Hepatitis D Virus

Introduction

Hepatitis D Virus (HDV), also known as the delta virus, is a unique and rare cause of liver disease that occurs only in people already infected with the Hepatitis B Virus (HBV). HDV cannot reproduce without HBV, making it a defective RNA virus that relies on HBV  surface antigens (HBsAg) to complete its life cycle.

HDV infection can lead to severe liver damage, rapid cirrhosis, and increased risk of liver cancer. Although it is preventable through HBV vaccination, treatment options for chronic HDV infection are still limited.

Key Facts

• Virus Type: Defective, single-stranded, negative-sense RNA virus
• Family: Unclassified (requires HBV  for replication)
• Genome Size: ~1.7 kb
• Envelope Protein: Derived from HBV  surface antigen (HBsAg)
• Global Burden: ~12 million people coinfected with HBV  and HDV
• High-Risk Groups: People who inject drugs, hemodialysis patients
• Treatment: Pegylated Interferon-α (Peg-IFNα)
• Vaccine: No direct HDV vaccine — prevented through HBV  immunization

Keywords

Hepatitis D Virus (HDV), Delta Virus, Hepatitis B Virus (HBV ), Coinfection, Superinfection, Cirrhosis, Liver Cancer, Pegylated Interferon, Bulevirtide, HBV  Vaccination, Chronic Hepatitis D.

Characteristics of HDV

Hepatitis D Virus is a small, enveloped RNA virus with a circular, single-stranded, negative-sense genome of about 1.7 kilobases. It encodes only one major protein — the delta antigen (HDAg) — which is essential for replication.

HDV is defective, meaning it cannot form infectious particles without HBV . It uses HBV ’s surface antigen (HBsAg) as its outer envelope to assemble and exit infected liver cells.

Replication occurs in the nucleus of hepatocytes, where HDV hijacks host RNA polymerase II to replicate its RNA genome. New HDV particles are released only when HBsAg is available from HBV .

Epidemiology

Globally, around 5% of people with chronic HBV  are coinfected with HDV — approximately 12 million individuals. The highest prevalence is reported in:

• Mongolia
• Republic of Moldova
• Western and Central Africa
• Parts of the Middle East and Eastern Europe

HDV is also more common among people who inject drugs and patients on long-term dialysis. It accounts for nearly 20% of HBV -related cirrhosis and liver cancer cases worldwide.

Transmission

HDV spreads in the same way as HBV , since it depends on HBV  for infection. Transmission occurs through:

• Contact with infected blood (shared needles, transfusions)
• Sexual contact with an infected person
• Perinatal transmission (rare but possible from mother to child)

Because HDV requires HBsAg, it cannot infect people who are immune to HBV . Therefore, HBV  vaccination effectively prevents HDV infection.

High-risk environments such as unscreened blood transfusions, needle sharing, and unsafe medical procedures contribute to outbreaks in endemic areas.

Pathogenesis: How HDV Damages the Liver

HDV infection causes liver injury through both direct cytopathic effects and immune-mediated mechanisms:

• The delta antigen triggers strong activation of innate immunity and inflammatory responses.
• Cytotoxic T lymphocytes (CTLs) attack infected liver cells, leading to cell death (apoptosis).
• In superinfection (HDV infecting someone with chronic HBV ), liver damage accelerates rapidly, causing fibrosis, cirrhosis, and increased risk of hepatocellular carcinoma (HCC).

Because of this combined viral and immune injury, HDV is considered the most severe form of viral hepatitis.

Immunity and Chronic Infection

There is no separate immune protection for HDV — immunity to HBV  automatically protects against HDV.

• People who have recovered from HBV  (anti-HBs positive) cannot get HDV.
• Those with chronic HBV  (HBsAg positive) are at risk if exposed to HDV.

Infections occur in two main patterns:

1. Coinfection (HBV  + HDV at the same time):

• Leads to acute, severe hepatitis but usually clears in most patients.
• Chronic HDV infection is uncommon (<5%).

2. Superinfection (HDV infects someone already with chronic HBV ):

• Causes severe liver inflammation and often becomes chronic (70–90% of cases).
• Associated with rapid fibrosis, cirrhosis, and high HCC risk.

Clinical Features and Symptoms

Symptoms vary depending on whether HDV occurs as a coinfection or superinfection:

Coinfection (Acute HBV  + HDV):

• Fever and fatigue
• Nausea and loss of appetite
• Jaundice (yellowing of eyes and skin)
• Sometimes a biphasic illness with two peaks of liver enzyme elevation (ALT)
  Most patients recover completely, and chronic infection is rare.

Superinfection (HDV in Chronic HBV  Carriers):

• Worsening jaundice and abdominal pain
• Dark urine and light-colored stools
• Rapid progression to chronic hepatitis D, cirrhosis, or liver cancer

This form of HDV is much more aggressive and dangerous than HBV  infection alone.

Diagnosis

HDV testing is performed only in HBV -positive individuals (HBsAg+).

Laboratory Tests:

• Anti-HDV antibodies (IgM and IgG): Detect current or past infection.
• HDV RNA PCR: Confirms active replication and measures viral load.
• IgM anti-HBc: Indicates recent HBV  infection in coinfection cases.
• Liver function tests (ALT/AST): Show inflammation or liver damage.

A sudden worsening of liver disease in a known HBV  patient should always prompt HDV testing.

Treatment

Current treatment options for HDV are limited but evolving.

1. Pegylated Interferon-α (Peg-IFNα)

• The only approved therapy for chronic HDV infection.
• Usually given for 48 weeks.
• Clears HDV RNA in 25–30% of patients, but relapse can occur.

2. New Therapies (Under Development or Recently Approved)

• Bulevirtide: A viral entry inhibitor approved in Europe; prevents HDV from entering liver cells.
• Lonafarnib: Targets viral assembly and replication (under clinical trials).

It is important to note that HBV  antiviral drugs (like tenofovir or entecavir) do not directly affect HDV.

Prevention

Since HDV depends entirely on HBV , preventing HBV  infection automatically prevents HDV.

Effective Prevention Strategies:

1.     Universal HBV  vaccination (especially birth-dose immunization).

2.     Safe injection practices and screened blood transfusions.

3.     Avoid sharing needles or razors among drug users or in medical settings.

4.     Testing and monitoring of HBV -infected patients for possible HDV coinfection.

By controlling HBV  transmission, global HDV infection rates can be greatly reduced.

Conclusion

Hepatitis D Virus (HDV) is a serious viral infection that worsens the course of Hepatitis B. It leads to faster liver damage, cirrhosis, and liver cancer. Although treatment options remain limited, progress with new drugs like bulevirtide is promising. The best defense remains HBV  vaccination, which protects against both HBV  and HDV. Early detection and regular monitoring in HBV -positive individuals are vital to prevent complications and improve outcomes.