BACKGROUND:Novel models of ambulatory care have been used in chronic disease management, but implementation in advanced chronic liver disease remains limited. AIMS:We aimed to explore clinical outcomes of a multidisciplinary clinic for patients with chronic liver disease. METHODS:We performed a retrospective cohort study of patients attending a multidisciplinary liver clinic between February 2019 and May 2024. The clinic comprised co-located hepatologists, a dietitian, a pharmacist and an addiction medicine specialist, coordinated by a hepatology nurse. Patients accessed on-site point-of-care ultrasound, abdominal paracentesis and albumin infusions. The primary outcome was liver-related admission. Secondary outcomes were 12-month admission-free survival and change in liver disease prognostic scores at 3 and 6 months. RESULTS:A total of 285 patients were included, of whom 61% were men, 56% had alcohol-related liver disease and 95% had cirrhosis. The median baseline model for end-stage liver disease (MELD) score was 14.6 (interquartile range (IQR): 10.6-18.9) and 52% were in Child-Pugh B class at index appointment. The liver-related admission rate was 33% at a median of 546 days (IQR: 149-1095 days) from index appointment, and 12-month admission-free survival was 40.4% (IQR: 34.6-46.1). Median MELD improved at 3 months (12.8 months (IQR: 9.8-15.9 months), P < 0.05) and plateaued by 6 months (11.9 months (IQR: 9.4-16.2 months), P = 0.29). The proportion of patients with ascites decreased at each time point (54% vs 35% vs 27%, P < 0.05). CONCLUSIONS:Two-thirds of patients attending a multidisciplinary liver clinic had no subsequent liver-related admissions, with a median 18-month latency to admission in the remainder. Co-location of clinicians and supportive measures may contribute to these findings.

The burden of hepatitis C virus (HCV) infection often falls disproportionately on migrant populations within high-income countries. Differences in health literacy, language, comorbidities, and HCV genotype may influence HCV natural history. 3537 persons including 652 migrants treated for HCV infection with direct-acting antiviral (DAA) (2016-2021) were analysed. We describe the epidemiology of HCV in migrant people compared to Australian-born individuals and examine rates of sustained viral response (SVR), advanced liver fibrosis, cirrhosis, and all-cause mortality. Multivariable logistic and Cox regression analyses examined differences by migrant status. At enrolment, Australian-born patients were younger (mean 51.5 vs. 54.2 years; p < 0.001) and more likely to report injection drug use (p = 0.011), risky alcohol use (p < 0.001), or opioid replacement therapy (p < 0.001). Among migrants, diabetes (13.9% vs. 10.3%; p = 0.008), hepatitis B virus (HBV) exposure (43.3% vs. 29.7%; p < 0.001), active HBV infection (3.1% vs. 1.6%; p = 0.033), and genotypes 4, 5, and 6 (18.3% vs. 6.6%; p < 0.001) was more common. Overall SVR rates were comparable (p = 0.69), but SVR rates among migrants with cirrhosis were lower (88.2% vs. 95.2%; p = 0.002). Advanced fibrosis (24.5%), cirrhosis (35.0%), and five-year survival did not differ by migrant status (all p > 0.05). In migrants, genotype 3 was associated with more advanced liver fibrosis (adj-OR = 1.70, 95% CI 1.40-2.06) and cirrhosis (adj-OR = 1.74, 95% CI 1.48-2.04; p < 0.001), relative to Australian-born patients. Genotypes 2, 4 and 6 HCV were not associated with liver fibrosis and cirrhosis (all p > 0.05). In conclusion, migrants experienced equivalent SVR and rates of liver fibrosis and cirrhosis, and have equivalent or better survival compared to Australian-born patients.

Background Metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis and hepatocellular carcinoma (HCC) describe progressive stages of liver disease that occurs secondary to inflammation driven by abnormal hepatic lipid accumulation. Treatment that addresses the pathophysiology that underlies MASH/HCC progression is currently lacking. Human amniotic epithelial cell derived EVs (hAEC-EVs) demonstrate anti-inflammatory, anti-fibrotic and reparative properties. Methods We aimed to investigate the therapeutic efficacy of immortalised hAEC-EVs (ihAEC-EVs) in a murine model of MASH and HCC and characterize both protein and miRNA cargo to explain therapeutic mechanisms. MASH and HCC was induced in mice following a ‘western diet’ and carbon tetrachloride (CCl4) exposure for 12 weeks or 24 weeks respectively. 10µg of ihAEC EVs (treatment) and 10mg/kg obeticholic acid (treatment benchmark) was administered via oral gavage. Serum was collected for metabolic parameter analysis and livers were collected for histological and molecular analysis. Results Oral administration of ihAEC-derived extracellular vesicles (EVs) significantly reduced liver fibrosis and inflammation in MASH by reducing hepatic stellate cells and macrophages. These findings are supported by protein and miRNA analysis that reveals presence of EV cargo that modulates pathways linked to hepatic inflammation, fibrosis, and LPC response. Conclusions These findings indicate that oral administration of ihAEC-EVs is a promising cell-free therapy for the treatment of MASLD and MASH, having a significant impact on the treatment possibilities for patient's suffering from chronic liver disease. Further, this study allowed us to deduce and validate pathways involved in MASH progression and identify candidate proteins and miRNAs to focus on for future mechanism of action experiments.

Abstract Background Quantitative assessment of fibro-inflammation in Crohn’s disease strictures remains a challenge despite its role in clinical decision making using immunomodulatory drugs or endoscopic/surgical interventions. While histology remains the gold standard, no validated histological scoring systems for Crohn’s disease strictures exist and assessment is subject to significant intra- and inter-observer variability. Fourier-transform infra-red (FTIR) microspectroscopy is a reproducible, label-free and non-destructive approach for analysing tissue biochemistry via molecular vibrations. We have previously shown accurate assessment of inflammation severity using this technique in colitis models (1). The aim of this study was to assess Crohn’s disease strictures using FTIR spectroscopy and to evaluate if tissue spectra can predict post-operative Crohn’s disease recurrence. Methods Full-thickness Crohn’s stricture resections (n=72) were obtained in paraffin and sectioned for hyperspectral imaging using the Agilent Cary 670 FPA-IR coupled with the Agilent Cary 620 microscope in transflection mode in the wavenumber region 1800–800 cm-1. Nearly 8 million spectra in total were acquired from regions of interest in each of the bowel wall layers per sample (Figure 1). Spectra was transformed to the second derivative, normalised and reduced to 25 spectra per sample prior to analysis using partial least squares discriminant analysis (PLSDA) with internal cross-validation. Adjacent tissue sections were stained with H&E, Masson’s trichrome and α-smooth muscle actin. Histology was scored based on the averaged scores of three independent clinical histopathologists for inflammation, fibrosis and muscular changes. Results Tissue infra-red spectra demonstrated excellent performance defined by area under the receiver operating characteristic curve (AUC) of ≥0.9 using PLSDA to classify severe from mild inflammation and good (AUC ≥0.8) to excellent (AUC ≥0.9) performance to classify severe from mild fibrosis and muscular hyperplasia/hypertrophy. In those with complete macroscopic Crohn’s disease resection (n=51), spectra from index stricture resections demonstrated good performance (AUC ≥0.8) in discriminating between future significant endoscopic recurrence defined by Rutgeert’s score ≥ i2 (2) and excellent performance for surgical recurrence (AUC ≥0.9) defined as future surgical resection of Crohn’s recurrence. Conclusion FTIR microspectroscopy can detect biochemical differences underlying inflammation, fibrosis and muscular changes in Crohn’s strictures and provide simultaneous quantitative assessment. The biochemical tissue fingerprints demonstrate good to excellent discrimination for predicting endoscopic and surgical Crohn’s recurrence, respectively. References 1. Keung C, Heraud P, Kuk N, Lim R, Sievert W, Moore G, et al. Fourier-Transform Infra-Red Microspectroscopy Can Accurately Diagnose Colitis and Assess Severity of Inflammation. Int J Mol Sci. 2022;23(5). 2. Rutgeerts P, Geboes K, Vantrappen G, Beyls J, Kerremans R, Hiele M. Predictability of the postoperative course of Crohn's disease. Gastroenterology. 1990;99(4):956-63.

Abstract Background Fibrostenotic strictures are common in Crohn’s disease, have limited treatment options and lack validated biomarkers to predict treatment response. Fourier-transform infra-red (FTIR) spectroscopy provides reproducible biochemical information from biospecimens using a rapid, label-free, non-destructive technique via molecular vibrations. We previously completed a proof-of-concept study that identified spectral biomarkers for inflammation in a model of colitis.1 The aim of this study was to investigate whether the tissue biochemical "fingerprint" using FTIR spectroscopy can predict patient clinical response to anti-tumour necrosis-factor-α (anti-TNFα) therapy, and identify spectral biomarkers for treatment response. Methods Hyperspectral images were acquired using the Agilent Cary 670 FPA-IR coupled with the Agilent Cary 620 microscope in transflection mode in the wavenumber region 1800 – 800 cm-1 from fixed ileo-colonoscopic biopsies from 62 patients with Crohn’s disease and 12 healthy controls. A subset of patients (n = 24) were included from STRIDENT2, a randomised study assessing adalimumab therapy for intestinal Crohn’s strictures. Thousands of spectra were obtained per sample, pre-processed via transformation to the second derivative, normalised and reduced to 25 spectra per sample prior to analysis using partial least squares discriminant analysis (PLSDA) with internal cross-validation. Spectral biomarkers were identified by the most contributive infra-red bands from the latent variables (LV) and significant variable importance in projection (VIP) scores of >1. Adjacent histological sections were stained with H&E, Masson’s trichrome and α-smooth muscle actin with inflammation and fibrosis scored by a clinical pathologist. Results Spectra from baseline biopsies from the 24 patients in the STRIDENT study demonstrated excellent performance using PLSDA in discriminating between responders and non-responders in relation to the 12 month clinical outcomes, defined by area under the receiver operating characteristic curve (AUC) >0.9 for MRI and IUS responses, normalisation of faecal calprotectin and CRP, CDAI and pain responses (Table 1). Spectral biomarkers of interest for stricture response to anti-TNFα are shown in Figure 1 and include the amide I and II protein bands (peaks at 1651 and 1543 cm-1, respectively), the carboxylate group of proteins (1454 cm-1), lipid bands (1750 and 1395 cm-1), collagen band (1236 cm-1), glycoprotein bands (1081 and 1030 cm-1), and nucleic acid bands (1236, 1081 and 966 cm-1). Conclusion The novel technique of FTIR spectroscopy detects tissue biochemical "fingerprints" in fibrostenotic Crohn’s disease that demonstrate excellent discrimination for predicting clinical response to adalimumab therapy. References 1.Keung C, Heraud P, Kuk N, et al. Fourier-Transform Infra-Red Microspectroscopy Can Accurately Diagnose Colitis and Assess Severity of Inflammation. Int J Mol Sci. 2022;23(5). 2.Schulberg JD, Wright EK, Holt BA, et al. Intensive drug therapy versus standard drug therapy for symptomatic intestinal Crohn's disease strictures (STRIDENT): an open-label, single-centre, randomised controlled trial. Lancet Gastroenterol Hepatol. 2022;7(4):318-331. 3.Rimola J, Ordas I, Rodriguez S, et al. Magnetic resonance imaging for evaluation of Crohn's disease: validation of parameters of severity and quantitative index of activity. Inflamm Bowel Dis. 2011;17(8):1759-1768.

BACKGROUND AND AIMS:Cure of hepatitis C virus (HCV) infection decreases liver- and all-cause mortality. However, the risk of early mortality after HCV cure remains. We examined factors associated with cause-specific mortality after direct-acting antiviral (DAA) therapy. METHODS:DAA-treated adults (recruited 2016-2021) were followed up to September 2023. Medication, health-service use, and deaths were obtained from population databases. The primary outcome was all-cause and cause-specific mortality. RESULTS:Among 3619 patients (average 52.0 years (SD = 10.5), 66.0% male, 33.6% with cirrhosis) followed for a median of 6.8 years (IQR 5.5-7.4), 423 (11.7%) died (40.6% due to liver disease, 13.2% self-harm/accidental poisoning and 12.3% respiratory disease/lung cancer). Cirrhosis (adjusted hazard ratio (adj-HR) = 14.51, 95% CI 6.87-30.64), FIB4 > 3.25 (adj-HR = 4.22, 95% CI 2.63-6.80), nonsustained virological response (SVR) (adj-HR = 3.94, 95% CI 2.64-5.88) and age ≥ 60 years (adj-HR = 1.88, 95% CI 1.32-2.69) increased liver-related mortality risk. Mortality was threefold higher in non-SVR (32.4% of 210 patients vs. 10.2% of 2894 with SVR, p < 0.001). Non-SVR increased risk of liver mortality (adj-HR = 4.30, 95% CI 2.90-6.37). Mental health medication use (adj-HR = 2.82, 95% CI 1.40-5.67), loss to clinical follow-up (adj-HR = 2.61, 95% CI 1.31-5.21) and injection drug use/opioid replacement therapy (adj-HR = 2.26, 95% CI 1.23-4.14) increased risk of self-harm/accidental poisoning-related mortality. Age ≥ 60 years and diabetes increased mortality risk from other extrahepatic cancer (adj-HR = 2.68, 95% CI 1.31-5.51 and adj-HR = 2.57, 95% CI 1.15-5.72) and cardiovascular disease (adj-HR = 2.71, 95% CI 1.06-4.19 and adj-HR = 2.28, 95% CI 1.03-5.05). CONCLUSIONS:Liver-related death drives mortality for cirrhotic patients. Curing HCV remains critical. Holistic HCV care, with attention to mental health illnesses in younger patients, metabolic comorbidities, and better cancer screening for older patients may reduce excess mortality.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) has a 22%-74% 28-day mortality rate and 30%-40% 30-day readmission rate. We investigated the acceptability and feasibility of a multimodal community intervention for ACLF. METHODS: A single-arm nonrandomized pilot study of consecutive participants with ACLF was conducted in a tertiary health service. Participants received weekly medical and nursing reviews, dietetics, physiotherapy, pharmacy, social work, addiction medicine, and neuropsychiatry, where indicated. A digital platform included remote weight monitoring and online surveys. The primary outcome was acceptability/ feasibility. Secondary outcomes included safety, mortality, readmission, liver disease severity, and costs. RESULTS: Fiftynine patients were enrolled with median age 51 years (inter- quartile range (IQR): 45-59); majority alcohol etiology (74%),and median Model for End-Stage Liver Disease Sodium score 16 (IQR: 12-21). LivR Well was acceptable with low attrition (8 of 59), adherence to the program including home visits (mean 8.4 +/- 4.2) and consultations (mean 2.4 +/- 1.5) per patient. This was supported by positive feedback and themes identified through a qualitative subanalysis. Feasibility was demonstrated by recruitment rate of 4.94 patients/month and 86% completion. Mortality was lower than expected at 3%, 30- day readmission rate was 15%, and median Model for End- Stage Liver Disease Sodium score reduced to 15 (P = .01). Median 6-month costs reduced from $30,454 (IQR: $21,953-$65,657) to $17,657 ($4249-$42,876) (P = .009). The total 6-month health-care cost was $1,868,859 (95% confi- dence interval 1,081,821-2,655,897) compared to $2,518,227 (95% confidence interval 1,959,610-3,076,844). CONCLUSION: LivR Well was acceptable, feasible, and safe with low shortterm mortality and readmission rates. Health-care costs were reduced by 26% driven by a 40% reduction in 30-day readmission. Further evaluation includes a randomized controlled trial of LivR Well compared to standard care.

INTRODUCTION:Alcohol use is common in patients with chronic hepatitis C virus (HCV) infection. We examined the impact of alcohol use on direct-acting antiviral (DAA) therapy outcome and the clinical course of liver disease and 2-year survival for patients receiving HCV DAA therapy. METHODS:Adults (n = 2624) recruited from 26 Australian hospital liver clinics during 2016-2021 were followed up for 2 years. Risky alcohol use was defined by a combination of self-report (≥40 g/day of ethanol), physician-reported history of problematic alcohol use, and anti-craving medication prescription via population-based database linkage. We examined factors associated with advanced liver fibrosis and survival using multivariable logistic and Cox regression. RESULTS:Among 1634 patients (62.3%) with risky alcohol use, 24.6% reported consuming ≥40 g/day of alcohol, 98.3% physician-reported problematic alcohol use; only 4.1% were dispensed naltrexone/acamprosate. One hundred and forty-three patients with cirrhosis reported ≥40 g/day of alcohol, 6 (4.3%) were prescribed naltrexone/acamprosate. Risky alcohol use was associated with advanced fibrosis (adjusted-odds ratio 1.69, 95% confidence interval 1.32-2.17) and patients were over-represented for cirrhosis (45.1% vs. 25.6% in no-risky alcohol use [p < 0.001]) and hepatocellular carcinoma (5.7% vs. 2.5% [p < 0.001]). Sustained viral response (p = 0.319) and 2-year survival (adjusted-hazard ratio 1.98, 95% confidence interval 0.84-4.63) after DAA therapy were not associated with risky alcohol use. DISCUSSION AND CONCLUSIONS:Risky alcohol use in HCV patients was prevalent, but did not reduce HCV cure. Treatment for alcohol dependence was low. Risky alcohol use may be under-recognised in liver clinics. Better integration of addiction medicine into liver services and increased resourcing and addiction medicine training opportunities for hepatologists may help address this.

BACKGROUND AND AIMS:Accurate biomarkers to predict outcomes following discontinuation of nucleos(t)ide analogue (NA) therapy are needed. We evaluated serum hepatitis B core-related antigen (HBcrAg) level as a biomarker for predicting outcomes after NA discontinuation. METHODS:Patients with HBeAg-negative chronic hepatitis B (CHB) without cirrhosis were enrolled in a prospective trial evaluating clinical outcomes until 96 weeks after NA discontinuation. End of treatment (EOT) and off-treatment levels of serum HBcrAg, HBsAg, HBV RNA and HBV DNA were used to predict key clinical outcomes including hepatitis flare (ALT ≥5 × ULN and HBV DNA > 2000 IU/mL). The SCALE-B score was calculated for the purposes of model validation. RESULTS:HBcrAg was tested amongst 65 participants. The median age was 54 years, 54% were male and 83% were Asian. HBcrAg was detectable in 86% patients. HBcrAg level ≥4 log U/mL at EOT was predictive of hepatitis flare [8/10 (80%) vs. 17/55 (31%), p = .001]. The presence of either HBcrAg ≥4 log U/mL or detectable HBV RNA at EOT predicted for both biochemical relapse and hepatitis flare. The SCALE-B model at EOT predicted for virological relapse, biochemical relapse, hepatitis flare and HBsAg loss in this cohort. An increase in the serum HBcrAg level off-treatment was also associated with hepatitis flare. No participant with EOT HBcrAg level ≥4 log U/mL achieved HBsAg loss. CONCLUSIONS:High levels of serum HBcrAg predict for hepatitis flare after stopping NA therapy and low likelihood of HBsAg loss at week 96. People with high levels of serum HBcrAg are not suitable candidates for NA discontinuation.

Background & AimMetabolic dysfunction-associated steatohepatitis (MASH) is a liver disease driven by a chronic inflammatory response following prolonged fat accumulation. MASH can result in hepatocellular carcinoma (HCC). Currently, there is no cure for MASH or HCC. Extracellular vesicles derived from human amniotic epithelial cells (hAEC-EVs) show therapeutic potential against liver injury. However, the high costs associated with production of EVs from primary cells has hindered clinical uptake. To overcome this challenge, we have developed a line of immortalized hAECs (ihAECs) to serve as a continual source of EVs. We aimed to investigate the therapeutic potential of ihAEC-EVs on fibrosis, inflammation, and the liver progenitor cell response in an experimental model of MASH and HCC.Methods, Results & ConclusionMASH was induced in ∼8-week-old male mice via exposure to a high-fat, fructose and cholesterol diet, combined with weekly carbon tetrachloride (CCl4) administration for 12 weeks. HCC was induced in mice following 24-week exposure to the same protocol. Mice were randomized to receive 10μg of ihAEC EVs via oral gavage either twice or thrice a week from week 6 until week 12 for the MASH model or from week 12 to 24 for the HCC model. Obeticholic acid via oral gavage thrice weekly acted as a comparison. Control mice were fed normal diets. Mice were euthanized at week 12, 18 or 24. Serum was collected for metabolic parameter analysis (ALT, AST, insulin and cholesterol) and livers were collected for histological and molecular analysis.Mice placed on the MASH induction diet resulted in hepatic fibrosis, inflammation and steatosis. Thrice weekly treatment of ihAEC-EVs resulted in significantly reduced liver fibrosis at 12, 18 and 24 weeks (∼2-fold reduction, p<0.05). Macrophage numbers were also reduced at 12, 18 and 24 weeks (1.6-, 3- and 3.6-fold reduction respectively, p<0.05). A reduction in steatosis was also observed following ihAEC-EVs treatment.ihAEC-EVs reduced hepatic fibrosis and steatosis in an experimental model of MASH and HCC when administered orally thrice weekly, suggesting that repeated administration is required for circulating EVs to prevent the progression of MASH. These findings are supportive of clinical translation of ihAEC-EVs as a therapy for MASH.

Placenta-derived human amniotic epithelial cells (hAEC) exhibit anti-inflammatory and anti-fibrotic effects in cirrhosis models. We conducted a first-in-human phase I clinical trial to assess the safety and tolerability of hAEC in adults with compensated cirrhosis. We examined increasing and repeated doses of hAEC in 9 patients in 3 cohorts. Cohort 1 patients received 0.5 × 106/kg hAEC in one IV infusion. Cohort 2 patients received 1 × 106/kg hAEC in one IV infusion. The patients in cohort 3 received 1 × 106/kg hAEC on days 0 and 28. Here, we report follow-up to post-infusion day 56 (D56), during which no serious adverse events occurred. Six patients experienced no study-related adverse events, while 3 patients reported mild (grade 1) headaches that were possibly infusion-related. A transient decrease in serum platelet count occurred in all patients, which returned to baseline screening values by day 5. FIB-4 values to assess fibrosis were significantly lower at D56. Although not statistically significant, serum AST levels and liver stiffness measurements at D56 were lower than those at baseline. The hepatic venous pressure gradient, a measure of portal hypertension, declined in 4 patients, did not change in 3 patients, and increased in 2 patients. In conclusion, intravenous infusion of allogeneic hAEC in patients with compensated cirrhosis at the doses used in this study was safe and well tolerated, with no difference observed between 1 and 2 doses. Decreased hepatic inflammation, liver stiffness, and portal hypertension support larger studies aimed at identifying patients who may benefit from this therapy. Clinical Trial registration: The trial was prospectively entered on the Australian Clinical Trials Registry (ANZCTR12616000437460).

Background: Non-alcoholic fatty liver disease (NAFLD) is associated with visceral adiposity. We assessed the effectiveness of time-restricted fasting (TRF) for 16 h daily without calorie restrictions compared to standard care (SC; diet and lifestyle advice) in improving visceral adiposity and steatosis via controlled attenuation parameter (CAP). Methods: In a prospective single-blind randomized controlled trial, 32 participants with NAFLD were randomly assigned to TRF or SC for 12 weeks. The secondary endpoints were changes in liver stiffness, anthropometry, blood pressure, and other metabolic factors. Results: Twenty-eight participants completed the first arm of the study (TRF = 14, SC = 14), with 23 completing the crossover arm (TRF = 10, SC = 13). The baseline demographics were similar between the groups. Intermittent fasting caused a significant decrease in hepatic steatosis (p = 0.038), weight (p = 0.005), waist circumference (p = 0.001), and BMI (p = 0.005) compared to standard care. Intermittent fasting also resulted in additional within-group changes that were not seen in the standard care intervention. Conclusion: TRF offers superior improvements in patients with NAFLD, improving steatosis, weight, and waist circumference despite a lack of change in overall caloric intake. Time-restricted fasting should be considered as a primary weight loss intervention in the context of NAFLD. Trial registration: ACTRN12613000935730.

Background The 2016 World Health Assembly endorsed the elimination of hepatitis B virus (HBV) infection as a public health threat by 2030; existing therapies and prophylaxis measures make such elimination feasible, even in the absence of a virological cure. We aimed to estimate the national, regional, and global prevalence of HBV in the general population and among children aged 5 years and younger, as well as the rates of diagnosis, treatment, prophylaxis, and the future burden globally. Methods In this modelling study, we used a Delphi process with data from literature reviews and interviews with country experts to quantify the prevalence, diagnosis, treatment, and prevention measures for HBV infection. The PRoGReSs Model, a dyn amic Markov model, was used to estimate the country, regional, and global prevalence of HBV infection in 2022, and the effects of treatment and prevention on disease burden. The future incidence of morbidity and mortality in the absence of additional interventions was also estimated at the global level. Findings We developed models for 170 countries which resulted in an estimated global prevalence of HBV infection in 2022 of 3.2% (95% uncertainty interval 2.7-4.0), corresponding to 257.5 million (216.6-316.4) individuals positive for HBsAg. Of these individuals, 36.0 million were diagnosed, and only 6.8 million of the estimated 83.3 million eligible for treatment were on treatment. The prevalence among children aged 5 years or younger was estimated to be 0.7% (0.6-1.0), corresponding to 5.6 million (4.5-7.8) children with HBV infection. Based on the most recent data, 85% of infants received three-dose HBV vaccination before 1 year of age, 46% had received a timely birth dose of vaccine, and 14% received hepatitis B immunoglobulin along with the full vaccination regimen. 3% of mothers with a high HBV viral load received antiviral treatment to reduce mother-to-child transmission. Interpretation As 2030 approaches, the elimination targets remain out of reach for many countries under the current frameworks. Although prevention measures have had the most success, there is a need to increase these efforts and to increase diagnosis and treatment to work towards the elimination goals.