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This study aimed to evaluate the safety and efficacy of antiviral therapy in this patient population and analyze peripheral immunological characteristics in relation to treatment response. In this randomized controlled trial, HBeAg\u2010positive patients with normal ALT and elevated HBV DNA were randomly allocated 1:1 to receive TAF 25\u2009mg\/day or observation. The primary endpoint was the decline from baseline in HBsAg at Week 48. Secondary endpoints included HBV DNA response rates and the magnitude of HBV DNA reduction. The treatment group was further divided into virological response (VR) and low\u2010level viremia (LLV) subgroups based on HBV DNA response at Week 48. PBMCs from VR (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20093) and LLV (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20093) patients underwent scRNA\u2010seq for comparative immunological analysis. A total of 59 patients were allocated to the treatment (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200930) and control (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200929) groups. No serious adverse events occurred, except for one control patient who developed an ALT flare and required antiviral initiation. At Week 48, the treatment group demonstrated significantly greater reductions in HBsAg (0.19 vs. 0 log10 IU\/mL,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.005) and HBV DNA (6.32 vs. 0.19 log10 IU\/mL,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) compared to controls. In the treatment group, 20% achieved HBV DNA\u2009&lt;\u200920\u2009IU\/mL and 3.3% achieved HBeAg seroconversion, while none occurred in the untreated patients. PBMCs scRNA\u2010seq revealed dominant distributions of NK_FCER1G, NK_KLRF1, NK_XCL1, and NKT_FCGR3A subclusters in the VR group, with upregulated expression of genes such as\n                      <jats:italic>SLC27A4<\/jats:italic>\n                      and\n                      <jats:italic>PTMA<\/jats:italic>\n                      . Taken together, our findings revealed that TAF demonstrates favorable safety and antiviral efficacy in patients with high\u2010replicative, low\u2010inflammatory HBV infection during the 48\u2010week follow\u2010up period, although complete virological suppression rates remain suboptimal. NK\u2010mediated mechanisms may contribute to antiviral success.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>\n                      <jats:bold>Trial Registration:<\/jats:bold>\n                      The trial was registered on ClinicalTrials.gov (NCT 04231565).\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jmv.70960","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T10:52:24Z","timestamp":1778151144000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tenofovir Alafenamide in the Treatment of Chronic Hepatitis B Virus Infection in the High\u2010Replicative Low\u2010Inflammatory Phase: A 48\u2010Week Randomized Controlled Trial"],"prefix":"10.1002","volume":"98","author":[{"given":"Qiumin","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Infectious Disease The Third Affiliated Hospital of Sun Yat\u2010Sen University Guangzhou Guangdong China"},{"name":"Guangdong Key Laboratory of Liver Disease Research The Third Affiliated Hospital of Sun Yat\u2010Sen University Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruixuan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease The Third Affiliated Hospital of Sun Yat\u2010Sen University Guangzhou Guangdong China"},{"name":"Guangdong Key Laboratory of Liver Disease Research The Third Affiliated Hospital of Sun Yat\u2010Sen University Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeqiong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease The Third Affiliated 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