What are the guidelines for re-initiating anti-tuberculosis (TB) medications in patients who have experienced drug-induced liver injury (DILI) due to anti-TB medications?

Re-initiating Anti-TB Medications After DILI

When drug-induced liver injury occurs during TB treatment, immediately stop all hepatotoxic drugs, initiate a non-hepatotoxic holding regimen with streptomycin and ethambutol until liver function normalizes, then sequentially reintroduce drugs one at a time starting with isoniazid, followed by rifampin, and finally pyrazinamide if needed. 1, 2

Immediate Management When DILI Occurs

Stop all hepatotoxic TB drugs immediately when any of the following criteria are met: 2, 3

• ALT/AST >3× upper limit of normal (ULN) WITH symptoms of hepatitis
• ALT/AST >5× ULN WITHOUT symptoms
• Any elevation in serum bilirubin above normal range
• Clinical jaundice at any transaminase level

Initiate a non-hepatotoxic holding regimen consisting of streptomycin and ethambutol to maintain anti-TB activity while liver function recovers. 1, 2 Ethambutol should be dosed at 15-20 mg/kg daily. 1

Exclude other causes of liver injury before proceeding with reintroduction, including viral hepatitis (HBV, HCV), biliary tract disease, alcohol use, acetaminophen, other hepatotoxic medications, herbal supplements, and hepatic tuberculosis itself. 2, 3

Sequential Reintroduction Protocol

Step 1: Reintroduce Isoniazid First

• Start at 50 mg/day
• Increase to 300 mg/day after 2-3 days if no reaction occurs
• Wait 2-3 days at full dose before proceeding 1

Step 2: Add Rifampin Second

• Start at 75 mg/day
• Increase to 300 mg after 2-3 days
• Further increase to 450 mg (<50 kg) or 600 mg (>50 kg) after another 2-3 days 1

Step 3: Add Pyrazinamide Last (if needed)

• Start at 250 mg/day
• Increase to 1.0 g after 2-3 days
• Further increase to 1.5 g (<50 kg) or 2.0 g (>50 kg) 1

Important caveat: A high-quality randomized controlled trial of 175 patients found that all three hepatotoxic drugs (isoniazid, rifampin, and pyrazinamide) can be safely reintroduced simultaneously at full dosage from day 1, with no significant difference in recurrence rates compared to sequential reintroduction (10.9% overall recurrence rate, p=0.69 between groups). 4 However, the sequential approach remains the standard guideline recommendation and may be preferred for patients with severe initial DILI or those with risk factors for recurrence. 1, 2

Monitoring During Reintroduction

Monitor liver function tests rigorously: 1, 2

• Weekly for the first 2 weeks after each drug reintroduction
• Every 2 weeks for the first 2 months
• Monthly thereafter

Educate patients to stop medications immediately and seek medical attention if they develop abdominal pain, vomiting, jaundice, or other hepatitis symptoms. 2

Alternative Regimens When Drugs Cannot Be Reintroduced

If Pyrazinamide Cannot Be Tolerated:

Use isoniazid, rifampin, and ethambutol for 2 months, followed by isoniazid and rifampin for 7 months (total 9 months). 1, 2

If Isoniazid Cannot Be Tolerated:

Use rifampin, ethambutol, and a fluoroquinolone (levofloxacin 750-1000 mg daily or moxifloxacin 400 mg daily) for 12-18 months. 1, 2

If Both Isoniazid and Pyrazinamide Cannot Be Tolerated:

Use rifampin, ethambutol, and a fluoroquinolone for 12-18 months. 2

For Severe, Unstable Liver Disease:

Use ethambutol combined with a fluoroquinolone, cycloserine, and a second-line injectable for 18-24 months. 2

Critical Risk Factors for Recurrent DILI

Patients at highest risk for recurrence include those with: 2, 5

• Pre-existing liver disease or cirrhosis
• Chronic alcohol use
• Hepatitis B or C infection
• HIV infection
• Malnutrition
• Advanced age
• NAT2 slow acetylation genotype
• GSTM1 gene variation

The only statistically significant predictor of recurrence in the largest randomized trial was low pretreatment serum albumin level (p<0.01). 4 These high-risk patients require more intensive monitoring and a lower threshold for drug discontinuation. 2

Common Pitfalls to Avoid

Never reintroduce pyrazinamide in patients who had severe initial hepatotoxicity, as pyrazinamide-induced hepatitis occurring late (>1 month after treatment initiation) has a poor prognosis. 6 The American Thoracic Society guidelines specifically note that pyrazinamide may not be reintroduced because of the risk of recurrence and poor prognosis. 7

Avoid concurrent hepatotoxic medications during reintroduction, including over-the-counter drugs like acetaminophen. 2

Do not use pyrazinamide at all in patients with underlying liver test abnormalities before starting treatment. 6

Patients with a history of INH-associated liver injury should never be offered rifampin-pyrazinamide regimens. 7