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.

Hepatocellular carcinoma (HCC) is changing its face: analysis of the temporal trends in aetiology and clinical patterns of HCC in South Australia.

BACKGROUND: The epidemiology of chronic liver disease is changing with the introduction of potent antiviral therapies for chronic hepatitis C virus (HCV) and the increasing prevalence of non-alcoholic steatohepatitis (NASH). AIM: To establish the impact of this change on the rates and clinical patterns of hepatocellular carcinoma (HCC) in South Australia (SA). METHODS: Newly diagnosed HCC patients from January 2014 until December 2019 from four tertiary centres in SA were included. The overall age-standardised incidence rates (ASIR) of HCC were calculated using 2016 SA population as the standard. To assess the trends, Join-Point regression models were used to calculate the average annual percentage change (AAPC). Forecasting of overall and aetiology-specific HCC from 2020 to 2024 was performed using linear regression. RESULTS: There were 626 new cases of HCC in SA (males 80%; median age 64 years) during the study period. There was a significant increase in NASH-related HCC (AAPC: +7.0%; P < 0.05) from 2014 to 2019. However, there were no significant differences in the ASIR for overall HCC (AAPC: -4.1%), HCV-related HCC (AAPC: -8.0%) and stage of HCC diagnosis (AAPC: +3.0%; P > 0.05). Forecasting analysis projected the decline and increase in the incidence of HCV and NASH-related HCC, respectively, over the next few years. CONCLUSION: Overall ASIR of HCC has plateaued in SA. However, NASH-related HCC has increased significantly and is expected to continue to increase in the near future. Further research and intervention is required to reduce NASH-related HCC, a major contributor to the current and future burden of HCC.

Cost effectiveness of treatment models of care for hepatitis C: the South Australian state-wide experience.

AIM: The objective was to study the long-term (lifetime) cost effectiveness of four different hepatitis C virus (HCV) treatment models of care (MOC) with directly acting antiviral drugs. METHODS: A cohort Markov model-based probabilistic cost-effectiveness analysis (CEA) was undertaken extrapolating to up to 30 years from cost and outcome data collected from a primary study involving a real-life Australian cohort. In this study, noncirrhotic patients treated for HCV from 1 March 2016 to 28 February 2017 at four major public hospitals and liaising sites in South Australia were studied retrospectively. The MOC were classified depending on the person providing patient workup, treatment and monitoring into MOC1 (specialist), MOC2 (mixed specialist and hepatitis nurse), MOC3 (hepatitis nurse) and MOC4 (general practitioner, GP). Incremental costs were estimated from the Medicare perspective. Incremental outcomes were estimated based on the quality-adjusted life years (QALY) gained by achieving a sustained virological response. A cost-effectiveness threshold of Australian dollar 50 000 per QALY gained, the implicit criterion used for assessing the cost-effectiveness of new pharmaceuticals and medical services in Australia was assumed. Net monetary benefit (NMB) estimates based on this threshold were calculated. RESULTS: A total of 1373 patients, 64% males, mean age 50 (SD ±11) years, were studied. In the CEA, MOC4 and MOC2 clearly dominated MOC1 over 30 years with lower costs and higher QALYs. Similarly, NMB was the highest in MOC4, followed by MOC2. CONCLUSION: Decentralized care using GP and mixed consultant nurse models were cost-effective ways of promoting HCV treatment uptake in the setting of unrestricted access to new antivirals.

Stereotactic body radiation therapy for early hepatocellular carcinoma: a retrospective analysis of the South Australian experience.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is an emerging treatment option for liver tumours unsuitable for established curative treatment such as ablation or surgery. The aim of the study is to evaluate the efficacy and safety of SBRT in the treatment of small hepatocellular carcinoma (HCC) in South Australia. METHODS: From 2014 to 2018, 13 HCC patients were treated with SBRT. Eligibility criteria for SBRT included: unsuitable for standard curative therapies (resection or percutaneous ablation), lack of complete response to prior transarterial chemoembolization, Child-Pugh classification ≤B7, tumours ≤5 cm and minimum of up to 6 months follow-up post-SBRT. The prescribed radiation dose was determined by liver function with doses ranging from 40 to 45 Gy in three or five fractions. Records for all patients were reviewed, and treatment response was scored according to the modified response evaluation criteria in solid tumours. Toxicity was graded according to the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: The median follow-up time was 22.7 months, and the median tumour size was 40 mm. The 1 year local control was 92.3%, recurrence-free survival was 67.7% and overall survival was 86.4% at end of study. Three patients underwent liver transplant. No grade ≥3 non-haematological toxicities were observed. One patient experienced acute grade ≥3 haematological toxicity. CONCLUSION: SBRT is a safe, effective and non-invasive alternative treatment option for patients with small HCCs, unsuitable for standard, evidence-based therapies and lacking complete response to transarterial chemoembolization. Randomized controlled trials are required to further investigate the role of SBRT in HCC.

Improved Survival of Hepatocellular Carcinoma Patients Diagnosed with a Dedicated Screening Programme-a Propensity Score Adjusted Analysis.

AIM: To assess the overall survival (OS) in those with hepatocellular carcinoma (HCC) diagnosed within a programmatic, centrally co-ordinated, regional screening programme. METHODS: A retrospective cohort analysis of consecutive HCC patients diagnosed between 2004 and 2013. Patients were followed up till death or end of study period (30 April 2015). A dedicated screening programme was commenced in 2009 to screen high-risk patients for HCC. Primary objective is to compare the OS between HCC patients diagnosed within the screening group versus those diagnosed outside this group. Other objectives were to compare tumour stage at diagnosis and the proportion having curative treatments in the two groups. Propensity score adjustments were performed to assess the survival benefit. RESULTS: HCC was diagnosed in 130 subjects during the study period (82.3% males, median [IQR] age 62 [± 19] years and median [IQR] follow-up of 11.3 (± 23.5) months). Ninety-six patients (73.8%) died during the follow-up, and the median (95%CI) OS was 15.7 (9.7-21.8) months. HCC diagnosed within the screening programme had a better OS compared to those diagnosed outside this programme (26.8 vs 11.5 months, p = 0.01). Further, those diagnosed within the programme had an earlier stage HCC ([58.3% vs 23.6%], Ó¼2 = 11.3, p = 0.001), and a significant proportion were treated with curative intent ([62.5% vs 31.1%], Ó¼2 = 8.3, p = 0.004). Propensity score adjustment showed a 58% reduction in mortality for HCC diagnosed within the screening programme (HR [95%CI] 0.42 [0.20-0.89], p = 0.02). CONCLUSION: A programmatic, regional HCC screening programme improved the OS and detected tumours at an earlier stage enabling more patients to have curative therapies.

Assessing the clinical and economic impact of increasing treatment uptake in chronic hepatitis B infection using a Markov model.

Treatment uptake in chronic hepatitis B virus (HBV) infection is low in South Australia, and the cost-effectiveness of increasing treatment uptake rates in this population has not been assessed. AIMS AND METHODS: Using a cohort Markov model, cost-effectiveness was assessed for three different treatment uptake scenarios: 2.9% (current level-scenario 1), 10% (scenario 2), and 15% (scenario 3). The initial HBV population included 2550 treatment eligible patients who transitioned between six different health states over a 10-year period. Treatment transition probabilities were based on tenofovir therapy, while those not assigned to treatment followed the natural history transition probabilities. We estimated the incremental cost per quality adjusted life year gained using the prevented number of deaths, hepatocellular carcinoma, and liver transplants. RESULTS: Scenario 3 was associated with the lowest mean cost/person over 10 years (AU$60 133), compared with scenario 2 (AU$61 964) and scenario 1 (AU$64 597). Scenario 3 was also associated with the highest quality adjusted life year gained (8.196) compared with scenario 2 (7.985) and scenario 1 (7.684). Scenario 3 would result in 50% reduction in hepatocellular carcinoma and 30% reduction in HBV-related mortality compared with scenario 1, over a 10-year period. Higher treatment uptake was found to be cost-effective with at least 2 years of treatment at either 10% or 15% of the target population. CONCLUSION: Maximizing the treatment uptake in the existing HBV population from 2.9% to 15% was cost-effective for periods of 2 years or more. This was due to a reduction in the number of expected clinical events.

Percutaneous thermal ablation for primary hepatocellular carcinoma: A systematic review and meta-analysis.

BACKGROUND AND AIM: Percutaneous thermal ablation using radiofrequency ablation (RFA) and microwave ablation (MWA) are both widely available curative treatments for hepatocellular carcinoma. Despite significant advances, it remains unclear which modality results in better outcomes. This meta-analysis of randomized controlled trials (RCT) and observational studies was undertaken to compare the techniques in terms of effectiveness and safety. METHODS: Electronic reference databases (Medline, EMBASE and Cochrane Central) were searched between January 1980 and May 2014 for human studies comparing RFA and MWA. The primary outcome was the risk of local tumor progression (LTP). Secondary outcomes were complete ablation (CA), overall survival, and major adverse events (AE). The ORs were combined across studies using the random-effects model. RESULTS: Ten studies (two prospective and eight retrospective) were included, and the overall LTP rate was 13.6% (176/1298). There was no difference in LTP rates between RFA and MWA [OR (95% CI): 1.01(0.67-1.50), P = 0.9]. The CA rate, 1- and 3-year overall survival and major AE were similar between the two modalities (P > 0.05 for all). In subgroup analysis, there was no difference in LTP rates according to study quality, but LTP rates were lower with MWA for treatment of larger tumors [1.88(1.10-3.23), P = 0.02]. There was no significant publication bias or inter-study heterogeneity (I(2) < 50% and P > 0.1) observed in any of the measured outcomes. CONCLUSION: Overall, both RFA and MWA are equally effective and safe, but MWA may be more effective compared to RFA in preventing LTP when treating larger tumors. Well-designed, larger, multicentre RCTs are required to confirm these findings.

Topical Steroid Therapy for the Treatment of Eosinophilic Esophagitis (EoE): A Systematic Review and Meta-Analysis.

OBJECTIVES: Current guidelines recommend topical steroids as first-line treatment for patients with eosinophilic esophagitis (EoE). However, the evidence for this approach has been inconsistent in earlier reports. This meta-analysis aimed to clarify the efficacy of topical steroid treatment in active EoE using updated evidence. METHODS: CENTRAL, MEDLINE and EMBASE databases were searched for randomized controlled trials (RCTs) published up to May 2014 that compared topical steroids with control treatments for active EoE. Study bias was assessed using the Cochrane Collaboration Tool, and outcomes were pooled using random effects models. The primary outcome was the mean change in eosinophil counts. Secondary outcomes were symptom responses and adverse events. RESULTS: In total, seven RCTs (226 patients) were included. Topical steroids were associated with a significant reduction in esophageal mucosal eosinophil counts compared with control therapy although substantial heterogeneity between studies was observed (weighted mean difference (WMD) -27.2, 95% confidence interval (CI) -45.3 to -9.1, I(2)=56.2%). Subgroup analysis indicated the reduction in eosinophil counts was only present in studies where a proton pump inhibitor (PPI) trial was used to exclude other diagnoses (WMD -46.3, 95% CI -61.3 to -31.4, I(2)=0.0%). Subdivision of studies on the use of a PPI trial also accounted for the majority of heterogeneity among RCTs. No clear trends in symptom resolution were observed. Eleven out of 127 patients who received topical steroids developed asymptomatic esophageal candidiasis. CONCLUSIONS: These data provide updated high-quality evidence that support current guidelines for first-line EoE treatment with topical steroids after an initial PPI trial to exclude non-EoE pathologies (PROSPERO ID: CRD42014008828).

High local recurrence of early-stage hepatocellular carcinoma after percutaneous thermal ablation in routine clinical practice.

BACKGROUND AND AIM: The risk of local tumour progression (LTP) and factors predicting LTP following percutaneous thermal ablation (PTA) of early-stage hepatocellular carcinoma (HCC) have not been well studied in non-trial settings and may be underestimated. We aimed to assess these outcomes in a multicentre study. PATIENTS AND METHODS: This was a retrospective review of consecutive patients with early-stage HCC treated with a curative intent across three tertiary Australian centres between 2006 and 2012 with either radiofrequency ablation or microwave ablation. The primary endpoint was LTP and multivariate analysis was carried out to identify the independent predictors of LTP. RESULTS: In total 145 HCC nodules were treated in 126 patients (78% men, mean±SD age 62±10 years) with a mean±SD follow-up of 13.5±13 months. Local recurrence was observed in 23.4% (34/145). Mean±SD LTP-free survival was 46.9±3.6 months. For HCC nodules 2 cm or less, local recurrence rates were lower (15.9%), with a mean±SD LTP-free survival of 48.8±4.2 months. Poorly differentiated HCC [hazard ratio (95% confidence interval)=4.8 (1.1-20.4), P=0.032] and pretreatment α-fetoprotein more than 50 kIU/l [8.2 (1.7-39.0), P=0.008] were independent predictors of LTP. LTP rates were not significantly different between the radiofrequency ablation and the microwave ablation groups (22.8 vs. 25.8%, P=0.7). There were six (4.8%) procedure-related adverse events, but no deaths. CONCLUSION: Local recurrence after PTA for early-stage HCC is high in routine clinical practice. Poorly differentiated HCC and pretreatment α-fetoprotein are important, independent predictors of LTP. Further well-designed randomized controlled trials with larger sample sizes using adjuvant therapies in combination with PTA to decrease LTP rates are warranted.

Liver transplantation outcomes for Australian Aboriginal and Torres Strait Islanders.

An increased liver disease burden has been reported for Aboriginal and Torres Strait Islanders (ATSIs) in Australia; however, few proceed to liver transplantation (LT). We aimed to compare overall survival and graft survival after LT between ATSI and non-ATSI populations, assess the factors influencing survival within ATSIs, and finally examine the proportion of ATSIs undergoing LT. This study was a retrospective review of the Australia and New Zealand Liver Transplant Registry from 1985 to 2012 and examined consecutive primary LT performed in Australia. Overall and graft survival were compared between ATSI and non-ATSI groups. The Accessibility/Remoteness Index of Australia (ARIA) was used to calculate the remoteness of individuals. There were 3493 primary LT performed, and 45 patients (1.3%; 14 children and 31 adults) were ATSIs. The median (range) ages of the ATSI children and adults at the time of LT were 9.6 (0.2-15.3) years and 44.5 (19.5-65.5) years, respectively. There were 10 deaths in the ATSI cohort. The median (range) overall survival was similar for ATSI and non-ATSI children [6.5 (0.1-23.5) years versus 9.0 (0-28.2) years, P = 0.9] and adults [7.1 (0.1-15.7) years versus 6.3 0-26.7) years, P = 0.8]. The cumulative graft survival was similar for ATSI and non-ATSI children (P = 0.8) and adults (P = 0.8). High ARIA scores [hazard ratio (HR) = 1.2, 95% confidence interval (CI) = 1.01-1.53, P = 0.03] in children and blood group O (HR = 3.8, 95% CI = 1.1-12.7, P = 0.03) in adults predicted worse outcomes for ATSIs. Although ATSIs accounted for 4.7% and 1.8% of the Australian pediatric and adult populations, respectively, they represented only 2.2% of pediatric LT recipients (χ(2) = 8.2, P = 0.004) and 1.1% of adult LT recipients (χ(2) = 7.9, P = 0.005). In conclusion, overall survival and graft survival after LT are comparable in ATSIs and non-ATSIs. There is a trend toward increased death/retransplantation in ATSIs from remote areas. ATSI children and adults appear to be underrepresented in the Australian LT population.

Prediction of morbidity and mortality in patients with chronic hepatitis C by non-invasive liver fibrosis models.

BACKGROUND & AIMS: Liver fibrosis is prognostic of outcomes among patients with chronic hepatitis C (CHC). We evaluated the accuracy of non-invasive markers and liver biopsy in predicting morbidity and mortality in CHC patients. METHODS: Compensated CHC patients were evaluated over a 10-year period. Non-invasive markers including Hepascore, FIB-4, APRI and liver biopsy results were retrospectively collated. Follow-up morbidity and mortality data were obtained from the Western Australian Data Linkage System. The prognostic significance of baseline non-invasive markers and biopsy were assessed using Kaplan-Meier analysis. RESULTS: A total of 406 subjects (64% male, mean age 48 ± 11 years) were followed up for 2385 person-years, during which there were 22 (5.4%) deaths including 14 (3.4%) who died from liver disease or required liver transplantation. Sixteen (3.9%) subjects developed liver decompensation. Hepascore and liver biopsy (P < 0.005) but not APRI or FIB-4 were predictive of overall and liver-related mortality as well as liver decompensation. A Hepascore>0.5 was associated with increased overall mortality [Hazard Ratio (95%CI) 6.7 (2.6-17), P < 0.001], liver-related mortality [32.8 (4.3-250), P = 0.001] and risk of future decompensation [11.8 (3.3-41), P < 0.001], whereas a Hepascore ≤0.5 was associated with a 99% probability of not dying from liver-related causes over 10 years. Hepascore had comparable accuracy with liver biopsy in predicting liver-related mortality with AUROC of 0.86 (95%CI 0.80-0.90) and 0.87 (0.79-0.96), respectively. CONCLUSION: Hepascore is predictive of overall and liver-related mortality and morbidity in CHC patients with comparable accuracy to liver biopsy. Hepascore may be a useful prognostic marker in clinical practice.