What is the appropriate rechallenge protocol for a patient with a history of adverse effects from first-line anti-Tuberculosis (TB) medications, such as hepatotoxicity or severe allergic reactions to drugs like isoniazid?

Rechallenge Protocol for Anti-TB Drugs

When a patient experiences drug-induced hepatotoxicity or severe hypersensitivity reactions to first-line anti-TB medications, immediately stop all hepatotoxic drugs, continue treatment with non-hepatotoxic agents (streptomycin, ethambutol, fluoroquinolones) if the patient is infectious or clinically unwell, wait for complete normalization of liver function or resolution of symptoms, then sequentially reintroduce drugs one at a time every 2-3 days with daily clinical and biochemical monitoring. 1, 2, 3

Immediate Management of Drug Reactions

For Hepatotoxicity

• Stop rifampicin, isoniazid, and pyrazinamide immediately if ALT/AST rises ≥5 times the upper limit of normal, or ≥3 times the upper limit of normal with hepatitis symptoms (nausea, vomiting, abdominal pain, jaundice). 1, 2, 3
• Investigate non-drug causes including viral hepatitis (A, B, C, E), biliary tract disease, alcohol use, and other hepatotoxic medications before attributing hepatotoxicity to TB drugs. 1, 3
• Continue treatment with non-hepatotoxic drugs (ethambutol 15-20 mg/kg daily, streptomycin, fluoroquinolones) if the patient has infectious TB or is clinically unwell until liver function normalizes. 1, 2, 3
• For non-infectious TB in stable patients, treatment can be held completely until liver function normalizes. 3

For Severe Hypersensitivity Reactions

• For Stevens-Johnson syndrome or severe cutaneous reactions, immediately stop all TB drugs (and antiretroviral drugs if applicable) until symptoms completely resolve. 1
• Mild rashes can be managed with symptomatic relief while continuing treatment. 1

Sequential Drug Reintroduction Protocol

Order of Reintroduction

The American Thoracic Society recommends reintroducing drugs in the following sequence: isoniazid first, then rifampicin, then pyrazinamide last, as isoniazid alone causes hepatitis in nearly 0% of cases, while pyrazinamide has the highest hepatotoxic potential. 2, 3

Isoniazid Reintroduction

• Start at 50 mg/day. 2, 3
• Increase to 300 mg/day after 2-3 days if no reaction occurs (no elevation in transaminases, no symptoms). 2, 3
• Continue at full dose for 2-3 more days without reaction before adding the next drug. 2, 3
• Monitor liver function tests daily during this period. 3

Rifampicin Reintroduction

• Start at 75 mg/day after 2-3 days of full-dose isoniazid without reaction. 2, 3
• Increase to 300 mg after 2-3 days if no reaction occurs. 2, 3
• Further increase to weight-appropriate dose (450 mg if <50 kg, 600 mg if >50 kg) after another 2-3 days without reaction. 2, 3
• Rifampicin is critical for short-course therapy and should generally be included despite hepatic disease history, but with increased monitoring frequency. 2

Pyrazinamide Reintroduction

• Start at 250 mg/day after rifampicin is successfully reintroduced. 2, 3
• Increase to 1.0 g after 2-3 days if no reaction occurs. 2, 3
• Further increase to weight-appropriate dose (1.5 g if <50 kg, 2.0 g if >50 kg). 2, 3
• Avoid reintroducing pyrazinamide in patients who had severe initial hepatotoxicity, as pyrazinamide-induced hepatitis occurring late (>1 month after treatment initiation) has a poor prognosis. 3

For Hypersensitivity Reactions

• Restart TB medications one by one every 2 days with careful monitoring for recurrence of rash or systemic symptoms. 1
• If the patient was on antiretroviral therapy, restart all ART medications simultaneously after TB drugs are reestablished to prevent resistance development. 1

Monitoring During Reintroduction

• Check liver function tests (ALT, AST, bilirubin, alkaline phosphatase) daily during the reintroduction phase. 3
• Assess for hepatotoxicity symptoms daily: fever, malaise, nausea, vomiting, abdominal pain (especially right upper quadrant), jaundice, dark urine. 3, 4
• Stop the most recently added drug immediately if transaminases rise again or symptoms develop; this identifies the offending agent. 2, 3
• After successful reintroduction, monitor liver function tests weekly for 2 weeks, then every 2 weeks for the first 2 months. 3

Alternative Regimens When a Drug Must Be Permanently Excluded

If Pyrazinamide Cannot Be Used

• Treat with rifampicin and isoniazid for 9 months total, supplemented with ethambutol for the initial 2 months. 2, 3
• This extended duration is necessary because pyrazinamide's sterilizing activity contributes to treatment shortening in the standard 6-month regimen. 3

If Isoniazid Cannot Be Used

• Treat with rifampicin, ethambutol, and a fluoroquinolone for at least 12 months. 3, 5
• Alternatively, use rifampicin and ethambutol for at least 12 months, supplemented with pyrazinamide for the initial 2 months. 2

If Rifampicin Cannot Be Used

• This represents a more challenging situation requiring expert consultation, as rifampicin is critical for short-course therapy. 2
• Consider regimens with isoniazid, ethambutol, pyrazinamide, and a fluoroquinolone for extended duration (12-18 months). 5

Critical Risk Factors and Precautions

High-Risk Patients for Recurrent Hepatotoxicity

• Patients at highest risk for recurrent drug-induced liver injury include those with pre-existing liver disease or cirrhosis, chronic alcohol use, hepatitis B or C infection, HIV infection, malnutrition, advanced age (>35 years), and low pretreatment serum albumin. 3, 4
• These patients require more intensive monitoring with weekly liver function tests for 2 weeks after each drug introduction, then biweekly for the first 2 months. 3

Important Contraindications

• Patients with a history of isoniazid-associated liver injury should not be offered rifampin-pyrazinamide regimens due to increased risk of recurrent severe liver injury. 3
• Avoid concurrent use of other hepatotoxic medications (acetaminophen, alcohol, lipid-lowering agents) during TB treatment. 1, 3, 4

Special Populations

• For pregnant patients, avoid streptomycin due to risk of congenital deafness; rifampicin is not recommended during pregnancy. 3
• For children with drug-resistant TB, the same sequential reintroduction protocol applies, with dosing adjusted for weight. 1
• For HIV-infected patients, T-cell mediated hypersensitivity reactions are more frequent and require careful monitoring. 6

When to Seek Expert Consultation

• Consult TB experts (available through CDC-supported TB Centers of Excellence, local health department TB Control Programs, or international MDR-TB expert groups) for complicated cases including multiple drug intolerances, drug-resistant TB, or when treatment options are extremely limited. 1
• Expert consultation is particularly important when considering desensitization protocols, which should only be performed under the cover of two other anti-tuberculosis drugs. 2

Common Pitfalls to Avoid

• Never add a single drug to a failing regimen, as this creates de facto monotherapy and risks developing resistance to the new drug. 1
• Do not restart drugs at full dose after a severe reaction; always use the gradual dose escalation protocol. 2, 4
• Do not rely solely on liver function tests without clinical assessment; monthly clinical evaluation is mandatory even with normal laboratory values. 4
• If isoniazid must be reinstituted after hepatotoxicity, restart in very small and gradually increasing doses and withdraw immediately if there is any indication of recurrent liver involvement. 4