A randomised controlled trial of Standard Of Care versus RadioAblaTion in Early Stage HepatoCellular Carcinoma (SOCRATES HCC).

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.

High end-of-treatment hepatitis B core-related antigen levels predict hepatitis flare after stopping nucleot(s)ide analogue 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.

Screening patients in general practice for advanced chronic liver disease using an innovative IT solution: The Liver Toolkit.

BACKGROUND: Identifying patients with undiagnosed advanced chronic liver disease (ACLD) is a public health challenge. Patients with advanced fibrosis or compensated cirrhosis have much better outcomes than those with decompensated disease and may be eligible for interventions to prevent disease progression. METHODS: A cloud-based software solution ("the Liver Toolkit") was developed to access primary care practice software to identify patients at risk of ACLD. Clinical history and laboratory results were extracted to calculate aspartate aminotransferase-to-platelet ratio index and fibrosis 4 scores. Patients identified were recalled for assessment, including Liver Stiffness Measurement (LSM) via transient elastography. Those with an existing diagnosis of cirrhosis were excluded. RESULTS: Existing laboratory results of more than 32,000 adults across nine general practices were assessed to identify 703 patients at increased risk of ACLD (2.2% of the cohort). One hundred seventy-nine patients (26%) were successfully recalled, and 23/179 (13%) were identified to have ACLD (LSM ≥10.0 kPa) (10% found at indeterminate risk [LSM 8.0-9.9 kPa] and 77% low risk of fibrosis [LSM <8.0 kPa]). In most cases, the diagnosis of liver disease was new, with the most common etiology being metabolic dysfunction-associated steatotic liver disease (n=20, 83%). Aspartate aminotransferase-to-platelet ratio index ≥1.0 and fibrosis 4 ≥3.25 had a positive predictive value for detecting ACLD of 19% and 24%, respectively. Patients who did not attend recall had markers of more severe disease with a higher median aspartate aminotransferase-to-platelet ratio index score (0.57 vs. 0.46, p=0.041). CONCLUSIONS: This novel information technology system successfully screened a large primary care cohort using existing laboratory results to identify patients at increased risk ACLD. More than 1 in 5 patients recalled were found to have liver disease requiring specialist follow-up.

Different Patterns of Care and Survival Outcomes in Transplant-Centre Managed Patients with Early-Stage HCC: Real-World Data from an Australian Multi-Centre Cohort Study.

The management of early-stage hepatocellular carcinoma (HCC) is complex, with multiple treatment strategies available. There is a paucity of literature regarding variations in the patterns of care and outcomes between transplant and non-transplant centres. We conducted this real-world multi-centre cohort study in two liver cancer referral centres with an integrated liver transplant program and an additional eight non-transplant HCC referral centres across Australia to identify variation in patterns of care and key survival outcomes. Patients with stage Barcelona Clinic Liver Cancer (BCLC) 0/A HCC, first diagnosed between 1 January 2016 and 31 December 2020, who were managed at a participating site, were included in the study. Patients were excluded if they had a history of prior HCC or if they received upfront liver transplantation. A total of 887 patients were included in the study, with 433 patients managed at a liver cancer centre with a transplant program (LTC) and 454 patients managed at a non-transplant centre (NTC). Management at an LTC did not significantly predict allocation to resection (adjusted OR 0.75, 95% CI 0.50 to 1.11, p = 0.148). However, in those not receiving resection, LTC and NTC patients were systematically managed differently, with LTC patients five times less likely to receive upfront ablation than NTC patients (adjusted OR 0.19, 95% CI 0.13 to 0.28, p < 0.001), even after adjusting for tumour burden, as well as for age, gender, liver disease aetiology, liver disease severity, and medical comorbidities. LTCs exhibited significantly higher proportions of patients undergoing TACE for every tumour burden category, including those with a single tumour measuring 2 cm or less (p < 0.001). Using multivariable Cox proportional hazards analysis, management at a transplant centre was associated with reduced all-cause mortality (adjusted HR 0.71, 95% CI 0.51 to 0.98, p = 0.036), and competing-risk regression analysis, considering liver transplant as a competing event, demonstrated a similar reduction in risk (adjusted HR 0.70, 95% CI 0.50 to 0.99, p = 0.041), suggesting that the reduced risk of death is not fully explained by higher rates of transplantation. Our study highlights systematic differences in HCC care between large volume liver transplant centres and other sites, which has not previously been well-described. Further work is needed to better define the reasons for differences in treatment allocation and to aim to minimise unwarranted treatment variation to maximise patient outcomes across Australia.

Real-World Data on the Diagnosis, Treatment, and Management of Hepatocellular Carcinoma in the Asia-Pacific: The INSIGHT Study.

Introduction: Hepatocellular carcinoma (HCC) is the sixth most commonly diagnosed cancer and the third leading cause of cancer death worldwide. While there has been rapid evolution in the treatment paradigm of HCC across the past decade, the extent to which these newly approved therapies are utilized in clinical practice in the real world is, however, unknown. The INSIGHT study was an investigator-initiated, multi-site longitudinal cohort study conducted to reflect real-world epidemiology and clinical practice in Asia-Pacific in the immediate 7-year period after the conclusion of the BRIDGE study. Methods: Data were collected both retrospectively (planned 30% of the total cohort size) and prospectively (planned 70%) from January 2013 to December 2019 from eligible patients newly diagnosed with HCC from 33 participating sites across 9 Asia-Pacific countries. Results: A total of 2,533 newly diagnosed HCC patients (1,052 in retrospective cohort and 1,481 in prospective cohort) were enrolled. The most common risk factor was hepatitis B in all countries except Japan, Australia, and New Zealand, where the prevalence of hepatitis C and diabetes were more common. The top three comorbidities reported in the INSIGHT study include cirrhosis, hypertension, and diabetes. We observe high heterogeneity in the first-line treatment recorded across countries and across disease stages, which significantly affects survival outcomes. Stratification by factors such as etiologies, tumor characteristics, the presence of extrahepatic metastases or macrovascular invasion, and the use of subsequent lines of treatment were performed. Conclusion: The INSIGHT study describes a wide spectrum of clinical management practices in HCC, where patient demographics, differential costs, and patient access to therapies may lead to wide geographical variations through the patient's treatment cycle, from diagnosis to clinical outcome. The high heterogeneity in patient outcomes demonstrates the need for more robust and clinical management strategies to be designed and adopted to bring about better patient outcomes.

Low rate of surgical site infections after liver transplantation: A 5-year retrospective cohort study.

BACKGROUND: Surgical site infection (SSI) after liver transplant (LT) is common, but no studies have been conducted in Australia. The purpose of this study was to determine the proportion of patients who developed an SSI post-LT in Australia's largest LT unit. METHODS: This was a single-center retrospective cohort study. We included all LT recipients who were aged 18 years or more and received their transplant between March 1, 2018 and April 1, 2023. The primary outcome was to determine the proportion of LT recipients who developed an SSI within 30 days of transplantation. RESULTS: There were 404 LTs performed during the study period, and 375 met inclusion criteria. Of these, 8% (n = 31/375) developed an SSI and were classified as superficial (3%, n = 12/375) or deep/organ space (5%, n = 19/375). The most common antibiotics used for prophylaxis were amoxicillin/clavulanate (75%, n = 281/375), followed by piperacillin/tazobactam (17%, n = 62/375). Independent risk factors associated with the development of SSI were Roux-en-Y hepaticojejunostomy (aOR 3.16, 95% CI 1.17-8.28, p = .02), operative time (per 60-min increment) (aOR 1.23, 95% CI 1.02-1.48), and re-operation (aOR 4.16, 95% CI 1.81-9.58, p < .01). Type of antibiotic received perioperatively was not significantly associated with SSI. CONCLUSION: SSI occurred in 8% of LT recipients and was predominantly related to operation-related factors rather than patient- or antibiotic-related factors.

Global prevalence of MAFLD-related hepatocellular carcinoma: A systematic review and meta-analysis.

BACKGROUND & AIMS: The global proportion of hepatocellular carcinoma (HCC) attributable to metabolic dysfunction-associated fatty liver disease (MAFLD) is unclear. The MAFLD diagnostic criteria allows objective diagnosis in the presence of steatosis plus defined markers of metabolic dysfunction, irrespective of concurrent liver disease. We aimed to determine the total global prevalence of MAFLD in HCC cohorts (total-MAFLD), including the proportion with MAFLD as their sole liver disease (single-MAFLD), and the proportion of those with concurrent liver disease where MAFLD was a contributary factor (mixed-MAFLD). METHODS: This systematic review and meta-analysis included studies systematically ascertaining MAFLD in HCC cohorts, defined using international expert panel criteria including ethnicity specific BMI cut-offs. A comparison of clinical and tumour characteristics was performed between single-MAFLD, mixed-MAFLD and non-MAFLD HCC. RESULTS: 22 studies (56,565 individuals with HCC) were included. Total and single-MAFLD HCC prevalence was 48.7% (95% CI; 34.5% - 63.0%) and 12.4% (95% CI; 8.3% - 17.3%), respectively. In HCC due to chronic hepatitis B, C and alcohol-related liver disease, mixed-MAFLD prevalence was 40.0% (95% CI; 30.2% - 50.3%), 54.1% (95% CI; 40.4% - 67.6%) and 64.3% (95% CI; 52.7% - 75.0%), respectively. Mixed-MAFLD HCC had significantly higher likelihood of cirrhosis and lower likelihood of metastatic spread compared to single-MAFLD HCC, and a higher platelet count and lower likelihood of macrovascular invasion compared to non-MAFLD HCC. CONCLUSION: MAFLD is common as a sole aetiology, but more so and as a co-factor in mixed-aetiology HCC, supporting the use of a positive diagnostic criteria.

Incidence, epidemiology, and outcomes of acute allograft rejection following liver transplantation in Australia.

Acute allograft rejection is a well-known complication of liver transplantation (LT). The incidence, epidemiology, and outcomes of acute rejection have not been well described in Australia. We retrospectively studied consecutive adults who underwent deceased donor LT at a single center between 2010 and 2020. Donor and recipient data at the time of LT and recipient outcomes were collected from a prospective LT database. Liver biopsy reports were reviewed, and only a graft's first instance of biopsy-proven acute rejection was analyzed. During the study period, 796 liver transplants were performed in 770 patients. Biopsy-proven rejection occurred in 34.9% of transplants. There were no significant changes in the incidence of rejection over time (linear trend p =0.11). The median time to the first episode of rejection was 71 days after LT: 2.2% hyperacute, 50.4% early (≤90 d), and 47.5% late rejection (>90 d). Independent risk factors for rejection were younger recipient age at transplant (aHR 0.98 per year increase, 95% CI: 0.97-1.00, p =0.01), and ABO-incompatible grafts (aHR 2.55 vs. ABO-compatible, 95% CI: 1.27-5.09, p <0.01) while simultaneous multiorgan transplants were protective (aHR 0.21 vs. LT only, 95% CI: 0.08-0.58, p <0.01). Development of acute rejection (both early and late) was independently associated with significantly reduced graft (aHR 3.13, 95% CI: 2.21-4.42, p <0.001) and patient survival (aHR 3.42, 95% CI: 2.35-4.98, p <0.001). In this 11-year Australian study, acute LT rejection occurred in 35%, with independent risk factors of younger recipient age and ABO-incompatible transplant, while having a simultaneous multiorgan transplant was protective. Acute rejection was independently associated with reduced graft and patient survival after adjustment for other factors.

Hepatitis C Virus Antiviral Drug Resistance and Salvage Therapy Outcomes Across Australia.

Background: Hepatitis C virus (HCV) infection can now be cured with well-tolerated direct-acting antiviral (DAA) therapy. However, a potential barrier to HCV elimination is the emergence of resistance-associated substitutions (RASs) that reduce the efficacy of antiviral drugs, but real-world studies assessing the clinical impact of RASs are limited. Here, an analysis of the impact of RASs on retreatment outcomes for different salvage regimens in patients nationally who failed first-line DAA therapy is reported. Methods: We collected data from 363 Australian patients who failed first-line DAA therapy, including: age, sex, fibrosis stage, HCV genotype, NS3/NS5A/NS5B RASs, details of failed first-line regimen, subsequent salvage regimens, and treatment outcome. Results: Of 240 patients who were initially retreated as per protocol, 210 (87.5%) achieved sustained virologic response (SVR) and 30 (12.5%) relapsed or did not respond. The SVR rate for salvage regimens that included sofosbuvir/velpatasvir/voxilaprevir was 94.3% (n = 140), sofosbuvir/velpatasvir 75.0% (n = 52), elbasvir/grazoprevir 81.6% (n = 38), and glecaprevir/pibrentasvir 84.6% (n = 13). NS5A RASs were present in 71.0% (n = 210) of patients who achieved SVR and in 66.7% (n = 30) of patients who subsequently relapsed. NS3 RASs were detected in 20 patients (20%) in the SVR group and 1 patient in the relapse group. NS5B RASs were observed in only 3 patients. Cirrhosis was a predictor of relapse after retreatment, as was previous treatment with sofosbuvir/velpatasvir. Conclusions: In our cohort, the SVR rate for sofosbuvir/velpatasvir/voxilaprevir was higher than with other salvage regimens. The presence of NS5A, NS5B, or NS3 RASs did not appear to negatively influence retreatment outcomes.

Drug-induced liver injury from selective androgen receptor modulators, anabolic-androgenic steroids and bodybuilding supplements in Australia.

BACKGROUND: Reports of DILI due to herbal and dietary supplements have been increasing over time. AIMS: To characterise clinical, laboratory and histopathological phenotypes and outcomes of drug-induced liver injury (DILI) due to anabolic-androgenic steroids (AAS), selective androgen receptor modulators (SARMs), and bodybuilding supplements (BBS) in Australia. METHODS: Retrospective case series. Patients presented to nine Australian tertiary hospitals, 2017-2023. DILI was defined biochemically and patients were included if their treating physician attributed DILI to preceding use of AAS, SARMs or BBS. Primary endpoint was time to normalisation of liver biochemistry. Secondary endpoints were hospitalisation for investigation or management of DILI, death attributable to liver injury, and liver transplantation. RESULTS: Twenty-three cases of DILI were identified, involving 40 drugs: 18 AAS, 14 SARMs and eight BBS. Patients were predominantly male (22/23), with median age 30 years (IQR 26-42). Most were symptomatic (21/23). Median latency of onset was 58 days (IQR 28-112 days) from drug commencement. Most patients (17/23) were admitted to hospital. Based on updated Roussel Uclaf Causality Assessment Method, DILI was possible in 17/23, probable in 2/23 and unlikely in 4/23. Median time to normalisation of liver biochemistry was 175 days (IQR 70-292 days) from presentation. Three (3/23) were treated with corticosteroids, 14/23 were treated for itch, and one (1/23) underwent liver transplantation. There were no deaths. CONCLUSIONS: The prognosis of DILI from AAS, SARMs and BBS is good although liver transplantation may rarely be required. A detailed drug history is important in uncovering DILI due to these supplements.

Impact of Share 35 liver transplantation allocation in Australia and New Zealand.

Patients with high model for end-stage liver disease (MELD) scores waiting for liver transplantation in Australia and New Zealand (ANZ) have had limited access to deceased donor livers and therefore binational sharing of livers, for patients with a MELD score ≥35 was introduced in February 2016. Waiting list mortality, post-transplant outcomes and intention-to-treat survival were compared between patients whose MELD score reached 35 on the waiting list between October 2013 and April 2015 (Pre-Share 35 group, n = 23) and patients who were Share 35 listed between February 2016 and May 2022 (Share 35 group, n = 112). There was significantly reduced waiting list mortality in share 35 listed patients in comparison to the pre-Share 35 group (11.7% vs. 52.2%, OR .120 95% CI .044-.328, P < .001). Post-transplant patient and graft survival were not significantly different between the groups (5-year patient survival 82% vs. 84%, P = .991, 5-year graft survival 82% vs. 76%, P = .543). Intention-to-treat survival was superior in the Share 35 group (HR .302, 95% CI .149-.614, P < .001). Introduction of Share 35 in ANZ resulted in a 78% risk reduction in waiting list mortality, equivalent post-transplant survival and an improvement in intention-to-treat survival.

Broadening and strengthening the health providers caring for patients with chronic hepatitis C may improve continuity of care.

BACKGROUND: Direct-acting antiviral (DAA) therapies for hepatitis C virus infection (HCV) lead to excellent rates of sustained virological response (SVR). However, loss to follow-up (LTFU) for SVR testing remains a challenge. We examine factors associated with LTFU in a real-world setting. METHODS: Adults who received DAA therapy for HCV in one of 26 centers across Australia during 2016-2021 were followed up for 2 years. Data sources included the patient medical records and the national Pharmaceutical and Medicare Benefits Schemes. Linkage to Medicare provided utilization data of other health-care providers and re-treatment with DAAs. LTFU was defined as no clinic attendance for SVR testing by at least 52 weeks after DAA treatment commencement. Multivariable logistic regression assessed factors associated with LTFU. RESULTS: In 3619 patients included in the study (mean age 52.0 years; SD = 10.5), 33.6% had cirrhosis (69.4% Child-Pugh class B/C), and 19.3% had HCV treatment prior to the DAA era. Five hundred and fifteen patients (14.2%) were LTFU. HCV treatment initiation in 2017 or later (adj-OR = 2.82, 95% confidence interval [CI] 2.25-3.54), younger age (adj-OR = 2.63, 95% CI 1.80-3.84), Indigenous identification (adj-OR = 1.99, 95% CI 1.23-3.21), current injection drug use or opioid replacement therapy (adj-OR = 1.66, 95% CI 1.25-2.20), depression treatment (adj-OR = 1.49, 95% CI 1.17-1.90), and male gender (adj-OR = 1.31, 95% CI 1.04-1.66) were associated with LTFU. CONCLUSIONS: These findings stress the importance of strengthening the network of providers caring for patients with HCV. In particular, services targeting vulnerable groups of patients such as First Nations Peoples, youth health, and those with addiction and mental health disorders should be equipped to treat HCV.

Improved Survival Outcomes with Surgical Resection Compared to Ablative Therapy in Early-Stage HCC: A Large, Real-World, Propensity-Matched, Multi-Centre, Australian Cohort Study.

The optimal treatment approach in very-early and early-stage hepatocellular carcinoma (HCC) is not precisely defined, and there is ambiguity in the literature around the comparative efficacy of surgical resection versus ablation as curative therapies for limited disease. We performed this real-world propensity-matched, multi-centre cohort study to assess for differences in survival outcomes between those undergoing resection and those receiving ablation. Patients with Barcelona Clinic Liver Cancer (BCLC) 0/A HCC first diagnosed between 1 January 2016 and 31 December 2020 who received ablation or resection as initial treatment were included in the study. A total of 450 patients were included in the study from 10 major liver centres including two transplant centres. Following propensity score matching using key covariates, 156 patients were available for analysis with 78 in each group. Patients who underwent resection had significantly improved overall survival (log-rank test p = 0.023) and local recurrence-free survival (log rank test p = 0.027) compared to those who received ablation. Based on real-world data, our study supports the use of surgical resection in preference to ablation as first-line curative therapy in appropriately selected BCLC 0/A HCC patients.

BK viraemia as a cause of anaemia in after ABO-incompatible liver transplant: a case report.

BACKGROUND: While anaemia following liver transplant is common, anaemia in the context of BK viraemia is not a commonly recognised phenomenon. CASE PRESENTATION: We present the case of 59-year old gentleman with severe anaemia in the context of BK viraemia and nephropathy following ABO incompatible liver transplant. Severity of anaemia appeared to correlate with high titres of BK virus in the serum. Bone marrow biopsy revealed hypocellular marrow with normal cytogenetics. Anaemia improved with treatment with cidofovir, intravenous immunoglobulin, reduction in immunosuppression and erythropoietin stimulating agent. CONCLUSION: To our knowledge, this is the first case of anaemia post liver transplant contributed to by BK viraemia.

Vessels that encapsulate tumour clusters vascular pattern in hepatocellular carcinoma.

Vessels that encapsulate tumour clusters (VETC) is a distinct histologic vascular pattern associated with a novel mechanism of metastasis. First described in human cancers in 2004, its prevalence and prognostic significance in hepatocellular carcinoma (HCC) has only been appreciated in the past decade with a rapidly increasing body of literature. A robust biomarker of aggressive disease, the VETC pattern is easy to recognise but relies on histologic examination of tumour tissue for its diagnosis. Radiological recognition of the VETC pattern is an area of active research and is becoming increasingly accurate. As a prognostic marker, VETC has consistently proven to be an independent predictor of disease recurrence and overall survival in patients with HCC undergoing resection and liver transplantation. It can also guide treatment by predicting response to other therapies such as transarterial chemoembolisation and sorafenib. Without prospective randomised-controlled trials or routine evaluation of VETC in clinical practice, there are currently no firm treatment recommendations for VETC-positive tumours, although some perspectives are provided in this review based on the latest knowledge of their pathogenesis - a complex interplay between tumour angiogenesis and the immune microenvironment. Nevertheless, VETC has great potential as a future biomarker that could take us one step closer to precision medicine for HCC.

Baseline serum HBV RNA is associated with the risk of hepatitis flare after stopping nucleoside analog therapy in HBeAg-negative participants.

BACKGROUND AND AIMS: HBV RNA in peripheral blood reflects HBV cccDNA transcriptional activity and may predict clinical outcomes. The prospective Melbourne HBV-STOP trial studied nucleot(s)ide analog discontinuation in HBeAg-negative non-cirrhotic participants with long-term virological suppression. Ninety-six weeks after stopping treatment, the proportion of participants with virological relapse (HBV DNA > 2000 IU/mL), biochemical relapse (ALT > 2 × ULN and HBV DNA > 2000 IU/mL), or hepatitis flare (ALT > 5 × ULN and HBV DNA > 2000 IU/mL) was 89%, 58%, and 38%, respectively. We evaluated the ability of serum HBV RNA levels to predict these outcomes. APPROACH RESULTS: HBV RNA levels were measured using the Roche cobas 6800/8800 HBV RNA Investigational Assay. Sixty-five participants had baseline and longitudinal off-treatment specimens available for RNA testing. HBV RNA was detectable at baseline in 25% of participants and was associated with a higher risk of biochemical relapse (81% vs. 51%, p value 0.04) and hepatitis flare (63% vs. 31%, p value 0.04). Participants who had undetectable serum HBV RNA as well as HBsAg ≤ 100 IU/mL at baseline were less likely to experience virological relapse (4 of 9, 44%) than participants with detectable HBV RNA and HBsAg level > 100 IU/mL (15/15, 100%; p value 0.0009). Off-treatment levels of HBV RNA were correlated with HBV DNA and were associated with the risk of hepatitis flare. CONCLUSIONS: Serum HBV RNA may be a useful biomarker for guiding clinical decision-making before stopping nucleot(s)ide analog therapy. Baseline HBV RNA and HBsAg levels are associated with the risk of clinical relapse, hepatitis flare, and disease remission off-treatment.

Epidemiology, characteristics, and outcomes of patients with acute-on-chronic liver failure in Australia.

BACKGROUND AND AIM: Acute-on-chronic liver failure (ACLF) is distinct from acute decompensation (AD) of cirrhosis in its clinical presentation, pathophysiology, and prognosis. There are limited published Australian ACLF data. METHODS: We performed a single-center retrospective cohort study of all adults with cirrhosis admitted with a decompensating event to a liver transplantation (LT) centre between 2015 and 2020. ACLF was defined using the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) definition while those who did not meet the definition were classified as AD. The primary outcome of interest was 90-day LT-free survival. RESULTS: A total of 615 patients had 1039 admissions for a decompensating event. On their index admission, 34% (209/615) of patients were classified as ACLF. Median admission model for end-stage liver disease (MELD) and MELD-Na scores were higher in ACLF patients compared with AD (21 vs 17 and 25 vs 20 respectively, both P < 0.001). Both the presence and severity of ACLF (grade ≥ 2) significantly predicted worse LT-free survival compared with patients with AD. The EASL-CLIF ACLF score (CLIF-C ACLF), MELD and MELD-Na scores performed similarly in predicting 90-day mortality. Patients with index ACLF had a higher risk of 28-day mortality (28.1% vs 5.1%, P < 0.001) and shorter times to readmission compared with those with AD. CONCLUSION: ACLF complicates over a third of hospital admissions for cirrhosis with decompensating events and is associated with a high short-term mortality. The presence and grade of ACLF predicts 90-day mortality and should be identified as those at greatest risk of poor outcome without intervention such as LT.

Wide variation in pre-procedural blood product transfusion practices in cirrhosis: a national multidisciplinary survey.

BACKGROUND AND AIMS: Recent guidelines recognize the limitations of standard coagulation tests in predicting bleeding and guiding pre-procedural blood component prophylaxis in cirrhosis. It is unclear whether these recommendations are reflected in clinical practice. We performed a nationwide survey to investigate pre-procedural transfusion practices and opinions of key health care stakeholders involved in managing cirrhosis. METHODS: We designed a 36-item multiple-choice questionnaire to investigate the international normalized ratio and platelet cutoffs utilized to guide pre-procedural transfusion of fresh frozen plasma and platelets in patients with cirrhosis undergoing a range of low and high-risk invasive procedures. Eighty medical colleagues from all mainland States involved in managing patients with cirrhosis were invited by email to participate. RESULTS: Overall, 48 specialists across Australia completed the questionnaire: 21 gastroenterologists, 22 radiologists, and 5 hepatobiliary surgeons. 50% of respondents reported that their main workplace did not have written guidelines relating to pre-procedural blood component prophylaxis in patients with cirrhosis. There was marked variation in routine prophylactic transfusion practices across institutions for the different procedures and international normalized ratio and platelet cutoffs. This variation was present both within and between specialty groups and held for both low and high-risk procedures. For scenarios where the platelet count was ≤ 50 × 109/L, 61% of respondents stated that prophylactic platelet transfusions would be given before low-risk and 62% before high-risk procedures at their center. For scenarios where the international normalized ratio was ≥2, 46% of respondents stated that prophylactic fresh frozen plasma would be routinely given before low-risk procedures and 74% before high-risk procedures. CONCLUSION: Our survey reveals significant heterogeneity of pre-procedural prophylactic transfusion practices in patients with cirrhosis and discrepancies between guidelines and clinical practice.