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Its role in patients treated with nucleotide\/nucleoside analogues (NAs) is unclear. We aimed to study the role of hepatitis D in the development of HCC in CHB patients treated with NAs. Altogether, 1349 CHB patients treated with NAs were tested for anti-HDV antibody and RNA. The incidence and risk factors of HCC development were analyzed. Rates of anti-HDV and HDV RNA positivity were 2.3% and 1.0%, respectively. The annual incidence of HCC was 1.4 per 100 person-years after a follow-up period of over 5409.5 person-years. The strongest factor association with HCC development was liver cirrhosis (hazard ratio [HR]\/95% confidence interval [CI] 9.98\/5.11\u201319.46, <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001), followed by HDV RNA positivity (HR\/ CI 5.73\/1.35\u201324.29, <jats:italic>P<\/jats:italic>\u2009=\u20090.02), age\u2009&gt;\u200950\u00a0years old (HR\/CI 3.64\/2.03\u20136.54, <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001), male gender (HR\/CI 2.69\/1.29\u20135.60, <jats:italic>P<\/jats:italic>: 0.01), and body mass index (BMI, HR\/CI 1.11\/1.03\u20131.18, <jats:italic>P<\/jats:italic>\u2009=\u20090.004). The 5-year cumulative incidence of HCC was 7.3% for patients with HDV RNA negativity compared to that of 22.2% for patients with HDV RNA positivity (<jats:italic>P<\/jats:italic>\u2009=\u20090.01). In the subgroup of cirrhotic patients, the factors associated with HCC development were HDV RNA positivity (HR\/CI 4.45\/1.04\u201319.09, <jats:italic>P<\/jats:italic>\u2009=\u20090.04) and BMI (HR\/CI 1.11\/1.03\u20131.19, <jats:italic>P<\/jats:italic>\u2009=\u20090.01). HDV viremia played a crucial role in HCC development in CHB patients who underwent NA therapy.<\/jats:p>","DOI":"10.1038\/s41598-021-87679-w","type":"journal-article","created":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T10:05:44Z","timestamp":1618394744000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Role of hepatitis D virus infection in development of hepatocellular carcinoma among chronic hepatitis B patients treated with nucleotide\/nucleoside analogues"],"prefix":"10.1038","volume":"11","author":[{"given":"Tyng-Yuan","family":"Jang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Ju","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ta-Wei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Lun","family":"Yeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Fen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Ting","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po-Yao","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Hung","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po-Cheng","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Hsuan","family":"Hsieh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Min","family":"Ko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Shan","family":"Tsai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuan-Yu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Chih","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Chien","family":"Tsai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Chi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-I.","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zu-Yau","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinn-Cherng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Long","family":"Chuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jee-Fu","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Yen","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Feng","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Lung","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,4,14]]},"reference":[{"key":"87679_CR1","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1016\/S1607-551X(10)70073-5","volume":"26","author":"JF Yang","year":"2010","unstructured":"Yang, J. 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Consultant of Abbvie, Abbott, BMS, Gilead, Merck and Roche. Speaker of Abbvie, Abbott, BMS, Gilead, Merck, and IPSEN. Chung-Feng Huang: Speaker of Gilead, Abbie, Merck and BMS. Other authors share no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"8184"}}