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However, it is unclear whether soluble immune checkpoint proteins affect the development of hepatocellular carcinoma (HCC) during nucleos(t)ide analogue (NA) treatment in patients with chronic hepatitis B virus infection. This study included 122 NA-na\u00efve patients who received NA therapy. We assessed the associations of clinical factors, including soluble immune checkpoint proteins, with HCC development during NA treatment. The baseline serum concentrations of 16 soluble immune checkpoint proteins were measured using multiplexed fluorescent bead-based immunoassay. In total, 13 patients developed HCC during the follow-up period (median duration, 4.3\u00a0years). Of the 16 proteins, soluble inducible T-cell co-stimulator (\u2265\u2009164.71\u00a0pg\/mL;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.014), soluble programmed cell death-1 (sPD-1) (\u2264\u2009447.27\u00a0pg\/mL;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.031), soluble CD40 (\u2264\u2009493.68\u00a0pg\/mL;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.032), and soluble herpes virus entry mediator (\u2264\u20092470.83\u00a0pg\/mL;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.038) were significantly associated with HCC development (log-rank test). In multivariate analysis, an sPD-1 level\u2009\u2264\u2009447.27\u00a0pg\/mL (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.014; hazard ratio [HR], 4.537) and \u03b1-fetoprotein level\u2009\u2265\u20096.4\u00a0ng\/mL (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.040; HR, 5.524) were independently and significantly associated with HCC development. Pre-treatment sPD-1 is a novel predictive biomarker for HCC development during NA treatment.\n                  <\/jats:p>","DOI":"10.1038\/s41598-021-03706-w","type":"journal-article","created":{"date-parts":[[2022,1,7]],"date-time":"2022-01-07T06:03:34Z","timestamp":1641535414000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Soluble programmed cell death-1 predicts hepatocellular carcinoma development during nucleoside analogue treatment"],"prefix":"10.1038","volume":"12","author":[{"given":"Ritsuzo","family":"Kozuka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaru","family":"Enomoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minh Phuong","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoang","family":"Hai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le Thi Thanh","family":"Thuy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoshi","family":"Odagiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanako","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Kotani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Motoyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etsushi","family":"Kawamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Hagihara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Fujii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sawako","family":"Uchida-Kobayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Tamori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norifumi","family":"Kawada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,7]]},"reference":[{"key":"3706_CR1","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1016\/j.jhep.2017.03.021","volume":"67","author":"European Association for the Study of the Liver","year":"2017","unstructured":"European Association for the Study of the Liver. 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