Z, H, R, P, Eto or Pto, PAS, Bdq, Amx/Clv
All TB drugs may cause hepatotoxicity. However, certain drugs are likely more responsible than others for this adverse effect.
The liver function tests (LFTs) used for the diagnosis and monitoring of hepatotoxicity are serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin.
A mild, transient elevation of ALT and AST may be observed during treatment and usually remains asymptomatic. Significant hepatotoxicity is usually symptomatic.
Clinical features resemble that of viral hepatitis. Early symptoms include malaise, fatigue, loss of appetite, muscle and joint pain. Nausea, vomiting and abdominal pain are common in severe toxicity. Jaundice, scleral icterus, dark (tea-coloured) urine and discoloured stool are signs of clinical worsening.
Differential diagnosis includes infections (e.g. viral hepatitis, cytomegalovirus, leptospirosis, yellow fever, rubella), chronic alcohol use and hepatotoxicity due to other drugs (e.g. antiseizure medications, paracetamol, sulfa drugs, erythromycin).
Clinical hepatitis can be fatal and action should be taken immediately.
1) General management
- Patient with symptoms of hepatitis:
Stop all TB drugs and perform LFTs:
a) AST or ALT or bilirubin ≥ 3 times upper limit of normal (ULN): wait for resolution of symptoms, perform LFTs weekly and restart TB treatment when LFTs are < 3 times ULN.
b) AST, ALT and bilirubin < 3 times ULN and mild symptoms (no jaundice): restart TB treatment, closely monitor the patient and perform LFTs weekly. Continue TB treatment as long as LFTs levels remain < 3 ULN and there are no signs of worsening hepatitis.
- Patient without symptoms of hepatitis, but elevated LFTs:
a) AST or ALT ≥ 5 times ULN or bilirubin ≥ 3 ULN: stop all TB drugs and perform LFTs weekly. Restart TB treatment when LFTs return < 3 times ULN.
b) AST and ALT < 5 times ULN and bilirubin < 3 ULN: continue TB treatment and perform LFTs weekly.
If LFTs continue to increase after stopping TB treatment, then ongoing progressive drug-induced hepatitis or an unrelated cause of hepatitis should be suspected.
2) Patient on DS-TB treatment
In most cases, the same treatment can be resumed without incident. The objective is to resume the initial regimen or an alternative regimen as rapidly as possible.
If symptoms reappear or LFTs re-increase, try to reintroduce the TB drugs one by one. Start with E and R and reintroduce H three to 7 days later. If E, R and H have been introduced and the LFT abnormalities have not recurred, do not introduce Z as it is most likely the causative agent.
The alternative regimen depends on the drug causing hepatotoxicity:
- Z is involved: 2(HR)E/7(HR)
- H is involved: 6RZE-Lfx
- R is involved: treat as MDR/RR-TB
3) Patient on DR-TB treatment
When restarting TB treatment, start with the drugs least hepatotoxic (E, Lfx or Mfx, Cs or Trd, Dlm, Am or S, Ipm/Cln or Mpm), then drugs moderately hepatotoxic (Bdq, Cfz, Amx/Clav), then give the most hepatotoxic (Z, H, R, Eto or Pto, PAS). Add drugs one at a time every 5 to 7 days, and check LFTs.
The causative agent can generally be identified in this manner. It can be discontinued if not essential and replaced with another less hepatotoxic TB drug.
Note: hepatotoxicity may occur in patients receiving pretomanid-containing regimens. The contribution of pretomanid to hepatotoxicity of these regimens is not determined.