215.1 🎓 醫孞生版

215.1.0.1 📌 䞀頁重點

215.1.0.1.1 Hepatitis D Virus (HDV)
  • Defective ssRNA virus — requires HBV (HBsAg envelope) for replication
  • Only infects HBV-positive individuals
  • Worldwide ~ 15-20M chronic (some estimates higher up to 50M)
  • High prevalence: Mediterranean, Eastern Europe, Mongolia, Amazon Basin, parts of Asia
  • 2 patterns:
    • Co-infection (HBV + HDV simultaneously): acute illness; fulminant risk 5-20%; 90% resolution
    • Superinfection (HDV in chronic HBV carrier): severe acute exacerbation; 70-90% progress to chronic HDV
  • Clinical: more severe than HBV alone; accelerated progression to cirrhosis (10 yr); HCC risk higher; bimodal acute hepatitis course
  • Diagnosis: anti-HDV IgM/IgG + HDV RNA PCR; confirm HBsAg+
  • Treatment:
    • Bulevirtide (Hepcludex) — NTCP receptor inhibitor (HBV/HDV entry blocker); 2020 EU FDA-approved (orphan drug)
    • Peg-interferon-α — limited efficacy ~ 20-30% SVR
    • Lonafarnib (farnesyl transferase inhibitor) — in trials
    • Antisense oligonucleotides in development
    • No DAAs available for HDV directly (still under development)
215.1.0.1.2 Hepatitis E Virus (HEV)
  • ssRNA Hepeviridae; 4 main genotypes
  • Genotype 1, 2: human-only, fecal-oral, low-income waterborne outbreaks (Asia, Africa, Latin America)
  • Genotype 3, 4: zoonotic (pigs, wild boar, deer, rabbits), Europe + Asia, sporadic + foodborne (raw/undercooked pork, wild game)
  • Transmission: fecal-oral (genotypes 1, 2); foodborne pork/game (genotypes 3, 4); blood (rare); vertical
  • Acute Hepatitis E:
    • Self-limited in healthy
    • Severe in pregnancy (especially 3rd trimester): mortality 20-30% (vs HAV 0.3%); fulminant hepatic failure + obstetric emergency
    • Severe in chronic liver disease
  • Chronic HEV (genotype 3):
    • In immunocompromise (transplant, HIV, hematologic malignancy)
    • Can lead to cirrhosis
    • Ribavirin treatment + reduce immunosuppression
  • Extrahepatic: GBS, neuralgic amyotrophy, transverse myelitis
  • Diagnosis: anti-HEV IgM (acute) + HEV RNA PCR (active, especially chronic immunocompromise)
  • Treatment:
    • Acute: supportive
    • Chronic immunocompromise: ribavirin + reduce immunosuppression
  • Vaccine:
    • Hepai 239 (Hecolin) — China only (2011 licensed)
    • Not widely available globally
    • Limited efficacy data outside China

215.1.0.2 1⃣ Hepatitis D Virus (HDV)

215.1.0.2.1 Virology
  • Defective ssRNA virus, ~ 1.7 kb (smallest known mammalian virus)
  • Hepatitis Delta antigen (HDAg) — large + small forms
  • Uses HBV-encoded HBsAg envelope for entry + assembly
  • Cannot replicate without HBV
215.1.0.2.2 Genotypes
  • 8 genotypes (1-8)
  • Genotype 1: worldwide (most common)
  • Genotype 2, 4: East Asia
  • Genotype 3: Amazon Basin (high virulence)
215.1.0.2.3 Epidemiology
  • 15-20M chronic globally (some 50M estimates)
  • 5% of chronic HBV worldwide is HDV-coinfected (varies; up to 25% in some regions)
  • High prevalence regions:
    • Mediterranean (Italy, Greece, Turkey)
    • Eastern Europe (Bulgaria, Romania, Russia)
    • Mongolia (highest national prevalence)
    • Amazon Basin (Brazil, Peru)
    • Sub-Saharan Africa (some areas)
    • Asia (Taiwan, Vietnam — lower prevalence)
    • Pakistan + Central Asia
215.1.0.2.4 Transmission
  • Same routes as HBV: blood, sexual, vertical
  • Cannot infect HBV-negative individual
215.1.0.2.5 Clinical Patterns
215.1.0.2.5.1 Co-Infection (HBV + HDV Simultaneous)
  • Acute self-limited usually
  • Biphasic acute hepatitis (two ALT peaks — HBV then HDV)
  • Fulminant hepatic failure: 5-20% (much higher than HBV alone 1%)
  • 90% resolve; ~ 5% progress to chronic HDV
215.1.0.2.5.2 Superinfection (HDV on Chronic HBV)
  • Acute severe exacerbation
  • 70-90% progress to chronic HDV
  • Accelerated cirrhosis (10 yr median vs 30 yr HBV alone)
  • HCC risk much higher
215.1.0.2.6 Clinical Severity
  • More severe than HBV alone
  • Faster progression to cirrhosis + HCC
  • ~ 70% cirrhotic by 10 yr post-superinfection
  • 5-yr mortality 20-25% in chronic HDV cirrhosis
215.1.0.2.7 Diagnosis
  • Anti-HDV IgM + IgG screening
  • HDV RNA PCR (active infection)
  • HBV serology (always coexists)
  • Liver biopsy if needed
215.1.0.2.8 Treatment
215.1.0.2.8.1 Bulevirtide (Hepcludex)
  • NTCP receptor inhibitor (sodium-taurocholate cotransporting polypeptide)
  • Blocks HBV/HDV entry into hepatocytes
  • EMA approval 2020 (orphan drug, conditional)
  • FDA Breakthrough Therapy 2024
  • SC injection 2 mg daily

  • 50% achieve HDV RNA suppression + ALT normalization

  • ~ 12% achieve HBsAg loss (cure-related)
  • Continued therapy (no defined endpoint yet)
  • Drug interactions: OATP1B1/3 inhibition (statins, etc.)
  • Cost + access challenges
215.1.0.2.8.2 Peg-Interferon-α-2a
  • 180 µg SC weekly × 48 wk
  • Older standard
  • ~ 20-30% SVR (sustained virological response)
  • Side effects significant
  • Limited use now
215.1.0.2.8.3 Lonafarnib
  • Farnesyl transferase inhibitor (HDAg requires farnesylation)
  • In Phase 3 trials
  • Combination with peg-IFN + ritonavir
215.1.0.2.8.4 Antisense Oligonucleotides
  • ALN-HBV, JNJ-3989, AB-729 (target HBsAg) under study
  • Indirect HDV effect by HBsAg reduction
215.1.0.2.8.5 Other Investigational
  • Nucleic acid polymers (REP-2139, REP-2165)
  • Lambda-IFN
215.1.0.2.8.6 Liver Transplant
  • For decompensated cirrhosis
  • HBV + HDV recurrence prevented with HBIG + nucleoside analog

215.1.0.3 2⃣ Hepatitis E Virus (HEV)

215.1.0.3.1 Virology
  • ssRNA, ~ 7.2 kb
  • Hepeviridae family
  • 4 main genotypes:
    • Genotype 1, 2: human-only
    • Genotype 3, 4: zoonotic (pigs, wild boar, deer, rabbits)
    • Genotype 7 (camels — rare human)
215.1.0.3.2 Transmission
215.1.0.3.2.1 Genotype 1, 2 (Asia, Africa, Latin America)
  • Fecal-oral, contaminated water primarily
  • Waterborne outbreaks (refugee camps, floods)
  • Person-to-person
  • Vertical (high efficiency)
215.1.0.3.2.2 Genotype 3, 4 (Developed Countries — Europe, Asia)
  • Zoonotic foodborne: undercooked pork, wild boar, deer meat
  • Pet rabbits implicated
  • Blood transfusion (rare)
  • Drinking water (less)
  • Vertical (less common)
215.1.0.3.2.3 Genotype 3, 4 Risk Factors
  • Hunters, butchers, sausage workers
  • Wild game consumption
  • Raw pork sausage (Italy, France)
  • Pet rabbit ownership (recent reports)
215.1.0.3.3 Epidemiology
  • Genotype 1: India, Nepal, Pakistan, Bangladesh, Myanmar, China (older outbreaks)
  • Genotype 2: Mexico, Africa
  • Genotype 3: Europe (especially France, Germany, UK), Japan, Taiwan
  • Genotype 4: China, Japan, Taiwan, India
  • Outbreaks: Sudan, Yemen, Syria (refugee + flood)
215.1.0.3.4 Clinical
215.1.0.3.4.1 Acute HEV (Genotype 1, 2 Mostly)
  • 15-60 d incubation
  • Mild self-limited in healthy adult
  • Fever, malaise, anorexia, jaundice
  • 1-6 wk duration
215.1.0.3.4.2 Severe Pregnancy HEV
  • Genotype 1 in 3rd trimester maternal:
    • Mortality 20-30% (compared to HAV 0.3%, HBV 1%)
    • Fulminant hepatic failure common
    • Obstetric complications: stillbirth, preterm labor, severe maternal sepsis
    • Mechanism: hormonal + immune changes
  • Maternal vaccine could be lifesaving
  • Treatment: supportive + transplant if available
215.1.0.3.4.3 Chronic HEV (Genotype 3, 4)
  • In immunocompromise:
    • Solid organ transplant (kidney, liver, heart)
    • HIV + low CD4
    • HSCT
    • Hematologic malignancy
    • Chemotherapy
  • Persistent viremia + transaminitis
  • Can lead to cirrhosis if untreated
  • Treatment: reduce immunosuppression + ribavirin 600-1000 mg/d × 3-12 months
  • ~ 80% sustained virological response with treatment
215.1.0.3.4.4 Extrahepatic Manifestations
  • Neurologic:
    • GBS (Guillain-Barré syndrome) — HEV is common cause of post-infectious GBS in Europe
    • Bilateral brachial neuralgia / neuralgic amyotrophy
    • Transverse myelitis
    • Encephalitis
    • Peripheral neuropathy
  • Renal: cryoglobulinemia + MPGN
  • Hematologic: thrombocytopenia, aplastic anemia
215.1.0.3.5 Diagnosis
  • Anti-HEV IgM (acute infection)
  • Anti-HEV IgG (past or vaccine immunity)
  • HEV RNA PCR (active infection, especially for chronic; sensitivity varies)
  • Liver biopsy (chronic immunocompromise) shows persistent inflammation + fibrosis
215.1.0.3.6 Treatment
215.1.0.3.6.1 Acute (Healthy)
  • Supportive
  • Hospitalize if severe
215.1.0.3.6.2 Acute (Pregnancy)
  • Supportive + ICU + obstetric
  • Liver transplant if available
  • High mortality
215.1.0.3.6.3 Chronic (Immunocompromise)
  • Reduce immunosuppression (calcineurin inhibitor reduction)
  • Ribavirin 600-1000 mg/day × 3-12 months
  • ~ 80% SVR
  • Monitor HEV RNA monthly
  • Re-treatment if relapse
  • Caution: ribavirin hemolysis + teratogenicity (men + women)
215.1.0.3.6.4 Fulminant
  • ICU, liver transplant if criteria met
215.1.0.3.7 Vaccine
215.1.0.3.7.1 Hepai 239 (Hecolin)
  • China only, 2011 licensed
  • Recombinant subunit (E2 protein, genotype 1)
  • 3-dose schedule
  • ~ 95% efficacy preventing acute HEV in trial
  • Limited data on protection genotype 3/4
  • Not widely available globally
215.1.0.3.7.2 Future
  • Vaccine for pregnant women in high-risk regions (sub-Saharan Africa, S Asia)
  • WHO + Gavi exploring deployment
  • Combination Hepatitis A + E vaccines under study
215.1.0.3.8 Prevention
  • Sanitation + safe water
  • Cook pork + game meat thoroughly (≥ 70°C)
  • Pregnancy travel restrictions to endemic areas
  • Pre-pregnancy screening