There are several viruses that can cause acute and/or chronic infections of the liver. The most widespread such virus is known as hepatitis B virus (HBV). Maybe 400 million individuals are chronically infected with this virus, and with time such infections are associated with extensive liver damage and the risk of progressing to hepatocellular carcinoma.
Studies first reported in 1977 led to the realization that some patients with a more damaging form of HBV infection were also infected with a second virus. This second virus is now known as hepatitis delta virus, hepatitis D virus or simply HDV. The genomes of HBV and HDV are very different and replicate by different mechanisms.
Both HBV and HDV will only infect hepatocytes, the major cell type in the liver. However, HDV is unusual in that it needs specific help from HBV in order to infect and replicate in hepatocytes. HBV infections produce what are known as envelope proteins that are used to assemble new HBV particles. HDV needs HBV to produce these same envelope proteins for its own assembly. Thus, new HDV particles can only be produced in an hepatocyte that is infected with both viruses. Given that HBV and HDV share the same envelope proteins, it is presumed that they enter hepatocytes by a similar if not identical mechanism.
TRANSMISSION AND DISTRIBUTION
Although these two viruses replicate only in hepatocytes, they are released into the blood and it is from such blood that they are transmitted to new individuals. Blood transfusions are safe if the blood is prescreened. These viruses can accumulate to high levels in the blood of infected patients, and so they can be transmitted by exposure to very small amounts of infected blood, such as by abrasions, needle-sticks, contaminated shaving gear or toothbrushes. Like HBV, HDV could be transmitted from mother to child at and around birth. Both viruses can be sexually transmitted and shared needles are a major risk for intravenous drug users.
HDV infections were first found in Italy but since then have been reported in many regions worldwide. The incidence is decreasing for reasons including the impact of HBV vaccination: there is a good vaccine that induces antibodies against the HBV envelope proteins and thus protects against HBV since no HDV infection can occur without HBV, it also protects against HDV. In many countries the first of three doses of this vaccine is administered around the time of birth.
HDV infections are considered to be of two kinds. A co-infection is when an individual is exposed to the two viruses for the first time. This can produce an acute infection but rarely continues on as a chronic infection. A super-infection is when an individual already chronically infected with HBV, is then exposed to HDV. The latter is more likely to lead to life-threatening acute infection. Alternatively, such an acute infection might go on to become chronic for HDV as well as HBV. Such chronic infections have more liver damage than HBV alone.
Screening for HDV in blood can be via assays for a viral protein, the delta antigen, or a corresponding antibody. What can be more sensitive assays exist for the HDV genome, a small 1,700 nucleotide long circular RNA. However, there can be technical variations with such assays, together with difficulties due to nucleotide sequence changes between isolates. In the U.S.A. blood is routinely screened for HBV but not for HDV. In some European countries both viruses are screened for.
Several therapies are available to treat chronic HBV. These can involve nucleoside inhibitors or interferons. They may only reduce the HBV levels in blood rather than lead to total clearance. And such imperfect HBV therapies do not lead to clearance of HDV. Several new experimental approaches are being tested for HDV therapy. However, at this time the only available treatment for chronic HDV, and with only a 25% success rate, involves at least weekly injections, for one year, of high doses of pegylated interferons.
Text: John M. Taylor, Virologist, Hepatitis Delta expert and Professor of Microbiology at UPenn
Pictures: Stephan Urban, Molecular Virologist and Head of Hepatitis B Research Group at Heidelberg University Hospital