What is the recommended approach for reintroducing anti-tuberculosis (ATT) medications in patients with ATT-induced hepatitis?

From the Guidelines

The recommended approach for reintroducing anti-tuberculosis (ATT) medications in patients with ATT-induced hepatitis involves a sequential reintroduction once liver function tests normalize, starting with isoniazid at 50 mg/day, followed by rifampicin at 75 mg/day, and finally pyrazinamide at 250 mg/day, with close monitoring of liver function tests and clinical symptoms. This approach is based on the guidelines provided by the joint tuberculosis committee of the British Thoracic Society 1. The sequential reintroduction of ATT medications allows for the identification of the specific hepatotoxic drug while minimizing treatment interruption.

The process of reintroduction should be done under close supervision, with daily monitoring of the patient's clinical condition and liver function. If hepatotoxicity recurs with a specific drug, that medication should be permanently discontinued and replaced with an alternative agent. The use of reserve drugs should also be considered, taking into account their potential hepatotoxicity 1.

In contrast to other recommendations, the guidelines from the British Thoracic Society suggest starting with isoniazid at a lower dose and gradually increasing it, rather than starting with full therapeutic doses 1. This approach may help to minimize the risk of hepatotoxicity and allow for the safe reintroduction of ATT medications.

It is also important to note that the management of ATT-induced hepatitis may involve the use of alternative regimens, such as those without hepatotoxic drugs, in patients with severe hepatitis 1. Close monitoring of liver function tests and clinical symptoms should continue throughout the reintroduction period and treatment course.

While other studies provide guidance on the management of adverse events in the treatment of drug-resistant tuberculosis, including hepatitis 1, the guidelines from the British Thoracic Society provide a clear and specific approach for the reintroduction of ATT medications in patients with ATT-induced hepatitis.

• Key considerations for the reintroduction of ATT medications include:
  • Close monitoring of liver function tests and clinical symptoms
  • Sequential reintroduction of medications, starting with isoniazid
  • Use of alternative regimens in patients with severe hepatitis
  • Consideration of the potential hepatotoxicity of reserve drugs
  • Daily monitoring of the patient's clinical condition and liver function during the reintroduction period.

From the FDA Drug Label

If isoniazid must be reinstituted, it should be reinsti- tuted only after symptoms and laboratory abnormalities have cleared. The drug should be restarted in very small and gradually increasing doses and should be withdrawn immedi- ately if there is any indication of recurrent liver involvement. The recommended approach for reintroducing anti-tuberculosis (ATT) medications, specifically isoniazid, in patients with ATT-induced hepatitis is to:

• Reinstitute the drug only after symptoms and laboratory abnormalities have cleared.
• Restart the drug in very small and gradually increasing doses.
• Withdraw the drug immediately if there is any indication of recurrent liver involvement 2.

From the Research

Reintroduction Approach

The recommended approach for reintroducing anti-tuberculosis (ATT) medications in patients with ATT-induced hepatitis involves several steps:

• Sequential reintroduction of ATT medications after normalization of liver functions, with a weekly interval between each medication 3
• Reintroduction of isoniazid at a low daily dose, without rifampicin, after serum transaminase levels have returned to normal 4
• Avoidance of pyrazinamide reintroduction due to the risk of recurrence and poor prognosis of pyrazinamide-induced hepatitis 4
• Consideration of alternative medications, such as streptomycin, in patients with liver test abnormalities during antitubercular treatment 4

Success Rate of Reintroduction

The success rate of reintroducing ATT medications in patients with ATT-induced hepatitis is high:

• 97.4% of patients who survived and underwent reintroduction were able to tolerate the medications 3
• 96% of patients with ATT-induced hepatotoxicity were able to have isoniazid reintroduced, and 88% were able to have rifampicin reintroduced 5
• 41 out of 44 patients with ATT-induced hepatitis were able to have isoniazid and rifampicin reintroduced after resolution of the hepatitis 6

Risk Factors for Hepatotoxicity

Several risk factors have been identified for the development of hepatotoxicity during ATT:

• Presence of HBV infection or underlying silent chronic liver disease 5
• Advanced age, female sex, slow acetylator status, malnutrition, HIV, and pre-existent liver disease 7
• Continuation of ATT after development of jaundice, which is associated with a high fatality rate 5