213.1 🎓 醫孞生版

213.1.0.1 📌 䞀頁重點

  • Virus: dsDNA Hepadnaviridae; partially double-stranded circular DNA
  • Surface antigen (HBsAg) + core antigen (HBcAg) + e antigen (HBeAg)
  • Transmission:
    • Vertical (perinatal — primary in endemic regions)
    • Sexual (high-risk in adolescents/adults)
    • Blood (transfusion, IDU, healthcare exposures)
    • Horizontal household (rare with hygiene)
  • Global Burden: 296M chronic carriers; 887K deaths/yr from HBV (cirrhosis + HCC)
  • High prevalence regions: sub-Saharan Africa, E + SE Asia (Taiwan, Korea, Vietnam)
  • Pediatric infection → 90% chronic; adult acquisition → 95% clear (only 5% chronic)
  • Phases of Chronic HBV (AASLD 2018):
    • Immune tolerant (HBeAg+, high viral load, ALT normal)
    • Immune active (HBeAg+) (high viral load, ALT elevated)
    • Inactive carrier (HBeAg-, low viral load, ALT normal)
    • Immune reactivation (HBeAg-) (variable viral load, ALT elevated, mutations)
  • Diseases:
    • Acute hepatitis (mild to fulminant; chronic in pediatric > adult)
    • Chronic hepatitis with progression to cirrhosis + HCC
    • HBV reactivation with immunosuppression (anti-CD20 like rituximab, chemo, transplant)
    • Extrahepatic manifestations: glomerulonephritis (membranous), PAN (polyarteritis nodosa)
  • Diagnosis:
    • HBsAg — current infection (acute or chronic)
    • Anti-HBs — recovery or vaccination immunity
    • HBeAg / anti-HBe — replication marker
    • HBV DNA quantitative — viral load
    • Anti-HBc IgM — acute infection; IgG = chronic or past
  • Treatment:
    • Tenofovir alafenamide (TAF) — preferred (less renal/bone toxic than TDF)
    • Tenofovir disoproxil fumarate (TDF) — alternative
    • Entecavir — first-line oral (no NTC + nucleoside-naive)
    • Peg-interferon-α — limited use now (chronic HBeAg+ select)
    • Lifelong typically for chronic HBV (cure rare)
  • Cure Paradigm (2024-2025): novel therapeutics under trial:
    • Bulevirtide (Hepcludex) — NTCP receptor inhibitor (also for HDV)
    • GalNAc-siRNA (Vir-2218, etc.) — silences HBsAg
    • Capsid assembly modulators (e.g., vebicorvir)
    • Therapeutic vaccines + immune modulators
    • Goal: functional cure (HBsAg loss + ≀ 1000 IU/mL HBV DNA off-treatment)
  • Vaccine: recombinant HBsAg; universal childhood + at-birth doses; 3-dose series; > 95% protection
  • Prevention: birth-dose vaccine + HBIG + universal childhood vaccination + sexual safety

213.1.0.2 1⃣ Virology

213.1.0.2.1 Structure
  • 42 nm Dane particle (complete infectious virion)
  • Outer envelope: HBsAg
  • Inner core: HBcAg + viral DNA + DNA polymerase
213.1.0.2.2 Genome
  • Partially dsDNA, ~ 3.2 kb (smallest mammalian DNA virus)
  • 4 overlapping ORFs: S (surface), C (core/precore), P (polymerase), X (X protein — transactivator)
  • Polymerase = reverse transcriptase (replication via RNA intermediate, unusual for DNA virus)
213.1.0.2.3 Replication Cycle
  • Hepatocyte binding via NTCP receptor (sodium-taurocholate cotransporting polypeptide)
  • Nuclear import + conversion to cccDNA (covalently closed circular DNA) — major obstacle to cure (persists nuclear, transcription template)
  • Pre-genomic RNA → encapsidation → reverse transcription → new virions
  • Integration into host genome possible (oncogenic potential — HCC)
213.1.0.2.4 Genotypes
  • A, B, C, D, E, F, G, H, I, J
  • Taiwan + Asia: B, C predominant (C associated with worse HCC outcome)
  • Affects treatment response in some scenarios
213.1.0.2.5 Mutations
  • Precore mutations (G1896A): no HBeAg production but still replicating (“HBeAg-negative chronic hepatitis”)
  • Basal core promoter mutations (T1762/A1764): reduced HBeAg, increased HCC risk
  • Surface escape mutations: vaccine breakthrough rare
  • YMDD motif mutations: lamivudine resistance (historical)
  • rtN236T: adefovir resistance
  • Entecavir + tenofovir resistance very rare

213.1.0.3 2⃣ Epidemiology

213.1.0.3.1 Global Distribution
  • 296M chronic HBV globally (2024 WHO)
  • 887K HBV-related deaths/yr (cirrhosis + HCC)
  • High prevalence:
    • Sub-Saharan Africa (5-10% HBsAg+)
    • E + SE Asia (5-10%; China, Taiwan, Korea, Vietnam, Cambodia)
    • Indigenous populations (Alaskan, Aboriginal)
  • Intermediate (2-5%): Eastern Europe, Middle East
  • Low (< 2%): Western Europe, USA, Australia, Japan (rising due immigration)
213.1.0.3.2 Transmission
  • Vertical (perinatal):
    • Major route in endemic regions
    • Mother HBsAg+ + HBeAg+ → ~ 90% transmission without intervention
    • With birth-dose vaccine + HBIG → < 5% transmission
  • Sexual: high-risk adolescents + adults
  • Blood: transfusion (very rare now with screening); IDU; healthcare needlestick
  • Horizontal household contact: shared toothbrush, razor; rare with good hygiene
  • Tattoo, piercing, acupuncture: poorly sterilized equipment
213.1.0.3.3 Risk Groups
  • Children of HBsAg+ mothers
  • IDU
  • MSM
  • Multiple sexual partners
  • Healthcare workers (occupational exposure)
  • Hemodialysis patients
  • Recipients of unscreened blood (historical)
  • People from / travel to high-prevalence regions
213.1.0.3.4 Chronic Infection Risk by Age at Infection
  • Perinatal (< 1 yr): 90%+ chronic
  • Childhood (1-5 yr): 30-50% chronic
  • Adult: 5-10% chronic
  • Implication: vertical/childhood infection drives global HBV burden; vaccine + birth-dose critical

213.1.0.4 3⃣ Clinical

213.1.0.4.1 Acute HBV
  • 1-6 months incubation
  • 70% subclinical or mild
  • 30% symptomatic acute hepatitis:
    • Prodrome 1-2 wk: malaise, anorexia, nausea, fatigue
    • Icterus 2-4 wk: jaundice, hepatomegaly
    • Resolution 1-3 months
  • Fulminant hepatic failure: 1% adults (severe; transplant)
  • Adults: 95% clear; pediatric: 90% chronic
213.1.0.4.2 Chronic HBV (≥ 6 months HBsAg+)
213.1.0.4.2.1 Immune Tolerant Phase
  • Young, perinatally infected
  • HBeAg+, HBV DNA very high (10^7+ IU/mL)
  • ALT normal
  • No significant liver disease activity
  • May persist decades
213.1.0.4.2.2 Immune Active Phase (HBeAg+)
  • ALT elevated (immune-mediated hepatocyte damage)
  • HBV DNA still high
  • Liver biopsy: inflammation + fibrosis
  • Progressive without treatment
213.1.0.4.2.3 Inactive Carrier Phase
  • HBeAg seroconversion to anti-HBe
  • HBV DNA low (< 2,000 IU/mL)
  • ALT normal
  • Best prognosis but still risk of reactivation
213.1.0.4.2.4 Immune Reactivation / HBeAg-Negative Chronic Hepatitis
  • Often precore/BCP mutations
  • HBeAg negative, anti-HBe positive
  • HBV DNA elevated (fluctuating)
  • ALT elevated
  • Progressive disease
213.1.0.4.2.5 Cirrhosis + HCC
  • 20-30% of chronic HBV develop cirrhosis
  • HCC risk 100-200× general population
  • Even non-cirrhotic chronic HBV has HCC risk (integration + X protein effects)
  • Surveillance: liver US + AFP q6 mo in cirrhotic, high-risk Asian
213.1.0.4.2.6 HBV Reactivation
  • Major concern with immunosuppression:
    • Anti-CD20 (rituximab, ocrelizumab) — highest risk
    • High-dose steroids (≥ 20 mg prednisone × 4+ wk)
    • Chemotherapy
    • Anti-TNF
    • Solid organ + HSCT
    • Anti-CD52 (alemtuzumab)
  • Risk highest in HBsAg+ patients; even anti-HBc-only + HBsAg-negative patients can reactivate (occult HBV)
  • Mortality 30%+ if reactivation
  • Prophylaxis with TDF/TAF or entecavir in high-risk groups
  • AASLD recommendations for HBV screening before immunosuppression
213.1.0.4.2.7 Extrahepatic Manifestations
  • Membranous glomerulonephritis — children commonly
  • Polyarteritis nodosa (PAN) — chronic HBV-associated
  • Cryoglobulinemia (more common HCV)
  • Vasculitis

213.1.0.5 4⃣ Diagnosis

213.1.0.5.1 Serologic Markers
Marker Significance
HBsAg Current infection (acute or chronic)
Anti-HBs Immunity (vaccination or natural recovery)
HBeAg Active replication (high infectivity)
Anti-HBe Lower replication (better prognosis)
Anti-HBc IgM Acute infection
Anti-HBc IgG Past or chronic infection
HBV DNA quantitative Viral load (treatment monitoring)
213.1.0.5.2 Common Interpretation Patterns
HBsAg Anti-HBs Anti-HBc Pattern
+ - + IgM Acute HBV
+ - + IgG Chronic HBV
- + + IgG Past infection, immune
- + - Vaccine immunity
- - + IgG isolated Past infection + low titer; or occult HBV
- - - Susceptible
213.1.0.5.3 Liver Assessment
  • ALT/AST levels (varies by phase)
  • Bilirubin, albumin, INR
  • Platelets (cirrhosis indicator)
  • Liver biopsy (historical); now largely replaced by:
  • FibroScan (transient elastography) — non-invasive fibrosis
  • APRI + FIB-4 scores
  • Liver imaging (US + Doppler) for cirrhosis + HCC surveillance
213.1.0.5.4 HCC Surveillance
  • Cirrhotic patients + high-risk Asian / African (regardless of cirrhosis)
  • Liver US + AFP q6 months
  • AFP > 20 ng/mL = follow up imaging
  • MRI / CT with multiphasic contrast for suspicious lesions
  • Diagnostic: LIRADS criteria

213.1.0.6 5⃣ Treatment

213.1.0.6.1 Indications for Antiviral Therapy (AASLD 2018, EASL 2017)
  • Chronic HBV (HBsAg+ > 6 mo) AND:
    • HBV DNA > 2,000 IU/mL + ALT elevated + significant fibrosis/inflammation on biopsy/elastography — treat
    • Cirrhosis with any detectable HBV DNA — treat
    • HBV DNA > 20,000 IU/mL + ALT > 2× ULN — treat
    • Immune tolerant phase: treatment controversial (not routine in young, but case-by-case in older + high HBV DNA)
    • Pregnancy + high HBV DNA (> 200,000 IU/mL): treat from 3rd trimester to prevent vertical transmission
    • Immunosuppression / chemotherapy / anti-CD20: prophylaxis required
  • HBV DNA + 2,000 IU/mL ALT normal: watch (HBV reactivation if immune compromise — check)
  • Chronic HBV + extrahepatic disease (glomerulonephritis, PAN): treat
213.1.0.6.2 First-Line Drugs
213.1.0.6.2.1 Tenofovir Alafenamide (TAF)
  • 25 mg PO qd
  • Preferred (less renal + bone toxicity than TDF)
  • No resistance documented
  • Pregnancy: limited data but approved
213.1.0.6.2.2 Tenofovir Disoproxil Fumarate (TDF)
  • 300 mg PO qd
  • Standard since 2008
  • Renal + bone toxicity over years
  • Pregnancy: well-studied, safe
  • No clinical resistance
213.1.0.6.2.3 Entecavir
  • 0.5 mg PO qd (1 mg if prior lamivudine R)
  • First-line oral
  • Resistance rare in nucleoside-naive
  • Should not be used if lamivudine resistance (higher entecavir R risk)
213.1.0.6.2.4 Lamivudine (Older)
  • High resistance rate (~ 80% over 4 yr)
  • No longer first-line
  • Pregnancy historical
  • Cheap; still used in resource-limited
213.1.0.6.2.5 Adefovir, Telbivudine
  • Older agents
  • Higher toxicity / resistance
  • Not first-line
213.1.0.6.2.6 Peg-Interferon-α-2a
  • 180 µg SC weekly × 48 wk
  • Limited use: select HBeAg+ chronic hepatitis (younger, no cirrhosis, low HBV DNA, favorable genotype)
  • 30% seroconversion to anti-HBe
  • 5-10% HBsAg loss long-term
  • Side effects: flu-like, depression, cytopenia, autoimmune flare
  • Not for cirrhosis (decompensation risk)
213.1.0.6.3 Treatment Duration
  • Lifelong typically (suppression, not cure)
  • Stop criteria limited:
    • HBeAg seroconversion + sustained HBeAg negative (after 12+ mo continued)
    • HBsAg loss (rare, ~ 5% over years)
    • Older patients with low risk (case-by-case)
  • Don’t stop in cirrhosis (decompensation + HCC risk)
213.1.0.6.4 Vertical Prevention
  • Tenofovir 3rd trimester if maternal HBV DNA > 200,000 IU/mL
  • Birth-dose vaccine within 12 hours of delivery
  • HBIG if mother HBsAg+
  • With combination: < 5% vertical transmission
213.1.0.6.5 HBV/HDV Co-Infection
  • HDV requires HBsAg for entry
  • Treatment: see Ch 215 (bulevirtide, peg-IFN)
213.1.0.6.6 HBV/HIV Co-Infection
  • HBV-active ART agent included (TDF/TAF + emtricitabine)
  • Single regimen treats both
213.1.0.6.7 HCC Treatment
  • Surveillance + early detection critical
  • Curative: resection, transplant, ablation, transarterial chemoembolization
  • Advanced: sorafenib, lenvatinib, regorafenib, atezolizumab+bevacizumab, immune checkpoint inhibitors
  • TACE, Y-90 radioembolization for intermediate stage
213.1.0.6.8 HBV Cure Paradigm (2024-2025)
213.1.0.6.8.1 Goals
  • Functional cure: HBsAg loss + sustained suppression
  • Sterilizing cure (full cccDNA elimination): aspirational
213.1.0.6.8.2 Investigational Therapeutics
  • Bulevirtide (Hepcludex) — NTCP receptor inhibitor; HDV approved EU 2020; HBV ongoing trials
  • GalNAc-siRNA: VIR-2218 (Vir Biotechnology), bepirovirsen (GSK), ARC-520
    • Silences HBsAg expression via RNA interference
    • Combination with antiviral + immune modulator
  • Capsid assembly modulators: vebicorvir, JNJ-6379
    • Prevent capsid formation + viral assembly
  • Core protein inhibitors: alternative mechanism
  • Therapeutic vaccines: GS-4774, HepTcell — restore immune response
  • PD-1 inhibitors + checkpoint inhibitors: revive exhausted T cells
  • CRISPR + antisense oligonucleotides: research level
  • REEF-1 study: combination GalNAc-siRNA + bepirovirsen for sustained HBsAg loss

213.1.0.7 6⃣ Prevention

213.1.0.7.1 Vaccine
  • Recombinant HBsAg (yeast-produced, no infectious component)
  • 3-dose series: 0, 1, 6 months (some 2-dose alternatives — Heplisav-B 2 doses 1 mo apart)
  • > 95% efficacy seroconversion in healthy
  • Pregnancy: safe + recommended if at-risk
213.1.0.7.2 Recommendations (ACIP 2024)
  • Universal childhood vaccination + birth dose within 12 hr
  • Adults 19-59: universal vaccination 2022 update
  • Adults 60+ with risk factors: indicated
  • Higher-risk groups regardless of age:
    • Sexual partners of HBsAg+
    • MSM, multi-partner
    • IDU
    • Healthcare workers
    • HIV+, immunocompromise
    • Travelers to endemic regions
    • Hemodialysis
    • Chronic liver disease
213.1.0.7.3 Birth-Dose Vaccine
  • Within 12 hours of birth for all infants (WHO recommendation; many countries)
  • Plus HBIG within 12 hr if mother HBsAg+
    • 3-dose vaccination series completion
  • Reduces vertical transmission > 95%
213.1.0.7.4 HBIG (Hepatitis B Immunoglobulin)
  • Passive antibody
  • Used:
    • Newborns of HBsAg+ mothers (with birth-dose vaccine)
    • Post-exposure prophylaxis for unvaccinated or non-responder healthcare workers
    • Liver transplant for HBV+ recipients (to prevent recurrence)
213.1.0.7.5 Universal Precautions
  • Bloodborne pathogen safety (gloves, sharps disposal)
  • Safe injection practices
  • Tattoo/piercing sterilization
213.1.0.7.6 Sexual + IDU Prevention
  • Condoms
  • Sterile injection equipment
  • Harm reduction