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Ever growing evidence have highlighted the existence of multiple mechanisms underlying HDV persistence including integrated HBV\u2010DNA as a source of HBsAg production and the capability of the HDV genome to propagate through cell proliferation, thus supporting a potential HDV persistence even in the absence of HBV. Chronic HDV\u2010infection causes the most severe form of viral hepatitis, leading to the development of cirrhosis in 15% of cases within 1\u20132\u2009years and in 50%\u201360% of cases within 5\u201310\u2009years. The rates of hepatocellular carcinoma and hepatic decompensation are also 2\u20133\u2010fold higher than for HBV mono\u2010infection. There is the evidence that persistent viral replication plays a key role in triggering liver injury, suggesting the existence of direct viral cytopathic properties that can modulate, synergistically with immune\u2010responses, the progression towards end\u2010stage liver diseases. All these aspects can be further exacerbated by the extraordinary degree of viral genetic variability that can promote HDV evasion from immune responses and has enabled viral differentiation into genotypes and subgenotypes with potential different pathobiological properties. In this light, this review aims at providing comprehensive insights of mechanisms (with a focus on virological factors) underlying HDV persistence and pathogenesis, critical in shaping the clinical outcome of the infection. Dissecting these mechanisms is pivotal to optimize therapeutic strategies aimed at fully counteracting this fascinating and fearsome virus.<\/jats:p>","DOI":"10.1111\/jvh.13755","type":"journal-article","created":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T15:56:06Z","timestamp":1666108566000},"page":"1038-1047","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Novel concepts on mechanisms underlying Hepatitis Delta virus persistence and related pathogenesis"],"prefix":"10.1111","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2488-2082","authenticated-orcid":false,"given":"Romina","family":"Salpini","sequence":"first","affiliation":[{"name":"Department of Experimental Medicine University of Rome Tor Vergata  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"D'Anna","sequence":"additional","affiliation":[{"name":"Department of Experimental 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