Children and adolescents experience adverse events caused by TB medicines much less frequently than adults (6). The most important adverse event is the development of liver toxicity (hepatotoxicity), which can be caused by isoniazid, rifampicin or pyrazinamide. It is not necessary to monitor serum liver enzyme levels routinely, as mild elevation of serum liver enzymes (less than five times the upper normal value) without clinical symptoms is not an indication to stop TB treatment (106).
The following symptoms, however, should lead clinicians to promptly check liver function tests (as a minimum, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total bilirubin), and all potentially hepatotoxic medicines (e.g. isoniazid, rifampicin, pyrazinamide, co-trimoxazole) should be stopped immediately until results are obtained:
- liver tenderness;
- hepatomegaly;
- persistent nausea, vomiting or loss of appetite;
- jaundice.
If serum liver enzymes (ALT, AST) are more than five times the upper limit of normal, or more than three times the upper limit of normal with symptoms of hepatitis, hepatotoxic medicines should be stopped while liver enzymes are monitored. The child or adolescent should complete screening for other causes of hepatitis and be referred to an expert with experience in managing drug-induced hepatotoxicity for further management. In many cases, hospitalization will be necessary for close monitoring and management, as liver function tests will need to be done regularly after each adjustment to the treatment regimen (106).
In general, after liver function has normalized (ALT and total bilirubin less than two times the upper limit of normal), ethambutol and rifampicin may be reintroduced first, and liver function tests repeated after 3–7 days. If there is no worsening in the liver function tests, isoniazid can be restarted, and liver function tests repeated after another 3–7 days. If the liver function tests are stable, isoniazid, rifampicin and ethambutol can be continued. Pyrazinamide should not be reintroduced. Without pyrazinamide, treatment with isoniazid, rifampicin and ethambutol must be given for 9 months.
If liver function tests worsen with reintroduction of rifampicin, a liver-sparing regimen needs to be considered, in consultation with an expert in child and adolescent TB. If severe hepatoxicity occurs in the continuation phase, while on isoniazid and rifampicin, consultation with an expert in child and adolescent TB is indicated, unless the patient has completed more than 80% of all doses, at which point discontinuing treatment may be the most appropriate choice (106).
With severe forms of TB necessitating continuation of TB treatment, a liver-friendly regimen with nonhepatotoxic medicines may be introduced (e.g. combination of ethambutol, cycloserine, linezolid and a fluoroquinolone). This should be done only in consultation with an expert in the management of DR-TB in children and adolescents.