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Hepatitis D

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Hepatitis D is a unique type of viral infection that targets the human liver. It is caused by the hepatitis delta virus, often called HDV. Among the five known hepatitis viruses—A, B, C, D, and E—HDV is quite different from the others. Scientists classify it as a satellite, which is a type of subviral agent. This means HDV is unable to reproduce or spread without the presence of the hepatitis B virus (HBV).

Hep D Epidemiology Figure 1
Hep D Epidemiology Figure 1

There are two primary ways a person might become infected with HDV. The first is called coinfection, which happens when a person is infected with both HBV and HDV at the same time. The second is called superinfection, which occurs when HDV is superimposed on an existing chronic hepatitis B infection. Superinfection is considered the most serious form of the disease. It can lead to more severe complications, such as liver failure during acute infection. In chronic cases, it can cause rapid progression to liver cirrhosis or increase the risk of liver cancer.

Hep D Epidemiology Figure 1
Hep D Epidemiology Figure 1

The structure of the HDV virus is remarkably small and complex. It is a spherical, enveloped particle with a diameter of only 36 nanometers. The outer envelope contains host phospholipids and three specific proteins taken from the hepatitis B virus. These include the large, medium, and small hepatitis B surface antigens. Inside this envelope lies the ribonucleoprotein (RNP) particle. This inner part contains the viral genome, which is surrounded by about 200 molecules of hepatitis D antigen (HDAg).

Hep D Epidemiology Figure 1
Hep D Epidemiology Figure 1

HDV has one of the most unusual genomes in the animal kingdom. It is a negative-sense, single-stranded, closed circular RNA. With a genome of approximately 1,700 nucleotides, it is the smallest known virus to infect animals. Its sequence is about 70% self-complementary, which allows it to form a rod-like RNA structure. This structure is so tightly folded that the virus can use the host cell's DNA-dependent RNA polymerase II to replicate. This makes it the only known animal pathogen to use this specific mechanism for RNA replication.

Hep D Epidemiology Figure 1
Hep D Epidemiology Figure 1

The life cycle of HDV begins when it enters liver cells, known as hepatocytes. It uses a bile transporter called the sodium taurocholate cotransporting polypeptide (NTCP) to gain entry. The virus recognizes this receptor through the N-terminal domain of the large hepatitis B surface antigen. Once inside, the virus uncoats and its nucleocapsid moves to the nucleus. The virus then produces three forms of RNA: circular genomic RNA, circular antigenomic RNA, and linear polyadenylated antigenomic RNA. A special sequence called a ribozyme then helps cleave the linear RNA into smaller pieces to form circles.

Hep D Epidemiology Figure 1
Hep D Epidemiology Figure 1

A critical part of this cycle is the production of the hepatitis D antigen (HDAg). This protein exists in two distinct forms: a large version (27 kDa) and a small version (24 kDa). Both come from the same reading frame, but a cellular enzyme called adenosine deaminase acting on RNA (ADAR) performs RNA editing. This editing changes a stop codon, allowing the large HDAg to be produced. The small HDAg supports viral replication in the early stages of infection. In contrast, the large HDAg is required for assembling new viral particles and actually inhibits replication in later stages.

Hep D Epidemiology Figure 1
Hep D Epidemiology Figure 1

HDV is a significant global health concern with high stakes for those infected. When combined with hepatitis B, HDV has a fatality rate of 20%, the highest of all hepatitis infections. A 2020 estimate suggests that approximately 48 million people are currently infected. While it is rare in many developed nations, it is more common in the Mediterranean, sub-Saharan Africa, the Middle East, and northern South America.

Hep D Epidemiology Figure 1
Hep D Epidemiology Figure 1

Prevention and treatment are essential for managing this virus. Because HDV requires HBV to function, the hepatitis B vaccine provides protection against both. The World Health Organization recommends universal hepatitis B vaccination, often given to infants within 24 hours of birth. For those already living with the virus, new treatments like bulevirtide have been approved. This drug works by binding to and inactivating the NTCP transporter, which blocks the virus from entering liver cells. Other treatments, such as lonafarnib, are also being developed to stop the assembly of new viral particles.

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