A randomized multicenter trial of a chronic disease management intervention for decompensated cirrhosis. The Australian Liver Failure (ALFIE) trial.

BACKGROUND AND AIMS: Improving the care of decompensated cirrhosis is a significant clinical challenge. The primary aim of this trial was to assess the efficacy of a chronic disease management (CDM) model to reduce liver-related emergency admissions (LREA). The secondary aims were to assess model effects on quality-of-care and patient-reported outcomes. APPROACH AND RESULTS: The study design was a 2-year, multicenter, randomized controlled study with 1:1 allocation of a CDM model versus usual care. The study setting involved both tertiary and community care. Participants were randomly allocated following a decompensated cirrhosis admission. The intervention was a multifaceted CDM model coordinated by a liver nurse. A total of 147 participants (intervention=75, control=71) were recruited with a median Model for End-Stage Liver Disease score of 19. For the primary outcome, there was no difference in the overall LREA rate for the intervention group versus the control group (incident rate ratio 0.89; 95% CI: 0.53-1.50, p=0.666) or in actuarial survival (HR=1.14; 95% CI: 0.66-1.96, p=0.646). However, there was a reduced risk of LREA due to encephalopathy in the intervention versus control group (HR=1.87; 95% CI: 1.18-2.96, p=0.007). Significant improvement in quality-of-care measures was seen for the performance of bone density (p<0.001), vitamin D testing (p<0.001), and HCC surveillance adherence (p=0.050). For assessable participants (44/74 intervention, 32/71 controls) significant improvements in patient-reported outcomes at 3 months were seen in self-management ability and quality of life as assessed by visual analog scale (p=0.044). CONCLUSIONS: This CDM intervention did not reduce overall LREA events and may not be effective in decompensated cirrhosis for this end point.

COBALT: A Confirmatory Trial of Obeticholic Acid in Primary Biliary Cholangitis With Placebo and External Controls.

INTRODUCTION: Obeticholic acid (OCA) treatment for primary biliary cholangitis (PBC) was conditionally approved in the phase 3 POISE trial. The COBALT confirmatory trial assessed whether clinical outcomes in patients with PBC improve with OCA therapy. METHODS: Patients randomized to OCA (5-10 mg) were compared with placebo (randomized controlled trial [RCT]) or external control (EC). The primary composite endpoint was time to death, liver transplant, model for end-stage liver disease score ≥15, uncontrolled ascites, or hospitalization for hepatic decompensation. A prespecified propensity score-weighted EC group was derived from a US healthcare claims database. RESULTS: In the RCT, the primary endpoint occurred in 28.6% of OCA (n = 168) and 28.9% of placebo patients (n = 166; intent-to-treat analysis hazard ratio [HR] = 1.01, 95% confidence interval = 0.68-1.51), but functional unblinding and crossover to commercial therapy occurred, especially in the placebo arm. Correcting for these using inverse probability of censoring weighting and as-treated analyses shifted the HR to favor OCA. In the EC (n = 1,051), the weighted primary endpoint occurred in 10.1% of OCA and 21.5% of non-OCA patients (HR = 0.39; 95% confidence interval = 0.22-0.69; P = 0.001). No new safety signals were identified in the RCT. DISCUSSION: Functional unblinding and treatment crossover, particularly in the placebo arm, confounded the intent-to-treat estimate of outcomes associated with OCA in the RCT. Comparison with the real-world EC showed that OCA treatment significantly reduced the risk of negative clinical outcomes. These analyses demonstrate the value of EC data in confirmatory trials and suggest that treatment with OCA improves clinical outcomes in patients with PBC.

Circulating cell-specific extracellular vesicles as biomarkers for the diagnosis and monitoring of chronic liver diseases.

Chronic liver diseases represent a burgeoning health problem affecting billions of people worldwide. The insufficient performance of current minimally invasive tools is recognised as a significant barrier to the clinical management of these conditions. Extracellular vesicles (EVs) have emerged as a rich source of circulating biomarkers closely linked to pathological processes in originating tissues. Here, we summarise the contribution of EVs to normal liver function and to chronic liver pathologies; and explore the use of circulating EV biomarkers, with a particular focus on techniques to isolate and analyse cell- or tissue-specific EVs. Such approaches present a novel strategy to inform disease status and monitor changes in response to treatment in a minimally invasive manner. Emerging technologies that support the selective isolation and analysis of circulating EVs derived only from hepatic cells, have driven recent advancements in EV-based biomarker platforms for chronic liver diseases and show promise to bring these techniques to clinical settings.

Impact of cardiac dysfunction on morbidity and mortality in liver transplant candidates.

The prognostic role of cardiac dysfunction in cirrhotic patients is increasingly recognized. We studied its impact on morbidity and mortality before and after liver transplantation (LT) including development of post-transplant cardiovascular disease (CVD). In this retrospective study, cirrhotic patients who underwent LT assessment from January 2010 to December 2020 were reviewed. Demographics, cardiac investigations and clinical courses were analyzed to identify the prevalence of cardiac dysfunction and its role in LT outcomes. Survival analysis was performed using Cox proportional hazard regression modelling, with LT as a time-varying covariate and as an interaction variable with cardiac dysfunction. Three hundred and eight patients (70% male) were studied. The median (interquartile range) age at LT assessment was 56 (12) years. Cardiac dysfunction was found in 178 (58%) patients (diastolic, 169; systolic, 26; both, 17) and was significantly associated with hepatorenal syndrome/acute kidney injury and peri- and post-transplant morbidity (adjusted odds ratio [aOR] 1.94, 95% CI 1.06-3.52, P < .001; aOR 2.01, 95% CI 1.06-3.82, P = .033; aOR 1.9, 95% CI 1.01-3.65, P = .023, respectively). Cardiac dysfunction was not associated with mortality before (adjusted hazard ratio [aHR] 1.01, 95% CI .99-1.01) or after LT (aHR .74, 95% CI .4-1.05. Post-transplant CVD (61% cardiac failure) occurred in 36 patients, and there was no significant association with cardiac dysfunction (P = .11). Cardiac dysfunction was common in LT candidates and was significantly associated with morbidity before and after LT. Studies on the role of advanced echocardiographic parameters to improve diagnosis of cardiac dysfunction and optimize LT outcomes are needed.

Measuring quality of hepatitis B care in a remote Australian Aboriginal community: opportunities for improvement.

BACKGROUND: Chronic hepatitis B (CHB) infection remains a significant public health issue for Indigenous Australians, in particular for remote communities. AIM: To evaluate the spectrum of hepatitis B virus (HBV) care provided to a remote Aboriginal community. Measures studied included screening, seroprevalence, vaccination rates and efficacy, and HCC risk and surveillance adherence. METHODS: A retrospective audit of HBV care received by all permanent residents currently attending a remote Aboriginal Health service. This study was endorsed by both the local Aboriginal Health service and the Aboriginal Health Council of South Australia. RESULTS: A total of 208 patients attended the clinic, of whom 52% (109) were screened for HBV. Of these, 12% (13) had CHB and 20% (22) had evidence of past infection. Similarly, of the 208 attending patients, complete vaccination was documented in 48% (99). Of the 33 patients with post-vaccination serology, 24% (8) had subtherapeutic (<10 IU/mL) levels of HBsAb. Subtherapeutic HBsAb was independently associated with higher Charlson Comorbidity scores (odds ratio = 17.1; 95% confidence interval 1.2-243.3; P = 0.036). Definitive breakthrough infection was identified in 6% (2) patients. One HBsAg positive patient was identified as needing HCC surveillance, but had not undertaken HCC surveillance. CONCLUSION: Opportunities to improve the quality of CHB care through increased HBV vaccination, screening and adherence to HCC surveillance were identified. High rates of subtherapeutic vaccine responses and documented breakthrough infection raises concerns about the effectiveness of current CHB vaccines in this population.

Nurse Led Clinics; a Novel Model of Care for Compensated Liver Cirrhosis: A Qualitative Analysis.

A nurse-led cirrhosis clinic model for management of stable, compensated cirrhotic patients is practised in our unit since 2013, wherein these patients are reviewed every six months by specialist nurses in community clinics under remote supervision of hepatologists. We evaluated the experiences of patients and healthcare providers involved in the model to understand the acceptability, strengths, and limitations of the model and obtain suggestions to improve. A qualitative design using in-depth interviews was employed, followed by thematic analysis of eight patients, one attending physician both nurse and hospital clinics, four hepatologists, and three experienced specialist nurses running the nurse-led cirrhosis clinic. Patients expressed satisfaction and a good understanding of the nurse-led cirrhosis clinic, preferring it to hospital clinics for better accessibility and the unique nurse-patient relationship. Upskilling and provision of professional care in a holistic manner were appreciated by specialist nurses. The hepatologists expressed confidence and satisfaction, although they acknowledged the difference between the medical training of specialist nurses and hepatologists. The greater availability of hospital clinic time for sick patients was welcomed. Increased specialist nurse staffing, regular forums to promote specialist nurse learning, and formalization of the referral process were suggested. No adverse experiences were reported by patients or staff. The nurse-led cirrhosis clinic model for compensated liver cirrhosis was well received by patients, hepatologists, and specialist nurses. Wider implementation of the model could be considered after further investigations in other settings.

Management, outcomes and survival of an Australian IgG4-SC cohort: The MOSAIC study.

BACKGROUND AND AIMS: IgG4 sclerosing cholangitis (IgG4-SC) is the biliary component of the multisystem IgG4-related disease. We aimed to investigate the clinical features, demographics, treatment response and outcomes of IgG4-SC in a large Australian cohort. METHODS: We conducted nationwide retrospective cohort via the Australian Liver Association Clinical Trials Network (ALA-CRN). 39 sites were invited to participate. IgG4-SC was defined by the clinical diagnostic criteria established by the Japanese Biliary Association in 2012. Data were collected on patient demographic, clinical and laboratory information, presenting features, response to therapy and clinical outcomes. RESULTS: 67 patients meet inclusion criteria from 22 sites. 76% were male with mean age of 63.3 ± 14.5 years and a median IgG4 level of 3.6 g/L [0.09-67.1]. The most frequent presenting symptom was jaundice (62%) and abdominal pain (42%) and Type 1 biliary stricturing (52%) at the distal common bile duct was the most frequent biliary tract finding. Prednisolone was used as a primary treatment in 61 (91%) and partial or complete response occurred in 95% of subjects. Relapse was common (42%) in those who ceased medical therapy. After a median follow up of 3.9 years there was one hepatocellular carcinoma and no cholangiocarcinomas. CONCLUSIONS: Our study confirms the preponderance of IgG4-SC in males and highlights the steroid response nature of this condition although relapse is common after steroid cessation. Progression to malignancy was uncommon.

Psychometric validation of the Partners in Health scale as a self-management tool in patients with liver cirrhosis.

BACKGROUND AND AIM: Liver cirrhosis is a chronic disease complicated by recurrent hospital admissions. Self-management skills could facilitate optimal disease management. At present there is no validated instrument for measuring self-management in these patients. Hence, we evaluated the internal reliability and construct validity of the Partners in Health (PIH) scale, a chronic condition self-management tool in cirrhotic patients. METHODS: In this prospective cohort study, the PIH scale was administered to 133 consenting patients within a Chronic Liver Failure Program of a tertiary hospital from February 2017 to May 2018. A Bayesian confirmatory factor analysis was used to evaluate a priori four-factor structure. Omega coefficients and 95% credible intervals (CrI) were used to assess internal reliability. Known-group validity was assessed in patients receiving active case management (n = 60) versus those without (n = 73). RESULTS: The mean (± standard deviation (SD)) age of the participants was 62 (±11) years. Model fit for the hypothesised model was adequate (posterior predictive P-value = 0.073) and all hypothesised factor loadings were substantial (>0.6) and significant (P < 0.001). Omega coefficients (95% CrI) for the PIH subscales of Knowledge, Partnership, Management and Coping were 0.88 (0.82-0.91), 0.68 (0.57-0.76), 0.92 (0.89-0.94) and 0.89 (0.85-0.92) respectively. The mean (±SD) overall PIH score was higher in patients receiving case management compared to those without case management (81 ± 12 vs 73 ± 17, P < 0.001). CONCLUSION: The dimensionality, known-group validity and reliability of the PIH scale for measuring self-management in patients with liver cirrhosis were confirmed. Its clinical predictive value requires further assessment.

Outcomes of community-based hepatitis C treatment by general practitioners and nurses in Australia through remote specialist consultation.

BACKGROUND: A unique model of care was adopted in Australia following introduction of universal subsidised direct-acting antiviral (DAA) access in 2016 in order to encourage rapid scale-up of treatment. Community-based medical practitioners and integrated hepatitis nurses initiated DAA treatment with remote hepatitis specialist approval of the planned treatment without physical review. AIMS: To evaluate outcomes of community-based treatment of hepatitis C virus (HCV) through this remote consultation process in the first 12 months of this model of care. METHODS: A retrospective chart review of patients undergoing community-based HCV treatment from general practitioners and integrated hepatitis nurse consultants through the remote consultation model in three state jurisdictions in Australia from 1 March 2016 to 28 February 2017. RESULTS: Sustained virological response at 12 weeks (SVR12) was confirmed in 383 (65.1%) of 588 subjects intended for treatment with a median follow-up time of 12 months (interquartile range 9-14 months). The SVR12 test was not performed in 159 (27.0%) of 588 and 307 (52.2%) of 588 did not have liver biochemistry rechecked following treatment. Subjects who completed follow up exhibited high SVR12 rates (383/392; 97.7%). Nurse-led treatment was associated with higher confirmation of SVR12 (73.7% vs 62.4%; P = 0.01) and liver biochemistry testing post treatment (57.5% vs 45.0%; P = 0.01). CONCLUSIONS: Community-based management of HCV through remote specialist consultation may be an effective model of care. Failure to check SVR12, recheck liver biochemistry and appropriate surveillance in patients with cirrhosis may emerge as significant issues requiring further support, education and refinement of the model to maximise effectiveness of future elimination efforts.

Validation of Knowledge Questionnaire for Patients With Liver Cirrhosis.

BACKGROUND & AIMS: There is no validated questionnaire to assess disease knowledge and self-management in patients with liver cirrhosis. We developed and validated a Cirrhosis Knowledge Questionnaire (CKQ). METHODS: We created a preliminary CKQ comprising 10 questions relevant to self-management of cirrhosis, based on publications and clinical experiences. The CKQ was given to a pilot sample of 17 patients with decompensated cirrhosis to assess its face validity. In consultation with experts, we developed a second version of CKQ, comprising 14 multiple choice questions, and administered it to 116 patients with cirrhosis participating in a Chronic Liver Failure Program. The dimensionality of the construct was assessed using exploratory factor analysis and internal consistency was assessed with Cronbach's alpha. Known-group validity of the resulting instrument was assessed by comparing the performance of the CKQ in 69 patients with decompensated cirrhosis (mean age, 62 ± 13 years; 109 responses), with (n = 42) vs without (n = 67) case management. RESULTS: A 3-factor model with 7 questions related to variceal bleeding, ascites, and hepatic encephalopathy was considered the optimal dimensionality with excellent internal consistency (Cronbach's alpha = 0.82). The mean knowledge score was higher in patients with case management (5.6 ± 1.1) than in patients without case management (4.3 ± 2.1) (P = .002). CONCLUSIONS: We developed and validated a questionnaire with 7 questions on ascites, variceal bleeding, and hepatic encephalopathy to assess knowledge and self-management in patients with liver cirrhosis. Studies are needed to confirm its dimensionality and assess association of scores with patient outcomes.