New-onset jaundice in a 58 kg patient on HRZE with efavirenz-based ART
A 42-year-old man weighing 58 kg with newly diagnosed sputum smear-positive pulmonary tuberculosis and HIV infection (on tenofovir/lamivudine/efavirenz for three years, CD4 210 cells/microlitre) was started three weeks ago on weight-band fixed-dose HRZE: isoniazid 75 mg, rifampicin 150 mg, pyrazinamide 400 mg and ethambutol 275 mg, four tablets once daily. He returns with nausea, anorexia, dark urine and scleral icterus. Today's investigations: ALT 380 U/L (upper limit of normal 40), total bilirubin 3.2 mg/dL, INR 1.3, serum creatinine normal, HBsAg and anti-HCV negative. He admits to taking a herbal appetite tonic bought from a roadside shop and drinks whisky twice a week. His antiretroviral regimen has been unchanged and he reports good adherence. The medical officer asks the pharmacist three things: whether the antitubercular drugs must be stopped, whether ART should be interrupted, and how the patient should be rechallenged once he recovers.
1. Should the antitubercular drugs be stopped now? Give the decision thresholds you are applying and the other causes that must be excluded.
Read the worked answer
Yes - stop isoniazid, rifampicin and pyrazinamide immediately; ethambutol may be continued as a bridge because it is not hepatotoxic.
The reasoning is threshold-based, not impression-based:
- ALT is 380 U/L, i.e. about 9.5 times the upper limit of normal, with bilirubin 3.2 mg/dL and symptoms plus jaundice.
- Standard drug-induced liver injury rules: stop hepatotoxic drugs if ALT exceeds 3x ULN with symptoms or jaundice, or 5x ULN even without symptoms. He meets both arms.
- Isoniazid, rifampicin and pyrazinamide are all hepatotoxic; pyrazinamide is the most injurious. Do not blame a single drug at this stage.
Alternative causes must be actively excluded before labelling it drug-induced: repeat HBsAg/anti-HCV and add anti-HEV and IgM anti-HAV; ask exactly what the herbal tonic contains (pyrrolizidine alkaloids and heavy metals are common culprits); quantify alcohol; check for sepsis and biliary obstruction. Efavirenz can cause hepatitis, but after three years of stable therapy it is a less likely primary cause.
Monitor LFTs twice weekly, INR and mental status (fulminant hepatic failure), keep paracetamol at 2 g/day or less, and forbid alcohol. Record all of this in the case sheet - the causality assessment will be needed if he needs a levofloxacin-based regimen later.
2. Should the antiretroviral regimen be interrupted while the liver injury is managed? Justify your answer, including any interaction issue.
Read the worked answer
No - continue ART. Interrupting it risks viral rebound, immune deterioration and later resistance; hepatotoxicity is managed around ART, not by stopping it.
Reasoning points to state explicitly:
- His liver injury is most plausibly attributable to the antitubercular drugs (temporal pattern, regimen, bilirubin rise), not to a three-year-old stable efavirenz-based regimen. Stopping ART would remove the weaker suspect while creating a bigger harm.
- If efavirenz is later confirmed as a contributor, substitute rather than stop: a dolutegravir- or raltegravir-based regimen can be used with rifampicin, but dose frequency must be adjusted for the rifampicin induction effect (dolutegravir 50 mg twice daily with rifampicin; raltegravir 800 mg twice daily).
- Rifampicin is a potent CYP3A4 inducer and lowers efavirenz concentrations; conversely, any ART change must be checked against rifampicin before it is written.
- If the antitubercular drugs are held during the acute illness, TB treatment is simply paused for a few days - ART is not.
The pharmacist's concrete action is to flag the interaction check on the drug chart, ensure tenofovir/lamivudine/efavirenz continue unchanged, and schedule LFT monitoring alongside viral-load review at the next visit.
3. Set out a safe rechallenge plan once the liver injury resolves, including what is done if hepatitis recurs.
Read the worked answer
Rechallenge only after recovery: ALT below 2x ULN, bilirubin normal and symptoms resolved - usually within 2 to 3 weeks. Reintroduce sequentially, never all at once.
A workable sequence:
- Restart rifampicin at full dose first (it is the least hepatotoxic of the three and the backbone of every regimen).
- Check ALT every 3 days; if it stays below 2x ULN, add isoniazid.
- Recheck again; add pyrazinamide last, or omit it altogether if the reaction was severe. Pyrazinamide-free regimens of isoniazid, rifampicin and ethambutol for 2 months followed by isoniazid and rifampicin (extended to 9 months), or a levofloxacin-containing regimen, are acceptable alternatives.
- If hepatitis recurs after any single drug is added, stop that drug permanently and complete treatment with a regimen that avoids it.
Judgement points that examiners look for: rechallenge is not a routine step to be done on the ward without LFT access; ethambutol is continued while the rest are held so that TB is not completely untreated; the patient must be counselled to stop alcohol and all herbal products and to return immediately if nausea, dark urine or jaundice recur; and every decision, with dates and LFT values, is documented so that the DOTS record remains auditable.