Chronic Viral Hepatitis: Hepatitis B and D

Chronic Viral Hepatitis

Introduction to Chronic Hepatitis

• Definition: Any inflammation of the liver lasting longer than $6$ months.

• Causes:

  • Viral Hepatitis: Specifically Hepatitis B (HBV), Hepatitis D (HDV), and Hepatitis C (HCV).

  • Non-Viral Causes: Metabolic dysfunction-associated fatty liver disease, alcohol-related liver disease, autoimmune liver diseases, drug-induced liver injury, amongst others.

• Focus of this session: Chronic viral hepatitis.

Overview of Hepatitis Viruses

• There are five main hepatitis viruses: Hepatitis A, B, C, D, and E.

• Key Viruses Discussed (leading to chronic hepatitis):

  • Hepatitis B Virus (HBV):

    • Type: DNA virus.

    • Spread: Parenteral.

    • Incubation Period: Particularly long.

    • Outcomes: May lead to chronic hepatitis and liver cancer.

    • Vaccine: Available.

  • Hepatitis D Virus (HDV):

    • Type: Defective delta RNA virus.

    • Spread: Parenteral.

    • Infection Requirement: Only infects people with Hepatitis B or is acquired simultaneously with HBV infection.

  • Hepatitis C Virus (HCV):

    • Type: RNA virus.

    • Spread: Parenteral.

    • Incubation Period: Up to $150$ days.

    • Outcomes: Leads to chronic hepatitis, cirrhosis, and liver cancer.

    • Vaccine: No vaccine available.

Global Burden of Hepatitis B and C Viruses (WHO 2022 Estimates)

• Hepatitis B (HBV):

  • Infects approximately $254$ million people worldwide.

  • Particularly prevalent in Western Pacific and Southeast Asian regions.

• Hepatitis C (HCV):

  • Currently affects about $50$ million people worldwide.

  • Widely distributed due to its acquisition routes.

Hepatitis B Virus (HBV) in Detail

Virology

• Structure: Small, enveloped virus with an outer coat of Hepatitis B surface antigen (HBsAg).

• Contents: Contains DNA, DNA polymerase, core antigens, and E antigens within the outer coat.

• Genome: Partially double-stranded, circular DNA of about $3.2$ kilobase pairs ($kb$).

  • Encodes four overlapping reading frames that produce at least $7$ distinct proteins.

• Genotypes: At least $7$ genotypes (A to I) exist globally.

• Integration: HBV can integrate into the host genome, which can lead to genomic instability and liver cancer (hepatocellular carcinoma, HCC).

Life Cycle (Simplified)

• Entry: Virus enters the cell via a specific receptor.

• Uncoating & Transport: Virus is uncoated, and its genome is transported to the nucleus.

• Formation of cccDNA: The genome can encode a covalently closed circular DNA (cccDNA), which can persist in the nucleus long-term and is the basis of viral replication.

• Pre-genomic RNA (pgRNA) Pathways: pgRNA is exported from the nucleus into the cytoplasm and has two main pathways:

  1. New Virus Formation: Reverse transcribed, leading to the formation of a completely new virus that buds from the cell, is exported into the serum, and can infect other people and hepatocytes.

  2. Non-Infectious Particles: Translated into small particles of HBsAg and HBeAg, which circulate in the blood as non-infectious particles detectable by assays.

• Treatment Limitations: Current treatments primarily target the reverse transcription and polymerase step, with no impact on circulating HBsAg and HBeAg particles. Other treatments are under development.

Transmission

• High Endemicity Countries (e.g., Western Pacific region):

  • Most transmission is perinatal (at birth) or through early childhood contact.

  • This can be prevented by vaccination in early childhood or at birth.

• Low Endemicity Countries (e.g., Australia):

  • Primary transmission among adults in high-risk groups.

  • Occurs through parenteral and percutaneous routes (e.g., injecting drug use, tattooing, piercings) or sexual transmission.

  • Migrants, refugees, and Indigenous Australians often acquire HBV at birth or in the early neonatal period via perinatal transmission.

• Non-Risk Factors: Sharing food and drink is not a risk factor for HBV transmission.

• Concentration in Body Fluids:

  • Very High Levels: Blood/serum, wound exudates.

  • Moderate Levels: Semen, vaginal fluid, saliva.

  • Very Low Levels: Urine, feces, sweat, tears, breast milk.

Vaccination

• Vaccine Type: Recombinant Hepatitis B vaccine, highly effective.

• **Recommended Groups (Australia):

  • All Infants: At birth, and at months $2$, $4$, and $6$ after birth.

  • Aboriginal and Torres Strait Islanders: Of all ages.

  • Immunocompromised Individuals.

  • People with Medical Risk Factors.

  • Occupational Risk: All medical students, nursing students, other healthcare students, and practitioners (vaccinated and assessed for antibody status post-vaccination).

  • Travelers: To HBV endemic areas who are at increased risk.

  • Situational Risk: Anyone whose circumstances increase their risk of acquiring HBV.

• Non-Response to Vaccination: Causes for non-response include older age, male sex, obesity, smoking, chronic illness (e.g., diabetes, renal failure), genetic factors, and immunosuppression. Testing for anti-HBs is important to confirm an immune response in these individuals.

Epidemiology in Australia

• Estimated Prevalence: Approximately $220,000$ people chronically living with HBV.

• Demographics:

  • Vast majority from high endemicity countries (e.g., Northeast Asia, Southeast Asia, Sub-Saharan Africa, South and Eastern Europe, Oceania).

  • Aboriginal and Torres Strait Islander people account for about $6.7\%$ of people living with HBV in Australia.

  • Men who have sex with men (if unvaccinated) and people who inject drugs are at particular risk.

• Testing Implications: HBV is not exclusive to identifiable risk groups; non-Indigenous, Australian-born, non-migrants can also live with HBV, therefore anyone at risk should be tested and vaccinated.

Testing for Hepatitis B

• Recommended Tests:

  • Hepatitis B surface antigen (HBsAg)

  • Anti-HB core antibody (anti-HBc)

  • Anti-HBs antibody (anti-HBs)

• Who Should Be Tested (and vaccinated if susceptible):

  • All pregnant women.

  • People born in high endemicity regions.

  • Aboriginal and Torres Strait Islander people.

  • Household contacts and sexual partners of people with HBV.

  • People who inject drugs.

  • Men who have sex with men.

  • People with HIV, HCV, or unexplained liver disease.

  • Immunosuppressed individuals.

  • People on hemodialysis.

  • Prisoners.

Interpretation of Hepatitis B Serology

• Susceptible (No Infection, No Immunity):

  • HBsAg: Negative

  • Anti-HBc: Negative

  • Anti-HBs: Negative

  • Action: Vaccinate.

• Immune through Past Infection (Resolved Infection):

  • HBsAg: Negative

  • Anti-HBc: Positive

  • Anti-HBs: Positive

  • Note: No chronic HBV, but at risk of reactivation (especially with significant immunosuppression).

• Immune through Vaccination:

  • HBsAg: Negative

  • Anti-HBc: Negative

  • Anti-HBs: Positive

• Acute Hepatitis B Infection:

  • HBsAg: Positive

  • Anti-HBc IgM: Positive (high titer)

• Chronic Hepatitis B Infection:

  • HBsAg: Positive

  • Anti-HBc: Positive

  • Anti-HBs: Negative

• Isolated Anti-HBc Positive: (Various possibilities, requires further investigation)

  • HBsAg: Negative

  • Anti-HBc: Positive

  • Anti-HBs: Negative

Natural History of Chronic Hepatitis B Infection

• Assessment Markers: Hepatitis B E antigen (HBeAg), Anti-HBV (anti-HBe), HBV DNA, and Alanine Aminotransferase (ALT).

• **Stages (typically for perinatally acquired infection over decades):

  • Immune Tolerant (1st-2nd decade of life):

    • HBeAg: Positive

    • Anti-HBe: Negative

    • HBV DNA: Very high levels

    • ALT: Usually normal ($\leq 19$ U/L in women, $\leq 30$ U/L in men)

    • Note: Low liver inflammation despite high viral load.

  • Immune Clearance/Hepatitis Phase (E-antigen positive disease):

    • HBeAg: Positive

    • Anti-HBe: Negative

    • HBV DNA: Fluctuating levels in response to inflammation

    • ALT: Elevations (manifestation of active liver disease)

    • Note: Stage of active liver disease, can progress to significant fibrosis and cirrhosis.

  • Inactive Carrier State:

    • HBeAg: Negative (most people clear HBeAg and develop anti-HBe at some stage)

    • Anti-HBe: Positive

    • HBV DNA: Low levels ( < 2,000 IU/mL) or undetectable.

    • ALT: Normal liver enzymes.

    • Note: Disease becomes quiescent, but still at risk of reactivation and HCC.

  • Immune Escape/Reactivation Phase:

    • Occurs due to mutations in the virus.

    • HBeAg: Negative

    • Anti-HBe: Positive

    • HBV DNA: Detectable ( > 2,000 IU/mL)

    • ALT: Elevations (manifesting active disease with progressive fibrosis/cirrhosis).

Outcomes of Chronic Hepatitis B

• Progression: Many progress through active disease stages.

  • Can lead to compensated cirrhosis.

  • Some develop decompensated cirrhosis.

  • Many develop hepatocellular carcinoma (HCC).

• HCC Risk in Inactive Carriers: Even in the