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Guidelines of the major international liver organizations such as the American Association for the Study of Liver Diseases, European Association for the Study of the Liver, and Asian Pacific Association for the Study of the Liver provide recommendations for contemporary diagnosis and management of chronic HDV infection, including the incorporation of bulevirtide, a newly licensed antiviral agent in Europe. Significant unmet medical needs remain in the treatment of HDV, and recent advances in drug development offer hope for meaningful advances in drug therapy which may improve virologic response rates and clinical outcomes. This review summarizes trial design and available efficacy data from key phase 2 and 3 trials for investigational therapies including entry inhibitors (bulevirtide), prenylation inhibitors (lonafarnib), novel IFNs (peginterferon lambda), RNA interference molecules (JNJ-3989, elebsiran), monoclonal antibodies (tobevibart), and nucleic acid polymers (REP2139), and addresses future directions in HDV pharmacotherapy.<\/jats:p>","DOI":"10.5501\/wjv.v14.i2.102673","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T03:02:34Z","timestamp":1750647754000},"source":"Crossref","is-referenced-by-count":3,"title":["Advances in treatment of hepatitis delta virus infection: Update on novel investigational drugs"],"prefix":"10.5501","volume":"14","author":[{"given":"Jiyoon","family":"Park","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amr","family":"Sayed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed Alishan","family":"Nasir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph K","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2060","published-online":{"date-parts":[[2025,6,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.04.008"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1097\/HEP.0000000000000687"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/jvh.14005"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/HEP.0000000000001162"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-023-07960-y"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2213429"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/s0168-8278(86)80125-8"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199401133300202"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2004.03.017"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2023.05.001"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21325"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0912696"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3851\/IMP2728"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1111\/jvh.13366"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2022.05.023"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2020-323888"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(18)30663-7"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27102"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/s0016-5085(99)70409-9"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.5754\/hge10126"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3851\/IMP2381"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/apt.12788"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/cld.728"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1007\/s12072-015-9675-4"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2024.05.001"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1007\/s00103-022-03486-2"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2016.04.016"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(22)00318-8"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1111\/jvh.13831"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/s0618-8278(19)30141-0"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2314134"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.116.022188"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29658"},{"key":"B34","unstructured":"Lonafarnib Boosted with Ritonavir with and Without Peginterferon Alfa-2a (PEG IFN-a) in HDV (LOWR-2). 2014. 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