Condition

Acute Hepatitis B Virus (HBV) Infection

Editors: Sandeep Mukherjee MD, MPH, FRCPC; Zbigniew Fedorowicz PhD, MSc, DPH, BDS, LDSRCS; Paritosh Prasad MD

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Background Information

Description

  • Acute infection with HBV is often asymptomatic, but may present with constitutional symptoms such as fatigue, fever, and poor appetite as well as nausea, vomiting, abdominal pain, dark urine, changes in stool color, or jaundice.,
  • Usually acute HBV infection is self-limiting in immunocompetent adults, with spontaneous recovery in 95%, but it may lead to chronic HBV infection, especially in infants and young children.,

Definitions

  • Centers for Disease Control and Prevention (CDC) 2012 case definitions:
    • Acute hepatitis B:
      • Clinical case definition requires both of:
        • Acute illness with a discrete onset of any sign or symptom consistent with acute viral hepatitis (such as fever, headache, malaise, anorexia, nausea, vomiting, diarrhea, and abdominal pain) AND
        • Jaundice or elevated serum alanine aminotransferase (ALT) levels > 100 units/L
      • Laboratory criteria for diagnosis requires both of:
        • Positive result for hepatitis B surface antigen (HBsAg)
        • Positive result for IgM antibody to hepatitis B core antigen (IgM anti-HBc) (if done)
      • A confirmed case of acute hepatitis B is a person who meets the clinical case definition, is laboratory-confirmed, and is not known to have chronic hepatitis B.
      • Reference - CDC Case Definition 2012 Jan
    • Chronic hepatitis B: (see alsoChronic Hepatitis B Virus (HBV) Infection)
      • Clinical description:
        • No symptom required
        • Patient may have no evidence of liver disease, or may have a spectrum of disease ranging from chronic hepatitis to cirrhosis or liver cancer
      • Laboratory criteria for diagnosis requires either of:
        • Negative result for IgM anti-HBc plus positive result for any of:
          • HBsAg
          • Hepatitis B e antigen (HBeAg)
          • Hepatitis B virus (HBV) DNA
        • 2 positive tests at least 6 months apart for any combination of HBsAg, HBV DNA, or HBeAg
      • A probable case of chronic hepatitis B is a persons with single positive result for HBsAg, HBV DNA, or HBeAg and who does not meeting the case definition for acute hepatitis B.
      • A confirmed case of chronic hepatitis B is a person meeting either of the above laboratory criteria for diagnosis.
      • Reference - CDC Case Definition 2012 Jan
  • National Institute of Health consensus definition of clinical terms:
    • Chronic hepatitis B: a chronic necroinflammatory disease of the liver caused by persistent infection with HBV, subdivided into HBeAg-positive and HBeAg-negative
    • Inactive HBsAg carrier state: a persistent HBV infection of liver without significant, ongoing necroinflammatory disease.
    • Resolved hepatitis B: a previous HBV infection without further virologic, biochemical, or histological evidence of active virus infection or disease.
    • Acute exacerbation or flare: intermittent elevations of aminotransferase activity to > 10 times the upper limit of normal and more than twice the baseline value.
    • Reactivation of hepatitis B: reappearance of active necroinflammatory disease of the liver in a person known to have inactive HBsAg carrier state or resolved hepatitis B.
    • HBeAg clearance: loss of HBeAg in a person who was previously HBeAg-positive.
    • HBeAg seroconversion: loss of HBeAg and a detection of anti-HBe in a person who was previously HBeAg-positive and anti-HBe-negative.
    • HBeAg reversion: reappearance of HBeAg in a person who was previously HBeAg negative, anti-HBe positive.
    • References - Hepatology 2007 Apr;45(4):1056, Gastroenterology 2001 Jun;120(7):1828

Epidemiology

Geographic Distribution

  • Distribution is global, with significant disease burden in:
    • Asia
    • Pacific Islands
    • sub-Saharan Africa
    • Amazon Basin
    • Middle East
Global prevalence of hepatitis B virus infection

Image 1 of 5

Global prevalence of hepatitis B virus infection

Incidence/Prevalence

  • Actual incidence of acute HBV infection is unclear due to a lack of diagnosis.,
    • About 30% of the world's population has serological evidence of current or past HBV infection.
    • 2 billion people are estimated to have been infected, with > 350 million chronically infected.
  • In the United States:
    • 2,126 cases of acute HBV infections (0.6 cases per 100,000 population) were reported in the United States in 2022.
      • Estimated number of infection was 13,800 cases.
      • 13 cases of vertical HBV infection were reported.
      • Incidence was highest among non-Hispanic Black persons at 1 case per 100,000 population compared to groups of other races and ethnicity.
      • Hospitalization rate was 58% among 1,340 patients with acute HBV infection with available data.
      • Reference - CDC 2022 Viral Hepatitis Surveillance Report CDC 2024 Apr 3
    • A rise in incidents of HBV infection has been reported in the United States among persons who use injection drugs in the states of Kentucky, Tennessee, and West Virginia.
      • 3,305 cases of acute HBV infection were reported from Kentucky, Tennessee, and West Virginia between 2006 and 2013.
      • Incidence in these 3 states increased 114% from 2009 to 2013.
      • Among patients with ≥ 1 risk factor, injection drug use was reported in 75% of the patients during 2010-2013 vs. 53% of the patients during 2006-2009 (p < 0.001).
      • Reference - MMWR Morb Mortal Wkly Rep 2016 Jan 29;65(3):47
    • STUDY SUMMARY
      estimated 18,730 cases of acute HBV infection in United States in 2011
      META-ANALYSIS: Am J Public Health 2014 Mar;104(3):482

    • STUDY SUMMARY
      5.7% prevalence of HBV infection in resettled refugees in United States from 2006 to 2011
      COHORT STUDY: MMWR Morb Mortal Wkly Rep 2015 Jun 5;64(21):570

Risk Factors

  • Groups at increased risk for HBV infection:,
    • Persons born in areas of high or intermediate prevalence rates for HBV
    • Persons not vaccinated as infants whose parents were born in regions with high HBV endemicity
    • Household and sexual contacts of hepatitis B surface antigen-positive patients
    • Persons who inject drugs
    • Persons with multiple sexual partners or history of sexually transmitted disease
    • Men who have sex with men
    • Inmates at correctional facilities
    • Patients infected with hepatitis C virus or HIV
    • Patients having renal dialysis
    • Pregnant persons
    • Patients on immunosuppressive therapy

Associated Conditions

  • HIV infection:
    • An estimated 5%-20% of patients with HIV have HBV coinfection worldwide, with risk varying by region and risk group (Gastroenterol Hepatol (N Y) 2014 Dec;10(12):780).
    • PubMed27524946Gastroenterology & hepatologyGastroenterol Hepatol (N Y)201412011012780-8780An estimated 2-4 million persons have HIV/HBV coinfection (Gastroenterol Hepatol (N Y) 2014 Dec;10(12):780).
    • Clinical presentation of acute HBV infection in patients with HIV coinfection is similar to presentation in patients with HBV monoinfection, although the risk of progression to chronic HBV infection is increased (HIVinfo 2024 Jan 10).
  • Hepatitis C virus infection (HCV):
    • STUDY SUMMARY
      1.4% of patients with hepatitis C may be coinfected with HBV
      COHORT STUDY: Hepatology 2013 Aug;58(2):538

  • Hepatitis D infection (HDV):
    • STUDY SUMMARY
      8% of patients with chronic HBV also infected with HDV in Northern California, United States
      COHORT STUDY: J Gastroenterol Hepatol 2013 Sep;28(9):1521

    • STUDY SUMMARY
      50% of injection drug users may be coinfected with chronic HBV and HDV in Baltimore, Maryland
      CROSS-SECTIONAL STUDY: J Infect Dis 2010 Sep 15;202(6):845

Etiology and Pathogenesis

Pathogen

Classification
  • Hepatitis B virus (HBV) is the prototype virus of the Hepadnaviridae family.
  • Infectious HBV virion (Dane particle) is a spherical, double-shelled structure 40nm-42 nm in diameter.
    • The outer lipid envelope contains hepatitis B surface antigen (HBsAg).
    • The inner nucleocapsid is comprised of hepatitis B core antigen (HBcAg) which contains the virally encoded polymerase, and the viral DNA genome.
Hepatitis B virus capsid

Image 2 of 5

Hepatitis B virus capsid

Molecular model showing icosahedral virus capsid formed by four capsid proteins.

  • The HBV genome consists of a partially double-stranded circular DNA molecule of approximately 3.2 kilobase pairs that encodes 4 partially overlapping open-reading frames (ORF).
    • Pre-S/S ORF encodes 3 viral surface proteins which correspond to HBsAg.
    • Pre-C/C ORF encodes the core antigen (HBcAg) and the soluble antigen e (HBeAg).
    • P ORF encodes the terminal protein and the viral polymerase that possesses DNA polymerase, reverse transcriptase, and RNaseH activities.
    • X ORF encodes the regulatory X protein that activates the expression of numerous cellular and viral genes and is essential for virus replication.
  • References - , Hepatology 2009 May;49(5 Suppl):S13, Semin Immunopathol 2013 Jan;35(1):39
Strain Type
  • At least 10 genotypes of HBV (labeled A-J) have been identified.
    • These genotypes have distinct geographic distributions.
      • Africa: genotypes A, B, C, D, E are more common throughout Africa.
        • A is predominant in southern and eastern Africa.
        • D is found in northern Africa.
        • E is found in western and central Africa.
      • Asia:
        • A, D, and C are common in India (D is predominant).
        • B and C are common in China:
          • B is predominant in southern China.
          • C is found in northern China.
        • D is common in Mediterranean and Middle East countries.
        • E, F, G, and H are occasionally found in Asia.
        • Genotype I is uncommon, but present in Vietnam, Laos, India, and China.
        • J is found in Japan and Ryukyu Islands.
      • Oceania: predominantly B and C genotypes, though D is also present in Australia.
      • Europe: A and D genotypes are predominant throughout Europe.
        • A and D are common in Eastern Europe.
        • D is common in Southeastern Europe.
      • Latin America: A, D, F, H genotypes are found throughout Latin American countries.
        • F and H are predominate in indigenous populations.
        • A and D were introduced by European and African populations.
      • North America: genotypes A, B, C, and D are most common.
    • The relationship between genotype and liver disease progression is not well defined, but there is increasing evidence suggesting that:
      • Acute infection with genotypes A and D is associated with a higher rate of progression to chronic disease than genotypes B and C.
      • Infection with genotype C is associated with an increased risk of perinatal infection and progression to severe liver disease, including cirrhosis and hepatocellular carcinoma.
      • Genotypes A and B are more responsive to interferon therapy.
    • References - ,, World J Gastroenterol 2015 Nov 14;21(42):11941
Life Cycle
  • The virus binds to unidentified host cell membrane receptors.
  • Core nucleocapsid is released into the cytoplasm and transported to the nuclear membrane.
  • HBV genome enters the nucleus and is converted into a covalently closed circular DNA (cccDNA).
    • HBV cccDNA can persist as a stable chromatinized episome within the nucleus of the infected cell.
    • In this form, HBV is undetectable by innate immune defense mechanisms.
  • HBV cccDNA is transcribed by the host RNA polymerase II into viral mRNAs, including pregenomic RNA (pgRNA) and precore RNA.
    • The pgRNA serves as a template for reverse transcription and the messenger RNA for the core and polymerase.
    • The precore RNA directs translation of the precore gene product.
  • HBV transcripts enter the host cytoplasm and are translated into viral proteins.
  • Nucleocapsids are assembled and new viral DNA are synthesized from pgRNA by viral reverse transcriptase.
  • Nucleocapsids are coated with viral surface proteins in the endoplasmic reticulum and released as mature virions.
  • References - , Hepatology 2009 May;49(5 Suppl):S13, Semin Immunopathol 2013 Jan;35(1):39
Replication cycle of HBV

Image 3 of 5

Replication cycle of HBV

HBV virions bind to surface receptors and internalized. Viral core particles migrate to the nucleus, genomes are repaired to form a covalently closed circular DNA (cccDNA), the template for viral messenger RNA (mRNA) transcription. The viral mRNA is translated in the cytoplasm to produce viral surface, core, polymerase, and X proteins. Progeny viral capsids assemble, incorporating genomic viral RNA (RNA packaging). This RNA is reverse-transcribed into viral DNA. The resulting cores either bud into the endoplasmic reticulum to be enveloped and exported, or recycled into the nucleus for conversion to cccDNA. The small, peach-colored sphere inside the core particle is the viral DNA polymerase.

Transmission

  • HBV can survive outside body for > 7 days.
  • Primary routes of transmission include:
    • Sexual contact:
      • Common in areas of low HBV endemicity
      • Efficient means of transmission in heterosexual persons and men who have sex with men
      • Semen and vaginal secretions are infective
    • Perinatal exposure to an infected mother:
      • Predominant in areas of high HBV endemicity
      • Typically occurs in nonendemic countries when children born to HBV-infected mothers do not receive appropriate immunoprophylaxis at birth
    • Percutaneous exposure to infectious body fluids, such as:
      • Close person-to-person contact by open cuts and sores (often among children in hyperendemic areas)
      • Needle sharing by persons who inject drugs
      • Needlestick injury in a healthcare setting, with risk of developing clinical hepatitis being:
        • 22%-31% if the needle is contaminated with hepatitis B surface antigen (HBsAg)- and hepatitis B e antigen (HBeAg)-positive blood
        • 1%-6% if the needle is contaminated with hepatitis B surface antigen (HBsAg)-positive, HBeAg-negative blood
        • Reference - MMWR Recomm Rep 2001 Jun 29;50(RR-11):1PDF
  • Unvaccinated infants and children are at risk for horizontal transmission from infected contacts.
  • STUDY SUMMARY
    breaches in infection control in healthcare settings can lead to HBV outbreaks
    SYSTEMATIC REVIEW: BMC Med 2009 Apr 8;7:15

  • Risk of transmission via blood transfusion or tissue transplant appears to be low in the United States.
    • STUDY SUMMARY
      low risk of infection with HBV during blood transfusion in United States
      COHORT STUDY: Transfusion 2013 Oct;53(10 Pt 2):2449

    • STUDY SUMMARY
      low risk of infection with HBV during tissue transplant in United States
      COHORT STUDY: N Engl J Med 2004 Aug 19;351(8):751

  • Transmission between healthcare workers and patients is uncommon since the implementation of universal infection control precautions.

Pathogenesis

  • After a susceptible person is exposed, HBV is transported by bloodstream to the liver (the site of viral replication).
  • Clinical incubation period averages 2-3 months but may range from 1 to 6 months after the exposure.
  • A short preicteric period follows the incubation period.
    • This period lasts up to a week.
    • Symptoms include fever, fatigue, anorexia, nausea, and body aches.
    • Serum alanine aminotransferase (ALT) levels rise.
    • High levels of hepatitis B surface antigen (HBsAg) and HBV DNA are detectable.
  • The icteric phase of hepatitis B lasts 1-2 weeks.
    • Symptoms include abdominal pain and jaundice.
    • Viral levels decrease.
  • Convalescence:
    • Jaundice resolves, but constitutional symptoms may persist for weeks or months.
    • HBsAg is cleared, then HBV DNA disappears.
  • Acute liver failure occurs in about 1% of patients with acute HBV infection and jaundice.
    • HBsAg and HBV DNA levels fall as liver failure develops.
    • Symptoms include sudden onset of fever, abdominal pain, vomiting, and jaundice, followed by disorientation, confusion, and coma.
  • The outcome of acute HBV infection depends on age and immune competence when the infection occurs.
    • In adults:
      • About 95% of acute HBV infections are self-limited, with patients recovering completely after developing anti-HBs antibodies and clearing HBsAg from the blood
      • < 5% of adults develop chronic HBV infection with ongoing viral replication in the liver
    • In children, chronic infection occurs in:
      • Almost all children who are infected with HBV during the perinatal period
      • Up to 50% of children who become infected between ages 1 and 5 years
  • References - , Hepatology 2009 May;49(5 Suppl):S13

Immune Response

  • HBV is not directly cytopathic and the outcome of infection depends on the interaction between HBV replication and host immune response (Lancet 2014 Dec 6;384(9959):2053).
  • Unlike many viral infections, HBV infection is characterized by delayed viral replication and spread, and high quantities of viral proteins during chronic infection (Gut 2012 Dec;61(12):1754).
  • Innate immunity:
    • Acute infection is characterized by weak induction of the innate immune response.
      • Proinflammatory cytokines may be undetectable during the first 30 days of infection.
      • Type I interferons may not be activated.
    • HBV may evade innate immune recognition as replication involves a transcriptional template that is hidden within the host nucleus (covalently closed circular DNA [cccDNA]).
    • HBV appears to suppress the innate immune response.
      • HBV polymerase inhibits interferon beta production by interfering with interferon regulatory factor signaling.
      • HBV X protein may actively interfere with signaling mediated by cytosolic sensory molecules.
      • HBV proteins (including HBsAg and HBeAg) secreted by HBV during the replication cycle inhibit the Toll-like- receptor induced innate response to modulate the surface expression of TLR-2.
    • Reference - Gut 2012 Dec;61(12):1754
  • Adaptive immunity:
    • HBV-specific CD4 and CD8 T-cell mediated responses are detected immediately after the start of HBV replication, which is 7-10 weeks after infection (Dig Dis 2011;29(4):423).
    • Resolution of acute infection is primarily mediated through the adaptive immune response..
      • Patients with serological recovery from acute HBV infection have strong T cell responses to several epitopes in different regions of the HBV genome.
      • Patients with chronic HBV infection have a defective weak T cell response to few viral epitopes.
      • Reference - Lancet 2014 Dec 6;384(9959):2053
    • The role of HBV-specific antibodies in controlling chronic HBV infection is unclear (Dig Dis 2011;29(4):423).
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