Hepatitis B virus

Background

Microbiology

• Reverse-transcription double-stranded DNA (RT-dsDNA) virus
• Genotypes A through J vary in geographic distribution and clinical severity

Genotype	B	C	A	D	E-J
Clinical characteristics
Modes of transmission	Perinatal/vertical	Perinatal/vertical	Horizontal	Horizontal	Horizontal
Tendency of chronicity	Lower	Higher	Higher	Lower	No data
HBeAg positivity	Lower	Higher	Higher	Lower	No data
HBeAg seroconversion	Earlier	Later	Earlier	Later	No data
HBsAg seroclearance	More	Less	More	Less	No data
Histological activity	Lower	Higher	Lower	Higher	No data
Clinical outcomes
Response to interferon-α	Higher	Lower	Higher	Lower	Lower in G
Response to NRTIs	No significant differences				No data
Viroloical characteristics
Viral load	Lower	Higher	No data
Frequency of PC A1896 mutation	Higher	Lower	Lower	Higher	No data
Frequency of basal core promoter T1762/A1764 mutation	Lower	Higher	Higher	Lower	No data
Frequency of preS deletion utation	Lower	Higher	No data

Phases of Chronic Infection

• Phase 1: HBeAg + chronic infection (previously immune tolerant)
  • Viral replication including HBeAg without evidence of immune response
• Phase 2: HBeAg + chronic hepatitis (previously immune active)
  • Elevated liver enzymes and HBV DNA
• Phase 3: HBeAg – chronic infection (previously inactive carrier)
  • HBeAg clears and liver enzymes normalize, but ongoing low-level viral replication
• Phase 4: HBeAg – chronic hepatitis (previously HBeAg-negative chronic hepatitis)
  • Increasing viral load with fluctuating liver enzymes
• Phase 5: HBsAg negative
  • HBsAb positive or negative, other studies return to normal

Clinical Manifestations

Acute

• 75% are asymptomatic
• Symptoms range from self-resolving jaundice to fulminant liver failure in about 5%

Chronic

• Chronic hepatitis B begins as e antigen positive, usually with very high levels of HBV DNA and necroinflammation.
• Four types of chronic hepatitis B
  • Immunotolerant hepatitis B: HBV DNA levels (>20,000 IU/ml), HBeAg positive, with normal ALT
    • Common after vertical transmission and can persist for years before progressing to another form
  • HBeAg-positive immune-active chronic hepatitis B: HBsAg-positive, HBV DNA levels (>20,000 IU/ml), HBeAg positive, anti-HBe negative with elevated ALT
  • HBeAg-negative immune-active chronic hepatitis B: HBsAg-positive, HBV DNA levels (<20,000 IU/ml), HBeAg negative, anti-HBe positive, with elevated ALT
    • Results from anti-HBe seroconversion when a mutation decreases HBeAg expression
  • Inactive hepatitis B (healthy carrier): HBsAg for > 6 months without any evidence of necroinflammation and HBV DNA levels are < 2,000 IU/m
    • May still transmit it, but overall a better prognosis
• Hepatocellular carcinoma is a risk in chronic hepatitis B, but especially in certain populations including cirrhosis
• Polyarteritis nodosa
• Membranous nephropathy or membranoproliferative glomerulonephritis
• Sensorimotor neuropathy
• Sjogren syndrome

Investigations

• Hepatitis B serology

Management

Acute

• Supportive care

Chronic

• HBsAg present ≥6 months
• HBV-DNA is variable
• Can be HBeAg positive or negative, with generally higher HBV DNA levels in HBeAg-positive patients
• ALT can be normal or elevated
• Liver boipsy shows chronic hepatitis and variable necroinflammation or fibrosis

Immune-active

• HBsAg present ≥6 months and HBeAg either positive or negative
• Intermittently or persistently elevated ALT and AST

Indications for treatment

• ALT ≥2x ULN or evidence of significant histologic disease, AND
• Elevated HBV DNA
  • > 2000 IU/mL if HBeAg negative
  • > 20,000 IU/mL if HBeAg positive

Immune-tolerant

• HBsAg present for ≥6 months and HBeAg positive
• HBV DNA typically over 1 million
• Normal or minimally-elevated ALT and AST
• That is, high viral load but normal ALT

Indications for treatment

• Adults >40 years, AND
• ALT rises above 2x ULN (i.e. becomes immune-active), OR
• Liver biopsy showing significant necroinflammation or fibrosis

Surveillance

• Monitor at 3 to 6 month intervals, more frequently as ALT levels rise, consider treatment if >2x ULN/

Treatment Regimens

• One of pegylated-interferon (48 weeks), tenofovir (until 12 months post-HBeAg conversion), or entecavir (until 12 months post-HBeAg conversion)
  • Peg-IFN contraindicated in autoimmune disorders, uncontrolled psychiatric disease, cyptopenia, severe cardiac disease, uncontrolled seizures, and decompensated cirrhosis
  • Peg-IFN preferred in lamivudine resistance
  • Tenofovir is safe in pregnancy
• Duration depends on what stage is being treated
  • HBeAg positive and HBV DNA >20,000 and ALT >2 ULN
    • Peg-IFN for 48 weeks
    • Tenofovir or entecavir for at least 12 months after HBeAg seroconversion (Ag to Ab)
  • HBeAg negative and HBV DNA > 2000 and ALT >2x ULN (or biopsy shows necroinflammation or fibrosis, or non-invasive testing shows fibrosis)
    • Peg-IGN for 1 year
    • Tenofovir or entecavir for many years, possibly indefinitely
• Continue HCC surveillance regardless of treatment

Inactive chronic hepatitis B

• Defined by HBeAg-negative, anti-HBeAb-positive, normal ALT, and HBV DNA <2000 IU/mL
• Monitor ALT q3mo for 1 year, then q6-12mo
• If ALT rises, check HBV-DNA and HBsAg for activity

HCC screening

• Screen if HBsAg-positive with cirrhosis, or HBsAg-positive at higher risk (Asian men >40yrs, black men >40yrs, Asian women >50yrs, family history, HDV coinfection)
• First-line is ultrasound every 6 months
• Second-line is AFP levels every 6 months

Prophylaxis in Immunosuppression

• Risk stratify based on type of immune suppression and serologic status
  • High-risk (>10%):
    • HBsAg positive, or HBsAg negative but HBcAb positive, plus B-cell depletion such as rituximab and ofatumumab
    • HBsAg positive, plus anthracyclines (doxorubicin, epirubicin), prednisone >10-20 mg/day for ≥4 weeks
  • Moderate-risk (1-10%)
    • HBsAg positive, or HBsAg negative but HBcAb positive, plus TNF-α inhibitors (etanercept, adalimumab, certolizumab, certolizumab, infliximab), other cytokine or integrin inhibitors (abatacept, ustekinumab, natalizumab, vedolizumab), and tyrosine kinase inhibitors (imatinib, nilotinib, ibrutinib)
    • HBsAg positive: prednisone <10 mg/day for ≥4 weeks
    • HBsAg negative but HBcAb positive: prednisone >10-20 mg/day for ≥4 weeks, antracycline derivatives (doxorubicin and epirubicin)
  • Low-risk (<1%)
    • HBsAg positive, or HBsAg negative but HBcAb positive, plus traditional immunosuppressants (azathioprine, 6-MP, methotrexate)
    • HBsAg negative or HBcAb positive, plus prednisone <10 mg/day for ≥4 weeks
• Concern especially with chronic steroids and rituximab
• Can have the following effects
  • Asymptomatic HBV DNA and ALT
  • Hepatic failure
  • Death
• If ≥7.5mg/d should be screened
  • HBsAg +/- HBcAb if they're adding a second agent (rituximab, TNF-alpha inhibitors, or other)
  • Refer to Hepatology or Infectious Diseases
• Prophylaxis with lamivudine until 6 months after chemotherapy

Further Reading

• Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance
• Hepatitis B virus genotypes: Global distribution and clinical importance. World J Gastroenterol. 2014;20(18):5427–5434. doi: 10.3748/wjg.v20.i18.5427