Introduction:The phase 3 REFLECT trial demonstrated the efficacy and safety of lenvatinib versus sorafenib in the first-line treatment of patients with unresectable hepatocellular carcinoma (uHCC). We report results from STELLAR, a non-interventional post-marketing study. The primary objectives were to characterize hepatotoxicity and overall safety of lenvatinib in patients from Western regions with uHCC. Methods:STELLAR was a prospective, open-label, observational, phase 4 study of patients treated with lenvatinib (n = 193). A cohort of sorafenib-treated patients (n = 123) was included as an internal reference group. The treating physician made the decision to treat patients with lenvatinib or sorafenib before enrollment. Study drugs were administered according to the Summary of Product Characteristics guidelines. Safety and efficacy evaluations were performed according to standard clinical practice at each site. The primary endpoint was safety. Secondary endpoints included treatment exposure and overall survival. Results:The median duration of treatment with lenvatinib or sorafenib was 6.5 months (range, 0.2-33.1 months) and 4.4 months (range, 0.5-30.7 months), respectively. Hepatotoxicity treatment-emergent adverse events (TEAEs) were observed in 26.9% of lenvatinib-treated patients and 33.3% of sorafenib-treated patients. The most frequently reported hepatotoxicity TEAEs were hepatic encephalopathy (7.8%; lenvatinib cohort) and ascites (11.4%; sorafenib cohort), respectively. Overall, 85.0% of lenvatinib-treated patients and 84.6% of sorafenib-treated patients experienced ≥1 TEAE. Median overall survival (95% CI) was 16.9 months (14.1-not estimable) in lenvatinib-treated patients. Conclusion:Our findings support the established safety and efficacy of lenvatinib in first-line patients with uHCC.

Chronic hepatitis D virus (HDV) infection always occurs as a coinfection with hepatitis B virus (HBV) and is the most severe form of viral hepatitis, associated with a high risk of cirrhosis, liver cancer and death. Effective treatment is now available for HDV-HBV coinfection and HDV screening is recommended for all people living with HBV, yet most people in Australia with HDV-HBV are diagnosed too late to prevent complications. This article calls for an urgent change in HDV testing policy and funding to implement reflex HDV antibody (anti-HDV) testing for all people diagnosed with HBV infection, thus enabling timely diagnosis of HDV-HBV coinfection and rapid access to life-saving treatment.

Hepatitis B virus (HBV) DNA testing is essential for the management of HBV infection. Routine HBV DNA tests in central laboratories are expensive and require processed venous blood, limiting accessibility. This study is the first published assessment of the point-of-care Xpert HBV DNA assay performance using fingerstick capillary blood compared with standard-of-care venous blood testing. Participants with chronic HBV infection were enrolled from six hospitals. Fingerstick capillary blood was tested using Xpert HBV Viral Load assay (quantification lower limit: 100 IU/mL). Venipuncture whole blood was tested with COBAS AmpliPrep/COBAS TaqMan HBV DNA Test (gold standard). The sensitivity and specificity of the Xpert were evaluated for identifying HBV DNA ≥100 and >2,000 IU/mL. Agreement between quantitative measurements of assays was assessed. A total of 246 participants were included (median age 45, 46% female, 18% HBeAg positive, 48% on HBV treatment, 6% with cirrhosis). For HBV DNA ≥100 IU/mL, the sensitivity and specificity of the Xpert were 97.0% (95% CI: 94.9, 99.1) and 90.3% (86.6, 94.0), respectively. For HBV DNA >2,000 IU/mL, the sensitivity and specificity were 95.3% (92.7, 98.0) and 95.0% (92.4, 97.8), respectively. Viral load differences in non-concordant samples ranged from 0.1 to 1.1 log IU/mL. Overall, the Xpert viral loads were a mean 0.12 log IU/mL higher than gold standard (95%CI: -0.43, 0.67). In conclusion, minimal differences in HBV DNA levels were identified between the Xpert and gold standard assays, with differences in non-concordant results unlikely to impact clinical decisions. This evidence supports developing a dedicated Xpert HBV DNA fingerstick assay for decentralized care, crucial for remote, resource-limited settings and hard-to-reach populations, including prenatal care for women with HBV.IMPORTANCEThis study represents the first assessment of a point-of-care hepatitis B virus (HBV) DNA assay using fingerstick capillary blood (Xpert HBV Viral Load assay). Our findings demonstrated high sensitivity and specificity for the point-of-care test, with close agreement between the point-of-care and standard-of-care assays across the full quantitative spectrum of HBV viral load measurements. Importantly, the differences between the assays in participants with non-concordant results were not substantial enough to alter clinical management, suggesting that this point-of-care method is both accurate and reliable for clinical use. By highlighting the potential for decentralizing HBV care, our research provides compelling evidence to support the development of a dedicated Xpert HBV DNA point-of-care test. Such a development could greatly benefit patients in remote and resource-limited settings, where access to laboratory-based testing is limited.

BACKGROUND Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality. Liver resection provides a curative option, though recurrence following resection remains a major clinical challenge, as adjuvant therapies evolve, and preservation of liver function becomes increasingly important. AIM To evaluate factors associated with HCC recurrence in a real-world setting. METHODS We retrospectively reviewed records of patients with HCC who underwent primary liver resection at three tertiary referral hospitals between January 2008 and May 2022. Baseline patient and tumour characteristics were assessed. Risk factors for recurrence were analysed using multivariate Cox regression. RESULTS In this cohort, 235 patients underwent surgical resection for HCC. Median survival was 80.9 months. HCC recurred in 94 (40%) patients with median time to recurrence 18.8 months (interquartile range: 8.6-35). An albumin-bilirubin (ALBI) grade of >= 2 [adjusted hazard ratio (aHR): 2.02 (1.27-3.21), P = 0.003], the presence of cirrhosis [aHR: 2.03 (1.27-3.25), P = 0.003], and Barcelona Clinic Liver Cancer (BCLC) stage B/C [aHR: 2.23 (1.23-4.03) P = 0.008] were independently associated with increased risk of recurrence. When combining these risk factors, the adjusted HR for recurrence was 2.73 (1.57-4.75), 4.32 (2.29-8.12) and 7.52 (2.47-22.93) in those with 1, 2, or 3 factors compared to those with 0 (P < 0.001). CONCLUSION HCC recurrence following primary liver resection was independently associated with cirrhosis, ALBI grade >= 2 and BCLC stage B/C. The seed (the liver cancer as reflected by BCLC stage), and the soil (the liver function and presence or absence of cirrhosis) are relevant considerations for recurrence prediction.

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:Screening for viral hepatitis by automatically ordering hepatitis B and C serology on blood samples already collected from patients presenting to the emergency department (ED) is a relatively novel concept, with modest costs involved. AIM:The aim of this study was to determine patient and healthcare worker perspectives of automatic hepatitis screening at a large metropolitan hospital in Sydney, Australia. METHODS:In this cross-sectional survey study, patients admitted via ED and ED healthcare workers (HCWs) were invited to participate. The primary outcome was the level of patient and HCW acceptability of an automatic hepatitis screening process. Secondary outcomes were patient and HCW knowledge of viral hepatitis, perceptions and barriers to ED hepatitis screening in the absence of an automatic process. RESULTS:Ninety-two percent of 273 patients who participated in the survey wished to know their viral hepatitis status, and 82% found automatic hepatitis B and C testing acceptable as part of their ED blood work. HCWs surveyed (48) believed this strategy would increase testing, as most did not routinely interrogate patients for risk factors or other eligibility criteria for hepatitis testing, as the presenting ED complaint was their priority. Even when indications for testing based on current guidelines were present, few (32%) HCWs initiated testing. CONCLUSION:Automatic viral hepatitis testing in ED is supported by the majority of patients and HCWs, and the latter believe it would increase testing rates. Increasing identification of patients with hepatitis, if accompanied by effective linkage to care, could facilitate World Health Organization elimination goals.

BACKGROUND AND AIMS:Discontinuing nucleos(t)ide analogues (NAs) may lead to functional cure (HBsAg loss) in selected patients with chronic hepatitis B (CHB). We evaluated the rates and predictors of HBsAg loss during long-term follow-up in a prospective cohort. METHODS:This real-world extension study followed participants from a prospective trial of NA discontinuation. All patients had HBeAg-negative CHB without cirrhosis. Efficacy outcomes (including HBsAg loss and decline) and safety outcomes [including hepatitis flare and hepatocellular carcinoma (HCC)] were evaluated. RESULTS:Amongst 97 participants (85% Asian), with a median follow-up of 7 years, the cumulative incidence of HBsAg loss was 10%, 13% and 22% at 5, 7 and 9 years after stopping NA. HBsAg loss was associated with a lower end-of-treatment (EOT) HBsAg level (HR = 0.28, p < 0.001), older age (HR = 1.14, p = 0.005) and peak off-treatment HBV DNA level (OR = 0.50, p = 0.002). Participants with EOT HBsAg level ≤ 10 IU/mL experienced early HBsAg loss (< 96 weeks) without ALT flares whilst those with EOT HBsAg level ≥ 10 IU/mL experienced late (≥ 96 weeks) HBsAg loss, often following ALT flares (5/8 cases). No cases of hepatic decompensation, liver transplantation or death occurred. Median liver stiffness did not increase. HCC was diagnosed in three individuals (4.4/1000 person-years). CONCLUSION:The rate of functional cure increased during long-term follow-up but remained low. EOT HBsAg strongly predicted the likelihood and timing of HBsAg loss. ALT flares were associated with HBsAg decline, and in some cases, with delayed HBsAg loss. TRIAL REGISTRATION:The clinical study was supported by the National Health and Medical Research Council of the study clinical trial ID is NCT02581033.

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:Chronic secretory diarrhoea is a diagnostic challenge with a broad differential and significant impact on patient's quality of life. While common causes include microscopic colitis, bile acid diarrhoea, and laxative use, rarer aetiologies such as vasoactive intestinal peptide (VIP)-secreting neuroendocrine tumours (VIPomas) must be considered when standard investigations fail. Case Presentation:We present a 35-year-old woman with a two-year history of progressively worsening, fasting-persistent, high-volume watery diarrhoea leading to severe electrolyte abnormalities and weight loss requiring resuscitation in intensive care. Extensive biochemical, endoscopic, and radiological investigations-including faecal analysis, colonoscopy, neuroendocrine markers, multiphase CT, endoscopic ultrasound, and Ga-68 Dotatate PET imaging-failed to identify an underlying cause. Serum VIP levels remained within the normal range. Despite the absence of a definitive diagnosis, empirical treatment with the somatostatin analogue octreotide led to rapid and sustained symptom resolution. The patient was subsequently maintained on long-acting lanreotide with complete remission. Notably, diarrhoea recurred upon cessation of therapy, again resolving with reinitiation. After 4 years, the patient self-ceased lanreotide without symptom recurrence, and follow-up imaging remained unremarkable. Discussion:This case highlights a diagnostic dilemma: clinical and biochemical features were highly suggestive of a VIPoma, yet no tumour was identified despite repeated advanced imaging and biochemical workup. The patient's remarkable therapeutic response to somatostatin analogue therapy, in the absence of confirmed neuroendocrine neoplasia, suggests that somatostatin analogues may have a broader role in the management of idiopathic secretory diarrhoea than currently appreciated. Conclusion:We present a rare case of chronic secretory diarrhoea with suspected but unproven VIPoma, demonstrating sustained and reproducible response to somatostatin analogue therapy. This case supports the consideration of therapeutic trials of somatostatin analogues in refractory secretory diarrhoea of unknown origin.

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.

Abstract Background Therapeutic options for early-stage hepatocellular carcinoma (HCC) in individual patients can be limited by tumor and location, liver dysfunction and comorbidities. Many patients with early-stage HCC do not receive curative-intent therapies. Stereotactic ablative body radiotherapy (SABR) has emerged as an effective, non-invasive HCC treatment option, however, randomized evidence for SABR in the first line setting is lacking. Methods Trans-Tasman Radiation Oncology Group (TROG) 21.07 SOCRATES-HCC is a phase II, prospective, randomised trial comparing SABR to other current standard of care therapies for patients with a solitary HCC ≤ 8 cm, ineligible for surgical resection or transplantation. The study is divided into 2 cohorts. Cohort 1 will compromise 118 patients with tumors ≤ 3 cm eligible for thermal ablation randomly assigned (1:1 ratio) to thermal ablation or SABR. Cohort 2 will comprise 100 patients with tumors > 3 cm up to 8 cm in size, or tumors ≤ 3 cm ineligible for thermal ablation, randomly assigned (1:1 ratio) to SABR or best other standard of care therapy including transarterial therapies. The primary objective is to determine whether SABR results in superior freedom from local progression (FFLP) at 2 years compared to thermal ablation in cohort 1 and compared to best standard of care therapy in cohort 2. Secondary endpoints include progression free survival, overall survival, adverse events, patient reported outcomes and health economic analyses. Discussion The SOCRATES-HCC study will provide the first randomized, multicentre evaluation of the efficacy, safety and cost effectiveness of SABR versus other standard of care therapies in the first line treatment of unresectable, early-stage HCC. It is a broad, multicentre collaboration between hepatology, interventional radiology and radiation oncology groups around Australia, coordinated by TROG Cancer Research. Trial registration anzctr.org.au, ACTRN12621001444875, registered 21 October 2021.

Background Systemic therapy for hepatocellular carcinoma (HCC) can prolong survival, but outcomes vary, and predictors of response are not fully defined. Frailty is associated with worse outcomes in cirrhosis and liver transplantation, but its impact on patients with advanced HCC is unknown. Patients and methods An international, multicentre, prospective, observational cohort of adults commencing systemic therapy for HCC from 2019 to 2022 was analysed. Frailty was assessed by the Liver Frailty Index (LFI). The primary outcome was overall survival; secondary outcomes were disease progression, adverse events, and treatment discontinuation. Results Among 102 patients, 80% were male and the median age was 67 years [interquartile range (IQR) 60-73 years]. Most had viral hepatitis (hepatitis C virus 39%, hepatitis B virus 29%), were Child–Pugh A (75%), Eastern Cooperative Oncology Group (ECOG) 0-1 (89%), and Barcelona Centre Liver Cancer (BCLC) stage C (59%). Similar proportions received tyrosine kinase inhibitors (54%) and immunotherapy (46%). The median LFI was 4.13 (IQR 3.81-4.43): 4% were robust (LFI <3.2), 75% were pre-frail (LFI 3.2-<4.5), and 22% were frail (LFI 4.5+). LFI was independently associated with death (adjusted hazard ratio 1.74, 95% confidence interval 1.17-2.59, P = 0.006), after adjustment for Child–Pugh score and albumin–bilirubin grade. The optimal cut-off for survival at 1 year was LFI 4.2 (area under the curve 0.658), significant on univariable and multivariable analyses at predicting death. Frailty was associated with earlier systemic therapy discontinuation, despite similar rates of disease progression and adverse events; cessation of treatment due to functional decline was more common among frail patients. Sensitivity analysis excluding patients above Child–Pugh B8 or ECOG 2 did not change results. Conclusion The LFI is an independent predictor of death among patients with HCC undergoing systemic therapy.

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.