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Background: Hepatitis B virus (HBV)-specific T cell response is a major host immune response to control the virus. However, it is still unclear how it affects long-term outcomes of chronic hepatitis B patients, especially those who stop nucleos(t)ide analogue (NA) therapy. We aimed to explore whether the HBV-specific T cell response at the end of treatment (EOT) was associated with clinical outcomes., Methods: In a prospective cohort study, 51 HBeAg-negative patients who discontinued NA therapy were enrolled., Results: In a mean follow-up of 25.3 months, 25 patients developed clinical relapse. We found that a stronger hepatitis B core (HBc)-specific T cell response at EOT was associated with a lower risk of clinical relapse. Compared to the low-response group, the high-response group had a lower risk of clinical relapse with hazard ratio of 0.21 (95% CI: 0.05-0.88). The high HBc-specific T cell response was associated with reduced surge of HBV DNA and HBcrAg during the first year of follow-up. The T cell response at EOT was comparable between different NA treatments. Notably, the overall HBV-specific T cell response could be partially restored along with clinical relapse; however, such reinvigorated T cell response was not associated with HBsAg seroclearance., Conclusions: A higher HBc-specific T cell response at EOT was associated with lower risk of clinical relapse and reduced surge of HBV DNA and HBcrAg levels off NA therapy., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Chronic hepatitis B (CHB) was, and still is, a prevalent liver disease in the world, especially high in the Asia-Pacific areas. With the advent of preventive vaccines and effective viral suppression drugs and active implementations, CHB has gradually become under control. The world-wide prevalence reduces from 4.2% in 1980 to 3.2% in 2020 study. CHB patients receiving long-term antiviral therapies significantly improve the clinical outcomes, saving from end-stage liver diseases. Despite of these impressive progresses, to meet the WHO sustained development goals (SDG) for CHB control, a 90% reduction of incidence and a 65% reduction of mortality in year 2030, there is still a long way to go. In this review, four ongoing approaches have been proposed: (i) A continuous monitoring of long-term vaccine efficacy in vaccinated populations; (ii) consolidating the hepatitis B virus vaccination program against vaccine hesitancy and limited resources; (iii) rolling-out current oral antivirals to more CHB patients not only for diseases treatment but also for infection preventions; and (iv) development of curative therapies, both friendly-to-dispense and affordable. A coherent and persevere efforts by the society may succeed and achieve the SDG for CHB in the future., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background & Aims: HBV expresses more than 10 spliced RNAs from the viral pregenomic RNA, but their functions remain elusive and controversial. To address the function of HBV spliced RNAs, we generated splicing-deficient HBV mutants and conducted experiments to assess the impact of these mutants on HBV infection., Methods: HepG2-NTCP cells, human hepatocyte chimeric FRG mice (hu-FRG mice), and serum from patients with chronic hepatitis B were used for experiments on HBV infection. Additionally, SHifter assays and cryo-electron microscopy were performed., Results: We found the infectivity of splicing-deficient HBV was decreased 100-1,000-fold compared with that of wild-type HBV in hu-FRG mice. Another mutant, A487C, which loses the most abundant spliced RNA (SP1), also exhibits severely impaired infectivity. SP1 hypothetically encodes a novel protein HBc SP1 (HBc -Cys ) that lacks the C-terminal cysteine from full-length HBc. In the SHifter assay, HBc SP1 was detected in wild-type viral particles at a ratio of about 20-100% vs. conventional HBc, as well as in the serum of patients with chronic hepatitis B, but not in A487C particles. When infection was conducted with a shorter incubation time of 4-8 h at lower PEG concentrations in HepG2-NTCP cells, the entry of the A487C mutant was significantly slower. SP1 cDNA complementation of the A487C mutant succeeded in rescuing its infectivity in hu-FRG mice and HepG2-NTCP cells. Moreover, cryo-electron microscopy revealed a disulfide bond between HBc cysteine 183 and 48 in the HBc intradimer of the A487C capsid, leading to a locked conformation that disfavored viral entry in contrast to the wild-type capsid., Conclusions: Prior studies unveiled the potential integration of the HBc -Cys protein into the HBV capsid. We confirmed the proposal and validated its identity and function during infection., Impact and Implications: HBV SP1 RNA encodes a novel HBc protein (HBc SP1 ) that lacks the C-terminal cysteine from conventional HBc (HBc -Cys ). HBc SP1 was detected in cell culture-derived HBV and confirmed in patients with chronic infection by both immunological and chemical modification assays at 10-50% of capsid. The splicing-deficient mutant HBV (A487C) impaired infectivity in human hepatocyte chimeric mice and viral entry in the HepG2-NTCP cell line. Furthermore, these deficiencies of the splicing-deficient mutant could be rescued by complementation with the SP1-encoded protein HBc SP1 . We confirmed and validated the identity and function of HBc SP1 during infection, building on the current model of HBV particles., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Hepatitis B surface antigen (HBsAg) seroclearance is the goal of functional cure for hepatitis B virus (HBV) infection. However, the impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on this favorable outcome remains unclear., Methods: Patients with chronic hepatitis B (CHB) were consecutively recruited. MASLD was defined by the newly proposed disease criteria. Cumulative incidences and associated factors of HBsAg seroclearance/seroconversion were compared between the MASLD and non-MASLD groups., Results: From 2006 to 2021, 4084 treatment-naive hepatitis B e antigen (HBeAg)-negative CHB patients were included. At baseline, CHB patients with concurrent MASLD (n = 887) had significantly lower levels of HBsAg and HBV DNA than the non-MASLD group (n = 3197). During a median follow-up of 5.0 years, MASLD was associated with a higher likelihood of HBsAg seroclearance (adjusted hazard ratio [aHR], 1.43; 95% confidence interval [CI], 1.10-1.85; P = .007), and the accumulation of individual metabolic dysfunctions additively facilitated HBsAg seroclearance. In addition, a higher rate of HBsAg seroconversion was observed in patients with MASLD versus those without MASLD (aHR, 1.37; 95% CI, 1.00-1.86; P = .049). In sensitivity analysis, patients with intermittent MASLD had an intermediate probability of HBsAg seroclearance. After balancing clinical and virologic profiles by inverse probability of treatment weighting (IPTW), MASLD was still associated with a higher HBsAg seroclearance rate (IPTW-adjusted HR, 1.41; 95% CI, 1.09-1.84; P = .010)., Conclusions: In untreated HBeAg-negative CHB patients, concurrent MASLD is associated with higher rates of HBsAg seroclearance and seroconversion. Metabolic dysfunctions have additive effects on the functional cure of CHB., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

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., (© 2023 John Wiley & Sons Ltd.)

Background & Aims: A long immune-tolerant (IT) phase lasting for decades and delayed HBeAg seroconversion (HBe-SC) in patients with chronic hepatitis B (CHB) increase the risk of liver diseases. Early entry into the immune-active (IA) phase and HBe-SC confers a favorable clinical outcome with an unknown mechanism. We aimed to identify factor(s) triggering IA entry and HBe-SC in the natural history of CHB., Methods: To study the relevance of gut microbiota evolution in the risk of CHB activity, fecal samples were collected from CHB patients (n = 102) in different disease phases. A hepatitis B virus (HBV)-hydrodynamic injection (HDI) mouse model was therefore established in several mouse strains and germ-free mice, and multiplatform metabolomic and bacteriologic assays were performed., Results: Ruminococcus gnavus was the most abundant species in CHB patients in the IT phase, whereas Akkermansia muciniphila was predominantly enriched in IA patients and associated with alanine aminotransferase flares, HBeAg loss, and early HBe-SC. HBV-HDI mouse models recapitulated this human finding. Increased cholesterol-to-bile acids (BAs) metabolism was found in IT patients because R gnavus encodes bile salt hydrolase to deconjugate primary BAs and augment BAs total pool for facilitating HBV persistence and prolonging the IT course. A muciniphila counteracted this activity through the direct removal of cholesterol. The secretome metabolites of A muciniphila, which contained small molecules structurally similar to apigenin, lovastatin, ribavirin, etc., inhibited the growth and the function of R gnavus to allow HBV elimination., Conclusions: R gnavus and A muciniphila play opposite roles in HBV infection. A muciniphila metabolites, which benefit the elimination of HBV, may contribute to future anti-HBV strategies., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Coronavirus disease 2019 (COVID-19) vaccines were rapidly implemented globally and vaccine-associated immune-related hepatitis was recently reported. We aim to investigate its impact in regions endemic of chronic hepatitis B (CHB)., Methods: We retrospectively collected patients who developed hepatitis within 90 days after COVID-19 vaccination in Taiwan. The mechanisms of hepatitis included vaccine induced liver injury (VILI) and immune-related hepatitis, which are direct liver injuries defined as aspartate or alanine aminotransferase (AST or ALT) increased ≥ 5-fold upper limit of normal (ULN) and/or AST or ALT ≥ 3-fold of ULN with concurrent total bilirubin ≥ 2-fold of ULN. Indirect liver injury due to HBV reactivation was defined as HBsAg reverse seroconversion or significant rise in HBV DNA level. The demographics, clinical data, and course of hepatitis were compared statistically., Results: Twenty-five patients were included with a median age of 54. The culprit vaccines were ChAdOx1 nCoV-19 (n = 9), mRNA-1273 (n = 12), and BNT162b2 (n = 4). The characteristics of hepatitis were comparable regardless of vaccine subtypes. The median onset of hepatitis was 25 days post vaccination, with a peak of 10-fold ALT-increase. The etiologies included HBV reactivation (n = 10), VILI (n = 10), and immune-related hepatitis (n = 5). HBV reactivation accounts for 90% of vaccine-induced hepatitis in patients of CHB (n = 10), and two patients died. Patients with initial AST levels >500 U/L increased 27-fold risks of liver injury greater than moderate severity compared with those without., Conclusion: COVID-19 vaccine induced hepatitis is a clinical significant complication, and HBV reactivation may account for a possible mechanism., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2023 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Objective: Chronic hepatitis B (CHB) and metabolic dysfunction-associated fatty liver disease (MAFLD) are the leading causes of hepatocellular carcinoma (HCC). We aim to explore the impact of concurrent MAFLD on the risk of HCC in CHB., Methods: Patients with CHB were consecutively recruited from 2006 to 2021. MAFLD was defined by steatosis and either obesity, diabetes mellitus, or other metabolic abnormalities. The cumulative incidence of HCC and associated factors were compared between the MAFLD and non-MAFLD groups., Results: 10,546 treatment-naïve CHB patients were included with a median follow-up of 5.1 years. CHB patients with MAFLD (n = 2212) had fewer hepatitis B e antigen (HBeAg)-positivity, lower HBV DNA levels, and Fibrosis-4 index compared with the non-MAFLD group (n = 8334). MAFLD was independently associated with a 58% reduced risk of HCC (adjusted hazard ratio [aHR] 0.42, 95% confidence interval [CI] 0.25-0.68, p < 0.001). Furthermore, steatosis and metabolic dysfunction had distinct effects on HCC. Steatosis was protective against HCC (aHR 0.45, 95% CI 0.30-0.67, p < 0.001), while a greater burden of metabolic dysfunction increased the risk (aHR 1.40 per dysfunction increase, 95% CI 1.19-1.66, p < 0.001). The protective effect of MAFLD was further confirmed in analysis with inverse probability of treatment weighting (IPTW), patients who had undergone antiviral therapy, those with probable MAFLD, and after multiple imputation for missing data., Conclusions: Concurrent hepatic steatosis is independently associated with a lower risk of HCC, whereas the increasing burden of metabolic dysfunction aggravates the risk of HCC in untreated CHB patients., (© 2023. Asian Pacific Association for the Study of the Liver.)

Background/purpose: Distinct hepatitis relapse has been observed after discontinuing entecavir (ETV) or tenofovir disoproxil fumarate (TDF) therapy in chronic hepatitis B (CHB) patients. End-of-therapy (EOT) serum cytokines were compared and used for outcome prediction., Methods: A total of 80 non-cirrhotic CHB patients in a tertiary medical center in Taiwan who discontinued ETV (n = 51) or TDF (n = 29) therapy after fulfilling the APASL guidelines were prospectively enrolled. Serum cytokines were measured at EOT and 3rd month afterwards. Multivariable analysis was performed to predict virological relapse (VR, HBV DNA >2000 IU/mL), clinical relapse (CR, VR and alanine aminotransferase > 2-fold upper limit of normal) and hepatitis B surface antigen (HBsAg) seroclearance., Results: Compared with TDF group, ETV stoppers had greater interleukin 5 (IL-5), IL-12 p70, IL-13, IL-17 A and tumor necrosis factor alpha (TNF-alpha) (all P < 0.05) at EOT. Older age, TDF use, higher EOT HBsAg and IL-18 (Hazard ratio [HR], 1.01; 95% CI, 1.00-1.02) levels at EOT predicted VR, while older age, higher EOT HBsAg and IL-7 (HR, 1.25; 95% CI, 1.00-1.56) levels predicted CR. In TDF stoppers, higher IL-7 (HR, 1.29; 95% CI, 1.05-1.60) and IL-18 (HR, 1.02; 95% CI, 1.00-1.04) levels predicted VR, while IL-7 (HR, 1.34; 95% CI, 1.08-1.65) and interferon-gamma (IFN-gamma) (HR, 1.08; 95% CI, 1.02-1.14) levels predicted CR. A lower EOT HBsAg level was associated with HBsAg seroclearance., Conclusion: Distinct cytokine profiles were observed after stopping ETV or TDF. Higher EOT IL-7, IL-18, and IFN-gamma could be probable predictors for VR and CR in patients discontinuing NA therapies., Competing Interests: Declaration of competing interest T.-H. S. received research grant from Gilead Sciences, and was on speaker's bureaus for Abbvie, Bayer, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp and Dohme, and Takeda. J.-H. K. has served as a consultant for Abbvie, Gilead Sciences, Merck Sharp and Dohme, and Roche and on speaker's bureaus for Abbvie, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp and Dohme. No disclosure for other authors., (Copyright © 2023 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Seroclearance of hepatitis B surface antigen (HBsAg) indicates functional cure for hepatitis B virus (HBV) infection. Low HBsAg levels can predict HBsAg seroclearance over time. However, little is known about the association between hepatitis B core-related antigen (HBcrAg) levels and spontaneous seroclearance of HBsAg., Methods: We conducted a retrospective cohort study including 2614 treatment-naïve patients with chronic HBV infection who received long-term follow-up at the National Taiwan University Hospital. The primary end point was spontaneous HBsAg seroclearance. We aimed to explore whether HBcrAg levels could predict HBsAg seroclearance, especially for patients with HBsAg levels >1000 IU/mL., Results: There were 465 patients who cleared HBsAg with 32,414.72 person-years of follow-up, with a mean clearance rate of 1.43% per year. We found that lower HBcrAg levels at baseline were associated with an increased likelihood of HBsAg seroclearance (log rank P < .001). When restricting the study population to 1539 patients with HBsAg levels >1000 IU/mL, only HBcrAg <10,000 U/mL (vs ≥100,000 U/mL) served as an independent viral predictor for HBsAg seroclearance, with adjusted hazard ratio of 1.95 (95% CI, 1.16-3.27). In contrast to the late decline of HBsAg levels (5-9 years before HBsAg seroclearance), HBcrAg levels became undetectable 10-14 years before HBsAg seroclearance. This finding was confirmed by the different annual HBsAg seroclearance rates in the first and second decades of follow-up (0.97% vs 3.75%; P < .001) in patients achieving undetectable HBcrAg levels., Conclusions: Lower serum HBcrAg levels were associated with increased probability of HBsAg seroclearance over time. In patients with HBsAg levels >1000 IU/mL, clearing HBcrAg may serve as an early biomarker for HBsAg seroclearance., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Ropeginterferon alfa-2b is a novel mono-pegylated and extra-long-acting interferon, being developed for the treatment of myeloproliferative neoplasm (MPN) and chronic viral hepatitis. It has a favorable pharmacokinetic profile and less frequent dosing schedule, i.e., once every two to four weeks, compared to conventional pegylated interferon products, which have multiple isomers and are administered weekly. It was approved for the long-term treatment of polycythemia vera, an MPN, and has been included in the NCCN clinical practice guidelines for this indication. Ropeginterferon alfa-2b has demonstrated efficacy and showed a favorable safety profile for the treatment of chronic viral hepatitis in several clinical studies. In this article, we review its pharmacokinetics and available clinical data and suggest that ropeginterferon alfa-2b administered once every two weeks can serve as a new treatment option for patients with chronic viral hepatitis, including chronic hepatitis B, C, and D.

Introduction: Many patients with chronic hepatitis B (CHB) are classified as indeterminate patients because they fall outside the defined CHB phases. We aimed to explore hepatocellular carcinoma (HCC) risk in hepatitis B e antigen (HBeAg)-negative patients with indeterminate phase and investigated whether the risk could be stratified by serum levels of hepatitis B core-related antigen (HBcrAg)., Methods: Two retrospective cohorts enrolling HBeAg-negative, treatment-naïve CHB patients without cirrhosis were constructed (N = 2,150 in Taiwanese discovery cohort and N = 1,312 in Japanese validation cohort with a mean follow-up period of 15.88 and 12.07 years, respectively). The primary end point was HCC development., Results: According to the American Association for the Study of Liver Disease guidelines, 990 (46%) HBeAg-negative patients had indeterminate CHB phase at baseline in the Taiwanese cohort. Compared with the patients with inactive CHB and those with immune-active CHB, the indeterminate patients exhibited intermediate but diverse risk of HCC. When HCC risk was stratified by a HBcrAg level of 10,000 U/mL, 10-year HCC cumulative incidence was 0.51% and 5.33% for low HBcrAg and high HBcrAg groups, respectively, with a hazard ratio of 4.47 (95% confidence interval: 2.62-7.63). This cutoff was validated to stratify HCC risk not only in different subgroup analyses but also in an independent Japanese cohort. Finally, the overall HBeAg-negative CHB patients could be simply reclassified into high-risk and low-risk groups by combining ALT, hepatitis B virus DNA, and HBcrAg levels in both cohorts., Discussion: Serum HBcrAg level of 10,000 U/mL stratifies HCC risk in HBeAg-negative patients with indeterminate phase, which is useful for optimizing their clinical management., (Copyright © 2022 by The American College of Gastroenterology.)

Background: The risk of hepatocellular carcinoma (HCC) is reduced but not eliminated after nucleos(t)ide analogue (NA) therapy in chronic hepatitis B (CHB). We aimed to investigate the role of serum Prothrombin Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) and alpha-fetoprotein in predicting HCC and mortality in cirrhotic CHB patients at virological remission (VR) following NA therapy., Methods: Patients with CHB-related cirrhosis undergoing NA therapy from two medical centers in Taiwan were retrospectively included. Serum PIVKA-II were quantified by an automated chemiluminescence assay. Multivariable Cox proportional hazards regression models were used to identify predictors for HCC and death. Serial on-treatment PIVKA-II levels after VR were investigated., Results: Overall, 293 CHB-related cirrhosis patients were included. At VR, the mean age was 55, and the mean PIVKA-II level was 35 mAU/mL. After a mean follow-up of 78 months, 76 patients developed HCC and 19 died. After adjustment for confounding factors, alpha-fetoprotein >7 ng/mL (hazard ratio [HR]: 2.84, 95% confidence interval [CI]: 1.73-4.67) and PIVKA-II >50 mAU/mL (HR: 2.46, 95%CI: 1.35-4.49) at VR significantly predicted HCC development. In patients with alpha-fetoprotein ≤10 ng/mL or ≤20 ng/mL at VR, PIVKA-II >50 mAU/mL increased 2.45 or 3.16-fold risk of HCC, respectively. PIVKA-II levels after VR increased serially in patients who developed HCC afterwards., Conclusion: In patients with CHB-related cirrhosis, serum alpha-fetoprotein >7 ng/mL and PIVKA-II >50 mAU/mL at the time of antiviral therapy-induced VR is associated with a greater risk of HCC. PIVKA-II is a predictive marker for HCC in patients with low normal alpha-fetoprotein level., Competing Interests: Declaration of competing interest T.-H. S. received research grant from Gilead Sciences, and was on speaker's bureaus for Abbvie, Bayer, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp and Dohme, and Takeda. J.-H. K. has served as a consultant for Abbvie, Gilead Sciences, Merck Sharp and Dohme, and Roche and on speaker's bureaus for Abbvie, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp and Dohme. Others declare no conflict of interests., (Copyright © 2021. Published by Elsevier B.V.)

Hepatitis B virus (HBV) chronically infects 257 million people and is one of the most important liver diseases worldwide. A unique feature of HBV infection in humans is that viral clearance heavily depends on the age at exposure. Recent studies demonstrated that the virus takes advantage of immature innate immunity, especially hepatic macrophages, and not-yet-stabilized gut microbiota in early life to establish a chronic infection. The liver contains resident and infiltrating myeloid cells involved in immune responses to pathogens. They influence both innate and adaptive sectors of the immune system and their interplay with HBV has only been noticed recently. Here, we discuss how interactions between gut microbiota and hepatic macrophages influence the outcomes of HBV infection. Understanding the underlying mechanism would pave the way for the treatment of chronic HBV infection., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Persistent hepatitis B virus (HBV) infection results in chronic liver diseases that may progress to chronic hepatitis, liver cirrhosis, and subsequent hepatocellular carcinoma. Previous studies demonstrated that adaptive immunity, in particular CD8 T cells, is critical in HBV elimination. Recent studies have revealed a distinct tissue-localized T cell lineage, tissue-resident memory (TRM) cells, that is crucial for protective immunity in peripheral tissues. In this study, we showed that treatment with an anti-asialo GM1 (ASGM1) antibody (Ab), which depletes NK cells, led to impairment of HBV clearance in a mouse animal model. Unexpectedly, the ability to clear HBV was not significantly impaired in NFIL3 KO mice, which are deficient in NK cells, implying that other non-NK ASGM1-positive immune cells mediate HBV clearance. We isolated intrahepatic ASGM1-positive cells from NFIL3 KO mice and analyzed the immune phenotype of these cells. Our results demonstrated a distinct population of CD44 + LFA-1 hi CD8 T cells that were the major intrahepatic ASGM1-positive immune cells in NFIL3 KO mice. Importantly, transcriptome analysis revealed that these ASGM1-positive CD8 T cells had distinct gene profiles and shared a similar core gene signature with TRM cells. In addition to both transcriptional and phenotypic liver residency characteristics, ASGM1-positive CD8 T cells were able to home to and be retained in the liver after adoptive transfer. Taken together, our study results indicate that these ASGM1-positive liver-resident CD8 T cells are the major effector immune cells mediating anti-HBV immunity.

Background: Patients with chronic hepatitis B virus (HBV) infection are at risk of developing liver disease. Serum hepatitis B core-related antigen (HBcrAg) is a new biomarker for intrahepatic templates for HBV replication., Aim: To explore whether a high HBcrAg level is associated with increased risk of cirrhosis, especially in patients with intermediate viral load (HBV DNA 2000-19 999 IU/mL) due to their moderate risk of disease progression., Methods: A total of 1673 treatment-naïve, non-cirrhotic patients with negative hepatitis B e antigen (HBeAg) and alanine aminotransferase (ALT) level <40 U/L at baseline were enrolled. We explored the relationship between baseline levels of HBcrAg and cirrhosis development in all patients, and whether a higher HBcrAg level (<10 vs ≥10 KU/mL) was associated with an increased risk of disease progression in those with intermediate viral load., Results: Of the 1673 patients, 104 developed cirrhosis after a mean follow-up of 15.9 years. Higher HBcrAg levels were associated with increased incidence of cirrhosis, cirrhosis-related complications, and liver-related death. In 445 patients with intermediate viral load, the cirrhosis risk stratified by HBcrAg level of 10 KU/mL yielded a hazard ratio of 3.22 (95% CI: 1.61-6.47). The risk stratification remained significant when exploring other pre-cirrhosis endpoints, including HBeAg-negative hepatitis, hepatitis flare, and HBV DNA >20 000 IU/mL after 3 years of follow-up., Conclusions: In HBeAg-negative patients with normal ALT levels, higher HBcrAg levels are associated with increased risk of cirrhosis. Among those with intermediate viral load, HBcrAg <10 KU/mL defines a low-risk group for disease progression., (© 2021 John Wiley & Sons Ltd.)

Background: Ropeginterferon alfa-2b is a novel mono-pegylated interferon that has only one major form as opposed to 8-14 isomers of other on-market pegylated interferon, allowing injection every two or more weeks with higher tolerability. It received European Medicines Agency and Taiwan marketing authorization in 2019 and 2020, for treatment of polycythemia vera. This phase I/II study aimed to have preliminary evaluation of safety and efficacy in chronic hepatitis B., Methods: Thirty-one HBeAg-positive and 31 HBeAg-negative were stratified by HBeAg status and randomized at 1:1:1 ratio to q2w ropeginterferon alfa-2b 350 μg (group 1), q2w 450 μg (group 2) or q1w PEG-IFN alfa-2a 180 μg (group 3). Each patient received 48-week treatment (TW48) and 24-week post-treatment follow-up (FW24)., Results: The baseline demographics were comparable among the three groups, except for mean HBeAg in HBeAg-positive patients (2.90, 2.23, 2.99 log 10 S/CO, respectively). Cumulative HBeAg seroconversion rate at follow-up period was 27.3% (3/11), 36.4% (4/11), and 11.1% (1/9) with time to HBeAg seroconversion starting from TW24, TW16, and TW48 in group 1, 2, and 3, respectively. The rate of HBV DNA < 2000 IU/mL and HBsAg levels < 1500 IU/mL at FW24 were comparable in all groups. Ropeginterferon alfa-2b (group 1 & 2) had numerically lower incidence of rash (9.5% and 4.5%) as compared to PEG-IFN alfa-2a (36.8%). Ropeginterferon alfa-2b 350 μg (group 1) had more ALT elevation (38.1%), however the rate was comparable in group 2 (9.1%) and group 3 (10.5%)., Conclusion: In this preliminary study, ropeginterferon alfa-2b, although in only half the number of injections, is as safe and effective as pegylated interferon alfa-2a for chronic hepatitis B.

Background: Prophylaxis with nucleos(t)ide analogue (NA) is recommended to prevent hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)-positive patients receiving rituximab-based B-cell depletion therapy. However, little is known about the risk of clinical relapse after withdrawal of NA., Methods: We retrospectively analyzed 77 noncirrhotic HBsAg carriers with hematological cancer who received rituximab-containing chemotherapy. All of them received either prophylactic entecavir or tenofovir therapy. The risk of clinical relapse and hepatic decompensation after cessation of NA was explored., Results: Clinical relapse and hepatic decompensation developed in 25 (32.5 %) and 11 (14.3 %) of the patients, respectively, and 2 patients died of hepatic decompensation. Most of the hepatic events occurred within 1 year (20 of 25; 80.0%) after stopping NA. A higher pretreatment viral load (≥2000 vs <2000 IU/mL) was associated with increased risks of clinical relapse (hazard ratio, 3.47; 95% confidence interval, 1.56-7.73) and hepatic decompensation (9.91; 2.14-45.92). Of 51 patients with pretreatment viral load <2000 IU/mL, clinical relapse occurred in 10 (19.6 %) and hepatic decompensation in 2 (3.9%)., Conclusions: Pretreatment HBV DNA ≥2000 IU/mL is associated with increased risk of liver-related disease after cessation of prophylactic NA therapy in patients who received rituximab-containing chemotherapy., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Hepatitis B virus (HBV) infection and its related liver diseases are important health problems worldwide, particularly in the Asia-Pacific region. For the past 4-5 decades, Taiwan's government and scientists have cooperated together to control this virus infection and its related liver diseases. These efforts and achievements have made progress toward the elimination of HBV. Taiwan's government initiated the Viral Hepatitis Control Program (VHCP) in the1970s, and then launched the national vaccination program in 1984. This universal vaccination program effectively decreased the rate of hepatitis B carriage and the development of hepatocellular carcinoma (HCC) in the younger generation. Since 2003, approved anti-HBV treatments were reimbursed nationwide. This reimbursement program resulted in a higher uptake of anti-HBV treatments, which contributed to a decrease in liver-related disease progression and subsequently reduced attributable mortality in Taiwan. This experience can be shared by countries in other parts of the world regarding the control of chronic viral hepatitis B.

Background & Aims: Acute HEV infection causes varying degrees of liver damage. Although liver-related death due to HEV infection alone is rare in healthy individuals, it is unclear whether HEV superinfection is associated with worse outcomes in patients with chronic HBV infection. Thus, we explored whether HEV superinfection was associated with increased incidence of liver-related death, cirrhosis, and hepatocellular carcinoma (HCC)., Methods: Serum and data were collected from 2 independent retrospective cohorts of patients with chronic HBV infection, comprising 2,123 patients without cirrhosis and 414 with cirrhosis at baseline, respectively. All the patients were negative for HEV-IgG at enrolment and HEV superinfection was defined by the presence of HEV-IgG seroconversion., Results: In the non-cirrhotic cohort, 46 of 2,123 patients developed HEV superinfection. Though HEV superinfection was only associated with increased incidence of liver-related death in the overall cohort, it was a risk factor for all 3 endpoints (liver-related death, cirrhosis, and HCC) in a subgroup of 723 HBeAg-negative patients with chronic HBV infection. In addition, the 1-year mortality rate after HEV superinfection was higher in 4 patients who developed cirrhosis during the follow-up than in those who did not (50% vs. 2.4%, p = 0.001). To elucidate the perceived relationship between HEV superinfection and risk of mortality, an independent cohort of cirrhotic patients (n = 414) was further analyzed to control for the inherent increase in mortality risk due to cirrhosis. The 10 cirrhotic patients with HEV superinfection had a higher 1-year mortality rate than those without (30% vs. 0%, p <0.001)., Conclusions: In both cohorts of patients with chronic HBV infection, acute HEV superinfection increases the risk of liver-related death, especially in those with cirrhosis., Lay Summary: The mortality caused by acute hepatitis E virus infection is usually low in the healthy population, but it is unclear how it affects patients with chronic hepatitis B virus infection, as they already have compromised liver function. Our data show that the 1-year mortality rate is 35.7% in patients with hepatitis B-related cirrhosis who contract hepatitis E virus. Hepatitis E may accelerate disease progression in patients with chronic hepatitis B., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: To investigate serum Mac-2-binding protein glycosylation isomer (M2BPGi) levels in predicting hepatocellular carcinoma (HCC) and mortality at virological remission (VR, HBV DNA <20 IU/mL) following antiviral therapy in chronic hepatitis B (CHB) patients with cirrhosis., Methods: This retrospective cohort study included patients with CHB-related Child-Pugh A cirrhosis undergoing long-term antiviral therapy. Serum M2BPGi levels were quantified and multivariable Cox proportional hazards regression models were used to identify risk predictors for HCC and death., Results: A total of 126 and 145 patients were included in the derivation and validation cohorts, respectively. The mean age was 56, and the mean M2BPGi level was 1.86 cut-off index (COI) in the derivation cohort. After adjustment for confounders, a higher M2BPGi level at VR significantly predicted HCC (hazard ratio [HR]: 1.58, 95% confidence interval [CI]: 1.19-2.10, P=0.002) and death (HR: 2.17, 95% CI: 1.02-4.62, P=0.044). The M2BPGi ≥3 COI significantly increased the risk of HCC and death in the derivation and validation cohorts. Serial M2BPGi levels declined significantly (P=0.0001) in non-HCC patients only, and remained significantly lower than those who developed HCC afterwards (P=0.039)., Conclusions: Serum M2BPGi levels at antiviral therapy-induced VR predict HCC development and death in patients with CHB-related Child-Pugh A cirrhosis., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objective: This study aimed to develop a novel therapeutic vaccine based on a unique B cell epitope and investigate its therapeutic potential against chronic hepatitis B (CHB) in animal models., Methods: A series of peptides and carrier proteins were evaluated in HBV-tolerant mice to obtain an optimised therapeutic molecule. The immunogenicity, therapeutic efficacy and mechanism of the candidate were investigated systematically., Results: Among the HBsAg-aa119-125-containing peptides evaluated in this study, HBsAg-aa113-135 (SEQ13) exhibited the most striking therapeutic effects. A novel immunoenhanced virus-like particle carrier (CR-T3) derived from the roundleaf bat HBV core antigen (RBHBcAg) was created and used to display SEQ13, forming candidate molecule CR-T3-SEQ13. Multiple copies of SEQ13 displayed on the surface of this particulate antigen promote the induction of a potent anti-HBs antibody response in mice, rabbits and cynomolgus monkeys. Sera and purified polyclonal IgG from the immunised animals neutralised HBV infection in vitro and mediated efficient HBV/hepatitis B virus surface antigen (HBsAg) clearance in the mice. CR-T3-SEQ13-based vaccination induced long-term suppression of HBsAg and HBV DNA in HBV transgenic mice and eradicated the virus completely in hydrodynamic-based HBV carrier mice. The suppressive effects on HBsAg were strongly correlated with the anti-HBs level after vaccination, suggesting that the main mechanism of CR-T3-SEQ13 vaccination therapy was the induction of a SEQ13-specific antibody response that mediated HBV/HBsAg clearance., Conclusions: The novel particulate protein CR-T3-SEQ13 suppressed HBsAg effectively through induction of a humoural immune response in HBV-tolerant mice. This B cell epitope-based therapeutic vaccine may provide a novel immunotherapeutic agent against chronic HBV infection in humans., Competing Interests: Competing interests: We have read and understood BMJ policy on declaration of interests anddeclare that we have no competing interests., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/purpose: Hepatitis B virus (HBV) reactivation may occur in >10% of patients with lymphoma and resolved HBV infection who undergo rituximab-containing chemotherapy. Preventive strategies may have marked impact on resource allocation in HBV endemic areas. This study aims to compare the cost-effectiveness between prophylactic antiviral therapy and HBV DNA monitoring for the prevention of HBV-related complications., Methods: Data sources are studies of HBV-related events and survival for patients with lymphoma and resolved HBV infection published since 2006. Decision tree analysis was used to compare the incremental cost-effectiveness ratio (ICER) of preventing HBV-related death or liver decompensation for patients who undergo first-line rituximab-containing chemotherapy. Sensitivity analysis was performed to examine the impact of the preventive efficacy, the duration of prophylactic antiviral therapy, and the cost of different interventions. The direct medical cost was derived from the database of the NHI Administration, Taiwan. The time frame of our analysis was set to 3 years after the completion of chemotherapy., Results: The median ICER of prophylactic antiviral therapy, according to current practice guidelines, ranged between USD 150,000 and 250,000 if we apply the guidelines generally. When a long-course (12 months after completion of chemotherapy according to clinical guidelines) prophylactic therapy was assumed, Option A was cheaper and more effective only in the anti-HBs-negative subgroup (median ICER US$149,932 vs. US$161,526, p = 0.013)., Conclusion: Identification of anti-HBs-negative subgroups is critical to improve the cost-effectiveness of prophylactic antiviral therapy in lymphoma patients with resolved HBV infection., (Copyright © 2019 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

It is not clear whether baseline hepatitis B core antibody (anti-HBc) level in hepatitis B e antigen (HBeAg)-positive children with a normal alanine aminotransferase (ALT) level is predictive of spontaneous HBeAg seroconversion. We investigated the correlation between anti-HBc level and the natural course of chronic hepatitis B (CHB) virus (HBV) infection in children, particularly the ability of baseline anti-HBc level to predict spontaneous HBeAg seroconversion during long-term follow-up. HBeAg-positive children with untreated CHB and a normal ALT level were followed longitudinally. Anti-HBc level was determined by double-sandwich immunoassay. Effects of anti-HBc levels and other parameters on spontaneous HBeAg seroconversion and the natural course of CHB were assessed. A total of 182 children (106 males) with a median age at enrollment of 10.6 years (interquartile range [IQR], 10.3-15.3) were followed for a median of 19.8 years (IQR, 11.9-21.9). Spontaneous HBeAg seroconversion occurred in 85 children (46.7%) during the follow-up. A baseline anti-HBc titer of >500 IU/mL (hazard ratio [HR] = 2.81), HBV genotype B and B + C (HR = 3.46), and a baseline hepatitis B surface antigen titer of ≤4.8 log 10  IU/mL (HR = 3.09) were predictive of spontaneous HBeAg seroconversion, based on multivariable survival analysis (P < 0.001). In cases remaining HBeAg positive, their anti-HBc levels increased gradually during follow-up because of ongoing inflammation. Conclusion: Baseline anti-HBc level is predictive of spontaneous HBeAg seroconversion in HBeAg-positive children with a normal ALT level. Anti-HBc level reflects anti-HBV immune response in the HBeAg-positive normal ALT phase of CHB., (© 2019 by the American Association for the Study of Liver Diseases.)

Background & Aims: Chronic hepatitis B virus (HBV) infection is a risk factor for hepatocellular carcinoma (HCC). Serum levels of HB core-related antigen (HBcrAg) have been associated with active replication of HBV. We investigated whether HBcrAg levels are associated with development of HCC, especially in patients who do not require antiviral treatment., Methods: We collected data from 2666 adults positive for hepatitis B surface antigen (HBsAg), infected with HBV genotypes B or C, and without liver cirrhosis, who had long-term follow-up at the National Taiwan University Hospital from 1985 through 2000. None of the patients received antiviral treatment during the follow-up. Baseline levels of HBV DNA, HBsAg, and HBcrAg were determined retrospectively and participants were followed for a mean of 15.95 years. The primary end point was an association between serum level of HBcrAg and HCC development., Results: HCC developed in 209 patients in the cohort (incidence rate, 4.91 cases/1000 person-years). We found a positive association between baseline level of HBcrAg and HCC development; HBcrAg level was an independent risk factor in multivariable analysis. In the subgroup of hepatitis B e antigen-negative patients with HBV DNA levels from 2000 to 19,999 IU/mL (intermediate viral load [IVL]) and normal levels of alanine aminotransferase, HBcrAg levels of 10 KU/mL or more identified patients at increased risk of HCC (hazard ratio, 6.29; confidence interval, 2.27-17.48). Patients with an IVL and a high level of HBcrAg had a risk for HCC that did not differ significantly from that of patients with a high viral load (≥20,000 IU/mL). Patients with an IVL but a low level of HBcrAg had a low risk of HCC, with an annual incidence rate of 0.10% (95% confidence interval, 0.04%-0.24%)., Conclusions: In a long-term follow-up study of 2666 patients with chronic HBV infection (genotypes B or C), level of HBcrAg is an independent risk factor of HCC. Moreover, HBcrAg level of 10 KU/mL identifies patients with an IVL who are at high risk for HCC., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

For chronic hepatitis B patients, hepatitis B e antigen (HBeAg) seroclearance signals a transition from an immunologically active phase to an inactive carrier state with a reduction in hepatitis B virus (HBV) DNA levels and a reduced risk of hepatocellular carcinoma (HCC). 1 Predictors of HBeAg seroclearance include lower HBV DNA levels, viral genotype, the precore mutation, and higher serum alanine aminotransferase (ALT) levels. 2 ., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Chronic hepatitis B has been linked to lymphoma with contradictory results., Aim: To investigate the association between chronic hepatitis B and lymphoma by using a nationwide population-based cohort., Methods: Records of patients diagnosed with chronic hepatitis B (hepatitis B virus [HBV] cohort) or without (non-HBV cohort) during 2004-2007 were retrieved from the Taiwan National Health Insurance Research Database. Age, sex, comorbidities, and medical visits were matched using propensity scores between both cohorts, and they were followed up longitudinally until 2012 to determine any new lymphoma development., Results: A total of 203 031 patients were included in each cohort with a mean follow-up of 7-9 years. The lymphoma incidence rate was significantly higher in the HBV cohort than in the non-HBV cohort (29.4 vs 15.9 per 100 000 person-years, P < 0.0001). After adjustment for comorbidities and medical visits, HBV infection was found to be an independent risk factor associated with the development of lymphoma (hazard ratio [HR]: 2.07, 95% confidence interval [CI]: 1.76-2.43, P < 0.0001) and non-Hodgkin's lymphoma (HR: 2.18, 95% CI: 1.80-2.65, P < 0.0001); specifically with an increased risk of diffuse large B-cell lymphoma (HR: 2.69, 95% CI: 2.05-3.52, P < 0.0001), other B-cell lymphoma (HR: 3.11, 95% CI: 1.89-5.11, P < 0.0001), and also for multiple myeloma (HR: 1.63, 95% CI: 1.10-2.42, P = 0.016). The association was significant even after excluding lymphoma development within the first year (HR: 2.08, 95% CI: 1.75-2.47, P < 0.0001)., Conclusions: Chronic hepatitis B is temporally associated with a 2-fold increased risk of lymphoma, particularly with B-cell non-Hodgkin's lymphoma, and also an increased risk for multiple myeloma., (© 2019 John Wiley & Sons Ltd.)

Background and Aims: Patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection are at risk of developing adverse outcomes. Coinfection with both viruses may further increase the risk. Currently, little is known about the role of fibrosis-4 (FIB-4) index, a simple liver fibrosis stage biomarker, in predicting the clinical outcomes., Methods: We retrospectively enrolled 152 non-cirrhotic patients with dual chronic HCV and HBV infection: 56 patients received pegylated interferon/ribavirin therapy, while 96 patients remained untreated. The association between the FIB-4 index and the incidence of liver cirrhosis and hepatocellular carcinoma (HCC) was explored., Results: After a 9.88-year follow-up, the incidence of hepatitis B surface antigen seroclearance was 4.97 (95% confidence interval: 3.13-7.89) per 100 person-years in the treated group and was 1.77 (1.10-2.85) in the untreated group. Of the treated group, only three and six patients developed HCC and liver cirrhosis, respectively, while 17 and 23 patients developed HCC and liver cirrhosis, respectively, in untreated group. Baseline FIB-4 index correlated with the development of liver cirrhosis in multivariable analysis of all subjects. High baseline FIB-4 index (per 1 point increase) in the treated groups was associated with a higher risk of developing liver cirrhosis (P = 0.001) and HCC (P = 0.038) in univariable analysis. FIB-4 index decreased only in the treated group who achieved sustained virological response (n = 34, FIB-4 index decreasing from 1.84 to 1.55)., Conclusions: In Taiwanese patients coinfected with HCV and HBV, FIB-4 index helps identify patients at risk of developing adverse events, even in patients receiving pegylated interferon/ribavirin therapy., (© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

The experts of Taiwan Association for the Study of Liver (TASL) have actively participated and led the guidelines on hepatitis B virus (HBV) management by Asian Pacific Association for the Study of Liver (APASL) which is the first international association for the study of liver to publish the statement on HBV management before. However, there are more and more new data on the natural history and treatment of HBV infection in the past decade. These include new application of an old biomarker (quantitative HBsAg), clinical significance of HBV genotype and naturally occurring mutations, the role of non-invasive examination in evaluating severity of hepatic fibrosis, clinical significance of outcome calculators, new drug or new combination strategies towards more effective therapy and organ transplantation including liver and non-liver transplantation. It is time to publish the guidelines on HBV management of Taiwan. Hence, TASL have conducted an expert meeting to review, to discuss and to debate the relevant literatures, followed by draft the manuscript of HBV management guidelines and recommendations. The guidelines include general management, indications for fibrosis assessment, time to start or stop drug therapy, choice of drug to initiate therapy, when and how to monitor the patients during and after stopping drug therapy. Recommendations on the therapy of patients in special circumstances, including women in childbearing age, patients with antiviral drug resistance, concurrent viral infection, hepatic decompensation, patient receiving immune suppression or chemotherapy and patients in the setting of liver transplantation and hepatocellular carcinoma, are also included., (Copyright © 2018. Published by Elsevier B.V.)

Purpose To investigate the clinical utility and longitudinal change of acoustic radiation force impulse (ARFI) ultrasonographic (US) imaging in patients with chronic hepatitis B. Materials and Methods A retrospective cohort study of patients with chronic hepatitis B who underwent serial ARFI examinations in a tertiary referral center in Taiwan between 2012 and 2016 was conducted. The clinical information and noninvasive liver stiffness measurement tests (ARFI, Fibrosis-4 index [FIB-4], and FibroScan) were collected. Serial ARFI measurements were compared in patients without antiviral therapy (nontreatment group) and during antiviral therapy (treatment group). The linear mixed-effects model with random coefficients was used to compare longitudinal repeated measurements. Results A total of 559 patients undergoing serial ARFI examinations were included. The ARFI value correlated with FIB-4 (correlation coefficient = 0.55, P < .001) and FibroScan (correlation coefficient = 0.69, P < .001) results. There were 314 patients with five or more ARFI measurements in more than 3 years of follow-up. The ARFI value remained unchanged in the nontreatment group (n = 189, from 1.11 to 1.11 m/sec, time trend P = .911). However, the ARFI value declined significantly in the treatment group (n = 125, from 1.63 to 1.37 m/sec, time trend P < .001), both in patients with cirrhosis (n = 51, from 2.15 to 1.75 m/sec, time trend P < .001) and in those without (n = 74, from 1.27 to 1.11 m/sec, time trend P < .001). Conclusion ARFI US imaging is an important clinical noninvasive test for liver stiffness measurement and can be used for serial measurements in the management of chronic hepatitis B. Antiviral therapy significantly reduces liver stiffness during longitudinal follow-up., (© RSNA, 2018 Online supplemental material is available for this article.)

Background: We investigated the patterns and predictors for virological relapse (VR), clinical relapse (CR), and sustained clinical response (SCR) and the outcomes of retreatment after nucleos(t)ide analogue (NUC) therapy discontinuation., Methods: Patients with chronic hepatitis B who were discontinuing NUC therapy were prospectively enrolled. Viral and host predictors of relapse were evaluated, including hepatitis B virus (HBV) surface antigen (HBsAg) level, anti-HBV core antibody level, and presence of single-nucleotide polymorphisms in the genes encoding the receptors NTCP (rs2296651) and CTLA4 (rs231775) and in the 3' untranslated regions of the genes encoding HLA-DPA1 (rs3077) and HLA-DPB1 (rs9277535); posttherapy predictors of relapse were also investigated. Information about NUC retreatment and outcomes were recorded., Results: Overall, 100 patients discontinuing 3-year entecavir (ETV) or tenofovir (TDF) therapy were enrolled. Patients discontinuing TDF exhibited significantly higher rates of VR (52.9% vs 6.1%; P < .001) and CR (15.2% vs. 1.5%, P = .007) at 3 months than those discontinuing ETV, but relapse rates at 12 months were comparable. The end-of-therapy HBsAg levels predicted VR (hazard ratio [HR], 1.62; 95% confidence interval [CI], 1.19-2.21), CR (HR, 1.78; 95% CI, 1.13-2.81), and SCR (OR, 0.57; 95% CI, .35-.94). The CTLA4 (rs231775) non-GG genotype predicted VR (HR, 1.74; 95% CI, 1.01-3.00) and CR (HR, 2.06; 95% CI, 1.04-4.11), while the HLA-DPA1 (rs3077) AA genotype predicted SCR (OR, 10.84; 95% CI, 1.12-105). The HBV DNA 1 month after NUC treatment cessation was an early predictor of subsequent relapse., Conclusions: Discontinuation of tenofovir disoproxil fumarate treatment rather than entecavir treatment is associated with earlier relapse, and NUC-specific posttherapy monitoring is necessary.

Current antiviral therapy fails to cure chronic hepatitis B virus (HBV) infection, primarily because of the persistence of covalently closed circular DNA (cccDNA). Although nucleos(t)ide analogues (NAs) can inhibit the reverse transcriptase of HBV and suppress its replication to levels below the detection limit, viremia often rebounds after cessation of therapy. Nuclear cccDNA serves as the HBV replicative template and exhibits extraordinary stability, and is not affected by NAs. Therefore, curing chronic hepatitis B (CHB) requires novel therapy for purging cccDNA from patients. The CRISPR/Cas9 system is a newly developed programmable genome-editing tool and allows for sequence-specific cleavage of DNA. Compared to other genome-editing tools, the CRIPSR/Cas9 system is advantageous for its simplicity and flexibility of design. Theoretically, Cas9 can be redirected to specifically cleave any desired genome sequences simply by designing guide RNAs with about 20 nucleotides that match the particular sequences of genomes with downstream protospacer adjacent motifs. Recently, it has been demonstrated that the CRIPSR/Cas9 system can specifically destruct HBV genomes in vitro and in vivo. Although promising, the CRISPR/Cas9 system faces several challenges that need to be overcome for the clinical application, namely, off-target cleavage and the in vivo delivery efficiency. Cutting integrated HBV genomes by CRISPR/Cas9 also raises serious concern because this has the risk of genome instability. In summary, the CRISPR/Cas9 system bears the potential for curing CHB as long as several challenging issues can be successfully solved., (Copyright © 2017. Published by Elsevier B.V.)

Objectives: Several viral and host risk factors have been used to predict risks of hepatocellular carcinoma (HCC) in patients with chronic infection of hepatitis B virus (HBV). However, little is known whether fibrosis-4 (FIB-4) index, a liver fibrosis biomarker, helps identify non-cirrhotic patients with the lowest HCC risk., Methods: A total of 2075 treatment-naive Taiwanese patients with chronic HBV infection were followed for an average period of 16.02 years. None of them had liver cirrhosis at baseline. We explored whether a low FIB-4 index complements the favourable predictors to defines patients with the lowest HCC risk. The finding was validated in 532 non-cirrhotic patients receiving long-term nucleos(t)ide analogue (NUC) treatment with suppressed viral replication., Results: A total of 137 treatment-naive and 10 NUC-treated patients developed HCC, respectively. We found that HCC risk started to increase when baseline FIB-4 index >1.29 in the treatment-naive cohort. Patients with FIB-4 >1.29, compared to those with FIB-4 <1.29, were associated with a higher risk of HCC with hazards ratio of 5.56 (95% confidence interval: 3.93-7.86). More importantly, among patients with low viral load (HBV DNA level <2,000 IU/ml), baseline FIB-4 index helped stratify different HCC risks such that none of 326 HBeAg-negative patients with FIB-4 index <1.29, ALT level <40 U/l, and HBsAg level <1,000 IU/ml developed HCC. In addition, the patients with the FIB-4 index <1.29 consistently had the lowest HCC risks in the validation cohort receiving long-term NUC treatment., Conclusions: In non-cirrhotic patients with chronic HBV infection, FIB-4 index <1.29 complements the existing clinical profile to define patients with the lowest HCC risk.

The natural course of chronic hepatitis B (CHB) infection and treatment response are determined mainly by the genomic characteristics of the individual. We investigated liver gene expression profiles to reveal the molecular basis associated with chronic hepatitis B and IFN-alpha (IFNα) treatment response in CHB patients. Expression profiles were compared between seven paired liver biopsy samples taken before and 6 months after successful IFNα treatment or between pretreatment biopsy samples of 11 IFNα responders and 11 non-responders. A total of 132 differentially up-regulated and 39 down-regulated genes were identified in the pretreated livers of CHB patients. The up-regulated genes were mainly related to cell proliferation and immune response, with IFNγ and B cell signatures significantly enriched. Lower intrahepatic HBV pregenomic RNA levels and 25 predictive genes were identified in IFNα responders. The predictive gene set in responders significantly overlapped with the up-regulated genes associated with the pretreated livers of CHB patients. The mechanisms responsible for IFNα treatment responses are different between HBV and HCV patients. HBV infection evokes significant immune responses even in chronic infection. The up-regulated genes are predictive of responsiveness to IFNα therapy, as are lower intrahepatic levels of HBV pregenomic RNA and pre-activated host immune responses.

Background & Aims: Peginterferon lambda-1a (lambda) is a Type-III interferon, which, like alfa interferons, has antiviral activity in vitro against hepatitis B virus (HBV) and hepatitis C virus (HCV); however, lambda has a more limited extra-hepatic receptor distribution. This phase 2b study (LIRA-B) evaluated lambda in patients with chronic HBV infection., Methods: Adult HBeAg+ interferon-naive patients were randomized (1:1) to weekly lambda (180 μg) or peginterferon alfa-2a (alfa) for 48 weeks. The primary efficacy endpoint was HBeAg seroconversion at week 24 post-treatment; lambda non-inferiority was demonstrated if the 80% confidence interval (80% CI) lower bound was >-15%., Results: Baseline characteristics were balanced across groups (lambda N=80; alfa N=83). Early on-treatment declines in HBV-DNA and qHBsAg through week 24 were greater with lambda. HBeAg seroconversion rates were comparable for lambda and alfa at week 48 (17.5% vs. 16.9%, respectively); however lambda non-inferiority was not met at week 24 post-treatment (13.8% vs. 30.1%, respectively; lambda vs. alfa 80% CI lower bound -24%). Results for other key secondary endpoints (virologic, serologic, biochemical) and post hoc combined endpoints (HBV-DNA <2000 IU/ml plus HBeAg seroconversion or ALT normalization) mostly favored alfa. Overall adverse events (AE), serious AE, and AE-discontinuation rates were comparable between arms but AE-spectra differed (more cytopenias, flu-like, and musculoskeletal symptoms observed with alfa, more ALT flares and bilirubin elevations seen with lambda). Most on-treatment flares occurred early (weeks 4-12), associated with HBV-DNA decline; all post-treatment flares were preceded by HBV-DNA rise., Conclusions: On-treatment, lambda showed greater early effects on HBV-DNA and qHBsAg, and comparable serologic/virologic responses at end-of-treatment. However, post-treatment, alfa-associated HBeAg seroconversion rates were higher, and key secondary results mostly favored alfa. ClinicalTrials.gov number: NCT01204762., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Chronic hepatitis B virus (HBV) infection evolves from immune-tolerance phase, through immune clearance phase to a quiescent phase or reactivation as hepatitis B e antigen-negative hepatitis. Persistent infection may result in the development of cirrhosis and hepatocellular carcinoma (HCC). Host factors including gender, age, family history, HLA-DP, and viral factors including HBV DNA, genotypes, precore mutations, pre-S deletions, and hepatitis B surface antigen (HBsAg) level are associated with the development of these complications. Risk scores for the development of HCC have been derived. Patients with persistently elevated alanine aminotransferase levels (>30 for males; >19 U/L for females) and HBV DNA levels >2000 IU/mL should be treated. Patients with established cirrhosis with detectable HBV DNA should also be treated. The recommended first-line agents include pegylated interferon and 2 nucleos(t)ide analogs, entecavir and tenofovir. NAs require long-term treatment to maintain suppression of HBV DNA. They have been shown to decrease hepatic fibrosis, or reverse cirrhosis and to reduce the development of HCC. They have very low rates (0% to 1.2%) of resistance. HBsAg seroclearance, although the ideal endpoint, is only achievable in 10% to 12% of patients by multicenter trials usually studying relatively young patients. Patients on long-term treatment should be monitored for viral breakthrough that may be due to noncompliance or the development of resistance. Newer agents are under trials to enhance the rate of HBsAg seroclearance. However, even with the current NAs, long-term treatment of >6 years can markedly reduce the covalently closed circular DNA, the viral component responsible for initiation of viral replication.

Objective: This study aimed to investigate the therapeutic potential of monoclonal antibody (mAb) against HBV as a novel treatment approach to chronic hepatitis B (CHB) in mouse models., Methods: Therapeutic effects of mAbs against various epitopes on viral surface protein were evaluated in mice mimicking persistent HBV infection. The immunological mechanisms of mAb-mediated viral clearance were systematically investigated., Results: Among 11 tested mAbs, a novel mAb E6F6 exhibited the most striking therapeutic effects in several HBV-persistent mice. Single-dose administration of E6F6 could profoundly suppress the levels of hepatitis B surface antigen (HBsAg) and HBV DNA for several weeks in HBV-transgenic mice. E6F6 regimen efficiently prevented initial HBV infection, and reduced viral dissemination from infected hepatocytes in human-liver-chimeric mice. E6F6-based immunotherapy facilitated the restoration of anti-HBV T-cell response in hydrodynamic injection (HDI)-based HBV carrier mice. Immunological analyses suggested that the Fcγ receptor-dependent phagocytosis plays a predominant role in E6F6-mediated viral suppression. Molecular analyses suggested that E6F6 recognises an evolutionarily conserved epitope (GPCK(R)TCT) and only forms a smaller antibody-viral particle immune complex with limited interparticle crosslinking when it binds to viral particles. This unique binding characteristic of E6F6 to HBV was possibly associated with its effective in vivo opsonophagocytosis for viral clearance., Conclusions: These results provided new insight into understanding the therapeutic role and mechanism of antibody against persistent viral infection. The E6F6-like mAbs may provide a novel immunotherapeutic agent against human chronic HBV infection., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Hepatitis B virus (HBV) is a common human pathogen transmitted worldwide, and its chronic infection is a well-known risk factor for hepatocellular carcinoma (HCC). The sex disparity of HBV-related liver diseases has been noticed for a long time, which could be attributed to sex hormone effects, other than gender behaviors or environmental impact. This difference is experimentally confirmed in HBV transgenic mice, as well as in immunocompetent mice receiving hydrodynamic delivery of HBV. Androgen and estrogen pathways were identified to play opposite regulations of HBV transcription by targeting viral enhancer I at molecular level. In addition to the direct effects on HBV life cycle, sex hormones may be also involved in the immune response to HBV infection and the progression of associated liver diseases, although the detailed mechanisms are still unclear. Besides, several unaddressed issues such as HBV entry, microRNA profiles, viral integration, and adaptability in which androgen and estrogen axes might be involved are warranted to be delineated. The comprehensive understanding of the sex disparity in HBV virology and pathogenesis will be helpful to provide newly biomarkers for clinical diagnosis and develop novel drugs to manage HBV-related HCC patients., (© 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Background: Hepatitis B virus (HBV) surface antigen (HBsAg) seroclearance is the ultimate serological end point in chronic hepatitis B. This study aimed to develop and validate a prediction score for spontaneous HBsAg seroclearance in HBV e antigen (HBeAg)-negative patients with chronic hepatitis B due to HBV genotype B or C., Methods: The development cohort included 2491 untreated participants from the community-based REVEAL-HBV study, who were HBeAg negative, anti-hepatitis C virus negative, and cirrhosis free. The independent validation cohort consisted of 1934 hospital-based individuals from the National Taiwan University Hospital. Clinical markers included in the model were age and serum HBV DNA and HBsAg levels. Cox proportional hazards regression models were used to create the prediction model., Results: A prediction score ranging from 0 to 27 was developed. Predicted probabilities of 5- and 10-year HBsAg seroclearance ranged from 0.95% to 30.49% and from 2.58% to 62.52%, respectively. When applied to the independent validation cohort, the areas under the receiver operating characteristic curves for the 5- and 10-year prediction of HBsAg seroclearance in the validation cohort were 0.82 (95% confidence interval [CI], .76-.88) and 0.74 (95% CI, .70-.78). Model fit was still adequate, according to Hosmer-Lemeshow goodness of fit tests., Conclusions: A clinically applicable prediction score for HBsAg seroclearance was developed and externally validated. This model can assist clinicians in further stratifying risk groups., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Unlabelled: The evolutionary rates of hepatitis B virus (HBV) estimated using contemporary sequences are 10(2) to 10(4) times higher than those derived from archaeological and genetic evidence. This discrepancy makes the origin of HBV and the time scale of its spread, both of which are critical for studying the burden of HBV pathogenicity, largely unresolved. To evaluate whether the dual demands (i.e., adaptation within hosts and colonization between hosts) of the viral life cycle affect this conundrum, the HBV quasispecies dynamics within and among hosts from a family consisting of a grandmother, her 5 children, and her 2 granddaughters, all of whom presumably acquired chronic HBV through mother-to-infant transmission, were examined by PCR cloning and next-generation sequencing methods. We found that the evolutionary rate of HBV between hosts was considerably lower than that within hosts. Moreover, the between-host substitution rates of HBV decreased as transmission numbers between individuals increased. Both observations were due primarily to changes at nonsynonymous rather than synonymous sites. There were significantly more multiple substitutions than expected for random mutation processes, and 97% of substitutions were changed from common to rare amino acid residues in the database. Continual switching between colonization and adaptation resulted in a rapid accumulation of mutations at a limited number of positions, which quickly became saturated, whereas substitutions at the remaining regions occurred at a much lower rate. Our study may help to explain the time-dependent HBV substitution rates reported in the literature and provide new insights into the origin of the virus., Importance: It is known that the estimated hepatitis B virus (HBV) substitution rate is time dependent, but the reason behind this observation is still elusive. We hypothesize that owing to the small genome size of HBV, transmission between hosts and adaptation within hosts must exhibit high levels of fitness trade-offs for the virus. By studying the HBV quasispecies dynamics for a chain of sequentially infected transmissions within a family, we found the HBV substitution rate between patients to be negatively correlated with the number of transmissions. Continual switching between hosts resulted in a rapid accumulation of mutations at a limited number of genomic sites, which quickly became saturated in the short term. Nevertheless, substitutions at the remaining regions occurred at a much lower rate. Therefore, the HBV substitution rate decreased as the divergence time increased., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Background: The clinical significance of serum microRNA-122 (miR-122) has been shown in viral hepatitis B and C, respectively. Specifically, miR-122 stimulates hepatitis C virus (HCV) replication but suppresses hepatitis B virus (HBV) replication. The profile and clinical significance of serum miR-122 in patients with dual chronic hepatitis B and C would be an interesting and important clinical issue., Methods: A total of 76 patients with HBV/HCV dual infection, 105 with HCV monoinfection and 39 with HBV monoinfection were enrolled. All patients received peginterferon alfa-2a (PEG-IFN)-based treatment. Serum miR-122 levels were quantified by using a sensitive hybridization-based assay., Results: At baseline, the serum miR-122 level was lower in HCV-monoinfected patients than in HBV-monoinfected patients, whereas HBV coinfection increased the expression of miR-122. In multivariate analysis, the serum miR-122 level was positively correlated with the serum HBsAg level in patients with HBV/HCV dual infection and those with HBV monoinfection. In dually infected patients who received PEG-IFN-based treatment, a high baseline miR-122 level was positively correlated with a greater reduction of the posttreatment serum HBsAg level., Conclusion: In summary, the serum miR-122 level is highly correlated with the HBsAg level in HBV/HCV dually infected patients and may serve as a biomarker to predict posttreatment HBsAg decline.

Background and Aims: Albinterferon is a fusion of albumin and interferon-α2b developed to improve the pharmacokinetics, convenience, and potential efficacy of interferon-α for the treatment of chronic hepatitis infections., Methods: This open-label, randomized, active-controlled, multicenter study investigated the safety and efficacy of albinterferon in patients with chronic hepatitis B virus (HBV) infection who were e-antigen (HBeAg) positive. One hundred and forty-one patients received one of four albinterferon doses/regimens or pegylated-interferon-α2a. Primary efficacy outcomes were changes in serum HBeAg and antibody, HBV-DNA, and alanine aminotransferase. Principal safety outcomes were changes in laboratory values, pulmonary function, and adverse events., Results: The study was prematurely terminated as phase III trials in hepatitis C infection indicated noninferior efficacy but inferior safety compared with pegylated-interferon-α2a. Here, all treatment groups had a significant reduction in HBV-DNA from baseline. Reductions in HBV-DNA were not significantly different, except the 1200 μg every 4 weeks albinterferon dose which was inferior compared with pegylated-interferon-α2a. The serum alanine aminotransferase levels decreased in all arms. The per-patient incidence of adverse events was not significantly different for albinterferon (96.4-100%) and pegylated-interferon-α2a (93.1%). Total adverse events, however, were higher for albinterferon and correlated to dose. Decreased lung function was found in all arms (∼93% of patients), and was more common in some albinterferon groups., Conclusions: Albinterferon doses with similar anti-HBV efficacy to pegylated-interferon-α2a had higher rates of certain adverse events, particularly changes in lung diffusion capacity (http://www.clinicaltrials.gov number NCT00964665)., (© 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Objective: Recent evidence indicates a crucial role of the immunoinhibitory receptor programmed death-1 (PD-1) in enforcing T-cell dysfunction during chronic viral infection and cancer. We assessed the impact of circulating soluble PD-1 (sPD-1) levels on long-term dynamics of hepatitis B virus (HBV) load and hepatocellular carcinoma (HCC) risk., Methods: In a case-cohort study on longitudinal analysis of viral load within a cohort of 2903 men chronically infected with HBV, followed up from baseline (1989-1992) through 2010, we determined sPD-1 levels in baseline plasma with enzyme-linked immunosorbent assay from 126 men who subsequently developed HCC and 1155 men who did not develop HCC. To evaluate whether patients' characteristics involved the use of sPD-1 as a biomarker, sPD-1 was also tested in 614 newly-diagnosed patients with HBV-related HCC recruited from a multicenter study for comparison with the 1155 noncases in the case-cohort study., Results: Plasma quartile levels of sPD-1 were positively associated with HCC risk for men in the case-cohort analysis (vs. quartile 1: adjusted odds ratios [95% confidence intervals] for quartile 2-quartile 4 were 1.51 [0.75-3.03], 2.15 [1.12-4.13], and 2.29 [1.20-4.38], respectively), and in the case-control study regardless of age-of-onset and clinical stage. Furthermore, we found longitudinal effect of elevated sPD-1 levels to maintain higher viral load for 4 or more years, with greater and more prolonged effect among HBV genotype C- vs. non-C-infected participants. High levels of viral load and sPD-1 (vs. absence of both) was associated with a 6.29-fold increase in risk of HCC, and combining both conditions with HBV genotype C yielded an odds ratio of 30.47 with significant additive interaction (relative excess risk due to interaction: 27.08 [95% confidence interval = 8.76-45.41])., Conclusions: Our data suggest plasma sPD-1 as an important immune-related marker for assessment of HBV activity and HCC risk.

Background: Obesity is considered a risk factor for hepatocellular carcinoma (HCC). The relationship between adipocytokine and HCC in hepatitis B virus (HBV) carriers remains unclear. We prospectively investigated the association of adiponectin, leptin, and visfatin levels with HCC., Methods: We conducted a nested case-control study in a community-based cohort with 187 incident HCC and 374 HCC-free HBV carriers. Unconditional logistic regression was conducted to estimate the ORs and 95% confidence intervals (CI)., Results: Adiponectin, but not leptin and visfatin, levels were associated with an increased risk of HCC after adjustment for other metabolic factors and HBV-related factors. The risk was increased [OR = 0.51; 95% CI, 0.12-2.11; OR = 4.88 (1.46-16.3); OR = 3.79 (1.10-13.0); OR = 4.13 (1.13-15.1) with each additional quintiles, respectively] with a significant dose-response trend (P(trend) = 0.003). HCC risk associated with higher adiponectin level was higher in HBV carriers with ultrasonographic fatty liver, genotype C infection, higher viral load, and with elevated alanine aminotransferase. Longitudinally, participants with higher adiponectin were less likely to achieve surface antigen of hepatitis B virus (HBsAg) seroclearance and more likely to have persistently higher HBV DNA. Eventually, they were more likely to develop liver cirrhosis [OR = 1.65 (0.62-4.39); OR = 3.85 (1.47-10.1); OR = 2.56 (0.96-6.84); OR = 3.76 (1.33-10.7) for the second, third, fourth, and fifth quintiles, respectively; P(trend) = 0.017] before HCC., Conclusions: Elevated adiponectin levels were independently associated with an increased risk of HCC., Impact: Adiponectin may play different roles in the virus-induced and metabolic-related liver diseases, but the underlying mechanism remains unknown., (©2014 American Association for Cancer Research.)

Background and Aims: Acute exacerbation (AE) of chronic hepatitis B virus (HBV) infection is common and negatively impacts the clinical outcome. Although upsurge of viral load always precedes or coincides with AE, the underlying immunological mechanisms remain unclear and were investigated., Methods: We prospectively followed the serum cytokine/chemokine profiles, viral load, and alanine aminotransferase (ALT) levels in 250 patients and identified 44 consecutive patients (male: 72.7%; age: 40.4 ± 9.7 years; hepatitis B e antigen [HBeAg] positivity: 63.6%; genotype B/C: 75%/25%) who developed AE during the follow-up in a medical center. The impact of clinical characteristics (age, gender, HBeAg, ALT, HBV genotype), cytokines (tumor necrosis factor-alpha, interferon gamma, interleukin [IL]-2, IL-4, IL-6, and IL-10), and chemokines (CXCL10/interferon gamma-induced protein [IP]-10, CCL2/MCP-1, CXCL9/MIG, CCL5/RANTES, and CXCL8/IL-8) on the serum HBV DNA dynamics at different time points (baseline, peak of serum HBV DNA level, peak of serum ALT level, and after AE) were analyzed., Results: Of 44 patients, serum HBV DNA level surged before the peak of serum ALT level in 23 (52.3%), and coincided with the peak of ALT in 21 (47.7%). The upsurge of serum viral load significantly correlated with the increase of IL-10 (P = 0.0037) and CXCL10/IP-10 (P = 0.0044). Upsurge of serum viral load was preceded by an increase in serum IL-4 (P < 0.05), IL-6 (P < 0.05), and IL-10 (P < 0.05). Combination of HBV genotype, IL-6 level at baseline, and ALT level at the peak of serum HBV DNA reliably predicted subsequent AE pattern (P = 0.0116)., Conclusions: Enhanced Th2 activity is likely involved in the surge of HBV DNA level before hepatitis exacerbation., (© 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Background: Limited information about tumor status and the time at which antiviral therapy was initiated may have influenced effect estimation in previous research. The aim of this study was to investigate the effect of antiviral therapies on HBV-related HCC progression and deaths in patients receiving curative treatment based on clear clinical-pathological cancer status and the association of start time of adjuvant antiviral therapy initiation and outcomes., Methodology: A nationwide inception cohort study of newly diagnosed HCC patients who suffered from viral hepatitis B and received curative HCC therapy as the first course of treatment were identified from the Taiwan Cancer Registry between January 1, 2004, and December 31, 2009. Matched Cox proportional hazards models based on propensity score matching and incorporated time-varying exposure were used to estimate adjusted hazard ratios and 95% confidence intervals (CIs)., Findings: Among 3,855 HCC patients with HBV, antiviral therapy was administered to 490 (12.7%) following curative treatment. Antiviral-treated patients had a higher percentage of young age, early stage, and smaller tumor size of HCC compared with untreated patients. After propensity score matching, treated patients demonstrated a higher risk of HCC progression (hazard ratio, 1.42; 95%CI, 1.20-1.69) and death from all causes (1.45; 1.15-1.82) than untreated patients. Similar results were also obtained in sub-cohort of patients who were alive with cancer-free status at least one year after receiving curative treatment and the sub-cohort of patients with liver resection. The interval length between initiation of antiviral therapy and first-line curative treatment did not show a significant association with all-cause mortality., Conclusions: This study found that adjuvant antiviral therapy did not reduce the risk of HCC progression or mortality in HBV-related HCC patients after cancer status adjusting.

Background: Occult hepatitis B virus (HBV) infection (OHB) may exist in patients experiencing hepatitis B surface antigen (HBsAg) seroclearance., Aims: We examined the clinical and virological features of OHB in patients who lost HBsAg post-treatment or spontaneously., Methods: We collected 44 patients with HBsAg seroclearance: 15 patients with dual HBV/hepatitis C virus (HCV) infection who lost HBsAg after peginterferon alfa-2a (PEG-IFN) plus ribavirin therapy; 13 HBV mono-infected patients who lost HBsAg after various oral antiviral therapies; and 16 patients who lost HBsAg spontaneously. OHB was defined as detectable serum HBV DNA in the absence of HBsAg. Viral mutations associated with OHB were identified by comparison with matched controls that remained positive for HBsAg, and further characterized in vitro., Results: The prevalence of OHB was 34.1% (15/44) in all patients, which was not significantly different among three groups. One mutation in surface promoter/polymerase region, C3050T (preS1T68I), was identified to be associated with the seroclearance of HBsAg in six cases. This mutation does not change the amino acid sequence of the polymerase protein. The S promoter activity was significantly lower in the construct containing C3050T mutation as compared with the wild-type (P = 0.0008). However, this mutation did not affect HBV replication, transcription and translation in the context of the full-length HBV genome. OHB was not rare in patients with HBsAg seroclearance., Conclusions: One mutation, C3050T (preS1T68I), decreased S promoter activity; nevertheless, other factors may play more important role in the clearance of HBsAg in these OHB patients., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Aims: The level of hepatitis B surface antigen (HBsAg) has been shown to complement hepatitis B virus (HBV)-DNA level in predicting disease progression in hepatitis B e antigen (HBeAg)-negative patients, especially those with low viral loads. Whether this finding could be seen in spontaneous HBeAg seroconverters remains unclear., Methods: A retrospective cohort of 390 Taiwanese spontaneous HBeAg seroconverters with a mean follow-up period of 7.4 years was enrolled. The relationships between HBV-DNA/HBsAg levels and HBeAg-negative hepatitis/active viral replication (HBV-DNA level ≥ 2000 IU/mL) were investigated., Results: In the overall cohort, serum HBV-DNA level served as a better predictor for HBeAg-negative hepatitis compared with HBsAg level. However, in those with HBV-DNA level < 2000 IU/mL, a higher HBsAg level was associated with a higher risk of HBeAg-negative hepatitis (P = 0.015). Multivariate analysis showed the hazard ratio of HBsAg level ≥ 1000 IU/mL versus < 1000 IU/mL was 4.1 (95% confidence interval: 1.3-13.6). When using the end-point of active viral replication, HBsAg ≥ 1000 IU/mL remained as an independent risk factor, with a hazard ratio of 2.5 (95% confidence interval: 1.1-5.9)., Conclusions: In spontaneous HBeAg seroconverters with HBV-DNA level < 2000 IU/mL, HBsAg level ≥ 1000 IU/mL is associated with increased risks of HBeAg-negative hepatitis and active viral replication. Combining HBV-DNA < 2000 IU/mL and HBsAg level < 1000 IU/mL may be used to define minimal viral activity., (© 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)