Alcohol does not impact chronic hepatitis C treatment outcomes but increases risk for progressive liver disease: Findings from a prospective multicentre Australian study (OPERA-C).

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.

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.

Human Amniotic Epithelial Cell Transplantation is Safe and Well Tolerated in Patients with Compensated Cirrhosis: A First-in-Human Trial.

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).

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.

Time-Restricted Fasting Improves Liver Steatosis in Non-Alcoholic Fatty Liver Disease-A Single Blinded Crossover Trial.

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.

Local fistula injection of allogeneic human amnion epithelial cells is safe and well tolerated in patients with refractory complex perianal Crohn's disease: a phase I open label study with long-term follow up.

BACKGROUND: Local fistula injection of mesenchymal stromal/stem cells (MSC) is effective for complex perianal Crohn's fistulas but is also expensive and requires specialised facilities for cell revival before administration. Human amnion epithelial cells (hAEC) are non-MSC cells with therapeutic properties. The primary aim of this study was safety of hAEC therapy. Secondary aims included hAEC efficacy, feasibility of the protocol and impact on quality of life. METHODS: A phase I open label study of ten adults with active complex Crohn's perianal fistulas refractory to conventional treatment, including anti-tumour necrosis factor alpha therapy, was undertaken. A single dose of hAEC was injected into the fistula tract(s) after surgical closure of the internal opening(s). Study outcomes were assessed at week 24 with follow up for at least 52 weeks. FINDINGS: Local injection of hAEC was safe, well tolerated and the injection procedure was feasible. Complete response occurred in 4 patients, and a partial response in an additional 4 patients. There was a mean reduction in the Perianal Disease Activity Index of 6.5 points (95% CI -9.0 to -4.0, p = 0.0002, paired t-test), modified Van Assche MRI Index of 2.3 points (95% CI -3.9 to -0.6, p = 0.012, paired t-test) and a mean improvement of 15.8 points (95% CI 4.9 to 26.8, p = 0.010, paired t-test) in quality of life using the Short IBD-Questionnaire in complete responders. INTERPRETATION: Local injection of hAEC therapy for refractory complex perianal fistulising Crohn's disease appears safe, well-tolerated, feasible and demonstrated improvement. Quality of life is improved in those who achieve complete fistula healing. FUNDING: This study was funded by competitive research grant funding from the Gastroenterological Society of Australia Seed Grant 2018.

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.

First-in-human randomized study of RNAi therapeutic RG6346 for chronic hepatitis B virus infection.

BACKGROUND & AIMS: RG6346 is an N-acetyl-D-galactosamine (GalNAc)-conjugated, double-stranded RNA interference agent targeting the HBV genome S-region. We investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RG6346 in healthy volunteers and patients with chronic HBV infection (CHB). METHODS: This first-in-human, adaptive, randomized, double-blinded, phase I study recruited three groups of participants: Group A, 30 healthy volunteers received single-dose RG6346 at 0.1, 1.5, 3.0, 6.0, or 12.0 mg/kg, or placebo; Group B, nucleos(t)ide analogue-naïve participants with CHB received single-dose RG6346 at 3.0 mg/kg (n = 6) or placebo (n = 3); Group C, participants with nucleos(t)ide-suppressed CHB received four doses (every 28 days) of RG6346 at 1.5, 3.0, or 6.0 mg/kg (n = 4 in each cohort) or placebo (n = 6). RESULTS: RG6346 treatment for up to 4 months was safe and well tolerated. The most common adverse event was a mild injection site reaction. Several nucleos(t)ide-naïve participants exhibited self-resolving transaminase elevations with preserved liver function. By the end of RG6346 treatment in Group C (Day 112), the mean reduction from baseline in hepatitis B surface antigen (HBsAg) was 1.39, 1.80, and 1.64 log10 IU/ml in the 1.5, 3.0, and 6.0 mg/kg cohorts, respectively. Of the 12 participants in Group C, 11 (91.7%) achieved a ≥1 log10 IU/ml reduction in HBsAg (3 of 11 [27.3%] had the response sustained at conditional follow-up Day 448). No dose-response relationship was apparent between RG6346 and serum HBsAg levels. The RG6346-induced HBsAg response was independent of hepatitis B e antigen status. Moderate-to-marked sustained reductions of hepatitis B core-related antigen, HBV RNA, HBV DNA (in nucleos[t]ide analogue-naïve participants), and hepatitis B e antigen levels were observed. CONCLUSIONS: These favorable safety and pharmacodynamic data support the clinical development of RG6346 as the backbone of a finite antiviral treatment regimen, with the goal of sustained HBsAg loss (functional cure) in patients with CHB. CLINICAL TRIAL NUMBER: ClinicalTrials.gov NCT03772249. IMPACT AND IMPLICATIONS: Currently available therapies for chronic HBV infection are associated with low rates of functional cure and new, more efficacious treatments are needed. This first-in-human study of RG6346, an RNA interference therapy, showed a favorable safety profile as well as marked and durable reductions in hepatitis B surface antigen levels. These results support the continued development of RG6346 as the backbone of a finite treatment regimen targeting high functional cure rates and are important for HBV researchers and physicians.

Hepatitis C virus in people with serious mental illness: an analysis of the care cascade at a tertiary health service with a pilot 'identify and treat' strategy.

BACKGROUND: People with serious mental illness (SMI) are underserved from a hepatitis C virus (HCV) screening and treatment perspective. AIMS: To examine the HCV care cascade in people with SMI and to pilot a supported HCV treatment integration programme. METHODS: HCV prevalence was retrospectively analysed from 4492 consecutive individuals admitted to a tertiary hospital mental health service between January 2017 and December 2018. Subcohort analysis of screening patterns and predictors of seropositive infection was performed. Referral pathways and community care integration were analysed for HCV-positive individuals, and a prospective community-based 'identify and treat' HCV programme was assessed. RESULTS: Screening for HCV had been performed in 18.6% (835/4492) of the cohort. Seroprevalence was 4.6% (207/4492). HCV seropositivity was associated with age >40 years (odds ratio (OR) = 9.30; confidence interval (CI) 3.69-23.45; P < 0.01), injecting drug use (OR = 24.26; CI 8.99-65.43; P < 0.01) and previous incarceration (OR = 12.26; CI 4.51-33.31; P < 0.01). In a cohort of treatment-eligible individuals, 43.3% (90/208) had neither been referred to specialist services or general practitioners for HCV management. Amongst those referred to specialist services, 64.7% (57/88) did not attend scheduled follow up, and 48.3% (15/31) of attendees were lost to follow up. Through an intensified community access programme, 10 people were successfully treated for HCV, although 22 could not be engaged. CONCLUSION: People with SMI are underserved by traditional models of HCV healthcare. Intensified community-based support can partially bolster the treatment cascade, although investment in innovative screening and management strategies are required to achieve healthcare parity.

Healthcare utilisation and costing for decompensated chronic liver disease hospitalisations at a Victorian network.

BACKGROUND: The economic burden of decompensated chronic liver disease (CLD) on Australian healthcare services is poorly characterised. AIMS: To evaluate the in-patient healthcare utilisation costs associated with decompensated CLD at Monash Health, an Australian tertiary healthcare service. METHODS: The current retrospective cost analysis examined patients with decompensated CLD admitted between 1 January 2012 and 31 December 2018. Hospitalisations were identified using CLD-specific International Classification of Diseases, Tenth Revision, codes. Cost measures were estimated using the Victorian Weighted Inlier Equivalent Separation funding data based on the Australian Refined Diagnosis Related Groups cost weights. RESULTS: There were 707 hospitalisations in 435 adult patients. The mean age was 56.7 ± 11.7 years and the mean length of stay was 10.28 ± 11.2 days. Median survival was 31 months (interquartile range, 2-94 months) and 177 (40.8%) patients died within 1 year of admission. The cost of admission varied according to decompensation: hepatorenal syndrome ($20 162 AUD), variceal bleed ($16 630 AUD), spontaneous bacterial peritonitis ($12 664 AUD), hepatic encephalopathy ($9973 AUD) and ascites ($9001 AUD). There was no significant difference in the admissions or 30-day readmission rate from 2012 to 2018 financial year (FY). The total adjusted cost of cirrhotic admissions per year increased by 78% from FY2012 to FY2018. CONCLUSION: Hospital admission and readmission for decompensated CLD is common and associated with 40.8% 1-year mortality and high costs. Clearer delineation of goals of care and alternative ambulatory care models for decompensated CLD are urgently required to reduce the high costs and burden on health services.

Liver Disease and Poor Adherence Limit Hepatitis C Cure: A Real-World Australian Treatment Cohort.

BACKGROUND AND AIMS: In 2016, direct-acting antiviral (DAA) treatment for hepatitis C (HCV) became available through Australia's universal health care system, with the aim of HCV elimination. We report real-world effectiveness of DAA HCV treatment in Australia from a clinically well-informed cohort, enriched for cirrhosis and prior HCV treatment. METHODS: 3413 patients were recruited from 26 hospital liver clinics across Australia from February 2016 to June 2020. Clinical history and sustained viral response (SVR) were obtained from medical records and data linkage to the Australian Pharmaceutical Benefits Scheme. Factors associated with SVR were assessed by multivariable logistic regression (MVR). RESULTS: At recruitment, 32.2% had cirrhosis (72.9% Child Pugh class B/C), and 19.9% were treatment experienced. Of the 2,939 with data, 93.3% confirmed SVR. 137 patients received second-line therapy. Patients with cirrhosis had lower SVR rate (88.4 vs. 95.8%; p < 0.001). On MVR, failure to achieve SVR was associated with Genotype 3 (adj-OR = 0.42, 95%CI 0.29-0.61), male gender (adj-OR = 0.49, 95%CI 0.31-0.77), fair/poor adherence (adj-OR = 0.52, 95%CI 0.28-0.94), cirrhosis (adj-OR = 0.57, 95%CI 0.36-0.88), FIB-4 > 3.25 (adj-OR = 0.52, 95%CI 0.33-0.83) and MELD score ≥ 20 (adj-OR = 0.25, 95%CI 0.08-0.80). Consistent results were seen in cirrhotic sub-analysis. CONCLUSIONS: Excellent SVR rates were achieved with DAAs in this real-world cohort of patients with chronic HCV infection. More advanced liver disease and clinician impression of poor adherence were associated with HCV treatment failure. Supports to improve liver fibrosis assessment skills for non-specialist DAA prescribers in the community and to optimize patient adherence are likely to enable more effective pursuit of HCV elimination in Australia.

Liver stiffness (Fibroscan®) is a predictor of all-cause mortality in people with non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: Progressive liver fibrosis related to non-alcoholic fatty liver disease (NAFLD) is associated with all-cause and liver-related mortality. We assessed vibration-controlled transient elastography (VCTE) as a predictor of mortality. METHOD: Data from patients who underwent VCTE for NAFLD at four large health services in Victoria, Australia between the years 2008 and 2019 were linked to state-wide data registries. Cause of death (COD) and predictors of all-cause mortality were subsequently analysed using descriptive statistics and Cox-proportional regression analysis. RESULTS: Of 7079 VCTE records submitted for data linkage, 6341 were matched via data registry linkage. There were 217 deaths over a 22 653 person-year follow-up. COD included malignancies other than hepatocellular carcinoma (HCC) (18.0%, n = 39), sepsis (16.1%, n = 35), decompensated liver disease (15.2%, n = 33), cardiac disease (15.2%, n = 33) and HCC 6.0% (n = 13). Controlled attenuation parameter (CAP) was not associated with mortality in univariable analysis (HR = 1.00, CI 1.0-1.0, p = .488). Increased liver stiffness measurement (LSM) (HR 1.02 per kiloPascal, CI 1.01-1.03, p < .001), Charlson comorbidity index (CCI) (HR 1.32 for each point, CI 1.27-1.38, p < .001) and age (HR 1.05 per annum, CI 1.03-1.07, p < .001) were each associated with higher rates of all-cause mortality in multivariable analysis. LSM ≥10 kPa suggestive of compensated advanced chronic liver disease (cACLD) was associated with mortality in multivariable analysis (HR 2.31, CI 1.73-3.09, p < .001). CONCLUSION: VCTE LSM, in addition to age and CCI, is independently associated with increased all-cause mortality in a large cohort with NAFLD.

Hepatitis B Virus Flares After Nucleot(s)ide Analogue Cessation Are Associated With Activation of Toll-Like Receptor Signaling Pathways.

BACKGROUND: We evaluated the patterns of peripheral Toll-like receptor (TLR) signaling activity and the expression of TLRs and natural killer (NK) cell activation in a cohort of patients experiencing severe hepatitis flares after stopping nucleot(s)ide analogues (NAs) therapy. METHODS: Samples were collected longitudinally from patients with chronic hepatitis B who were enrolled in a prospective study of NA discontinuation. Patients experiencing hepatitis flares were compared with patients with normal alanine aminotransferase. Peripheral blood mononuclear cells (PBMCs) were stimulated with TLR ligands and cytokine secretion in the cell culture supernatant measured. Expression of TLR2/4, NKG2D, NKp46, and triggering receptor expressed on myeloid cells 1 (TREM-1) on monocytes, NK, and NK-T cells was measured. RESULTS: Seventeen patients with severe reactivation hepatitis flares were compared to 12 nonflare patients. Hepatitis flares were associated with increased activity of TLR2-8 and TLR9 signaling in PBMCs at the time of peak flare compared to baseline. Hepatitis flares were also associated with (1) upregulation of TLR2 and (2) TREM-1 receptor expression on NK. There were no differences at baseline between flare patients and nonflare patients. CONCLUSIONS: Hepatitis flares off NA therapy have a significant innate inflammatory response with upregulation of TLR signaling on peripheral monocytes and TLR2 and TREM-1 expression on NK cells. This implicates the innate immune system in the immunopathogenesis of hepatitis B flares.

A home-based, multidisciplinary liver optimisation programme for the first 28 days after an admission for acute-on-chronic liver failure (LivR well): a study protocol for a randomised controlled trial.

BACKGROUND: Acute-on-chronic liver failure (ACLF) represents a rising global healthcare burden, characterised by increasing prevalence among patients with decompensated cirrhosis who have a 28-day transplantation-free mortality of 33.9%. Due to disease complexity and a high prevalence of socio-economic disadvantage, there are deficits in quality of care and adherence to guideline-based treatment in this cohort. Compared to other chronic conditions such as heart failure, those with liver disease have reduced access to integrated ambulatory care services. The LivR Well programme is a multidisciplinary intervention aimed at improving 28-day mortality and reducing 30-day readmission through a home-based, liver optimisation programme implemented in the first 28 days after an admission with either ACLF or hepatic decompensation. Outcomes from our feasibility study suggest that the intervention is safe and acceptable to patients and carers. METHODS: We will recruit adult patients with chronic liver disease from the emergency departments, in-patient admissions, and an ambulatory liver clinic of a multi-site quaternary health service in Melbourne, Australia. A total of 120 patients meeting EF-Clif criteria will be recruited to the ACLF arm, and 320 patients to the hepatic decompensation arm. Participants in each cohort will be randomised to the intervention arm, a 28-day multidisciplinary programme or to standard ambulatory care in a 1:1 ratio. The intervention arm includes access to nursing, pharmacy, physiotherapy, dietetics, social work, and neuropsychiatry clinicians. For the ACLF cohort, the primary outcome is 28-day mortality. For the hepatic decompensation cohort, the primary outcome is 30-day re-admission. Secondary outcomes assess changes in liver disease severity and quality of life. An interim analysis will be performed at 50% recruitment to consider early cessation of the trial if the intervention is superior to the control, as suggested in our feasibility study. A cost-effectiveness analysis will be performed. Patients will be followed up for 12 weeks from randomisation. Three exploratory subgroup analyses will be conducted by (a) source of referral, (b) unplanned hospitalisation, and (c) concurrent COVID-19. The trial has been registered with the Australian New Zealand Clinical Trials Registry. DISCUSSION: This study implements a multidisciplinary intervention for ACLF patients with proven benefits in other chronic diseases with the addition of novel digital health tools to enable remote patient monitoring during the COVID-19 pandemic. Our feasibility study demonstrates safety and acceptability and suggests clinical improvement in a small sample size. An RCT is required to generate robust outcomes in this frail, high healthcare resource utilisation cohort with high readmission and mortality risk. Interventions such as LivR Well are urgently required but also need to be evaluated to ensure feasibility, replicability, and scalability across different healthcare systems. The implications of this trial include the generalisability of the programme for implementation across regional and urban centres. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12621001703897 . Registered on 13 December 2021. WHO Trial Registration Data Set. See Appendix 1.

Hepatitis C treatment outcomes for Australian First Nations Peoples: equivalent SVR rate but higher rates of loss to follow-up.

BACKGROUND: First Nations Peoples of Australia are disproportionally affected by hepatitis C (HCV) infection. Through a prospective study we evaluated the outcome of direct-acting antiviral (DAA) therapy among First Nations Peoples with HCV infection. METHODS: Adults who initiated DAA therapy at one of 26 hospitals across Australia, 2016-2019 were included in the study. Clinical data were obtained from medical records and the Pharmaceutical and Medicare Benefits Schemes. Outcomes included sustained virologic response (SVR) and loss to follow-up (LTFU). A multivariable analysis assessed factors associated with LTFU. RESULTS: Compared to non-Indigenous Australians (n = 3206), First Nations Peoples (n = 89) were younger (p < 0.001), morel likely to reside in most disadvantaged (p = 0.002) and in regional/remote areas (p < 0.001), and had similar liver disease severity. Medicines for mental health conditions were most commonly dispensed among First Nations Peoples (55.2% vs. 42.8%; p = 0.022). Of 2910 patients with follow-up data, both groups had high SVR rates (95.3% of First Nations Peoples vs. 93.2% of non-Indigenous patients; p = 0.51) and 'good' adherence (90.0% vs. 86.9%, respectively; p = 0.43). However, 28.1% of First Nations Peoples were LTFU vs. 11.2% of non-Indigenous patients (p < 0.001). Among First Nations Peoples, younger age (adj-OR = 0.93, 95% CI 0.87-0.99) and treatment initiation in 2018-2019 vs. 2016 (adj-OR = 5.14, 95% CI 1.23-21.36) predicted LTFU, while higher fibrosis score was associated with better engagement in HCV care (adj-OR = 0.71, 95% CI 0.50-0.99). CONCLUSIONS: Our data showed that First Nations Peoples have an equivalent HCV cure rate, but higher rates of LTFU. Better strategies to increase engagement of First Nations Peoples with HCV care are needed.

Combination treatments including the small-interfering RNA JNJ-3989 induce rapid and sometimes prolonged viral responses in patients with CHB.

BACKGROUND & AIMS: RNA interference therapy has been shown to reduce hepatitis B surface antigen (HBsAg) levels in preclinical models, which could confer functional cure in patients with chronic hepatitis B. This phase IIa trial (ClinicalTrials.gov Identifier: NCT03365947) assessed the safety and efficacy of the small-interfering RNA JNJ-73763989 (JNJ-3989) plus a nucleos(t)ide analogue (NA), with/without the capsid assembly modulator JNJ-56136379 (JNJ-6379) in patients with chronic hepatitis B. METHODS: Treatment-naïve and NA-suppressed patients received 3 subcutaneous JNJ-3989 doses every week (QW; 100, 200, or 300 mg), 2 weeks (Q2W; 100 mg) or 4 weeks (Q4W; 25, 50, 100, 200, 300, or 400 mg), or JNJ-3989 Q4W (200 mg) plus oral JNJ-6379 250 mg daily for 12 weeks. Patients received NAs throughout. RESULTS: Eighty-four patients were recruited. All treatments were well tolerated, with all 5 serious adverse events considered unrelated to study drugs. JNJ-3989 100 to 400 mg Q4W resulted in HBsAg reductions ≥1 log10 IU/ml from baseline in 39/40 (97.5%) patients at the nadir. All patients receiving the triple combination (n = 12) had HBsAg reductions ≥1 log10 IU/ml from baseline at the nadir. HBsAg reductions were similar for HBeAg-positive (n = 21) and HBeAg-negative (n = 47) patients in all JNJ-3989 Q4W treatment arms, including the triple combination (n = 68). Smaller HBsAg reductions were seen with 25 mg (n = 8) and 50 mg (n = 8) than with 100 to 400 mg (n = 40). Shorter dosing intervals (QW [n = 12] and Q2W [n = 4]) did not improve response vs. Q4W dosing. HBsAg reductions ≥1 log10 IU/ml from baseline persisted in 38% of patients 336 days after the last JNJ-3989 dose. CONCLUSIONS: JNJ-3989 plus an NA, with/without JNJ-6379, was well tolerated and resulted in HBsAg reductions up to 336 days after the last JNJ-3989 Q4W dose. CLINICAL TRIAL NUMBER: NCT03365947. LAY SUMMARY: Hepatitis B virus affects people's livers and produces particles called hepatitis B surface antigen (HBsAg) that damage a person's liver and can help the virus infect a person for a long time, known as chronic hepatitis B (CHB). In this study, a new treatment called JNJ-3989 was assessed (in combination with normal treatment known as nucleos(t)ide analogues), for its safety and effectiveness in reducing the number of HBsAg particles in people with CHB. The results of this study showed that treatment with JNJ-3989 could be safe for people with CHB, lowered their HBsAg levels, and kept HBsAg levels lowered for 336 days in 38% of patients after receiving their last dose of JNJ-3989.

Stopping nucleot(s)ide analogues in non-cirrhotic HBeAg-negative chronic hepatitis B patients: HBsAg loss at 96 weeks is associated with low baseline HBsAg levels.

BACKGROUND AND AIMS: Current guidelines recommend long-term nucleot(s)ide analogue (NA) therapy for patients with HBeAg-negative chronic hepatitis B (CHB). However, disease remission has been described after stopping NA therapy, as well as HBsAg loss. METHODS: We performed a prospective multi-centre cohort study of stopping NA therapy. Inclusion criteria were HBeAg-negative CHB, the absence of cirrhosis and HBVDNA5× ULN occurred in 35 (32%); ALT flares were not associated with HBsAg loss. There were no unexpected safety issues. CONCLUSION: Virological reactivation was very common after stopping NA therapy and occurred earlier after stopping TDF versus ETV. The majority of patients had ALT <2× ULN at week 96, but only one-third achieved disease remission and HBsAg loss was rare. Very low HBsAg levels at baseline were uncommon but predicted for HBsAg loss and disease remission.

Fourier-Transform Infra-Red Microspectroscopy Can Accurately Diagnose Colitis and Assess Severity of Inflammation.

The diagnosis and management of inflammatory bowel disease relies on histological assessment, which is costly, subjective, and lacks utility for point-of-care diagnosis. Fourier-transform infra-red spectroscopy provides rapid, non-destructive, reproducible, and automatable label-free biochemical imaging of tissue for diagnostic purposes. This study characterises colitis using spectroscopy, discriminates colitis from healthy tissue, and classifies inflammation severity. Hyperspectral images were obtained from fixed intestinal sections of a murine colitis model treated with cell therapy to improve inflammation. Multivariate analyses and classification modelling were performed using supervised and unsupervised machine-learning algorithms. Quantitative analysis of severe colitis showed increased protein, collagen, and nucleic acids, but reduced glycogen when compared with normal tissue. A partial least squares discriminant analysis model, including spectra from all intestinal layers, classified normal colon and severe colitis with a sensitivity of 91.4% and a specificity of 93.3%. Colitis severity was classified by a stacked ensemble model yielding an average area under the receiver operating characteristic curve of 0.95, 0.88, 0.79, and 0.85 for controls, mild, moderate, and severe colitis, respectively. Infra-red spectroscopy can detect unique biochemical features of intestinal inflammation and accurately classify normal and inflamed tissue and quantify the severity of inflammation. This is a promising alternative to histological assessment.

Integrating Hepatitis C Virus Treatment Programs Within Community Mental Health.

Conventional models of health care for the hepatitis C virus (HCV) underserve people with serious mental illness. In a 6-month proof-of-concept study, colocated HCV care coordination was assessed within community mental health settings. The program, which relied on referrals to a visiting hepatologist and was augmented by a part-time nurse practitioner, received 18 referrals for HCV management. From this group, 11 individuals achieved sustained virological response at 12 weeks after direct-acting antiviral therapy. Seven individuals declined treatment or were lost to follow-up. Overall, colocated integrated services may play an important role in HCV health care parity for people with serious mental illness.

Determinants of Hepatitis C Virus Prevalence in People With Serious Mental Illness: A Systematic Review and Meta-Analysis.

Objective: To perform a meta-analysis of hepatitis C virus (HCV) prevalence in people with serious mental illness (SMI) and to systematically review barriers to care with the contention that both individual complications and HCV community transmission can be reduced with enhanced health care strategies.Data Sources: PubMed, Scopus, Embase, CINAHL, and Web of Science were searched for articles published in English between April 21, 1989, and July 1, 2020. The terms Hepatitis C Virus, HCV, HCV seroprevalence, and HCV prevalence were cross-referenced with serious mental illness, severe mental illness, psychiatric illness, mental illness, and psychiatric patients.Study Selection: We identified 230 titles after removing duplicates. The final analysis included 36 publications drawn from prospective and large retrospective cohort studies that cross-sectionally screened for HCV in people with SMI ≥ 18 years of age.Data Extraction: Pooled HCV prevalence was analyzed, with random effects modeling due to significant attributable study heterogeneity. Demographic data and HCV risk factors were subanalyzed. Qualitative and semiqualitative data relating to control cohort prevalence and the HCV care cascade were also extracted.Results: The pooled HCV prevalence was 8.0% (95% CI, 6.0%-9.0%). Subanalysis of prospective studies (n = 9,015 individuals) demonstrated a similar prevalence, 8.0% (CI, 5.0%-11.0%), to retrospective studies (n = 289,247), 8.0% (CI, 6.0%-10.0%). HCV was 3.0- to 11.3-fold higher in people with SMI relative to controls. Semiqualitative analysis of seropositive cases showed that (1) 20.0%-58.1% did not have an identified HCV risk factor; (2) 12.5%-100% of cases were not previously known to have HCV; and (3) the majority, 57.0%-96.6%, of people with SMI were receptive to HCV screening.Conclusions: People with SMI have high HCV seroprevalence and should be recognized as a priority group for HCV screening and health care access.