Hepatitis D Virus Infection in Children

Hepatitis D Virus Introduction Epidemiology Transmission Pathophysiology Clinical Presentation Diagnosis Treatment Prevention Complications

Introduction to Hepatitis D Virus Infections in Children

Hepatitis D virus (HDV) infection is a unique and severe form of viral hepatitis that only occurs in individuals infected with hepatitis B virus (HBV). HDV is a defective RNA virus that requires the presence of HBV to replicate and cause infection. While less common than other forms of viral hepatitis, HDV infection can lead to more severe liver disease and poorer outcomes, especially in children. Understanding its impact on pediatric populations is crucial for effective management and prevention strategies.

Epidemiology

The epidemiology of HDV infection in children is closely linked to HBV prevalence:

• Global prevalence: Estimated 12-15 million people infected with HDV worldwide
• Higher prevalence in:
  • Mediterranean basin
  • Middle East
  • Central and Northern Asia
  • West and Central Africa
  • Amazon Basin
• Lower rates in North America, Northern Europe, and Oceania
• Pediatric prevalence:
  • Generally lower than in adults
  • Higher in endemic regions with high HBV prevalence
• Risk factors in children:
  • Living in endemic areas
  • Born to HDV-infected mothers
  • Household contact with HDV-infected individuals

Transmission

HDV transmission in children occurs through similar routes as HBV:

• Vertical transmission (mother-to-child):
  • Less efficient than HBV transmission alone
  • Risk increases with high maternal HDV viral load
• Horizontal transmission:
  • Close contact with infected individuals (e.g., household contacts)
  • Exposure to contaminated blood or body fluids
  • Unsafe medical procedures (more common in resource-limited settings)
• Parenteral transmission:
  • Intravenous drug use (more relevant in adolescents)
  • Blood transfusions (rare in countries with blood screening)
• Sexual transmission (rare in young children, more relevant in adolescents)

Pathophysiology

The pathogenesis of HDV infection involves complex interactions with HBV:

1. HDV requires HBV surface antigen (HBsAg) for viral assembly and entry into hepatocytes
2. Two main patterns of infection:
   • Coinfection: Simultaneous infection with HBV and HDV
   • Superinfection: HDV infection in a person already chronically infected with HBV
3. Viral replication:
   • HDV uses host RNA polymerases for replication
   • Produces both genomic and antigenomic RNA
4. Immune-mediated liver damage:
   • Direct cytopathic effect of HDV
   • Enhanced immune response against infected hepatocytes
   • Increased production of inflammatory cytokines
5. Interaction with HBV:
   • HDV can suppress HBV replication
   • Complex dynamics between the two viruses affect disease progression

The presence of HDV generally leads to more severe liver disease compared to HBV infection alone.

Clinical Presentation

HDV infection in children can present in various forms:

• Acute coinfection (HBV and HDV):
  • Often more severe than acute HBV alone
  • Symptoms may include jaundice, fatigue, nausea, and abdominal pain
  • Risk of fulminant hepatitis is higher
• Chronic HDV infection (usually superinfection):
  • May be asymptomatic in early stages
  • Accelerated progression of liver disease compared to HBV alone
  • Symptoms of chronic liver disease may develop earlier
• Clinical phases:
  • Immune-tolerant phase (rare in children with HDV)
  • Immune-active phase (more common and prolonged)
  • Inactive phase (less common than in HBV monoinfection)
• Extrahepatic manifestations:
  • Glomerulonephritis
  • Polyarteritis nodosa (rare in children)

Diagnosis

Diagnosis of HDV infection in children involves:

• Serological testing:
  • HBsAg: Must be positive for HDV infection
  • Anti-HDV antibodies: Indicate exposure to HDV
  • IgM anti-HDV: Suggests recent or active infection
• Molecular testing:
  • HDV RNA: Confirms active HDV replication
  • Quantitative PCR used for monitoring treatment response
• Liver function tests: Often show more severe elevations compared to HBV alone
• Assessment of liver fibrosis:
  • Non-invasive methods: Transient elastography, serum biomarkers
  • Liver biopsy: May be needed for accurate staging but less commonly performed in children
• HBV markers: HBeAg, anti-HBe, HBV DNA for assessing HBV status

Treatment

Management of HDV infection in children is challenging:

• Pegylated interferon-alpha (PEG-IFN-α):
  • Currently the only approved treatment for HDV
  • Duration: 48 weeks or longer
  • Limited efficacy and high relapse rates
  • Significant side effects, particularly in children
• Nucleos(t)ide analogues for HBV:
  • May be used to suppress HBV replication
  • Limited direct effect on HDV
• Emerging therapies (under investigation):
  • Bulevirtide (Hepcludex): Entry inhibitor, not yet approved for pediatric use
  • Lonafarnib: Prenylation inhibitor, in clinical trials
• Supportive care:
  • Nutritional support
  • Management of complications
  • Regular monitoring of liver function and viral markers
• Liver transplantation: For end-stage liver disease or hepatocellular carcinoma

Prevention

Prevention strategies for HDV infection in children focus on preventing HBV infection:

• HBV vaccination:
  • Universal infant vaccination against HBV
  • Catch-up vaccination for older children and adolescents
• Prevention of mother-to-child transmission:
  • Screening pregnant women for HBV and HDV
  • HBV immunoglobulin and vaccine for infants born to HBsAg-positive mothers
• Education on transmission routes and risk factors
• Safe injection practices and medical procedures
• Screening of blood and organ donors
• Harm reduction strategies for adolescents at risk of drug use
• No specific vaccine available for HDV

Complications

HDV infection can lead to more severe complications compared to HBV alone:

• Accelerated progression of liver fibrosis and cirrhosis
• Increased risk of hepatic decompensation
• Higher incidence of hepatocellular carcinoma at a younger age
• Fulminant hepatitis:
  • More common in acute HDV/HBV coinfection
  • Can be life-threatening, may require liver transplantation
• Portal hypertension and its sequelae
• Extrahepatic manifestations:
  • Glomerulonephritis
  • Cryoglobulinemia (rare in children)
• Growth and developmental issues in children with advanced liver disease
• Psychosocial impact:
  • Stigma associated with chronic viral hepatitis
  • Potential effects on quality of life and social interactions

Hepatitis D Virus Infection in Children

1. What is Hepatitis D virus?
   A defective RNA virus that requires hepatitis B virus (HBV) for its replication and expression
2. How is HDV transmitted to children?
   Through blood and body fluids, similar to HBV transmission
3. What are the two patterns of HDV infection in children?
   Coinfection (simultaneous infection with HBV and HDV) and superinfection (HDV infection in a chronic HBV carrier)
4. Which pattern of HDV infection is more severe in children?
   Superinfection generally leads to more severe disease and rapid progression
5. What is the global prevalence of HDV infection in children?
   Estimated to be 0.1-5% of HBV-infected children, with geographical variations
6. How does HDV affect the course of HBV infection in children?
   It can accelerate the progression of liver disease and increase the risk of cirrhosis and hepatocellular carcinoma
7. What is the gold standard for diagnosing HDV infection in children?
   Detection of HDV RNA in serum by RT-PCR
8. How long do HDV antibodies (anti-HDV) persist after infection in children?
   IgM anti-HDV can persist for months to years; IgG anti-HDV can persist indefinitely
9. What is the primary treatment for chronic HDV infection in children?
   Pegylated interferon-alpha for at least 48 weeks
10. Can nucleos(t)ide analogues used for HBV treatment effectively treat HDV in children?
    No, they are not effective against HDV directly but may be used to manage HBV coinfection
11. What is the risk of vertical transmission of HDV?
    Low, but possible if the mother is coinfected with HBV and HDV
12. How does HDV infection affect liver transplantation outcomes in children?
    It can lead to more rapid and severe recurrence of liver disease post-transplantation
13. What are the typical symptoms of acute HDV infection in children?
    Similar to other viral hepatitis: fatigue, nausea, anorexia, right upper quadrant pain, and jaundice
14. How does HDV infection impact HBV replication in children?
    HDV usually suppresses HBV replication, leading to lower HBV DNA levels
15. What is the risk of fulminant hepatitis in children with HDV infection?
    Higher risk compared to HBV monoinfection, especially in superinfection cases
16. Can children clear HDV infection spontaneously?
    Spontaneous clearance is rare in chronic infection but can occur in acute coinfection
17. What is the role of liver biopsy in diagnosing HDV infection in children?
    It can assess the degree of liver damage but is not routinely required for diagnosis
18. How does HDV genotype affect disease progression in children?
    Genotype 1 is associated with more severe disease compared to other genotypes
19. What is the recommended follow-up for children with chronic HDV infection?
    Regular monitoring of liver function, HDV RNA levels, and liver imaging every 6-12 months
20. Can HDV infection occur in children vaccinated against HBV?
    Extremely rare, as HBV vaccination indirectly protects against HDV infection
21. What is the role of HDV antigen testing in diagnosing infection in children?
    HDV antigen testing can be useful in early infection before antibody development
22. How does HDV affect the immune system in infected children?
    It can lead to immune-mediated liver damage and altered cytokine profiles
23. What is the significance of HDV RNA quantification in infected children?
    It helps in monitoring treatment response and assessing disease activity
24. Can HDV infection in children lead to extrahepatic manifestations?
    Yes, including glomerulonephritis, vasculitis, and polyneuropathy
25. What is the role of new antiviral agents like Bulevirtide in treating HDV-infected children?
    Promising in adults, but safety and efficacy in children are still under investigation
26. How does HDV infection affect growth and development in children?
    Chronic infection can lead to growth retardation and delayed puberty
27. What is the impact of HDV infection on hepatocellular carcinoma risk in children?
    It significantly increases the risk compared to HBV monoinfection
28. How does HDV affect the natural history of HBV infection in children?
    It can accelerate progression to cirrhosis and end-stage liver disease
29. What is the role of immunosuppression in HDV-infected children post-liver transplantation?
    It requires careful management to prevent severe HDV recurrence
30. Can HDV infection affect the efficacy of HBV vaccination in children?
    No, but HBV vaccination is crucial to prevent both HBV and HDV infections

Further Reading

• World Health Organization: Hepatitis D Fact Sheet
• Centers for Disease Control and Prevention: Hepatitis D Information
• EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection
• Hepatitis Delta Virus: From Biological and Medical Aspects to Current and Investigational Therapeutic Options