Liver Part 1: Viral Hepatitis and Acute Liver Failure
Hepatitis B nucleos(t)ide analogues · Hepatitis C direct-acting antivirals · Hepatitis D · N-acetylcysteine
Hepatitis B: Nucleos(t)ide Analogues
Agent Resistance Barrier Key Advantage Key Caution
Entecavir High (3 mutations needed) First-line treatment-naive; potent suppression Not preferred after lamivudine failure (cross-resistance)
Tenofovir disoproxil fumarate Highest (no documented resistance) Preferred after lamivudine failure Nephrotoxicity; bone mineral density loss with long-term use
Tenofovir alafenamide Highest Lower nephrotoxicity and bone effects; preferred in renal impairment Higher cost; not approved in all markets for all HBV indications
Lamivudine (old) Low (~20%/year) Historical; widely available No longer first-line; high resistance rate
Hepatitis C: Direct-Acting Antiviral Drug Classes
NS3/4A Protease Inhibitors (-previr)
Glecaprevir, Voxilaprevir, Grazoprevir
  • Block viral serine protease → prevents polyprotein cleavage
  • Contraindicated in decompensated cirrhosis (worsens liver function)
  • CYP3A4 inhibitors: strong CYP3A4 inducers (rifampin) cause treatment failure
NS5B Polymerase Inhibitor
Sofosbuvir (Nucleoside Analogue)
  • Chain terminator of RNA-dependent RNA polymerase
  • Pan-genotypic; backbone of most regimens
  • P-glycoprotein substrate: P-gp inducers reduce absorption
  • Fatal bradycardia with amiodarone — contraindicated combination
NS5A Inhibitors (-asvir)
Velpatasvir, Ledipasvir, Pibrentasvir
  • Block replication complex assembly and virion assembly
  • Ledipasvir: requires acidic absorption environment — avoid high-dose proton pump inhibitors
  • Pan-genotypic agents: velpatasvir, pibrentasvir
Acute Liver Failure: N-Acetylcysteine and King’s College Criteria
N-Acetylcysteine Mechanism
Glutathione Replenishment
  • Acetaminophen → CYP2E1/3A4 → NAPQI (reactive metabolite)
  • NAPQI + glutathione → detoxified (normal doses)
  • Overdose: glutathione depleted → NAPQI causes centrilobular necrosis
  • N-acetylcysteine: cysteine precursor → replenishes glutathione
  • Start within 8 hours: virtually eliminates severe hepatotoxicity
  • Give even at >24 hours: still reduces mortality in established ALF
King’s College Criteria
Urgent Transplant Evaluation Threshold
  • Acetaminophen ALF: arterial pH <7.3 after resuscitation; OR all three of: PT >100 s + creatinine >300 µmol/L + grade III–IV encephalopathy
  • Non-acetaminophen ALF: PT >100 s alone; OR any 3 of 5: unfavorable etiology, age extremes, jaundice-to-encephalopathy >7 days, bilirubin >300 µmol/L, PT >50 s
  • Meeting criteria: refer immediately for liver transplant evaluation
Critical Rule — Sofosbuvir + Amiodarone

Sofosbuvir combined with amiodarone has caused serious and fatal bradycardia including complete heart block. Amiodarone is absolutely contraindicated with sofosbuvir-containing hepatitis C regimens. Screen for amiodarone use before starting any direct-acting antiviral.