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Summary: Background: Lipid‐lowering effect was observed during treatment with tenofovir disoproxil fumarate (TDF) for chronic hepatitis B (CHB). However, the metabolic features in patients switching from TDF to tenofovir alafenamide (TAF) remain unclear. Aims: To compare the impacts of switching from TDF to TAF or from entecavir to TAF on body weight and metabolic features in patients with CHB. Methods: This was a multi‐centre, prospective, observational study in patients with CHB on TDF or entecavir who switched to TAF. Baseline characteristics, lipid profile and sugar profile were determined. This study received IRB approval from each hospital. Results: We enrolled 177 patients on TDF (99) or entecavir (78) and followed them for 48 weeks after the switch to TAF. At baseline, TDF‐experienced patients had lower serum triglyceride, total cholesterol, high‐density lipoprotein (HDL) cholesterol and low‐density lipoprotein (LDL) cholesterol than entecavir‐experienced patients. The switch from TDF to TAF significantly increased body weight, triglyceride, total cholesterol, HDL, LDL, fasting glucose, glycaemic haemoglobin, insulin and insulin resistance. The switch from entecavir to TAF did not affect these measures. There was no significant difference in atherosclerotic cardiovascular disease risk scores between groups. Conclusions: The switch from TDF to TAF was associated with weight gain, derangements of lipid profile, and increased insulin resistance in patients with CHB. Long‐term effects on these metabolic features need further investigation. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) usually recurs after curative surgical resection. Currently, no approved adjuvant therapy has been shown to reduce HCC recurrence rates. In this study, the in vivo effect of sequential combination treatment with recombinant mouse interferon-alpha (rmIFN-α) and an anti-mouse-PD1 antibody on hepatitis B virus (HBV) clearance in mice was evaluated. A Phase I clinical trial was then conducted to assess the safety, tolerability, and inhibitory activity of sequential therapy with ropeginterferon alfa-2b and nivolumab in patients with HCC recurrence who underwent curative surgery for HBV-related HCC. The animal modeling study showed that HBV suppression was significantly greater with the rmIFN-α and anti-PD1 sequential combination treatment in comparison with sole treatment with rmIFN-α or anti-PD1. In the Phase I study, eleven patients completed the sequential therapy with ropeginterferon alfa-2b every two weeks for six doses at 450 µg, followed by three doses of nivolumab every two weeks up to 0.75 mg/kg. A notable decrease in or clearance of HBV surface antigen was observed in two patients. The dose-limiting toxicity of grade 3 alanine transaminase and aspartate aminotransferase increases was observed in one patient. The maximum tolerated dose was then determined. To date, no HCC recurrence has been observed. The treatment modality was well tolerated. These data support the further clinical development of sequential combination therapy as a post-surgery prophylactic measure against the recurrence of HBV-related HCC. [ABSTRACT FROM AUTHOR]

Introduction: Optimal treatment of hepatocellular carcinoma (HCC) beyond the Milan criteria is in debate. We aimed to identify candidates for surgical resection (SR) in Barcelona Clinic Liver Cancer (BCLC)-A/B HCC beyond the Milan criteria with survival benefit. Methods: Patients with BCLC-A/B HCC beyond the Milan criteria at the National Taiwan University Hospital during 2005 and 2019 were screened, and those who received transarterial chemoembolization (TACE) or SR were consecutively included. The tumor burden was classified by the seven-eleven criteria into low (≤7), intermediate (7–11), or high (>11). Multivariable Cox proportional hazard regression analysis was used for outcome prediction. Results: Overall, 474 patients who received SR (n = 247) and TACE (n = 227) were enrolled. Patients who underwent SR were significantly younger with better liver reserve. There were 76 (31%) and 129 (57%) deaths in the SR and TACE groups after a median follow-up of 3.9 and 2.1 years, respectively. The seven-eleven criteria could distinguish median overall survival (OS) among low (n = 149), intermediate (n = 203), and high (n = 122) tumor burden groups (7.7 vs. 6.9 vs. 2.8 years, respectively, p < 0.001). Patients receiving SR had a significantly higher median OS compared with TACE in those with intermediate (8.2 vs. 2.6 years, p < 0.001) and high (5.6 vs. 1.5 years, p = 0.001) tumor burden. After adjustment for age, sex, and liver reserve, SR was predictive for better OS in intermediate (adjusted hazard ratio [aHR]: 0.45, 95% confidence interval [CI]: 0.27–0.75) and high tumor burden groups (aHR: 0.54, 95% CI: 0.32–0.92). The survival benefit of SR especially confines to patients within 3 tumors. Conclusions: In patients with BCLC-A/B HCC beyond the Milan criteria with tumor burden beyond the up-to-7 criteria but within 3 tumors, SR has better OS than TACE and should be considered in resectable patients. [ABSTRACT FROM AUTHOR]

Summary: Background: Data are limited regarding the risk of hepatitis C virus (HCV) reinfection after treatment‐induced sustained virologic response (SVR) in patients on haemodialysis. Aims: To assess the risk of HCV reinfection among patients on haemodialysis with treatment‐induced SVR. Methods: Patients on haemodialysis patients who achieved SVR12 with interferon (IFN) or direct‐acting antiviral (DAA)‐based treatment received follow‐up at SVR24 and then biannually with HCV RNA measurements. HCV reinfection was defined as the resurgence of viremia by different viral strains beyond SVR12. The low‐risk general population who achieved SVR12 and who underwent the same post‐SVR12 surveillance served as the reference group. Crude reinfection rates per 100 person‐years (PYs) were calculated. Multivariate Cox regression analysis was performed to estimate the relative risk of HCV reinfection between the two groups. Results: We recruited 374 patients on haemodialysis and 1571 reference patients with a mean post‐SVR12 follow‐up of 4.7 and 6.1 years. All haemodialysis patients who achieved SVR12 also achieved SVR24. The incidence rates of HCV reinfection were 0.23 per 100 PYs (95% confidence interval [CI]: 0.09‐0.59) in haemodialysis patients and 0.16 per 100 PYs (95% CI: 0.10‐0.26) in the reference group. The risk of HCV reinfection in patients on haemodialysis was comparable to that in the reference patients (hazard ratio [HR]: 1.39; 95% CI: 0.44‐4.38, P = 0.57). Conclusions: The risk of HCV reinfection in patients on haemodialysis who achieve SVR12 is low and comparable to that in the low‐risk general population. HCV microelimination in this special population is feasible once universal screening and scaled‐up treatment are implemented. [ABSTRACT FROM AUTHOR]

Genotoxic insult causes nuclear and mitochondrial DNA damages with macroautophagy/autophagy induction. The role of mitochondrial DNA (mtDNA) damage in the requirement of autophagy for nuclear DNA (nDNA) stability is unclear. Using site-specific DNA damage approaches, we show that specific nDNA damage alone does not require autophagy for repair unless in the presence of mtDNA damage. We provide evidence that after IR exposure-induced mtDNA and nDNA damages, autophagy suppression causes non-apoptotic mitochondrial permeability, by which mitochondrial ENDOG (endonuclease G) is released and translocated to nuclei to sustain nDNA damage in a TET (tet methylcytosine dioxygenase)-dependent manner. Furthermore, blocking lysosome function is sufficient to increase the amount of mtDNA leakage to the cytosol, accompanied by ENDOG-free mitochondrial puncta formation with concurrent ENDOG nuclear accumulation. We proposed that autophagy eliminates the mitochondria specified by mtDNA damage-driven mitochondrial permeability to prevent ENDOG-mediated genome instability. Finally, we showed that HBx, a hepatitis B viral protein capable of suppressing autophagy, also causes mitochondrial permeability-dependent ENDOG mis-localization in nuclei and is linked to hepatitis B virus (HBV)-mediated hepatocellular carcinoma development. Abbreviations: 3-MA: 3-methyladenine; 5-hmC: 5-hydroxymethylcytosine; ACTB: actin beta; ATG5: autophagy related 5; ATM: ATM serine/threonine kinase; DFFB/CAD: DNA fragmentation factor subunit beta; cmtDNA: cytosolic mitochondrial DNA; ConA: concanamycin A; CQ: chloroquine; CsA: cyclosporin A; Dox: doxycycline; DSB: double-strand break; ENDOG: endonuclease G; GFP: green fluorescent protein; Gy: gray; H2AX: H2A.X variant histone; HBV: hepatitis B virus; HBx: hepatitis B virus X protein; HCC: hepatocellular carcinoma; I-PpoI: intron-encoded endonuclease; IR: ionizing radiation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MOMP: mitochondrial outer membrane permeability; mPTP: mitochondrial permeability transition pore; mtDNA: mitochondrial DNA; nDNA: nuclear DNA; 4-OHT: 4-hydroxytamoxifen; rDNA: ribosomal DNA; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; TET: tet methylcytosine dioxygenase; TFAM: transcription factor A, mitochondrial; TOMM20: translocase of outer mitochondrial membrane 20; VDAC: voltage dependent anion channel. [ABSTRACT FROM AUTHOR]

Pre-treatment host and viral factors may affect serum ferritin levels in patients with hepatitis C virus (HCV) infection. We delineated pre-treatment factors associated with hyperferritinemia in these patients. 1682 eligible patients underwent pre-treatment assessment for serum ferritin and various host/viral factors. Univariate and multivariate logistic regression analyses were conducted to evaluate factors associated with hyperferritinemia. Multivariate logistic regression analyses revealed that age > 50 years (adjusted odds ratio [OR]: 1.38 (95% confidence interval [CI] 1.09-1.74), p = 0.008), fibrosis stage ≥ F3 (adjusted OR: 1.36 (95% CI 1.04-1.77), p = 0.02), fibrosis index based on four parameters (FIB-4) > 3.25 (adjusted OR: 1.46 (95% CI 1.11-1.92), p = 0.01), presence of metabolic dysfunction-associated steatotic liver disease (MASLD) (adjusted OR: 1.43 (95% CI 1.21-1.76), p = 0.001), and alanine transaminase (ALT) > 2 folds upper limit of normal (ULN) (adjusted OR: 2.87 (95% CI 2.20-3.75), p < 0.001) were associated hyperferritinemia. The log 10 value of HBV or HCV viral load was not associated with the log 10 value of ferritin level (Spearman's rank correlation coefficient: - 0.025, p = 0.81 and 0.002, p = 0.92). In conclusion, host factors, rather than viral factors, are associated with hyperferritinemia in patients with HCV., (© 2024. The Author(s).)

Background and Aims: Risk stratification for patients with a higher risk of hepatocellular carcinoma (HCC) is crucial. We aimed to investigate the role of the Fibrosis-4 (FIB-4) index in predicting chronic hepatitis C (CHC)-related HCC., Methods: A retrospective cohort study consecutively included treatment-naive CHC patients receiving longitudinal follow-up at the National Taiwan University Hospital from 1986 to 2014. The clinical data were collected and traced for HCC development. Multivariable Cox proportional hazard regression analysis was used to investigate the predictors for HCC., Results: A total of 1285 patients in the ERADICATE-C cohort were included. The median age was 54, 56% were females, and 933 had HCV viremia. There were 33%, 38%, and 29% of patients having FIB-4 index <1.45, 1.45-3.25, and ≥3.25, respectively. After a median of 9-year follow-up, 186 patients developed HCC. Multivariable analysis revealed that older age, AFP≥20 ng/mL, cirrhosis, and a higher FIB-4 index were independent predictors for HCC. Compared with patients with FIB-4 index <1.45, those with FIB-4 1.45-3.25 had a 5.51-fold risk (95% confidence interval [CI]: 2.65-11.46), and those with FIB-4 ≥ 3.25 had 7.45-fold risk (95% CI: 3.46-16.05) of HCC. In CHC patients without viremia, FIB-4 index 1.45-3.25 and FIB-4 ≥ 3.25 increased 6.78-fold and 16.77-fold risk of HCC, respectively, compared with those with FIB-4 < 1.45., Conclusion: The baseline FIB-4 index can stratify the risks of HCC in untreated CHC patients, even those without viremia. The FIB-4 index should thus be included in the management of CHC., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Epitranscriptomic RNA modifications have emerged as important regulators of the fate and function of viral RNAs. One prominent modification, the cytidine methylation 5-methylcytidine (m 5 C), is found on the RNA of HIV-1, where m 5 C enhances the translation of HIV-1 RNA. However, whether m 5 C functionally enhances the RNA of other pathogenic viruses remains elusive. Here, we surveyed a panel of commonly found RNA modifications on the RNA of hepatitis B virus (HBV) and found that HBV RNA is enriched with m 5 C as well as ten other modifications, at stoichiometries much higher than host messenger RNA (mRNA). Intriguingly, m 5 C is mostly found on the epsilon hairpin, an RNA element required for viral RNA encapsidation and reverse transcription, with these m 5 C mainly deposited by the cellular methyltransferase NSUN2. Loss of m 5 C from HBV RNA due to NSUN2 depletion resulted in a partial decrease in viral core protein (HBc) production, accompanied by a near-complete loss of the reverse transcribed viral DNA. Similarly, mutations introduced to remove the methylated cytidines resulted in a loss of HBc production and reverse transcription. Furthermore, pharmacological disruption of m 5 C deposition led to a significant decrease in HBV replication. Thus, our data indicate m 5 C methylations as a critical mediator of the epsilon elements' function in HBV virion production and reverse transcription, suggesting the therapeutic potential of targeting the m 5 C methyltransfer process on HBV epsilon as an antiviral strategy., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background & Aims: Risk scores have been designed to predict the development of hepatocellular carcinoma (HCC) in treatment-naive patients with chronic hepatitis B (CHB). However, little is known about their predictive accuracy in HBeAg-negative patients in the grey zone (GZ). We aimed to develop a HBcrAg-based HCC risk score and explore whether it outperforms other risk scores in GZ patients., Methods: Two retrospective cohorts of HBeAg-negative patients with American Association for the Study of Liver Diseases-defined GZ were established for derivation and validation (Taiwanese, N = 911; Japanese, N = 806). All of them were non-cirrhotic at baseline and remained treatment-naive during the follow-up. The primary endpoint was HCC development., Results: In a median follow-up period of 15.5 years, 85 patients developed HCC in the derivation cohort. We found that age, sex, alanine aminotransferase, platelet count, and HBcrAg, but not HBV DNA levels, were independent predictors and a 20-point GZ-HCC score was developed accordingly. The 10-year and 15-year area under the ROC curve (AUROC) ranged from 0.83 to 0.86, which outperformed the HBV DNA-based HCC risk scores, including REACH-B and GAG-HCC scores (AUROC ranging from 0.66 to 0.74). The better performance was also validated in EASL- and Asian Pacific Association for the Study of the Liver-defined GZ patients. These findings remained consistent in the validation cohort. Finally, the low-risk and high-risk GZ patients (stratified by a score of 8) had an HCC risk close to inactive CHB and immune-active CHB patients, respectively, in both cohorts., Conclusions: The HBcrAg-based GZ-HCC score predicts HCC better than other HBV DNA-based risk scores in GZ patients who are HBeAg-negative patients, which may help optimise their clinical management., Impact and Implications: We have developed a risk score based on HBcrAg, which has shown better predictive ability for HCC compared with other risk scores based on HBV DNA. Using a score of 8, GZ patients can be classified into low- and high-risk groups, which can guide follow up and early treatment, respectively. This validated risk score is a valuable tool for optimising the management of GZ patients who are HBeAg-negative., Competing Interests: T-CT has served on speaker’s bureaus for Fujirebio, Bristol-Myers Squibb, and Gilead Sciences and received grant support from Gilead Sciences. TH served as a speaker for Gilead Sciences, Eisai Co., Ltd, and Fujirebio. FS served as a speaker for Gilead Sciences. HK served as a speaker for Gilead Sciences, AbbVie Inc., MSD K.K., Eisai Co., Ltd, and Sumitomo Pharma. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Introduction: A set of genetic mutations to classify hepatocellular carcinoma (HCC) useful to clinical studies is an unmet need. Hepatitis B virus-related HCC (HBV-HCC) harbors a unique genetic mutation, namely, the HBV integration, among other somatic endogenous gene mutations. We explored a combination of HBV DNA integrations and common somatic mutations to classify HBV-HCC by using a capture-sequencing platform., Methods: A total of 153 HBV-HCCs after surgical resection were subjected to capture sequencing to identify HBV integrations and three common somatic mutations in genomes. Three mutually exclusive mutations, HBV DNA integration into the TERT promoter, HBV DNA integration into MLL4, or TERT promoter point mutation, were identified in HBV-HCC., Results: They were used to classify HBV-HCCs into four groups: G1 with HBV-TERT integration (25.5%); G2 with HBV-MLL4 integration (10.5%); G3 with TERT promoter mutation (30.1%); and G4 without these three mutations (34.0%). Clinically, G3 has the highest male-to-female ratio, cirrhosis rate, and associated with higher early recurrence and mortality after resection, but G4 has the best outcome. Transcriptomic analysis revealed a grouping different from the published ones and G2 with an active immune profile related to immune checkpoint inhibitor response. Analysis of integrated HBV DNA provided clues for HBV genotype and variants in carcinogenesis of different HCC subgroup. This new classification was also validated in another independent cohort., Conclusion: A simple and robust genetic classification was developed to aid in understanding HBV-HCC and in harmonizing clinical studies., Competing Interests: P.J.C. is the consultant and received a grant from TCM Biotech. S.T.T., C.F.H., and Y.C.W. are employees of TCM Biotech., (© 2023 The Author(s). Published by S. Karger AG, Basel.)