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Although there are several established international guidelines on the management of hepatocellular carcinoma (HCC), there is limited information detailing specific indicators of good quality care. The aim of this study was to develop a core set of quality indicators (QIs) to underpin the management of HCC. We undertook a modified, two-round, Delphi consensus study comprising a working group and experts involved in the management of HCC as well as consumer representatives. QIs were derived from an extensive review of the literature. The role of the participants was to identify the most important and measurable QIs for inclusion in an HCC clinical quality registry. From an initial 94 QIs, 40 were proposed to the participants. Of these, 23 QIs ultimately met the inclusion criteria and were included in the final set. This included (a) nine related to the initial diagnosis and staging, including timing to diagnosis, required baseline clinical and laboratory assessments, prior surveillance for HCC, diagnostic imaging and pathology, tumor staging, and multidisciplinary care; (b) thirteen related to treatment and management, including role of antiviral therapy, timing to treatment, localized ablation and locoregional therapy, surgery, transplantation, systemic therapy, method of response assessment, and supportive care; and (c) one outcome assessment related to surgical mortality. Conclusion: We identified a core set of nationally agreed measurable QIs for the diagnosis, staging, and management of HCC. The adherence to these best practice QIs may lead to system-level improvement in quality of care and, ultimately, improvement in patient outcomes, including survival.

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.

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 End-stage liver disease is a leading cause of mortality. Fewer than 60% of patients with decompensated cirrhosis survive after two years, with patients often experiencing distressing symptoms impairing quality of life. Early advanced care planning and timely palliative care referral can improve quality of life and the end of life experience. We aimed to determine palliative care referral rates and patterns for patients admitted with decompensated cirrhosis, and to identify the factors associated with referral. Methods This was a retrospective, single-centre study undertaken at a metropolitan tertiary referral hospital. Patients admitted between the 1st June 2016 to 31st January 2019 with a Child-Pugh score of B or C, and a Model for End-Stage Liver Disease score ≥15 were included. We assessed survival and compared those referred and not referred to palliative care, adjusting for lag-time to referral (Kaplan-Meier analysis). Results One-hundred-and-sixteen admissions met eligibility criteria for referral. The median age at admission was 59 years, with 76% male. Only a fifth of eligible patients (25/116) were referred to palliative care. The median survival (from referral) for those referred to palliative care was 20 days, versus 148 days for those not referred. Conclusions Despite benefits from timely referral, less than one-quarter of palliative care eligible patients were referred. Referral appears reserved for those facing imminent death - surviving just under three weeks post-referral, yet mortality in non-referred patients remained high (148-day median). Low rates and late referral are a missed opportunity to improve the end of life care for patients with end-stage liver disease.

Patients with cirrhosis have significant physical, psychological, and practical needs. We documented patients’ perceived need for support with these issues and the differences with increasing liver disease severity, etiology, and age. Using the supportive needs assessment tool for cirrhosis (SNAC), we examined the rate of moderate‐to‐high unmet needs (Poisson regression; incidence rate ratio [IRR]) and the correlation between needs and sociodemographic/clinical characteristics (multivariable linear regression) in 458 Australians adults with cirrhosis. Primary liver disease etiology was alcohol in 37.6% of patients, chronic viral hepatitis C in 25.5%, and nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) in 23.8%. A total of 64.6% of patients had Child‐Pugh class A cirrhosis. Most patients (81.2%) had at least one moderate‐to‐high unmet need item; more than 25% reported a moderate‐to‐high need for help with “lack of energy,” “sleep poorly,” “feel unwell,” “worry about … illness getting worse (liver cancer),” “have anxiety/stress,” and “difficulty with daily tasks.” Adjusting for key sociodemographic/clinical factors, patients with Child‐Pugh C had a greater rate of “practical and physical needs” (vs. Child‐Pugh A; IRR = 2.94, 95% confidence interval [CI] 2.57‐3.37), patients with NAFLD/NASH had a greater rate of needs with “lifestyle changes” (vs. alcohol; IRR = 1.81, 95% CI 1.18‐2.77) and “practical and physical needs” (IRR = 1.43, 95% CI 1.23‐1.65), and patients aged ≥65 years had fewer needs overall (vs. 18‐64 years; IRR = 0.70, 95% CI 0.64‐0.76). Higher overall SNAC scores were associated with Child‐Pugh B and C (both P

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.

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.

Background and aims:While chronic liver disease is a major global public health problem, it has not been recognized as a National Health Priority Area in Australia. A population-based study using hospital admission data for cirrhosis in the large state of Queensland, Australia during 2008-2016 was performed. Method:Hospital data on all patient admissions (public and private)and deaths during 2008-2016 in the state of Queensland were obtained. Queensland is a large state in the north-east of Australia with a population of 4.9 million. We identified all hospital admissions for cirrhosis for patients aged 20 years or older. We reported age-standardized hospitalization rates/10, 000 person-years by gender and per calendar year, in-hospital case fatality rate among these admissions (n = 30, 327) and examined the factors associated with hospital deaths. Results:Age-adjusted hospitalization rates increased by 32%between 2008 and 2016, from 8.50/10, 000 (95%CI 8.18-8.82) to11.21/10, 000 (95%CI 10.87-11.54). Admission rates peaked in men at34.03/10, 000 in 55-59 year-olds. The age-standardized admission rate for Indigenous Australians was 32.79/10, 000 (95%CI 31.28-34.31). Alcohol misuse was a contributing factor in over half (55.1%) of all admissions, and in 26.8% of admissions patients resided in most socio-economically disadvantaged areas. The overall in-hospital case fatality rate was 9.7% for males and 9.3% for females, and decreased significantly in males from 10.25% in 2008 to 8.32% in 2016 (p Conclusion:Our data highlights the increasing healthcare use by Australians with cirrhosis and this has major resource and economic implications. Greater awareness and emphasis on preventive care is needed to reduce the increasing prevalence of cirrhosis and the personal, social and economic burden of its complications.

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.

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).

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.

In 2009, an association between the interleukin-28B (IL28B) polymorphism and treatment outcome for genotype 1 (G1) hepatitis C virus (HCV) infection, as well as spontaneous clearance of HCV, was reported. Since the initial publications, over 100 articles have appeared in the peer-reviewed literature, with many more manuscripts in press and abstracts presented at scientific meetings. Despite the proliferation of data concerning the IL28B polymorphism and HCV infection, there remain many critical unanswered questions about clinical implications and the underlying biological mechanisms. In this review, we discuss the basic principles of genome-wide association study methodologies that are important for interpreting the results of genetic association studies. We then review the current literature concerning the association between IL28B variants and interferon (IFN) treatment response in patients with chronic HCV infection, as well as spontaneous HCV clearance. We consider the relevance of the IL28B polymorphism to non-G1 HCV, as well as the special treatment populations of HIV/HCV co-infection and recurrent HCV post-liver transplantation. We review current knowledge of the biological mechanisms underlying this genetic association, including the link to liver IFN-stimulated gene expression, and identify continuing gaps in our knowledge and key research priorities. Finally, pegylated-IFN and ribavirin is no longer the standard of care for the treatment of G1 HCV, and we conclude by considering the relevance of IL28B polymorphisms in the era of direct-acting antivirals.

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)

Background and Aim: The role of insulin resistance (IR) and hepatic steatosis in fibrogenesis in chronic hepatitis C infection (CHC) has yielded conflicting data and few studies have been performed in Asian-region populations. We retrospectively investigated the relationship between host metabolic variables, including IR and hepatic steatosis, to hepatic fibrosis in Asian-region CHC genotype 2/3 patients.

Recently, single-nucleotide polymorphisms near the IL28B gene have been identified as important in predicting treatment response and spontaneous clearance of the hepatitis C virus (HCV). In the less than 12 months since the initial genetic discoveries, our knowledge base has rapidly expanded regarding the significance of the IL28B polymorphism in a variety of clinical settings. For genotype 1 HCV infection, it is clear that IL28B genotype has an important role in the prediction of treatment-induced and spontaneous clearance. This association remains important in the HIV/HCV-coinfected population. Host genotype adds further discriminatory information in HCV genotype 2/3 infection. IL28B genotype may remain significant with direct-acting antiviral therapy, although further studies are needed for antiviral agents and novel immunotherapy. Information on IL28B genotype improves treatment prediction with standard of care and will integrate with existing pretreatment clinical factors and measures of on-treatment response. Pretreatment knowledge of sustained viral response may help to reshape treatment regimens of the future with the possibility of reducing therapy duration and improving tolerability, safety, and efficacy.

Background & Aims: Incidence and mortality of hepatocellular carcinoma (HCC) is increasing globally, but varies between countries and regions. To target scarce resources to most need, clinical services must be informed by regional epidemiology. Using population-based data, we sought to document the incidence and mortality of HCC in Queensland, Australia, a state occupying a vast land area with diverse at-risk subpopulations. Methods: Using population-based data from 1996 to 2011, the age-standardised incidence rate (ASR), annual percentage change (APC) and survival of HCC in Queensland were assessed with negative binomial regression, Kaplan-Meier and Cox survival analysis. Spatial patterns of HCC incidence and survival and relevant predictors were mapped. Results: Thousand six hundred and twenty HCCs were diagnosed during this study period, with an overall ASR of 2.00-cases/1000 population. ASR increased by 3.5% per year, (95% CI: 2.1 to 5.0), P < 0.001) among males to 5.6/100,000 in 2011 and a non-significant increase of 2.6% per year, (95% CI = 0.7 to 6.0), P = 0.111) among females to 1.6/100,000 in 2011. Higher incidence was associated with male gender, older age, major city residence and proportionally higher area Indigenous population. Thousand and two hundred and eighty-seven patients died. Median survival was approximately 10 months. Five-year survival improved from 18% in 1996-2000 to 24% in 2006-2011 (P < 0.001). Poorer survival was associated with older age, less recent period of diagnosis, lower hepatitis B prevalence in country of origin and greater area-level social disadvantage. Conclusions: Over this study period, HCC incidence increased significantly. HCC survival improved but remains poor. Social determinants are critical to HCC epidemiology.

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.

Anaemia frequently complicates peginterferon/ribavirin therapy for chronic hepatitis C infection. Better prediction of anaemia, ribavirin dose reduction or erythropoietin (EPO) need, may enhance patient management. Inosine triphosphatase (ITPA) genetic variants are associated with ribavirin-induced anaemia and dose reduction; however, their impact in real-life clinic patient cohorts remains to be defined. We studied 193 clinic patients with chronic hepatitis C infection of mixed viral genotype (genotype 1/4 n = 123, genotype 2/3, n = 70) treated with peginterferon/ribavirin. Patients were genotyped for ITPA polymorphisms rs1127354 and rs7270101 using Taqman primers. Hardy-Weinberg equilibrium was present. Estimated ITPA deficiency was graded on severity (0-3, no deficiency/mild/moderate/severe, n = 126/40/24/3, respectively). Multivariable models tested the association with anaemia at 4 weeks of treatment [including decline in haemoglobin (g/dL); haemoglobin10 g/dL and haemoglobin decline3 g/dL]; ribavirin dose reduction and EPO use and explored sustained viral response (SVR) to peginterferon/ribavirin. More severe ITPA deficiency was associated with less reduction in haemoglobin level (P0.001; R(2) = 0.34), less ribavirin dose reduction (OR 0.42; (95% CI = 0.23-0.77); P = 0.005) and less EPO use [OR 0.53; (0.30-0.94); P = 0.029]. ITPA deficiency was associated with SVR [OR: 1.70; (1.02-2.83); P = 0.041] independently of clinical covariates (adjusted R(2) = 0.31). In this clinical cohort, ITPA deficiency helped predict the risk of on-treatment anaemia, ribavirin dose reduction, need for EPO support and was associated with SVR. For patients on HCV regimens including peginterferon/ribavirin, testing for ITPA deficiency may have clinical utility.

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

Single-nucleotide polymorphisms (SNPs) in the IL28B and PNPLA3 gene regions have been associated with hepatic steatosis in genotype 1 (G1) chronic HCV infection but their clinical impacts remain to be determined.We sought to validate these associations and to explore their impact on treatment response to peginterferon and ribavirin therapy.A total of 972 G1 HCV-infected Caucasian patients were genotyped for the SNPs rs12979860 (IL28B) and rs2896019 (PNPLA3). Multivariable analysis tested IL28B and PNPLA3 for association with the presence of any steatosis (0 %); clinically significant steatosis (5 %); steatosis severity (grade 0-3/4); and the interacting associations of the SNPs and hepatic steatosis to sustained viral response (SVR).IL28B and PNPLA3 polymorphisms were associated with the presence of any steatosis (rs12979860, p = 1.87 × 10(-7); rs2896019, p = 7.56 × 10(-4)); clinically significant steatosis (rs12979860, p = 1.82 × 10(-3); rs2896019, p = 1.27 × 10(-4)); and steatosis severity (rs12979860, p = 2.05 × 10(-8); rs2896019, p = 2.62 × 10(-6)). Obesity, hypertriglyceridemia, hyperglycemia, liver fibrosis, and liver inflammation were all independently associated with worse steatosis. Hepatic steatosis was associated with lower SVR, and this effect was attenuated by IL28B. PNPLA3 had no independent association with SVR.IL28B and PNPLA3 are associated with hepatic steatosis prevalence and severity in Caucasians with G1 HCV, suggesting differing potential genetic risk pathways to steatosis. IL28B attenuates the association between steatosis and SVR. Remediable metabolic risk factors remain important, independently of these polymorphisms, and remain key therapeutic goals to achieve better outcomes for patients with HCV-associated hepatic steatosis.

Hepatitis C virus (HCV) subverts host cholesterol metabolism for key processes in its lifecycle. How this interference results in the frequently observed, genotype-dependent clinical sequelae of hypocholesterolemia, hepatic steatosis, and insulin resistance (IR) remains incompletely understood. Hypocholesterolemia typically resolves after sustained viral response (SVR), implicating viral interference in host lipid metabolism. Using a targeted cholesterol metabolomic platform we evaluated paired HCV genotype 2 (G2) and G3 patient sera for changes in in vivo HCV sterol pathway metabolites. We compared HCV genotypic differences in baseline metabolites and following antiviral treatment to assess whether sterol perturbation resolved after HCV eradication. We linked these metabolites to IR and urine oxidative stress markers. In paired sera from HCV G2 (n = 13) and G3 (n = 20) patients, baseline sterol levels were lower in G3 than G2 for distal metabolites (7-dehyrocholesterol (7DHC) 0.017 versus 0.023 mg/dL; P adj = 0.0524, cholesterol 140.9 versus 178.7 mg/dL; P adj = 0.0242) but not the proximal metabolite lanosterol. In HCV G3, SVR resulted in increased levels of distal metabolites (cholesterol [Δ55.2 mg/dL; P adj = 0.0015], 7DHC [Δ0.0075 mg/dL; P adj = 0.0026], lathosterol [Δ0.0430 mg/dL P adj = 0.0405]). In contrast, lanosterol was unchanged after SVR (P = 0.9515). Conclusion: HCV G3, but not G2, selectively interferes with the late cholesterol synthesis pathway, evidenced by lower distal sterol metabolites and preserved lanosterol levels. This distal interference resolves with SVR. Normal lanosterol levels provide a signal for the continued proteolysis of 3-hydroxyl-3-methylglutaryl coenzyme A reductase, which may undermine other host responses to increase cholesterol synthesis. These data may provide a hypothesis to explain why hypocholesterolemia persists in chronic HCV infection, particularly in HCV G3, and is not overcome by host cholesterol compensatory mechanisms.

Background & Aims IL28B polymorphisms have been associated with both treatment induced and spontaneous clearance of hepatitis C virus (HCV). We previously found that LDL cholesterol levels were higher in chronic hepatitis C (CHC) patients with the CC genotype at the rs12979860 polymorphism, located proximal to the IL28 gene. Here we analyzed the association of steatosis with IL28B genotype in treatment naive patients with CHC. Methods Two independent cohorts of 145 genotype 1 infected patients from an antifibrotic study and 180 genotype 1 patients from Duke were analyzed for the presence and severity of steatosis in relation to the rs12979860 polymorphism at the IL28B locus. TaqMan assay based genotyping classified three groups CC, CT, and TT. Results CC genotype was associated with a lower prevalence of steatosis. In the antifibrotic study, steatosis was found in 47.6% (50/105) of IL28B non-CC vs . 22.5% (9/40; p =0.008) in CC patients. Similarly, steatosis was found in 67.4% (89/132) of non-CC patients compared to only 39.6% (19/48; p =0.001) of CC patients in the Duke cohort. Conclusions IL28B CC genotype is associated with less pronounced disturbances of lipid metabolism, as reflected both in serum lipoprotein levels and hepatic steatosis, in HCV infection.

Genome-wide association studies (GWAS) have recently identified host genetic variation to be critical for predicting treatment response and spontaneous clearance in patients infected with hepatitis C virus (HCV). These important new studies are reviewed and their future clinical implications discussed. Single-nucleotide polymorphisms in the region of the IL28B gene on chromosome 19, coding for the interferon (IFN)-λ-3 or IL28B gene, are strongly associated with treatment response to pegylated IFN and ribavirin in patients infected with genotype 1 HCV. The good response variant is associated with a twofold increase in the rate of cure. Allele frequencies differ between ethnic groups, largely explaining the observed differences in response rates between Caucasians, African Americans and Asians. IL28B polymorphism is also strongly associated with spontaneous clearance of HCV. The biological mechanisms responsible for these genetic associations remain unknown and are the focus of ongoing research. Knowledge of a patient's IL28B genotype is likely to aid in clinical decision making with standard of care regimens. Future studies will investigate the possibility of individualizing treatment duration and novel regimens according to IL28B type.

Note: Letter / Comment on: Hepatology. 2010 Aug;52(2):421-9 Reference EPFL-ARTICLE-165071doi:10.1002/hep.23826 Record created on 2011-04-15, modified on 2016-08-09

Two functional variants in the inosine triphosphatase (ITPA) gene causing inosine triphosphatase (ITPase) deficiency protect against ribavirin (RBV)-induced hemolytic anemia and the need for RBV dose reduction in patients with genotype 1 hepatitis C virus (HCV). No data are available for genotype 2/3 HCV. We evaluated the association between the casual ITPA variants and on-treatment anemia in a well-characterized cohort of genotype 2/3 patients treated with variable-duration pegylated interferon alfa-2b (PEG-IFN-α2b) and RBV. Two hundred thirty-eight Caucasian patients were included in this retrospective study [185 (78%) with genotype 2 and 53 (22%) with genotype 3]. Patients were treated with PEG-IFN-α2b plus weight-based RBV (1000/1200 mg) for 12 (n = 109) or 24 weeks (n = 129). The ITPA polymorphisms rs1127354 and rs7270101 were genotyped, and an ITPase deficiency variable was defined that combined both ITPA variants according to their effect on ITPase activity. The primary endpoint was hemoglobin (Hb) reduction in week 4. We also considered Hb reduction over the course of therapy, the need for RBV dose modification, and the rate of sustained virological response (SVR). The ITPA variants were strongly and independently associated with protection from week 4 anemia (P = 10-6 for rs1127354 and P = 10-7 for rs7270101). Combining the variants into the ITPase deficiency variable increased the strength of association (P = 10-11). ITPase deficiency protected against anemia throughout treatment. ITPase deficiency was associated with a delayed time to an Hb level < 10 g/dL (hazard ratio = 0.25, 95% confidence interval = 0.08-0.84, P = 0.025) but not with the rate of RBV dose modification (required per protocol at Hb < 9.5 g/dL). There was no association between the ITPA variants and SVR. Conclusion: Two ITPA variants were strongly associated with protection against treatment-related anemia in patients with genotype 2/3 HCV, but they did not decrease the need for RBV dose reduction or increase the rate of SVR.

20 G2) were included. SVR was defined as undetectable HCVRNA at 24 weeks of follow up. The SNP analysis of rs12979860 variant was determined in 50ng of DNA by RT-PCR using specific oligonucleotide primers and probes to amplify the sequence target in DNA (Tib MoLBIOL GmbH, Berlin Germany). All HCV patients were genotyped as CC, CT or TT. Results: CT and TT variants were present in 45 and 18 subjects (56% and 23%, respectively) of the studied population. CC polymorphism had the lowest frequency in our cohort (21%, CI 95%: 12.89–31.83%) and it was strongly associated with response to standard treatment (OR 2.95); 76% of CC carriers achieved SVR compared with 55.5% and 44.4% of SVR in patients with CT and TT variants.