{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T18:22:29Z","timestamp":1791829349078,"version":"4.3.4"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immune checkpoint inhibitors (ICIs) have revolutionized the front-line treatment of advanced hepatocellular carcinoma (HCC). However, the comparative efficacy and safety of different ICI-based regimens\u2014and their consistency across etiologic subgroups [HBV, HCV, and non-HBV\/non-HCV (NBNC)]\u2014remain uncertain. This study conducted a Bayesian network meta-analysis (NMA) of recent randomized controlled trials (RCTs) to compare the first-line immunotherapy strategies both overall and by viral etiology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A systematic search of PubMed, Embase, the Cochrane Library, and Web of Science was conducted from inception through August 1, 2025. Prespecified primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes included objective response rate (ORR) and grade \u22653 treatment-related adverse events (TRAEs). Hazard ratios (HRs) and odds ratios (ORs) were pooled in a Bayesian NMA contrasting ICI-based regimens with tyrosine kinase inhibitor (TKI) monotherapy in the overall advanced HCC population and in HBV, HCV, and NBNC strata. Protocol registration: PROSPERO CRD420251131167.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Ten RCTs (n=7,301) evaluating 14 first-line regimens were included. Compared to TKI monotherapy, immunotherapy significantly improved OS (HR\u00a0=\u00a00.79, 95% CI 0.74-0.84) and PFS (HR\u00a0=\u00a00.70, 95% CI 0.58-0.85), increased ORR (OR\u00a0=\u00a03.20, 95% CI 2.49-4.12), and did not significantly increase grade \u22653 TRAEs (OR\u00a0=\u00a01.16, 95% CI 0.75-1.80). Benefits were more pronounced in HBV-positive patients (OS: HR\u00a0=\u00a00.73, 95% CI 0.67-0.79; PFS: HR\u00a0=\u00a00.54, 95% CI 0.48-0.61). HCV-positive patients also derived an OS benefit (HR\u00a0=\u00a00.82, 95% CI 0.72-0.93), whereas PFS improvement in NBNC patients was not statistically significant (HR\u00a0=\u00a00.74, 95% CI 0.52-1.06). In the NMA, sintilimab plus a bevacizumab biosimilar (Sinti-Bev) showed the greatest OS improvement versus sorafenib (HR\u00a0=\u00a00.57, 95% CI 0.43-0.75), followed by camrelizumab plus rivoceranib (Camre-Rivo; HR\u00a0=\u00a00.62, 95% CI 0.49-0.80). For PFS, anlotinib plus penpulimab (Anlo-Penpu) and Camre-Rivo ranked the highest (both HR\u00a0=\u00a00.52, 95% CI 0.41-0.66). Tislelizumab and nivolumab were associated with lower risks of grade \u22653 TRAEs. In etiology-stratified network analyses, atezolizumab plus bevacizumab (Atezo-Bev) showed the most consistent efficacy profile across virally mediated subgroups, with significant advantages for both OS and PFS in HBV-positive disease and a significant OS advantage in HCV-positive disease. However, no regimen achieved a statistically significant PFS advantage in the HCV-positive subgroup.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>First-line immunotherapy, compared to TKI monotherapy, provides meaningful survival benefits in advanced HCC, particularly in virally mediated disease, without significantly increasing severe toxicity. Among regimens, Sinti-Bev offers the most substantial OS advantage, while Anlo-Penpu and Camre-Rivo rank highest for PFS. Etiology-stratified analyses highlight Atezo-Bev as the most consistent regimen in virally mediated disease, with significant OS and PFS benefits in HBV-positive patients and a significant OS benefit in HCV-positive patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic Review Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/prospero\/display_record.php?ID=CRD420251131167<\/jats:ext-link>\n                      , identifier CRD420251131167.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1693251","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T04:25:37Z","timestamp":1778732737000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["First-line immunotherapy for advanced hepatocellular carcinoma: a network meta-analysis of randomized trials with overall and HBV\/HCV-stratified efficacy and safety"],"prefix":"10.3389","volume":"17","author":[{"given":"Wei","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Emergency General Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boyan","family":"Chen","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, Nanjing University of Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunbin","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiance","family":"Wei","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Emergency General Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenwen","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Clinical Nutrition, The Sixth Affiliated Hospital, Sun Yat-sen University","place":["Guangzhou, Guangdong, China"]},{"name":"Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 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