hepatitis D

**Virology** - Delta virus is the sole member of genus Deltavirus. It is a small, circular, negative-sense, single-stranded RNA virus. It is the smallest known human virus and is a "viroid-like" satellite virus. - It is defective. It needs HBsAg (HBV surface envelope protein) to form its envelope, which it uses for assembly, release, and hepatocyte entry. So HDV cannot infect anyone without HBV. - Hepatitis delta antigen (HDAg) is the only protein it encodes. It has a short (S-HDAg) and a long (L-HDAg) form. S-HDAg promotes replication. L-HDAg inhibits replication and promotes assembly. - HDV RNA replicates by host RNA polymerase II. The genome has a ribozyme activity that self-cleaves.

**Transmission** - It is transmitted parenterally through blood and body fluids, as HBV is. Risk groups are IV drug users, people receiving multiple transfusions or clotting factors, and people from endemic areas (Mediterranean basin, Eastern Europe, Mongolia, Amazon basin, parts of Africa). It can also spread sexually and perinatally, though less efficiently. - Prevention is HBV vaccination, because it also prevents HDV. There is no vaccine for people already chronically infected with HBV, so they should avoid exposure.

**Two patterns of infection** 1. **Coinfection** means HBV and HDV are acquired simultaneously. - It causes acute hepatitis, sometimes with a biphasic ALT peak. - It is usually self-limited. Most patients (>90%) clear both viruses, and the risk of chronicity is the same as for HBV alone. - It carries a modestly higher risk of fulminant hepatitis than HBV alone. 2. **Superinfection** means HDV infects a chronic HBV carrier. - It causes a severe acute hepatitis flare, a high risk of fulminant hepatitis, and a high rate (up to ~80–90%) of chronic HDV. - It leads to rapid progression to cirrhosis and carries a higher risk of hepatocellular carcinoma and decompensation. - It should be suspected in a chronic HBV patient who suddenly worsens.

**Diagnosis** - Order anti-HDV IgM and IgG, then confirm with HDV RNA by PCR. Test for HDV in all HBsAg-positive patients, especially with risk factors or unexplained worsening. - Coinfection: HBsAg+, anti-HBc IgM+, and anti-HDV IgM+. HDV RNA also appears. - Superinfection: HBsAg+, anti-HBc IgG+ with anti-HBc IgM negative (chronic HBV), and anti-HDV positive. - HBV DNA is often low or suppressed because HDV suppresses HBV replication. This is a classic point. - Histology can show hepatocyte necrosis, inflammation, and HDAg on immunostaining.

**Treatment** - Pegylated interferon-alpha for 48 weeks has long been the mainstay, but response is limited and relapse is common. - Bulevirtide, an entry inhibitor that blocks the NTCP receptor, is approved in the EU. It is an emerging therapy. - Nucleos(t)ide analogs (such as tenofovir and entecavir) treat HBV but do not directly treat HDV. - Liver transplantation is used for end-stage disease. HBV immunoglobulin plus nucleoside analog prophylaxis reduces reinfection.

**Board pearls** - Hepatitis D requires HBV, so "no HBV, no HDV." - Think of it when a chronic HBV patient has acute decompensation or fulminant liver failure. - Hepatitis viruses by genome: - A, C, and E are RNA viruses (HAV is a picornavirus, HCV is a flavivirus, HEV is a hepevirus). - B is a DNA virus. - D is a circular RNA virus. - Only HBV is a DNA virus, and it is the only one with a reverse-transcriptase-dependent genome replication. - The mnemonic "D = Dependent on B" helps recall that D is a defective virus.