How to restart HRZE (isoniazid, rifampicin, pyrazinamide, ethambutol) after it was stopped due to elevated liver enzymes?

Restarting HRZE After Drug-Induced Hepatotoxicity

Immediate Action and Monitoring

Once liver enzymes normalize to baseline levels, restart tuberculosis medications using sequential reintroduction with one drug added at a time every 2-3 days, beginning with isoniazid, followed by rifampicin, then pyrazinamide, while monitoring liver function and clinical symptoms daily. 1, 2

Pre-Reintroduction Requirements

Before restarting any hepatotoxic drugs:

• Wait until liver enzymes return completely to normal (or pre-treatment baseline if previously abnormal) 3, 1, 2
• Ensure patient is asymptomatic with no fever, malaise, nausea, vomiting, or jaundice 4, 2
• Consider viral hepatitis testing to exclude coexistent causes 4, 2

Bridge Therapy for Infectious Cases

If the patient has infectious TB (smear-positive) or is clinically unwell while waiting for liver function to normalize:

• Continue treatment with non-hepatotoxic drugs: streptomycin and ethambutol 4, 1, 2
• This maintains treatment efficacy while protecting the liver 1, 2
• For non-infectious TB in stable patients, no treatment is needed during the waiting period 2

Sequential Drug Reintroduction Protocol

Step 1: Isoniazid First

• Start with isoniazid 50 mg daily 1, 2
• After 2-3 days without reaction, increase to 300 mg daily 1, 2
• Continue for 2-3 more days before adding the next drug 1
• Monitor liver function and clinical symptoms daily 1, 2

Step 2: Add Rifampicin

• Start with rifampicin 75 mg daily 1, 2
• After 2-3 days, increase to 300 mg daily 1, 2
• After another 2-3 days, increase to full weight-appropriate dose (450-600 mg) 1, 2

Step 3: Add Pyrazinamide Last

• Start with pyrazinamide 250 mg daily 1, 2
• After 2-3 days, increase to 1.0 g daily 1
• Then increase to full weight-appropriate dose 1

Critical Monitoring During Reintroduction

• Perform daily clinical assessment and liver function tests during the entire reintroduction period 1, 2
• If hepatotoxicity recurs (AST/ALT >5× normal or bilirubin rises), immediately stop the most recently added drug 4, 1, 5
• The drug causing the recurrent reaction should be permanently excluded from the regimen 1, 2

Alternative Regimens When a Drug Must Be Excluded

If Pyrazinamide is the Culprit:

• Treat with rifampicin and isoniazid for 9 months (instead of 6 months) 4, 1, 2
• Add ethambutol for the initial 2 months 4, 1
• This 3-month extension compensates for loss of pyrazinamide's sterilizing activity 4

If Isoniazid is the Culprit:

• Treat with rifampicin and ethambutol for at least 12 months 1
• Add pyrazinamide for the initial 2 months 1

If Rifampicin is the Culprit:

• Consider consultation with TB specialist for complex regimen design 1

Important Pitfalls to Avoid

• Never use fixed-dose combination tablets during reintroduction - you must identify the specific offending drug 4, 1
• Do not restart all drugs simultaneously - this prevents identification of the causative agent 3, 1
• Do not restart drugs at full doses immediately - gradual dose escalation is essential 1, 2, 5
• Never ignore symptoms between scheduled visits - instruct patients to report immediately any anorexia, nausea, vomiting, dark urine, jaundice, or right upper quadrant discomfort 5

Enhanced Monitoring for High-Risk Patients

For patients with risk factors (age >35, alcohol use, chronic liver disease, female gender especially Black/Hispanic, postpartum period):

• Consider more frequent laboratory monitoring beyond the standard protocol 5
• Some authorities recommend checking liver enzymes twice weekly for the first 2 weeks, then biweekly for 2 months 2, 6

Special Consideration: Rifampicin-Isoniazid Interaction

Be aware that rifampicin enhances isoniazid hepatotoxicity through enzyme induction 6, 7. If hepatotoxicity recurs when rifampicin is added to isoniazid (early pattern, within 15 days), this suggests rifampicin-enhanced isoniazid toxicity rather than rifampicin alone being the culprit 6, 7. Late-onset hepatotoxicity (>1 month) more commonly suggests pyrazinamide as the cause 6.