Hepatitis B virus: Difference between revisions

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*Reverse-transcription double-stranded DNA (RT-dsDNA) virus
*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 severity[[CiteRef::sunbul2014he]]
*Genotypes A through J vary in geographic distribution and clinical severity[[CiteRef::sunbul2014he]]


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| colspan="2" |No data
| colspan="2" |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===
===Epidemiology===


*Approximately 260 million chronic carriers worldwide, and 900,000 deaths annually from [[cirrhosis]] and [[Hepatocellular carcinoma|HCC]]
*Genotypes very by location
**Prevalence of chronic carriers is estimated at 2% of the Canadian population
*In Canada, there is a range of genotypes due to high rate of immigration, but genotypes B and C are the most common
*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===
===Risk Factors for Hepatocellular Carcinoma===
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*Male sex
*Male sex
*Immunocompromise
*Immunocompromise
*Family historyof [[HCC]]
*Family history of [[HCC]]
*Presence of [[cirrhosis]], conferring 2-3% risk per year
*Presence of [[cirrhosis]], conferring 2-3% risk per year
*HBV DNA >2000 IU/mL
*HBV DNA >2000 IU/mL
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*75% are asymptomatic
*75% are asymptomatic
*95% are self-limited
*Symptoms range from self-resolving jaundice to fulminant liver failure in about 5%
*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===
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==Diagnosis==
==Diagnosis==


=== Serology ===
===Serology===


*Standard workup is for diagnosing [[Hepatitis B virus|hepatitis B]] infection is HBsAg, HBsAb, HBcAb-IgG
*Standard workup is for diagnosing [[Hepatitis B virus|hepatitis B]] infection is HBsAg, HBsAb, HBcAb-IgG
*'''Surface antigen (HBs)'''
*'''Surface antigen (HBs)'''
**HBsAg indicates current infection, either active or chronic. First positive biomarker.
**'''HBsAg''' indicates current infection, either active or chronic
***First positive biomarker
**HBsAb indicates immunity, either from remote exposure (now cleared) or immunization. Negative in chronic infections.
***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)'''
*'''Core antigen (HBc)'''
**HBcAg is not routinely available. HBeAg is a splice variant.
**HBcAg is not routinely available. HBeAg is a splice variant.
**HBcAb-IgM indicates acute infection or reactivation
**Total anti-HBcAb indicates past or active natural infection
***Does not provide evidence of immunity
**HBcAb-IgG indicates either chronic or remote infection
***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)'''
*'''Envelope antigen (HBe)'''
**HBeAg indicates active viral replication and high infectivity
**HBeAg indicates active viral replication and high infectivity
**HBeAb indicates chronic infection
**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
*'''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
**Anti-HBcAb-IgM should be measured to cover this window period
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|Past infection (resolved)
|Past infection (resolved)
Acute infection (window period)
Acute infection (window period)

Low level chronic infection
Low level chronic infection

False positive (susceptible)
False positive (susceptible)
| align="center" |–
| align="center" |–
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|}
|}


* See also:
*See also:
**[https://www.cdc.gov/hepatitis/resources/professionals/training/serology/training.htm CDC Viral Hepatitis Serology Training]
**[https://www.cdc.gov/hepatitis/resources/professionals/training/serology/training.htm CDC Viral Hepatitis Serology Training]
**[https://www.cdc.gov/hepatitis/hbv/pdfs/serologicchartv8.pdf CDC Interpretation of Hepatitis B Serologic Test Results]
**[https://www.cdc.gov/hepatitis/hbv/pdfs/serologicchartv8.pdf CDC Interpretation of Hepatitis B Serologic Test Results]
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====Indications for Treatment====
====Indications for Treatment====


*The goal of treatment is to decrease the risk of cirrhosis and hepaticellular carcinoma, so is generally reserved for those at higher risk of these sequelae
*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 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)
*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)
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*First-line is ultrasound every 6 months
*First-line is ultrasound every 6 months
*Second-line is AFP levels every 6 months
*Second-line is AFP levels every 6 months

=Prevention=

=== Needlestick Injury ===

* See [[Needlestick injuries and post-exposure prophylaxis]]


===Prophylaxis in Immunosuppression===
===Prophylaxis in Immunosuppression===


*Immunosuppression in patients with latent hepatitis B infection can lead to reactivation, which can cause:
*Risk stratify based on type of immune suppression and serologic status
**Asymptomatic hepatitis B viremia and elevated ALT
**'''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 β‰₯4 weeks
**'''Moderate-risk''' (1-10%)
***HBsAg positive, or HBsAg negative but HBcAb positive, plus TNF-Ξ± 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 β‰₯4 weeks
***HBsAg negative but HBcAb positive: prednisone >10-20 mg/day for β‰₯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 β‰₯4 weeks
*Concern especially with chronic steroids and rituximab
*Can have the following effects
**Asymptomatic HBV DNA and ALT
**Hepatic failure
**Hepatic failure
**Death
**Death
*Prophylaxis can prevent hepatitis B reactivation
*If β‰₯7.5mg/d should be screened
*Current Canadian guidelines recommend risk stratifying based on type of immune suppression and serologic status[[CiteRef::coffin2018ma]]
**HBsAg +/- HBcAb if they're adding a second agent (rituximab, TNF-alpha inhibitors, or other)

**Refer to Hepatology or Infectious Diseases
==== Risk Stratification ====
*Prophylaxis with lamivudine until 6 months after chemotherapy
{| class="wikitable"
! rowspan="2" |Immunosuppression
! rowspan="2" |HBsAg +
! colspan="2" |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 β‰₯4 weeks
|High risk
|Moderate risk*
|No risk
|-
|Anti-TNF-Ξ± 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 β‰₯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==
==Further Reading==

Latest revision as of 18:03, 6 August 2024

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-Ξ± 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

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

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)

– – +

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)β€”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-naΓ―ve 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, Β± 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 Ξ±-2a 180 ΞΌg 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

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 β‰₯4 weeks High risk Moderate risk* No risk
Anti-TNF-Ξ± 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 β‰₯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

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

  1. ^  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.

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