Hepatitis B virus (HBV)

Approximately 350 million people are infected globally with Hepatitis B Virus (HBV) and an estimated of 1 million people die from complications of Hepatitis B virus each year. Hepatitis B virus (HBV) are extremely resistant strain capable of withstanding extreme temperatures and humidity.

Taxonomy of Hepatitis B virus (HBV):

› Viruses
› Retro-transcribing viruses
› Hepadnaviridae
› Orthohepadnavirus
› Hepatitis B virus

Structure of HBV:

• Also called Dane particle; 42 nm in diameter
• Lipid envelope with surface antigen (HBs Ag)
• Icosahedral capsid (spherical) composed of core antigen (HBc Ag)
• Small, circular, double stranded (ds) DNA genome
• DNA polymerase

Associated Antigens of HBV and Serology:

1. HBs Ag:

• Antigen found on surface of HBV
• May be spherical or filamentous
• Continued presence indicates carrier state
• HBs Ab (antigen to HBs Ag) provides immunity to hepatitis B

2. HBc Ag:

• Antigen associated with core of HBV
• HBc Ab (antibody to HBc Ag) is positive during window period
• IgM HBc Ab is an indicator of recent disease
• IgG HBc Ab signifies chronic disease

3. HBe Ag:

• Non-particulate form of HBc Ag
• Cleavage product of the viral core structural polypeptide
• Found dissolved in serum
• Important indicator of active viral replication and therefore transmissibility
• High HBe Ag level indicates high infectivity
• HBe Ab (antibody to HBe Ag) indicates low transmissibility
• Pregnant mothers with HBeAg in their blood will almost always transmit HBV to their offspring (90% transmission rate), whereas mothers who have no HBeAg will rarely infect the neonate (10% transmission rate)

Classification of HBV:

The glycoproteins of HBs Ag contain:

1. A group-specific antigen: “a”
2. 2 type-specific antigenic determinants: “d or y” and “w or r”

Based on this, the virus is divided into 4 major serotypes:

1. adw (Worldwide distribution)
2. adr (Asia)
3. ayw (Africa, India, Russia)
4. ayr (Africa, India, Russia)

Epidemiology of HBV:

1. The virus is extremely contagious
2. Virus lives in all human body fluids (semen, urine, saliva, tears, blood, breast milk, vaginal and menstrual secretions, amniotic fluid, CSF, etc.)
3. Blood and blood products constitute the most important vehicle for parenteral transmission
4. Saliva and semen are responsible for veneral transmission
5. Congenital or vertical transmission from carrier mother is common
6. Vulnerable group includes healthcare personnels, intravenous drug users, hemophiliacs, babies of mothers with chronic HBV, renal dialysis patients, individuals with multiple sex partners, residents and staff members of institutions for the mentally retarded
7. High prevalence in developing countries
8. Highest incidence in 15-19 years age

Pathogenesis of HBV:

1. The HBV virion binds to a receptor at the surface of the hepatocyte and enters the cell and begins to replicate
2. The copies of HBV genome integrate into the hepatocyte chromosome and remain latent
3. Incubation period of 40 to 180 days, depending on the infectious dose, the route of infection, and the person
4. Cytopathic effect: The intracellular accumulation of filamentous form of HBs Ag produces the ground-glass appearance of affected heaptocyte. Single cells of liver parenchyma show ballooning and form acidophilic (councilman) bodies as they die.
5. Hypoimmune response:
   • IFN↓, HLA-I↓ → CTL↓ (An insufficient T cell response) →acute hepatitis/chronic hepatitis
6. Immune complexes formed between HBs Ag and anti-HBs (HBs Ab) contribute to the development of hypersensitivity reactions, leading to problems such as vasculitis, arthralgia, rash, and renal damage.
7. Pathogenic damage caused by autoimmunity against liver specific protein (LSP)
8. Patients who have immunosuppressed states, such as malnutrition, AIDS, and chronic illness, are more likely to be asymptomatic carriers because their immune system does not attack.

Clinical Syndromes:

A. Acute infection

Subclinical infections: Fever, rash, arthritis

Clinical infections: Malaise, anorexia, nausea
a) Anicteric infection: dark urine, elevated transaminases
b) Icteric infection: jaundice, itching

Fulminant hepatitis: Severe acute hepatitis with rapid destruction of the liver

Complications:

1. Serum sickness type syndrome
2. Polyarteritis nodosa
3. Membranous glomerulonephritis

B. Chronic infection

Carriers: those persons in whom HBs Ag persists beyond 6 months
a) Simple carriers: HBe Ag absent but low titre of HBs Ag present in blood
b) Super carriers: HBe Ag present in blood

Chronic persistent Hepatitis B

• Low grade “smoldering” hepatitis with slightly raised transaminases
• Can result in terminal hepatic failure

Chronic active hepatitis
Acute hepatitis state that continues without the normal recovery (lasts longer than 6-12 months)

Complications

1. Cirrhosis: permanent liver scarring and loss of hepatocytes
2. Primary Hepatocellular Carcinoma (PHC): HBV may induce PHC by promoting continued liver repair and cell growth in response to tissue damage or by integrating into the host chromosome and stimulating cell growth directly.

C. Co-infection or superinfection with hepatitis delta virus (HDV)

Laboratory Diagnosis of HBV:

The initial diagnosis of hepatitis can be made on the basis of the clinical symptoms and the presence of liver enzymes in the blood.

• In viral hepatitis:  ALT > AST
• In alcoholic hepatitis: AST > ALT

The standard test of HBV is the detection of HBs Ag

Direct Examination:

Immunofluorescent staining:

• Infected heaptocyte shows HBV core protein in the nucleus and infectious Dane particles in the cytoplasm

Detection of viral DNA:

• DNA hybridisation
• PCR (Polymerase chain reaction)

Serology:

Interpretation:

1. HBs Ag is the 1st marker to appear in the blood (3-5 weeks before the onset of symptoms and 2-4 weeks before serum ALT becomes abnormal). Serum HBsAg rises and then declines when the immune responds to the infection.
2. Anti-HBs Ag may not be detected for weeks soon after disappearance of HBs Ag because of formation of antigen-antibody complexes and the period is called “window period”.
3. The best way to diagnose a recent acute infection, during the window period (when neither HBsAg nor anti-HBs can be detected) is to measure IgM anti-HBc.
4. Presence of IgG anti-HBc in blood indicates chronic infection.
5. Presence of HBeAg in blood is and indicator of chronic infection reflecting high infectivity.

 

Tests	Results	Interpretation
HBsAg anti-HBc anti-HBs	negative negative negative	Susceptible
HBsAg anti-HBc anti-HBs	negative positive positive	Immune due to natural infection
HBsAg anti-HBc anti-HBs	negative negative positive	Immune due to hepatitis B vaccination**
HBsAg anti-HBc IgM anti-HBc anti-HBs	positive positive positive negative	Acutely infected
HBsAg anti-HBc IgM anti-HBc anti-HBs	positive positive negative negative	Chronically infected
HBsAg anti-HBc anti-HBs	negative positive negative	Might be recovering from acute HBV infection / Might be distantly immune and test not sensitive enough to detect very low serum anti-HBs / May be susceptible with a false positive anti-HBc / Might be undetectable level of HBs present in the serum and the person is chronically infected

 

Treatment:

• Currently, interferon alfa (IFN-a), lamivudine, telbivudine, adefovir, entecavir, and tenofovir are the main treatment drugs approved globally.
• Initiation of treatment with adefovir or entecavir or tenofovir or in combination with lamivudine is of cardinal importance before and after liver transplantation to achieve viral suppression and to prevent recurrence of the disease after the procedure.

Vaccination:

A. Passive immunisation: Hyperimmune hepatitis B immunoglobulin (HBIG) prepared from donors with high titres of anti-HBs Ag is indicated for:

1. Non-immune individuals accidentally exposed to potentially infectious material
2. Individuals having an intimate personal contact with a patient of carrier of HBV
3. Neonates born to infectious mother

Administration: 300-500 IU in 3 ml as soon as possible after the incident, preferably at birth in neonate and within 48 hours for others. A second dose is administered 4 weeks after the 1st.

B. Active immunization: Subunit vaccines prepared by cloning the surface antigen in yeast cells (Saccharomyces cerevisiae) is indicated for infansts, children, especially people in high risk groups (healthcare personnel), who are HBs Ag negative, sexual partners of those known to be infected with HBV, drug abusers, and patients requiring freqent blood or blood product transfusion.

Administration:

• Adults: Administer missing doses to complete a 3-dose series of hepatitis B vaccine to those persons not vaccinated or not completely vaccinated. 2 doses 1 month apart, followed by a booster dose at 6 months
• Newborns: at 0 (If HBs Ag + mother, HBIG also given), 1 and 6 months