired resistance 2
• The combination of pyrazinamide and ethionamide is frequently hepatotoxic and should be avoided 5
• Rifampicin can reduce serum concentrations of many drugs including methadone, corticosteroids, and oral contraceptives 2, 5
• Patients who are rapid acetylators of isoniazid are not at special risk for hepatotoxicity as previously thought 4

Remember that untreated TB can be fatal, and the risk of mortality from TB often outweighs the risk of drug-induced liver injury when properly monitored 1.