{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:59:58Z","timestamp":1790315998344,"version":"4.1.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"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. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To determine whether IFI44L and SAMHD1 mRNA expression in peripheral blood mononuclear cells (PBMCs) is associated with treatment response and HBsAg clearance in patients with HBeAg-negative chronic hepatitis B (CHB) receiving pegylated interferon alpha (Peg-IFN-\u03b1).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this prospective cohort, HBeAg-negative patients with CHB received Peg-IFN-\u03b1 for 48\u202fweeks, with virological and serological responses assessed at week 48. Virological response (VR) or non-virological response (NVR) was defined according to serum HBV DNA, whereas serological response (SR) or non-serological response (NSR) was based on HBsAg loss. IFI44L and SAMHD1 mRNA levels in PBMCs collected at baseline and weeks 12 and 24 were quantified by quantitative real-time PCR. Correlation analyses were used to examine associations with changes in HBsAg and HBV DNA. Univariable and multivariable logistic regression analyses were conducted to identify factors independently associated with VR and SR, and receiver operating characteristic (ROC) curves were used to assess the discriminatory performance of the two genes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Following 48\u202fweeks of Peg-IFN-\u03b1 treatment, 53.95% of patients achieved VR and 36.84% achieved SR. IFI44L and SAMHD1 expression showed distinct on-treatment patterns according to virological and serological outcomes. Higher expression of either gene at weeks 12 and 24 was associated with greater reductions in HBsAg and HBV DNA at the corresponding time points, and week 12 expression was also positively associated with the subsequent declines in both markers by week 24. In multivariable analyses, IFI44L and SAMHD1 expression at weeks 12 and 24 remained independently associated with VR and SR at week 48. ROC analysis showed greater discriminatory performance at the on-treatment assessment points, with the highest AUCs observed at week 24. At this time point, IFI44L yielded AUCs of 0.8822 for VR and 0.8445 for SR, while SAMHD1 yielded AUCs of 0.8627 and 0.8400, respectively.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>IFI44L and SAMHD1 may represent candidate dynamic on-treatment biomarkers of host interferon responsiveness during Peg-IFN-\u03b1 therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmicb.2026.1976096","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:32:53Z","timestamp":1790314373000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Dynamic changes in IFI44L and SAMHD1 mRNA levels in PBMCs are associated with treatment response in HBeAg-negative chronic hepatitis B during peg-IFN-\u03b1 therapy"],"prefix":"10.3389","volume":"17","author":[{"given":"Hao","family":"Pang","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, The First Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinglin","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, The First Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianju","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Beibei Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, The First Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"7644","DOI":"10.3748\/wjg.v20.i24.7644","article-title":"HbeAg negative variants and their role in the natural history of chronic hepatitis B virus infection","volume":"20","author":"Alexopoulou","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1016\/j.jhep.2013.10.021","article-title":"Immune cell responses are not required to induce substantial hepatitis B virus antigen decline during pegylated interferon-alpha administration","volume":"60","author":"Allweiss","year":"2014","journal-title":"J. Hepatol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"S160","DOI":"10.1016\/s0168-8278(03)00319-2","article-title":"Chronic hepatitis B e antigen (HbeAg) negative, anti-Hbe positive hepatitis B: an overview","volume":"39","author":"Bonino","year":"2003","journal-title":"J. Hepatol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"691","DOI":"10.3390\/v14081691","article-title":"HbeAg-negative\/anti-Hbe-positive chronic hepatitis B: a 40-year-old history","volume":"14","author":"Bonino","year":"2022","journal-title":"Viruses"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"723196","DOI":"10.3389\/fimmu.2021.723196","article-title":"Hcv cure with direct-acting antivirals improves liver and immunological markers in Hiv\/Hcv-Coinfected patients","volume":"12","author":"Brochado-Kith","year":"2021","journal-title":"Front. Immunol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.1002\/hep.22760","article-title":"Hepatitis B virus surface antigen levels: a guide to sustained response to peginterferon alfa-2a in HbeAg-negative chronic hepatitis B","volume":"49","author":"Brunetto","year":"2009","journal-title":"Hepatology"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1462","DOI":"10.1016\/j.cgh.2007.09.005","article-title":"Serum hepatitis B surface antigen quantitation can reflect hepatitis B virus in the liver and predict treatment response","volume":"5","author":"Chan","year":"2007","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1407","DOI":"10.1016\/j.jhep.2014.08.033","article-title":"Hepatitis B flares in chronic hepatitis B: pathogenesis, natural course, and management","volume":"61","author":"Chang","year":"2014","journal-title":"J. Hepatol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1462","DOI":"10.1016\/j.bbrc.2014.07.023","article-title":"Inhibition of hepatitis B virus replication by Samhd1","volume":"450","author":"Chen","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1128\/JVI.00442-20","article-title":"Interferon alpha induces multiple cellular proteins that coordinately suppress Hepadnaviral covalently closed circular Dna transcription","volume":"94","author":"Cheng","year":"2020","journal-title":"J. Virol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1111\/jvh.13722","article-title":"Real-world study on HbsAg loss of combination therapy in HbeAg-negative chronic hepatitis B patients","volume":"29","author":"Chu","year":"2022","journal-title":"J. Viral Hepat."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1274","DOI":"10.1097\/HEP.0000000000001260","article-title":"Global burden of Hbv-related liver disease: primary liver cancer due to chronic Hbv infection increased in over one-third of countries globally from 2000 to 2021","volume":"82","author":"Danpanichkul","year":"2025","journal-title":"Hepatology"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1436576","DOI":"10.3389\/fonc.2024.1436576","article-title":"Unraveling Ifi44L's biofunction in human disease","volume":"14","author":"Du","year":"2024","journal-title":"Front. Oncol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1016\/j.jhep.2025.03.018","article-title":"Easl clinical practice guidelines on the management of hepatitis B virus infection","volume":"83","year":"2025","journal-title":"J. Hepatol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"e1005103","DOI":"10.1371\/journal.ppat.1005103","article-title":"Intrahepatic transcriptional signature associated with response to interferon-\u03b1 treatment in the woodchuck model of chronic hepatitis B","volume":"11","author":"Fletcher","year":"2015","journal-title":"PLoS Pathog."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"2972","DOI":"10.1128\/JCM.00760-17","article-title":"Serum hepatitis B virus Dna, Rna, and HbsAg: which correlated better with intrahepatic covalently closed circular Dna before and after Nucleos(t)ide analogue treatment?","volume":"55","author":"Gao","year":"2017","journal-title":"J. Clin. Microbiol."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1654","DOI":"10.1097\/HEP.0000000000000431","article-title":"Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D: report from the 2022 Aasld-Easl Hbv-Hdv treatment endpoints conference","volume":"78","author":"Ghany","year":"2023","journal-title":"Hepatology"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1111\/imm.12841","article-title":"Genome-wide host Rna signatures of infectious diseases: discovery and clinical translation","volume":"153","author":"Gliddon","year":"2018","journal-title":"Immunology"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.antiviral.2017.10.003","article-title":"Altered expression of interferon-stimulated genes is strongly associated with therapeutic outcomes in hepatitis B virus infection","volume":"147","author":"Han","year":"2017","journal-title":"Antivir. Res."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1186\/s12885-018-4529-9","article-title":"Ifi44L is a novel tumor suppressor in human hepatocellular carcinoma affecting cancer stemness, metastasis, and drug resistance via regulating met\/Src signaling pathway","volume":"18","author":"Huang","year":"2018","journal-title":"BMC Cancer"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"13383","DOI":"10.1038\/s41598-017-13747-9","article-title":"Switching to Pegifn\u03b1-2b leads to HbsAg loss in patients with low HbsAg levels and Hbv Dna suppressed by Nas","volume":"7","author":"Huang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1038\/nri3581","article-title":"Regulation of type I interferon responses","volume":"14","author":"Ivashkiv","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1016\/S0140-6736(22)01468-4","article-title":"Hepatitis B","volume":"401","author":"Jeng","year":"2023","journal-title":"Lancet"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1034968","DOI":"10.3389\/fimmu.2022.1034968","article-title":"Interferon and interferon-stimulated genes in Hbv treatment","volume":"13","author":"Li","year":"2022","journal-title":"Front. Immunol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1002\/cpt.3287","article-title":"Optimal treatment based on interferon no longer makes clinical cure of chronic hepatitis B far away: an evidence-based review on emerging clinical data","volume":"116","author":"Li","year":"","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/j.virs.2024.03.003","article-title":"Precore mutation enhances viral replication to facilitate persistent infection especially in HbeAg-negative patients","volume":"39","author":"Li","year":"","journal-title":"Virol. Sin."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1093\/infdis\/jiv547","article-title":"Peginterferon is superior to Nucleos(t)ide analogues for prevention of hepatocellular carcinoma in chronic hepatitis B","volume":"213","author":"Liang","year":"2016","journal-title":"J. Infect. Dis."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative Pcr and the 2(-Delta Delta C(T)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"790036","DOI":"10.3389\/fcimb.2021.790036","article-title":"Interferon gamma-inducible protein 16 of peripheral blood mononuclear cells may sense hepatitis B virus infection and regulate the antiviral immunity","volume":"11","author":"Lu","year":"2021","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1126\/science.1243462","article-title":"Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccdna","volume":"343","author":"Lucifora","year":"2014","journal-title":"Science"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1016\/j.jhep.2021.04.051","article-title":"Ubiquitous expression of HbsAg from integrated Hbv Dna in patients with low viral load","volume":"75","author":"Meier","year":"2021","journal-title":"J. Hepatol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1111\/hepr.13722","article-title":"Regulatory function of interferon-inducible 44-like for hepatitis B virus covalently closed circular Dna in primary human hepatocytes","volume":"52","author":"Nosaka","year":"2022","journal-title":"Hepatol. Res."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1002\/hep.23722","article-title":"Early on-treatment prediction of response to peginterferon alfa-2a for HbeAg-negative chronic hepatitis B using HbsAg and Hbv Dna levels","volume":"52","author":"Rijckborst","year":"2010","journal-title":"Hepatology"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1038\/nri2314","article-title":"Interferon-inducible antiviral effectors","volume":"8","author":"Sadler","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/nature09907","article-title":"A diverse range of gene products are effectors of the type I interferon antiviral response","volume":"472","author":"Schoggins","year":"2011","journal-title":"Nature"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"e2411988","DOI":"10.1002\/advs.202411988","article-title":"Nuclear overexpression of Samhd1 induces M phase stalling in hepatoma cells and suppresses Hcc progression by interacting with the cohesin complex","volume":"12","author":"Shao","year":"2025","journal-title":"Adv Sci (Weinh)"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"26616","DOI":"10.1038\/srep26616","article-title":"Restrictive influence of Samhd1 on hepatitis B virus life cycle","volume":"6","author":"Sommer","year":"2016","journal-title":"Sci. Rep."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1002\/hep.26436","article-title":"Response-guided peginterferon therapy in hepatitis B e antigen-positive chronic hepatitis B using serum hepatitis B surface antigen levels","volume":"58","author":"Sonneveld","year":"2013","journal-title":"Hepatology"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"9","DOI":"10.3851\/IMP1887","article-title":"Durable hepatitis B surface antigen decline in hepatitis B e antigen-positive chronic hepatitis B patients treated with pegylated interferon-\u03b12b: relation to response and Hbv genotype","volume":"17","author":"Sonneveld","year":"2012","journal-title":"Antivir. Ther."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"3551","DOI":"10.1016\/j.celrep.2019.11.041","article-title":"Type-I-IFN-stimulated gene Trim5\u03b3 inhibits HBV replication by promoting HBx degradation","volume":"29","author":"Tan","year":"2019","journal-title":"Cell Rep."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"1560","DOI":"10.1002\/hep.29800","article-title":"Update on prevention, diagnosis, and treatment of chronic hepatitis B: Aasld 2018 hepatitis B guidance","volume":"67","author":"Terrault","year":"2018","journal-title":"Hepatology"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"1310","DOI":"10.1073\/pnas.252773599","article-title":"Transcriptional and posttranscriptional control of hepatitis B virus gene expression","volume":"100","author":"Uprichard","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1111\/apt.16659","article-title":"Systematic review with meta-analysis: the impact of functional cure on clinical outcomes in patients with chronic hepatitis B","volume":"55","author":"Vittal","year":"2022","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"1425","DOI":"10.1053\/jhep.2002.37139","article-title":"Hbv genotype B is associated with better response to interferon therapy in HbeAg(+) chronic hepatitis than genotype C","volume":"36","author":"Wai","year":"2002","journal-title":"Hepatology"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"S134","DOI":"10.3350\/cmh.2024.0780","article-title":"Update on the treatment navigation for functional cure of chronic hepatitis B: expert consensus 2.0","volume":"31","author":"Wu","year":"2025","journal-title":"Clin. Mol. Hepatol."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1186\/s12876-020-01263-6","article-title":"HbsAg quantification predicts off-treatment response to interferon in chronic hepatitis B patients: a retrospective study of 250 cases","volume":"20","author":"Wu","year":"2020","journal-title":"BMC Gastroenterol."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"15","DOI":"10.14218\/JCTH.2013.00030","article-title":"Epidemiology of hepatitis B virus infection in China: current status and challenges","volume":"2","author":"Yan","year":"2014","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"876","DOI":"10.7150\/ijbs.125688","article-title":"Hepatocyte Samhd1 deficiency attenuates hepatic steatosis via suppression of Srebp activation in a mouse model of metabolic-associated Steatotic liver disease","volume":"22","author":"Yin","year":"2026","journal-title":"Int. J. Biol. Sci."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"1425","DOI":"10.14218\/JCTH.2023.00320","article-title":"Guidelines for the prevention and treatment of chronic hepatitis B (version 2022)","volume":"11","author":"You","year":"2023","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"18035","DOI":"10.33073\/pjm-2020-044","article-title":"Hepatitis B virus infection","volume":"4","author":"Yuen","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"ofaa208","DOI":"10.1093\/ofid\/ofaa208","article-title":"Short-term peginterferon-induced high functional cure rate in inactive chronic hepatitis B virus carriers with low surface antigen levels","volume":"7","author":"Zeng","year":"2020","journal-title":"Open Forum Infect. Dis."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"383","DOI":"10.7150\/ijms.39775","article-title":"Hbv Dna and HbsAg: early prediction of response to Peginterferon \u03b1-2a in HbeAg-negative chronic hepatitis B","volume":"17","author":"Zhang","year":"2020","journal-title":"Int. J. Med. Sci."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"105782","DOI":"10.1016\/j.antiviral.2023.105782","article-title":"Mechanism of interferon alpha therapy for chronic hepatitis B and potential approaches to improve its therapeutic efficacy","volume":"221","author":"Zhao","year":"2024","journal-title":"Antivir. 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