Journal of Hepatology最新文献

{"title":"Liposomal irinotecan for previously treated patients with biliary tract cancer: A pooled analysis of NIFTY and NALIRICC trials","authors":"Changhoon Yoo, Anna Saborowski, Jaewon Hyung, Patrick Wenzel, Ilhwan Kim, Henning Wege, Kyu-pyo Kim, Gunnar Folprecht, Baek-Yeol Ryoo, Phillip Schütt, Jaekyung Cheon, Thorsten Götze, Hyewon Ryu, Ji Sung Lee, Arndt Vogel","doi":"10.1016/j.jhep.2025.03.013","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.03.013","url":null,"abstract":"<h3>Background &amp; Aim</h3>Liposomal irinotecan (nal-IRI) combined with fluorouracil (5-FU)/leucovorin (LV) as a second-line treatment for biliary tract cancer (BTC) following progression on gemcitabine-based therapy in the Korean NIFTY and German NALIRICC trials yielded conflicting outcomes. This necessitated a comprehensive pooled analysis to evaluate its efficacy and safety.<h3>Methods</h3>Individual patient data were pooled from the intention-to-treat populations of the NIFTY and NALIRICC trials. The primary endpoint was progression-free survival (PFS).<h3>Results</h3>A total of 278 patients were included: 137 in the nal-IRI plus 5-FU/LV group and 141 in the 5-FU/LV group. The nal-IRI plus 5-FU/LV group showed significantly longer median PFS (3.6 months [95% confidence interval [CI], 2.7–4.4] vs 1.8 months (95% CI, 1.5–2.6), hazard ratio [HR) 0.65, p&lt;0.001). Median overall survival was 8.1 months (95% CI, 6.0–8.9) and 6.1 months (95% CI, 5.3–7.5), respectively (HR 0.77, p=0.051). Overall response rates (ORR) was also higher in the nal-IRI plus 5-FU/LV group (17.5% vs 2.8%; p&lt;0.001) than in the 5-FU/LV group. Post-study irinotecan-containing therapy was administered in 4 (2.9%) and 21 (15.3%) patients in the nal-IRI plus 5-FU/LV group and 5-FU/LV group, respectively. Adverse events varied by ethnicity, with gastrointestinal toxicities more common in Germans and neutropenia more prevalent in Koreans; treatment discontinuation without disease progression was 31.3% vs 8.0%, respectively.<h3>Conclusion</h3>The addition of nal-IRI to 5-FU/LV significantly improved PFS and ORR, supporting its potential as subsequent-line therapy. Differences in safety profiles underscore the relevance of ethnicity for nal-IRI in patients with BTC.<h3>Impact and implications</h3>Current standard of care for second-line therapy in patients with advanced biliary tract cancer (BTC) is FOLFOX. This study provides robust evidence supporting the potential role of additional liposomal irinotecan (nal-IRI) to fluorouracil and leucovorin (5-FU/LV) as a subsequent therapy for patients with BTC who have progressed on gemcitabine-based regimens. The findings demonstrate significant improvements in progression-free survival and overall response rates, emphasizing its potential to address the limited treatment options in this patient population. Furthermore, the study underscores the necessity of considering ethnic differences in adverse event profiles to optimize treatment administration and patient outcomes.<h3>Clinical Trial Registration number</h3>NCT03524508 and NCT03043547","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"1 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FMT for Hepatic Encephalopathy? The THEMATIC Trial aims to make is a ‘no brainer’","authors":"Debbie L. Shawcross, Vishal C. Patel","doi":"10.1016/j.jhep.2025.03.009","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.03.009","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Conflict of interest</h2>DLS has undertaken consultancy for Norgine Pharmaceuticals Ltd, EnteroBiotix, MRM Health, Satellite Biosciences, Apollo Therapeutics Ltd and Genfit and has delivered paid lectures for Norgine Pharmaceuticals Ltd.VCP has undertaken consultancy for Norgine Pharmaceuticals Ltd, Alfasigma S.p.A. Menarini Diagnostics Ltd. and AstraZeneca UK and has delivered paid lectures for Norgine Pharmaceuticals Ltd.Please refer to the accompanying ICMJE disclosure forms for further details.</section></section><section><section><h2>Authors’ contributions</h2>Both authors contributed equally to the writing of this editorial.</section></section><section><section><h2>Financial support</h2>No funding was received for the preparation of this manuscript.</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"209 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Benefits of multi-day ex situ perfusion include dampened ischemia reperfusion injury in liver transplantation","authors":"Florian Huwyler, Matthias Pfister, Jonas Binz, Mark W. Tibbitt, Pierre-Alain Clavien","doi":"10.1016/j.jhep.2025.03.020","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.03.020","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Authors' contributions</h2>Study design: F.H., M.P. J.B. M.W.T., P.-A.C. Funding Acquisition: M.W.T., P.-A. C. Data collection: F.H., M.P., J.B. Data analysis: F.H., M.P., J.B. Manuscript writing: F.H., M.P., J.B. Manuscript review: all authors reviewed and approved the final version of the manuscript for submission.</section></section><section><section><h2>Financial support</h2>Research was supported by the Wyss Zurich Translational Center, the FZ-Healthcare Foundation, the Liver and Gastrointestinal Disease Foundation and an ETH Zurich Research Grant.</section></section><section><section><h2>Declaration of Competing Interest</h2>P.-A.C. is co-inventor on patents related to long-term machine perfusion. M.W.T. and P.-A.C. are co-founders of Apersys AG, that aims to commercialize long-term perfusion technologies.</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"41 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unpicking the senescence paradox in MASLD-associated HCC","authors":"Prakash Ramachandran","doi":"10.1016/j.jhep.2025.02.034","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.02.034","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Background and context</h2>Patients with MASLD are at risk of progressive liver disease and the development of hepatocellular carcinoma (HCC). In response to chronic injury, hepatocytes can become senescent, a state of cell cycle arrest. The accumulation of senescent hepatocytes correlates with fibrosis stage and predicts adverse clinical outcomes in patients with metabolic dysfunction-associated steatotic liver disease (MASLD).¹^,² Senescent hepatocytes secrete a range of factors (called the senescence-associated</section></section><section><section><h2>Objectives, methods and findings</h2>In a recent article by Gu <em>et al.</em> in <em>Nature</em>, the authors aimed to address the question of how metabolic dysfunction-associated steatohepatitis (MASH) can simultaneously increase HCC risk whilst inducing replicative senescence in injured hepatocytes.⁶ They focussed on the enzyme fructose-1,6-bisphosphatase 1 (FBP1), a regulator of gluconeogenesis which has been shown to protect against HCC.⁷^,⁸ Using immunohistochemistry of an HCC cohort and analyses of large HCC databases, the authors</section></section><section><section><h2>Significance of findings</h2>This is a complex study which has shed new light on the kinetics of senescent hepatocytes in MASLD and HCC. The data presented results in a proposed model where MASH initially induces cellular stress and DNA damage, leading to FBP1 upregulation, p53 elevation and hepatocyte senescence, which initially prevents propagation of mutations and HCC development. However, in a subpopulation of disease-associated hepatocytes, ongoing stress, alterations in metabolic function and epigenetic modulations</section></section><section><section><h2>Financial support</h2>P.R. was funded by an MRC Senior Clinical Fellowship (MR/W015919/1).</section></section><section><section><h2>Conflict of interest</h2>The author of this paper declares that they do not have any conflict of interest.Please refer to the accompanying ICMJE disclosure forms for further details.</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"24 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cause-specific mortality in 13,099 patients with metabolic dysfunction-associated steatotic liver disease in Sweden","authors":"Gabriel Issa, Ying Shang, Rickard Strandberg, Hannes Hagström, Axel Wester","doi":"10.1016/j.jhep.2025.03.001","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.03.001","url":null,"abstract":"<h3>Background and aims</h3>Data on cause-specific mortality in metabolic dysfunction-associated steatotic liver disease (MASLD) are limited. We aimed to determine the rate and risk of death from different causes in patients with MASLD compared to the general population in Sweden.<h3>Methods</h3>In this population-based cohort study, we identified individuals with an ICD-10 code for MASLD in inpatient or specialized outpatient care using Swedish healthcare registers 2002-2020 (n=13,099) and matched them with up to 10 controls (median 9) from the general population for age, sex, municipality, and calendar year (n=118,884). We used Cox regression to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for eleven different primary causes of death. 15-year cumulative incidences of death were calculated while accounting for competing risks.<h3>Results</h3>In total, 1,628 (12.4%) deaths occurred in patients with MASLD and 9,119 (7.7%) in controls during a median follow-up of 4.7 (interquartile range [IQR] 2.0-9.2) and 5.8 years (IQR 2.7-10.5), respectively. MASLD was associated with higher all-cause mortality (HR=1.85, 95%CI=1.74-1.96) and higher rates of all specific causes of death except mental health disorder. The strongest associations were observed for non-hepatocellular carcinoma (HCC) liver-related (HR=26.9, 95%CI=19.4-37.3) and HCC-related mortality (HR=35.0, 95%CI=17.0-72.1). However, the highest estimated 15-year cumulative incidence of death in patients with MASLD was for non-HCC cancer (7.3%) and cardiovascular disease (7.2%).<h3>Conclusions</h3>MASLD was strongly associated with liver- and HCC-related mortality, but the absolute risks of death were highest for non-HCC cancer and cardiovascular disease. Mortality was increased for nearly all causes in patients with MASLD, suggesting that earlier multidisciplinary care is needed to reduce excess mortality.<h3>Impact and implications</h3>Previous studies on mortality in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) were either small, restricted to liver-related mortality, relying on liver biopsy to identify patients and thus inducing selection bias, or mainly using data from old cohorts. In a nationwide cohort study of all patients diagnosed with MASLD in inpatient or specialized outpatient care in Sweden between 2002 and 2020, we found a nearly doubled all-cause mortality rate and higher mortality than the general population from a wide range of causes, indicating that earlier multidisciplinary care may be needed to reduce premature mortality in patients with MASLD. The absolute risk estimates of death in our study may be useful for clinicians and policymakers to inform patients about their prognosis and potentially implement clinical or public health strategies to reduce premature mortality.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"93 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply to: “An ER Transmembrane Protein Protects Against Hepatic Ischemia-Reperfusion Injury By Inhibiting ER-phagy and Apoptosis?”","authors":"Hongjun Yu, Yong Ma","doi":"10.1016/j.jhep.2025.03.014","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.03.014","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Financial support</h2>This work was jointly supported by grants from the National Natural Scientific Foundation of China (82370643, 81470876 and 81100305), the Natural Science Foundation of Heilongjiang Province of China (LC2018037), the Heilongjiang Postdoctoral Foundation (LBHQ17097 and LBH-Z11066), and the Scientific Foundation of the First Affiliated Hospital of Harbin Medical University (HYD2020JQ0007 and 2019L01).</section></section><section><section><section><h2>Authors' contributions</h2>H.Y. drafted the initial manuscript. Y.M. reviewed and revised the manuscript. All authors approved the final manuscript as submitted.</section></section></section><section><section><h2>Declaration of Competing Interest</h2>The authors declare no conflicts of interest associated with this study. The authors declare no financial relationships relevant to this article.</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"41 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of albumin treatment duration on response rates and outcomes in patients with cirrhosis and acute kidney injury","authors":"Eva Maria Schleicher, Henrik Karbannek, Julia Weinmann-Menke, Peter Robert Galle, Andreas Stallmach, Simon Johannes Gairing, Alexander Zipprich, Cristina Ripoll, Christian Labenz","doi":"10.1016/j.jhep.2025.03.008","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.03.008","url":null,"abstract":"<h3>Background and Aims</h3>Guidelines recommended volume expansion with albumin for 48 hours for patients with cirrhosis and acute kidney injury (AKI) to correct hypovolemia and rule out prerenal AKI. A recent update in the Acute Disease Quality Initiative (ADQI)-International Club of Ascites (ICA) consensus guidelines suggested shortening this duration to 24 hours, primarily based on expert opinion. This study aimed to evaluate the response rates to albumin treatment after 24 and 48 hours and to compare and assess the prognostic significance of three different definitions of response to albumin therapy.<h3>Methods</h3>Data from 127 prospectively recruited patients with cirrhosis and AKI from two German centers were analyzed. We examined three response definitions after 24 and 48 hours: (1) serum creatinine (SCr) decrease &gt; 0.3 mg/dl, (2) SCr decrease &gt;25 %, and (3) SCr decrease in at least one AKI stage. Follow-up was prolonged until liver transplantation, death or hemodialysis (HD).<h3>Results</h3>Overall, 30-54 % of the patients responded to albumin treatment depending on the definition, and response rates were balanced across AKI stages. Notably, a relevant number of patients who responded at 48 hours did not respond within the first 24 hours. Additional response to albumin during the second 24 hours were 38 %, 24 %, and 25 % (definitions 1, 2, and 3, respectively). Response according to definition 3 was associated with a better HD- and transplantation-free survival.<h3>Conclusion</h3>A substantial proportion of patients requires 48 hours to respond to albumin treatment. Shortening time of albumin therapy may lead to overtreatment with terlipressin.<h3>Impact and Implications</h3>This study provides valuable insights into the optimal duration of albumin treatment for patients with cirrhosis and acute kidney injury (AKI), challenging the recent recommendation of shortening the treatment period with albumin. Furthermore, the optimal definition for response to albumin (reduction of at least one AKI stage) has been assessed. The results of this study are highly clinically relevant since shortening albumin therapy may lead to overtreatment with terlipressin, and evidence to support the choice of the definition of response to albumin was lacking. Clinicians can use these findings to predict treatment outcomes better, avoid fluid overload, and improve patient prognosis while also considering the potential risks of early intervention with terlipressin.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"25 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Positioning the liver at the centre of fructose-associated extrahepatic cancer","authors":"Thomas Marjot","doi":"10.1016/j.jhep.2025.02.021","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.02.021","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Background and context</h2>The consumption of fructose, typically as sucrose or high-fructose corn syrup, has exploded over the last few decades. Nutritional survey data collected in North America between the 1970s and 2000s indicate that the contribution of fructose to daily calorie intake has increased by over 25% across all demographics including adolescents and children.¹ This trend coincides with an exponential rise in the prevalence of metabolic diseases including obesity, metabolic dysfunction-associated steatotic</section></section><section><section><h2>Objectives, methods and findings</h2>This body of work involved a variety of techniques including the use of stable isotopes to trace the fate of dietary fructose in mice and to characterise its impact on the growth of implanted tumour cells. The authors then aimed to identify the circulating mediators of tumour behaviour using a combination of untargeted metabolomics and co-culture experiments between hepatocytes and cancer cell lines.Firstly, fructose supplementation was found to promote tumour growth across a range of zebra</section></section><section><section><h2>Significance of findings</h2>Dietary fructose represents a shared risk factor for MASLD and extrahepatic cancers. The negative impact of fructose on the liver appears to be mediated by a number of pathogenic pathways including increased visceral adiposity, insulin resistance, and hepatic <em>de novo</em> lipogenesis (DNL). These effects are not entirely related to overnutrition, with calorie-matched clinical studies showing greater deterioration in metabolic parameters with high-fructose compared to high-glucose diets.¹³^,¹⁴ As is</section></section><section><section><h2>Financial support</h2>T.M. is supported by a <span>National Institute for Health Research</span> (NIHR) Academic Clinical Lectureship. The views expressed are those of the author and not necessarily those of the <span>National Health Service</span> (NHS), the NIHR or the Department of Health.</section></section><section><section><h2>Conflict of interest</h2>T.M. has no conflicts of interest to declare.Please refer to the accompanying ICMJE disclosure forms for further details.</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"78 2 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subtypes of MASLD confer distinct clinical trajectories","authors":"Panu K. Luukkonen","doi":"10.1016/j.jhep.2025.02.032","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.02.032","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Background and context</h2>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major global health concern, affecting up to one-third of the population.¹ It can progress from simple hepatic steatosis to more severe stages such as steatohepatitis and cirrhosis, and ultimately liver-related mortality, often as a result of hepatic decompensation.¹ Additionally, MASLD is strongly associated with extrahepatic complications, including cardiovascular disease and various malignancies, which further contribute</section></section><section><section><h2>Objectives, methods, and findings</h2>The primary aim of the study was to identify distinct subtypes of MASLD with similar histological severity but differing biological profiles and associated cardiovascular risk. To achieve this, the authors employed a data-driven clustering approach to classify a cohort of 1,389 bariatric surgery patients from France. The cohort was stratified into clusters based on six clinical variables: age, body mass index, plasma triglycerides, hemoglobin A1c, alanine aminotransferase (ALT), and LDL</section></section><section><section><h2>Significance of findings</h2>The study by Raverdy <em>et al.</em> advances our understanding of the clinical heterogeneity observed in MASLD. By applying a data-driven clustering approach, the authors identified two distinct subtypes of MASLD – ‘cardiometabolic’ and ‘liver-specific’ – that carry different prognostic implications for liver and cardiovascular disease. Both subtypes are associated with an increased risk of liver disease, but only the ‘cardiometabolic’ subtype is linked to a significantly higher risk of cardiovascular</section></section><section><section><h2>Declaration of AI-assisted technologies in the writing process</h2>During the preparation of this work the author used GPT-4 in order to proofread the manuscript. After using this tool, the author reviewed and edited the content as needed and takes full responsibility for the content of the publication.</section></section><section><section><h2>Financial support</h2>Dr. Luukkonen was supported by the <span>Academy of Finland</span> (<span>350545</span>), the Sigrid Jusélius Foundation, the <span>Novo Nordisk Foundation</span> (<span>NNF22OC0074397</span>), the <span>Emil Aaltonen Foundation</span>, the <span>Finnish Medical Foundation</span>, the Wilhelm and Else Stockmann's Foundation and the Early Career Investigator fund of the <span>University of Helsinki</span>.</section></section><section><section><h2>Conflict of interest</h2>The author of this study declares that they do not have any conflict of interest.Please refer to the accompanying ICMJE disclosure forms for further details.</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"50 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Norway rat hepacivirus resembles hepatitis C virus in terms of intra-host evolution and escape from neutralizing antibodies","authors":"Caroline E. Thorselius, Raphael Wolfisberg, Ulrik Fahnøe, Troels K.H. Scheel, Kenn Holmbeck, Jens Bukh","doi":"10.1016/j.jhep.2025.02.044","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.02.044","url":null,"abstract":"<h3>Background and Aims</h3>Norway rat hepacivirus 1 (NrHV) is an attractive surrogate model for evaluating vaccine strategies against hepatitis C virus (HCV). Yet the immune response in NrHV infections remains poorly understood, particularly the role of neutralizing antibodies (nAbs). Here, we explore nAb development and viral evolution during chronic NrHV infection of inbred rats to understand neutralization and viral escape dynamics.<h3>Methods</h3>Lewis rats inoculated with the NrHV RHV-rn1 strain were monitored for &gt;52 weeks. Viremia was quantified by RT-qPCR, and NrHV nAbs were characterized by infectious cell culture-based neutralization assays and challenge experiments. Viral evolution was followed over time by whole open reading frame deep sequencing.<h3>Results</h3>In most animals, high levels of nAbs appeared after 20 to 45 weeks of infection, coinciding with the emergence of numerous mutations in the envelope proteins. Incorporation of these E1/E2 mutations into cell-culture-adapted RHV-rn1 reduced sensitivity to neutralization by autologous contemporary serum. Five key recurrent E1/E2 substitutions (E209K, R224Q, V275I, T500K, and L569P) were identified, collectively impairing serum neutralization, with E209K in E1 alone proving sufficient to confer neutralization escape. In contrast, NrHV-infected rats devoid of nAbs displayed fewer envelope mutations. Finally, pretreatment of cells with rat serum with high-titer nAbs led to partial control of NrHV-infection, and passive immunization with such sera protected SCID mice from subsequent challenge.<h3>Conclusions</h3>This study demonstrates the correlation between nAbs and viral evolution during long-term NrHV infection. The observed humoral immunity for NrHV infection closely resembles that of chronic HCV infection, where late-emerging high-level nAbs fail to clear evolving viral populations, thereby contributing to the evasion of the adaptive immune response. Preexisting antibodies do, however, protect from infection.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"214 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143631290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}