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. 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 Function Tests (ALT or SGPT)

III. 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

IV. Labs: General

  1. Complete Blood Count with Platelets
  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)

V. Labs: Hepatitis B specific

  1. HBsAg positive
  2. HBeAg positive
  3. xHBeAb negative
  4. High Hepatitis B viral load
    1. HBV DNA hybridization positive
  5. HBV Genotype

VI. Labs: Monitoring

  1. Alanine Aminotransferase (ALT)
    1. Year 1: Every 3 months
    2. Year >1: Every 6-12 months (more often if becomes increased)
  2. HBV DNA
    1. Indicated for ALT increase

VII. 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. Transient elastography
    3. Serum fibrosis panel
  3. Hepatocellular cancer
    1. Right Upper Quadrant Ultrasound
    2. Serum Alpha-fetoprotein

VIII. Associated Conditions

  1. Polyarteritis Nodosa
  2. Systemic Vasculitis
  3. Glomerulonephritis

IX. 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 (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 (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
    2. ALT levels normal (no liver inflammation)
    3. If patient remains in this phase, they are at low risk of Hepatocellular Carcinoma or Cirrhosis
  4. Phase 4 (Active phase)
    1. HBeAg negative, HBsAg negative but HBV DNA very high
    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

X. 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

XI. Management: Antiviral Agents

  1. Goals of therapy
    1. Viral suppression (HBV DNA Suppression)
      1. Hepatitis BVirus 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
    2. Decreased liver inflammation and normalization of ALT
    3. Prevention of Hepatitis B complications
    4. Seroconversion (may lag therapy completion by 6 months)
      1. HBeAg Positive Genotype A: >50% seroconversion
      2. Non-A Genotype: 30% seroconversion
  2. Indications: 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 or fibrosis
      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 or fibrosis
        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. Pegylated Interferon Alfa-2A (Pegasys)
    1. First-line, preferred agent
    2. Contraindicated if HIV positive or advanced liver disease
    3. Adult Dose: 180 mcg weekly for 48 weeks (costs $33,000 per year)
    4. Highest seroconversion rate of any agent and no known resistance
    5. Poorly tolerated
      1. Flu-like symptoms, mood changes and Fatigue
      2. Cytopenias and Autoimmune Conditions
    6. Very expensive
    7. Indications
      1. Low pretreatment HBV DNA and High ALT
      2. HBV Genotypes A or B
      3. Younger women desiring future pregnancy
      4. Hepatitis C coinfection
      5. Younger age
  4. Oral agents: Nucleotide Reverse Transcriptase Inhibitors (nRTI)
    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)
      1. Entecavir (Baraclude)
        1. Adult dose: 0.5 mg to 1 mg orally daily for more than 48 weeks
      2. Tenefovir disoproxil fumarate (Viread)
        1. Adult dose: 300 mg daily for at least 52 weeks
        2. Tenefovir has been used in pregnancy
      3. Tenefovir alafenamide (Vemlidyl)
        1. Adult dose: 25 mg orally daily for 52 weeks
    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

XII. Complications: General

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

XIII. Complications: Hepatocellular Carcinoma (Hepatoma)

  1. Chronic Hepatitis B accounts for 50% of Hepatocellular Carcinoma cases
  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]

XIV. 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

XV. 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

XVI. 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. Singh (2008) J Antimicrob Chemother 62(2): 224-8 [PubMed]
  7. Wilkins (2019) Am Fam Physician 99(5): 314-23 [PubMed]
  8. Wilkins (2010) Am Fam Physician 81(8): 965-72 [PubMed]

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