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The majority of Australia's hepatitis B virus (HBV) burden is borne by culturally and linguistically diverse (CALD) populations, and antiviral treatment is the mainstay of intervention. Using modelling, we estimated the impact of targeted antiviral treatment scale-up and changes in migration on HBV-related mortality and HBV elimination in CALD populations in Australia. We fitted a deterministic mathematical model based on the natural history of HBV and the Australian migration effect in four CALD population groups according to country of birth. We used three antiviral treatment scale-up scenarios: baseline (9.3% coverage); intermediate (coverage of 80% of patients eligible for antiviral therapy by 2030); and optimistic (coverage of 20% of all patients living with HBV by 2022). Our model predicted that if the baseline treatment is followed between 2015 and 2030, the number of chronic HBV cases and HBV-related mortality will increase. Following the optimistic scale-up, the number of new HBV cases could be reduced by 78%, 73%, 74% and 83% in people born in Asia-Pacific, Europe, Africa and the Middle East, and Americas, respectively, between 2015 and 2030. An optimistic treatment scale-up could result in a 19.2%-24.5% reduction in HBV-related mortality and a 15%-25% reduction in HCC-related mortality in CALD populations between 2015 and 2030. In conclusion, our findings highlight that targeted antiviral treatment for CALD populations provides significant health system benefits by reducing HBV-related complications from cirrhosis and HCC. Expanded antiviral treatment programmes focusing on high-prevalence CALD populations may be an effective strategy to reduce HBV-related morbidity and mortality.

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

This study explored the epidemiology and health literacy of people affected by viral hepatitis (VH) from migrant culturally and linguistically diverse (CALD) backgrounds attending a community-based general practitioner and specialty hepatology shared-care (HEPREACH) clinic in Brisbane, Australia. Patient-reported data on health literacy and clinical information from adult patients (n = 66) of CALD background recruited from the liver clinic were analyzed. Health literacy was assessed using a 5-question, 12-point scale. Variance weighted multiple linear regression was used to identify factors associated with knowledge about VH. About three-quarters of patients (74.2%) were diagnosed with hepatitis B. The median knowledge score was 7.8 (interquartile range [IQR] 6‒9). One in five patients did not understand the infective nature of VH, 30.3% did not understand mother-to-child transmission risk, and 30–40% of patients thought activities such as kissing, sharing food or mosquito bites could spread VH. Only 6% of patients understood the risk of liver cancer and the need for regular screening. Higher educational level (secondary, β = 4.8, p

Background and Aim Surveillance and early detection and curative treatment of hepatocellular carcinoma (HCC) are the mainstay of improving survival for patients, but there are several barriers to achieving this goal. We reported the impact of remoteness of residence on receipt of treatment, tumor stage, and survival in patients with HCC in Queensland. Methods We conducted a retrospective cohort study of 1651 HCC patients (147 migrants) from 1 January 2007 to 31 December 2016. We used Wilcoxon rank‐sum test to compare the median age at the time of diagnosis and Bayesian Weibull accelerated failure time regression to identify independent predictors of time to death. Results The median survival time after HCC diagnosis was 9.0 months (interquartile range 2.0–24.0). Metropolitan residence (P = 0.02), non‐English language (P, In a cohort study of 1651 patients with hepatocellular carcinoma, we found patients living in rural and remote areas were more likely to present with late stage of tumor, less likely to receive curative treatment such as surgical resection, and experience 25% shorter survival time. In a multivariate analysis, remote residence, preferred language, older age at presentation, poorly differentiated tumor, and presence of medical comorbidity were associated with poorer HCC survival, possibly because of limited access to surveillance and curative treatment.

Background and Aim Health‐related quality‐of‐life measurements are important to understand lived experiences of patients who have cirrhosis. These measures also inform economic evaluations by modelling quality‐adjusted life years (QALYs). We aimed to describe health‐related quality of life, specifically multiattribute utility (scale anchors of death = 0.00 and full health = 1.00), across various stages and etiologies of cirrhosis. Methods Face‐to‐face interviews were used to collect Short Form 36 (SF‐36) questionnaire responses from CirCare study participants with cirrhosis (June 2017 to December 2018). The severity of cirrhosis was assessed using the Child‐Pugh score classified as class A (5–6 points), B (7–9), or C (10–15) and by the absence (“compensated”) versus presence (“decompensated”) of cirrhosis‐related complications. Results Patients (n = 562, average 59.8 years [SD = 11.0], male 69.9%) had a range of primary etiologies (alcohol‐related 35.2%, chronic hepatitis C 25.4%, non‐alcoholic fatty liver disease (NAFLD) 25.1%, chronic hepatitis B 5.9%, “other” 8.4%). Significantly lower (all P, Measuring health‐related quality of life is important for understanding patients' experiences living with cirrhosis. Multiattribute utility is a summary measure commonly derived from health‐related quality‐of‐life questionnaires by applying population‐based preference weights with anchors of death (0.00) and perfect health (1.00) and is used in health state modelling, including economic evaluations that incorporate quality‐adjusted life years (known as QALYs). Here, we report health‐related quality‐of‐life and multiattribute utility values for a range of cirrhosis disease stages. These values will inform both clinical and economic research, including cost‐effectiveness modelling that captures benefits to both the quantity and quality of people's lives through the better prevention and management of cirrhosis.

Background: We report the development and psychometric testing of a Supportive Needs Assessment tool for Cirrhosis (SNAC).Methods: The 50-item SNAC was administered to patients (n=465) diagnosed with cirrhosis recruited from five metropolitan hospitals in Queensland, Australia. Items were assessed for ceiling and floor effects, and exploratory factor analysis was used to assess the factor structure. Identified factors were assessed for internal consistency and convergent validity to validated psychosocial tools.Results: Exploratory factor analysis identified 4 factors (39 items), which together accounted for 49.2% of the total variance. The 39-item SNAC met the requirements of a needs assessment tool and identified a range of needs important to patients with cirrhosis that were grouped in four subscales: "Psychosocial issues", "Practical and physical needs", "Information needs", and "Lifestyle changes". Cronbach's alpha values for the four subscales ranged from 0.64 to 0.92. Convergent validity was supported by a strong correlation between the total SNAC score and that of the Chronic Liver Disease Questionnaire (CLDQ; Spearman rho -0.68; p

Christina M Bernardes,1 Paul J Clark,2 Cath Brown,1 Katherine Stuart,3 Gregory Pratt,1 Maree Toombs,4 Gunter Hartel,1 Elizabeth E Powell,3,5,&ast; Patricia C Valery1,&ast; 1QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; 2Department of Gastroenterology and Hepatology, Mater Hospitals, Brisbane, QLD, Australia; 3Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, QLD, Australia; 4Rural Clinical School, Faculty of Medicine, University of Queensland, Toowoomba, QLD, Australia; 5Centre for Liver Disease Research, Translational Research Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia&ast;These authors contributed equally to this workCorrespondence: Patricia C Valery Tel +61 07 3362 0376Email Patricia.Valery@qimrberghofer.edu.auPurpose: Understanding and responding to the supportive care needs of people with cirrhosis is essential to quality care. Indigenous Australians, Aboriginal and Torres Strait Islander people, are overrepresented amongst patients with cirrhosis. This study documented the nature and extent of supportive care needs of Indigenous Australians with cirrhosis, in comparison with non-Indigenous Australians.Patients and Methods: The supportive care needs of adult patients diagnosed with cirrhosis attending public hospitals in Queensland were assessed through the Supportive Needs Assessment tool for Cirrhosis (SNAC). Patients indicated how much additional help they needed on four subscales: 1. psychosocial issues; 2. practical and physical needs; 3. information needs; and 4. lifestyle changes. We examined the rate of moderate-to-high unmet needs based on Indigenous status (Poisson regression; incidence rate ratio (IRR)).Results: Indigenous (n=20) and non-Indigenous (n=438) patients included in the study had similar sociodemographic and clinical characteristics except for a lower educational level among Indigenous patients (p< 0.01). Most Indigenous patients (85.0%) reported having moderate-to-high unmet needs with at least one item in the SNAC tool. Following adjustment for key sociodemographic and clinical factors, Indigenous patients had a greater rate of moderate-to-high unmet needs overall (IRR=1.5, 95% CI 1.31– 1.72; p< 0.001), and specifically for psychosocial issues (IRR=1.7, 95% CI 1.39– 2.15; p< 0.001), and practical and physical needs subscales (IRR=1.5, 95% CI 1.22– 1.83; p< 0.001), compared to non-Indigenous patients.Conclusion: Indigenous Australians with cirrhosis more frequently had moderate-to-high unmet supportive care needs than non-Indigenous patients. Specific targeting of culturally appropriate supportive care for psychosocial, practical and physical needs may optimize cirrhosis care and improve the quality of life for Indigenous Australians with cirrhosis.Keywords: chronic liver disease, patient reported outcomes, perceived needs, unmet needs, Indigenous Australians

Background Culturally and linguistically diverse communities face several challenges to receiving screening and curative treatment of hepatocellular carcinoma (HCC). We reported the predictors of receipt of treatment and survival in a cohort of patients diagnosed with HCC in Southeast Queensland. Methods Data from 1651 HCC patients (147 migrants) followed between January 1, 2007, and December 31, 2016 were analyzed using chi-square statistic to test for the association between socio-economic variables and receipt of treatment. Bayesian Weibull Accelerated Failure Time regression was used to identify predictors of time to death, and we reported time ratios. Results Receipt of surgical resection for HCC was associated with non-metropolitan residence (P=0.02), non-English language (P Conclusions Improving access to HCC surveillance and uptake of timely curative treatment for persons living in remote areas and having socioeconomic disadvantage may help patients present to clinic with early stage tumor and provide better survival. Key messages Remoteness of residence is associated with late presentation, low rate of receipt of treatment and predicts survival of patients with HCC.

Background Antiviral treatment gap in culturally and linguistically diverse (CALD) populations may be a barrier progress in national elimination. Using modelling, we estimated and predicted the impact of antiviral treatment and migration on HBV burden, and HBV-related mortality in CALD populations in Australia. Methods We developed a dynamic, deterministic mathematical model using three antiviral treatment scale-up scenarios - the baseline treatment, intermediate treatment scale-up (80% of eligible by 2030), and optimistic scale-up (20% of all HBV by 2022) to predict the incidence of HBV infection, liver cirrhosis, hepatocellular carcinoma, and HBV-related mortality in four groups of people according to their country of birth. Results The number of chronic HBV cases will remain similar, and HBV-related morbidity and mortality will increase if the baseline approach is followed to 2030. Implementing an optimistic treatment scale-up could reduce the number of new cases of liver cirrhosis (30% in European-born, and 40% in Asia-Pacific-born) by 2030. Following the optimistic scale-up approach, the incidence of HCC decreased by 30% and a 15%-25% reduction in HCC-related mortality could be achieved in the four population subgroups by 2030. Conclusions Following the current antiviral treatment coverage, HBV elimination targets in migrants may not be achieved. A rapid treatment scale-up approach reduces HBV incidence, liver cirrhosis and HCC. Key messages Targeted antiviral treatment for migrants with HBV using rapid scale-up reduces HBV-related disease and mortality and contributes to achievement of national elimination targets.

Objective: Describe the sociodemographic and clinical characteristics of patients with Hepatitis C Virus (HCV) attending an urban Indigenous primary health clinic (IPHC) in Brisbane, Australia. Methods: A retrospective chart review of sociodemographic characteristics, presence of liver disease and treatments, lifestyle behaviours and comorbidities in patients with a HCV infection was conducted between October 2015 and March 2016. Results: One hundred and thirteen patients with confirmed HCV infection were aged between seven and 63 years; 66% were male, and 84% were Indigenous. Sixty‐nine per cent had been incarcerated; 41% had experienced conflict or domestic violence; 47% were injecting drugs; 72% had depression; and 61% had anxiety. Cirrhosis was present in 7/95 patients with adequate data and associated with age (p=0.02). Eleven patients had commenced direct acting antiviral (DAA) therapy in the 18 months that it had been available. Conclusions: The study highlights the opportunities for enhancing treatment of patients with HCV infection. Opportunities to improve treatment rates in an Indigenous primary healthcare include optimising diagnostic pathways, improving patient engagement, and general practitioner and peer worker participation. Implications for public health: HCV poses a serious threat to public health in Australia and IPHCs are key sites to addressing this for Indigenous people. Optimising care of patients with HCV attending IPHC requires recognition of the complex health needs and social context, to reduce the incidence and consequences of HCV infection.

Background Treatment seeking for people with alcohol use disorders (AUD), injecting drug use and viral hepatitis is low, and has worsened during the coronavirus disease 2019 (COVID-19) pandemic. Deferring clinical care and increasing drug and alcohol use exacerbate the risks of progression for individuals with chronic liver disease from viral hepatitis and/or alcohol-related liver disease (ALD). We explored the impact COVID-19 epidemic may have on patients with chronic liver disease and suggested mechanisms to protect this at-risk population during and after the pandemic. # Methods We searched PubMed, EMBASE, and Google Scholar for published articles and grey literature and synthesized information about the impact COVID-19 has on patients with chronic liver disease, specifically related to impacts and opportunities to prevent viral hepatitis and ALD. # Results The COVID-19 pandemic has caused significant disruption of clinical management of patients with liver disease, but also to alcohol and drug services, needle and syringe programs (NSP), hepatitis B (HBV) screening, and treatment efforts. Social isolation and pandemic-related anxiety have caused an increase in alcohol and drug use. COVID-19 pandemic disruptions may lead to an increase in the incidence of viral hepatitis and ALD, but also cause patients to undertake risky behaviours. The pandemic impacts people with chronic conditions such as HBV to defer medical visits or undertake screening tests. These factors may worsen rates of decompensation for patients with cirrhosis, for whom these deleterious impacts are believed to stay for some time after the pandemic. Interruption in screening, treatment, and monitoring services during the period disrupts chronic disease management of viral hepatitis and ALD and increases the risk of worsening the clinical course of liver disease and delayed diagnosis of hepatocellular carcinoma. # Conclusions Successful mitigation of the impact of COVID-19 on the incidence of viral hepatitis and alcoholic liver disease requires adaptive approaches to reach people with injecting drug use and AUD including community-based networks, fixed site and mobile NSP, mail delivery systems, the use of telehealth, and other digital media for promoting and implementing alcohol harm reduction during and after the COVID-19 pandemic.

Summary of recommendations and levels of evidence Chapter 2: Screening and assessment for unhealthy alcohol use Screening Screening for unhealthy alcohol use and appropriate interventions should be implemented in general practice (Level A), hospitals (Level B), emergency departments and community health and welfare settings (Level C). Quantity–frequency measures can detect consumption that exceeds levels in the current Australian guidelines (Level B). The Alcohol Use Disorders Identification Test (AUDIT) is the most effective screening tool and is recommended for use in primary care and hospital settings. For screening in the general community, the AUDIT-C is a suitable alternative (Level A). Indirect biological markers should be used as an adjunct to screening (Level A), and direct measures of alcohol in breath and/or blood can be useful markers of recent use (Level B). Assessment Assessment should include evaluation of alcohol use and its effects, physical examination, clinical investigations and collateral history taking (Level C). Assessment for alcohol-related physical problems, mental health problems and social support should be undertaken routinely (GPP). Where there are concerns regarding the safety of the patient or others, specialist consultation is recommended (Level C). Assessment should lead to a clear, mutually acceptable treatment plan which specifies interventions to meet the patient’s needs (Level D). Sustained abstinence is the optimal outcome for most patients with alcohol dependence (Level C). Chapter 3: Caring for and managing patients with alcohol problems: interventions, treatments, relapse prevention, aftercare, and long term follow-up Brief interventions Brief motivational interviewing interventions are more effective than no treatment for people who consume alcohol at risky levels (Level A). Their effectiveness compared with standard care or alternative psychosocial interventions varies by treatment setting. They are most effective in primary care settings (Level A). Psychosocial interventions Cognitive behaviour therapy should be a first-line psychosocial intervention for alcohol dependence. Its clinical benefit is enhanced when it is combined with pharmacotherapy for alcohol dependence or an additional psychosocial intervention (eg, motivational interviewing) (Level A). Motivational interviewing is effective in the short term and in patients with less severe alcohol dependence (Level A). Residential rehabilitation may be of benefit to patients who have moderate-to-severe alcohol dependence and require a structured residential treatment setting (Level D). Alcohol withdrawal management Most cases of withdrawal can be managed in an ambulatory setting with appropriate support (Level B). Tapering diazepam regimens (Level A) with daily staged supply from a pharmacy or clinic are recommended (GPP). Pharmacotherapies for alcohol dependence Acamprosate is recommended to help maintain abstinence from alcohol (Level A). Naltrexone is recommended for prevention of relapse to heavy drinking (Level A). Disulfiram is only recommended in close supervision settings where patients are motivated for abstinence (Level A). Some evidence for off-label therapies baclofen and topiramate exists, but their side effect profiles are complex and neither should be a first-line medication (Level B). Peer support programs Peer-led support programs such as Alcoholics Anonymous and SMART Recovery are effective at maintaining abstinence or reductions in drinking (Level A). Relapse prevention, aftercare and long-term follow-up Return to problematic drinking is common and aftercare should focus on addressing factors that contribute to relapse (GPP). A harm-minimisation approach should be considered for patients who are unable to reduce their drinking (GPP). Chapter 4: Providing appropriate treatment and care to people with alcohol problems: a summary for key specific populations Gender-specific issues Screen women and men for domestic abuse (Level C). Consider child protection assessments for caregivers with alcohol use disorder (GPP). Explore contraceptive options with women of reproductive age who regularly consume alcohol (Level B). Pregnant and breastfeeding women Advise pregnant and breastfeeding women that there is no safe level of alcohol consumption (Level B). Pregnant women who are alcohol dependent should be admitted to hospital for treatment in an appropriate maternity unit that has an addiction specialist (GPP). Young people Perform a comprehensive HEEADSSS assessment for young people with alcohol problems (Level B). Treatment should focus on tangible benefits of reducing drinking through psychotherapy and engagement of family and peer networks (Level B). Aboriginal and Torres Strait Islander peoples Collaborate with Aboriginal or Torres Strait Islander health workers, organisations and communities, and seek guidance on patient engagement approaches (GPP). Use validated screening tools and consider integrated mainstream and Aboriginal or Torres Strait Islander-specific approaches to care (Level B). Culturally and linguistically diverse groups Use an appropriate method, such as the “teach-back” technique, to assess the need for language and health literacy support (Level C). Engage with culture-specific agencies as this can improve treatment access and success (Level C). Sexually diverse and gender diverse populations Be mindful that sexually diverse and gender diverse populations experience lower levels of satisfaction, connection and treatment completion (Level C). Seek to incorporate LGBTQ-specific treatment and agencies (Level C). Older people All new patients aged over 50 years should be screened for harmful alcohol use (Level D). Consider alcohol as a possible cause for older patients presenting with unexplained physical or psychological symptoms (Level D). Consider shorter acting benzodiazepines for withdrawal management (Level D). Cognitive impairment Cognitive impairment may impair engagement with treatment (Level A). Perform cognitive screening for patients who have alcohol problems and refer them for neuropsychological assessment if significant impairment is suspected (Level A). Summary of key recommendations and levels of evidence Chapter 5: Understanding and managing comorbidities for people with alcohol problems: polydrug use and dependence, co-occurring mental disorders, and physical comorbidities Polydrug use and dependence Active alcohol use disorder, including dependence, significantly increases the risk of overdose associated with the administration of opioid drugs. Specialist advice is recommended before treatment of people dependent on both alcohol and opioid drugs (GPP). Older patients requiring management of alcohol withdrawal should have their use of pharmaceutical medications reviewed, given the prevalence of polypharmacy in this age group (GPP). Smoking cessation can be undertaken in patients with alcohol dependence and/or polydrug use problems; some evidence suggests varenicline may help support reduction of both tobacco and alcohol consumption (Level C). Co-occurring mental disorders More intensive interventions are needed for people with comorbid conditions, as this population tends to have more severe problems and carries a worse prognosis than those with single pathology (GPP). The Kessler Psychological Distress Scale (K10 or K6) is recommended for screening for comorbid mental disorders in people presenting for alcohol use disorders (Level A). People with alcohol use disorder and comorbid mental disorders should be offered treatment for both disorders; care should be taken to coordinate intervention (Level C). Physical comorbidities Patients should be advised that alcohol use has no beneficial health effects. There is no clear risk-free threshold for alcohol intake. The safe dose for alcohol intake is dependent on many factors such as underlying liver disease, comorbidities, age and sex (Level A). In patients with alcohol use disorder, early recognition of the risk for liver cirrhosis is critical. Patients with cirrhosis should abstain from alcohol and should be offered referral to a hepatologist for liver disease management and to an addiction physician for management of alcohol use disorder (Level A). Alcohol abstinence reduces the risk of cancer and improves outcomes after a diagnosis of cancer (Level A).

Background This study explored the epidemiology and health literacy of people affected by viral hepatitis (VH) from migrant culturally and linguistically diverse (CALD) backgrounds attending a community-based general practitioner and specialty hepatology shared-care (HEPREACH) clinic in Brisbane, Australia.Methods Self-reported data on health literacy and clinical information from adult patients (n=66) of CALD background recruited from the liver clinic were analyzed. Health literacy was assessed using a 5-question, 12-point scale. Variance weighted multiple linear regression was used to identify factors associated with knowledge about VH.Results About three-quarters of patients (74.2%) were diagnosed with hepatitis B. The median knowledge score was 7.8 (interquartile range(IQR) 6‒9). One in five patients did not understand the infective nature of VH, 30.3% did not understand mother-to-child transmission risk, and 30%‒40% of patients thought activities such as kissing, sharing food or mosquito bites could spread VH. Only 6% of patients understood the risk of liver cancer and the need for regular screening. Higher educational level (secondary, β=4.8, pDiscussion Country of origin, refugee status and opportunities for tertiary education impact patients’ understanding of VH. Ensuring delivery of culturally appropriate care and education is critical to improve knowledge, reduce misconceptions to improve care and outcomes for viral hepatitis in CALD migrant communities.

Background: Liver disease and hepatocellular carcinoma (HCC) are important contributors to the mortality gap between Indigenous and non-Indigenous Australians. However, there is a lack of population based high quality data assessing the differences in HCC epidemiology and outcomes according to Indigenous status. The aim of this study was therefore to perform a large epidemiological study of HCC investigating differences between Indigenous and non-Indigenous Australians with HCC. Methods: Study design was a retrospective cohort study. Data linkage methodology was used to link data from cancer registries with hospital separation summaries across three Australian jurisdictions during 2000–2017. Cumulative survival (Kaplan-Meier) and the differences in survival (Multivariable Cox-regression) by Indigenous status were assessed. Findings: A total of 229 Indigenous and 3587 non-Indigenous HCC cases were included in the analyses. Significant epidemiological differences identified for Indigenous HCC cases included younger age at onset, higher proportion of females, higher rurality, lower socioeconomic status, and higher comorbidity burden (all p < 0.001). The distribution of cofactors was also significantly different for Indigenous Australians including higher prevalence of alcohol misuse, hepatitis B, and diabetes and more frequent presence of multiple HCC cofactors (all p < 0.001). Indigenous Australians received curative HCC therapies less frequently (6.6% vs. 14.5%, p < 0.001) and had poorer 5-year survival (10.0% vs. 17.3%, p < 0.001; unadjusted hazard ratio (HR) =1.42 96%CI 1.21–1.65) compared to non-Indigenous Australians. The strength of the association between indigenous status and survival was weaker and statistically non-significant after adjusting for rurality, comorbidity burden and lack of curative therapy (adjusted-HR=1.20 95%CI 0.97–1.47) Interpretation: Such data provide a call to action to help design and implement health literacy, liver management and HCC surveillance programs for Indigenous people to help close the liver cancer mortality gap.

Aim: To better understand the hepatocellular carcinoma (HCC) patient journey, we conducted a patient survey across 13 countries. Methods: The survey included closed- and open-ended questions developed using an iterative process to gather information on demographics, diagnosis and treatment. Patients self-selected or were directed to the online survey by their doctor. Results: A total of 256 patients completed the survey. More than two-thirds (68%) felt they did not receive enough information about HCC at diagnosis. Treatments included oral anticancer therapy, transarterial chemoembolization (TACE), and selective internal radiation therapy (SIRT). A total of 81% receiving sorafenib, 45% receiving SIRT and 32% receiving TACE reported impaired quality-of-life (QoL). A total of 42, 19 and 0% of patients using sorafenib rated their current QoL as ‘poor’, ‘good’ and ‘excellent’, respectively; compared with SIRT (22, 33 and 6%) or TACE (11, 37 and 13%). Conclusion: Most patients with HCC require additional accessible information. People with incurable HCC require treatments that preserve QoL.

Background: Many patients with cirrhosis follow complex medication and dietary regimens, and those with decompensated cirrhosis suffer debilitating complications. These factors impact activities of daily living and quality of life. Aims: To explore the concerns and challenges of people with cirrhosis and their use of support services and to also describe health professionals’ (HP) perspectives of patients’ concerns. Methods: This is a cross-sectional study at a tertiary liver clinic involving 50 patients and 54 HP. Data were collected using structured questionnaires. The study includes patients’ report of their challenges/problems now that they have cirrhosis (‘patient-volunteered concerns’) and HP’ report of patients’ concerns. Both also ranked a list of 10 potential concerns. Results: Patients were, on average, 58 years old (SD = 10.2), mostly male (78%), Caucasian (86%) and with compensated cirrhosis (60%). The patients’ most common volunteered concerns related to managing symptoms, emotional issues and disease. Most ranked ‘developing liver cancer’ (79%), ‘losing ability to do daily tasks for yourself’ (76%), ‘fear of dying’ (64%) and ‘fear of the unknown’ (64%) as priority concerns. Regarding the use of support services, 24% of patients had accessed a dietician, 20% a pharmacist and 18% a psychologist. From the HP’ perspective, the patients’ most significant challenges related to managing disease (65%) and symptoms (48%), access to healthcare (56%) and information/knowledge (48%). Conclusions: Our findings demonstrate that cirrhosis (its symptoms, complications and treatment) is associated with significant concerns for patients. The discrepancies between the views of HP and patients suggest that we may not be measuring or addressing patients’ needs appropriately.

BACKGROUND The rate of hospital admissions for cirrhosis increased 1.3-fold during 2008-2016 in Queensland. Alcohol misuse was a contributing factor for cirrhosis in 55% of admissions and 40% of patients had at least one comorbidity. AIMS To examine the temporal change in aetiology of liver disease and presence of comorbidity in patients admitted with cirrhosis. METHODS Population-based retrospective cohort study of all people treated in hospital for cirrhosis (10 254 patients) in Queensland during 2008-2016. Data were sourced from Queensland Hospital Admitted Patient Data Collection. RESULTS The commonest aetiology was alcohol (49.5%), followed by cryptogenic (unspecified cirrhosis; 28.5%), hepatitis C virus (19.3%), non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) (4.8%) and hepatitis B virus (HBV) (4.3%). The prevalence of alcohol-related (P = 0.41) and hepatitis C virus (P = 0.08) remained stable between 2008-2010 and 2014-2016, that of NAFLD/NASH, cryptogenic and HBV-cirrhosis increased by 67% (P

Rash impulsiveness, the propensity for approach behaviour despite potential negative consequences, is associated with stronger alcohol craving in patients with Alcohol Use Disorder (AUD). This relationship is poorly understood and implications for treatment response are unexamined. This study explored the relationship between rash impulsiveness, craving, and treatment response among 304 outpatients enrolled in a 12-week abstinence-based Cognitive-Behavioural Therapy (CBT) program for AUD. Assessments were completed pre-and-post treatment, with craving and alcohol consumption monitored at each treatment session. Higher rash impulsiveness predicted more frequent craving over treatment (b = 0.95, 95% CI = 0.40, 1.50). Higher craving was associated with greater lapse-risk (b = 0.04, 95% CI = 0.03, 0.05), with the association between craving and lapse-risk increasing as treatment progressed (b = 0.01, 95% CI = 0.01, 0.02). Craving positively mediated the relationship between rash impulsiveness and lapse-risk (µ = 0.38, 95% CI = 0.10, 0.70). Contrary to hypotheses, the risk of lapse in response to craving was not moderated by rash-impulsiveness. These results suggest that AUD patients with a predisposition for rash impulsiveness are more vulnerable to alcohol craving, and subsequently, poorer treatment outcomes.

Introduction A BSG-endorsed care bundle for the management of decompensated cirrhosis in the first 24 hours of admission has been implemented in the North East of England resulting in improved management of these patients; however in this study patient outcomes were not followed up and there have been no subsequent published studies of its use.1,2 In our expanding hepatology unit of a small tertiary hospital in Brisbane, Australia we reviewed inpatient management of decompensated cirrhotic patients to assess morbidity, mortality and if adherence to the care bundle improves patient outcomes. Methods We retrospectively reviewed patient notes for hospital admissions due to decompensated cirrhosis between 1/6/16 – 1/6/17. Admissions were scored according to care bundle adherence and divided into tertiles. Mortality, rates of readmission and inpatient length of stay (LOS) were compared between the most adherent and least adherent groups using Fisher’s exact test with p values Results 59 admissions were reviewed consisting of 39 patients (69% male, median age 60 years) with a median MELD 19. Only Child-Pugh B (33/59, 56%) and C (26/59, 44%) patients were included. The most adherent group had numerically lower 1-year mortality (5/16, 31%) than the least adherent group (7/15, 47%, p=0.4725). Readmission rates within 1 year were reduced in the most adherent group (6/17, 35%) compared to the least adherent group (8/16, 50%), though not statistically significant (p=0.4905). Readmission rates at 30 days and 6 months were also reduced with care bundle adherence however again were not statistically significant. There was no effect on the length of hospital stay between groups. Conclusions Our results suggest reduced mortality and hospital readmission in patients more closely adherent to the BSG care bundle, however this difference did not reach statistical significance. Reasons for this include a small sample size which limited statistical power and that overall adherence to the care bundle was poor. Following this study, we plan to implement a care bundle systematically to further evaluate patient outcomes. References McPherson, S., Dyson, J., Austin, A. & Hudson, M. Response to the NCEPOD report: development of a care bundle for patients admitted with decompensated cirrhosis—the first 24|h. Frontline Gastroenterol. 7, 16–23 ( 2016). Dyson, J. K. et al. Implementation of a ‘care bundle’ improves the management of patients admitted to hospital with decompensated cirrhosis. Aliment. Pharmacol. Ther. 44, 1030–1038 ( 2016).

Summary Background Liver-related mortality varies across developed nations. Aim To assess the relative role of various risk factors in relation to liver-related mortality in an ecological study approach. Methods Data for liver-related mortality, prevalence data for hepatitis B and C, human immunodeficiency virus (HIV), alcohol consumption per capita, Type 2 Diabetes mellitus (T2DM), overweight and obesity were extracted from peer-reviewed publications or WHO databases for different developed countries. As potential other risk-modifying factors, purchase power parity (PPP)-adjusted gross domestic product (GDP) per capita and health expenditure per capita were assessed. As an environmental ‘hygiene factor’, we also assessed the effect of the prevalence of Helicobacter pylori. Only countries with a PPP-adjusted GDP greater than $20 000 and valid information for at least 8 risk modifiers were included. Univariate and multivariate analyses were utilised to quantify the contribution to the variability in liver-related mortality. Results The proportion of chronic liver diseases (CLD)-related mortality ranged from 0.73–2.40% [mean 1.56%, 95% CI (1.43–1.69)] of all deaths. Univariately, CLD-related mortality was significantly associated with Hepatitis B prevalence, alcohol consumption, PPP-adjusted GDP (all P < 0.05) and potentially H. pylori prevalence (P = 0.055). Other investigated factors, including hepatitis C, did not yield significance. Backward elimination suggested hepatitis B, alcohol consumption and PPP-adjusted GDP as risk factors (explaining 66.3% of the variability). Conclusion Hepatitis B infection, alcohol consumption and GDP, but not hepatitis C or other factors, explain most of the variance of liver-related mortality.

Purpose In the interferon era of hepatitis C virus (HCV) therapies, genotype/subtype, cirrhosis, prior treatment failure, sex, and race predicted relapse. Our objective is to validate a targeted proteomics platform of 17 peptides to predict sustained virologic response (SVR). Experimental design Stored plasma from three, open-label, trials of HIV/HCV-coinfected subjects receiving interferon-containing regimens is identified. LC-MS/MS is used to quantitate the peptides directly from plasma, and IL28B genotyping is completed using stored peripheral blood mononuclear cells (PBMC). A logistic regression model is built to analyze the probability of SVR using responders and nonresponders to interferon-based regimens. Results The cohort (N = 35) is predominantly black (51.4%), male (86%), and with median age 48 years. Most patients achieve SVR (54%). Using multivariable models, it is verified that three human corticosteroid binding globulin (CBG) peptides are predictive of SVR in patients with the unfavorable IL28B genotypes (CT/TT). The model performs better than IL28B alone, with an area under the curve of 0.870. Conclusions and clinical relevance In HIV/HCV-coinfected patients, three human CBG peptides that accurately predict treatment response with interferon-based therapy are identified. This study suggests that a stepwise approach combining a genetic predictor followed by targeted proteomics can improve the accuracy of clinical decision-making.

Bilirubin, a potentially toxic catabolite of heme and indicator of hepatobiliary insufficiency, exhibits potent cardiac and vascular protective properties. Individuals with Gilbert’s syndrome (GS) may experience hyperbilirubinemia in response to stressors including reduced hepatic bilirubin excretion/increased red blood cell breakdown, with individuals usually informed by their clinician that their condition is of little consequence. However, GS appears to protect from all-cause mortality, with progressively elevated total bilirubin associated with protection from ischemic heart and chronic obstructive pulmonary diseases. Bilirubin may protect against these diseases and associated mortality by reducing circulating cholesterol, oxidative lipid/protein modifications, and blood pressure. In addition, bilirubin inhibits platelet activation and protects the heart from ischemia-reperfusion injury. These effects attenuate multiple stages of the atherosclerotic process in addition to protecting the heart during resultant ischemic stress, likely underpinning the profound reduction in cardiovascular mortality in hyperbilirubinemic GS. This review outlines our current knowledge of and uses for bilirubin in clinical medicine and summarizes recent progress in revealing the physiological importance of this poorly understood molecule. We believe that this review will be of significant interest to clinicians, medical researchers, and individuals who have GS.

Hepatitis C virus (HCV) modulates host lipid metabolism for its replication and lifecycle. Our aims were to assess changes in the serum lipid and distal (post-squalene) cholesterol biosynthesis metabolite profile of HCV genotypes (GT) 2 and 3 patients treated with sofosbuvir+ribavirin.Serum samples [baseline, treatment week 12, 4weeks post-treatment] were analyzed for apolipoproteins B and E (apoB/E), total cholesterol, HDL, LDL, and 11 post-squalene sterol metabolites using a GC/MS platform.We selected 127 patients (GT2 n=50, GT3 n=77), 50% cirrhotic patients, and 42% who experienced a virological relapse. At baseline, GT3 patients had lower level of serum lipids, apoB/E, 7-dehydrocholesterol, desmosterol, lathosterol, compared to GT2 (p0.006). Baseline lathosterol was lower in relapsers with cirrhosis compared to cirrhotic patients with SVR (p=0.003). From baseline to treatment week 12, serum lipids, apoB/E, and key sterol pathway metabolites (7-dehydrocholesterol, desmosterol, lathosterol, lanosterol) increased in GT3. In contrast, in GT2 patients, apoB/E and dihydrolanosterol decreased with viral suppression (p0.025). At follow-up week 4, cirrhotic SVR patients showed substantially greater increases in apoB and total sterols compared to cirrhotic relapsers regardless of HCV genotype. After adjustment for genotype and gender, baseline lathosterol was independently associated with virologic response (p=0.04).HCV GT3 is associated with reduced circulation of lipids involved in the distal cholesterol biosynthesis pathway, resulting in relative hypocholesterolemia. HCV suppression during sofosbuvir+ribavirin restores distal sterol metabolites indicating viral interference with de novo lipogenesis or selective retention by hepatocytes.

Background Atypical iron overload without variation in the five clinically associated hereditary hemochromatosis genes is now recognized; however, their etiology remains unknown. Since the identification of iron overload in the bone morphogenetic protein 6 (Bmp6) knockout mouse, the search has been on for clinically pathogenic variants in the BMP6 gene. A recent report proposes that variants in the pro-peptide region of BMP6 are the underlying cause of several cases of iron overload. We performed targeted next-generation sequencing on three cases of atypical iron overload with Asian ethnicity and identified a p.Q118dup (aka p.E112indelEQ, p.Q115dup, p.Q118_L119insQ) variant in BMP6. The purpose of this study was to characterize the molecular function of the identified BMP6 variant. Molecular characterization by immunofluorescence microscopy and Western blotting of transfected cells, bioinformatics, and population analyses was performed. Results In contrast to reports for other BMP6 pro-peptide variants in this region, our data indicates that this variant does not affect the function of the mature BMP6 protein. Conclusions Our data suggest that assignment of disease causation in clinical cases of iron overload to pro-peptide variants in BMP6 should thus be treated with caution and requires biological characterization.

Primary liver cancer (PLC) is the sixth most common cancer worldwide and the second most common cause of cancer death. Future predictions can inform health planners and raise awareness of the need for cancer control action. We predicted the future burden of PLC in 30 countries around 2030. Incident cases of PLC (International Classification of Diseases, Tenth Revision, C22) were obtained from 30 countries for 1993-2007. We projected new PLC cases to 2030 using age-period-cohort models (NORDPRED software). Age-standardized incidence rates per 100,000 person-years were calculated by country and sex. Increases in new cases and rates of PLC are projected in both sexes. The largest increases in rates are, among men, in Norway (2.9% per annum), US whites (2.6%), and Canada (2.4%) and, among women, in the United States (blacks 4.0%), Switzerland (3.4%), and Germany (3.0%). The projected declines are in China, Japan, Singapore, and parts of Europe (e.g., Estonia, Czech Republic, Slovakia). A 35% increase in the number of new cases annually is expected compared to 2005. This increasing burden reflects both increasing rates (and the underlying prevalence of risk factors) and demographic changes. Japan is the only country with a predicted decline in the net number of cases and annual rates by 2030. Conclusion: Our reporting of a projected increase in PLC incidence to 2030 in 30 countries serves as a baseline for anticipated declines in the longer term through the control of hepatitis B virus and hepatitis C virus infections by vaccination and treatment; however, the prospect that rising levels of obesity and its metabolic complications may lead to an increased risk of PLC that potentially offsets these gains is a concern. (Hepatology 2018;67:600-611).

Determining risk for recurrence of hepatocellular carcinoma (HCC) following liver transplantation (LT) is an important clinical need. We assessed consecutive patients who underwent LT for HCC following sequential transarterial chemoembolization (TACE). Treatment response was assessed using modified response evaluation criteria in solid tumors (mRECIST) categories: complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Cox proportional hazard models were used to predict HCC recurrence. One hundred seventy-three patients underwent TACE and imaging to assess response prior to LT. TACE responses were: CR = 23.7%, PR = 24.3%, SD = 27.7% and PD = 24.3%. Five-year HCC recurrence rate was 5.3% in patients responding to TACE (CR/PR), versus 17.6%, among patients who did not respond (SD/PD, p = 0.014). In multivariate analysis, independent pre-LT predictors of recurrence were response to TACE and largest radiologic size of tumor (>3 cm vs. ≤3 cm). HCC recurrence rate for patients with tumor size >3 cm and no response to TACE was 35.8%, compared with 1.9% for patients with tumor size ≤3 cm and response to TACE (p = 0.0007). We conclude that mRECIST criteria and tumor size differentiate patients with high or low likelihood of HCC recurrence after LT. These findings raise the possibility of incorporating response to TACE and largest tumor size to identify patients at highest risk for HCC recurrence.

The interleukin 28B (IL28B) rs12979860 polymorphism is associated with treatment outcome in hepatitis C virus (HCV) genotype 1 and 4 patients. Its association with the histological features of chronic hepatitis C and disease severity needs further clarifications. To assess the correlation between IL28B genotype, HCV genotype and liver biopsy findings in untreated patients. Materials and Methods: Pre-treatment liver biopsies from 335 HCV Caucasian patients (59% males, age 50 years) enrolled in the MIST study were staged for fibrosis and inflammation according to the METAVIR and the Ishak scoring systems, steatosis was dichotomized as &lt, 5% or ≥5%. IL28B was typed by Taqman Single Nucleotide Polymorphism (SNP) genotyping assay. HCV genotype was 1 in 151 (45%), 2 in 99 (30%), 3 in 50 (15%) and 4 in 35 (10%) patients. IL28B genotype was CC in 117 (34%), CT in 166 (49%) and TT in 52 (15%). At univariate analysis, the IL28B CC genotype was associated with severe portal inflammation in HCV-1 patients (CC vs. CT/TT: 86% vs. 63%, p = 0.005), severe lobular inflammation in HCV-2 patients (CC vs. CT/TT: 44% vs. 23%, p = 0.03), and less fatty infiltration in HCV-1 patients (CC vs. CT/TT: 72% vs. 51%, p = 0.02). Despite the lack of any association between IL28B and fibrosis stage, in HCV-3 patients IL28B CC correlated with METAVIR F3-F4 (CC vs. CT/TT: 74% vs. 26%, p = 0.05). At multivariate analysis, the genotype CC remained associated with severe portal inflammation in HCV-1, only (Odds Ratio (OR): 95% Confidence Interval (CI): 3.24 (1.23–8.51)). IL28B genotype is associated with the histological features of chronic hepatitis C in a HCV genotype dependent manner, with CC genotype being independently associated with severe portal inflammation.

Low-density lipoprotein cholesterol (LDL-C) levels and interleukin 28B (IL28B) polymorphism are associated with sustained viral response (SVR) to peginterferon/ribavirin (pegIFN/RBV) for chronic hepatitis C (CHC) infection. IL28B has been linked with LDL-C levels using a candidate gene approach, but it is not known whether other genetic variants are associated with LDL-C, nor how these factors definitively affect SVR. We assessed genetic predictors of serum lipid and triglyceride levels in 1604 patients with genotype 1 (G1) chronic hepatitis C virus (HCV) infection by genome-wide association study and developed multivariable predictive models of SVR. IL28B polymorphisms were the only common genetic variants associated with pretreatment LDL-C level in Caucasians (rs12980275, P = 4.7 × 10−17, poor response IL28B variants associated with lower LDL-C). The association was dependent on HCV infection, IL28B genotype was no longer associated with LDL-C in SVR patients after treatment, while the association remained significant in non-SVR patients (P < 0.001). LDL-C was significantly associated with SVR for heterozygous IL28B genotype patients (P < 0.001) but not for homozygous genotypes. SVR modelling suggested that IL28B heterozygotes with LDL-C > 130 mg/dL and HCV RNA ≤600 000 IU/mL may anticipate cure rates >80%, while the absence of these two criteria was associated with an SVR rate of

Background & Aims Interferon-alfa (IFN)-related cytopenias are common and may be dose-limiting. We performed a genome wide association study on a well-characterized genotype 1 HCV cohort to identify genetic determinants of peginterferon-α (pegIFN)-related thrombocytopenia, neutropenia, and leukopenia. Methods 1604/3070 patients in the IDEAL study consented to genetic testing. Trial inclusion criteria included a platelet (Pl) count ⩾80×10 9 /L and an absolute neutrophil count (ANC) ⩾1500/mm 3 . Samples were genotyped using the Illumina Human610-quad BeadChip. The primary analyses focused on the genetic determinants of quantitative change in cell counts (Pl, ANC, lymphocytes, monocytes, eosinophils, and basophils) at week 4 in patients >80% adherent to therapy (n=1294). Results 6 SNPs on chromosome 20 were positively associated with Pl reduction (top SNP rs965469, p =10 −10 ). These tag SNPs are in high linkage disequilibrium with 2 functional variants in the ITPA gene, rs1127354 and rs7270101, that cause ITPase deficiency and protect against ribavirin (RBV)-induced hemolytic anemia (HA). rs1127354 and rs7270101 showed strong independent associations with Pl reduction ( p =10 −12 , p =10 −7 ) and entirely explained the genome-wide significant associations. We believe this is an example of an indirect genetic association due to a reactive thrombocytosis to RBV-induced anemia: Hb decline was inversely correlated with Pl reduction (r=−0.28, p =10 −17 ) and Hb change largely attenuated the association between the ITPA variants and Pl reduction in regression models. No common genetic variants were associated with pegIFN-induced neutropenia or leucopenia. Conclusions Two ITPA variants were associated with thrombocytopenia; this was largely explained by a thrombocytotic response to RBV-induced HA attenuating IFN-related thrombocytopenia. No genetic determinants of pegIFN-induced neutropenia were identified.

Cytokeratin-18 (CK-18) is a major intermediate filament protein in liver cells. The M30 fragment of CK-18 has been identified as a useful marker of apoptosis associated with fibrosis and steatosis in nonalcoholic steatohepatitis (NASH). We sought to assess the relationship of this marker and steatosis in a cohort of adult patients with chronic hepatitis C. The study cohort included sera from 267 treatment-naive chronic hepatitis C (CHC) patients and 100 healthy controls with normal alanine aminotransferase (ALT). Biopsies from CHC patients were assessed for METAVIR fibrosis stage, Histology Activity Index (HAI) inflammation score and steatosis grade by expert histopathologists. The M30 fragment of CK-18 was quantified by ELISA. Wilcoxon Rank Sum, Spearman Correlation and Linear Regression tests were performed for statistical analysis. Median CK-18 levels were higher in CHC patients compared to controls (411 vs 196 U/L, P < 0.0001). Fibrosis stage was associated with increasing serum CK-18 levels (P = 0.015) and CK-18 levels were higher for F2-F4 vs F0-F1 (500 vs 344 U/L; P = 0.001). There was no association between CK-18 and increasing steatosis grade 1, 2 or 3 (460.7 vs 416.8 vs 508.3 U/L; P = 0.35) and presence or absence of steatosis (445.3 vs 365.8 U/L; P = 0.075). Fibrosis stage was independently associated with serum M30 in a multivariable linear regression model (P = 0.03). CK-18 levels were higher in CHC compared to healthy controls and associated with hepatic fibrosis. There was no difference in CK-18 M30 levels between CHC patients with and without steatosis. Although apoptosis may still contribute to hepatitis C virus (HCV)-mediated steatosis, our results suggest that serum CK-18 will not be a clinically useful test for identifying significant steatosis in CHC.

Natural killer (NK) cells constitute a first line of defense against viral infections; their function is governed by the integration of signals from multiple activating and inhibitory surface receptors. We hypothesized that because NKs become rapidly activated by cytokines, response to anti-hepatitis C virus (HCV) therapy would be predicted by the phenotype and function of NKs. We used a cohort of 101 patients (55 African, 46 Caucasian-American) who received pegylated-interferon (IFN) and ribavirin for 48 weeks. Multiparameter FACS analysis was used to examine relative expression of 14 different inhibitory/activating receptors. Interleukin (IL)-28B genotyping (rs12979860) was also performed. Pretreatment levels of inhibitory receptors CD158a, CD158b, and CD158e were higher in patients who demonstrated poor viral decline within the first 28 days of therapy. Higher expression levels of inhibitory receptors NKG2A, CD158b, and CD158e were demonstrable in patients who failed to achieve sustained virologic response (SVR). Patients carrying the IL-28B T allele had higher NKG2A expression on effector NKs. We created a mathematical regression model incorporating race, viral level, and two inhibitory receptors. The area-under-the curve was 0.88, which is highly predictive of SVR. Moreover, the model performed complementarily with IL-28B across the CC, CT, and TT genotypes. Purified NKG2A neg NKs treated with pegylated-IFN-a for 4 hours demonstrated higher levels of IFN-c-inducible protein-10 (IP-10) and tumor necrosis factor-related apoptosisinducing ligand (TRAIL) compared with their NKG2A pos counterparts. Conclusions: These results provide novel insights into the associations of NK phenotype with IL-28B genotype and gene expression patterns, as well as the role of NKs in mediating IFN-induced viral clearance of chronic HCV infection. (HEPATOLOGY 2011;54:1559-1569)

Objective People with chronic liver disease, particularly those with decompensated cirrhosis, experience several potentially debilitating complications that can have a significant impact on activities of daily living and quality of life. These impairments combined with the associated complex treatment mean that they are faced with specific and high levels of supportive care needs. We aimed to review reported perspectives, experiences and concerns of people with chronic liver disease worldwide. This information is necessary to guide development of policies around supportive needs screening tools and to enable prioritisation of support services for these patients. Design Systematic searches of PubMed, MEDLINE, CINAHL and PsycINFO from the earliest records until 19 September 2014. Data were extracted using standardised forms. A qualitative, descriptive approach was utilised to analyse and synthesise data. Results The initial search yielded 2598 reports: 26 studies reporting supportive care needs among patients with chronic liver disease were included, but few of them were patient-reported needs, none used a validated liver disease-specific supportive care need assessment instrument, and only three included patients with cirrhosis. Five key domains of supportive care needs were identified: informational or educational (eg, educational material, educational sessions), practical (eg, daily living), physical (eg, controlling pruritus and fatigue), patient care and support (eg, support groups), and psychological (eg, anxiety, sadness). Conclusions While several key domains of supportive care needs were identified, most studies included hepatitis patients. There is a paucity of literature describing the supportive care needs of the chronic liver disease population likely to have the most needs—namely those with cirrhosis. Assessing the supportive care needs of people with chronic liver disease have potential utility in clinical practice for facilitating timely referrals to support services.

The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people. Current therapy relies upon a combination of pegylated interferon-alpha and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus. The development of direct-acting antiviral agents to treat HCV has focused predominantly on inhibitors of the viral enzymes NS3 protease and the RNA-dependent RNA polymerase NS5B. Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations (EC ) towards replicons expressing a broad range of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients chronically infected with HCV, administration of a single 100-mg dose of BMS-790052 was associated with a 3.3 log10 reduction in mean viral load measured 24 h post-dose that was sustained for an additional 120 h in two patients infected with genotype 1b virus. Genotypic analysis of samples taken at baseline, 24 and 144 h post-dose revealed that the major HCV variants observed had substitutions at amino-acid positions identified using the in vitro replicon system. These results provide the first clinical validation of an inhibitor of HCV NS5A, a protein with no known enzymatic function, as an approach to the suppression of virus replication that offers potential as part of a therapeutic regimen based on combinations of HCV inhibitors.

OPN (osteopontin)) is a Hh (Hedgehog)-regulated cytokine that is up-regulated during chronic liver injury and directly promotes fibrosis. We have reported that Hh signalling enhances viral permissiveness and replication in HCV (hepatitis C virus)-infected cells. Hence we hypothesized that OPN directly promotes HCV replication, and that targeting OPN could be beneficial in HCV. In the present study, we compared the expression of OPN mRNA and protein in HCV (JFH1)-infected Huh7 and Huh7.5 cells, and evaluated whether modulating OPN levels using exogenous OPN ligands (up-regulate OPN) or OPN-specific RNA-aptamers (neutralize OPN) leads to changes in HCV expression. Sera and livers from patients with chronic HCV were analysed to determine whether OPN levels were associated with disease severity or response to therapy. Compared with Huh7 cells, Huh7.5 cells support higher levels of HCV replication (15-fold) and expressed significantly more OPN mRNA (30-fold) and protein. Treating Huh7 cells with OPN ligands led to a dose-related increase in HCV (15-fold) and OPN (8-fold) mRNA. Conversely, treating Huh7.5 cells with OPN-specific RNA aptamers inhibited HCV RNA and protein by >50% and repressed OPN mRNA to basal levels. Liver OPN expression was significantly higher (3-fold) in patients with advanced fibrosis. Serum OPN positively correlated with fibrosis-stage (P=0.009), but negatively correlated with ETBCR (end-of-treatment biochemical response), ETVR (end-of-treatment virological response), SBCR (sustained biochemical response) and SVR (sustained virological response) (P=0.007). The OPN fibrosis score (serum OPN and presence of fibrosis ≥F2) may be a predictor of SVR. In conclusion, OPN is up-regulated in the liver and serum of patients with chronic hepatitis C, and supports increased viral replication. OPN neutralization may be a novel therapeutic strategy in chronic hepatitis C. © The Authors Journal compilation.

IntroductionPharmacogenomic testing is important in developing individualized therapeutic approaches. In the phase 3 IDEAL (Individualized Dosing to Assess Optimal Pegylated Interferon Therapy) clinical trial, a subset of patients receiving peginterferon and ribavirin for treatment of chronic hepatitis C agreed to provide blood samples for genetic testing. Genome-wide association studies subsequently identified associations between IL28B polymorphism and sustained virologic response, and ITPA polymorphism and ribavirin-associated anemia.ObjectiveTo characterize the groups of patients who accepted or declined pharmacogenomic testing in the IDEAL study.MethodsClinical and demographic factors and treatment outcomes were compared at all sites that had approved pharmacogenomic testing. Differences between patients who consented to and declined pharmacogenomic testing were analyzed using Student's t-test and (2)-test.ResultsIn total, 109 of 118 sites participated in the pharmacogenomic substudy, and 1674 of 2949 (57%) patients enrolled at these sites consented to pharmacogenomic testing. More patients treated in academic medical centers than in community centers (60 vs. 52%, P

Recent studies have shown that a single-nucleotide polymorphism upstream of the interleukin-28B (IL28B) gene plays a major role in predicting therapeutic response in hepatitis C virus (HCV)-infected patients treated with pegylated interferon (PEG-IFN)/ribavirin. We sought to investigate the mechanism of the IL28B polymorphism, specifically as it relates to early HCV viral kinetics, IFN pharmacokinetics, IFN pharmacodynamics, and gene expression profiles. Two prospective cohorts (human immunodeficiency virus [HIV]/HCV-coinfected and HCV-monoinfected) completing treatment with IFN/ribavirin were enrolled. Patients were genotyped at the polymorphic site rs12979860. In the HIV/HCV cohort, frequent serum sampling was completed for HCV RNA and IFN levels. DNA microarray of peripheral blood mononuclear cells and individual expression of IFN-stimulated genes (ISGs) were quantified on IFN therapy. The IL28B-favorable (CC) genotype was associated with improved therapeutic response compared with unfavorable (CT or TT) genotypes. Patients with a favorable genotype had greater first- and second-phase viral kinetics (P = 0.004 and P = 0.036, respectively), IFN maximum antiviral efficiency (P = 0.007) and infected cell death loss (P = 0.009) compared with unfavorable genotypes. Functional annotation analysis of DNA microarray data was consistent with depressed innate immune function, particularly of natural killer cells, from patients with unfavorable genotypes (P