Risk assessment of hepatitis D viruses

The eight different hepatitis D viruses known to date (HDV-1 to -8) are RNA viruses with a circular, single-stranded genome with negative polarity. The RNA is present in the virus particle as a nucleoprotein complex with the only protein encoded by HDV, the delta antigen. HDVs are defective viruses whose infectivity depends on simultaneous infection with the hepatitis B virus (HBV), since its surface proteins (HBsAg) also function as envelope proteins for HDV. Recent data also show that the envelope proteins of other viruses, some of which are not related to HBV (e.g., dengue virus, West Nile virus), can mediate infection by HDV and subsequent release of HDV particles. However, the clinical relevance of complementation by these alternative helper viruses has not yet been proven. In addition to humans as natural hosts, chimpanzees (Pan troglodytes) and northern tree shrews (Tupaia belangeri sinensis) are also susceptible to co-infection with HDV and HBV. Replication of the HDV genome can, in principle, occur in many different cell types, but is limited to hepatocytes due to the tropism mediated by HBsAg during natural human infection. An estimated 12 million people are infected with HDV worldwide. HDV co-infections occur with the highest prevalence in HBV-infected individuals in Southern Europe, the Middle East, East Africa, and Asia, while the lowest prevalences are observed in Northern Europe, North America, and South Africa. In Germany, HDV infections are relatively rare (41 reported infections in 2020). The course of the disease depends on the timing of the HDV infection and HBV infection. Co-infection with HBV and HDV typically leads to an acute and self-limiting infection. About 2% of co-infected patients develop a chronic infection. Superinfection occurs when chronic HBV carriers become infected with HDV. In 90% of cases, it leads to severe acute hepatitis and a chronic course of HDV infection. Superinfection is often associated with a fulminant form of hepatitis. Chronic HDV infection leads to liver cirrhosis in 50–70% of patients within 5 to 10 years. The likelihood of developing liver cirrhosis is therefore three times higher in HDV-infected patients than in patients chronically infected with HBV alone. The question of whether the incidence of hepatocellular carcinoma is also increased in HDV co-infection has not been conclusively clarified. HDV is transmitted horizontally (parenterally or through sexual contact) and vertically (perinatally), but not through the air, food, or water. Treatment options for HDV infections exist, but are currently limited. Antiviral therapies against HBV, for example with nucleoside and nucleotide analogues, are ineffective against HDV. However, vaccination against HBV also protects against co-infection with HDV. However, if HBV infection is already present, subsequent vaccination does not protect against HDV superinfection. According to the current TRBA 462 "Classification of viruses into risk groups", HDV is assigned to risk group 2 according to the Biological Agents Ordinance. HBV, on which an HDV infection depends, is assigned to risk group 2 as a donor and recipient organism for genetic engineering work according to Section 5 Paragraph 1 GenTSV in conjunction with Appendix 1.

The ZKBS recommends classifying HDV as donor and recipient organisms for genetic engineering work in risk group 2 according to Section 5 (1) of the GenTSV in conjunction with the criteria in Annex 1 of the GenTSV. The rationale for this is that an effective hepatitis B vaccine is available for prophylaxis. Furthermore, targeted treatment of chronic HDV infection with an antiviral agent with moderate efficacy is possible. With competent handling by trained personnel, the risk of infection in genetic engineering facilities is considered low due to the limited transmission routes. One possible source of infection could be injury from contaminated equipment, which can be avoided by taking special precautionary measures. Furthermore, level 2 safety measures are sufficient to protect against infection and to protect the legal interests specified in Section 1 of the GenTG. The ZKBS recommends that HBV-infected individuals refrain from performing genetic engineering work involving HDV. In addition, people performing genetic engineering work with HDV are recommended to be vaccinated against HBV and to have their immune status regularly monitored.

The current ZKBS risk assessment for HDV can be found at File number 6790-10-93 can be retrieved.