The updated EASL Clinical Practice Guidelines on the management of hepatitis B virus (HBV) infection provide comprehensive, evidence-based recommendations for its management. Spanning ten thematic sections, the guidelines address diagnostics, treatment goals, treatment indications, therapeutic options, hepatocellular carcinoma surveillance, management of special populations, HBV reactivation prophylaxis, post-transplant care, HBV prevention strategies, and finally address open questions and future research directions. Chronic HBV remains a global health challenge, with over 250 million individuals affected and significant mortality due to cirrhosis and hepatocellular carcinoma. These guidelines emphasise the importance of early diagnosis, risk stratification based on viral and host factors, and tailored antiviral therapy. Attention is given to simplified algorithms, vaccination, and screening to support global HBV elimination targets. The guidelines also discuss emerging biomarkers and evolving definitions of functional and partial cure. Developed through literature review, expert consensus, and a Delphi process, the guidelines aim to equip healthcare providers across disciplines with practical tools to optimise HBV care and outcomes worldwide.

The relapse pattern following the discontinuation of tenofovir alafenamide (TAF) in patients with chronic hepatitis B (CHB) remains unclear. This study aimed to compare the 2-year incidences of virological and clinical relapses among patients who discontinued TAF versus those who discontinued tenofovir disoproxil fumarate (TDF) or entecavir (ETV).

This multicenter retrospective study enrolled noncirrhotic hepatitis B e antigen (HBeAg)-negative CHB patients who discontinued TAF, TDF, or ETV with undetectable HBV DNA at treatment cessation. For patients who switched from ETV or TDF to TAF, a minimum TAF exposure duration of 12 months was required for inclusion in the off-TAF group. Inverse probability of treatment weighting was employed to adjust for baseline differences.

A total of 162 patients (off-TAF: 37, off-TDF: 87, off-ETV: 38) were included in the primary analysis. The 2-year cumulative incidence of virological relapse was significantly higher in the off-TAF group (85.0%) compared to the off-TDF group (69.5%, p = 0.024) and the off-ETV group (51.5%, p = 0.010). Similarly, the 2-year cumulative incidence of clinical relapse was significantly higher in the off-TAF group (62.4%) compared to the off-TDF group (39.0%, p = 0.026) and the off-ETV group (22.5%, p = 0.024). Consistent results were observed in patients meeting the 2012 APASL stopping criteria.

HBeAg-negative patients who discontinue TAF face a higher risk of both virological and clinical relapses compared to those discontinuing TDF or ETV. These findings underscore the need for more intense monitoring in CHB patients after TAF cessation.

The severity of liver fibrosis (LF) in chronic hepatitis B (CHB) affects the outcome and treatment. We probed plasma miR-30a expression in CHB patients and its value in assessing LF severity.

This retrospective study included 160 CHB patients and another 98 controls. Levels of lipid parameters, liver function parameters, hemoglobin, and alpha-fetoprotein were quantified by ELISA and chemiluminescence immunoassay. White blood cell, platelet, and red blood cell counts were determined using an automatic hematology analyzer. Fibrosis index based on four factors (FIB-4) was calculated. miR-30a level was determined, followed by the analysis of correlations of miR-30a expression with LF classification or with FIB-4 in CHB patients. The diagnostic value of plasma miR-30a for mild-to-moderate and severe LF in CHB patients was analyzed by receiver operating characteristic (ROC) curve.

Plasma miR-30a was poorly expressed in CHB patients and decreased dependently with LF aggravation. miR-30a was negatively interrelated with LF classification and FIB-4. Plasma miR-30a had high diagnostic value for mild-to-moderate LF in CHB patients [area under the ROC curve (AUC) = 0.775, cutoff value = 0.71, 95% confidence interval (CI) = 0.685-0.849]. Plasma miR-30a had high diagnostic value for severe LF in CHB patients (AUC = 0.873, cutoff value = 0.49, 95% CI = 0.804-0.924).

Plasma miR-30a was weakly expressed in CHB patients. miR-30a expression was negatively correlated with LF severity in CHB patients. miR-30a had high diagnostic value for mild-to-moderate and severe LF in CHB patients. miR-30a might serve as a promising target for LF treatment.

Updated data on the survival of patients with cirrhosis are limited, especially for subgroups by specific liver disease aetiology. To inform practice, future modelling studies, and public health planning, our study aimed to provide updated and granular data on survival outcomes of patients with cirrhosis stratified by liver disease aetiology. We also assessed their changes over time.

We analysed 8726 consecutive adult patients with cirrhosis who presented at Stanford university medical center during 1/2005-1/2022.

8726 Patients had the following etiologies: hepatitis C virus (HCV) (28.1%), hepatitis B virus (HBV) (4.8%), alcohol-associated (ALD, 33.3%), metabolic-associated steatotic liver disease (MASLD) (9.5%), autoimmune (9.6%), cryptogenic (8.2%) and other etiologies (6.5%). Patients with cryptogenic cirrhosis had the lowest overall 5-, 10-, and 15-year cumulative survival (57.5%, 34.3% and 21.4%), as well as for liver and nonliver-related death, followed by ALD, MASLD, HCV, and autoimmune, while HBV patients had the best survival (86.0%, 70.1% and 65.1%), respectively. On multivariable Cox regression, cryptogenic cirrhosis (vs. HBV) was associated with the highest risk of all-cause death (aHR: 2.24, 95% CI 1.67-3.00), followed by MASLD and ALD (all p < 0.001). Post-2010 time was associated with a 33% lower risk of all-cause death (p = 0.0011); While in the post-2010 period, MASLD (vs. HBV) was associated with the highest risk of all-cause death (aHR: 1.92, 95% CI 1.32-2.80, p < 0.001) followed by cryptogenic and ALD.

Survival outcomes in patients with cirrhosis varied by aetiology and have changed over time, which should be taken into account for future practice guidelines and modelling studies.

Several meta-analyses have investigated the association between chemopreventive agents (CPAs) and the risk of gastrointestinal cancers, but syntheses of the quality of evidence in aggregate are lacking. This umbrella review aimed to assess the quality of evidence from meta-analyses of randomized controlled trials (RCTs) and cohort studies that examine inverse associations between CPAs and the risk of gastrointestinal cancers or any premalignant conditions. Summary effect sizes from random-effects models, between-study heterogeneity, 95% prediction interval, small-study effect, excess significance, and credibility ceilings were devised to classify the credibility of evidence from meta-analyses of cohort studies, whereas the GRADE approach was used for meta-analyses of RCTs. From 20,296 publications, 577 full-text articles were evaluated for eligibility, and 69 articles that provided 194 unique meta-analyses were included. Among meta-analyses of RCTs (N = 93), 26 reached statistical significance (p < 0.05). Seven inverse associations were graded as either high quality (celecoxib and colorectal adenomas, (N = 4)) or moderate (aspirin and colorectal adenomas, (N = 2) and H-pylori eradication and gastric cancer (N = 1)). Among meta-analyses of cohort studies (N = 101), 60 reached statistical significance. Four inverse associations were graded as either convincing (antivirals with hepatocellular carcinoma (HCC); N = 1) or highly suggestive (aspirin with HCC (N = 2) and colorectal cancer (N = 1)). This review suggests that the associations with the most consistent empirical evidence were confined to those targeting the well-established risk factors of gastrointestinal cancer progression. Despite the limited established evidence, the inverse associations observed between metformin and colorectal, esophageal, and gastric cancers, as well as between statins and HCC and gastric cancer, merit further research.

Chronic hepatitis B is a major worldwide public health concern. Entecavir, one nucleos(t)ide analogue antiviral therapy option, is recommended as the first-line drug for chronic hepatitis B in many clinical guidelines. However, none of the guideline recommendations are based on the findings of a systematic review with meta-analysis, where entecavir versus no treatment or placebo are compared directly.

To evaluate the benefits and harms of entecavir versus no treatment or placebo in children and adults with chronic hepatitis B, who are either hepatitis B e-antigen (HBeAg)-positive or HBeAg-negative.

We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials, MEDLINE Ovid, Embase Ovid, three other databases, online trial registries, and reference lists, and contacted authors. The latest search was on 19 July 2024.

We included randomised clinical trials comparing entecavir versus no treatment or placebo in children or adults, or both, with chronic hepatitis B, and irrespective of treatment history with other antiviral drugs and other viral co-infections. We allowed co-interventions when administered equally to all intervention groups.

The outcomes reported in this abstract and in the summary of findings table are all-cause mortality, health-related quality of life, and proportion of people with serious adverse events at the longest follow-up.

We used the Cochrane RoB 2 tool to assess risk of bias in the included trials.

We used a random-effects model to meta-analyse outcome results, where possible, and presented the results as a risk ratio (RR) with 95% confidence interval (CI). Where there was considerable heterogeneity, we performed a narrative analysis. We used a fixed-effect model for sensitivity analysis. We used GRADE to evaluate the certainty of evidence.

We included 22 randomised clinical trials (published from 2005 to 2022) with 2940 participants diagnosed with chronic hepatitis B. All trials had a parallel-group design. The experimental intervention was oral entecavir, with a follow-up duration of 5 weeks to 228 weeks. The comparator in 12 trials was no treatment, and in 10 trials was placebo. Fourteen trials equally administered co-interventions to the trial participants in the entecavir and no treatment and placebo groups. One trial included participants between 14 years and 55 years of age, one trial included only children, 19 trials included only adults, and one trial did not provide the age of participants.

Twenty trials contributed data to the quantitative analysis. Ten trials (1379 participants) reported all-cause mortality with a mean follow-up duration of 48.9 weeks (range 5 to 100 weeks). The result was not estimable because no deaths occurred in any of the entecavir and no treatment or placebo groups. None of the trials provided data on health-related quality of life. We are very uncertain about the effect of entecavir versus no treatment or placebo on the proportion of people with serious adverse events (RR 0.66, 95% CI 0.33 to 1.32; absolute risk difference 22 fewer per 1000 (from 44 fewer to 21 more); 15 trials, 1676 participants; very low-certainty evidence). The mean follow-up duration was 58.4 weeks (range 5 weeks to 228 weeks). We downgraded the certainty of evidence for these outcomes to very low, mainly because the overall risk of bias in most trials was with some concerns or high, and serious imprecision (no events or few events).

Given the issues of risk of bias and insufficient power of the included trials and the very low certainty of the available evidence, we could not determine the effect of entecavir versus no treatment or placebo on critical outcomes such as all-cause mortality and serious adverse events. There is a lack of data on health-related quality of life. Given the first-line recommendation and wide usage of entecavir in people with chronic hepatitis B, further evidence on clinically important outcomes, analysed in this review, is needed.

This Cochrane review had no dedicated funding.

Registration: Entecavir for children and adults with chronic hepatitis B, CD015536 via DOI 10.1002/14651858.CD015536.

Bicyclol, a drug stemmed from the traditional Chinese medicine Schisandra chinensis, has been widely utilized in clinical practice due to its efficacy and safety to manage hepatopathy. Its diverse biological properties-including antiviral, anti-inflammatory, antifibrotic, immunomodulatory, antioxidative, antisteatotic, and antitumor effects-underscore its significant medicinal effects in versatile hepatic disorders, incorporating viral hepatitis, non-alcoholic fatty liver disease, hepatocellular carcinoma, acute hepatic failure, hepatic fibrosis as well as drug-induced liver injury. Furthermore, ongoing researches into the molecular mechanisms, biological activities and mode of actions concerning bicyclol have uncovered its potential therapeutic implications in other multiple diseases/conditions. Studies have indicated promising efficacy pertaining to bicyclol to treat idiopathic pulmonary fibrosis, acute lung injury, cerebral ischemia/reperfusion injury, renal dysfunction, renal cell carcinoma, and cardiovascular diseases. Accordingly, this narrative review article summarizes the current understanding of diverse biological activities and underpinning mechanisms of bicyclol across a range of diseases, as well as its pharmacokinetics, toxicity profile and shed light on future perspectives.

The Asia-Pacific (AP) region carries a substantial burden of HBV. Affordable HBV treatment is crucial to attain WHO's elimination goal. This study assesses the pricing and affordability of HBV treatment in AP.

A survey conducted among APASL members from 2 Aug to 30 Oct, 2023, gathered data on antiviral HBV drugs, treatment costs covering stages of chronic hepatitis B (CHB), compensated cirrhosis (CC), hepatocellular carcinoma (HCC), liver transplant, and monitoring expenses. Drug costs for TDF and ETV were compared to international reference price (TDF: $30, ETV: $36 per person per year), generating a median price ratio (MPR) where MPR < 1 indicated an acceptable local price. Affordability was evaluated by comparing yearly CHB treatment cost to yearly minimum wage in each country/area, all converted to 2023 US$.

ETV costs ranged from $42 per person per year in Pakistan to $2640 in Malaysia, while TDF costs varied from $12 in mainland China to $2446 in Hong Kong. Almost all MPR exceeded 1. Affordability of HBV treatment varied, with CHB patients in Australia paying 1.4% of minimum yearly wage to get 1 year CHB treatment, in contrast to Myanmar's 78.6%. Affordability disparities were also evident for patients with CC, HCC, and liver-transplant needs, though monitoring costs were generally affordable.

Despite patent expiration and availability of low-cost generics for TDF and ETV, HBV medication costs in Asia-Pacific region remain high. CHB treatment is generally unaffordable for patients, posing a significant barrier to HBV elimination in this endemic region.

Identifying hepatitis B virus (HBV) patients eligible for safe nucleos(t)ide analogues (NAs) discontinuation remains challenging. Discrepant data on combined HBV DNA and quantitative HBV surface antigen (qHBsAg) assessments are available. This study aimed to identify potential predictors for safe treatment discontinuation by evaluating clinical/virological outcomes in patients on long-term NA therapy.

A retrospective cohort of 139 chronic hepatitis B (CHB) patients - who consecutively started Entecavir or Tenofovir from 2007 to 2011 - was evaluated. The study population was selected based on anti-HBe positivity, absence of prior antiviral treatment, absence of non-HBV-related liver diseases or hepatocellular carcinoma (HCC), and long-term clinical/ultrasonographic/laboratory evaluations post-NA initiation. Serum samples collected before starting NA (T0) and over ten years (T1-T10) were tested for HBV DNA and qHBsAg.

Twenty-two/139 (15.8 %) CHB patients (12 chronic hepatitis, 10 cirrhosis) met the inclusion criteria. All patients showed a significant decrease in liver stiffness values in the ten years of follow-up (p = 0.001), and no hepatic decompensation occurred. Three/22 (13.6 %) patients developed HCC. Ten/22 patients (45.5 %; group-A) had fluctuating HBV DNA, while other 10/22 (45.5 %; group-B) showed undetectable HBV DNA for 5-9 years with more significant qHBsAg decline (p = 0.04) than group-A. Two/22 (9.1 %) patients showed a critical qHBsAg decline up to seroconversion together with undetectable HBV DNA.

Persistent undetectable HBV DNA levels correlate with qHBsAg reduction and the potential HBsAg seroclearance, suggesting that long-term HBV DNA monitoring in NA-treated CHB patients might help identify candidates for treatment discontinuation.

Hepatitis B virus (HBV) remains a leading etiology for liver transplantation (LT). In a large cohort of HBsAg-positive patients, this study evaluates long-term patient and graft survival after LT over the past 30 years while analyzing trends and outcomes following waiting list (WL) inclusion over the last 15 years.

HBsAg-positive patients who underwent transplantation between 1991 and 2020 and were waitlisted from 2006 to 2020 at Padua Hospital were included in the analysis. Patients were stratified according to hepatitis delta virus (HDV) coinfection, transplant indication (decompensated cirrhosis vs. hepatocellular carcinoma (HCC)), and WL inclusion period.

Among 321 HBsAg-positive LT recipients (31.5% HDV-coinfected, 46.4% HCC), 1-year and 5-year patient/graft survival rates were 87.6%/86.7% and 82.6%/82.2%, respectively. From 2006 to 2020, 284 HBsAg-positive patients were waitlisted (32.6% HDV-coinfected), with a significantly higher prevalence of HCC compared to non-HBV patients (p = 0.008). High-barrier nucleos(t)ide analogues (hbNUCs) significantly reduced mortality (p = 0.041) and improved survival post-WL inclusion (p = 0.007). Survival rates were consistent regardless of LT indication, HDV coinfection, or WL inclusion period. Post-transplant prophylaxis predominantly involved immunoglobulins (HBIG) + NUCs, resulting in only two cases of HBV reactivation, both clinically inconsequential.

Over the past 30 years, HBV has remained a consistent indication for LT at our center. Thanks to hbNUCs, WL outcomes have improved and HCC has become the main indication for LT.

Viral infections persist as a significant cause of morbidity and mortality worldwide. Conventional therapeutic approaches often fall short in fully eliminating viral infections, primarily due to the emergence of drug resistance. Natural killer (NK) cells, one of the important members of the innate immune system, possess potent immunosurveillance and cytotoxic functions, thereby playing a crucial role in the host's defense against viral infections. Chimeric antigen receptor (CAR)-NK cell therapy has been developed to redirect the cytotoxic function of NK cells specifically towards virus-infected cells, further enhancing their cytotoxic efficacy. In this manuscript, we review the role of NK cells in antiviral infections and explore the mechanisms by which viruses evade immune detection. Subsequently, we focus on the optimization strategies for CAR-NK cell therapy to address existing limitations. Furthermore, we discuss significant advancements in CAR-NK cell therapy targeting viral infections, including those caused by severe acute respiratory syndrome coronavirus 2, human immunodeficiency virus, hepatitis B virus, human cytomegalovirus, and Epstein-Barr virus.

Infections can mimic Primary Systemic Vasculitis. Many clinical features and investigations maybe very similar between the two conditions. It is very important for the clinician to be aware of the various infections which mimic vasculitis, since inadvertent immunosuppression in these patients can be fatal. Infections can mimic small, medium or large vessel vasculitis. Infections can produce autoantibodies such as Anti-neutrophil cytoplasmic antibody through molecular mimicry and could confound clinical judgement. In addition to the many infections causing vasculitis, more recently COVID-19 associated vasculitis has been described. The exact pathogenesis of infection associated vasculitis is not clear although direct spread, immune complex deposition and T/B cell activation are proposed. Infection as an etiological agent for primary systemic vasculitis has long been debated but definite evidence for the same is lacking. Many drugs used in daily clinical practice can rarely cause vasculitis. More recently Immune-check point inhibitors-induced vasculitis has been described.

Hepatitis B virus (HBV) infection is a well-documented independent risk factor for developing hepatocellular carcinoma (HCC). Consequently, extensive research has focused on elucidating the mechanisms by which HBV induces hepatocarcinogenesis. The majority of studies are dedicated to understanding how HBV DNA integration into the host genome, viral RNA expression, and the resulting protein transcripts affect cellular processes and promote the malignant transformation of hepatocytes. However, considering that most acute HBV infections are curable, immune suppression potentially contributes to the critical challenges in the treatment of chronic infections. Regulatory T cells (Tregs) are crucial in immune tolerance. Understanding the interplay of Tregs within the liver microenvironment following HBV infection could offer novel therapeutic approaches for treating HBV infections and preventing HBV-related HCC. Two viewpoints to targeting Tregs in the liver microenvironment include means of reducing their inhibitory function and decreasing Treg frequency. As these strategies may disrupt the immune balance and lead to autoimmune responses, careful and comprehensive profiling of the patient's immunological status and genetic factors is required to successfully employ this promising therapeutic approach.

Successful antiviral therapy significantly decreases the incidence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Alpha-fetoprotein (AFP) in the serum is a valuable early indicator of HCC. However, it is unclear whether different antiviral medications have varying effects on AFP levels. The purpose of this study was to evaluate this issue in those treated with entecavir (ETV) versus tenofovir disoproxil fumarate (TDF).

We prospectively enrolled treatment-naive CHB adults who commenced treatment with ETV or TDF. Their changes in biochemical, virological, and fibrosis parameters and the elevation of AFP or development of HCC during follow-up were analyzed.

A total of 1942 CHB patients were included (10-90% follow-up time 3-60 months), and 104 patients with elevated AFP (5.3%) and 27 patients with HCC development (1.4%) were identified during the follow-up. The difference in the cumulative incidence of AFP abnormalities and HCC was statistically significant between patients who received ETV or TDF therapy. Multivariate Cox regression showed that elevated liver stiffness with shear wave elastography (Hazard ratio (HR) = 1.05, 95% Confidence interval (CI) 1.03-1.08, P < 0.001) and abnormal AFP at baseline (HR = 1.00, 95% CI 1.00-1.00, P < 0.001) were independent risk factors for abnormal AFP in CHB patients, while shear wave elastography (HR = 1.07, 95% CI 1.02-1.12, P < 0.001) was also independent risk factor for HCC. Similar results were obtained after propensity score matching (PSM) analysis. The combination of shear wave elastography (SWE), mPage-B score, age and type 2 diabetes mellitus had an area under the curve of 0.838 (P < 0.001) in predicting the occurrence of HCC.

Similar AFP elevation and HCC development rates were observed in CHB patients treated with ETV or TDF. Elevated SWE and abnormal AFP at baseline were independent risk factors for abnormal AFP in CHB patients.

Chronic hepatitis B (CHB) infection affects nearly 300 million individuals worldwide and is a leading cause of hepatocellular carcinoma and liver-related mortality. However, major gaps in the CHB cascade of care persist, with the majority of individuals with CHB not diagnosed and not linked to care and treatment. Even among individuals with known CHB, existing studies report on major gaps and disparities in timely linkage to care and timely access to CHB therapies. While the momentum to expand and simplify CHB treatment guidelines is promising, access to treatment still relies on individuals being effectively engaged in clinical care and liver disease monitoring. The contributing factors to the observed gaps and disparities in the CHB cascade of care are complex and multifactorial, and there is no one-size-fits-all solution than can be easily applied across all global regions. However, any serious approach towards addressing the existing gaps in the CHB cascade of care to improve patient outcomes requires a concerted investment from healthcare institutions, governments, policymakers, and industry partners to provide the necessary resources to be able to achieve this goal. Anything less than a comprehensive and collaborative approach that engages all stakeholders to invest effort and resources into tackling the global epidemic of CHB will continue to fall short in making progress towards global viral hepatitis elimination goals.

Bepirovirsen, an antisense oligonucleotide, induces sustained reductions in hepatitis B surface antigen (HBsAg) and HBV DNA to below the lower limit of quantification (

METHODS

In this phase IIb, multicentre, open-label trial, participants on stable nucleos(t)ide analogue (NA) therapy were randomised 1:1 to bepirovirsen 300 mg once weekly (plus loading dose on Days 4 and 11) for 24 (Arm 1) or 12 (Arm 2) weeks followed by Peg-IFN 180 μg once weekly for up to 24 weeks, with up to 36 weeks follow-up. Participants continued NA therapy throughout. The primary outcome was the proportion of participants with HBsAg <0.05 IU/ml and HBV DNA

RESULTS

The intent-to-treat population included 108 participants (Arm 1, n = 55; Arm 2, n = 53). The primary outcome was achieved by 5 (9%) participants in Arm 1 and 8 (15%) in Arm 2. All responders had baseline HBsAg ≤3,000 IU/ml. Indirect comparison with the phase IIb study B-Clear indicates that sequential addition of Peg-IFN may reduce the relapse rates previously observed with bepirovirsen alone. The proportions of participants with adverse events and treatment-related adverse events in both treatment windows were similar between treatment arms.

CONCLUSIONS

Sequential therapy with bepirovirsen followed by Peg-IFN is tolerable and effective in participants with chronic HBV infection on stable NA therapy. This proof-of-concept trial demonstrates a potential strategy to extend responses to bepirovirsen by reducing relapse.

IMPACT AND IMPLICATIONS

This phase IIb study investigated whether sequential therapy with bepirovirsen followed by Peg-IFN could improve off-treatment response rates to bepirovirsen alone by converting partial bepirovirsen responders to full responders and/or reducing relapse rates in participants with chronic HBV. These data show that sequential therapy with bepirovirsen followed by Peg-IFN is tolerable and effective; in patients with a bepirovirsen response, sequential treatment with Peg-IFN may help to reduce off-treatment relapses in participants on stable NA. Participants had a similar response during bepirovirsen treatment as seen in B-Clear, with increased response rates in participants with lower baseline HBsAg; all responders to the sequential regimen had baseline HBsAg <3000 IU/mL. As the first study of antisense oligonucleotide-mediated RNA silencing followed by interferon immunomodulation in patients with chronic HBV infection, this study is an important proof-of-concept for sequential therapy, shedding light on the therapeutic potential of utilising immunomodulators following suppression of HBV antigens.

CLINICAL TRIAL NUMBER

NCT04676724.

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Key Words

• Hepatitis B
• antisense oligonucleotide
• bepirovirsen
• pegylated interferon-α-2a
• sequential therapy

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MESH Headings

• Humans
• Hepatitis B, Chronic/drug therapy
• Hepatitis B, Chronic/blood
• Hepatitis B, Chronic/virology
• Polyethylene Glycols/administration & dosage
• Polyethylene Glycols/adverse effects
• Male
• Female
• Interferon-alpha/administration & dosage
• Interferon-alpha/adverse effects
• Middle Aged
• Adult
• Antiviral Agents/administration & dosage
• Antiviral Agents/adverse effects
• Recombinant Proteins/administration & dosage
• Recombinant Proteins/adverse effects
• Recombinant Proteins/therapeutic use
• DNA, Viral/blood
• Hepatitis B virus/genetics
• Recurrence
• Hepatitis B Surface Antigens/blood
• Drug Therapy, Combination
• Oligonucleotides, Antisense/administration & dosage
• Treatment Outcome
• Oligonucleotides/administration & dosage
• Drug Administration Schedule

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Affiliation(s)

Maria Buti Liver Unit, Hospital Vall d'Hebrón, Barcelona and CIBER-EHD del Instituto Carlos III, Barcelona, Spain.
Jeong Heo Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Republic of Korea; Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea.
Yasuhito Tanaka Department of Gastroenterology and Hepatology, Kumamoto University Hospital, Kumamoto, Japan
Pietro Andreone Medicina Interna a indirizzo Metabolico-Nutrizionale, Ospedale Clinicizzato di Baggiovara, AOU di Modena, Modena, Italy; Dipartimento SMECHIMAI, Università di Modena e Reggio Emilia, Modena, Italy
Masanori Atsukawa Nippon Medical School Hospital, Tokyo, Japan
Joaquín Cabezas Gastroenterology and Hepatology Department, University Hospital Marques de Valdecilla, Santander, Spain; Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Santander, Spain
Eric Chak UC Davis, Sacramento, California, USA
Carla S Coffin Department of Medicine, Cumming School of Medicine, University of Calgary, Alberta, Calgary, Canada
Kei Fujiwara Nagoya City University Hospital, Aichi, Japan
Natalya Gankina Krasnojarsk Regional Center of AIDS prevention, Krasnojarsk, Russian Federation
Stuart C Gordon Henry Ford Health and Wayne State University School of Medicine, Detroit, MI, USA
Ewa Janczewska Department of Basic Medical Sciences, Faculty of Public Health in Bytom, Medical University of Silesia, Myslowice, Poland
Atsumasa Komori National Hospital Organization, NHO Nagasaki Medical Center, Nagasaki, Japan
Pietro Lampertico Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; CRC "A. M. and A. Migliavacca" Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
Stuart McPherson Hepatology and Newcastle NIHR Biomedical Research Centre, The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle-upon-Tyne, UK
Vyacheslav Morozov Hepatologist Medical Company, Samara, Russian Federation
Robert Plesniak University of Rzeszow Centrum Medyczne w Lancucie Sp. z o.o., Lancut, Poland
Sébastien Poulin Clinique Médecine Urbaine du Quartier Latin, Montréal, Québec, Canada
Pablo Ryan Hospital Infanta Leonor and CIBERINFEC, del Instituto Carlos III., Madrid, Spain
Olga Sagalova South Ural State Medical University, Chelyabinsk, Russian Federation
Guoping Sheng Department of Infectious Disease, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University, Shulan International Medical College, Hangzhou, Zhejiang, China
Natalya Voloshina Medical Centre Healthy Family, Novosibirsk, Russian Federation
Qing Xie Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Hyung Joon Yim Korea University Ansan Hospital, Ansan, Republic of Korea
Susan Dixon GSK, London, UK
Melanie Paff GSK, Collegeville, PA, USA
Leigh Felton GSK, London, UK
Maximilian Lee GSK, Collegeville, PA, USA
Thomas Greene GSK, Collegeville, PA, USA
Jessica Lim GSK, Collegeville, PA, USA
Divya Lakshminarayanan GSK, Collegeville, PA, USA
Grant McGonagle GSK, London, UK
Helene Plein GSK, London, UK
Amir S Youssef GSK, Collegeville, PA, USA
Rob Elston GSK, Stevenage, UK
Stuart Kendrick GSK, Stevenage, UK
Dickens Theodore GSK, Durham, NC, USA

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Morbidity and mortality from cirrhosis are substantial and increasing. Health disparities in cirrhosis and liver transplantation are reflective of inequities along the entire spectrum of chronic liver disease care, from screening and diagnosis to prevention and treatment of liver-related complications. The key populations experiencing disparities in health status and healthcare delivery include racial and ethnic minority groups, sexual and gender minorities, people of lower socioeconomic status and underserved rural communities. These disparities lead to delayed diagnosis of chronic liver disease and complications of cirrhosis (for example, hepatocellular carcinoma), to differences in treatment of chronic liver disease and its complications, and ultimately to unequal access to transplantation for those with end-stage liver disease. Calling out these disparities is only the first step towards implementing solutions that can improve health equity and clinical outcomes for everyone. Multi-level interventions along the care continuum for chronic liver disease are needed to mitigate these disparities and provide equitable access to care.

Treatment indications for patients with chronic hepatitis B (CHB) remain contentious, particularly for patients with mild alanine aminotransferase (ALT) elevation. We aimed to evaluate treatment effects in this patient population.

This rollover study extended a placebo-controlled trial that enrolled non-cirrhotic patients with CHB and ALT levels below two times the upper limit of normal. Following 3 years of randomized intervention with either tenofovir disoproxil fumarate (TDF) or placebo, participants were rolled over to open-label TDF for 3 years. Liver biopsies were performed before and after the treatment to evaluate histopathological changes. Virological, biochemical, and serological outcomes were also assessed (NCT02463019).

Of 146 enrolled patients (median age 47 years, 80.8% male), 123 completed the study with paired biopsies. Overall, the Ishak fibrosis score decreased in 74 (60.2%), remained unchanged in 32 (26.0%), and increased in 17 (13.8%) patients (p<0.0001). The Knodell necroinflammation score decreased in 58 (47.2%), remained unchanged in 29 (23.6%), and increased in 36 (29.3%) patients (p=0.0038). The proportion of patients with an Ishak score ≥ 3 significantly decreased from 26.8% (n=33) to 9.8% (n=12) (p=0.0002). Histological improvements were more pronounced in patients switching from placebo. Virological and biochemical outcomes also improved in placebo switchers and remained stable in patients who continued TDF. However, serum HBsAg levels did not change and no patient cleared HBsAg.

In CHB patients with minimally raised ALT, favorable histopathological, biochemical, and virological outcomes were observed following 3-year TDF treatment, for both treatment-naïve patients and those already on therapy.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections remain significant public health challenges in Asia, affecting millions and contributing to substantial morbidity and mortality. The prevalence of these infections varies across the region, with factors such as vaccination coverage, healthcare infrastructure, and sociocultural barriers influencing the epidemiology of both viruses. The persistent burden of chronic HBV, particularly in older populations, and the evolving HCV genotype landscape highlight the need for targeted, region-specific strategies. Universal screening programs have emerged as essential tools for detecting undiagnosed cases and optimizing healthcare resource allocation. Given the overlapping epidemiology of HBV and HCV, comprehensive public health interventions tailored to the unique contexts of different Asian countries are crucial for achieving global elimination goals. This review examines the epidemiological trends, challenges, and opportunities for addressing HBV and HCV in Asia, emphasizing the importance of overcoming sociocultural barriers to improve prevention, diagnosis, and treatment efforts across diverse populations.

Cirrhosis is a significant risk factor for the development of hepatocellular carcinoma (HCC). Variability in HCC risk among patients with cirrhosis is notable, particularly when considering the diverse etiologies of cirrhosis.

To identify specific risk factors contributing to HCC development in patients with cirrhosis.

This retrospective study analyzed data from cirrhotic patients at Beijing Youan Hospital from January 1, 2012 to September 30, 2022 with at least 6 mo of follow-up. Patient demographics, medical histories, etiologies, and clinical characteristics were examined. Cox regression analysis was used to analyze correlations of the above parameters with hepatocarcinogenesis, while competing risk regression was used to estimate their adjusted hazard ratios accounting for death. The cumulative incidence was plotted over time.

Overall, 5417 patients with cirrhosis (median age: 54 years; 65.8% males) were analyzed. Hepatitis B virus (HBV) was the most common etiology (23.3%), with 25% (n = 1352) developing HCC over a 2.9-year follow-up period. Patients with multiple etiologies had the HCC highest incidence (30.3%), followed by those with HBV-related cirrhosis (29.5%). Significant risk factors included male sex, advanced age, hepatitis C virus (HCV) infection, elevated blood ammonia, and low platelet count. Men had a higher 5-year HCC risk than women (37.0% vs 31.5%). HBV, HCV, and HBV/HCV co-infected patients had 5-year risks of HCC of 45.8%, 42.9%, and 48.1%, respectively, compared to 29.5% in nonviral hepatitis cases, highlighting the significant HCC risk from viral hepatitis, especially HBV, and underscores the importance of monitoring these high-risk groups.

In conclusion, HBV-related cirrhosis strongly correlates with HCC, with male sex, older age, viral hepatitis, elevated blood ammonia, and lower albumin and platelet levels increasing the risk of HCC.

Recommendations for stopping nucleoside analogue (NA) therapy in hepatitis B e antigen-negative chronic hepatitis B (CHB) are unclear. End-of-treatment quantitative hepatitis B serum antigen (EOTqHBsAg) thresholds <100 IU/mL or <1000 IU/mL have been proposed as stopping criteria, which we assessed by meta-analysis and meta-regression.

We searched PubMed, EMBASE, and conference abstracts for studies of hepatitis B e antigen-negative CHB NA discontinuation. Extracted studies were analyzed for risk of bias, pooled risk of hepatitis B serum antigen (HBsAg) loss, virological relapse (VR), and biochemical relapse (BR). Significant heterogeneity (I2) was addressed by subgroup analysis and random-effects meta-regression with known important covariates, including EOTqHBsAg thresholds, ethnicity, duration of therapy, and follow-up.

We found 24 articles (3732 subjects); 16 had low and 8 had moderate risk of bias. The pooled risks of HBsAg loss, VR, and BR for stopping therapy at EOTqHBsAg <100 IU/mL were 41.8%, 33.4%, and 17.3%, respectively, vs 4.6%, 72.1%, and 34.6%, respectively, for EOTqHBsAg ≥100 IU/mL. The pooled risks of HBsAg loss, VR, and BR for stopping therapy at EOTqHBsAg <1000 IU/mL were 22.0%, 52.7%, and 15.9%, respectively, vs 3.4%, 63.8%, and 26.4%, respectively, for EOTqHBsAg ≥1000 IU/mL. Multivariable analysis for HBsAg loss showed that ethnicity, follow-up duration, and EOTqHBsAg <100 IU/mL and ≥100 IU/mL explained 85% of the variance in heterogeneity; Asians with EOTqHBsAg <100 IU/mL had 28.2%, while non-Asians with EOTqHBsAg <1000 IU/mL had 38.4% HBsAg loss. Multivariable analysis showed EOTqHBsAg <100 IU/mL and ≥100 IU/mL and other covariates only explained 43% and 63% of the variance in heterogeneity for VR and BR, respectively, suggesting that other factors are also important for relapse.

While EOTqHBsAg thresholds, ethnicity, and follow-up duration strongly predict HBsAg loss, this is not true for VR and BR, hence stopping NA therapy should be considered cautiously.

The most common cause of hepatocellular carcinoma (HCC) worldwide is chronic hepatitis B virus (HBV) infection (CHB). Long-term suppression of HBV replication by antiviral treatment reduces the risk of HCC and mortality. Nonetheless, only 2.2% of CHB patients globally received the treatment in 2019. Current international CHB guidelines recommend antiviral treatment only in subsets of patients with clear evidence of liver damage as evidenced by elevation of alanine aminotransferase (ALT). This review aims to provide existing evidence that the risk of HCC is significantly associated with serum levels of HBV DNA, and the association is non-linear parabolic, in both untreated and treated CHB patients, regardless of HBeAg status or ALT levels. Therefore, the decision for the antiviral treatment should be based on serum HBV DNA levels and age, rather than ALT levels or liver biopsy, to reduce or prevent the risk of HCC in CHB patients. The potential impact and cost-effectiveness data on early antiviral treatment initiation were also collated.

Whether patients with compensated cirrhosis and low-level viremia (LLV) of hepatitis B should receive antiviral therapy (AVT) is still controversial, and published results are inconsistent.

To investigate the link between LLV in compensated cirrhosis and prognosis concerning hepatocellular carcinoma (HCC), decompensation, and liver-related events.

The PubMed, EMBASE, and Cochrane Library databases were searched up to March 5, 2023. Outcomes of interest were assessed by pooled hazard ratios (HRs). The study was registered with PROSPERO (CRD42023405345).

Six cohort studies representing 3155 patients were included. Compared with patients with undetectable HBV DNA, patients with LLV was associated with increased risk of HCC (HR: 2.06, 95%CI: 1.36-3.13; Q-statistic-P = 0.07, I 2 = 51%) regardless of receiving AVT or not (AVT group: HR: 3.14; 95%CI: 1.73-5.69; Q-statistic-P = 0.60, I 2 = 0%; un-AVT group: HR: 1.73, 95%CI: 1.09-2.76; Q-statistic-P = 0.11, I 2 = 50%). The pooled results showed no statistical association between LLV and decompensation of cirrhosis (HR: 2.06, 95%CI: 0.89-4.76; Q-statistic-P = 0.04, I 2 = 69%), and liver-related events (HR: 1.84, 95%CI: 0.92-3.67; Q-statistic-P = 0.03, I 2 = 72%), respectively. Grading of Recommendations Assessment, Development and Evaluation assessment indicated moderate certainty for HCC, very low certainty for decompensation of cirrhosis and liver-related clinical events.

LLV in compensated cirrhotic patients is associated with increased risk of HCC, higher tendency for hepatic decompensation and liver-related events. Closer screening of HCC should be conducted in this population.

The burden of liver cancer varies worldwide. An upward trend in both hepatocellular carcinoma (HCC) incidence and mortality in the past 2 decades has been observed.

To assess observed HCC-related age-standardized mortality rates (ASMRs) in the US for 2006 to 2022 and provide ASMR projections through 2040.

This cross-sectional study used data from the National Vital Statistics System, which is accessible through the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research website. Data on deaths attributed to HCC (from January 1, 2006, to December 31, 2022) were obtained for adults 25 years or older and were stratified by liver disease etiology, age, sex, and race and ethnicity. Etiologies included alcohol-associated liver disease (ALD), hepatitis B virus (HBV), hepatitis C virus (HCV), and metabolic dysfunction-associated steatotic liver disease (MASLD).

The main outcomes were (1) observed ASMRs of HCC per 100 000 persons using Joinpoint regression (National Cancer Institute) to assess trends during 2006 to 2022 and (2) ASMRs projected for 2023 to 2040 using Prophet and AutoARIMA modeling.

This study included 188 280 HCC-related deaths from 2006 to 2022. Most deaths occurred among males (77.4%). The annual percentage change was 4.1% (95% CI, 2.2% to 7.7%) for 2006 to 2009 and decreased to 1.8% (95% CI, 0.7% to 2.0%) for 2009 to 2022, with an overall observed ASMR of 5.03 per 100 000 persons in 2022 and a projected ASMR of 6.39 per 100 000 persons by 2040, with consistent trends for both sexes. By etiology, ASMRs decreased for HCV- and HBV-related mortality but increased for ALD- and MASLD-related mortality. In 2022, MASLD surpassed HBV as the third-leading cause of HCC-related death and was projected to overtake HCV in 2032 as the second-leading cause; ALD was projected to be the leading cause of HCC-related death in 2026. In 2022, the ASMR was higher among individuals aged 65 years or older compared with those aged 25 to 64 years (18.37 vs 1.79 per 100 000 persons). The American Indian or Alaska Native population had the largest increase in projected ASMR by 2040 (14.71 per 100 000 persons) compared with the Asian population (3.03 per 100 000 persons).

In this cross-sectional study, ASMRs for ALD- and MASLD-related HCC death increased rapidly from 2006 to 2022; ALD-related HCC was projected to be the leading cause by 2026, with MASLD as the second-leading cause by 2032. These findings may serve as a reference for public health decision-making and timely identification of groups at high risk of HCC death.

Incidence of hepatocellular carcinoma (HCC) had been increasing steadily among older Americans but plateaued in 2015-2017. Chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) are important causes of HCC. The impact of improved treatments for these infections on recent trends in HCC incidence is unclear.

To examine the relationship between use of antiviral therapy for chronic viral hepatis and HCC incidence in older Americans.

We used 2007-2017 data from the Surveillance, Epidemiology, and End Results-Medicare database to estimate age-standardized incidence rates and average annual percent changes (AAPCs) for viral hepatitis-attributable HCC among individuals ≥66 years. We analyzed data from Medicare Part D to determine the frequency of HBV and HCV treatment utilization in this population.

Overall HCC incidence increased 10.5%, from 22.2/100,000 in 2007 to 24.5/100,000 in 2017 (AAPC, 1.3%). During that time, HBV-attributable HCC rates decreased from 2.5 to 2.0/100,000 (AAPC, -1.6%), while HCV-attributable HCC rose from 6.6 to 8.0/100,000 (AAPC, 2.0%). HBV treatment among patients with HBV infection increased by 66% (2007, 7.4%; 2015, 12.3%). Treatment for HCV was stable at <2% during 2006-2013 but rose to 6.9% in 2014 and 12.7% in 2015, coinciding with the introduction of direct acting antiviral agents for HCV.

A decreased incidence of HBV-attributable HCC corresponded with an increased uptake in treatment for that infection. Despite a marked increase in the effectiveness and frequency of HCV treatment in 2014 and 2015, HCV-attributable HCC had not begun to fall as of 2017.

Chronic hepatitis B virus (HBV) infection is a global issue and can lead to cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B surface antigen (HBsAg) is an important marker of HBV infection and HBsAg quantification could be a useful tool in clinical practice. This systematic literature review aimed to explore the association between HBsAg titres and long-term disease outcomes and evaluate the relationship between HBsAg titres, or changes in HBsAg titres, and clinical and treatment characteristics in patients with chronic HBV infection. Structured searches were performed in MEDLINE and Embase (January 2000 to 31 March 2023). Eighty-two studies were included, comprising 51% retrospective cohort studies, mostly conducted in Asia (85%). HBsAg levels were shown to predict the long-term development of cirrhosis and HCC in patients who were untreated prior to and during follow-up; however, these data were inconclusive in mixed and treated populations. HBsAg titres were significantly associated with various virological markers including serum HBV DNA, HBcrAg, HBeAg, HBV RNA levels, intrahepatic covalently closed circular DNA (cccDNA) and intrahepatic HBsAg expression. HBsAg titres generally declined over time; this decline was more pronounced in early (HBeAg-positive) than later disease phases (HBeAg-negative). Higher decline in HBsAg levels was consistently associated with subsequent HBsAg seroclearance and a greater decline in total intrahepatic HBV DNA and cccDNA levels. In conclusion, this review showed that HBsAg levels and rates of decline could inform assessment, management and prediction of outcomes in chronic HBV infection. Further studies in broader, more diverse populations and treated patients are needed.

Hepatitis B remains a significant global health challenge, contributing to substantial morbidity and mortality. Approximately 254 million people worldwide live with Chronic hepatitis B (CHB), with the majority of cases occurring in sub-Saharan Africa and the Western Pacific regions. Alarmingly, only about 13.4% of the individuals infected with this disease have been diagnosed, and awareness of hepatitis B virus (HBV) infection status is as low as 1% in sub-Saharan Africa. In 2022, CHB led to 1.1 million deaths globally. The World Health Organization (WHO) has set a target of eliminating hepatitis B as a public health concern by 2030; however, this goal appears increasingly unattainable due to multiple challenges. These challenges include low vaccination coverage; a large number of undiagnosed cases; a low proportion of patients eligible for treatment under current guidelines; limited access to healthcare; and the costs associated with lifelong treatment. Treatment of HBV can yield significant clinical benefits within a long window of opportunity. However, the benefits of therapy are markedly diminished when the disease is detected at the advanced cirrhosis stage. This editorial aim to highlight the current challenges in hepatitis care and the necessary steps to achieve the WHO's hepatitis elimination goals for 2030.

Chronic hepatitis B virus (HBV) infection is still a major public health problem. In response to the World Health Organization (WHO), Tanzania implemented immunization and treatment to achieve the eradication of HBV infection by 2030. To achieve this goal, frequent updates of demographic data, antiviral therapy eligibility, and uptake are essential. We therefore evaluated demographic data, antiviral therapy eligibility, and uptake among chronically HBV-infected patients attending at Bugando Medical Centre (BMC), Tanzania.

A cross-sectional study enrolled 196 chronic HBV patients from April 23, 2023, to October 10, 2023, at BMC, where 100 and 96 patients were retrospectively and prospectively enrolled, respectively. Study's ethical clearance and permission were observed by the Catholic University of Health and Allied Sciences/Bugando Medical Centre research ethics and review committee and the Bugando Medical Centre management respectively. For all patients, socio-demographic data and whole blood samples were obtained. Full blood picture, alanine and aspartate amino transferases, and HBV viral load parameters were determined. Aspartate-Platelet Ratio Index (APRI) and Fibrosis Four (FIB-4) scores were calculated according to their respective formulas. Therapy eligibility and uptake were evaluated according to the 2015 WHO HBV prevention, treatment, and care guidelines. The data were summarized and analysed using STATA version 15.

The median age for all patients was 39 [IQR: 32-47.5] years. Nearly all study patients, 99% (194/196), were older than 20 years old, with significant male dominance (73.5% [144/196] versus 26.5% [52/196]; p<0.0001). Anti-HBV antiviral therapy eligibility was 22.4%, while uptake was 6.8% (3/4), which was significantly lower than the WHO expectation of 80% (p <0.0001).

Almost all chronically HBV-infected patients attending at BMC were older than 20 years old and were significantly dominated by males. Antiviral therapy uptake was remarkably lower than expected by the WHO towards combating HBV infection by 2030.

Hepatitis B surface antigen (HBsAg) loss is regarded as a pivotal criterion for assessing functional cure in patients diagnosed chronic hepatitis B (CHB). We conducted the research to investigate the real-world performance of HBsAg seroconversion in sustaining HBsAg loss.

This retrospective analysis confirmed 295 patients who attained HBsAg loss through combination therapy involving nucleos(t)ide analogues (NAs) and pegylated interferon alpha (peg-IFNα). Employing Kaplan-Meier estimates method to conduct survival analysis. The forest plot was used to visualize the results of multivariate Cox regression, and selected variables were included in the nomogram.

HBsAg seroreversion was observed in 45 patients during follow-up periods, with a lower recurrence risk in patients with HBsAg seroconversion at the end of peg-IFNα therapy (EOT) (10.3% vs 37.3% at 96-week, P < 0.0001). Moreover, the sustainability of hepatitis B surface antibody (anti-HBs) in participants continuing therapy after HBsAg seroconversion was superior to those discontinued prematurely (72.5% vs 54.5% at 96 weeks, P = 0.012). Additionally, the former group was also relatively less likely to experience HBsAg reversion during long-term observation (8.4% vs 14.3% at 96 weeks, P = 0.280). Hepatitis B envelope antigen (HBeAg) status, anti-HBs status and consolidation treatment screened by multivariable analysis were utilized to construct a predictive model for HBsAg reversion. The concordance index(C-index = 0.77) and calibration plots indicated satisfactory discrimination and consistency of nomogram.

HBsAg seroconversion was beneficial for sustaining functional cure in patients treated with peg-IFNα. Continuing consolidation therapy after HBsAg seroconversion also contributed to maintain HBsAg seroconversion and improve the durability of HBsAg loss. The nomogram illustrated its efficacy as a valuable instrument in showcasing survival probability of functional cure.

A nonlinear association between serum hepatitis B virus (HBV) DNA levels and hepatocellular carcinoma (HCC) risk has been suggested in patients with chronic hepatitis B (CHB).

To develop and externally validate a prognostic model for HCC risk in noncirrhotic adult patients with CHB and no notable alanine aminotransferase (ALT) elevation.

Multinational cohort study.

A community-based cohort in Taiwan (REVEAL-HBV [Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus]; REACH-B [Risk Estimation for HCC in CHB] model cohort) and 8 hospital-based cohorts from Korea and Hong Kong (GAG-HCC [Guide with Age, Gender, HBV DNA-HCC] and CU-HCC [Chinese University-HCC] cohorts).

Model development: 6949 patients with CHB from a Korean hospital-based cohort. External validation: 7429 patients with CHB combined from the Taiwanese cohort and 7 cohorts from Korea and Hong Kong.

Incidence of HCC.

Over median follow-up periods of 10.0 and 12.2 years, the derivation and validation cohorts identified 435 and 467 incident HCC cases, respectively. Baseline HBV DNA level was one of the strongest predictors of HCC development, demonstrating a nonlinear parabolic association in both cohorts, with moderate viral loads (around 6 log10 IU/mL) showing the highest HCC risk. Additional predictors included in the new model (Revised REACH-B) were age, sex, platelet count, ALT levels, and positive hepatitis B e antigen result. The model exhibited satisfactory discrimination and calibration, with c-statistics of 0.844 and 0.813 in the derivation and validation cohorts with multiple imputation, respectively. The model yielded a greater positive net benefit compared with other strategies in the 0% to 18% threshold.

Validation in cohorts of other races and receiving antiviral treatment was lacking.

Our new prognostic model, based on the nonlinear association between HBV viral loads and HCC risk, provides a valuable tool for predicting and stratifying HCC risk in noncirrhotic patients with CHB who are not currently indicated for antiviral treatment.

Korean government.

The relationship between chronic hepatitis B (CHB) infection and natural killer (NK) cell dysfunction is well-established, but the specific role of HBV viral antigens in driving NK cell impairment in patients with CHB remains unclear. This study investigates the modulatory effects of hepatitis B virus subviral particles (HBVsvp, a representative model for HBsAg) on the phenotypic regulation (activating and inhibitory receptors), cytokine production and cytotoxic potential of peripheral blood mononuclear cell-derived natural killer cells (PBMCs-derived NK cell), which contributes to NK cell dysfunction in CHB infection, potentially serving as an effective HBV immune evasion strategy by the virus.

NK cells were isolated from peripheral blood of patients with CHB (n=5) and healthy individuals (n=5), stimulated with HBVsvp. Subsequent flow cytometric characterization involved assessing changes in activating (NKp46 and NKG2D) and inhibitory (CD94) receptors expression, quantifying TNF-α and IFN- γ cytokine secretion, and evaluating the cytotoxic response against HepG2.2.15 cells with subsequent HBVsvp quantification.

In CHB patients, in vitro exposure of PBMCs-derived NK cell with HBVsvp (represent HBsAg model) significantly reduced NK cell-activating receptors expression (P = 0.022), increased expression of CD94 + NK cells (p = 0.029), accompanied with a reduced TNF-α - IFN-γ cytokine levels, and impaired cytotoxic capacity (evidenced by increased cell proliferation and elevated HBVsvp levels in co-cultures with HepG2.2.15 cells in a time-dependent), relative to healthy donors.

These findings suggest that HBVsvp may induce dysfunctional NK cell responses characterized by phenotypic imbalance with subsequent reduction in cytokine and cytotoxic levels, indicating HBVsvp immunosuppressive effect that compromises antiviral defense in CHB patients. These data enhance our understanding of NK cell interactions with HBsAg and highlight the potential for targeting CD94 inhibitory receptors to restore NK cell function as an immunotherapeutic approach. Further clinical research is needed to validate these observations and establish their utility as reliable biomarkers.

Functional cure for chronic hepatitis B (CHB) requires finite treatment. Two agents under investigation with the goal of achieving functional cure are the small-interfering RNA JNJ-73763989 (JNJ-3989) and the capsid assembly modulator JNJ-56136379 (JNJ-6379; bersacapavir).

REEF-2, a phase IIb, double-blind, placebo-controlled, randomized study, enrolled 130 nucleos(t)ide analogue (NA)-suppressed hepatitis B e-antigen (HBeAg)-negative patients with CHB who received JNJ-3989 (200 mg subcutaneously every 4 weeks) + JNJ-6379 (250 mg oral daily) + NA (oral daily; active arm) or placebos for JNJ-3989 and JNJ-6379 +active NA (control arm) for 48 weeks followed by 48 weeks off-treatment follow-up.

At follow-up Week 24, no patients achieved the primary endpoint of functional cure (off-treatment hepatitis B surface antigen [HBsAg] seroclearance). No patients achieved functional cure at follow-up Week 48. There was a pronounced on-treatment reduction in mean HBsAg from baseline at Week 48 in the active arm vs. no decline in the control arm (1.89 vs. 0.06 log10 IU/ml; p = 0.001). At follow-up Week 48, reductions from baseline were >1 log10 IU/ml in 81.5% vs. 12.5% of patients in the active and control arms, respectively, and 38/81 (46.9%) patients in the active arm achieved HBsAg <100 IU/ml vs. 6/40 (15.0%) patients in the control arm. Off-treatment HBV DNA relapse and alanine aminotransferase increases were less frequent in the active arm, with 7/77 (9.1%) and 11/41 (26.8%) patients in the active and control arms, respectively, restarting NAs during follow-up.

Finite 48-week treatment with JNJ-3989 + JNJ-6379 + NA resulted in fewer and less severe post-treatment HBV DNA increases and alanine aminotransferase flares, and a higher proportion of patients with off-treatment HBV DNA suppression, with or without HBsAg suppression, but did not result in functional cure.

Achieving a functional cure from chronic hepatitis B (CHB) with finite treatments is a major unmet medical need. The current study assessed the rate of functional cure and clinical outcome after controlled nucleos(t)ide analogue (NA) withdrawal in patients with low levels of HBsAg induced by 48 weeks of treatment with the small-interfering RNA JNJ-3989 and the capsid assembly modulator JNJ-6379 plus NA vs. patients who only received NA treatment. Though functional cure was not achieved by any patient in either arm, the 48-week treatment regimen of JNJ-3989, JNJ-6379, and NA did result in more patients achieving pronounced reductions in HBsAg, with clinically meaningful reductions maintained for up to 48 weeks off all treatments, as well as fewer off-treatment HBV DNA increases and alanine aminotransferase flares. These findings provide valuable insights for future studies investigating potential finite treatment options, while the reported efficacy and safety outcomes may be of interest to healthcare providers making treatment decisions for patients with NA-suppressed HBeAg-negative CHB.

NCT04129554.

Liver stiffness measurement (LSM) using vibration-controlled transient elastography (VCTE) can assess fibrotic burden in chronic liver diseases. The systematic review and meta-analysis was conducted to determine whether LSM using VCTE can predict the risk of development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients.

A systematic literature search of the Ovid-Medline, EMBASE, Cochrane, and KoreaMed databases (from January 2010 to June 2023) was conducted. Of the 1,345 individual studies identified, 10 studies that used VCTE were finally registered. Hazard ratios (HRs) and the 95% confidence intervals (CIs) were considered summary estimates of treatment effect sizes of ≥11 kilopascal (kPa) standard for HCC development. Meta-analysis was performed using the restricted Maximum Likelihood random effects model.

Among the ten studies, data for risk ratios for HCC development could be obtained from nine studies. When analyzed for the nine studies, the HR for HCC development was high at 3.33 (95% CI, 2.45-4.54) in CHB patients with a baseline LSM of ≥11 kPa compared to patients who did not. In ten studies included, LSM of ≥11 kPa showed the sensitivity and specificity for predicting HCC development were 61% (95% CI, 50-71%) and 78% (95% CI, 66-86%), respectively, and the diagnostic accuracy was 0.74 (95% CI, 0.70-0.77).

The risk of HCC development was elevated in CHB patients with VCTE-determined LSM of ≥11 kPa. This finding suggests that VCTE-determined LSM values may aid the risk prediction of HCC development in CHB patients.