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Background & Aims: Hepatitis B infection is the most frequent cause of chronic hepatitis and liver cancer worldwide. Active searching for individuals with chronic hepatitis B has been proposed as a strategy to achieve the elimination of this virus. The primary aim of this study was to link to specialists HBsAg‐positive individuals detected in a laboratory database and to characterize individuals who were not linked to care. Methods: We performed a retrospective–prospective evaluation of all HBsAg‐positive serum samples identified in the central laboratory of the Northern Barcelona area between January 2018 and June 2022. After reviewing the patients' clinical charts, all those not linked to care were given an appointment with a specialist. Results: Medical records of 2765 different HBsAg‐positive serum samples were reviewed and 2590 individuals were identified: 844 (32.6%) were not linked to a specialist, 653 were candidates for linkage, and 344 attended the specialist visit. The two main reasons why they were not under specialist care were administrative issues, such as living in another region (12.1%) and lacking contact details (4.1%), and low life expectancy (2.8%). Individuals who did not attend their scheduled visit were mainly young [38.1 ± 12.9 vs. 44.0 ± 14.0 (p <.001)], non‐White European [75.3% vs. 58.1% (p <.001)] and men [70.7% vs. 56.4% (p <.001)]. Conclusions: One in every three HBsAg‐positive individuals in our setting was not currently under specialist care. Of particular note, half of them had never attended a specialist consultation, an essential step for evaluating the disease and starting therapy in some countries. [ABSTRACT FROM AUTHOR]

Introduction: Prevalence and severity of pruritus among US patients with chronic hepatitis B and C (HBV, HCV) are not well-documented. Chronic Hepatitis Cohort Study (CHeCS) patients were surveyed to examine pruritus prevalence and impact on quality of life (QoL). Methods: Patients who reported experiencing pruritus ≥3 on a Numeric Rating Scale (NRS) within the past 30 days were invited to participate in a 6-month study using the SF-36 questionnaire. General regression (univariate followed by multivariable modelling) was used to analyse pruritus intensity and eight QoL dimensions. Results: Among 1654 patients (HBV = 358, HCV = 1296, HBV/HCV = 6), pruritus prevalence was significantly higher among patients with HCV than those with HBV (44% vs. 35%; p < .05). One hundred and twenty-three patients (21 HBV and 102 HCV) participated in the QoL study (72% ≥60 years; 50% men; 25% Black; 37% with cirrhosis; 66% had BMI > 25). Mean NRS was 4.9--5.3. QoL responses for social functioning and emotional well-being were higher (70--72 points) than responses for energy/fatigue (50--51). Antiviral treatment rates were higher in HCV (92%, SVR 99%) than HBV (71% ever, 43% ongoing). Multivariable analyses showed no significant effect of hepatitis type or antiviral treatments on itch. Antihistamines were associated with severe itch. Higher NRS was associated with significantly reduced QoL. Each unit increase in NRS was associated with a 2--3 unit decline in emotional well-being, general health, physical function, energy/fatigue, social functioning and emotional health. Conclusion: Pruritus negatively affects many viral hepatitis patients, regardless of antiviral treatment status. Improved treatment options are needed to address its impact on QoL. [ABSTRACT FROM AUTHOR]

Background and Aims: Previous studies have shown suboptimal screening for hepatitis D virus (HDV) among patients with chronic hepatitis B (CHB). This study presents the cascade of care for HDV infection in a major secondary referral centre in Southern Stockholm, Sweden. Methods: HBsAg+ve patients attending Karolinska University Hospital (KUH) from 1992 to 2022 were identified. The prevalence of anti‐HDV and/or HDV RNA positivity, interferon (IFN) therapy and maintained virological responses (MVR) after HDV treatment were assessed. Also, time to anti‐HDV testing was analysed in relation to liver‐related outcomes with logistic regression. Results: Among 4095 HBsAg+ve persons, 3703 (90.4%) underwent an anti‐HDV screening; within a median of 1.8 months (range 0.0–57.1) after CHB diagnosis. This screening rate increased over time, to 97.9% in the last decade. Overall, 310 (8.4%) were anti‐HDV+ve, of which 202 (65.2%) were HDV RNA+ve. Eighty‐five (42%) received IFN, and 9 (10.6%) achieved MVR at the last follow‐up. The predictive factors for anti‐HDV screening were Asian origin, diagnosis after the year 2012, HIV co‐infection (negative factor) and HBV DNA level < 2000 IU/mL in univariable analysis, while HIV co‐infection was the only remaining factor in multivariable analysis. Delayed anti‐HDV test >5 years was independently associated with worsened liver‐related outcomes (adjusted odds ratio = 7.6, 95% CI 1.8–31.6). Conclusion: Higher frequency of HDV screening than previously published data could be seen among CHB patients at KUH in a low‐endemic setting. Receiving a delayed screening test seems to be associated with worse outcomes, stressing the need of a strategy for timely HDV diagnosis. [ABSTRACT FROM AUTHOR]

A recent study published in Liver International explores the need for imaging biomarkers to predict the prognosis of early-stage hepatocellular carcinoma (HCC). The study developed a deep learning model to predict the presence of microvascular invasion (MVI) using pre-treatment magnetic resonance imaging (MRI). The model achieved high performance in predicting MVI in a cohort of surgically resected HCC and showed clinical relevance as a companion biomarker for adjuvant therapies. The study highlights the importance of exploiting the full potential of MRI and calls for further research and clinical trials to refine and test these imaging-based biomarkers. [Extracted from the article]

Background and Aims: This study aimed to update the epidemiology, clinical, and economic outcomes of patients diagnosed with chronic hepatitis B (CHB) infection in Taiwan. Methods: This is a retrospective observational study using claims data from the National Health Insurance Research Database. Cases were identified between 2010 and 2019 using CHB diagnosis codes and claims for alanine aminotransferase laboratory tests or CHB treatment within one year of the first CHB diagnosis. Patient characteristics, epidemiology, clinical, and economic outcomes were described. Results: A total of 730 154 CHB‐diagnosed cases were identified. The prevalence of diagnosed CHB increased from 1.13% in 2010 to 2.43% in 2019, with the highest occurring among those aged 55–64 years (4.76%) and 45–54 years (4.37%) and being higher in men (2.98%) than in women (2.21%). The majority of newly diagnosed CHB patients were 35 years of age or older (86.6%), with a median age of 49 years. After a median follow‐up period of 6.42 years, 12.5%, 7.9%, 2.8%, and 0.35% were diagnosed with cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, and liver transplantation respectively. Among 456 706 incident CHB‐diagnosed patients, 17.4% had received at least one CHB medication, with the majority taking entecavir (67.9%). Patients with increasing disease severity had higher healthcare resource utilization, and inpatient costs accounted for 48.9%–65.5% of the overall medical cost in different health states. Conclusion: Despite the decreasing incidence of newly diagnosed CHB, the prevalence of diagnosed CHB remains high and poses a significant healthcare challenge owing to the high economic burden associated with the complications of CHB. [ABSTRACT FROM AUTHOR]

Background and Aims: Hepatitis D virus (HDV) underdiagnosis remains common. We assessed the HDV screening and prevalence rates in HBsAg‐positive patients seen at tertiary liver centres throughout Greece as well as factors affecting HDV diagnosis. Methods: All adult HBsAg‐positive patients seen within the last 5 years were included. Non‐screened patients who visited or could be recalled to the clinics over a 6‐month period were prospectively tested for anti‐HDV. Results: Of 5079 HBsAg‐positive patients, 53% had anti‐HDV screening (41% before and 12% after study initiation). Pre‐study (8%–88%) and total screening rates (14%–100%) varied widely among centres. Screening rates were associated with older age, known risk group, elevated ALT, centre location and size and period of first visit. Anti‐HDV prevalence was 5.8% without significant difference in patients screened before (6.1%) or after study initiation (4.7%, p = 0.240). Anti‐HDV positivity was associated with younger age, parenteral drug use, born abroad, advanced liver disease and centre location. Overall, HDV RNA detectability rate was 71.6% being more frequent in anti‐HDV‐positive patients with elevated ALT, advanced liver disease and hepatitis B therapy. Conclusions: Anti‐HDV screening rates and recall capabilities vary widely among Greek liver clinics being higher in HBsAg‐positive patients of known risk group with active/advanced liver disease seen at smaller centres, while non‐medical factors are also important. Anti‐HDV prevalence varies throughout Greece being higher in patients born abroad with younger age, parenteral drug use and advanced liver disease. Viremia is more frequently but not exclusively detected in anti‐HDV‐positive patients with elevated ALT and advanced liver disease. [ABSTRACT FROM AUTHOR]

Background and Aims: Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC) development and progression. The aim of this study was to mechanistically investigate the involvement of Hippo signalling in HBV surface antigen (HBsAg)‐dependent neoplastic transformation. Methods: Liver tissue and hepatocytes from HBsAg‐transgenic mice were examined for the Hippo cascade and proliferative events. Functional experiments in mouse hepatoma cells included knockdown, overexpression, luciferase reporter assays and chromatin immunoprecipitation. Results were validated in HBV‐related HCC biopsies. Results: Hepatic expression signatures in HBsAg‐transgenic mice correlated with YAP responses, cell cycle control, DNA damage and spindle events. Polyploidy and aneuploidy occurred in HBsAg‐transgenic hepatocytes. Suppression and inactivation of MST1/2 led to the loss of YAP phosphorylation and the induction of BMI1 expression in vivo and in vitro. Increased BMI1 directly mediated cell proliferation associated with decreased level of p16INK4a, p19ARF, p53 and Caspase 3 as well as increased Cyclin D1 and γ‐H2AX expression. Chromatin immunoprecipitation and the analysis of mutated binding sites in dual‐luciferase reporter assays confirmed that the YAP/TEAD4 transcription factor complex bound and activated the Bmi1 promoter. In chronic hepatitis B patients, paired liver biopsies of non‐tumour and tumour tissue indicated a correlation between YAP expression and the abundance of BMI1. In a proof‐of‐concept, treatment of HBsAg‐transgenic mice with YAP inhibitor verteporfin directly suppressed the BMI1‐related cell cycle. Conclusion: HBV‐associated proliferative HCC might be related to the HBsAg‐YAP‐BMI1 axis and offer a potential target for the development of new therapeutic approaches. [ABSTRACT FROM AUTHOR]

Management of chronic hepatitis D (CHD) has entered a new era. In this new era, the virus entry inhibitor bulevirtide has received conditional approval as a treatment for compensated CHD. Three phase 3 studies with two new compounds are ongoing for the treatment of CHD. In this context, surrogate markers of treatment efficacy have been well defined for chronic hepatitis B (CHB) (7) and chronic hepatitis C (8) but not for CHD. The aim of this review is to give a perspective on treatment endpoints in CHD. For this, we took guidance from CHB studies and tried to make suggestions which differed according to finite versus prolonged treatment durations and also took into account the different characteristics of the new compounds. [ABSTRACT FROM AUTHOR]

The introduction of Hepatitis B Immunoglobulins (HBIg) prophylaxis at and after liver transplantation (LT) facilitated excellent long‐term survival of transplant patients with chronic hepatitis B virus (HBV) infection. Several studies suggested that only short‐term (i.e. 4–8 weeks) HBIg prophylaxis after LT followed by the long‐term administration of HBV polymerase inhibitors prevents HBV recurrence. In hepatitis D virus (HDV)/HBV co‐infected patients, the need for long‐term HBIg prophylaxis on top of HBV polymerase inhibitors is unknown. HDV requires HBV surface antigen (HBsAg) for uptake into hepatocytes to subsequently establish HDV replication. Data on HDV recurrence and its impact on outcomes after LT are limited. In this review, we evaluated the available data on post‐LT recurrence of HBV and/or HDV. Overall, HBIg prophylaxis was effective, but 10–13% of patients became HBsAg positive after LT. Only a single study from Turkey reported HDV recurrence, which was not observed in other LT centres. Since all studies administered continuous HBIg prophylaxis, the post‐LT recurrence rates without HBIg prophylaxis remain unknown. In a German study, the clinical course and histopathological aspects of liver injury (inflammation, fibrosis and steatosis) were similar in post‐LT patients on continuous HBIg and those who stopped HBIg after a median of 72 months. Discontinuation of HBIg in stable patients after LT for HBV/HDV co‐infection did not lead to impaired overall survival or a higher recurrence rate in this long‐term follow‐up. In summary, discontinuation of HBIg after liver transplantation for HBV/HDV liver disease seems safe, but randomized controlled studies are needed before it can be generally recommended. [ABSTRACT FROM AUTHOR]

Hepatitis delta virus (HDV) is a defective agent that only infects individuals with hepatitis B virus (HBV). Around 5–10% of chronic hepatitis B patients worldwide are superinfected with HDV, which means 15–25 million people. Hepatitis delta is the most severe of all chronic viral hepatitis, leading to cirrhosis, liver cancer and/or transplantation in most patients. Despite it, many HDV patients remain undiagnosed. The only treatment available until recently was peginterferon alfa, with poor results and significant side effects. The recent approval of bulevirtide, a lipopeptide that blocks HBV/HDV entry, has revolutionized the field. Another drug, lonafarnib, already approved to treat progeria, is expected to be available soon as HDV therapy. Since there is no cell reservoir for the HDV RNA genome, hypothetically viral clearance could be achieved if complete blocking of viral replication occurs for a minimum time frame. This is what happens in hepatitis C using direct‐acting antivirals, with the achievement of cure in nearly all treated patients. We envision the cure of hepatitis delta using combination antiviral therapy. Given that sexual and parenteral transmission routes are the most frequent for the acquisition of HBV and HDV, shared with HIV infection and HBV/HDV and HIV coinfection. The clinical outcome of hepatitis delta is worst in the HIV setting, with more frequent liver complications. Since most persons infected with HIV are on regular health care follow‐up, we propose that HIV‐HDV patients should be prioritized for moving forward new and potentially curative treatments for hepatitis delta. [ABSTRACT FROM AUTHOR]

Background: Machine learning (ML) algorithms can be used to overcome the prognostic performance limitations of conventional hepatocellular carcinoma (HCC) risk models. We established and validated an ML‐based HCC predictive model optimized for patients with chronic hepatitis B (CHB) infections receiving antiviral therapy (AVT). Methods: Treatment‐naïve CHB patients who were started entecavir (ETV) or tenofovir disoproxil fumarate (TDF) were enrolled. We used a training cohort (n = 960) to develop a novel ML model that predicted HCC development within 5 years and validated the model using an independent external cohort (n = 1937). ML algorithms consider all potential interactions and do not use predefined hypotheses. Results: The mean age of the patients in the training cohort was 48 years, and most patients (68.9%) were men. During the median 59.3 (interquartile range 45.8–72.3) months of follow‐up, 69 (7.2%) patients developed HCC. Our ML‐based HCC risk prediction model had an area under the receiver‐operating characteristic curve (AUC) of 0.900, which was better than the AUCs of CAMD (0.778) and REAL B (0.772) (both p <.05). The better performance of our model was maintained (AUC = 0.872 vs. 0.788 for CAMD and 0.801 for REAL B) in the validation cohort. Using cut‐off probabilities of 0.3 and 0.5, the cumulative incidence of HCC development differed significantly among the three risk groups (p <.001). Conclusions: Our new ML model performed better than models in terms of predicting the risk of HCC development in CHB patients receiving AVT. [ABSTRACT FROM AUTHOR]

Background: Chronic hepatitis B (CHB) is endemic to Asia and is a leading cause of liver‐related morbidity. The prevalence of concomitant CHB and hepatic steatosis (HS) is increasing in Asia. Non‐invasive tests (NITs) including FIB‐4, NFS and APRI assess fibrosis in populations with a single aetiology, but not in subjects with concomitant CHB and HS. Aim: To explore the accuracy of NITs in predicting advanced fibrosis in patients with concomitant CHB and HS. Methodology: This multicentre study of CHB patients who underwent liver biopsy explored clinical characteristics of these subjects, stratified by presence of HS. Fibrosis scores from NITs were compared against histological fibrosis stage in CHB subjects with and without HS. Results: 2262 subjects were enrolled, 74.5% were males, and the mean age was 39.5 years ±11.8 SD. 984 (44.4%) had HS, 824 (36.4%) had advanced fibrosis. In the CHB group, the AUROC for advanced fibrosis were 0.65 (95% CI 0.62–0.69) for FIB‐4 and 0.63 (95% CI 0.60–0.66) for APRI. The specificities were 0.94 for FIB‐4 greater than 3.25 and 0.81 for APRI greater than 1.5. In the CHBHS group, the AUROC for advanced fibrosis were 0.67 (95% CI 0.63–0.71) for FIB‐4, 0.60 (95% CI 0.56–0.64) for APRI and 0.65 (95% CI 0.61–0.69) for NFS. The specificities were 0.95 for FIB‐4 greater than 3.25, 0.88 for APRI greater than 1.5 and 0.99 for NFS greater than 0.675. Conclusion: The performance of NITs to exclude advanced fibrosis did not differ greatly regardless of HS. FIB‐4 and NFS have the best negative predictive values of 0.80 and 0.78, respectively, to exclude advanced fibrosis in CHBHS subjects. [ABSTRACT FROM AUTHOR]

Background: Alanine aminotransferase (ALT) measurement is essential for evaluation of liver disease. We validated a novel rapid point‐of‐care (POC) test for ALT1 against laboratory ALT. Methods: Stored plasma samples from adults with chronic liver disease (Test cohort n = 240; Validation cohort n = 491) were analysed using the BioPoint® antigen immunoassay POC ALT1 lateral flow test, which provides quantitative ALT results (Axxin handheld reader) or semi‐quantitative results (visual read, cut off 40 IU/ml). The accuracy of POC ALT1 to detect ALT > 40 IU/L was determined by ROC analysis. In patients with chronic hepatitis B, treatment eligibility (EASL criteria) was determined using POC ALT1 and compared to laboratory ALT. Results: POC ALT1 test had good accuracy for laboratory ALT > 40 IU/L: AUROC 0.93 (95% CI: 0.89–0.96) in the Test cohort and AUROC 0.92 (95% CI: 0.88–0.95) in the Validation cohort. POC ALT1 cut off of 0.8 for ALT > 40 IU/L maximised sensitivity (97%) and specificity (71%) in the Test cohort (42% laboratory ALT > 40 IU/L) and yielded PPV 84% and NPV 91% in the Validation cohort (19% laboratory ALT > 40 IU/L). Semi‐quantitative POC ALT1 had good accuracy for laboratory ALT in the Validation cohort (AUROC 0.85, 95% CI: 0.81–0.99; sensitivity 77% and specificity 93%). Combined with HBV DNA and transient elastography, both quantitative and semi‐quantitative POC ALT1 tests had good accuracy for excluding hepatitis B treatment needs (sensitivity 96%, specificity 78% and NPV 99%). Conclusion: The POC ALT1 test had good accuracy for elevated ALT levels and for determining treatment eligibility among people with chronic hepatitis B. [ABSTRACT FROM AUTHOR]

Background & Aims: Chronic infection with hepatitis B and C viruses (HBV & HCV) is a major contributor to liver disease and liver‐related mortality in Uzbekistan. There is a need to demonstrate the feasibility of large‐scale simplified testing and treatment to implement a national viral hepatitis elimination program. Methods: Thirteen polyclinics were utilized to screen, conduct follow‐up biochemical measures and treat chronic HBV and HCV infection in the general adult population. Task shifting and motivational interviewing training allowed nurses to provide rapid screening and general practitioners (GPs) to treat individuals on‐site. An electronic medical system tracked individuals through the cascade of care. Results: The use of rapid tests allowed for screening of 60 769 people for HCV and HBV over 6 months and permitted outdoor testing during the COVID‐19 pandemic along with COVID testing. 13%–14% of individuals were lost to follow‐up after the rapid test, and another 62%–66% failed to come in for their consultation. One stop testing and treatment did not result in a statistically increase in retention and lack of patient awareness of viral hepatitis was identified as a key factor. Despite training, there were large differences between GPs and patients initiating treatment. Conclusions: The current study demonstrated the feasibility of large‐scale general population screening and task shifting in low‐ and middle‐income countries. However, such programs need to be proceeded by awareness campaign to minimize loss to follow up. In addition, multiple trainings are needed for GPs to bolster their skills to talk to patients about treatment. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B virus (HBV) infection is a global public health problem affecting over 296 million people, with a global prevalence of 3.8%.[1] Current clinical guidelines recommend potent HBV antiviral treatment in CHB patients who are at risk of disease progression to cirrhosis, hepatocellular carcinoma (HCC) and hepatic decompensation.[[2], [4]] Nucleos(t)ide analogues (NA) including entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide are the first-line oral antiviral therapies that effectively suppress HBV replication and decrease the risk of developing HCC in CHB patients.[[5]] Nevertheless, the risk of HCC is not completely abolished in CHB patients receiving NA therapy.[[5], [7]] Therefore, the Hepatology field has been devoted to better predicting the risk of HCC in NA-treated CHB patients using various risk scoring systems,[[8], [10], [12]] aiming to inform strategies on HCC surveillance.[[14]] In recent years, machine-learning and deep-learning models have been popularized in different domains for enhancing the prediction power over traditional statistical regression models. Real-world effectiveness from the Asia Pacific rim liver consortium for HBV risk score for the prediction of hepatocellular carcinoma in chronic hepatitis B patients treated with oral antiviral therapy. Risk score model for the development of hepatocellular carcinoma in treatment-naive patients receiving oral antiviral treatment for chronic hepatitis B. Clin Mol Hepatol. In the original training cohort, a lazy algorithm that predicts all patients will not develop HCC has a high yet unmeaningful accuracy of 92.8% as only 7.2% of patients developed HCC in 5 years. [Extracted from the article]

Background and Aims: Myeloid‐derived suppressor cells (MDSCs) and CD4+ regulatory T cells (Tregs) expand during chronic hepatitis B virus (HBV) infection and inhibit antiviral immunity. However, the relationship between antiviral effect and the frequencies of those immune suppressive cells after pegylated interferon α‐2a (PegIFNα‐2a) therapy is not clearly understood. This study aimed to investigate the contribution of monocytic MDSCs (mMDSCs) and CD4+ Tregs to functional cure (HBsAg seroclearance) after PegIFNα‐2a therapy and evaluate the effect of PegIFNα‐2a therapy on these cells. Methods: Flow cytometry analysis was performed along with longitudinal immune monitoring of 97 hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) patients receiving PegIFNα‐2a weekly for 48 weeks. Results: The frequencies of mMDSCs and CD4+ Tregs increased in all HBV patients, and they were higher in the HBsAg persistence group than in the HBsAg seroclearance group. A significant decline in the frequency of mMDSCs was found in patients who realized functional cure after PegIFNα‐2a treatment. In contrast, the frequency of CD4+ Tregs in both the HBsAg seroclearance and persistence groups significantly increased. Multivariate analyses indicated that the baseline serum HBsAg levels (p <.001) and mMDSCs frequency (p =.027) were independently associated with the HBsAg clearance, and the combined marker (HBsAg plus mMDSCs) displayed the highest specificity (93.1%) than any other markers in predicting HBsAg seroclearance. Conclusions: These results suggest that a poor response to PegIFNα‐2a treatment in CHB patients may be related to the frequencies of immune suppressive cells, while the therapeutic targeting of these cells might be effective in boosting anti‐HBV immunity. [ABSTRACT FROM AUTHOR]

Background/Aims: Novel agents acting against hepatitis B virus (HBV) are needed to improve HBsAg seroclearance or termed as 'functional cure'. Inarigivir (retinoic acid‐inducible gene I agonist) has immunomodulatory and direct antiviral actions against HBV. We aimed to determine the safety and efficacy of Inarigivir for the treatment of HBV infection. Patients/Methods: 80 treatment‐naïve patients were randomized in 4 ascending dose cohorts to receive 12 weeks of Inarigivir 25, 50, 100, 200 mg or placebo in a ratio of 4:1. All patients were then given tenofovir for another 12 weeks. Results: Least squares (LS) mean reductions in HBV DNA from baseline increased with higher doses of Inarigivir (0.6116 in 25 mg and 1.5774 in 200 mg groups vs. 0.0352 in placebo group) (95% CI 0.9518–0.2011 and 1.921–1.1634 respectively). LS mean changes in HBV RNA and HBsAg from baseline ranged from −0.3856 to −0.5794 versus −0.1474 and −0.0956 to −0.1818 versus +0.0026 in Inarigivir‐treated versus placebo groups respectively. During the tenofovir‐treated period, LS mean reductions in HBsAg in the Inarigivir‐treated groups ranged from 0.1709 to 0.3529 versus 0.1984 in the placebo group. Inarigivir‐treated groups showed mean reductions in ALT from baseline between 23.3 and 33.8 versus 0.7 U/L in the placebo group. Treatment‐emergent adverse events related to Inarigivir and placebo occurred in 4.7% and 6.3% patients respectively. Conclusions: Twelve‐week Inarigivir up to 200 mg dose was associated with a reduction of HBV DNA, HBV RNA and antigen levels. A trend for greater HBsAg reduction was observed in Inarigivir pre‐treated patients after switching to tenofovir. [ABSTRACT FROM AUTHOR]

Background and Aims: Achieving Hepatitis B e antigen seroconversion (HBeAg SC) at an earlier age confers a better prognosis. We examined baseline and post‐partum factors associated with HBeAg SC after pregnancy. We developed a tool, the SydPregScore, to estimate the likelihood of HBeAg SC in the years after pregnancy. Methods: A retrospective analysis of an HBeAg‐positive pregnant cohort was conducted. Variables including baseline age, parity, alanine aminotransferase level, HBV viral load, quantitative HBsAg, use of antiviral therapy and post‐partum flare were collected. Univariate and multivariate Cox regression analyses to determine predictors of HBeAg SC and develop a predictor score were performed. Results: We analysed HBeAg SC rates in 220 pregnancies to 149 HBeAg‐positive women from 2006 to 2019. At baseline, their median age was 33 (IQR 29–37), ALT 23 U/L (IQR 17–33) and viral load 8 log10IU/mL (IQR 6.3–8.2 log10IU/mL). The majority (133/198, 67.2%) received short‐course antiviral therapy to prevent mother‐to‐child transmission, and 109/192 (56.8%) had a post‐partum flare. HBeAg SC occurred in 74/220 (33.6%) after pregnancy (median follow‐up 814 days, IQR 405–1531). Multivariate analysis identified baseline viral load <8 log10IU/mL (HR 2.426 [1.224–4.809], p =.011), baseline ALT ≥2 ULN (HR 2.726 [1.299–5.721], p =.008) and age <35 (HR 2.859 [1.255–6.513], p =.012) to be positive predictors of HBeAg SC. The 'SydPreg Score' estimated the probability of HBeAg SC at 2000 days as 10%, 30%, 70% and 80% for 0, 1, 2, and 3 predictors respectively. Conclusion: The SydPreg Score allows the prediction of HBeAg SC in the years after pregnancy. Even in those without elevated ALT, age <35 and viral load <8 log10IU/mL can identify women with a good chance of subsequent HBeAg SC. Those without a chance may benefit from viral suppression. [ABSTRACT FROM AUTHOR]

Background and Aims: Low anti‐HBc serum levels at the time of therapy cessation were linked to a higher relapse risk in predominantly HBeAg‐positive cohorts. We investigated the association of anti‐HBc levels with relapse in HBeAg‐negative patients. Methods: Serum levels of anti‐HBc, HBsAg and HBcrAg were determined in 136 HBeAg‐negative patients, participating in a vaccination trial (ABX‐203, NCT02249988), before treatment cessation or vaccination. Importantly, vaccination showed no impact on relapse. The correlation between the biomarkers and their predictive value for relapse (HBV DNA >2000 IU/ml ± ALT >2xULN) was investigated. Results: After therapy cessation 50% (N = 68) of patients relapsed. Median anti‐HBc prior to treatment stop was significantly higher among relapsers compared to off‐treatment responders (520 IU/ml vs. 330 IU/mL, p =.0098). The optimal anti‐HBc cut‐off to predict relapse was 325 IU/ml according to the Youden‐Index. About 35% of patients with anti‐HBc level < 325 IU/ml versus 60% of those with values ≥325 IU/mL relapsed (p =.0103; sensitivity 50%, specificity 75%). Combining the optimal cut‐offs of HBsAg (>3008 IU/mL) or HBcrAg (≥1790 U/ml) with anti‐HBc increased the proportion of patients with relapse to 80% (p <.0001) and 74% (p =.0006), respectively. Conclusion: In contrast to predominantly HBeAg‐positive cohorts, in our cohort of HBeAg‐negative patients lower anti‐HBc levels are associated with a significantly lower relapse risk after nucleos(t)ide analogue cessation. The vast majority of included patients were either genotype B or C and the applicability to other genotypes has to be further evaluated. However, anti‐HBc level as an indicator of the host response might be prospectively further explored for prediction models. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a common complication in patients with chronic liver disease and leads to significant morbidity and mortality. Liver disease and liver cancer are preventable by mitigating and managing common risk factors, including chronic hepatitis B and C infection, alcohol use, diabetes, obesity and other components of the metabolic syndrome. The management of patients with HCC requires treatment of the malignancy and adequate control of the underlying liver disease, as preserving liver function is critical for successful cancer treatment and may have a relevant prognostic role independent of HCC management. Hepatologists are the ideal providers to guide the care of patients with HCC as they are trained to identify patients at risk, apply appropriate surveillance strategies, assess and improve residual liver function, evaluate candidacy for transplant, provide longitudinal care to optimize and preserve liver function during and after HCC treatment, survey for cancer recurrence and manage its risk factors, and prevent and treat decompensating events. We highlight the need for a team‐based holistic approach to the patient with liver disease and HCC and identify necessary gaps in current care and knowledge. [ABSTRACT FROM AUTHOR]

Background and Aims: Although tenofovir alafenamide (TAF) and besifovir dipivoxil maleate (BSV) are potent antiviral agents in the treatment of chronic hepatitis B (CHB) infection, their renal safety profiles have not been previously compared. This study compared the risk of kidney function decline among patients with treatment‐naïve CHB treated with TAF or BSV. Methods: This multicenter, retrospective, longitudinal cohort study included 556 patients with treatment‐naïve CHB treated with TAF (n = 366) or BSV (n = 190) between November 2017 and August 2021. The primary outcome was chronic kidney disease (CKD) progression, defined as an increase in CKD stage by at least one stage for at least three consecutive months. Results: 1:1 Propensity score matching yielded 154 patients in each treatment group. The mean estimated glomerular filtration rate (eGFR) was 100.4 vs. 100.3 ml/min/1.73 m2 in the TAF and BSV groups respectively. A total of 25 patients developed a progression in CKD stage ≥1, of which 13 and 12 patients were from the TAF and BSV treated groups respectively (3.1 vs. 3.3 per 1000 person‐years; p =.751). The unadjusted hazard ratio for risk of progression in CKD stage ≥1 of the BSV group (vs. the TAF group) was 1.13 (95% confidence interval, 0.50–2.58; p =.758). This association persisted even after adjusting for potential confounders. Virological, serological and biochemical responses were also similar between the two treatment groups (all p >.05). Conclusions: TAF and BSV showed a similar risk of kidney function decline in patients with treatment‐naïve CHB. Further prospective randomized studies are warranted for validation. [ABSTRACT FROM AUTHOR]

Background and Aims: The immunologic features involved in the immune‐tolerant phase of chronic hepatitis B (CHB) virus (HBV) infection are unclear. The hepatitis B virus X (HBx) protein disrupts IFN‐β induction by downregulating MAVS and may destroy subsequent HBV‐specific adaptive immunity. We aimed to analyse the impacts of genetic variability of HBx in CHB patients on the immune‐tolerant phase during long‐term follow‐up. Methods: Children with CHB in the immune‐tolerant phase were recruited and followed longitudinally. HBx gene sequencing of infecting HBV strains was performed, and the effects of HBx mutations on the immune‐tolerant phase were assessed. Restoration of the host immune response to end the immune‐tolerant phase was investigated by immunoblotting, immunostaining, ELISA and reporter assays of MAVS/IFN‐β signalling in liver cell lines, patient liver tissues and the HBV plasmid replication system. Results: A total of 173 children (median age, 6.92 years) were recruited. Patients carrying HBx R87G, I127V and R87G + I127V double mutations exhibited higher cumulative incidences of immune‐tolerant phase breakthrough (p =.011, p =.006 and p =.017 respectively). Cells transfected with HBx R87G and I127V mutants and pHBV1.3‐B6.3 replicons containing the HBx R87G and I127V mutations exhibited statistically increased levels of IFN‐β, especially under poly(I:C) stimulation or Flag‐MAVS cotransfection. HA‐HBx wild‐type interacted with Flag‐MAVS and enhanced its ubiquitination, but this ability was diminished in the R87G and I127V mutants. Conclusions: HBx suppresses IFN‐β induction. R87G and I127V mutation restored IFN‐β production by preventing MAVS degradation, contributing to curtailing the HBV immune‐tolerant phase in CHB patients. [ABSTRACT FROM AUTHOR]

Background and Aims: Advances in hepatitis B virus (HBV) and hepatitis C virus (HCV) therapies have improved morbidity and mortality, but global disparities in viral hepatitis outcomes remain. We evaluate global trends in the impact of HBV and HCV on disability‐adjusted life years (DALYs). Methods: Using data from the 2010–2019 Global Burden of Diseases Study (GBD), overall all‐cause DALYs for patients with acute HBV or HCV, HBV‐ or HCV‐related cirrhosis, and HBV‐ or HCV‐related hepatocellular carcinoma (HCC) was calculated as the sum of years of life lost because of premature death and years lived with disability. DALYs were presented as age‐standardized rates per 100 000 population stratified by age and sex. Results: From 2010 to 2019, the overall global impact of HBV on DALYs per 100 000 decreased from 27.6 to 20.9 for acute HBV and 168.6 to 129.8 for HBV‐related cirrhosis but remained stable for HBV‐related HCC. The impact of HCV on DALYs per 100 000 decreased from 5.23 to 3.3 for acute HCV, 159.2 to 146.2 for HCV‐related cirrhosis, and 37.5 to 34.9 for HCV‐related HCC. We observed significant differences in the impact of HBV and HCV on DALYs when stratified by world regions. Conclusion: Decreases in HBV and HCV DALYs from 2010 to 2019 were observed. Disparities in DALY improvements across world regions suggest unequal access to viral hepatitis care and treatment. Achieving goals of viral hepatitis elimination will require enhanced prevention efforts and funding for high‐burden regions and regions that have not had substantial reductions in DALYs because of HBV and HCV. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) infection and nonalcoholic fatty liver disease (NAFLD) are two major causes of chronic liver disease (CLD) that can cause liver cirrhosis and hepatocellular carcinoma (HCC). It is a trend to superimpose NAFLD on chronic HBV infection in Asia. This review presents the epidemiology of concurrent NAFLD in chronic hepatitis B (CHB) patients and focuses on the impact of concurrent NAFLD on the outcome of CHB patients in Asia. Although CHB patients tend to have a lower prevalence and incidence of NAFLD than the general population, concurrent NAFLD among CHB patients is still common and has an upward trend over time. Concurrent NAFLD can promote hepatitis B surface antigen (HBsAg) seroclearance and might inhibit HBV replication but exacerbate liver fibrosis. The impacts of concurrent NAFLD on HCC risk, all-cause mortality and antiviral treatment response in CHB patients remain controversial. [ABSTRACT FROM AUTHOR]

Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Abbreviations AFP alpha-foetoprotein ALT alanine aminotransferase AVT antiviral therapy CHB chronic hepatitis B CI confidence interval HBeAg hepatitis B virus e antigen HBV hepatitis B virus HCC hepatocellular carcinoma HR hazard ratio IQR interquartile range kPa kilopascals LS liver stiffness OR odds ratio TE transient elastography INTRODUCTION Potent antiviral therapy (AVT) against chronic hepatitis B (CHB) can induce regression of liver fibrosis, thereby reducing the development of cirrhosis and hepatocellular carcinoma (HCC) among CHB patients.1 While the prognostic significance of hepatitis B virus (HBV)-DNA levels have diminished because of potent AVT, fibrotic burden, not HBV-DNA level or type of AVT, remains the strongest predictor of HCC development.2 Fibrotic burden is undoubtedly the most critical predictor of HCC development.3 Considering that ALT rapidly normalizes up to 49% after 1-year AVT,4 the prognostic significance of alanine aminotransferase (ALT) levels may be unclear. [Extracted from the article]

Hepatitis B virus (HBV) infection and nonalcoholic fatty liver disease (NAFLD) are two major causes of chronic liver disease (CLD) that can cause liver cirrhosis and hepatocellular carcinoma (HCC). It is a trend to superimpose NAFLD on chronic HBV infection in Asia. This review presents the epidemiology of concurrent NAFLD in chronic hepatitis B (CHB) patients and focuses on the impact of concurrent NAFLD on the outcome of CHB patients in Asia. Although CHB patients tend to have a lower prevalence and incidence of NAFLD than the general population, concurrent NAFLD among CHB patients is still common and has an upward trend over time. Concurrent NAFLD can promote hepatitis B surface antigen (HBsAg) seroclearance and might inhibit HBV replication but exacerbate liver fibrosis. The impacts of concurrent NAFLD on HCC risk, all‐cause mortality and antiviral treatment response in CHB patients remain controversial. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) is a global health problem. Vertical transmission of HBV from HBV surface antigen (HBsAg)‐positive mothers to their infants is the most common cause of HBV infection worldwide. The use of passive–active immunoprophylaxis is >90% effective in reducing the risk of vertical transmission, but immunoprophylaxis failure can occur in infants born to mothers with high viraemia. Thus, it is recommended that pregnant women with HBV‐DNA level >200 000 IU/ml receive nucleos(t)ide analogue (NA) treatment [i.e. tenofovir disoproxil fumarate (TDF), lamivudine or telbivudine] during third trimester to prevent infant immunoprophylaxis failure. TDF is recommended as the first‐line therapy based on available data on efficacy, safety and resistance profile. However, maternal immunological reconstitution following parturition can increase immune‐mediated flares to viral antigens that is potentially exacerbated following TDF withdrawal. In this article, we review available data on the efficacy and safety of TDF administration to prevent HBV mother‐to‐child transmission. We also discuss changes in maternal viral markers [i.e. HBV‐DNA, HBV e antigen and HBsAg] and alanine aminotransferase during follow‐up post‐partum in mothers received NA to prevent HBV vertical transmission. [ABSTRACT FROM AUTHOR]

Background and Aims: Evidence suggests that interferon alpha (IFNα) plays an essential role in decreasing the HBsAg quantification and elevating the rate of clinical cure in chronic hepatitis B (CHB). However, the mechanisms underlying the effects of the exosomes on the expression of host genes in IFNα treatment remain unclear. Methods: CHB patients with IFNα treatment were divided into responders and non‐responders according to the degree of HBsAg decline. Through microRNA sequencing and a series of molecular biology methods, the key microRNAs in serum exosomes associated with clinical antiviral response of Peg‐IFNα treatment in nucleotide analogue‐treated CHB patients were investigated. The roles of exosomal miRNAs on the IFNα signal pathway were explored in macrophages. Results: MicroRNA sequencing and RT‐qPCR assays confirmed six distinctly declined miRNAs in serum exosomes of responders at week 12 compared with levels at baseline. Exosomes with declined miR27b‐3p in the serum of Peg‐IFNα‐treated responders activated phosphorylation of interferon regulatory factor 3/7 (IRF3/7) in IFNα synthesis pathway in macrophages. However, miR27b‐3p overexpression in HepAD38 cells suppressed IFNα synthesis in macrophages, resulting in insufficient ability to eliminate HBV, whereas the inhibitory effect could be blocked by inhibitors of exosomes release. Luciferase assay showed miR‐27b‐3p directly suppressed retinoic acid‐inducible gene I (RIG‐I) and TANK‐binding kinase 1 (TBK1) expressions, and these effects could be abrogated in mutation experiments. Conclusions: In IFNα treatment, exosomes with declined miR‐27b‐3p triggered activation of RIG‐I/TBK1 signalling in macrophages against HBV. Serum exosomal miR‐27‐3p might represent a potential biomarker for patients with CHB. [ABSTRACT FROM AUTHOR]

Background and Aims: We used real‐world data to evaluate the efficacy and safety of tenofovir alafenamide (TAF) compared with tenofovir disoproxil fumarate (TDF) in treatment‐naïve patients with CHB. Methods: We analysed 2747 patients with CHB under TAF (n = 502) or TDF (n = 2245) treatments. Virological responses (VR: HBV DNA <15 IU/ml), on‐treatment ALT normalization, the incidence of HCC, renal function and lipid profiles were compared between these groups. Propensity score matching of 495 pairs was conducted for these comparisons. Results: The mean age of the total cohort was 48.6 years and 58.2% of the subjects were male. Cirrhosis had a 33.3% prevalence in the population. VRs at 12, 24 and 36 months were achieved in 70.3%, 81.2% and 83.3% of the TAF and 67.9%, 84.3% and 86.1% in the TDF cases respectively (p > 0.05 for all). Normalized ALT, as determined by local laboratory criteria (<40 U/L), occurred in 79.7%, 90.6% and 86.2% of TAF the group and 78.2%, 85.8% and 85.7% of the TDF group at 12, 24 and 36 months respectively (p > 0.05 for all). The HCC risk did not statistically differ across the entire cohort or in the PS‐matched cohort. The TAF group showed a lower median increase in serum creatinine from baseline during the early study period. Compared with the TAF, the TDF group showed significant decreases in total cholesterol, triglyceride and HDL, but not in LDL. Conclusions: Real‐word data indicate that TAF has comparable efficacies to TDF in terms of VR and ALT normalization, with no higher risk of HCC. [ABSTRACT FROM AUTHOR]

Secondly, Talbot et al[11] validate the pattern of progression[12] in the context of ICI-based systemic therapies, confirming that patients with new vascular invasion (nVI) have a poorer prognosis. From this study, we could keep in mind that different parameters will influence patients' prognosis and treatment decision at progression under ICI (Figure 1). Firstly, and as expected, the median PPS after ICI therapies for patients receiving further-line therapies was significantly longer than those who have not received further lines of treatment (10.3 months vs. 1.9 months, respectively; I p i < .0001). Keywords: competing risk; immune checkpoint inhibitors; immunotherapy; liver cancer; overall survival; prognosis; progression; surrogacy; tyrosine kinase inhibitors EN competing risk immune checkpoint inhibitors immunotherapy liver cancer overall survival prognosis progression surrogacy tyrosine kinase inhibitors 528 530 3 02/21/23 20230301 NES 230301 Hepatocellular carcinoma (HCC) is the most common primary liver cancer; it represents the fifth most common cancer and the second most frequent cause of cancer-associated death worldwide and will rise over the next 20 years.[1] Despite the application of surveillance programs,[[2]] many patients have disease that is not amenable to curative treatments at presentation, and for this reason, they undergo treatments such as transarterial chemoembolization (TACE), radioembolization (also known as selective internal radiation therapy, or SIRT) and systemic treatment. [Extracted from the article]

HBsAg loss did not occur in any of the patients, while five patients from the Inarigivir treatment groups showed HBeAg loss. Furthermore, low baseline HBsAg levels were associated with better suppression of HBV DNA and RNA during Inarigivir treatment indicating that a less immune exhaustive state may support immunomodulatory capacities of Inarigivir. Chronic hepatitis B virus (HBV) infection remains a global health burden with estimated 1.5 million new infections and more than 800 000 deaths per year.[1] The goal of antiviral treatment is functional cure - meaning HBsAg loss and maintained HBV DNA undetectability after end of antiviral therapy. During the subsequent TDF treatment, HBV DNA suppression was higher if patients had received Inarigivir before. [Extracted from the article]

Background and Aims: The safety and antibody responses of coronavirus disease 2019 (COVID‐19) vaccination in patients with chronic hepatitis B (CHB) virus infection is still unclear, and exploration in safety and antibody responses of COVID‐19 vaccination in CHB patients is significant in clinical practice. Methods: 362 adult CHB patients and 87 healthy controls at an interval of at least 21 days after a full‐course vaccination (21–105 days) were enrolled. Adverse events (AEs) were collected by questionnaire. The antibody profiles at 1, 2 and 3 months were elucidated by determination of anti‐spike IgG, anti‐receptor‐binding domain (RBD) IgG, and RBD‐angiotensin‐converting enzyme 2 blocking antibody. SARS‐CoV‐2 specific B cells were also analysed. Results: All AEs were mild and self‐limiting, and the incidence was similar between CHB patients and controls. Seropositivity rates of three antibodies were similar between CHB patients and healthy controls at 1, 2 and 3 months, but CHB patients had lower titers of three antibodies at 1 month. Compared to healthy controls, HBeAg‐positive CHB patients had higher titers of three antibodies at 3 months (all P <.05) and a slower decline in antibody titers. Frequency of RBD‐specific B cells was positively correlated with titers of anti‐RBD IgG (OR = 1.067, P =.004), while liver cirrhosis, antiviral treatment, levels of HBV DNA, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and total bilirubin (TB) were not correlated with titers of anti‐RBD IgG. Conclusions: Inactivated COVID‐19 vaccines were well tolerated, and induced effective antibody response against SARS‐CoV‐2 in CHB patients. [ABSTRACT FROM AUTHOR]

Background and Aims: Entecavir (ETV) and tenofovir alafenamide (TAF) are the preferred agents in patients with predisposing factors for nephrotoxicity, but no studies to date have directly compared the renal safety of the two antiviral agents. Hence, we compared the risk of kidney function decline among patients with treatment‐naïve chronic hepatitis B (CHB) treated with ETV or TAF. Methods: This study included 1988 patients with treatment‐naïve CHB who were treated with ETV (n = 1839) or TAF (n = 149) between 2007 and 2020 for ETV and between 2017 and 2020 for TAF. The primary outcome was chronic kidney disease (CKD) progression, defined as an increase in CKD stage by at least one stage for at least three consecutive months. Results: A 1:1 propensity score match yielded 149 patients in each treatment group. The mean estimated glomerular filtration rate (eGFR) was 100.6 ml/min/1.73 m2 vs. 101.3 ml/min/1.73 m2 in the ETV and TAF groups respectively. A total of 61 patients developed a progression in CKD stage ≥ 1, of which 47 and 14 patients were from the ETV‐ and TAF‐treated groups respectively (19.9 vs. 5.1 per 1000 person‐years; p <.001). The risk of progression in CKD stage ≥1 was significantly higher in patients treated with ETV, even when adjusted for potential confounders (adjusted hazard ratio 4.05; 95% CI 2.14–7.68; p <.001). Conclusions: ETV was associated with a higher risk of kidney function decline than TAF in patients with treatment‐naïve CHB. Therefore, further prospective randomized studies are needed. [ABSTRACT FROM AUTHOR]

Background & Aims: Clinical relapse occurs much earlier and more frequently in hepatitis B e antigen (HBeAg)‐negative chronic hepatitis B (CHB) patients after stopping tenofovir (TDF) therapy than those off‐entecavir (ETV). Clinical relapse may subside or progress to hepatitis flare which poses a safety concern. This study compared the incidence, timing and severity of hepatitis flares after stopping TDF and ETV. Methods: HBeAg‐negative CHB patients who had stopped ETV or TDF were included in the study. Off‐therapy hepatitis flare patterns were compared between off‐ETV and off‐TDF patients before and after propensity score matching (PSM). Results: The off‐therapy hepatitis flares occurred more frequently (2‐year: 58% vs 38%, P <.001) and much earlier (12 vs. 38 weeks, P <.001) in TDF group, with higher alanine aminotransferase (ALT) levels (after PSM: 536 vs. 419 U/L, P =.020) and two times rate of hepatic decompensation (4.0% vs. 2.1%, P =.322). The cirrhotic status [aHR: 20.531 (2.645‐159.365), P =.004] and off‐TDF [aHR: 5.530 (1.728‐17.694), P =.004] were two independent predictors for hepatic decompensation. Conclusions: Hepatitis flare occurred more frequently, earlier, and more severe in off‐TDF than off‐ETV patients. More stringent off‐therapy monitoring within 6 months off‐TDF is mandatory whereas more attention is needed after 6 months off‐ETV. [ABSTRACT FROM AUTHOR]

Background and Aims: Scarce data exist on the effect of nucleos(t)ide analogue (NA) discontinuation on hepatocellular carcinoma (HCC) risk in HBeAg‐negative chronic hepatitis B (CHBe−). Therefore, we assessed whether HCC risk is increased in non‐cirrhotic CHBe− patients who discontinue compared to those remaining on NAs. Methods: This cohort study included 650 consecutive non‐cirrhotic Caucasian or Asian patients with CHBe− without a history of HCC who discontinued NAs after a median of 5 or 3 years (cases, n = 325; Caucasians: 143, Asians: 182) or remained on NA therapy beyond 5 or 3 years respectively (controls, n = 325; Caucasians: 223, Asians: 102). Propensity score (PS) 1:1 matching was applied to adjust for patients' origin, age and sex. Results: During a median follow‐up of 44 months, HCC developed in 7/325 cases and 9/325 controls or 7/245 PS‐matched cases and 7/245 PS‐matched controls with 5‐year cumulative HCC incidence of 5.1% and 4.9% respectively (log‐rank, P =.836). No difference in 5‐year HCC risk was observed between cases and controls of Caucasian (3.0% vs 4.8%; log‐rank, P =.510) or Asian origin (1.3% vs 2.2%; log‐rank, P =.873). In both cases and controls, HCC incidence was independently associated with age and PAGE‐B score. In cases alone, HCC development after NA discontinuation was associated only with pretreatment platelet counts and PAGE‐B score, but not with any type of relapse or HBsAg loss. Conclusions: Our findings suggest that discontinuation of effective long‐term NA therapy in non‐cirrhotic CHBe− patients are not associated with increased HCC risk, which is not affected by post‐NA relapses and/or HBsAg loss. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B virus (HBV) infection is the major aetiology of hepatocellular carcinoma (HCC). The optimal goal of therapy, hepatitis B surface antigen (HBsAg) loss and anti‐HBs production, is achieved rarely and HBsAg‐associated HCC risk is well recognized. Here we review the role of HBsAg in HCC, the link between HBsAg and HCC recurrence post‐liver transplantation or resection, and the implications for therapy. HBV‐associated carcinogenesis is a multifactorial process. The observation that HBV‐related HCC can occur in the absence of cirrhosis is compatible with a direct oncogenic effect of the virus, which may occur via multiple mechanisms, including those mediated by both mutated and unmutated HBsAg. HCC recurrence in HBsAg‐positive patients post‐liver transplantation has been reported in 10%‐15% of patients and is likely to be because of expansion of residual HCC tumour cell populations containing integrated HBV DNA, which expand and independently replicate HBV, leading to the recurrence of both HCC and HBV. The direct role of HBsAg in HCC recurrence post‐liver resection is less clear. Cirrhosis is the most important risk factor for HCC development, and precancerous cirrhotic liver remains after resection, with the potential to undergo malignant transformation regardless of the existence of HBV‐derived oncogenic drivers. The role of HBsAg in the development of HCC and its recurrence post‐surgical intervention has multiple implications for therapy and suggests a potential role for immunotherapy in the future management of HCC, in particular post‐liver transplantation. Use of hepatitis B immunoglobulins that target HBsAg directly, alongside immune‐oncology therapies, may be relevant in this setting. [ABSTRACT FROM AUTHOR]

Background & Aims: This multicenter cohort study aimed to compare the real‐world biochemical response rates during tenofovir alafenamide (TAF), tenofovir disoproxil fumarate (TDF), and entecavir (ETV) treatment in chronic hepatitis B virus (HBV) infection patients. Methods: Overall, 1282 treatment‐naïve patients with CHB who commenced TAF (n = 270), TDF (n = 617), or ETV (n = 395) were analysed for biochemical response rates during the antiviral treatment using a time‐dependent Cox proportional hazard model after the inverse probability of treatment weighting (IPTW). Results: Patients treated with ETV were older (55.1 ± 11.5 years) than TAF or TDF (P <.0001). ETV was more frequently prescribed to patients with diabetes mellitus (DM, P =.003), hypertension (P <.0001), chronic kidney disease (P <.0001), and negative e‐antigen (P <.0001). Cumulative biochemical response rate was independently lower in patients with radiologic fatty liver (HR, 0.75; 95% CI, 0.61‐0.94) and obese patients without DM (HR, 0.85; 95% CI, 0.68‐0.98) according to multivariable Cox analyses based on time‐dependent variables after IPTW for age, sex, liver cirrhosis, baseline e‐antigen, ALT, and HBV DNA levels. ETV treated patients (HR, 1.38; 95% CI, 1.13‐1.68) showed higher biochemical response rates compared with TAF‐ or TDF‐treated patients after adjusting for similar parameters. Conclusions: In real‐world practice, ETV was preferable for older, hepatitis B e‐antigen negative patients with underlying comorbidities. Biochemical responses in patients treated with ETV, TAF, and TDF were significantly affected by metabolic factors such as fatty liver, obesity, and DM. However, the mechanism behind the higher biochemical response rate in patients treated with ETV should be investigated further. [ABSTRACT FROM AUTHOR]

Novel treatments for hepatitis Delta virus (HDV) infection provide promising opportunities to treat patients with hepatitis B virus (HBV) and HDV co‐infection. However, current clinical trials on HDV treatment rarely explore patients' barriers to treatments. In Europe, HDV infection mostly affects young migrants from HDV‐endemic areas who experience early liver‐related mortality. Migrants are more likely to face multiple situations of statutory and socioeconomic insecurity and structural barriers than non‐migrants. These obstacles may impact their quality of life and can (i) lead them to give secondary importance to certain HDV care options, (ii) delay treatment initiation and (iii) affect their adherence and commitment to care. Preliminary results from the ANRS CO22 HEPATHER cohort show that the majority (61.6%) of HBV‐HDV co‐infected migrants live in poverty. Moreover, half were diagnosed and a quarter of those who initiated HBV treatment had been in France for no more than two years, a period when language skills are often still poor and when knowledge of the health and administrative system may be lacking. We advocate for increased social science research, in particular qualitative studies, to investigate the effects that multiple forms of precarity (weak access to social rights, language barriers, housing insecurity, unexpected expenditures and other difficulties) may have on HDV screening opportunities, follow‐up, and treatment pathways in migrants. This will help adapt communication and care around viral hepatitis, as well as inform and orient medical services and public health actors about the difficulties that migrants encounter. [ABSTRACT FROM AUTHOR]

Background & Aims: Gamma‐glutamyl transferase (GGT) has been predictive of chronic hepatitis C‐related hepatocellular carcinoma (HCC) development. Its role in the risk of HCC in chronic hepatitis B (CHB) patients treated with nucleotide/nucleoside analogues (NAs) is elusive. Methods: A total of 2172 CHB patients from East Asia were randomized into development and validation groups in a 1:2 ratio. Serum GGT levels before and 6 months (M6) after initiating NAs and the potential risk factors were measured. The primary endpoint was HCC development 12 months after NA initiation. Results: The annual incidence of HCC was 1.4/100 person‐years in a follow‐up period of 11 370.7 person‐years. The strongest factor associated with HCC development was high M6‐GGT levels (>25 U/L; hazard ratio [HR]/95% confidence interval [CI]: 3.31/2.02‐5.42, P <.001), followed by cirrhosis (HR/CI: 2.06/1.39‐3.06, P <.001), male sex (HR/CI: 2.01/1.29‐3.13, P =.002) and age (HR/CI: 1.05/1.03‐1.17, P <.001). Among cirrhotic patients, the incidence of HCC did not differ between those with high or low M6‐GGT levels (P =.09). In contrast, among non‐cirrhotic patients, the incidence of HCC was significantly higher for those with M6‐GGT level >25 U/L than for their counterparts (P <.001). Cox regression analysis revealed that the strongest factor associated with HCC development in non‐cirrhotic patients was high M6‐GGT levels (HR/CI: 5.05/2.52‐10.16, P <.001), followed by age (HR/CI: 1.07/1.04‐1.09, P <.001). Non‐cirrhotic elderly patients with high M6‐GGT levels had a similarly high HCC risk as cirrhotic patients did (P =.29). Conclusions: On‐treatment serum GGT levels strongly predicted HCC development in CHB patients, particularly non‐cirrhotic patients, treated with NAs. [ABSTRACT FROM AUTHOR]

Background: GALAD is an algorithm model estimating the presence of hepatocellular carcinoma (HCC). However, the participants enrolled in the GALAD differ from those of Chinese subjects whose HCCs are mainly hepatitis B virus infection related. Therefore, the cross‐sectional as well as longitudinal multicenter study was designed to assess the clinical performances of GALAD in the Chinese population. Methods: A case‐control study of 602 patients with HCC (34.10% within Barcelona Clinic Liver Cancer 0‐A stage) and 923 subjects without HCC from five Chinese medical centres was conducted. Longitudinally the performances of GALAD identifying HCC were assessed using receiver operating characteristic curves analyses. Furthermore, the surveillance performance of GALAD for 204 HCC patients after radical surgery and for the early detection of HCC prospectively in an independent cohort of chronic hepatitis B were analysed, respectively. Results: We found the GALAD identified early stage HCC at an area under the receiver operating characteristic curve (AUC) above 0.85 and outperformed significantly than AFP, PIVKAII, AFP‐L3 and BALAD‐2 respectively. Meanwhile the GALAD could stratify HCC into two distinct subgroups with high or low risks of overall survival and recurrence. The GALAD could detection HCC 24 (AUC: 0.848) or even 48 (AUC: 0.833) weeks before clinical diagnosis. Conclusions: Our study indicates that the GALAD exhibits outstanding performance in the early diagnosis, prognosis prediction as well as risk monitoring of HCC in our cross‐sectional and longitudinal multicenter study of 1561 patients. GALAD should be implanted into clinical practice early so as to improve the clinical efficacy of individual biomarkers in HCC early monitoring and prognosis prediction. [ABSTRACT FROM AUTHOR]

Background & Aims: We aim to capture the economic impact of a potential cure for chronic hepatitis B infection (CHB) in three countries (USA, China and Australia) with different health systems and epidemics to estimate the threshold drug prices below which a CHB cure would be cost‐saving and/or highly cost‐effective. Methods: We simulated patients' hepatitis B progression, under three scenarios: current long‐term suppressive antiviral therapy, functional cure defined as sustained undetectable HBsAg and HBV DNA, and partial cure defined as sustained undetectable HBV DNA only after a finite, 48‐week treatment. Results: Compared with current long‐term antiviral therapy, a 30% effective functional cure among patients with and without cirrhosis in the USA, China and Australia would yield 17.50, 17.32 and 20.42 QALYs per patient, and 20.61, 20.42 and 20.62 QALYs per patient respectively. In financial terms, for CHB patients with and without cirrhosis, this would be cost‐saving at a one‐time treatment cost under US$11 944 and US$6694, respectively, in the USA, US$1744 and US$1001 in China, and US$12 063 and US$10 983 in Australia. Conclusion: We show that in purely economic terms, a CHB cure will be highly cost‐effective even if effective in only 30% of treated patients. The threshold price for cure is largely determined by the current antiviral drug costs, since it will replace a daily antiviral pill that is inexpensive and effective, although not curative. The likely need for combination therapies to achieve cure will also present cost challenges. While cost‐effectiveness is important, it cannot be the only consideration, as cure will provide many benefits in addition to reduced liver disease and HCC, including eliminating the need for a long‐term daily pill and reducing stigma often associated with chronic viral infection. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B virus (HBV) infection is a worldwide health problem leading to severe liver dysfunction, including liver cirrhosis and hepatocellular carcinoma. Although current antiviral therapies for chronic HBV infection have been improved and can lead to a strong suppression of viral replication, it is difficult to completely eliminate the virus with these therapies once chronic HBV infection is established in the host. Furthermore, chronic HBV infection alters intracellular metabolism and signalling pathways, resulting in the activation of carcinogenesis in the liver. HBV produces four viral proteins: hepatitis B surface‐, hepatitis B core‐, hepatitis B x protein, and polymerase; each plays an important role in HBV replication and the intracellular signalling pathways associated with hepatocarcinogenesis. In vitro and in vivo experimental models for analyzing HBV infection and replication have been established, and gene expression analyses using microarrays or next‐generation sequencing have also been developed. Thus, it is possible to clarify the molecular mechanisms for intracellular alterations, such as endoplasmic reticulum stress, oxidative stress, and epigenetic modifications. In this review, the impact of HBV viral proteins and intracellular alterations in HBV‐associated hepatocarcinogenesis are discussed. [ABSTRACT FROM AUTHOR]

Background & Aims: Data on liver fibrosis evolution and its involvement in liver‐related morbidity are scarce in individuals with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) co‐infection during treatment. We identified profiles of liver fibrosis evolution in coinfected patients undergoing tenofovir (TDF). Methods: We included 169 HIV‐HBV‐coinfected patients on TDF‐based antiretroviral therapy. Virological and clinical data were obtained at TDF‐initiation and every 6‐12 months. From data on non‐invasive liver fibrosis assessments collected yearly (FibroTest®), we established clusters of individuals with similar liver fibrosis evolution using group‐based trajectory models. Results: Four profiles of liver fibrosis evolution were established from a median follow‐up of 7.6 years (IQR = 3.1‐13.1): low fibrosis with no progression (29.6%, profile A), low fibrosis with progression (22.5%, profile B), moderate fibrosis with high fluctuation (39.6%, profile C), and cirrhosis with no regression (8.3%, profile D). When compared to profile A, baseline HBeAg‐positive status was associated with profiles B (P =.007) and C (P =.004), older age with profiles C (P <.001) and D (P =.001), exposure to second‐generation protease inhibitors with profile C (P =.004), and CD4+ <500/mm3 at the last visit with profiles C (P =.02) and D (P =.002). Incident liver‐related events occurred in profiles other than A (B, n = 1/38; C, n = 6/67; D, n = 3/14) and all five cases of hepatocellular carcinoma occurred in profiles C (n = 2) and D (n = 3). Conclusions: TDF‐treated HIV‐HBV coinfected individuals do not seem to benefit from comparable levels of liver fibrosis regression as in HBV mono‐infection. Liver‐related morbidity occurs mainly in those with fluctuating or consistently high fibrosis levels. [ABSTRACT FROM AUTHOR]

Background & Aims: Liver Imaging Reporting and Data System (LI‐RADS) and European Association for the Study (EASL) criteria for hepatocellular carcinoma (HCC) diagnosis have been updated in 2018. We aimed to compare the HCC diagnostic performance of LI‐RADS and EASL criteria with extracellular contrast agents‐MRI (ECA‐MRI) and hepatobiliary agents‐MRI (HBA‐MRI). Methods: We prospectively evaluated 179 participants with cirrhosis (n = 105) or non‐cirrhotic chronic hepatitis B (CHB) (n = 74) who underwent both ECA‐MRI and HBA‐MRI before surgery for de novo nodule(s) measuring 10‐30 mm. We compared the HCC diagnostic performance of EASL and LR‐5 in both MRIs. Results: In an analysis of 215 observations (175 HCCs, 17 non‐HCC malignancies and 23 benign lesions) identified from cirrhotic or non‐cirrhotic CHB participants, LR‐5 with ECA‐MRI provided the highest sensitivity (80.7%), followed by EASL with ECA‐MRI (76.2%), LR‐5 with HBA‐MRI (67.3%) and EASL with HBA‐MRI (63.0%, all P <.05). The specificities were comparable (89.4%‐91.5%). When the analysis is limited to participants with pathological cirrhosis (123 observations), the sensitivity of LR‐5 with ECA‐MRI was similar to that of EASL with ECA‐MRI (82.7% vs 80.2%, P =.156), but higher than LR‐5 with HBA‐MRI (65.1%) or EASL with HBA‐MRI (62.8%, both P <.001), with comparable specificities (87.5%‐91.7%). Conclusions: The LR‐5 with ECA‐MRI yielded the highest sensitivity with a similar specificity for HCC diagnosis in cirrhosis and non‐cirrhotic CHB participants, while the sensitivities of LR‐5 and EASL with ECA‐MRI are similar for cirrhosis participants. This indicates non‐invasive diagnosis criteria can differ by contrast agents and presence of cirrhosis. [ABSTRACT FROM AUTHOR]

Background & Aims: Aspirin and statins have been suggested to prevent hepatocellular carcinoma (HCC). However, the combined effects of aspirin and statins on HCC risk in patients with chronic hepatitis B (CHB) are not clear. Methods: A nationwide nested case‐control study was performed with data from the National Health Insurance Service gathered between 2005 and 2015 in Korea. In a cohort of 538,135 treatment‐naïve, non‐cirrhotic patients with CHB, 6,539 HCC cases were matched to 26,156 controls and were analysed by conditional logistic regression. Separate historical cohort studies for each drug were analysed by time‐dependent Cox regression as a sensitivity analysis. Results: In the nested case‐control study, statins (OR 0.34; 95% CI 0.32‐0.37) and aspirin (OR 0.92; 95% CI 0.85‐0.99) were significantly associated with a HCC risk reduction. However, dose‐dependent risk reduction was observed only with statins. By sensitivity analysis in the historical cohorts, statin users (n = 244,455; HR 0.67; 95% CI 0.66‐0.68) and aspirin users (n = 288,777; HR 0.81; 95% CI 0.80‐0.82) had significantly lower HCC risk. In the drug‐stratified analyses, statins were associated with significantly reduced risk of HCC regardless of aspirin, whereas aspirin did not show such associations. Conclusions: In this nationwide population‐based study of patients with CHB, statin use was consistently associated with a significant and dose‐dependent reduction in HCC risk. In contrast, the association between aspirin use and HCC risk reduction was not dose‐dependent and was suggested to be confounded by statins. [ABSTRACT FROM AUTHOR]

Background & Aims: The effectiveness and safety of peginterferon alpha (peg‐IFN‐α) monotherapy in inactive hepatitis B virus (HBV) carriers (IHCs) have not been fully evaluated. Methods: This observational study prospectively enrolled 298 IHCs in China from 2015 to 2019. Participants were given the right to choose to either receive peg‐IFN‐α monotherapy (treatment group, n = 142) or be monitored without treatment (control group, n = 156) according to their wishes. The scheduled treatment duration was 48 weeks. All participants were followed up to 72 weeks. The main efficacy endpoint was hepatitis B surface antigen (HBsAg) clearance at 72 weeks. Results: Baseline characteristics were similar between both groups. At 72 weeks, intention‐to‐treat analysis showed that the rates of HBsAg clearance and seroconversion of the treatment group were 47.9% (68/142) and 36.6% (52/142), respectively, which were significantly higher than the HBsAg clearance rate of 1.9% (3/156) and the seroconversion rate of 0.6% (1/156) in the control group (both P <.001). Baseline HBV DNA < 20 IU/mL, lower HBsAg levels at baseline, 12 and 24 weeks, alanine aminotransferase elevation at 12 weeks, and greater HBsAg reduction from baseline to 12 and 24 weeks were independent predictors of HBsAg clearance. Generally, the therapy was well tolerated. Only five participants discontinued therapy as a result of peg‐IFNα‐related adverse events. Conclusions: Peg‐IFN‐α monotherapy results in high rates of HBsAg clearance and seroconversion and the treatment is safe for IHCs. [ABSTRACT FROM AUTHOR]

Background & Aims: During chronic hepatitis B virus (HBV) infection, suppressed functionality of natural killer (NK) cells might contribute to HBV persistence but the underlying mechanisms remain elusive. A peculiar feature of HBV is the secretion of large amount of hepatitis B surface antigen (HBsAg). However, the effect of HBsAg quantities on NK cells is unclear. The aim was to determine the effects of HBsAg quantities on NK cell functionality in patients with chronic hepatitis B (CHB). Methods: Eighty CHB patients were included and categorized into four groups based on their HBsAg levels. As a control, 30 healthy donors were enrolled. NK cell frequency, phenotype and function were assessed using flow cytometry and correlated with HBsAg levels and liver enzymes. Results: Compared to the healthy controls, a reshaping of NK cell pool towards more CD56bright NK cells was observed during CHB infection. Importantly, NK cells in patients with low HBsAg levels (<100 IU/mL) displayed an activated phenotype with increased expression of activation makers CD38, granzyme B and proliferation marker Ki‐67 while presenting with defective functional responses (MIP‐1β, CD107a) at the same time. Furthermore, NK cell activation was negatively correlated with patient HBsAg levels while NK function correlated with patient age. Conclusions: The differential regulation of NK cell phenotype and function suggests that activation of NK cells in patients with low serum HBsAg levels may contribute to HBV clearance. [ABSTRACT FROM AUTHOR]

Aims: This study aims to assess the trend of hepatitis B virus (HBV)‐attributable liver cancer as well as the impact of HBV vaccine on it. Methods: We retrieved data from Global Burden Disease study to estimate trends of HBV‐attributable liver cancer by region and age from 1990 to 2017 and HBV vaccine data from World Health Organization to assess its impact on these trends for children (0‐14 years), adolescents and young adults (15‐29 years). Change of cancer cases, age‐standardized incidence rate (ASR) and estimated annual percentage change (EAPC) were used to quantify the trends of HBV‐attributable liver cancer. Results: In this study, reduction in HBV‐attributable cancer incident cases was found among children (from 2080 to 1430), adolescents and young adults (from 10 890 to 9090). In terms of ASR, overall reduction was observed globally by an average of −0.45% (95% CI: −0.62 to −0.29) per year in the same period. The highest reduction in ASR was found in adolescents and young adults with EAPC of −3.02 (95% CI: −3.57 to −2.46). Although the ASR has decreased from all the five regions with universal HBV immunization programme, it has increased in the region without universal vaccination and the highest increase was found among children with EAPC of 1.97 (95% CI: 1.71‐2.23). Conclusion: Significant reduction in HBV‐attributable liver cancer among children was mainly because of the universal HBV vaccination. However, the increasing trend of HBV‐attributable liver cancer in region without universal HBV vaccination suggested the necessity of introducing universal immunization. [ABSTRACT FROM AUTHOR]

Hepatitis delta virus (HDV) infection is the most severe form of viral hepatitis. Bulevirtide (BLV, Hepcludex®) is an HDV/HBV entry inhibitor approved in June 2020 in the European Union for adult patients with chronic hepatitis delta (CHD) and compensated liver disease and positive HDV RNA viral load. This real‐life preliminary report described early virological efficacy and safety of BLV in six patients with CHD and compensated liver disease: four patients were treated with the combination of BLV (2 mg/d in subcutaneous injection) and pegylated interferon (PEG‐IFN) and two patients with BLV monotherapy. Four patients treated with combined therapy had a decline of a minimum of 1 log10 and 3/3 of 2 log10 of HDV‐VL at 12 and 24 weeks, respectively. One patient among four had stopped the treatment at 12 weeks because of thrombocytopenia and an HDV‐VL relapse was notified 24 weeks after treatment cessation. Three patients among four (3/4) had undetectable HDV‐VL during the therapy (<100 IU/ml). One patient (1/2) treated with BLV monotherapy had a decline of HDV‐VL by 1 log10 at 8 weeks and 1/1 by 2 log10 at 28 week on‐treatment. Two patients among four (2/4) with combined therapy had normal ALT reached at 4 and 56 weeks. One patient (1/2) with BLV monotherapy achieves ALT normalization at​ 4 weeks on treatment. Hepatitis B surface antigen (HBsAg) levels remain unchanged. Three among six (3/6) patients had an elevation of total biliary acids without pruritus. These early data generated confirm the interest in this new treatment. Final results will be important to demonstrate long‐term clinical benefit (fibrosis reversibility and reduction in hepato‐cellular carcinoma [HCC]). [ABSTRACT FROM AUTHOR]

Background & Aims: There are currently several prediction models for hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) receiving oral antiviral therapy. However, most models are based on pre‐treatment clinical parameters. The current study aimed to develop a novel and practical prediction model for HCC by using both pre‐ and post‐treatment parameters in this population. Methods: We included two treatment‐naïve CHB cohorts who were initiated on oral antiviral therapies: the derivation cohort (n = 1480, Korea prospective SAINT cohort) and the validation cohort (n = 426, the US retrospective Stanford Bay cohort). We employed logistic regression, decision tree, lasso regression, support vector machine and random forest algorithms to develop the HCC prediction model and selected the most optimal method. Results: We evaluated both pre‐treatment and the 12‐month clinical parameters on‐treatment and found the 12‐month on‐treatment values to have superior HCC prediction performance. The lasso logistic regression algorithm using the presence of cirrhosis at baseline and alpha‐foetoprotein and platelet at 12 months showed the best performance (AUROC = 0.843 in the derivation cohort. The model performed well in the external validation cohort (AUROC = 0.844) and better than other existing prediction models including the APA, PAGE‐B and GAG models (AUROC = 0.769 to 0.818). Conclusions: We provided a simple‐to‐use HCC prediction model based on presence of cirrhosis at baseline and two objective laboratory markers (AFP and platelets) measured 12 months after antiviral initiation. The model is highly accurate with excellent validation in an external cohort from a different country (AUROC 0.844) (Clinical trial number: KCT0003487). [ABSTRACT FROM AUTHOR]