Hepatitis B virus

Background

Microbiology

• Reverse-transcription double-stranded DNA (RT-dsDNA) virus
• Genome encodes seven proteins:
  • Surface proteins (large, middle, and small) which form the envelope or surface antigen (HBsAg)
  • Nucleocapsid core or C protein (HBcAg)
  • Secretory envelope antigen (HBeAg)
  • Viral reverse transcriptase or polymerase
  • X protein
• Genotypes A through J vary in geographic distribution and clinical severity1

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

Pathophysiology

• Virion binds its receptor, NTCP, on the hepatocyte cell membrane
• Nucleocapsid is released into cytosol and transported to the nucleus
  • Occasionally integrates into host genome around this stage
• Relaxed circular DNA (rcDNA) is converted into covalently closed circular DNA (cccDNA)
• cccDNA forms the template for synthesis of RNA, which is reverse-transcribed into negative-sense DNA and positive-sense DNA to give partially double-stranded rcDNA, which is packaged in the endoplasmic reticulum into a new infectious virion

Epidemiology

• Approximately 260 million chronic carriers worldwide, and 900,000 deaths annually from cirrhosis and HCC
  • Prevalence of chronic carriers is estimated at 2% of the Canadian population
• Bloodborne and sexually-transmitted, transmitted primarily by intravenous drug use drug use and sexual contact
• Genotypes vary by region and country
  • In Canada, there is a range of genotypes due to high rate of immigration, but genotypes B and C are the most common

Risk Factors for Hepatitis B Infection

• Chronic carrier within the family
• Injection drug use
• High-risk sexual activity
• Body piercing and tattooing
• History of blood transfusion
• Chronic carrier status within Canada: immigrants, Indigenous people, and stree-connected people

Risk Factors for Hepatocellular Carcinoma

• Ethnicity: Asians more than Caucasians
• Age over 40 years
• Male sex
• Immunocompromise
• Family history of HCC
• Presence of cirrhosis, conferring 2-3% risk per year
• HBV DNA >2000 IU/mL
• Elevated ALT
• Prolonged time to HBeAg seroconversion
• Genotype C
• Concurrent infection with another viral hepatitis
• Heavy alcohol use
• Non-alcoholic fatty liver disease
• Smoking

Clinical Manifestations

Acute

• 75% are asymptomatic
• 95% are self-limited
• Symptoms range from self-resolving jaundice to fulminant liver failure (in about 1%)
• Progresses to chronic in 5-10% of adults but 80-90% of neonates

Chronic

• Chronic hepatitis B begins as e antigen positive, usually with very high levels of HBV DNA and necroinflammation.
• Five phases of chronic infection:
  • Phase 1: HBeAg + chronic infection (previously immune tolerant)
    • Active viral replication including HBeAg without evidence of immune response
    • 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
  • Phase 2: HBeAg + chronic hepatitis (previously immune active)
    • Elevated liver enzymes and HBV DNA
    • HBsAg-positive, HBV DNA levels (>20,000 IU/ml), HBeAg positive, anti-HBe negative with elevated ALT
    • Anti-HBcAb-IgM can be positive
    • In perinatal infection, usually occurs in second or third decade of life
  • Phase 3: HBeAg – chronic infection (previously inactive carrier)
    • HBeAg clears and liver enzymes normalize, but ongoing low-level viral replication
    • 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
    • Staying in Phase 3 has a good prognosis
    • Can rarely (1%) clear HBsAg
  • Phase 4: HBeAg – chronic hepatitis (previously HBeAg-negative chronic hepatitis)
    • Increasing viral load with fluctuating liver enzymes
    • Can serorevert to phase 2 (HBsAg-positive)
  • Phase 5: HBsAg negative
    • HBsAb positive or negative, other studies return to normal

Phase	Old Terminology	HBsAg	HBeAg	HBV DNA	ALT
1	immune tolerant	+++	+	>107 IU/mL	normal
2	immune active	++	+	104-107 IU/mL	high
3	inactive carrier	+	–	<2000 IU/mL	normal
4	chronic hepatitis	++	–	>2000 IU/mL	high
5	resolved	–	–	<10 IU/mL	normal

Complications

• 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
• Sjögren syndrome

Diagnosis

Serology

• Standard workup is for diagnosing hepatitis B infection is HBsAg, HBsAb, HBcAb-IgG
• Surface antigen (HBs)
  • HBsAg indicates current infection, either active or chronic
    • First positive biomarker
    • Sensitivity very high and can detect down to 0.15 ng/mL, and specificity 99.5%
  • Anti-HBsAb indicates immunity, either from remote exposure (now cleared) or immunization
    • Negative in chronic infections
    • Protective level is >10 IU/mL
• Core antigen (HBc)
  • HBcAg is not routinely available. HBeAg is a splice variant.
  • Total anti-HBcAb indicates past or active natural infection
    • Does not provide evidence of immunity
    • Specificity 99.9%
  • Anti-HBcAb-IgM indicates acute infection or reactivation
  • Anti-HBcAb-IgG inferred by total antibody minus IgM, and indicates either chronic or remote infection
• Envelope antigen (HBe)
  • HBeAg indicates active viral replication and high infectivity
  • Anti-HBeAb indicates chronic infection
    • Good prognostic sign
    • Spontaneous seroconversion of 10 to 20% per year
• Window period can occur around 1 months, when HBsAg is negative but anti-HBs is not yet positive
  • Anti-HBcAb-IgM should be measured to cover this window period

Population	HBsAg	HBsAb	HBcAb-IgG	HBcAb-IgM
Susceptible	–	–	–
Vaccinated	–	+	–
Vaccinated (recently)	+	+	–	–
Natural immunity	–	+	+
Acute infection	+	–	+	+
Acute infection (window period)	–	–	–	+
Chronic infection	+	–	+	–
Past infection (resolved) Acute infection (window period) Low level chronic infection False positive (susceptible)	–	–	+

• See also:
  • CDC Viral Hepatitis Serology Training
  • CDC Interpretation of Hepatitis B Serologic Test Results

Management

Acute

• Supportive care

Chronic

• Diagnosed with HBsAg present for 6 or more 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 biopsy shows chronic hepatitis and variable necroinflammation or fibrosis
• Bloodwork should be monitored every 3 months looking at ALT and HBV DNA to assess for indications for treatment

Indications for Treatment

• The goal of treatment is to decrease the risk of cirrhosis and hepatocellular carcinoma, so is generally reserved for those at higher risk of these sequelae
  • The risk is generally higher with higher HBV-DNA and HBsAg titres, and possibly higher ALT
• The decision to treat requires consideration of patient age, viral load, HBeAg, and evidence of significant liver disease (i.e. persistent ALT elevation, fibrosis or inflammation on biopsy, or non-invasive assessment of hepatic fibrosis)
• Treatment is generally indicated when:
  • HBV DNA >2000 IU/mL and ALT is elevated for 3-6 months (regardless of HBsAg)—corresponds to phase 2 and 4, essentially
  • Evidence of significant hepatic fibrosis (even if HBV DNA <2000 IU/mL and ALT normal)
  • Cirrhosis and detectable HBV DNA
• Treatment may also be indicated for other patients with elevated HBV DNA regardless of ALT level
  • If inactive for a year (e.g. HBeAg negative, HBeAb positive, normal ALT, and HBV DNA <2000 IU/mL), then can back off to q6-12mo

Treatment Regimens

• Choose one of pegylated-interferon (48 weeks), tenofovir (until 12 months post-HBeAg conversion), or entecavir (until 12 months post-HBeAg conversion)
  • Tenofovir or entecavir are preferred for treatment-naïve patients
  • Peg-IFN contraindicated in autoimmune disorders, uncontrolled psychiatric disease, cyptopenia, severe cardiac disease, uncontrolled seizures, and decompensated cirrhosis
  • Peg-IFN preferred in lamivudine resistance
  • Peg-IFN avoided if HBeAg negative
  • Tenofovir preferred in cirrhosis, ± entecavir
  • Tenofovir is safe in pregnancy
  • Entecavir avoided in lamivudine resistance
• Duration depends on what stage is being treated
  • HBeAg-positive patients
    • Peg-IFN for 48 weeks; however, if HBsAg >20000 IU/mL at week 24 then treatment should be stopped for futility
    • Tenofovir or entecavir for at least 12 months after HBeAg seroconversion (Ag to Ab), or until HBsAg loss
  • HBeAg-negative patients, or patients with cirrhosis or HCC, tenofovir or entecavir is continued until HBsAg loss
• Continue HCC surveillance regardless of treatment

Drug	Dose	Duration
		HBeAg positive	HBeAg negative	Cirrhosis	HCC
pegylated interferon α-2a	180 μg SC weekly	48 weeks	avoid
tenofovir disoproxil fumarate	300 mg PO daily	at least 12 months after HBeAg seroconversion, or until HBsAg loss	until HBsAg loss
tenofovir alafenamide	25 mg PO daily
entecavir	0.5 mg PO daily
lamivudine	do not use
adefovir	do not use

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

Prevention

Needlestick Injury

• See Needlestick injuries and post-exposure prophylaxis

Prophylaxis in Immunosuppression

• Immunosuppression in patients with latent hepatitis B infection can lead to reactivation, which can cause:
  • Asymptomatic hepatitis B viremia and elevated ALT
  • Hepatic failure
  • Death
• Prophylaxis can prevent hepatitis B reactivation
• Current Canadian guidelines recommend risk stratifying based on type of immune suppression and serologic status2

Risk Stratification

Immunosuppression	HBsAg +	HBsAg –
		HBcAb +	HBcAb –
B-cell depleting therapy (rituximab and ofatumumab)	High risk	High risk	No risk
Anthracyclines (doxorubicin and epirubicin)	High risk	Moderate risk	No risk
Prednisone >10-20 mg/d for ≥4 weeks	High risk	Moderate risk*	No risk
Anti-TNF-α therapy (etanercept, adalimumab, certolizumab, certolizumab, infliximab)	Moderate risk*	Moderate risk*	No risk
Other cytokine or integrin inhibitors (abatacept, ustekinumab, natalizumab, vedolizumab)	Moderate risk*	Moderate risk*	No risk
Tyrosine kinase inhibitors (imatinib, nilotinib, ibrutinib)	Moderate risk*	Moderate risk*	No risk
Prednisone <10 mg/d for ≥4 weeks	Moderate risk	Low risk	No risk
Traditional immunosuppressants (azathioprine, 6-MP, methotrexate)	Low risk	Low risk	No risk
Prednisone ≤1 week	Low risk	Low risk	No risk

• * May be at lower risk if HBsAb titres are > 100 IU/L
• High risk indicates >10% risk of reactivation, moderate indicates 1-10%, and low is <1%

Prophylaxis

• Indications:
  • HBsAg positive with moderate- or high-risk immunosuppression
  • HBsAg negative with B-cell depleting therapies or haematologic or solid-organ stem cell transplant
• Lamivudine, tenofovir, or entecavir; entecavir or tenofovir are preferred for high-risk patients
• Continue until 6 months after end of chemotherapy, or until 12 months after anti-CD20 immunotherapy like rituximab
• Monitor ALT and HBV-DNA every 3 months until 12 months after stopping therapy

Monitoring

• Indicated for all other patients
• Monitor ALT q3mo and HBV DNA q6-12mo
• Continue for at least 6 months after stopping therapy
• Treat if increasing viral load

Vaccination

• See Hepatitis B vaccine

Further Reading

• Management of Hepatitis B Virus Infection: 2018 Guidelines from the Canadian Association for the Study of the Liver and Association of Medical Microbiology and Infectious Disease Canada. Can Liver J. 2018;1(4):156-217. doi: 10.3138/canlivj.2018-0008
• Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560-1599.doi: 10.1002/hep.29800
• Hepatitis B virus genotypes: Global distribution and clinical importance. World J Gastroenterol. 2014;20(18):5427–5434. doi: 10.3748/wjg.v20.i18.5427