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Non-alcoholic fatty liver disease (NAFLD) is common, affecting approximately 25% of the general population. The evidence base for the investigation and management of NAFLD is large and growing, but there is currently little practical guidance to support development of services and delivery of care. To address this, we produced a series of evidence-based quality standard recommendations for the management of NAFLD, with the aim of improving patient care. A multidisciplinary group of experts from the British Association for the Study of the Liver and British Society of Gastroenterology NAFLD Special Interest Group produced the recommendations, which cover: management of people with, or at risk of, NAFLD before the gastroenterology or liver clinic; assessment and investigations in secondary care; and management in secondary care. The quality of evidence for each recommendation was evaluated by the Grading of Recommendation Assessment, Development and Evaluation tool. An anonymous modified Delphi voting process was conducted individually by each member of the group to assess the level of agreement with each statement. Statements were included when agreement was 80% or greater. From the final list of statements, a smaller number of auditable key performance indicators were selected to allow services to benchmark their practice. It is hoped that services will review their practice against our recommendations and key performance indicators and institute service development where needed to improve the care of patients with NAFLD.

Sustained virologic response at posttreatment Week 12 (SVR12) is the widely accepted efficacy endpoint for direct-acting antiviral agents. Those with hepatitis C virus (HCV) are presenting younger with milder liver disease, potentially reducing need for long-term liver posttreatment monitoring. This analysis aimed to determine the positive predictive value (PPV) of SVR at posttreatment Week 4 (SVR4) for achieving SVR12 in patients with HCV, without cirrhosis or with compensated cirrhosis, receiving glecaprevir/pibrentasvir (G/P) in clinical trials. An integrated dataset from 20 Phase 2 and 3 clinical trials of G/P was evaluated in patients with 8-, 12- or 16-week treatment duration consistent with the current label (label-consistent group), and in all patients regardless of treatment duration consistency with the current label (overall group). Sensitivity analyses handled missing data either by backward imputation or were excluded. SVR4 PPV, negative predictive value (NPV), sensitivity and specificity were calculated for achieving SVR12 in both groups, and by treatment duration in the label-consistent group. SVR was defined as HCV ribonucleic acidlower limit of quantification. The label-consistent group and overall group included 2890 and 4390 patients, respectively. PPV of SVR4 for SVR12 was99% in both groups regardless of treatment duration. Not achieving SVR4 had 100% NPV and sensitivity for all groups. SVR4 measure had 79.5% specificity for identifying patients who did not achieve SVR12. Across 20 Phase 2/3 clinical trials of G/P, SVR4 was highly predictive of SVR12. Long-term follow-up to confirm SVR may not be necessary for certain populations of patients with HCV.

Objectives: Micro-elimination of hepatitis C virus (HCV) in people living with HIV (PLHIV) and co-infected with HCV has been proposed as a key contribution to the overall goal of HCV elimination. While other studies have examined micro-elimination in HIV-treated cohorts, few have considered HCV micro-elimination among those not treated for HIV or at a national level. Methods: Through data linkage of national and sentinel surveillance data, we examined the extent of HCV testing, diagnosis and treatment among a cohort of PLHIV in Scotland identified through the national database of HIV-diagnosed individuals, up to the end of 2017. Results: Of 5018 PLHIV, an estimated 797 (15%) had never been tested for HCV and 70 (9%) of these had undiagnosed chronic HCV. The odds of never having been tested for HCV were the highest in those not on HIV treatment [adjusted odds ratio (aOR) = 7.21, 95% confidence interval (CI): 5.15–10.10). Overall HCV antibody positivity was 11%, and it was at its highest among people who inject drugs (49%). Most of those with chronic HCV (91%) had attended an HCV treatment clinic but only half had been successfully treated (54% for those on HIV treatment, 12% for those not) by the end of 2017. The odds of never having been treated for HCV were the highest in those not on HIV treatment (aOR = 3.60, 95% CI: 1.59–8.15). Conclusions: Our data demonstrate that micro-elimination of HCV in PLHIV is achievable but progress will require increased effort to engage and treat those co-infected, including those not being treated for their HIV.

Background: Highly effective direct-acting antiviral drugs provide the opportunity to eliminate hepatitis C virus (HCV) infection, but established pathways can be ineffective. We aimed to examine whether a community pharmacy care pathway increased treatment uptake, treatment completion, and cure rates for people receiving opioid substitution therapy, compared with conventional care. Methods: This cluster-randomised trial was done in Scottish community pharmacies. Before participants were recruited, pharmacies were randomly assigned (1:1) to refer patients with evidence of HCV antibodies to conventional care or offered them care in the pharmacy (pharmacist-led care). Pharmacies were stratified by location. All pharmacies were trained to offer dried blood spot testing. All eligible participants had received opioid substitution therapy for approximately 3 months, and those eligible to receive treatment in the pharmacist-led care pathway were HCV PCR positive, were infected with HCV genotype 1 or 3, and were willing to have a pharmacist supervise their antiviral drug administration. Neither pharmacists nor patients were masked to treatment allocation. In both groups, assessment blood samples were taken, infection with HCV was confirmed, and daily oral ledipasvir–sofosbuvir (90 mg ledipasivir plus 400 mg sofosbuvir) for 8 weeks for genotype 1 or daily oral sofosbuvir (400 mg) plus oral daclatasvir (60 mg) for 12 weeks for genotype 3 was prescribed by a nurse (conventional care group) or pharmacist (pharmacist-led care group). In the conventional care group, the patient received care at a treatment centre. Once prescribed, medication in both groups was delivered as daily modified directly observed therapy alongside opioid substitution therapy in the participants' pharmacy where treatment was observed on 6 days per week. The primary outcome was the number of patients with sustained virological response 12 weeks after completion of treatment (SVR12) as a proportion of the number of people receiving opioid substitution therapy at participating pharmacies. Participants were monitored at each visit for nausea and fatigue; other adverse events were recorded as free text. Secondary outcomes compared key points on treatment pathway between the two groups. These key points were the proportion of patients having dry blood spot testing, the proportion of patients initiating HCV treatment, the proportion of patients completing the 8 or 12 week HCV course of treatment, and the proportion of patients with sustained virological response at 12 months. This study is registered with ClinicalTrials.gov, NCT02706223. Findings: 56 pharmacies were randomly assigned (28 to each group; one pharmacy withdrew from the conventional care group). The 55 participating pharmacies included 2718 patients receiving opioid substitution therapy (1365 in the pharmacist-led care group and 1353 in the conventional care group). More patients met the primary endpoint of SVR12 in the pharmacist-led care group (98 [7%] of 1365) than in the conventional care group (43 [3%] of 1353; odds ratio 2·375, 95% CI 1·555–3·628, p

Introduction: More than 70 million people are estimated to be infected with hepatitis C virus globally. Glecaprevir/pibrentasvir is a widely used treatment and has recently been approved for an 8-week regimen for treatment-naïve patients with compensated cirrhosis in Europe and the USA, who would previously have received glecaprevir/pibrentasvir for 12 weeks. This label update was based on the EXPEDITION-8 study, which included 343 treatment-naïve patients with compensated cirrhosis. However, there is currently a lack of similarly large-scale real-world studies of the 8-week glecaprevir/pibrentasvir regimen in this population. Methods: This summary of seven separate smaller real-world studies aims to validate the results seen in EXPEDITION-8 and provide an up-to-date real-world reference for clinicians making treatment decisions for patients with compensated cirrhosis (Child–Pugh A) who may benefit from a shorter-duration therapy with glecaprevir/pibrentasvir. The newly emerging real-world effectiveness data on treatment-naïve patients with compensated cirrhosis treated with 8 weeks of glecaprevir/pibrentasvir help to understand where further research is needed to support patients with hepatitis C virus. Results: Across all seven studies, glecaprevir/pibrentasvir showed high effectiveness with an average sustained virologic response rate of 98.1%, similar to that found in a clinical trial setting (99.7%). Only one patient (0.5%) experienced virologic failure and treatment was well tolerated. Conclusion: Expanding the number of patients eligible for the shortened treatment duration will potentially increase treatment initiation and completion, particularly in underserved populations, contributing to the elimination of hepatitis C virus.

ObjectivePopulation-based studies demonstrating the clinical impact of interferon-free direct-acting antiviral (DAA) therapies are lacking. We examined the impact of the introduction of DAAs on HCV-related decompensated cirrhosis (DC) through analysis of population-based data from Scotland.DesignThrough analysis of national surveillance data (involving linkage of HCV diagnosis and clinical databases to hospital and deaths registers), we determined i) the scale-up in the number of patients treated and achieving a sustained viral response (SVR), and ii) the change in the trend of new presentations with HCV-related DC, with the introduction of DAAs.ResultsApproximately 11 000 patients had been treated in Scotland over the 8-year period 2010/11 to 2017/18. The scale-up in the number of patients achieving SVR between the pre-DAA and DAA eras was 2.3-fold overall and 5.9-fold among those with compensated cirrhosis (the group at immediate risk of developing DC). In the pre-DAA era, the annual number of HCV-related DC presentations increased 4.6-fold between 2000 (30) and 2014 (142). In the DAA era, presentations decreased by 51% to 69 in 2018 (and by 67% among those with chronic infection at presentation), representing a significant change in trend (rate ratio 0.88, 95% CI 0.85 to 0.90). With the introduction of DAAs, an estimated 330 DC cases had been averted during 2015–18.ConclusionsNational scale-up in interferon-free DAA treatment is associated with the rapid downturn in presentations of HCV-related DC at the population-level. Major progress in averting HCV-related DC in the short-term is feasible, and thus other countries should strive to achieve the same.

BACKGROUND & AIMS: Scale-up of highly-effective direct-acting antivirals (DAAs) for hepatitis C virus (HCV) among people who inject drugs (PWID) in Scotland has led to a reduction in prevalence of viraemia in this population. However, the extent of reinfection among those treated with DAAs remains uncertain. We estimated HCV reinfection rates among PWID in Scotland by treatment setting, pre and post-introduction of DAAs, and the potential number of undiagnosed reinfections resulting from incomplete follow-up testing.METHODS: Through linkage of national clinical and laboratory HCV data, a retrospective cohort of PWID who commenced treatment between 2000-2018 and achieved a sustained virological response (SVR) were followed up for reinfection to December 2019. Reinfection was defined as a positive HCV antigen or RNA test.RESULTS: Of 5686 SVRs among 5592 PWID, 4126 (73%) had an HCV RNA or antigen test post-SVR. Of those retested, we identified 361 reinfections (3.9/100 person-years (PY)). The reinfection rate increased from 1.5/100 PY among PWID treated in 2000-2009 to 8.8/100 PY in 2017-2018. The highest reinfection rates were observed among those treated in prison (14.3/100 PY) and community settings (9.5/100 PY). Among those treated in the DAA era (2015-2018), 68% were tested within the first year post-SVR but only 30% in the second year; while 169 reinfections were diagnosed in follow-up, an estimated 200 reinfections (54% of the estimated total) had gone undetected.CONCLUSIONS: HCV reinfection rates among PWID in Scotland have risen contemporaneous with the scale-up of DAAs and broadened access of treatment to those at highest risk, through delivery in community drug services. Promotion of HCV testing post-SVR among PWID is essential to ensure those reinfected are identified and retreated promptly.LAY SUMMARY: Increased rates of hepatitis C reinfection in Scotland were observed following the early phase of rapid scale-up in highly-effective direct-acting antiviral (DAA) treatment among people who inject drugs. This demonstrates that community-based treatment pathways are reaching high risk groups, regarded vital in efforts to eliminate the virus. However, we estimate that less than half of reinfections have been detected in the DAA era as a result of inadequate levels of retesting beyond the first-year following successful treatment. Sustained efforts that involve high coverage of harm reduction measures and high uptake of annual testing are required to ensure prompt diagnosis and treatment of those reinfected if the goals of elimination are to be met.

BACKGROUND & AIMS:The impact of interferon (IFN)-free therapies on the epidemiology of hepatitis C virus (HCV) related hepatocellular carcinoma (HCC) is not well understood at a population level. Our goal was to bridge this evidence gap.METHODS: This study included all patients in Scotland with chronic HCV and a diagnosis of cirrhosis during 1999-2019. Incident cases of HCC, episodes of curative HCC therapy, and HCC-related deaths were identified through linkage to nationwide registries. Three time periods were examined: 1999-2010 (pegylated interferon-ribavirin [PIR]); 2011-2013 (First-generation DAA); and 2014-2019 (IFN-free era). We used regression modelling to determine time trends for: i) number diagnosed and living with HCV cirrhosis, ii) HCC cumulative incidence, iii) HCC curative treatment uptake and iv) post-HCC mortality. RESULTS: 3347 cirrhosis patients were identified of which 381 (11.4%) developed HCC. After HCC diagnosis, 140 (36.7%) received curative HCC treatment and there were 202 deaths from HCC. The average annual number of patients diagnosed and living with HCV cirrhosis was approximately seven times higher in the IFN-free versus the PIR era, whereas the number of incident HCCs was four times higher. However, the cumulative incidence of HCC was significantly lower in the IFN-free versus PIR era (sdHR: 0.65; 95%CI:0.47-0.88; P=0.006). Among HCC patients, diagnosis in the IFN-free era was not associated with improved uptake of curative treatment (aOR:1.18; 95%CI:0.69-2.01; P=0.54), or reduced post-HCC mortality (sdHR: 0.74; 95%CI:0.53-1.05; P=0.09).CONCLUSIONS: The cumulative incidence of HCC is declining in HCV cirrhosis patients, but uptake of curative HCC therapy and post-HCC survival remain suboptimal. LAY SUMMARY: Individuals with hepatitis C cirrhosis are at high risk of developing hepatocellular carcinoma (HCC), which is the main form of primary liver cancer. Here, we shown that the incidence of hepatitis C related HCC has declined in recent years, following the introduction of new hepatitis C therapies. However, for individuals who do develop HCC, survival and uptake of curative treatment still remains poor.

Background High cure rates with licensed durations of therapy for chronic hepatitis C virus suggest that many patients are overtreated. New strategies in individuals who find it challenging to adhere to standard treatment courses could significantly contribute to the elimination agenda. Objectives To compare cure rates using variable ultrashort first-line treatment stratified by baseline viral load followed by retreatment, with a fixed 8-week first-line treatment with retreatment with or without adjunctive ribavirin. Design An open-label, multicentre, factorial randomised controlled trial. Randomisation Randomisation was computer generated, with patients allocated in a 1 : 1 ratio using a factorial design to each of biomarker-stratified variable ultrashort strategy or fixed duration and adjunctive ribavirin (or not), using a minimisation algorithm with a probabilistic element. Setting NHS. Participants A total of 202 adults (aged ≥ 18 years) infected with chronic hepatitis C virus genotype 1a/1b or 4 for ≥ 6 months, with a detectable plasma hepatitis C viral load and no significant fibrosis [FibroScan® (Echosens, Paris, France) score F0–F1 or biopsy-proven minimal fibrosis], a hepatitis C virus viral load 24 weeks on anti-human immunodeficiency virus drugs. Interventions Fixed-duration 8-week first-line therapy compared with variable ultrashort first-line therapy, initially for 4–6 weeks (continuous scale) stratified by screening viral load (variable ultrashort strategy 1, mean 32 days of treatment) and then, subsequently, for 4–7 weeks (variable ultrashort strategy 2 mean 39 days of duration), predominantly with ombitasvir, paritaprevir, ritonavir (Viekirax®; AbbVie, Chicago, IL, USA), and dasabuvir (Exviera®; AbbVie, Chicago, IL, USA) or ritonavir. All patients in whom first-line treatment was unsuccessful were immediately retreated with 12 weeks’ sofosbuvir, ledipasvir (Harvoni®, Gilead Sciences, Inc., Foster City, CA, USA) and ribavirin. Main outcome measure The primary outcome was overall sustained virological response (persistently undetectable) 12 weeks after the end of therapy (SVR12). Results A total of 202 patients were analysed. All patients in whom the primary outcome was evaluable achieved SVR12 overall [100% (197/197), 95% confidence interval 86% to 100%], demonstrating non-inferiority between fixed- and variable-duration strategies (difference 0%, 95% confidence interval –3.8% to 3.7%, prespecified non-inferiority margin 4%). A SVR12 following first-line treatment was achieved in 91% (92/101; 95% confidence interval 86% to 97%) of participants randomised to the fixed-duration strategy and by 48% (47/98; 95% confidence interval 39% to 57%) allocated to the variable-duration strategy. However, the proportion achieving SVR12 was significantly higher among those allocated to variable ultrashort strategy 2 [72% (23/32), 95% confidence interval 56% to 87%] than among those allocated to variable ultrashort strategy 1 [36% (24/66), 95% confidence interval 25% to 48%]. Overall, a SVR12 following first-line treatment was achieved by 72% (70/101) (95% confidence interval 65% to 78%) of patients treated with ribavirin and by 68% (69/98) (95% confidence interval 61% to 76%) of those not treated with ribavirin. A SVR12 with variable ultrashort strategies 1 and 2 was 52% (25/48) (95% confidence interval 38% to 65%) with ribavirin, compared with 44% (22/50) (95% confidence interval 31% to 56) without. However, at treatment failure, the emergence of viral resistance was lower with ribavirin [12% (3/26), 95% confidence interval 2% to 30%] than without [38% (11/29), 95% confidence interval 21% to 58%; p = 0.01]. All 10 individuals who became undetectable at day 3 of treatment achieved first-line SVR12 regardless of treatment duration. Five participants in the variable-duration arm and five in the fixed-duration arm experienced serious adverse events (p = 0.69), as did five participants receiving ribavirin and five participants receiving no ribavirin. Conclusions SVR12 rates were significantly higher when ultrashort treatment varied between 4 and 7 weeks, rather than between 4 and 6 weeks. We found no evidence of ribavirin significantly affecting first-line SVR12, with unsuccessful first-line short-course therapy also not compromising subsequent retreatment with sofosbuvir, ledipasvir and ribavirin. Future work A priority for future work needs to be the development and evaluation of robust predictive measures to identify those patients who can be cured with ultrashort courses of therapy. Trial registration Current Controlled Trials ISRCTN37915093, EudraCT 2015-005004-28 and CTA 19174/0370/001-0001. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a MRC and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 17. See the NIHR Journals Library website for further project information.

INTRODUCTION This study set out to examine the association between deprivation and the incidence of HCC and survival following diagnosis in the West of Scotland. METHODS Data were gathered on patients from the prospective West of Scotland regional HCC database from November 2014 to August 2017. Patients were included if they had a new diagnosis of HCC. Data on deprivation were taken from the Scottish Index of Multiple Deprivation (SIMD) 2016. RESULTS 357 patients were included in the study. There was a higher incidence rate in patients in SIMD quintile 1 (most deprived) compared with quintile 5 (least deprived) (8.4 vs 4.3 per 100,000, respectively, p

BACKGROUND AND AIMS: There has been little empirical evidence to show the 'real-world' impact of scaling-up direct-acting anti-viral (DAA) treatment among people who inject drugs (PWID) on hepatitis C virus (HCV) viraemia at a population level. We aimed to assess the population impact of rapid DAA scale-up to PWID delivered through community services-including drug treatment, pharmacies, needle exchanges and prisons-in the Tayside region of Scotland, compared with Greater Glasgow and Clyde (GGC) and the Rest of Scotland (RoS).DESIGN, SETTING AND PARTICIPANTS: Natural experiment, evaluated using data from national biennial surveys of PWID and national clinical data. Services providing injecting equipment (2010-18) and HCV treatment clinics (2017-18) across Scotland. A total of 12 492 PWID who completed a questionnaire and provided a blood spot (tested for HCV-antibodies and RNA); 4105 individuals who initiated HCV treatment.INTERVENTION AND COMPARATOR, MEASUREMENTS: The intervention was rapid DAA scale-up among PWID, which occurred in Tayside. The comparator was GGC/RoS. Trends in HCV viraemia and uptake of HCV therapy over time; sustained viral response (SVR) rates to therapy by region and treatment setting.FINDINGS: Uptake of HCV therapy (last year) among PWID between 2013-14 and 2017-18 increased from 15 to 43% in Tayside, 6 to 16% in GGC and 11 to 23% in RoS. Between 2010 and 2017-18, the prevalence of HCV viraemia (among antibody-positives) declined from 73 to 44% in Tayside, 67 to 58% in GGC and 64 to 55% in RoS. The decline in viraemia was greater in Tayside [2017-18 adjusted odds ratio (aOR) = 0.47, 95% confidence interval (CI) = 0.30-0.75, P = 0.001] than elsewhere in Scotland (2017-18 aOR = 0.89, 95% CI = 0.74-1.07, P = 0.220) relative to the baseline of 2013-14 in RoS (including GGC). Per-protocol SVR rates among PWID treated in community sites did not differ from those treated in hospital sites in Tayside (97.4 versus 100.0%, P = 0.099).CONCLUSIONS: Scale-up of direct-acting anti-viral treatment among people who inject drugs can be achieved through hepatitis C virus (HCV) testing and treatment in community drug services while maintaining high sustained viral response rates and, in the Tayside region of Scotland, has led to a substantial reduction in chronic HCV in the population.

Summary Twelve weeks sofosbuvir/velpatasvir (SOF/VEL) is a highly effective pan‐genotypic regimen for hepatitis C. Phase 2 data suggest 8 weeks of treatment may be sufficient for previously untreated noncirrhotic patients with genotype 3 (GT3) infection. To maximize the number of patients potentially cured within a fixed treatment budget, we elected to treat such patients locally eligible for treatment (F2/3), with 8 weeks of SOF/VEL. By local protocol, treatment‐naive patients with F2 (LSM > 6.9kPa

Direct‐acting antivirals (DAAs) have revolutionised the management of chronic hepatitis C virus (HCV) infection. We describe UK real‐world DAA experience. Individuals commencing HCV treatment containing a DAA regimen (Mar 2014‐Nov 2016), participating in the National HCV Research UK (HCVRUK) Cohort Study were recruited from 33 UK HCV centers. The data were prospectively entered at sites onto a centralised database. The data were reported as median (Q1‐Q3). Of the 1448 treated patients, 1054 (73%) were males, the median age being 54 years (47‐60), 900 (62%) being genotype 1 and 455 (31%) genotype 3. The majority, 887 (61%) had cirrhosis, and 590 (41%) were treatment‐experienced. DAA regimens utilised: genotype1 sofosbuvir (SOF)/Ledipasvir/±Ribavirin (625/900, 69%) and Ombitasvir/Paritaprevir/Dasabuvir/±RBV (220/900, 24%), and in genotype 3 SOF/Daclatasvir + RBV (256/455, 56%) and SOF/pegylated interferon/RBV (157/455, 35%). Overall, 1321 (91%) achieved sustained virological response (SVR12), genotype 1 vs 3, 93% vs 87%, P

Introduction: Surveillance for hepatocellular carcinoma (HCC) is recommended by national and international guidelines. However, there are no trial data on whether surveillance improves clinical outcomes in a UK cirrhosis population of mixed aetiology. Our aim was to determine the impact of, and adherence to, surveillance on overall survival. Methods: We prospectively collected data on consecutive patients diagnosed with HCC between January 2009 and December 2015 at two large UK centres. We assessed outcomes depending on whether they had been entered into an HCC surveillance programme, and if they had adhered to that. Results: Out of 985 patients diagnosed with HCC in this study, 40.0% had been enrolled in a surveillance programme. Of these, 76.6% were adherent with surveillance and 24.4% were not. Adherence to surveillance was significantly associated with improved overall survival, even when accounting for lead-time bias using different approaches (HR for 270 days lead-time adjustment 0.64, 0.53 to 0.76, p &lt, 0.001). Conclusions: When adjusted for lead-time bias, HCC surveillance is associated with improved overall survival, however, the beneficial effect of surveillance on survival was lower than reported in studies that did not account fully for lead-time bias.

Interferon-free DAA therapies have recently been licensed for patients infected with hepatitis C virus (HCV) who have decompensated cirrhosis (DC). Our aim was to describe factors associated with uptake of IFN-free DAAs in DC patients and to compare mortality risk and hospital admission rates between pre-DAA and DAA eras. This observational study used record-linkage between Scotland's HCV Clinical Database and national inpatient hospitalization and mortality registers. For the DAA uptake analysis, the study population (n = 297) was restricted to patients alive on 1 November 2014, and Cox regression was used to estimate uptake associated with various covariates. For the Cox regression of mortality comparing pre-DAA and DAA eras, the study population (n = 624) comprised those diagnosed with DC in 2005-2018; follow-up was censored at two years. DAA uptake was 63% overall and was significantly higher for treatment-experienced patients (adjusted hazard ratio (aHR) = 1.64, 95% CI:1.14-2.34), genotype 1 vs. other genotypes (aHR = 1.55. 95% CI:1.15-2.10) and lower for persons diagnosed with DC pre-2014 (0.47, 95% CI:0.33-0.68) and in Greater Glasgow (0.64, 95% CI:0.47-0.88). The intention-to-treat SVR rate was 89% (95% CI:83-93%). All-cause and liver-related mortality risk were significantly reduced among patients diagnosed with DC in the DAA era (November 2014-December 2018) compared with the pre-DAA era (2005-October 2014) (aHRs of 0.68, 95% CI:0.49-0.93; 0.69, 95% CI:0.50-0.95, respectively); in contrast, hospital admission rates were higher in the DAA era (aRR = 1.14, 95% CI:1.04-1.26). The majority of HCV-infected DC patients engaged with specialist services can be treated with IFN-free DAAs. Improved survival among patients diagnosed with DC in the DAA era supports the beneficial impact of IFN-free therapies among those with advanced liver disease.

BackgroundBereavement can have significant impacts on physical and mental health, and a minority of people experience complicated and prolonged grief responses. Primary care is ideally situated to offer bereavement care, yet UK provision remains variable and practitioners feel uncertain how best to support bereaved patients.AimTo identify what works, how, and for whom, in the management of complicated grief (CG) in primary care.Design & settingA review of evidence on the management of CG and bereavement in UK primary care settings.MethodA realist approach was taken that aims to provide causal explanations through the generation and articulation of contexts, mechanisms, and outcomes.ResultsForty-two articles were included. Evidence on the primary care management of complicated or prolonged grief was limited. GPs and nurses view bereavement support as part of their role, yet experience uncertainty over the appropriate extent of their involvement. Patients and clinicians often have differing views on the role of primary care in bereavement. Training in bereavement, local systems for reporting deaths, practitioner time, and resources can assist or hinder bereavement care provision. Practitioners find bereavement care can be emotionally challenging. Understanding patients’ needs can encourage a proactive response and help identify appropriate support.ConclusionBereavement care in primary care remains variable and practitioners feel unprepared to provide appropriate bereavement care. Patients at higher risk of complicated or prolonged grief may fail to receive the support they need from primary care. Further research is required to address the potential unmet needs of bereaved patients.

Providing person-centred end-of-life care at home and in care homes during the COVID-19 pandemic is challenging. These challenges extend beyond the interpersonal communication barriers created by wearing personal protective equipment for infection control. Visors and facemasks make it harder to hear soft voice tones or read facial expressions: key tools in empathetic communication. Traditional models of care, based on predominantly face-to-face multidisciplinary clinical consultations, have been radically overhauled in the UK and other countries worse affected by the pandemic (Costantini et al, 2020; Antunes et al, 2020). The unprecedented rapid adoption of technology including video and telehealth consultations, alongside virtual ward rounds and online team meetings, reduce infection risks and may have the advantage of enabling faster access to clinical advice (Powell et al, 2020). However, concerns that healthcare professional home visits would reduce has led to an increased focus on family members’ provision of care, including potentially the administration of end-of-life care medications (Antunes et al, 2020; Johnson et al, 2020). The pandemic has imposed massive stress on care resources and the changes in healthcare service delivery post COVID-19 look set to be substantial (Kasaraneni, 2020; Antunes et al, 2020). New models of care delivery have also created opportunities for nurses supporting people in community settings to develop their role and skills.

Introduction Hepatocellular carcinoma (HCC) causes more than 5,400 deaths per year in the UK and is rising in incidence. Previously in the UK, HCC in non-cirrhotic livers was felt to be uncommon. We sought to establish the proportion of HCC occurring in patients without cirrhosis in our region of the UK and compare characteristics of those with cirrhosis. Methods Data was collected from our prospectively collected database on patient demographics, liver aetiology, stage at presentation and outcome for patients diagnosed with HCC at our regional MDT from 2009 to 2015. Results A total of 638 patients with HCC were included. 140 (21.9%) had no underlying cirrhosis. Non-cirrhotic HCCs were older at diagnosis (72 years vs 68 years, p = 0.001), with a similar male to female ratio. Alcohol related liver disease (ArLD) was the most common underlying aetiology in patients with cirrhosis (59%; see table 1), and along with Viral hepatitis was significantly more common than patients without cirrhosis. In contrast, unknown aetiology represented the majority of diagnoses, and was significantly greater in the non-cirrhotic cohort. Patients with non-cirrhotic HCC had more advanced malignant disease at diagnosis compared to cirrhotic HCC using Barcelona Clinic Liver Cancer (BCLC) staging, p Conclusion In our study nearly 22% of HCCs occurred in patients without underlying cirrhosis. A high proportion of non-cirrhotic HCC patients had unknown aetiology of liver disease. Patients with non-cirrhotic HCC were diagnosed at an older age with more advanced disease but lower mortality compared to patients with cirrhotic HCC.

Introduction Hepatocellular carcinoma (HCC) is rising in incidence both in Scotland and the UK.1 This study set out to examine whether there is an association between deprivation and the incidence of HCC and survival following diagnosis in the West of Scotland. Methods Data was collected on patients from the prospectively collected West of Scotland regional HCC database from November 2014 to August 2017. Patients were included if they had a new diagnosis of HCC not previously diagnosed or treated elsewhere. Data on deprivation was taken from the Scottish Index of Multiple Deprivation (SIMD) 2016 Data was collected on Excel and the statistical analysis was performed using R. Chi squared, unpaired t-test and log rank tests were used as appropriate. Incidence rates were age adjusted using the European standard population. Results 357 patients were included in the study. 45% of all new cases of HCC were in patients living in the most deprived 20% postcodes. There was a higher incidence rate in patients in SIMD quintile 1 (most deprived) compared with quintile 5 (least deprived) (10.3 vs 5.5 per 100,000, respectively, p Patients in SIMD quintile 1 were younger compared with those in SIMD quintile 5, with a mean age 65.4 yrs vs 69.5 yrs respectively, p = 0.027). A significantly higher proportion of people in SIMD quintile 1 had HCV as the aetiology of their cirrhosis compared with SIMD quintile 5 (30% vs 7%, respectively, p = 0.01). There was no significant difference in patients with alcohol as the aetiology between SIMD quintile 1 and 5 (48% vs 50%, respectively, p = 0.6). Following diagnosis there was no significant difference in survival between patients in the most deprived and least deprived quintiles (median survival 368 days vs 325 days, p = 0.8). The only predictors of survival after diagnosis of HCC were BCLC stage (p Conclusions In contrast to previous studies, we found a higher incidence of HCC in both men and women living in the most deprived areas.1 The proportion of HCC patients with HCV (but not alcohol) as the aetiology of cirrhosis was higher in the most deprived compared with least deprived quintile. Following diagnosis of HCC, we found no difference in survival between patients living in the most and least deprived areas. Reference Cancer Research UK. Liver cancer incidence statistics. https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/liver-cancer/incidence (accessed 19/1/2020). Age adjusted incidence ratesSave

[BACKGROUND & AIMS] Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intra-hepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. [METHODS] We combined new and existing genotype data for 10, 516 cases and 20, 772 controls from five European and two East Asian cohorts. [RESULTS] We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, each having key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, Jak-STAT signalling, and differentiation of TH1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some well-established in the treatment of other autoimmune disorders. [CONCLUSIONS] This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. [Lay summary] Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10, 516 people with PBC and 20, 772 healthy individuals recruited in Canada, China, Italy, Japan, UK, or USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these ‘candidate genes’ to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC., 原発性胆汁性胆管炎のゲノムワイド関連解析 --国際メタ解析による新規疾患感受性遺伝子と治療薬候補の同定--. 京都大学プレスリリース. 2021-06-28.

Background & Aims: Hepatocellular carcinoma (HCC) is the leading cause of death in patients with chronic hepatitis. In this international collaboration, we sought to develop a global universal HCC risk score to predict the HCC development for patients with chronic hepatitis.Methods: A total of 17,374 patients, comprising 10,578 treated Asian patients with chronic hepatitis B (CHB), 2,510 treated Caucasian patients with CHB, 3,566 treated patients with hepatitis C virus (including 2,489 patients with cirrhosis achieving a sustained virological response) and 720 patients with non-viral hepatitis (NVH) from 11 international prospective observational cohorts or randomised controlled trials, were divided into a training cohort (3,688 Asian patients with CHB) and 9 validation cohorts with different aetiologies and ethnicities (n = 13,686).Results: We developed an HCC risk score, called the aMAP score (ranging from 0 to 100), that involves only age, male, albumin–bilirubin and platelets. This metric performed excellently in assessing HCC risk not only in patients with hepatitis of different aetiologies, but also in those with different ethnicities (C-index: 0.82–0.87). Cut-off values of 50 and 60 were best for discriminating HCC risk. The 3- or 5-year cumulative incidences of HCC were 0–0.8%, 1.5–4.8%, and 8.1–19.9% in the low- (n = 7,413, 43.6%), medium- (n = 6,529, 38.4%), and high-risk (n = 3,044, 17.9%) groups, respectively. The cut-off value of 50 was associated with a sensitivity of 85.7–100% and a negative predictive value of 99.3–100%. The cut-off value of 60 resulted in a specificity of 56.6–95.8% and a positive predictive value of 6.6–15.7%.Conclusions: This objective, simple, reliable risk score based on 5 common parameters accurately predicted HCC development, regardless of aetiology and ethnicity, which could help to establish a risk score-guided HCC surveillance strategy worldwide.Lay summary: In this international collaboration, we developed and externally validated a simple, objective and accurate prognostic tool (called the aMAP score), that involves only age, male, albumin–bilirubin and platelets. The aMAP score (ranged from 0 to 100) satisfactorily predicted the risk of hepatocellular carcinoma (HCC) development among over 17,000 patients with viral and non-viral hepatitis from 11 global prospective studies. Our findings show that the aMAP score had excellent discrimination and calibration in assessing the 5-year HCC risk among all the cohorts irrespective of aetiology and ethnicity.© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. This is an open access article under the CC BY-NC-NDlicense (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Severe alcoholic hepatitis (AH) is a dynamic process with patients presenting at different phases of disease. Change in bilirubin over 7 days has been used as an indicator of prognosis and response to corticosteroid treatment in AH. However clinical decisions are influenced by disease trajectory in the first few days of admission. We aimed to test the prognostic validity of bilirubin change within four days of admission prior to exposure to corticosteroid treatment. Data collected from patients recruited to the STOPAH trial from three Scottish centres were analysed retrospectively. The gradient of the best fit line (m) was used to calculate change in bilirubin across the first four days (mBili4) and first seven days (mBili7) of admission for each patient. Bilirubin difference (Δ) from baseline was calculated from the average bilirubin of day three/four (ΔBili4) and day six/seven (ΔBili7) and compared to baseline bilirubin (bBili). Patients exposed to corticosteroids within these time periods were excluded from analysis. Area under the receiver operator curve (AUC) was performed for day 28 and day 90 survival. A total of 155 patients had at least two datapoints across the four days, including a bBili and values at either day three or four. A total of 106 patients had at least three datapoints across seven days including a bBili and values at either day six or seven. bBili did not predict day 28 survival (AUC 0.53, p = 0.70), or day 90 survival (AUC 0.52, p = 0.74). mBili4 and ΔBili4 did not predict day 28 survival (AUC 0.57, p = 0.26; AUC 0.53, p = 0.69) or day 90 survival (AUC 0.46, p = 0.46; AUC 0.48, p = 0.67). mBili7 moderately predicted day 28 survival (AUC 0.67, p = 0.04) but not so ΔBili7 (AUC 0.66, p = 0.05). Neither mBili7 or ΔBili7 predicted day 90 survival (AUC 0.57, p = 0.27; AUC 0.57, p = 0.31). Baseline bilirubin and changes in bilirubin within the first four days of admission were not predictive of day 28 and day 90 outcome. Only 7 days after admission did a change in bilirubin reflect subsequent outcome at day 28 but not at day 90. These results suggest that the trajectory of bilirubin in the first four days of admission with severe AH prior to corticosteroid treatment are not indicative of subsequent outcome. Alternative biomarkers of disease evolution are required if informed therapeutic decisions are to be made within this early stage of hospital admission.

Doctors, nurses, and family caregivers worldwide are facing tough decisions concerning the supply and administration of medications to manage symptoms when patients are dying from covid-19 or other conditions in the community or care homes. Proposed changes in practice aimed at ensuring adequate end-of-life symptom control need careful consideration alongside appropriate training and support. Updated UK advice, including NICE rapid guidance on managing covid-19 symptoms in the community, reiterates the importance of prescribing medications in advance of need for pain, nausea and vomiting, agitation, and respiratory secretions.1-4 These drugs may be administered if needed by visiting doctors or nurses, as is already well established in some countries.4-6 However, this practice is being overhauled radically in response to the pandemic.1-3

More than 70 million people are estimated to be infected with hepatitis C virus globally. Glecaprevir/pibrentasvir is a widely used treatment and has recently been approved for an 8-week regimen for treatment-naïve patients with compensated cirrhosis in Europe and the USA, who would previously have received glecaprevir/pibrentasvir for 12 weeks. This label update was based on the EXPEDITION-8 study, which included 343 treatment-naïve patients with compensated cirrhosis. However, there is currently a lack of similarly large-scale real-world studies of the 8-week glecaprevir/pibrentasvir regimen in this population.This summary of seven separate smaller real-world studies aims to validate the results seen in EXPEDITION-8 and provide an up-to-date real-world reference for clinicians making treatment decisions for patients with compensated cirrhosis (Child-Pugh A) who may benefit from a shorter-duration therapy with glecaprevir/pibrentasvir. The newly emerging real-world effectiveness data on treatment-naïve patients with compensated cirrhosis treated with 8 weeks of glecaprevir/pibrentasvir help to understand where further research is needed to support patients with hepatitis C virus.Across all seven studies, glecaprevir/pibrentasvir showed high effectiveness with an average sustained virologic response rate of 98.1%, similar to that found in a clinical trial setting (99.7%). Only one patient (0.5%) experienced virologic failure and treatment was well tolerated.Expanding the number of patients eligible for the shortened treatment duration will potentially increase treatment initiation and completion, particularly in underserved populations, contributing to the elimination of hepatitis C virus.

Following positive serology, the gold standard confirmatory test of hepatitis C virus (HCV) infection is detection of HCV RNA by PCR. We assessed the utility of HCV core antigen testing to identify active infection among those positive for anti-HCV antibodies, when introduced to routine testing. We identified serum samples that were tested at a single laboratory in Scotland from June 2011to December 2017. Serum samples testing positive for HCV antibodies (HCV Ab positive) followed by reflex HCV core antigen (Ag) testing during the study period were identified. Those patients for whom a PCR test was requested on the baseline sample were also identified. For this group, the sensitivity and specificity of HCV Ag as a diagnostic tool were assessed using HCV PCR as gold standard. In our cohort of 744 patients, we demonstrated a sensitivity of 82.1% (95% CI 77.1%-86.2%) and a specificity of 99.8% (95% CI 98.6%-100%). Genotype 3 was associated with increased odds of a false-negative result (OR = 3.59, 95% CI: 1.32-9.71), and reduced odds of a false negative were associated with older age (odds ratio (OR)=0.92, 95% CI: 0.88-0.97 per year) and viral load (OR = 0.10, 95% CI: 0.05-0.21 per log10 IU/ml). While the implementation of HCV core antigen testing for diagnosis could lead to significant cost savings in national screening programmes, our data suggest that a significant proportion of HCV-infected individuals may be missed. These findings have implications for HCV diagnosis and determination of viral clearance after treatment, particularly in low- and middle-income regions, where genotype 3 is prevalent.

Background: Highly-effective direct acting antiviral drugs (DAAs) provide the opportunity to eliminate Hepatitis C (HCV) infection. This study examined whether a community pharmacy pathway increased treatment uptake, treatment completion and cure rates for people receiving opioid substitution therapy (OST), compared to conventional care. Methods: This cluster randomised trial was performed in 55 community pharmacies with patients receiving OST. Pharmacists either referred patients with evidence of HCV antibodies to conventional care (27 pharmacies) or assessed them in the pharmacy (28 pharmacies). All pharmacies were trained to offer dried blood spot testing (DBST). In the pharmacy arm, infection with HCV genotype 1 or 3 was confirmed, assessment bloods were taken, and DAAs were prescribed by a pharmacist. In the comparison arm, the patient received care outside the pharmacy. Once prescribed, medication in both arms was delivered as daily modified directly observed therapy alongside OST. The primary outcome was number of patients achieving sustained virologic response 12 weeks (SVR12) after treatment completion compared to total number of people receiving OST treatment at participating pharmacies. Findings: More OST users in the pharmacy arm versus the conventional care arm agreed to DBST (245 vs 145, OR 2∙292, 0∙968-5∙427, p=0∙059); more patients diagnosed with HCV, initiated (112 vs 61, OR 1∙889, 1∙276-2∙789, p=0∙0015) and completed treatment (108 vs 58, OR 1∙928, 1∙321-2∙813, p=0∙0007); more patients achieved the primary endpoint SVR12 in the pharmacy arm compared to the conventional arm (98 vs 43, OR 2∙375, 1∙555-3∙628, p< 0∙0001). Interpretation: Utilising pharmacists to deliver an HCV pathway, made testing and treatment more accessible for patients, whilst ensuring improved reach and maintaining high treatment success rates. Use of this pathway could form a key part on an integrated approach to HCV elimination. Trial Registration: Trial registration: NCT02706223. Funding Statement: Partnership between the Scottish Government, Gilead Sciences Inc. and Bristol Myers-Squib. Declaration of Interests: Dr Radley: Honorariums from Gilead and Abbvie; Research Grants from Gilead and Roche. Prof Donnan: Research grants from Novo Nordisk, GSK, Shire pharmaceuticals, Gilead and Bristol Myers Squibb. Member of the New Drugs Committee of the Scottish Medicines Consortium. Dr Barclay: Speakers fees from Abbvie, Gilead, and advisory board fees from Abbvie, BMS, Gilead, MSD. Professor Dillon: Research Grants, and Honorariums from Abbvie, Bristol Myers Squibb, Gilead, Janssen, Merck Roche Sharp & Dohme and Roche. All other authors declare no competing interests. Ethics Approval Statement: Ethics approval granted by East of Scotland Research Ethics Committee 2 (15/ES/0086), sponsor, research & development and Caldecott approvals by University of Dundee, NHS Tayside, NHS Grampian and NHS Greater Glasgow and Clyde.

BACKGROUND Primary measures for preventing morbidity and mortality associated with bleeding gastroesophageal varices in cirrhotic patients include endoscopic screening. AIM To identify factors associated with (a) screening and (b) first hospital admission for variceal bleeding among cirrhotic hepatitis C virus (HCV) patients attending specialist care in Scotland. METHODS The Scottish Hepatitis C Clinical Database was linked to national hospitalisation and deaths records to identify all chronic HCV patients diagnosed with compensated cirrhosis in 2005-2016 (n = 2741). The adjusted odds of being screened by calendar year period were estimated using logistic regression, and the adjusted hazard ratio (HR) of a first variceal bleed using Cox regression. RESULTS About 34% were screened within the period starting 12 months before and ending 12 months after cirrhosis diagnosis. The proportion screened was stable in 2005-2010 at 42%, declining to 37% in 2011-2013 and 26% in 2014-2016. Odds of screening were decreased for age-groups

Few studies have investigated clinical outcomes among patients with cirrhosis who were treated with interferon (IFN)-free direct-acting antiviral (DAA). We aimed to quantify treatment impact on first decompensated cirrhosis hospital admission, first hepatocellular carcinoma (HCC) admission, liver-related mortality and all-cause mortality among a national cohort of cirrhotic patients. Through record linkage between Scotland's HCV Clinical Database and inpatient/day-case hospitalization and deaths records, a study population comprising chronic HCV-infected patients with compensated cirrhosis and initiated on IFN-free DAA between 1 March 2013 and 31 March 2018 was analysed. Cox regression evaluated the association of each clinical outcome with time-dependent treatment status (on treatment, responder, nonresponder or noncompliant), adjusting for patient factors including Child-Pugh class. Among the study population (n = 1073) involving 1809 years of follow-up, 75 (7.0%) died (39 from liver-related causes), 47 progressed to decompensated cirrhosis, and 28 developed HCC. Compared with nonresponders, treatment response (96% among those attending their 12 weeks post-treatment SVR test) was associated with a reduced relative risk of decompensated cirrhosis (hazard ratio [HR] = 0.14; 95% CI: 0.05-0.39), HCC (HR = 0.17; 95% CI: 0.04-0.79), liver-related death (HR = 0.13; 95% CI: 0.05-0.34) and all-cause mortality (HR = 0.30; 95% CI: 0.12-0.76). Compared with responders, noncompliant patients had an increased risk of liver-related (HR = 6.73; 95% CI: 2.99-15.1) and all-cause (HR = 5.45; 95% CI: 3.07-9.68) mortality. For HCV patients with cirrhosis, a treatment response was associated with a lower risk of severe liver complications and improved survival. Our findings suggest additional effort is warranted to address the higher mortality among the minority of cirrhotic patients who do not comply with DAA treatment or associated RNA testing.

Introduction Prognosis in refractory ascites (RA) is poor and patient selection for TIPSS challenging. In 2011 Bureau et al identified Bilirubin 75 x 109/L, the ‘Bureau Criteria’ (BC), to be predictive of survival post-TIPSS in 73% vs 31% in those out with the BC. Age over 65 yrs has also been considered a risk factor for poor outcome post-TIPSS. In this study we analyse the BC and age in a Glasgow cohort. Methods Retrospective analysis of all patients undergoing TIPSS for RA between 2011–17 in Glasgow was undertaken. Baseline pre-TIPSS data was recorded and actuarial survival at 1 year assessed in 2 groups: those that did, and did not, fulfil the BC. Age >65, in isolation of other variables, with 1 year survival was also assessed. Results 31 patients underwent TIPSS for RA in this 7 year period. Liver disease aetiology was alcohol (± Hepatitis C) in 87%. At baseline pre-TIPSS the mean age was 58.1 yrs (range 36–79), MELD 12.5 (7–21), Bilirubin 30 (5–127) and Platelet count 161 (15–364). 22 patients fulfilled the BC, 2 were transplanted within 1 year of TIPSS. None of the 9 non-BC patients were transplanted. Actuarial 1 year survival was 14/22 (63.6%) in the BC group and 3/9 (33.3%) in the non-BC group. Of the 6 patients over 65 yrs, all - except 1 who was transplanted - died within 1 year of TIPSS, this was despite 5 of those 6 fulfilling the BC. Mean transplant-free survival in patients over 65 yrs was 4.1 months (Range 0.75–8 months). Of those that were both Conclusion The combination of bilirubin 75 is predictive of survival post-TIPSS for refractory ascites in our regional cohort and these outcomes are similar to those in the published literature. However, regardless of the bilirubin and platelet count, great caution should be exercised when considering TIPSS in any patient over the age of 65.

BackgroundThe WHO has identified the need for a better understanding of which patients can be cured with ultrashort course hepatitis C (HCV) therapyMethods202 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. 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.ResultsAll 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).ConclusionsUnsuccessful 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.RegistrationISRCTN 37915093.FundingNational Institutes of Health Research.

ObjectivesTo investigate the experiences and views of practitioners in the UK and Ireland concerning changes in bereavement care during the COVID-19 pandemic.DesignOnline survey using a snowball sampling approach.SettingPractitioners working in hospitals, hospices, care homes and community settings across the UK and Ireland.ParticipantsHealth and social care professionals involved in bereavement support.InterventionsBrief online survey distributed widely across health and social care organisations.Results805 respondents working in hospice, community, and hospital settings across the UK and Ireland completed the survey between 3 August and 4 September 2020. Changes to bereavement care practice were reported in: the use of telephone, video and other forms of remote support (90%); supporting people bereaved from non-COVID conditions (76%), from COVID-19 (65%) and people bereaved before the pandemic (61%); funeral arrangements (61%); identifying bereaved people who might need support (56%); managing complex forms of grief (48%) and access to specialist services (41%). Free-text responses demonstrated the complexities and scale of the impact on health and social care services, practitioners and their relationships with bereaved families, and on bereaved people.ConclusionsThe pandemic has created major challenges for the support of bereaved people: increased needs for bereavement care, transition to remote forms of support and the stresses experienced by practitioners, among others. The extent to which services are able to adapt, meet the escalating level of need and help to prevent a ‘tsunami of grief’ remains to be seen. The pandemic has highlighted the need for bereavement care to be considered an integral part of health and social care provision.

Background & Aims The number of people living with previous hepatitis C infection that have attained a sustained viral response (SVR) is expected to grow rapidly. So far, the prognosis of this group relative to the general population is unclear. Methods Individuals attaining SVR in Scotland in 1996–2011 were identified using a national database. Through record-linkage, we obtained cause-specific mortality data complete to Dec 2013. We calculated standardised mortality ratios (SMRs) to compare the frequency of mortality in SVR patients to the general population. In a parallel analysis, we used Cox regression to identify modifiable patient characteristics associated with post-SVR mortality. Results We identified 1824 patients, followed on average for 5.2years after SVR. In total, 78 deaths were observed. Overall, all-cause mortality was 1.9 times more frequent for SVR patients than the general population (SMR: 1.86; 95% confidence interval (CI): 1.49–2.32). Significant cause-specific elevations were seen for death due to primary liver cancer (SMR: 23.50; 95% CI: 12.23–45.16), and death due to drug-related causes (SMR: 6.58, 95% CI: 4.15–10.45). Together these two causes accounted for 66% of the total excess death observed. All of the modifiable characteristics associated with increased mortality were markers either of heavy alcohol use or injecting drug use. Individuals without these behavioural markers (32.8% of cohort) experienced equivalent survival to the general population (SMR: 0.70; 95% CI: 0.41–1.18) Conclusions Mortality in Scottish SVR patients is higher overall than the general population. The excess was driven by death from drug-related causes and liver cancer. Health risk behaviours emerged as important modifiable determinants of mortality in this population. Lay summary Patients cured of hepatitis C through treatment had a higher mortality rate overall than the general population. Most of the surplus mortality was due to drug-related causes and death from liver cancer. A history of heavy alcohol and injecting drug use were associated with a higher mortality risk.

Prisoners are a priority group for hepatitis C (HCV) treatment. Although treatment durations will become shorter using directly acting antivirals (DAAs), nearly half of prison sentences in Scotland are too short to allow completion of DAA therapy prior to release. The purpose of this study was to compare treatment outcomes between prison- and community-based patients and to examine the impact of prison release or transfer during therapy. A national database was used to compare treatment outcomes between prison treatment initiates and a matched community sample. Additional data were collected to investigate the impact of release or transfer on treatment outcomes. Treatment-naïve patients infected with genotype 1/2/3/4 and treated between 2009 and 2012 were eligible for inclusion. 291 prison initiates were matched with 1137 community initiates: SVRs were 61% (95% CI 55%–66%) and 63% (95% CI 60%–66%), respectively. Odds of achieving a SVR were not significantly associated with prisoner status (P=.33). SVRs were 74% (95% CI 65%–81%), 59% (95% CI 42%– 75%) and 45% (95% CI 29%–62%) among those not released or transferred, transferred during treatment, or released during treatment, respectively. Odds of achieving a SVR were significantly associated with release (P

Background & Aims Spontaneous clearance of chronic hepatitis C virus (HCV) infection (CHC) is rare. We conducted a retrospective case-control study to identify rates and factors associated with spontaneous clearance of CHC. Methods We defined cases as individuals who spontaneously resolved CHC, and controls as individuals who remained chronically infected. We used data obtained on HCV testing between 1994 and 2013 in the West of Scotland to infer case/control status. Specifically, untreated patients with ⩾2 sequential samples positive for HCV RNA ⩾6months apart followed by ⩾1 negative test, and those with ⩾2 positive samples ⩾6months apart with no subsequent negative samples were identified. Control patients were randomly selected from the second group (4/patient of interest). Case notes were reviewed and patient characteristics obtained. Results 25,113 samples were positive for HCV RNA, relating to 10,318 patients. 50 cases of late spontaneous clearance were identified, contributing 241 person-years follow-up. 2,518 untreated, chronically infected controls were identified, contributing 13,766 person-years follow-up, from whom 200 controls were randomly selected. The incidence rate of spontaneous clearance was 0.36/100 person-years follow-up, occurring after a median 50months' infection. Spontaneous clearance was positively associated with female gender, younger age at infection, lower HCV RNA load and co-infection with hepatitis B virus. It was negatively associated with current intravenous drug use. Conclusions Spontaneous clearance of CHC occurs infrequently but is associated with identifiable host and viral factors. More frequent HCV RNA monitoring may be appropriate in selected patient groups. Lay summary Clearance of hepatitis C virus infection without treatment occurs rarely once chronic infection has been established. We interrogated a large Scottish patient cohort and found that it was more common in females, patients infected at a younger age or with lower levels of HCV in the blood, and patients co-infected with hepatitis B virus. Patients who injected drugs were less likely to spontaneously clear chronic infection.

Background: The anticipatory prescribing of injectable medications to provide end-of-life symptom relief is an established community practice in a number of countries. The evidence base to support this practice is unclear. Aim: To review the published evidence concerning anticipatory prescribing of injectable medications for adults at the end of life in the community. Design: Systematic review and narrative synthesis. Registered in PROSPERO: CRD42016052108, on 15 December 2016 ( https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=52108 ). Data sources: Medline, CINAHL, Embase, PsycINFO, Web of Science, Cochrane Library, King’s Fund, Social Care Online, and Health Management Information Consortium databases were searched up to May 2017, alongside reference, citation, and journal hand searches. Included papers presented empirical research on the anticipatory prescribing of injectable medications for symptom control in adults at the end of life. Research quality was appraised using Gough’s ‘Weight of Evidence’ framework. Results: The search yielded 5099 papers, of which 34 were included in the synthesis. Healthcare professionals believe anticipatory prescribing provides reassurance, effective symptom control, and helps to prevent crisis hospital admissions. The attitudes of patients towards anticipatory prescribing remain unknown. It is a low-cost intervention, but there is inadequate evidence to draw conclusions about its impact on symptom control and comfort or crisis hospital admissions. Conclusion: Current anticipatory prescribing practice and policy is based on an inadequate evidence base. The views and experiences of patients and their family carers towards anticipatory prescribing need urgent investigation. Further research is needed to investigate the impact of anticipatory prescribing on patients’ symptoms and comfort, patient safety, and hospital admissions.

The United Kingdom National Review of Asthma Deaths (NRAD) recommends that patients who require ≥3 courses of oral corticosteroids (OCS) for exacerbations in the past year or those on British Thoracic Society (BTS) Step 4/5 treatment must be referred to a specialist asthma service. The aim of the study was to identify the proportion of asthma patients in primary care that fulfil NRAD criteria for specialist referral and factors associated with frequent exacerbations. A total of 2639 adult asthma patients from 10 primary care practices in Glasgow, UK were retrospectively studied between 2014 and 2015. Frequent exacerbators and short-acting β2-agonist (SABA) over-users were identified if they received ≥2 confirmed OCS courses for asthma and ≥13 SABA inhalers in the past year, respectively. Community dispensing data were used to assess treatment adherence defined as taking ≥75% of prescribed inhaled corticosteroid (ICS) dose. The study population included 185 (7%) frequent exacerbators, 137 (5%) SABA over-users, and 319 (12%) patients on BTS Step 4/5 treatment. Among frequent exacerbators, 41% required BTS Step 4/5 treatment, 46% had suboptimal ICS adherence, 42% had not attended an asthma review in the past year and 42% had no previous input from a specialist asthma service. Older age, female gender, BTS Step 4/5, SABA over-use and co-existing COPD diagnosis increased the risk of frequent exacerbations independently. Fourteen per 100 asthma patients would fulfil the NRAD criteria for specialist referral. Better collaboration between primary and secondary care asthma services is needed to improve chronic asthma care., Asthma: A need for integrated care An audit of asthma patients in Scotland reveals the need for better integration between primary care providers and secondary asthma specialists. The UK National Review of Asthma Deaths highlighted 19 recommendations to prevent avoidable asthma deaths, including specialist referrals for those who over-use reliever inhalers or are admitted to hospital regularly. Wai-Ting Lee at the University of Glasgow, Scotland, and co-workers conducted an audit of 2,639 adult asthma patients from across Glasgow between 2014 and 2015. Their data suggest around 15 per cent of active asthma sufferers would benefit from secondary specialist asthma referrals, yet 42 per cent of those with the most severe symptoms had not attended annual asthma reviews. The patients in this group were also more likely to expose themselves to avoidable asthma triggers such as smoking and over-use of reliever inhalers.

Chronic coinfection with hepatitis C virus (HCV) and hepatitis B virus (HBV) is associated with adverse liver outcomes. The clinical impact of previous HBV infection on liver disease in HCV infection is unknown. We aimed at determining any association of previous HBV infection with liver outcomes using antibodies to the hepatitis B core antigen (HBcAb) positivity as a marker of exposure. The Scottish Hepatitis C Clinical Database containing data for all patients attending HCV clinics in participating health boards was linked to the HBV diagnostic registry and mortality data from Information Services Division, Scotland. Survival analyses with competing risks were constructed for time from the first appointment to decompensated cirrhosis, hepatocellular carcinoma (HCC) and liver-related mortality. Records of 8513 chronic HCV patients were included in the analyses (87 HBcAb positive and HBV surface antigen [HBsAg] positive, 1577 HBcAb positive and HBsAg negative, and 6849 HBcAb negative). Multivariate cause-specific proportional hazards models showed previous HBV infection (HBcAb positive and HBsAg negative) significantly increased the risks of decompensated cirrhosis (hazard ratio [HR]: 1.29, 95% CI: 1.01-1.65) and HCC (HR: 1.64, 95% CI: 1.09-2.49), but not liver-related death (HR: 1.02, 95% CI: 0.80-1.30). This is the largest study to date showing an association between previous HBV infection and certain adverse liver outcomes in HCV infection. Our analyses add significantly to evidence which suggests that HBV infection adversely affects liver health despite apparent clearance. This has important implications for HBV vaccination policy and indications for prioritization of HCV therapy.

Introduction Surveillance for hepatocellular carcinoma (HCC) is recommended by national and international guidelines. However, there are limited data on the impact of surveillance on clinical outcome. Our aim was to compare the stage of disease at diagnosis, treatment employed and survival, among those patients complying with, not complying with, or never entered into, a surveillance programme over a 7 year period at our regional centre. Methods We analysed data from our prospectively collected regional HCC MDT database on patients diagnosed with HCC from January 2009 to December 2015. Demographics, Child Pugh score and Barcelona-Clinic Liver Cancer (BCLC) stage at diagnosis were collated, as were the treatment strategy employed and survival. We compared the stage of disease, treatment undertaken and survival across 3 pre-identified groups: 1. Compliant with surveillance (enrolled in surveillance and last ultrasound (US) 9 months); 3. Never enrolled into a surveillance programme. Kaplan-Meier, log rank analysis and chi-squared tests were used as appropriate. Results 641 patients were diagnosed with HCC over this period. Follow up data was available for 638 (99.5%) patients with mean follow-up 15 months. Mean age at diagnosis was 69 years and 82.3% were male. HCC diagnoses increased from 62 in 2009, to 143 in 2015. 52.8% of patients had alcoholic liver diseases, 16.8% NAFLD and 15.4% hepatitis C. 160 (25.1%) patients were from Group 1, 54 (8.5%) from group 2 and 424 (66.5%) from group 3. There was an increase in the proportion of patients with HCC who were diagnosed in a surveillance programme during the study period (p Conclusions The annual number of patients diagnosed with HCC at our regional Centre increased by over 100% during the 7 year study period. A minority of patients diagnosed with HCC were enrolled in a surveillance programme, although the proportion increased over time. HCC Patients enrolled in a surveillance programme had lower BCLC stage at diagnosis, were more likely to receive curative treatment and had improved survival.

Aim Previous studies have suggested an unmet symptom burden in patients with decompensated chronic liver disease (DCLD). The Bristol Prognosis Score (BPS) has been designed to identify patients with DCLD likely to be in the last year of their life, who may benefit from Specialist Palliative Care team input. We aimed to audit the prevalence of symptoms appropriate to trigger referal to the Hospital Specialist Palliative Care Team (HSPCT), (using the Integrated Palliative care Outcome Score (IPOS)), rates of recognition of these by physicians, and rates of referral to HPSCT according to BPS status. Methods A prospective audit of all inpatients with DCLD admitted over 3 months was conducted. Patients completed IPOS questionnaires. Demographic data were collated in order to calculate BPS. Case notes were reviewed following discharge to assess if significant symptoms (regarded as scoring ‰¥ 2 on IPOS) were identified by the medical team. Referral rates to HSPCT were also recorded. Results 40 patients with DCLD were included. 36 (90%) scored ‰¥2 in at least one IPOS category. Most patients (20(55.6%)) had only some of their significant symptoms recognised by medical staff. 27/40 (67.5%) patients were BPS positive. Of these only 1 (3.7%) was referred to HSPCT. Conclusions This work demonstrates a significant symptom burden in patients with DCLD. This does not appear to be recognised by the medial team, meaning referral rates to HSPCT are low. Routine use of the IPOS in conjunction with BPS may aid identification and referral of patients to HSPCT, and help address this.