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BACKGROUND AND AIMS: Little is known regarding the epidemiology and outcomes of patients with primary sclerosing cholangitis (PSC) in Australia. We, therefore, evaluated the epidemiology and clinical outcomes of PSC in a large cohort of Australian patients and compared these to the general population. METHODS: We conducted a multicentre, retrospective cohort study of PSC patients at nine tertiary liver centers across three Australian states, including two liver transplant centers. RESULTS: A total of 413 PSC patients with 3,285 person-years of follow-up were included. Three hundred and seventy-one (90%) patients had large duct PSC and 294 (71%) had associated inflammatory bowel disease. A total of 168 (41%) patients developed cirrhosis (including 34 at the time of PSC diagnosis) after a median of 15.8 (95% CI 12.4, NA) years. The composite endpoint of death or liver transplantation occurred in 49 (12%) and 78 (19%) patients, respectively, with a median transplant-free survival of 13.4 (95% CI 12.2-15) years. Compared to the general population, PSC accounted for a 240-fold increased risk of development of cholangiocarcinoma (CCA) and CCA-related death. CCA risk was increased with older age of PSC diagnosis, presence of dominant stricture and colectomy. Compared to same-aged counterparts in the general population, PSC patients who were diagnosed at an older age or with longer disease duration had reduced relative survival. CONCLUSION: In this large retrospective cohort study of PSC patients in Australia, increased age and time from diagnosis was associated with increased mortality and morbidity particularly from CCA and development of cirrhosis, necessitating need for liver transplant.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a serious complication of chronic liver disease. Lenvatinib is an oral multikinase inhibitor registered to treat advanced HCC. This study evaluates the real-world experience with lenvatinib in Australia. METHODS: We conducted a retrospective cohort study of patients treated with lenvatinib for advanced HCC between July 2018 and November 2020 at 11 Australian tertiary care hospitals. Baseline demographic data, tumor characteristics, lenvatinib dosing, adverse events (AEs) and clinical outcomes were collected. Overall survival (OS) was the primary outcome. Progression free survival (PFS) and AEs were secondary outcomes. RESULTS: A total of 155 patients were included and were predominantly male (90.7%) with a median age of 65 years (interquartile range [IQR]: 59-75). The main causes of chronic liver disease were hepatitis C infection (40.0%) and alcohol-related liver disease (34.2). Median OS and PFS were 7.7 (95% confidence interval [CI]: 5.8-14.0) and 5.3 months (95% CI: 2.8-9.2) respectively. Multivariate predictors of mortality were the need for dose reduction due to AEs (Hazard ratio [HR] 0.41, p < 0.01), new or worsening hypertension (HR 0.42, p < 0.01), diarrhoea (HR 0.47, p = 0.04) and more advanced BCLC stage (HR 2.50, p = 0.04). Multivariable predictors of disease progression were higher Child-Pugh score (HR 1.25, p = 0.04), the need for a dose reduction (HR 0.45, p < 0.01) and age (HR 0.96, p < 0.001). AEs occurred in 83.9% of patients with most being mild (71.6%). CONCLUSIONS: Lenvatinib remains safe and effective in real-world use. Treatment emergent diarrhoea and hypertension, and the need for dose reduction appear to predict better OS.

BACKGROUND & AIMS: Necroptosis is a highly inflammatory mode of cell death that has been implicated in causing hepatic injury including steatohepatitis/ nonalcoholic steatohepatitis (NASH); however, the evidence supporting these claims has been controversial. A comprehensive, fundamental understanding of cell death pathways involved in liver disease critically underpins rational strategies for therapeutic intervention. We sought to define the role and relevance of necroptosis in liver pathology. METHODS: Several animal models of human liver pathology, including diet-induced steatohepatitis in male mice and diverse infections in both male and female mice, were used to dissect the relevance of necroptosis in liver pathobiology. We applied necroptotic stimuli to primary mouse and human hepatocytes to measure their susceptibility to necroptosis. Paired liver biospecimens from patients with NASH, before and after intervention, were analyzed. DNA methylation sequencing was also performed to investigate the epigenetic regulation of RIPK3 expression in primary human and mouse hepatocytes. RESULTS: Identical infection kinetics and pathologic outcomes were observed in mice deficient in an essential necroptotic effector protein, MLKL, compared with control animals. Mice lacking MLKL were indistinguishable from wild-type mice when fed a high-fat diet to induce NASH. Under all conditions tested, we were unable to induce necroptosis in hepatocytes. We confirmed that a critical activator of necroptosis, RIPK3, was epigenetically silenced in mouse and human primary hepatocytes and rendered them unable to undergo necroptosis. CONCLUSIONS: We have provided compelling evidence that necroptosis is disabled in hepatocytes during homeostasis and in the pathologic conditions tested in this study.

Background: In clinical trials, hepatitis C virus (HCV) salvage treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) achieved an SVR12 rate of >95% in NS5A-experienced participants. Lower SVR12 rates have been reported in real-world studies, particularly for genotype (GT)3 infection and cirrhosis. We determined the efficacy and safety of SOF/VEL/VOX in a large real-world cohort. Method(s): We assessed the efficacy of salvage SOF/VEL/VOX for HCV infection in NS5A-inhibitor experienced participants with cirrhosis and portal hypertension, prior liver transplantation (LT) or severe extra-hepatic manifestations. SOF/VEL/VOX was available via an early access program. The primary outcome was SVR12. Secondary outcome was frequency of adverse events (AE). Finding(s): Ninety-seven participants were included. Median age was 58, 82% were male, 78% had cirrhosis, most with portal hypertension (61%, n=46/76), and 18% had prior-LT. Of the cirrhotic participants, 96% were Child-Turcotte-Pugh class A, and 4% were class B. Of the 72% with GT3, 76% were also cirrhotic. By intention-to-treat analysis, SVR12 rate was 85% (n=82/97). Per protocol, the SVR12 rate was 90%, including 91% in GT1 (GT1a n=18/18, GT1b n=2/4), 89% in GT3 (n=59/66) and 100% in GT6 (n=3/3). SVR12 in participants with GT3 and cirrhosis was 90%. No predictors of non-SVR12 were identified. There were 4 serious AEs including 1 death and 3 hepatic decompensation events. NS5A resistance-associated substitutions detected at baseline did not affect SVR12. Conclusion(s): This real-world study confirms high efficacy of SOF/VEL/VOX for the treatment of difficult-to-cure NS5A-inhibitor experienced patients, including those with GT3 and cirrhosis. Treatment was well tolerated in most; however, serious AEs can occur in those with advanced liver disease.Copyright © 2020 The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail

Background and Aim: Transient elastography with liver stiffness measurement (LSM) is known to correlate with liver fibrosis and liver-related outcomes. 4AGP is a new algorithm that uses indirect biomarkers to determine those who are at risk of elevated LSM (> 12.5 kPa). It is calculated using alpha-fetoprotein, albumin, aspartate aminotransferase, age, sex (gender), and platelet count. Although 4AGP correlates with elevated LSM in patients with chronic hepatitis C (CHC) virus infection, it is unknown whether it also predicts liver-related outcomes. We aimed to determine whether LSM or 4AGP, or other indirect biomarkers such as aspartate aminotransferase to platelet ratio index (APRI), Fibrosis-4 (FIB-4), or Forns index, can best predict liver-related outcomes in a cohort of patients with CHC. Method(s): The Community Approach Targeting Cirrhosis and Hepatocellular Carcinoma (CATCH) study is a prospective study that recruited patient with CHC. Baseline LSM and indirect biomarkers were assessed (all were before treatment), along with outcomes (hepatocellular carcinoma [HCC], decompensation, or liver-related death). Survival curves were analyzed using a log-rank test, along with receiver operator characteristic (ROC) curves and Cox proportional hazard ratios. Optimal cut-off points were calculated, accounting for sensitivity, specificity, false positives and negatives, as well as the area under the ROC curve (AUROC). Result(s): A total of 1049 patients with CHC were recruited between October 2014 and June 2018. Mean follow-up was 3.4 +/- 0.7 years, indicating 3631 patient-years. Patients' mean age was 45.1 years (19-82), and 31.3% were female. Seven patients developed HCC; the best predictors of HCC development were, in order, 4AGP, Forns index, FIB-4, LSM, and APRI (Fig. 1a). An LSM of 21.3 kPa was the optimal cut-off point for predicting HCC, with a sensitivity of 85.7%, specificity of 92.2%, and a hazard ratio (HR) of 30 (95% CI, 5.7-150). A 4AGP value of -2.81 had

Background and Aims: In clinical trials, salvage therapy including Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX) achieved an SVR12 rate of 96% in NS5A-experienced participants. An extended access program (EAP) for SOF/VEL/VOX was sponsored by Gilead Pharmaceuticals for Australian patients with advanced liver disease or prior liver transplantation (LT), who had relapsed. We determined the real-world efficacy and safety of this regimen in this cohort with advanced liver disease. Method(s): In this Australian multicentre EAP study, adult patients with chronic HCV infection genotype(GT)1-6 with prior failure on a DAA NS5A inhibitor containing regimen were eligible to access 12 weeks of SOF/VEL/VOX 400 mg/100 mg/100 mg. Other eligibility criteria included compensated liver disease with at least one of the following i) Child Pugh (CP)A cirrhosis with clinically significant portal hypertension or platelets <100 x 109/L, ii) prior LT, or iii) severe extra hepatic manifestations. Hospitals with >1 EAP recipient were invited to participate. Clinical characteristics and treatment outcomes were recorded at baseline, end-of-treatment (EOT) and SVR12. HCV NS5A RAS testing was performed prior to retreatment, where serum was available. The primary outcomes was SVR12 rate. Result(s): To date, baseline data is available for 89 patients from 24 participating hospitals. 85 have reached end-of-treatment (EOT), and 80 have SVR12 data available for analysis. Four patients have incomplete data due to early discontinuation of therapy (n = 2), loss to follow up (n = 1) and death (n = 1). 74 (83%) were male and the median age was 53. GT3 was the most common (n = 64), then GT1a (n = 18), GT1b (n = 4), GT6 (n = 2) and GT4 (n = 1). The median platelet count was 127. 68 (75%) had cirrhosis and of these, 35 (51%) had portal hypertension. 14 (16%) had prior hepatoma and 15 (17%) prior LT. All participants were NS5A-experienced and 8 (9%) had received?>1 DAA course (1-4). Three participants were

Abstract Background In clinical trials, hepatitis C virus (HCV) salvage treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) achieved an SVR12 rate of >95% in NS5A-experienced participants. Lower SVR12 rates have been reported in real-world studies, particularly for genotype (GT)3 infection and cirrhosis. We determined the efficacy and safety of SOF/VEL/VOX in a large real-world cohort. Methods We assessed the efficacy of salvage SOF/VEL/VOX for HCV infection in NS5A-inhibitor experienced participants with cirrhosis and portal hypertension, prior liver transplantation (LT) or severe extra-hepatic manifestations. SOF/VEL/VOX was available via an early access program. The primary outcome was SVR12. Secondary outcome was frequency of adverse events (AE). Findings Ninety-seven participants were included. Median age was 58, 82% were male, 78% had cirrhosis, most with portal hypertension (61%, n = 46/76), and 18% had prior-LT. Of the cirrhotic participants, 96% were Child-Turcotte-Pugh class A, and 4% were class B. Of the 72% with GT3, 76% were also cirrhotic. By intention-to-treat analysis, SVR12 rate was 85% (n = 82/97). Per protocol, the SVR12 rate was 90%, including 91% in GT1 (GT1a n = 18/18, GT1b n = 2/4), 89% in GT3 (n = 59/66) and 100% in GT6 (n = 3/3). SVR12 in participants with GT3 and cirrhosis was 90%. No predictors of non-SVR12 were identified. There were 4 serious AEs including 1 death and 3 hepatic decompensation events. NS5A resistance-associated substitutions detected at baseline did not affect SVR12. Conclusions This real-world study confirms high efficacy of SOF/VEL/VOX for the treatment of difficult-to-cure NS5A-inhibitor experienced patients, including those with GT3 and ci

BACKGROUND: In clinical trials, HCV salvage treatment with Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX) achieved an SVR12 rate of >95% in NS5A-experienced participants. Lower SVR12 rates have been reported in real-world studies, particularly for genotype (GT)3 infection and cirrhosis. We determined the efficacy and safety of SOF/VEL/VOX in a large real-world cohort. METHOD(S): We assessed the efficacy of salvage SOF/VEL/VOX for HCV infection in NS5A-inhibitor experienced participants with cirrhosis and portal hypertension, prior liver transplantation (LT) or severe extra-hepatic manifestations. SOF/VEL/VOX was available via an early access program. The primary outcome was SVR12. Secondary outcome was frequency of adverse events (AE). FINDINGS: Ninety-seven participants were included. Median age was 58, 82% were male, 78% had cirrhosis, most with portal hypertension (61%, n=46/76), and 18% had prior-LT. Of the cirrhotic participants, 96% were Child-Turcotte-Pugh class A and 4% were class B. Of the 72% with GT3, 76% were also cirrhotic. By intention-to-treat analysis, SVR12 rate was 85% (n=82/97). Per protocol, the SVR12 rate was 90%, including 91% in GT1 (GT1a n=18/18, GT1b n=2/4), 89% in GT3 (n=59/66) and 100% in GT6 (n=3/3). SVR12 in participants with GT3 and cirrhosis was 90%. No predictors of non-SVR12 were identified. There were four serious AEs including one death and three hepatic decompensation events. NS5A resistance-associated substitutions detected at baseline did not affect SVR12. CONCLUSION(S): This real-world study confirms high efficacy of SOF/VEL/VOX for the treatment of difficult-to-cure NS5A-inhibitor experienced patients, including those with GT3 and cirrhosis. Treatment was well tolerated in most however serious AEs can occur in those with advanced liver disease.Copyright © The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions

Background and Aim: The Community Approach Targeting Cirrhosis and Hepatocellular Carcinoma (CATCH) study is a large prospective community-based cohort of patients with viral hepatitis B and C (HBV/ HCV). The study aimed to detect patients with unrecognized cirrhosis using transient elastography liver stiffness measurement (LSM). The hypothesis was that this screening program could identify asymptomatic individuals with cirrhosis and identify those at risk of liver-related events and hepatocellular carcinoma (HCC). Method(s): Participants with either HBV or HCV were prospectively recruited from 23 primary care practices in Victoria. A hospital cohort of patients was also recruited and acted as a comparator group. All patients underwent clinical assessment, transient elastography LSM, and biochemical evaluation. Patients with LSM of >= 12.5 kPa or other features of advanced fibrosis were referred for non-general practitioner specialist care. Before December 2015, when direct-acting antivirals (DAAs) became available in Australia through Medicare, all patients with HCV and an LSM of > 8 kPa were also referred. All patients were invited for annual re-evaluation. Result(s): Between October 2014 and June 2018, a total of 1431 patients were recruited. There were 1049 patients with HCV (776 from the community and 273 from hospital) and 382 patients with HBV (294 from the community and 88 from hospital). Of the community HCV patients, 31.6% (245/776) were referred to specialist care due to an elevated LSM or other features of advanced fibrosis (93.5%, 229/245) or dual infection with HBV (6.5%, 16/245). Of the remaining 531 community patients with HCV, 75.3% (400/531) received DAA therapy via their GP, and 374 patients completed therapy as prescribed. Overall, 59% (237/400) had a confirmed sustained virological response (SVR), 4.3% (17/400) are known to have failed DAA therapy, and the remaining 36.5% have no documented SVR (146/400). At the last contact, there were 18.8% (1

Background and Aim: The aim of the Community Approach Targeting Cirrhosis and Hepatocellular Carcinoma (CATCH) study is to detect cirrhosis using transient elastography liver stiffness measurement (LSM) in a large community-based, prospective cohort of patients with hepatitis B virus (HBV) infection to identify asymptomatic individuals with cirrhosis and ensure appropriate hepatocellular carcinoma (HCC) screening. The aim of this substudy was to compare HCC screening patterns between general practitioners and non-GP specialists for patients without cirrhosis based on age, sex, ethnicity, and family history criteria and whether treatment plans for GPs change screening practices over time. Method(s): Participants with HBV infection were prospectively recruited from 23 primary care practices in Victoria. A hospital cohort of patients was also prospectively recruited and used as the comparator. All patients underwent clinical assessment, transient elastography LSM, and biochemical evaluation. Liver radiological evaluation using ultrasound (US) within the previous 12 months was recorded. Patients with LSM of > 8 kPa or other features of advanced fibrosis were referred for non-GP specialist care. All patients were invited for annual re-evaluation. For those patients with HBV who remained in GP care, a treatment plan was provided, with instructions regarding HCC screening requirements based on age, sex, ethnicity, and family history. Follow-up data included US use within the 12 months before their last follow up; only patients without cirrhosis or known liver lesions were included to ensure that the GP and non-GP specialist groups were similar. The HCC screening practices were then compared between GP management and non-GP specialist management. Result(s): Between October 2014 and June 2018, a total of 382 patients with HBV were recruited (294 from the community and 88 from a tertiary center). Of these, 54.2% (207/382) qualified for HCC screening: 26.6% (55/ 207) based on

Chronic hepatitis B (CHB) is a major health problem worldwide and is associated with significant long-term morbidity and mortality. The hepatitis B virus (HBV) is a hepatotropic virus that is capable of integrating in the host nucleus permanently resulting in lifelong infection. To date, there is no definitive cure for HBV, as our current treatments cannot eradicate the viral reservoir that has integrated in the liver. Elucidating the immunopathogenesis is key to finding a therapeutic target for HBV as the virus is not in itself cytopathic but the immune response to the virus causes the majority of the cellular injury. In most cases, the virus reaches a state of equilibrium with low viral replication constrained by host immunity. Multiple cytokines have been implicated in the pathogenesis of CHB. Tumor necrosis factor (TNF) has emerged as a key player; on one hand it can facilitate immune-mediated virological control but on the other hand it can cause collateral hepatocyte damage, cirrhosis and possibly promote hepatocellular carcinoma. In this review, we discuss the current understanding of the immunopathogenesis of HBV, focusing on TNF and whether it can be harnessed in therapeutic strategies to cure HBV infection.

Introduction: The protease inhibitors (PIs) telaprevir (TVR) and boceprevir (BOC) were PBS-listed in April 2013. Both drugs significantly improve rates of SVR, but are associated with additional morbidity. Recent data suggest that adverse events (AEs) may be more common in real world practice than was observed in the registration studies, particularly in patients with cirrhosis1. The Australian experience in the use of these triple therapy regimens has not been previously reported. In this study we present the combined experience of adverse events (AEs) associated with PI therapy at two large treatment centres in Melbourne. Method(s): Treatment experience with TVR or BOC-based regimens at St Vincent's Hospital Melbourne and Monash Medical Centre was collected in comprehensive HCV databases, including baseline patient characteristics, on-treatment virological responses and adverse events (AEs). Advanced liver fibrosis was defined as a composite of histology (METAVIR F3-4) and transient elastography (>9.5 kPa). We considered the following AEs: on-treatment anemia (endpoints - haemoglobin (Hb) reduction of >3 g/dL from baseline, Hb < 10 g/dL, RBV dose reduction, blood transfusion), clinically significant rash (indicated by need for topical steroid treatment), treatment discontinuation, need for hospitalization, and death. Result(s): 150 patients have started DAA treatment (BOC, n = 80 and TVR, n = 70). Patients were older (mean 51 yrs), male (69%), and advanced fibrosis was common (50%). 34% had previously failed pIFN plus RBV therapy. No patient had Child-Pugh B or C cirrhosis. Baseline characteristics were similar for BOC and TVR-treated patients. At the time of submission, 64% remained on treatment. Adverse events were common. Comparison of the rates of anemia, anemia complications and rash are presented in Table 1. Among BOC-treated patients, 10 (13%) patients stopped treatment due to AEs: severe depression (n = 2), refractory insomnia (n = 1), and profound letharg

Introduction: The introduction of direct-acting antivirals (DAAs) has resulted in increasing numbers of patients with genotype 1 HCV receiving triple therapy. The majority of data relating to treatment experience has originated from Europe or North America, with a paucity of data from Australia.We aimed to evaluate the treatment efficacy of Telaprevir (TVR) and Boceprevir (BOC) based triple therapy in a uniquely Australian population, more reflective of real-world clinical practice. Method(s): A retrospective observational analysis was conducted in two large tertiary referral centres. Patients receiving Telaprevir (TVR) or Boceprevir (BOC) combined with peginterferon-alpha-2a/2b and ribavirin (PR) were identified via electronic hospital databases. Demographic, clinical and virological data were then collected through medical and pathology records. Advanced liver fibrosis was characterised by histology (METAVIR 3-4) and/or transient elastography (>9.5 kPa). Virological response (VR) was defined as undetectable HCV RNA using a sensitive quantitative PCR assay. Result(s): In this interim analysis, a total of 153 patients (BOCN = 80,TVR N = 73) at different stages of treatment were included. The majority were male (63%) and Caucasian (65%), with mean age of 51 years. Advanced fibrosis was present in 51% and 27% had prior PR treatment. The IL28B genotype distribution was 38% CC, 50% CT and 12% TT. HCV Genotype distribution comprised 68% 1a, 27% 1b and 5% 6C-1. 50% were eligible for response guided therapy. 54% of the BOC group and 37% of the TVR group had completed the prescribed treatment course at the time of submission. Baseline characteristics were comparable between both groups. Table 1 presents an interim analysis of virological responses and early discontinuation rates for each drug. Virological responses were consistently lower in cirrhotic patients at all time-points for both drugs. 37/153 (24%) stopped treatment early, 14% due to treatment futility and 10% due