Chronic Hepatitis B Infection

Aka: Chronic Hepatitis B Infection, Chronic Hepatitis B, Chronic Active Type B Viral Hepatitis, Chronic Persistent Type B Viral Hepatitis, Chronic Hepatitis B Antiviral Therapy

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II. Epidemiology

  1. See Hepatits B
  2. HBV is associated with high morbidity and mortality related to Hepatocellular Carcinoma and Cirrhosis
  3. However, chronic HBV Is underdiagnosed and undertreated
    1. HBV diagnosed cases: 19% of U.S. cases
    2. HBV receiving Antiviral treatment: 30% of U.S. cases (2% worldwide)

III. Pathophysiology

  1. Acute Hepatitis B Infection becomes chronic in 10% (higher risk in younger ages)
  2. Chronic Hepatitis B (HBsAg present >6 months)
    1. Chronic Hepatitis B Carrier
    2. Chronic Hepatitis B Infection
      1. High viral load
      2. Elevated liver transaminase (ALT or AST)

IV. History

  1. Cirrhosis symptoms and signs
  2. Family History of Hepatocellular Carcinoma
  3. Immunization history
    1. Hepatitis A Vaccine
    2. Hepatitis B Vaccine
  4. Comorbidities
    1. Alcohol Abuse
    2. HIV Infection
    3. IV Drug Abuse
    4. Diabetes Mellitus (and associated metabolic conditions)

V. Labs: General

  1. Complete Blood Count with Platelets
    1. Platelet Count is an indirect marker of Portal Hypertension induced Splenomegaly
    2. Platelets <150,000 occur with increased Platelet sequestration and destruction
  2. Liver Function Tests
    1. Liver transaminases (ALT, AST)
    2. Total Bilirubin
    3. Alkaline Phosphatase
    4. Serum Albumin
    5. INR
  3. Coinfections
    1. Hepatitis C Antibody
    2. HIV Test
  4. Prevention
    1. Hepatitis A VirusAntibody (immunize if negative)

VI. Labs: Hepatitis B VirusSerology and other specific testing

  1. See Hepatitis B Serology
  2. HBsAg positive
  3. HBeAg and HBeAb
    1. HBeAg+/xHBeAb-: Chronic Active Hepatitis B
    2. HBeAg-/xHBeAb+: Chronic Persistent Hepatitis B or Chronic Hepatitis B Carrier
      1. Differentiate inactive infection from chronic HBV without HBeAg expression
  4. High Hepatitis B viral load
    1. HBV DNA hybridization positive
  5. HBV Genotype

VII. Labs: Monitoring of UNTREATED patients

  1. Labs most every 3-6 months unless otherwise specified
    1. Antiviral Agent-specific monitoring for toxicity
    2. Alanine Aminotransferase (ALT)
    3. HBV DNA
    4. HBeAg and HBeAb (every 6-12 months if HBeAg positive)
    5. HBsAg yearly
  2. Fibrosis Testing (e.g. FIB-4 Score)
    1. Obtain every 2 years
    2. Strongly consider Nucleotide analog Antiviral therapy if consistent with >=F2 Fibrosis

VIII. Labs: Monitoring of TREATED patients

  1. Labs every 3 months until viral suppression, then every 6 months
    1. Antiviral Agent-specific monitoring for toxicity
    2. Alanine Aminotransferase (ALT)
    3. HBV DNA
    4. HBeAg and HBeAb (every 6-12 months if HBeAg positive)
    5. HBsAg yearly

IX. Diagnostics: Complication Screening

  1. Re-activation of inactive Hepatitis B
    1. Recheck labs every 6-12 months
  2. Cirrhosis (inflammation activity and fibrosis evaluation)
    1. Liver biopsy
    2. Noninvasive testing of Hepatic Fibrosis
      1. Serum fibrosis panel
      2. Fibrosis Probability Score (FIB-4 Index)
        1. FIB-4 >2.67 (F2 - significant fibrosis) to >3.25 (F4 - Cirrhosis)
      3. Transient elastography (TE)
        1. TE >7 kPa (F2 - significant fibrosis) to >11 (F4 - Cirrhosis)
      4. Aspartate Transaminase to Platelet ratio index (APRI)
        1. APRI >0.7 (F2 - significant fibrosis) to >2.0 (F4 - Cirrhosis)
  3. Hepatocellular cancer
    1. Right Upper Quadrant Ultrasound
    2. Serum Alpha-fetoprotein

X. Associated Conditions

  1. Polyarteritis Nodosa
  2. Systemic Vasculitis
  3. Glomerulonephritis

XI. Types: Phases of Chronic Hepatitis B Infection

  1. Phase 1 (Immune Tolerant)
    1. HBeAg positive, HBsAg positive with high titers and HBV DNA very high (>10^7, highly infectious)
    2. ALT levels normal (no or mimimal liver inflammation)
  2. Phase 2 (Immune Reactive)
    1. HBeAg positive, HBsAg positive and HBV DNA increased (>10^4, infectious)
    2. ALT levels increased (moderate to severe liver inflammation)
  3. Phase 3 (Inactive Hepatitis B Carrier)
    1. HBeAg negative, HBsAg positive and HBV DNA undectable or low positive (<2000 IU/ml)
    2. ALT levels normal (no liver inflammation)
    3. If patient remains in this phase, they are at low risk of Hepatocellular Carcinoma or Cirrhosis
      1. However 20-30% will lose immune control and develop increased HBV replication
  4. Phase 4 (Active phase or Reactivation)
    1. HBeAg negative, HBsAg negative but HBV DNA increased at least low to moderate (>2000 IU/ml)
    2. ALT levels increased (moderate to severe liver inflammation)
    3. HBeAb positive
    4. Low rates of spontaneous disease remission
  5. Phase 5 (Occult Hepatitis B)
    1. HBeAg negative, HBsAg negative and HBV DNA undetectable
    2. ALT normal with variable liver inflammation
    3. HBcAb positive

XII. Management: General

  1. See prevention below
  2. Prevent transmission to close contacts
    1. See Chronic Hepatitis B Carrier
  3. Gastroenterology Referral
  4. Liver Transplant
    1. Indicated in decompensated Cirrhosis refractory to Antiviral therapy

XIII. Management: Antiviral Agents

  1. Goals of therapy
    1. Viral suppression (HBV DNA Suppression)
      1. Hepatitis B Virus covalently closed DNA may lie dormant and protected within the hepatocyte nucleus
      2. Antivirals do not eradicate the virus fully, and reactivation may occur after treatment
      3. Antivirals have no effect on integrated HBV DNA (responsible for HBsAg)
        1. Viral replication restarts when Antivirals are discontinued
      4. Expect viral suppression to undectable levels of HBV DNA by 96 weeks of treatment
    2. Decreased liver inflammation, fibrosis and normalization of ALT
    3. Prevention of vertical transmission in pregnancy (used in third trimester)
    4. Seroconversion (may lag therapy completion by 6 months)
      1. HBeAg seroconversion is 20% after 3 years on a preferred Antiviral
        1. Genotype A: >50% seroconversion
        2. Non-A Genotype: 30% seroconversion
      2. HBsAg loss and functional cure is uncommon with Antiviral treatment (<1%/year)
    5. Prevention of Hepatitis B complications
      1. Reduced Cirrhosis risk
      2. Reduced Hepatocellular Carcinoma (HCC) risk
      3. Reduced need for Liver Transplantation
      4. Reduced mortality
    6. Management of extrahepatic manifestations
      1. Polyarteritis Nodosa
      2. HBV Nephropathy
      3. Cryoglobulinemic Vasculitis
  2. Indications: AASLD Guideline - Active Phase of Chronic Hepatitis B (see above)
    1. HBeAg negative
      1. HBV DNA >2000 IU/ml AND ALT >2x normal
      2. HBV DNA >2000 IU/ml AND ALT abnormal AND liver biopsy moderate inflammation/fibrosis (or noninvasive)
      3. Otherwise (if criteria not met), monitor HBV DNA and ALT every 3-6 months
    2. HBeAg positive
      1. HBV DNA >20,000 IU/ml AND ALT >2x normal
      2. HBV DNA >20,000 IU/ml AND ALT abnormal AND liver biopsy moderate inflammation/fibrosis (or noninvasive)
        1. Liver biopsy indicated in age >40, FHx HCC, prior HBV treatment
      3. HBV DNA >1,000,000 IU/ml AND age>40 AND liver biopsy necroinflammation or fibrosis
  3. Indications: Simplified Algorithm (2022)
    1. HBV DNA >2000 IU/ml and age >= 30 years (or ALT>Upper limit if age <30 years) OR
    2. Detectable HBV DNA and F4 Cirrhosis (APRI >2 or FIB-4 >3.25)
  4. Indications: Other high risk cohorts
    1. Pregnancy
      1. Prevention of vertical transmission in pregnancy (used in third trimester)
    2. Highest risk patients for Cirrhosis and Hepatocellular Carcinoma
      1. Comorbid other Viral Hepatitis (Hepatitis C, D)
      2. HIV Infection
      3. Immunosuppression (esp. Stem Cell Transplant, CD20 Monoclonal Antibody)
    3. Lifelong Nucleotide analog treatment recommended
      1. Hepatocellular cancer
      2. Decompensated Cirrhosis
      3. Liver Transplant for HBV
  5. Pegylated Interferon Alfa-2A (Pegasys)
    1. First-line, preferred agent
    2. Contraindicated if HIV positive, pregnancy or advanced liver disease (decompensated)
    3. Adult Dose: 180 mcg SQ weekly for 48 weeks (costs $33,000 per year)
      1. Renal Dosing 135 mcg SQ weekly if eGFR <30 ml/min or on Hemodialysis
    4. Child Dose (age >=3 years): 180 mcg/1.73 m2 x BSA
    5. Highest seroconversion rate of any agent and no known resistance
    6. Monitoring
      1. CBC baseline, monthly for 3 months, then every 3 months
      2. TSH baseline and then every 3 months
    7. Poorly tolerated
      1. Flu-like symptoms, mood changes and Fatigue
      2. Cytopenias and Autoimmune Conditions
      3. Requires subcutaneous dosing
    8. Very expensive
    9. Indications
      1. Low pretreatment HBV DNA and High ALT
      2. HBV Genotypes A or B
        1. HBeAg clearance in 30%
        2. HBsAg clearance in 2 to 7%
      3. Younger women desiring future pregnancy (but cannot be used during pregnancy)
      4. Hepatitis C coinfection
      5. Younger age
  6. Oral agents: Nucleotide Reverse Transcriptase Inhibitors (nRTI, Nucleoside analogues or NA)
    1. Not as effective as Peg-Interferon (until 3 years of therapy, when seroconversion rates are similar)
    2. Higher Drug Resistance rates with Lamivudine (Epivir), Telbivudine (Tyzeka), Adefovir Dipivoxil (Hepsera)
    3. Indications
      1. Intolerance to Peg-Interferon
      2. Peg-Interferon contraindicated (severe liver disease or HIV positive status)
      3. Active Chronic Hepatitis B in first trimester pregnancy
    4. Protocol
      1. Monitor Renal Function tests during therapy
      2. Combine more than one agent if no effect on HBV DNA levels in 6-12 months
      3. Continue agents for additional 6 months beyond seroconversion
    5. First-line agents (lowest resistance rates, preferred, may be used in decompensated liver disease)
      1. Entecavir (Baraclude)
        1. Adult dose (and children weight >30 kg): 0.5 mg to 1 mg orally daily for more than 48 weeks
        2. Children (age >2 years and weight 10 to 30 kg): Weight based dosing
        3. Preferred agent in age >60, Osteoporosis
        4. Preferred agent in renal dysfunction (dose adjust at eGFR <50 ml/min)
        5. Obtain HIV Screening before starting
      2. Tenefovir alafenamide (Vemlidyl)
        1. Adult dose (and children >=6 years, >=25 kg): 25 mg orally daily for 52 weeks
          1. Active metabolite has higher liver penetration
          2. Requires lower drug doses, less systemic adverse effects
        2. May be used in pregnancy (low placental transfer, and no evidence of Teratogenicity)
        3. Preferred agent in age >60, Osteoporosis
        4. Preferred agent in renal dysfunction (avoid if eGFR <15 ml/min and not on Hemodialysis)
        5. Preferred in comorbid HIV or treatment experienced patients
      3. Tenefovir disoproxil fumarate (Viread)
        1. Adult dose: 300 mg daily for at least 52 weeks
        2. Dose adjustment if eGFR <50 ml/min
        3. Obtain baseline Creatinine Clearance and then annually (also Serum Phosphorus, Urine Protein)
        4. May be used in pregnancy (high placental transfer, but no evidence of Teratogenicity)
        5. Obtain baseline DEXA Scan if Osteoporosis risk
        6. Preferred in comorbid HIV or treatment experienced patients
    6. Second-line agents (higher resistance rates)
      1. Lamivudine (Epivir-HBV)
        1. Adult Dose: 100 mg daily for at least 48 to 52 weeks
        2. Viral suppression only persists while on medication
        3. Higher risk for resistance (risk at 1 year: 24%)
      2. Adefovir Dipivoxil (Hepsera)
        1. Adult dose: 10 mg daily for at least 48 weeks
        2. Higher risk of resistance
      3. Telbivudine (Tyzeka)
        1. Adult dose: 600 mg daily for at least 52 weeks
        2. Higher risk of resistance
        3. Not available in the U.S.
          1. Novartis discontinued in 2016, as Tenefovir disoproxil was widely available, effective and generic
  7. Duration
    1. Most patients are maintained longterm on Nucleotide analog (NA) Antiviral therapy
    2. Indications for trial of NA cessation
      1. Loss of HBsAg with or without HBsAb development (2 consecutive negative tests) AND
      2. Negative HBV DNA persistently undectable AND
      3. Normal Alanine Aminotransferase (ALT) AND
      4. Continuation of NA for 1 year beyond criteria AND
      5. No comorbid HIV Infection, HDV or Cirrhosis AND
      6. Ongoing monitoring of ALT and HBV DNA planned after stopping NA
        1. Every 1-3 months for 6 months
        2. Then every 3 months for 6-12 months
        3. Then every 3-6 months
    3. Indications to restart NA
      1. HBV DNA >=10,000 IU/ml (or >2000 IU/ml and ALT >2x normal)
      2. ALT >5x upper limit normal
      3. Total Bilirubin >2.5 mg/dl
      4. Hepatic decompensation

XIV. Complications: General

  1. Cirrhosis
    1. Annual risk: 12%
  2. Mortality
    1. Lifetime risk of HBV related death: 15 to 25%

XV. Complications: Hepatocellular Carcinoma (Hepatoma)

  1. Chronic Hepatitis B accounts for 50% of Hepatocellular Carcinoma cases
    1. HBV is the leading cause of Hepatocellular Carcinoma worldwide
  2. Risk factors for developing hepatocellular cancer in Chronic Hepatitis B patients
    1. Men over age 45 years
    2. Cirrhosis as diagnosed by liver biopsy
    3. Family History of Hepatocellular Carcinoma
    4. Coinfection with Hepatitis CVirus or Hepatitis DVirus
    5. HBV DNA Viral Load >10,000 IU/ml
    6. HBV Genotype C
    7. Tobacco Abuse
    8. HBeAg positive
  3. Screening for Hepatocellular Carcinoma
    1. Indications for highest risk patients as described above
    2. Protocol: Every 6-12 months (AASLD recommendation)
      1. Hepatic Ultrasound
      2. Serum Alpha-fetoprotein
  4. References
    1. Singal (2009) Aliment Pharmacol Ther 30(1): 37-47 [PubMed]
    2. Yang (2002) N Engl J Med 347:168-74 [PubMed]

XVI. Course

  1. Hepatitis B Resolution in those with inactive Hepatitis B
    1. Clearance of HBsAg and development of HBsAb occurs in those with inactive Hepatitis B at 0.5% yearly
  2. Cirrhosis Risk
    1. Untreated Chronic Hepatitis B five year Incidence: 8-20% develop Cirrhosis
  3. Hepatocellular Carcinoma
    1. Untreated Chronic Hepatitis B five year Incidence: 2-5% develop Hepatocellular Carcinoma

XVII. Prevention: Disease progression

  1. See Prevention of Liver Disease Progression
  2. Tobacco Cessation (decreases risk of Hepatoma)
  3. Avoid Alcohol and other liver toxins
  4. Hepatitis A Vaccine

XVIII. References

  1. Berenguer in Feldman (2002) Sleisenger GI, p. 1285-303
  2. Dienstag (1999) N Engl J Med 341:1256-63 [PubMed]
  3. Dienstag (2008) N Engl J Med 359(14): 1486-500 [PubMed]
  4. Lok (2001) Hepatology 34:1225-41 [PubMed]
  5. Malik (2000) Ann Intern Med 132:723-31 [PubMed]
  6. Moore (2026) Am Fam Physician 113(3): 235-43 [PubMed]
  7. Singh (2008) J Antimicrob Chemother 62(2): 224-8 [PubMed]
  8. Wilkins (2019) Am Fam Physician 99(5): 314-23 [PubMed]
  9. Wilkins (2010) Am Fam Physician 81(8): 965-72 [PubMed]

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