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One of its unique characteristics is the requirement for the presence of a helper virus for its replication, and in particular enveloping its virion, a role often played by the hepatitis B virus (HBV). Infection with HDV is frequently associated with more severe disease, which may present with fulminant hepatitis or a more rapid progression to cirrhosis and hepatocellular carcinoma (HCC), when compared to HBV mono-infection. HDV exhibits many peculiarities and enigmas, which have led to it being considered a neglected virus. This review aims to identify the most important gaps in knowledge and peculiarities in the study of this enigmatic virus, from virology to clinical implications.<\/jats:p>","DOI":"10.3390\/v18020244","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T11:11:28Z","timestamp":1771240288000},"page":"244","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hepatitis D Virus: Enigmas and Gaps of Knowledge"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6086-6883","authenticated-orcid":false,"given":"Flor H.","family":"Pujol","sequence":"first","affiliation":[{"name":"Laboratorio de Virolog\u00eda Molecular, Centro de Microbiolog\u00eda y Biolog\u00eda Celular, Instituto Venezolano de Investigaciones Cient\u00edficas (IVIC), Caracas 1020A, Venezuela"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4816-1378","authenticated-orcid":false,"given":"Rossana Celeste","family":"Jaspe","sequence":"additional","affiliation":[{"name":"Laboratorio de Virolog\u00eda Molecular, Centro de Microbiolog\u00eda y Biolog\u00eda Celular, Instituto Venezolano de Investigaciones Cient\u00edficas (IVIC), Caracas 1020A, Venezuela"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2245-3831","authenticated-orcid":false,"given":"Armando Andres","family":"Roca Suarez","sequence":"additional","affiliation":[{"name":"INSERM Unit\u00e9 Mixte de Recherche 1350, PaThLiv IHU EVEREST, Universit\u00e9 Claude-Bernard Lyon 1, 69003 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enkhtuul","family":"Batbold","sequence":"additional","affiliation":[{"name":"INSERM Unit\u00e9 Mixte de Recherche 1350, PaThLiv IHU EVEREST, Universit\u00e9 Claude-Bernard Lyon 1, 69003 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2245-0083","authenticated-orcid":false,"given":"Fabien","family":"Zoulim","sequence":"additional","affiliation":[{"name":"INSERM Unit\u00e9 Mixte de Recherche 1350, PaThLiv IHU EVEREST, Universit\u00e9 Claude-Bernard Lyon 1, 69003 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5588-5465","authenticated-orcid":false,"given":"Barbara","family":"Testoni","sequence":"additional","affiliation":[{"name":"INSERM Unit\u00e9 Mixte de Recherche 1350, PaThLiv IHU EVEREST, Universit\u00e9 Claude-Bernard Lyon 1, 69003 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7188-5489","authenticated-orcid":false,"given":"Isabelle","family":"Chemin","sequence":"additional","affiliation":[{"name":"INSERM Unit\u00e9 Mixte de Recherche 1350, PaThLiv IHU EVEREST, Universit\u00e9 Claude-Bernard Lyon 1, 69003 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Perez-Vargas, J., Pereira de Oliveira, R., Jacquet, S., Pontier, D., Cosset, F.L., and Freitas, N. 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