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 1: HBeAg + chronic infection (previously immune tolerant)
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
- HBsAg indicates current infection, either active or chronic
- 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:
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
- 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
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
- 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, anthracycline 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
- High-risk (>10%):
- Prophylaxis is indicated for high- and moderate-risk patients
- Lamivudine, tenofovir, or entecavir
- Continue until 6 months after end of chemotherapy, or until 12 months after anti-CD20 immunotherapy like rituximab
- Monitoring is indicated for low-risk patients
- Monitor HBV-DNA and liver enzymes every 1 to 3 months until 6 months after end of chemotherapy
Prevention
Vaccination
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
References
- ^ Mustafa Sunbul. Hepatitis B virus genotypes: Global distribution and clinical importance. World Journal of Gastroenterology. 2014;20(18):5427. doi:10.3748/wjg.v20.i18.5427.