Developing a generic business case for an advanced chronic liver disease support service.

Introduction: Liver disease deaths are rising, but specialist palliative care services for hepatology are limited. Expansion across the NHS is required. Methods: We surveyed clinicians, patients and carers to design an 'ideal' service. Using standard NHS tariffs, we calculated the cost of this service. In hospitals where specialist palliative care was available for liver disease, patient-level costs and bed utilisation in last year of life (LYOL) were compared between those seen by specialist palliative care before death and those not. Results: The 'ideal' service was described. Costs were calculated as whole time equivalent for a minimal service, which could be scaled up. From a hospital with an existing service, patients seen by specialist palliative care had associated costs of £14 728 in LYOL, compared with £18 558 for those dying without. Savings more than balanced the costs of introducing the service. Average bed days per patient in LYOL were reduced (19.4 vs 25.7) also intensive care unit bed days (1.1 vs 1.8). Despite this, time from first admission in LYOL to death was similar in both groups (6 months for the specialist palliative care group vs 5 for those not referred). Conclusions: We have produced a template business case for an 'ideal' advanced liver disease support service, which self-funds and saves many bed days. The model can be easily adapted for local use in other trusts. We describe the methodology for calculating patient-level costs and the required service size. We present a financially compelling argument to expand a service to meet a growing need.

Excellent hepatitis C virus cure rates despite increasing complexity of people who use drugs: Integrated-Test-stage Treat study final outcomes.

Achieving hepatitic C virus (HCV) elimination requires linking people who use drugs (PWUD) into care. We report final direct-acting antivirals (DAAs)-based outcomes from the Integrated-Test-stage -Treat (ITTREAT) study. Project ITTREAT (2013-2021), based at an addiction centre, was a 'one-stop' service with innovative linkage to care strategies. Primary outcome was sustained virological response (SVR12) (intention to treat ITT) including whether individuals were recruited in first (period 1) versus last four (period 2 included the COVID-19 pandemic) years of the study. Number recruited were n = 765, mean age 40.9 ± 10.1 years, 78% males, history of current/past injecting drug use (IDU) and alcohol use being 77% and 90%, respectively. Prevalence of a positive HCV PCR was 84% with 19% having cirrhosis. Comparing those recruited in period 2 versus period 1, there was increasing prevalence of IDU, 90% versus 72% (p < .001); homelessness, 67% versus 50% (p < .001); psychiatric diagnosis, 84% versus 50% (p < .001); overdose history 71% versus 31% (p < .001), receiving opioid agonist treatment (OAT) 75% versus 52% (p < .001) and comorbidity 44% versus 25% (p < .001). Of those treated with DAAs (n = 272), ITT SVR rates were 86% (95% CI: 81%-90%), being similar in period 2 versus period 1. Predictors of non-SVR were receiving OAT (OR 0.33, 95% CI: 0.12-0.87, p = .025) and ≥80% adherence (OR 0.01, 95% CI: 0.003-0.041, p < .001). Reinfection rates period 2 versus period 1 (per 100 person-years) were 1.84 versus 1.70, respectively. In the treated cohort, mortality was 15%, being mostly drug-related. Despite increasing complexity of PWUD, high SVR12 rates are achievable with use of OAT and good adherence.

Nonviral Liver Disease Burden in People Living With HIV and Elevated Transaminases: A Cross-Sectional Study.

INTRODUCTION: Because of improved life expectancy in people living with HIV (PLWH), liver disease is increasingly being recognized. We assessed nonviral chronic liver disease burden in PLWH. METHODS: The HIV non-virAL liver disease study (2014-2021) prospectively recruited PLWH with elevated serum alanine aminotransferase levels and negative hepatitis serology. Clinically significant hepatic fibrosis (CSHF) was defined as liver stiffness measurement of >7.1 kPa and hazardous alcohol use as Alcohol Use Disorders Identification Test score ≥ 8. Primary outcome was prevalence/predictors of CSHF. RESULTS: Total recruited were n = 274, 92% male, median age 52 (45-59) years, and 96% having undetectable HIV viral load. Overall, n = 97 (35%) had hazardous alcohol use, n = 72 (26%) had metabolic syndrome, and 17%-27% had exposure to hepatotoxic antiretrovirals. Prevalence of CSHF was 20% (n = 54), prevalence of cirrhosis (liver stiffness measurement > 12.5 kPa) being 7% (19/274). Risk factors for CSHF were hazardous alcohol use in 44% (n = 24), metabolic syndrome in 46% (n = 25), and hepatotoxic antiretrovirals in 56% (n = 30), most having more than one risk factor. Independent predictors of CSHF were serum high-density lipoprotein (odds ratio [OR] 0.220; 95% confidence interval [CI]: 0.061 to 0.790, P = 0.020) (inverse relationship); serum aspartate aminotransferase (OR 1.033, 95% CI: 1.001 to 1.067, P = 0.045), and didanosine use (OR 2.878, 95% CI: 1.228 to 6.774, P = 0.015). Moderate-severe hepatic steatosis was identified in 52% (n = 142). FIB-4 and aspartate aminotransferase-to-platelet ratio index performed poorly in predicting CSHF (positive predictive value 27.3% and 30.6%, respectively) and advanced fibrosis (≥F3) (positive predictive value 17.6% and 5.9%, respectively). CONCLUSION: In this study, 20% of PLWH had CSHF associated with high prevalence of hazardous alcohol use/metabolic syndrome/potentially hepatotoxic antiretrovirals. These potentially modifiable risk factors need addressing.

Hepmarc: A 96 week randomised controlled feasibility trial of add-on maraviroc in people with HIV and non-alcoholic fatty liver disease.

OBJECTIVES: Maraviroc may reduce hepatic inflammation in people with HIV and non-alcoholic fatty liver disease (HIV-NAFLD) through CCR5-receptor antagonism, which warrants further exploration. METHODS: We performed an open-label 96-week randomised-controlled feasibility trial of maraviroc plus optimised background therapy (OBT) versus OBT alone, in a 1:1 ratio, for people with virologically-suppressed HIV-1 and NAFLD without cirrhosis. Dosing followed recommendations for HIV therapy in the Summary of Product Characteristics for maraviroc. The primary outcomes were safety, recruitment and retention rates, adherence and data completeness. Secondary outcomes included the change in Fibroscan-assessed liver stiffness measurements (LSM), controlled attenuation parameter (CAP) and Enhanced Liver Fibrosis (ELF) scores. RESULTS: Fifty-three participants (53/60, 88% of target) were recruited; 23 received maraviroc plus OBT; 89% were male; 19% had type 2 diabetes mellitus. The median baseline LSM, CAP & ELF scores were 6.2 (IQR 4.6-7.8) kPa, 325 (IQR 279-351) dB/m and 9.1 (IQR 8.6-9.6) respectively. Primary outcomes: all individuals eligible after screening were randomised; there was 92% (SD 6.6%) adherence to maraviroc [target >90%]; 83% (95%CI 70%-92%) participant retention [target >65%]; 5.5% of data were missing [target <20%]. There were noo Serious Adverse Reactions; mild-moderate intensity Adverse Reactions were reported by five participants (5/23, 22% (95%CI 5%-49%)) [target <10%]. All Adverse Reactions resolved. Secondary outcomes: no important differences were seen by treatment group for the change from baseline in LSM, CAP or ELF scores. CONCLUSIONS: This feasibility study provides preliminary evidence of maraviroc safety amongst people with HIV-NAFLD, and acceptable recruitment, retention, and adherence rates. These data support a definitive randomised-controlled trial assessing maraviroc impact on hepatic steatosis and fibrosis. TRIAL REGISTRATION: Clinical trial registry: ISCRTN, registration number 31461655.

Palliative clinical trials in advanced chronic liver disease: Challenges and opportunities.

Patients with advanced chronic liver disease have a complex symptom burden and many are not candidates for curative therapy. Despite this, provision of palliative interventions remains woefully inadequate, with an insufficient evidence base being a contributory factor. Designing and conducting palliative interventional trials in advanced chronic liver disease remains challenging for a multitude of reasons. In this manuscript we review past and ongoing palliative interventional trials. We identify barriers and facilitators and offer guidance on addressing these challenges. We hope that this will reduce the inequity in palliative care provision in advanced chronic liver disease.

Tandem mass tag-based quantitative proteomic profiling identifies candidate serum biomarkers of drug-induced liver injury in humans.

Diagnosis of drug-induced liver injury (DILI) and its distinction from other liver diseases are significant challenges in drug development and clinical practice. Here, we identify, confirm, and replicate the biomarker performance characteristics of candidate proteins in patients with DILI at onset (DO; n = 133) and follow-up (n = 120), acute non-DILI at onset (NDO; n = 63) and follow-up (n = 42), and healthy volunteers (HV; n = 104). Area under the receiver operating characteristic curve (AUC) for cytoplasmic aconitate hydratase, argininosuccinate synthase, carbamoylphosphate synthase, fumarylacetoacetase, fructose-1,6-bisphosphatase 1 (FBP1) across cohorts achieved near complete separation (range: 0.94-0.99) of DO and HV. In addition, we show that FBP1, alone or in combination with glutathione S-transferase A1 and leukocyte cell-derived chemotaxin 2, could potentially assist in clinical diagnosis by distinguishing NDO from DO (AUC range: 0.65-0.78), but further technical and clinical validation of these candidate biomarkers is needed.

Outcomes after hospitalisation with spontaneous bacterial peritonitis over a 13-year period: a retrospective cohort study.

GOALS: Assess outcomes in patients with an index presentation of spontaneous bacterial peritonitis (SBP) over a 13-year period. BACKGROUND: SBP, a bacterial infection of ascites, has a poor prognosis. STUDY: Retrospective cohort study assessing mortality (standardised to 32 months) and prognostic factors in patients with SBP during two periods: period 1 (June 2006-November 2012) and period 2 (December 2012-May 2019). RESULTS: The study included 178 patients who were followed up for 11.6 (29.2) months. Mortality was high, with 12-, 24- and 32-month survival being 32%, 26% and 24%, respectively. Inpatient mortality was 36% with mortality in those surviving hospitalisation being 62%. Serum creatinine at the time of SBP diagnosis was an independent predictor of mortality at 32 months [hazard ratio (HR) 1.002, P = 0.023] and inpatient mortality (HR 1.003, P = 0.035). Positive ascitic fluid culture and ascitic fluid neutrophil count were independent predictors of 32-month (HR 1.679, P = 0.008) and inpatient mortality (HR 1.0001, P = 0.005), respectively. Patients in period 2 had lower ascitic fluid albumin (5.9 ± 3.3 g/L vs. 10.8 ± 5.4 g/L, P < 0.001), higher ascitic fluid neutrophil count (815.0 cells/mm3 vs. 345.0 cells/mm3, P < 0.001) and higher rates of hepatorenal syndrome-acute kidney injury (58 vs. 35%, P = 0.002). Mortality at 32 months and mortality in those surviving hospitalisation were similar at 78 vs. 73%, P = 0.392 and 66 vs. 58%, P = 0.355, for periods 1 and 2, respectively. CONCLUSIONS: Despite more advanced initial presentations, mortality rates have remained similar over the last 13 years. Serum creatinine at the time of SBP diagnosis is an independent predictor of mortality.

Delivery of biannual ultrasound surveillance for individuals with cirrhosis and cured hepatitis C in the UK.

BACKGROUND: Previous studies show the uptake of biannual ultrasound (US) surveillance in patients with cirrhosis is suboptimal. Here, our goal was to understand in broader terms how surveillance is being delivered to cirrhosis patients with cured hepatitis C in the UK. METHODS: Hepatitis C cirrhosis patients achieving a sustained viral response (SVR) to antiviral therapies were identified from the national Hepatitis-C-Research-UK resource. Data on (i) liver/abdominal US examinations, (ii) HCC diagnoses, and (iii) HCC curative treatment were obtained through record-linkage to national health registries. The rate of US uptake was calculated by dividing the number of US episodes by follow-up time. RESULTS: A total of 1908 cirrhosis patients from 31 liver centres were followed for 3.8 (IQR: 3.4-4.9) years. Overall, 10 396 liver/abdominal USs were identified. The proportion with biannual US was 19% in the first 3 years after SVR and 9% for all follow-up years. Higher uptake of biannual US was associated with attending a liver transplant centre; older age and cirrhosis decompensation. Funnel plot analysis indicated significant inter-centre variability in biannual US uptake, with 6/29 centres outside control limits. Incident HCC occurred in 133 patients, of which 49/133 (37%) were treated with curative intent. The number of US episodes in the two years prior to HCC diagnosis was significantly associated with higher odds of curative-intent treatment (aOR: 1.53; 95% CI: 1.12-2,09; p = .007). CONCLUSIONS: This study provides novel data on the cascade of care for HCC in the UK. Our findings suggest biannual US is poorly targeted, inefficient and is not being delivered equitably to all patients.

Palliative long-term abdominal drains for the management of refractory ascites due to cirrhosis: a consensus document.

Palliative care remains suboptimal in advanced cirrhosis, in part relating to a lack of evidence-based interventions. Ascites remains the most common cirrhosis complication resulting in hospitalisation. Many patients with refractory ascites are not candidates for liver transplantation or transjugular intrahepatic portosystemic shunt, and therefore, require recurrent palliative large volume paracentesis in hospital. We review the available evidence on use of palliative long-term abdominal drains in cirrhosis. Pending results of a national trial (REDUCe 2) and consistent with recently published national and American guidance, long-term abdominal drains cannot be regarded as standard of care in advanced cirrhosis. They should instead be considered only on a case-by-case basis, pending definitive evidence. This manuscript provides consensus to help standardise use of long-term abdominal drains in cirrhosis including patient selection and community management. Our ultimate aim remains to improve palliative care for this under researched and vulnerable cohort.

Chronic liver disease in homeless individuals and performance of non-invasive liver fibrosis and injury markers: VALID study.

BACKGROUND/AIMS: Community-based assessment and management of chronic liver disease (CLD) in people who are homeless (PWAH) remain poorly described. We aimed to determine prevalence/predictors of CLD in PWAH and assess the performance of non-invasive liver fibrosis and injury markers. METHODS: The Vulnerable Adult LIver Disease (VALID) study provided a "one-stop" liver service based at homeless hostels. Our primary outcome was the prevalence of clinically significant hepatic fibrosis (CSHF; liver stiffness measurement (LSM) ≥8 kPa). RESULTS: Total individuals recruited were 127, mean ± SD age 47 ± 9.4 years, 50% (95% CI 41%-59%) and 39% (95% CI 31%-48%) having alcohol dependence and a positive HCV RNA respectively. CSHF was detected in 26% (95% CI 17%-35%), independent predictors being total alcohol unit/week (OR 1.01, 95% CI 1.00-1.02, P = .002) and HCV RNA positivity (OR 2.93, 95% CI 1.12-7.66, P = .029). There was moderate agreement between LSM and Enhanced Liver Fibrosis (ELF) score (kappa 0.536, P < .001) for CSHF as assessed by LSM ≥8 kPa. Those with CSHF had significantly higher levels of IFN-γ (P = .002), IL-6 (P = .001), MMP-2 (P = .006), ccCK-18 (P < .001) and ELF biomarkers (P < .001), compared to those without CSHF. Service uptake was ≥95%. Direct acting antiviral (DAA) treatment completion was 93% (95% CI 77%-99%), sustained virological response (SVR) being 83% (95% CI 64%-94%). CONCLUSION: There is a significant liver disease burden from HCV and alcohol in PWAH. Non-invasive liver fibrosis and injury markers can help in identifying such individuals in the community. Despite a challenging cohort, excellent service uptake and high DAA-based SVRs can be achieved.

Strategic treatment optimization for HCV (STOPHCV1): a randomised controlled trial of ultrashort duration therapy for chronic hepatitis C.

Background: The world health organization (WHO) has identified the need for a better understanding of which patients with hepatitis C virus (HCV) can be cured with ultrashort course HCV therapy. Methods: A total of 202 individuals with chronic HCV were randomised to fixed-duration shortened therapy (8 weeks) vs variable-duration ultrashort strategies (VUS1/2). Participants not cured following first-line treatment were retreated with 12 weeks' sofosbuvir/ledipasvir/ribavirin. The primary outcome was sustained virological response 12 weeks (SVR12) after first-line treatment and retreatment. Participants were factorially randomised to receive ribavirin with first-line treatment. Results: All evaluable participants achieved SVR12 overall (197/197, 100% [95% CI 98-100]) demonstrating non-inferiority between fixed-duration and variable-duration strategies (difference 0% [95% CI -3.8%, +3.7%], 4% pre-specified non-inferiority margin). First-line SVR12 was 91% [86%-97%] (92/101) for fixed-duration vs 48% [39%-57%] (47/98) for variable-duration, but was significantly higher for VUS2 (72% [56%-87%] (23/32)) than VUS1 (36% [25%-48%] (24/66)). Overall, first-line SVR12 was 72% [65%-78%] (70/101) without ribavirin and 68% [61%-76%] (69/98) with ribavirin (p=0.48). At treatment failure, the emergence of viral resistance was lower with ribavirin (12% [2%-30%] (3/26)) than without (38% [21%-58%] (11/29), p=0.01). Conclusions: Unsuccessful first-line short-course therapy did not compromise retreatment with sofosbuvir/ledipasvir/ribavirin (100% SVR12). SVR12 rates were significantly increased when ultrashort treatment varied between 4-7 weeks rather than 4-6 weeks. Ribavirin significantly reduced resistance emergence in those failing first-line therapy. ISRCTN Registration: 37915093 (11/04/2016).

Guidelines on the management of ascites in cirrhosis.

The British Society of Gastroenterology in collaboration with British Association for the Study of the Liver has prepared this document. The aim of this guideline is to review and summarise the evidence that guides clinical diagnosis and management of ascites in patients with cirrhosis. Substantial advances have been made in this area since the publication of the last guideline in 2007. These guidelines are based on a comprehensive literature search and comprise systematic reviews in the key areas, including the diagnostic tests, diuretic use, therapeutic paracentesis, use of albumin, transjugular intrahepatic portosystemic stent shunt, spontaneous bacterial peritonitis and beta-blockers in patients with ascites. Where recent systematic reviews and meta-analysis are available, these have been updated with additional studies. In addition, the results of prospective and retrospective studies, evidence obtained from expert committee reports and, in some instances, reports from case series have been included. Where possible, judgement has been made on the quality of information used to generate the guidelines and the specific recommendations have been made according to the 'Grading of Recommendations Assessment, Development and Evaluation (GRADE)' system. These guidelines are intended to inform practising clinicians, and it is expected that these guidelines will be revised in 3 years' time.

Palliative Long-Term Abdominal Drains Versus Large Volume Paracentesis in Refractory Ascites Due to Cirrhosis (REDUCe Study): Qualitative Outcomes.

CONTEXT: Palliative care remains suboptimal in end-stage liver disease (ESLD). OBJECTIVES: We report qualitative outcomes from the REDUCe study. We aimed to explore and contrast experiences/perceptions/care pathways of patients with refractory ascites due to ESLD randomized to either palliative long-term abdominal drains (LTADs) (allow home drainage) vs. large volume paracentesis (LVP) (hospital drainage). METHODS: Concurrent embedded qualitative study in a 12-week feasibility randomized controlled trial. Telephone interviews were conducted, data being recorded, transcribed verbatim, and analyzed using applied thematic analysis, considered in terms of a pathway approach toward accessing health care. Quantitative outcomes were collected (integrated palliative outcome scale, short-form liver disease quality of life, EQ-5D-5 L, Zarit Burden Interview-12). RESULTS: Fourteen patients (six allocated LTAD and eight LVP) and eight nurses participated in the qualitative study. The patient journey in the LVP group could be hindered by challenges along the entire care pathway, from recognizing the need for drainage to a lengthy wait in hospital for drainage and/or to be discharged. These issues also impacted upon caregivers. In contrast, LTADs appeared to transform this care pathway at all levels across the patient's journey by removing the need for hospital drainage. Additional benefits included personalized care, improved symptom control of ascites, being at home, and regular support from community nurses. Nurses also viewed the LTAD favorably, though expressed the need for additional support should this become standard of care. CONCLUSION: Patients and nurses expressed acceptability of palliative LTAD in ESLD and preference for this approach in enabling care at home. Proceeding to a definitive trial is feasible. TRIAL REGISTRATION: ISRCTN30697116, date assigned: 07/10/2015.