How should antituberculosis therapy be rechallenged after drug‑induced liver injury, including timing after normalization of liver enzymes, step‑wise drug sequence (ethambutol → rifampicin → isoniazid → pyrazinamide), and monitoring thresholds (bilirubin >3 mg/dL, INR >1.5, ALT/AST <5× ULN)?

Rechallenge of Antituberculosis Therapy After Drug-Induced Liver Injury

Immediate Management When DILI Occurs

Stop all hepatotoxic drugs (isoniazid, rifampicin, pyrazinamide) immediately when ALT/AST rises to ≥5× upper limit of normal (ULN) in asymptomatic patients, or ≥3× ULN with symptoms (jaundice, nausea, vomiting, right upper quadrant pain), or when bilirubin rises to ≥2× ULN or INR >1.5. 1, 2

• Initiate non-hepatotoxic bridge therapy with streptomycin and ethambutol (15-20 mg/kg daily) immediately if the patient is clinically unwell or has smear-positive sputum, continuing until liver enzymes normalize 2, 3
• For stable patients with non-infectious tuberculosis, no treatment is required during the normalization period 2
• Exclude competing causes: viral hepatitis (A, B, C, E), alcohol use, other hepatotoxic medications, and biliary tract disease 1, 2

Timing of Rechallenge Initiation

Begin sequential drug reintroduction only after transaminases return to normal (or <2-3× ULN for those with near-normal baseline). 1, 2

• For patients with elevated baseline ALT (≥1.5× ULN), wait until ALT returns to <4× ULN if baseline was 1.5-3× ULN, or <6× ULN if baseline was 3-5× ULN 1
• Monitor liver function tests daily during the reintroduction phase 2

Sequential Drug Reintroduction Protocol

The recommended sequence is: rifampicin first, then isoniazid, and pyrazinamide last (if at all)—contrary to the traditional ethambutol → rifampicin → isoniazid → pyrazinamide sequence. 4, 2, 3

Step 1: Rifampicin Reintroduction

• Start rifampicin at 75 mg/day 4, 2, 3
• Increase to 300 mg after 2-3 days if no reaction occurs 2, 3
• Further increase to 450 mg (<50 kg) or 600 mg (≥50 kg) after another 2-3 days without reaction 2, 3
• Rifampicin alone causes hepatitis in nearly 0% of cases, making it the safest first choice 3

Step 2: Isoniazid Reintroduction

• Add isoniazid only after 2-3 days of full-dose rifampicin without reaction 2
• Start at 50 mg/day 4, 2, 3
• Increase to 300 mg/day after 2-3 days if no reaction occurs 2, 3
• Continue for 2-3 more days before adding the next drug 2, 3

Step 3: Pyrazinamide Reintroduction (Use With Extreme Caution)

• Add pyrazinamide last, starting at 250 mg/day 2, 3
• Increase to 1.0 g after 2-3 days 2, 3
• Further increase to 1.5 g (<50 kg) or 2.0 g (≥50 kg) 2, 3
• Avoid pyrazinamide reintroduction entirely if the initial hepatotoxicity was severe or occurred late (>1 month after treatment initiation), as pyrazinamide-induced hepatitis has a poor prognosis 2, 5

Absolute Contraindications to Rechallenge

Do not rechallenge if the patient met Hy's Law criteria (ALT ≥3× ULN with bilirubin ≥2× ULN), had hepatic decompensation (ascites, encephalopathy), or presented with hypersensitivity features (rash, fever, eosinophilia, lymphadenopathy). 1

• Cirrhosis or advanced liver disease generally precludes rechallenge due to risk of hepatic decompensation 1
• Patients with a history of isoniazid-associated liver injury should not receive rifampin-pyrazinamide regimens 2

Monitoring Thresholds During Rechallenge

Stop the most recently added drug immediately if ALT/AST rises to ≥3× ULN or if any hepatotoxicity symptoms develop (fever, malaise, vomiting, jaundice). 2, 3

• Check liver function tests (ALT, AST, bilirubin) daily during reintroduction 2
• After successful reintroduction, monitor weekly for 2 weeks, then every 2 weeks for the first 2 months 2
• For patients with pre-existing liver disease or cirrhosis, measure AST/ALT and bilirubin at baseline and at 2,4, and 8 weeks 4

Alternative Regimens When Drugs Cannot Be Reintroduced

If pyrazinamide cannot be tolerated: Use rifampicin + isoniazid for 9 months total, with ethambutol for the initial 2 months 2, 3

If isoniazid cannot be tolerated: Use rifampicin + ethambutol + fluoroquinolone (levofloxacin or moxifloxacin) for 12 months 2, 3

If rifampicin cannot be tolerated: Use isoniazid + ethambutol + fluoroquinolone for 18-24 months (similar to MDR-TB regimen) 1

Risk Factors for Recurrent DILI

• Female sex (particularly Black and Hispanic women) 6, 7
• Pyrazinamide rechallenge 7
• First episode of tuberculosis 7
• Pre-existing liver disease or cirrhosis 2
• Chronic alcohol use 2, 6
• Advanced age (>35 years) 6, 8
• HIV infection 2
• Malnutrition 2, 8

Critical Pitfalls to Avoid

• Never reintroduce pyrazinamide if severe hepatotoxicity occurred, especially if it developed late (>1 month) after treatment initiation—the prognosis is poor and recurrence risk is high 2, 5
• Avoid concurrent use of other hepatotoxic medications during rechallenge 2
• Do not use combined drug preparations during reintroduction, as this prevents identification of the offending agent 3
• Streptomycin carries risk of nephrotoxicity and ototoxicity; two cases of hearing loss and three of acute kidney injury occurred in one rechallenge cohort 7
• Interrupt ART temporarily during rechallenge in HIV-positive patients to reduce hepatotoxicity risk, though this requires careful consideration of CD4 count and viral load 7