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 |
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+ | *Genome encodes seven proteins: |
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β | *Genotypes A through J vary in geographic distribution and clinical severity |
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+ | **Surface proteins (large, middle, and small) which form the envelope or surface antigen (HBsAg) |
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+ | **Nucleocapsid core or C protein (HBcAg) |
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+ | **Secretory envelope antigen (HBeAg) |
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+ | **Viral reverse transcriptase or polymerase |
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+ | **X protein |
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+ | *Genotypes A through J vary in geographic distribution and clinical severity[[CiteRef::sunbul2014he]] |
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{| class="wikitable" |
{| class="wikitable" |
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β | !Genotype!! |
+ | !Genotype!!A!!B!!C!!D!!E-J |
|- |
|- |
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! colspan="6" |Clinical characteristics |
! colspan="6" |Clinical characteristics |
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|- |
|- |
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|Modes of transmission |
|Modes of transmission |
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+ | |Horizontal |
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|Perinatal/vertical |
|Perinatal/vertical |
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|Perinatal/vertical |
|Perinatal/vertical |
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β | |Horizontal |
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|Horizontal |
|Horizontal |
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|Horizontal |
|Horizontal |
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|- |
|- |
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|Tendency of chronicity |
|Tendency of chronicity |
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+ | |Higher |
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|Lower |
|Lower |
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β | |Higher |
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|Higher |
|Higher |
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|Lower |
|Lower |
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|- |
|- |
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|HBeAg positivity |
|HBeAg positivity |
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+ | |Higher |
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|Lower |
|Lower |
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β | |Higher |
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|Higher |
|Higher |
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|Lower |
|Lower |
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|HBeAg seroconversion |
|HBeAg seroconversion |
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|Earlier |
|Earlier |
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β | |Later |
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|Earlier |
|Earlier |
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+ | |Later |
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|Later |
|Later |
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|No data |
|No data |
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|HBsAg seroclearance |
|HBsAg seroclearance |
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|More |
|More |
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β | |Less |
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|More |
|More |
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+ | |Less |
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|Less |
|Less |
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|No data |
|No data |
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|Histological activity |
|Histological activity |
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|Lower |
|Lower |
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β | |Higher |
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|Lower |
|Lower |
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+ | |Higher |
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|Higher |
|Higher |
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|No data |
|No data |
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|Response to interferon-Ξ± |
|Response to interferon-Ξ± |
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|Higher |
|Higher |
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β | |Lower |
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|Higher |
|Higher |
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+ | |Lower |
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|Lower |
|Lower |
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|Lower in G |
|Lower in G |
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|- |
|- |
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|Viral load |
|Viral load |
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+ | |No data |
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|Lower |
|Lower |
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|Higher |
|Higher |
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β | | colspan=" |
+ | | colspan="2" |No data |
|- |
|- |
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|Frequency of PC A1896 mutation |
|Frequency of PC A1896 mutation |
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β | |Higher |
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|Lower |
|Lower |
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+ | |Higher |
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|Lower |
|Lower |
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|Higher |
|Higher |
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|- |
|- |
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|Frequency of basal core promoter T1762/A1764 mutation |
|Frequency of basal core promoter T1762/A1764 mutation |
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+ | |Higher |
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|Lower |
|Lower |
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β | |Higher |
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|Higher |
|Higher |
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|Lower |
|Lower |
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|- |
|- |
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|Frequency of preS deletion utation |
|Frequency of preS deletion utation |
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+ | |No data |
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|Lower |
|Lower |
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|Higher |
|Higher |
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β | | colspan=" |
+ | | colspan="2" |No data |
|} |
|} |
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+ | ===Pathophysiology=== |
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β | ===Phases of Chronic Infection=== |
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+ | |||
+ | *Virion binds its receptor, NTCP, on the hepatocyte cell membrane |
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+ | *Nucleocapsid is released into cytosol and transported to the nucleus |
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+ | **Occasionally integrates into host genome around this stage |
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+ | *Relaxed circular DNA (rcDNA) is converted into covalently closed circular DNA (cccDNA) |
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+ | *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 |
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+ | |||
+ | ===Epidemiology=== |
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+ | |||
+ | *Approximately 260 million chronic carriers worldwide, and 900,000 deaths annually from [[cirrhosis]] and [[Hepatocellular carcinoma|HCC]] |
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+ | **Prevalence of chronic carriers is estimated at 2% of the Canadian population |
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+ | *Bloodborne and sexually-transmitted, transmitted primarily by intravenous drug use drug use and sexual contact |
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+ | *Genotypes vary by region and country |
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+ | **In Canada, there is a range of genotypes due to high rate of immigration, but genotypes B and C are the most common |
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+ | |||
+ | ===Risk Factors for Hepatitis B Infection=== |
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+ | |||
+ | *Chronic carrier within the family |
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+ | *Injection drug use |
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+ | *High-risk sexual activity |
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+ | *Body piercing and tattooing |
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+ | *History of blood transfusion |
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+ | *Chronic carrier status within Canada: immigrants, Indigenous people, and stree-connected people |
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+ | |||
+ | ===Risk Factors for Hepatocellular Carcinoma=== |
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+ | *Ethnicity: Asians more than Caucasians |
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β | *'''Phase 1:''' HBeAg + chronic infection (previously immune tolerant) |
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+ | *Age over 40 years |
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β | **Viral replication including HBeAg without evidence of immune response |
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+ | *Male sex |
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β | *'''Phase 2:''' HBeAg + chronic hepatitis (previously immune active) |
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+ | *Immunocompromise |
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β | **Elevated liver enzymes and HBV DNA |
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+ | *Family history of [[HCC]] |
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β | *'''Phase 3:''' HBeAg β chronic infection (previously inactive carrier) |
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+ | *Presence of [[cirrhosis]], conferring 2-3% risk per year |
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β | **HBeAg clears and liver enzymes normalize, but ongoing low-level viral replication |
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+ | *HBV DNA >2000 IU/mL |
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β | *'''Phase 4:''' HBeAg β chronic hepatitis (previously HBeAg-negative chronic hepatitis) |
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+ | *Elevated ALT |
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β | **Increasing viral load with fluctuating liver enzymes |
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+ | *Prolonged time to HBeAg seroconversion |
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β | *'''Phase 5:''' HBsAg negative |
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+ | *Genotype C |
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β | **HBsAb positive or negative, other studies return to normal |
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+ | *Concurrent infection with another [[viral hepatitis]] |
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+ | *[[Alcohol use disorder|Heavy alcohol use]] |
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+ | *[[Non-alcoholic fatty liver disease]] |
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+ | *[[Nicotine use disorder|Smoking]] |
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==Clinical Manifestations== |
==Clinical Manifestations== |
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*75% are asymptomatic |
*75% are asymptomatic |
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+ | *95% are self-limited |
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β | *Symptoms range from self-resolving jaundice to fulminant liver failure in about 5% |
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+ | *Symptoms range from self-resolving jaundice to fulminant liver failure (in about 1%) |
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+ | *Progresses to chronic in 5-10% of adults but 80-90% of neonates |
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===Chronic=== |
===Chronic=== |
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*Chronic hepatitis B begins as e antigen positive, usually with very high levels of HBV DNA and necroinflammation. |
*Chronic hepatitis B begins as e antigen positive, usually with very high levels of HBV DNA and necroinflammation. |
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β | * |
+ | *Five phases of chronic infection: |
+ | **'''Phase 1:''' HBeAg + chronic infection (previously immune tolerant) |
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β | **'''Immunotolerant''' hepatitis B: HBV DNA levels (>20,000 IU/ml), HBeAg positive, with normal ALT |
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+ | ***Active viral replication including HBeAg without evidence of immune response |
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+ | ***HBV DNA levels (>20,000 IU/ml), HBeAg positive, with normal ALT |
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***Common after vertical transmission and can persist for years before progressing to another form |
***Common after vertical transmission and can persist for years before progressing to another form |
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+ | **'''Phase 2:''' HBeAg + chronic hepatitis (previously immune active) |
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β | **'''HBeAg-positive immune-active''' chronic hepatitis B: HBsAg-positive, HBV DNA levels (>20,000 IU/ml), HBeAg positive, anti-HBe negative with elevated ALT |
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+ | ***Elevated liver enzymes and HBV DNA |
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β | **'''HBeAg-negative immune-active''' chronic hepatitis B: HBsAg-positive, HBV DNA levels (<20,000 IU/ml), HBeAg negative, anti-HBe positive, with elevated ALT |
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+ | ***HBsAg-positive, HBV DNA levels (>20,000 IU/ml), HBeAg positive, anti-HBe negative with elevated ALT |
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+ | ***Anti-HBcAb-IgM can be positive |
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+ | ***In perinatal infection, usually occurs in second or third decade of life |
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+ | **'''Phase 3:''' HBeAg β chronic infection (previously inactive carrier) |
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+ | ***HBeAg clears and liver enzymes normalize, but ongoing low-level viral replication |
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+ | ***HBsAg-positive, HBV DNA levels (<20,000 IU/ml), HBeAg negative, anti-HBe positive, with elevated ALT |
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***Results from anti-HBe seroconversion when a mutation decreases HBeAg expression |
***Results from anti-HBe seroconversion when a mutation decreases HBeAg expression |
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+ | ***Staying in Phase 3 has a good prognosis |
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β | **'''Inactive hepatitis B''' (healthy carrier): HBsAg for > 6 months without any evidence of necroinflammation and HBV DNA levels are < 2,000 IU/m |
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+ | ***Can rarely (1%) clear HBsAg |
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β | ***May still transmit it, but overall a better prognosis |
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β | *''' |
+ | **'''Phase 4:''' HBeAg β chronic hepatitis (previously HBeAg-negative chronic hepatitis) |
+ | ***Increasing viral load with fluctuating liver enzymes |
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β | *'''Polyarteritis nodosa''' |
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+ | ***Can serorevert to phase 2 (HBsAg-positive) |
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β | *'''Membranous nephropathy''' or '''membranoproliferative glomerulonephritis''' |
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+ | **'''Phase 5:''' HBsAg negative |
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β | *Sensorimotor neuropathy |
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+ | ***HBsAb positive or negative, other studies return to normal |
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β | *Sjogren syndrome |
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+ | {| class="wikitable" |
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β | ==Investigations== |
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+ | !Phase |
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+ | !Old Terminology |
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+ | !HBsAg |
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+ | !HBeAg |
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+ | !HBV DNA |
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+ | !ALT |
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+ | |- |
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+ | |1 |
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+ | |immune tolerant |
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+ | | +++ |
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+ | | + |
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+ | |>10<sup>7</sup> IU/mL |
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+ | |normal |
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+ | |- |
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+ | |2 |
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+ | |immune active |
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+ | | ++ |
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+ | | + |
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+ | |10<sup>4</sup>-10<sup>7</sup> IU/mL |
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+ | |high |
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+ | |- |
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+ | |3 |
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+ | |inactive carrier |
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+ | | + |
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+ | |β |
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+ | |<2000 IU/mL |
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+ | |normal |
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+ | |- |
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+ | |4 |
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+ | |chronic hepatitis |
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+ | | ++ |
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+ | |β |
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+ | |>2000 IU/mL |
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+ | |high |
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+ | |- |
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+ | |5 |
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+ | |resolved |
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+ | |β |
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+ | |β |
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+ | |<10 IU/mL |
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+ | |normal |
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+ | |} |
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+ | ====Complications==== |
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+ | |||
+ | *[[Hepatocellular carcinoma]] is a risk in chronic hepatitis B, but especially in certain populations including cirrhosis |
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+ | *[[Polyarteritis nodosa]] |
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+ | *[[Membranous nephropathy]] or [[membranoproliferative glomerulonephritis]] |
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+ | *[[Sensorimotor neuropathy]] |
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+ | *[[SjΓΆgren syndrome]] |
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+ | |||
+ | ==Diagnosis== |
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+ | |||
+ | ===Serology=== |
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+ | |||
+ | *Standard workup is for diagnosing [[Hepatitis B virus|hepatitis B]] infection is HBsAg, HBsAb, HBcAb-IgG |
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+ | *'''Surface antigen (HBs)''' |
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+ | **'''HBsAg''' indicates current infection, either active or chronic |
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+ | ***First positive biomarker |
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+ | ***Sensitivity very high and can detect down to 0.15 ng/mL, and specificity 99.5% |
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+ | **'''Anti-HBsAb''' indicates immunity, either from remote exposure (now cleared) or immunization |
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+ | ***Negative in chronic infections |
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+ | ***Protective level is >10 IU/mL |
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+ | *'''Core antigen (HBc)''' |
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+ | **HBcAg is not routinely available. HBeAg is a splice variant. |
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+ | **Total anti-HBcAb indicates past or active natural infection |
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+ | ***Does not provide evidence of immunity |
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+ | ***Specificity 99.9% |
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+ | **Anti-HBcAb-IgM indicates acute infection or reactivation |
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+ | **Anti-HBcAb-IgG inferred by total antibody minus IgM, and indicates either chronic or remote infection |
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+ | *'''Envelope antigen (HBe)''' |
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+ | **HBeAg indicates active viral replication and high infectivity |
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+ | **Anti-HBeAb indicates chronic infection |
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+ | ***Good prognostic sign |
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+ | ***Spontaneous seroconversion of 10 to 20% per year |
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+ | *'''Window period''' can occur around 1 months, when HBsAg is negative but anti-HBs is not yet positive |
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+ | **Anti-HBcAb-IgM should be measured to cover this window period |
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+ | |||
+ | {| class="wikitable sortable" |
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+ | !Population |
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+ | ! align="center" |HBsAg |
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+ | ! align="center" |HBsAb |
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+ | ! align="center" |HBcAb-IgG |
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+ | ! align="center" |HBcAb-IgM |
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+ | |- |
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+ | |Susceptible |
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+ | | align="center" |β |
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+ | | align="center" |β |
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+ | | align="center" |β |
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+ | | align="center" | |
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+ | |- |
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+ | |Vaccinated |
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+ | | align="center" |β |
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+ | | align="center" | + |
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+ | | align="center" |β |
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+ | | align="center" | |
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+ | |- |
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+ | |Vaccinated (recently) |
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+ | | align="center" | + |
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+ | | align="center" | + |
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+ | | align="center" |β |
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+ | | align="center" |β |
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+ | |- |
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+ | |Natural immunity |
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+ | | align="center" |β |
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+ | | align="center" | + |
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+ | | align="center" | + |
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+ | | align="center" | |
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+ | |- |
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+ | |Acute infection |
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+ | | align="center" | + |
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+ | | align="center" |β |
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+ | | align="center" | + |
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+ | | align="center" | + |
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+ | |- |
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+ | |Acute infection (window period) |
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+ | | align="center" |β |
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+ | | align="center" |β |
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+ | | align="center" |β |
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+ | | align="center" | + |
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+ | |- |
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+ | |Chronic infection |
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+ | | align="center" | + |
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+ | | align="center" |β |
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+ | | align="center" | + |
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+ | | align="center" |β |
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+ | |- |
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+ | |Past infection (resolved) |
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+ | Acute infection (window period) |
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+ | |||
+ | Low level chronic infection |
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+ | |||
+ | False positive (susceptible) |
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+ | | align="center" |β |
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+ | | align="center" |β |
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+ | | colspan="2" align="center" | + |
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+ | |} |
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+ | *See also: |
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β | *[[Hepatitis B serology]] |
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+ | **[https://www.cdc.gov/hepatitis/resources/professionals/training/serology/training.htm CDC Viral Hepatitis Serology Training] |
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+ | **[https://www.cdc.gov/hepatitis/hbv/pdfs/serologicchartv8.pdf CDC Interpretation of Hepatitis B Serologic Test Results] |
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==Management== |
==Management== |
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*Bloodwork should be monitored every 3 months looking at ALT and HBV DNA to assess for indications for treatment |
*Bloodwork should be monitored every 3 months looking at ALT and HBV DNA to assess for indications for treatment |
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β | ==== |
+ | ====Indications for Treatment==== |
β | *The goal of treatment is to decrease the risk of cirrhosis and |
+ | *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 |
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*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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*Treatment is generally indicated when: |
*Treatment is generally indicated when: |
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β | **HBV DNA >2000 IU/mL and ALT is elevated for 3-6 months (regardless of HBsAg) |
+ | **HBV DNA >2000 IU/mL and ALT is elevated for 3-6 months (regardless of HBsAg)βcorresponds to phase 2 and 4, essentially |
**Evidence of significant hepatic fibrosis (even if HBV DNA <2000 IU/mL and ALT normal) |
**Evidence of significant hepatic fibrosis (even if HBV DNA <2000 IU/mL and ALT normal) |
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**Cirrhosis and detectable HBV DNA |
**Cirrhosis and detectable HBV DNA |
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*If ALT rises, check HBV-DNA and HBsAg for activity |
*If ALT rises, check HBV-DNA and HBsAg for activity |
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β | ====HCC |
+ | ====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) |
*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) |
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*First-line is ultrasound every 6 months |
*First-line is ultrasound every 6 months |
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*Second-line is AFP levels every 6 months |
*Second-line is AFP levels every 6 months |
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+ | |||
+ | =Prevention= |
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+ | |||
+ | === Needlestick Injury === |
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+ | |||
+ | * See [[Needlestick injuries and post-exposure prophylaxis]] |
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===Prophylaxis in Immunosuppression=== |
===Prophylaxis in Immunosuppression=== |
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+ | *Immunosuppression in patients with latent hepatitis B infection can lead to reactivation, which can cause: |
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β | *Risk stratify based on type of immune suppression and serologic status |
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+ | **Asymptomatic hepatitis B viremia and elevated ALT |
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β | **'''High-risk''' (>10%): |
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β | ***HBsAg positive, or HBsAg negative but HBcAb positive, plus B-cell depletion such as rituximab and ofatumumab |
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β | ***HBsAg positive, plus anthracyclines (doxorubicin, epirubicin), prednisone >10-20 mg/day for β₯4 weeks |
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β | **'''Moderate-risk''' (1-10%) |
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β | ***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) |
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β | ***HBsAg positive: prednisone <10 mg/day for β₯4 weeks |
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β | ***HBsAg negative but HBcAb positive: prednisone >10-20 mg/day for β₯4 weeks, antracycline derivatives (doxorubicin and epirubicin) |
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β | **'''Low-risk''' (<1%) |
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β | ***HBsAg positive, or HBsAg negative but HBcAb positive, plus traditional immunosuppressants (azathioprine, 6-MP, methotrexate) |
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β | ***HBsAg negative or HBcAb positive, plus prednisone <10 mg/day for β₯4 weeks |
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β | *Concern especially with chronic steroids and rituximab |
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β | *Can have the following effects |
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β | **Asymptomatic HBV DNA and ALT |
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**Hepatic failure |
**Hepatic failure |
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**Death |
**Death |
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+ | *Prophylaxis can prevent hepatitis B reactivation |
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β | *If β₯7.5mg/d should be screened |
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+ | *Current Canadian guidelines recommend risk stratifying based on type of immune suppression and serologic status[[CiteRef::coffin2018ma]] |
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β | **HBsAg +/- HBcAb if they're adding a second agent (rituximab, TNF-alpha inhibitors, or other) |
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+ | |||
β | **Refer to Hepatology or Infectious Diseases |
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+ | ==== Risk Stratification ==== |
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β | *Prophylaxis with lamivudine until 6 months after chemotherapy |
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+ | {| class="wikitable" |
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+ | ! rowspan="2" |Immunosuppression |
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+ | ! rowspan="2" |HBsAg + |
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+ | ! colspan="2" |HBsAg β |
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+ | |- |
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+ | !HBcAb + |
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+ | !HBcAb β |
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+ | |- |
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+ | |B-cell depleting therapy ([[rituximab]] and [[ofatumumab]]) |
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+ | |High risk |
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+ | |High risk |
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+ | |No risk |
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+ | |- |
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+ | |Anthracyclines ([[doxorubicin]] and [[epirubicin]]) |
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+ | |High risk |
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+ | |Moderate risk |
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+ | |No risk |
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+ | |- |
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+ | |[[Prednisone]] >10-20 mg/d for β₯4 weeks |
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+ | |High risk |
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+ | |Moderate risk* |
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+ | |No risk |
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+ | |- |
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+ | |Anti-TNF-Ξ± therapy ([[etanercept]], [[adalimumab]], [[certolizumab]], [[certolizumab]], [[infliximab]]) |
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+ | |Moderate risk* |
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+ | |Moderate risk* |
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+ | |No risk |
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+ | |- |
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+ | |Other cytokine or integrin inhibitors ([[abatacept]], [[ustekinumab]], [[natalizumab]], [[vedolizumab]]) |
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+ | |Moderate risk* |
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+ | |Moderate risk* |
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+ | |No risk |
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+ | |- |
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+ | |Tyrosine kinase inhibitors ([[imatinib]], [[nilotinib]], [[ibrutinib]]) |
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+ | |Moderate risk* |
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+ | |Moderate risk* |
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+ | |No risk |
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+ | |- |
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+ | |[[Prednisone]] <10 mg/d for β₯4 weeks |
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+ | |Moderate risk |
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+ | |Low risk |
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+ | |No risk |
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+ | |- |
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+ | |Traditional immunosuppressants ([[azathioprine]], [[6-MP]], [[methotrexate]]) |
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+ | |Low risk |
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+ | |Low risk |
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+ | |No risk |
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+ | |- |
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+ | |[[Prednisone]] β€1 week |
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+ | |Low risk |
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+ | |Low risk |
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+ | |No risk |
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+ | |} |
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+ | |||
+ | * * May be at lower risk if HBsAb titres are > 100 IU/L |
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+ | *High risk indicates >10% risk of reactivation, moderate indicates 1-10%, and low is <1% |
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+ | |||
+ | ==== Prophylaxis ==== |
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+ | *Indications: |
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+ | **HBsAg positive with moderate- or high-risk immunosuppression |
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+ | **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== |
||
+ | *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: [https://doi.org/10.3138/canlivj.2018-0008 10.3138/canlivj.2018-0008] |
||
β | *[https://doi.org/10.1002/hep.29800 Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance] |
||
+ | *Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. ''Hepatol''ogy. 2018;67(4):1560-1599.doi: [https://doi.org/10.1002/hep.29800 10.1002/hep.29800] |
||
*Hepatitis B virus genotypes: Global distribution and clinical importance. ''World J Gastroenterol''. 2014;20(18):5427β5434. doi: [https://doi.org/10.3748/wjg.v20.i18.5427 10.3748/wjg.v20.i18.5427] |
*Hepatitis B virus genotypes: Global distribution and clinical importance. ''World J Gastroenterol''. 2014;20(18):5427β5434. doi: [https://doi.org/10.3748/wjg.v20.i18.5427 10.3748/wjg.v20.i18.5427] |
||
Latest revision as of 14:03, 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
- 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 β 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 β 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 | + | β | <2000 IU/mL | normal |
4 | chronic hepatitis | ++ | β | >2000 IU/mL | high |
5 | resolved | β | β | <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
- SjΓΆgren 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 | β | β | β | |
Vaccinated | β | + | β | |
Vaccinated (recently) | + | + | β | β |
Natural immunity | β | + | + | |
Acute infection | + | β | + | + |
Acute infection (window period) | β | β | β | + |
Chronic infection | + | β | + | β |
Past infection (resolved)
Acute infection (window period) Low level chronic infection False positive (susceptible) |
β | β | + |
- 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)βcorresponds 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
- 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 β | |
---|---|---|---|
HBcAb + | HBcAb β | ||
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 β€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):5427β5434. 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.
- ^ Carla S. Coffin, Scott K. Fung, Fernando Alvarez, Curtis L. Cooper, Karen E. Doucette, Claire Fournier, Erin Kelly, Hin Hin Ko, Mang M Ma, Steven R Martin, Carla Osiowy, Alnoor Ramji, Edward Tam, Jean Pierre Villeneuve. Management of Hepatitis B Virus Infection: 2018 Guidelines from the Canadian Association for the Study of Liver Disease and Association of Medical Microbiology and Infectious Disease Canada. Canadian Liver Journal. 2018;1(4):156-217. doi:10.3138/canlivj.2018-0008.