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Genotype-specific associations between hepatitis C virus (HCV) and insulin resistance (IR) have been described, but a causal relationship remains unclear. This study investigated the association between a sustained virological response (SVR) and IR after chronic HCV therapy.2255 treatment-naive patients with chronic HCV genotype 1 or 2/3 were enrolled in two phase 3 trials of albinterferon alpha-2b versus pegylated interferon alpha-2a for 48 or 24 weeks, respectively. IR was measured before treatment and 12 weeks after treatment using homeostasis model assessment (HOMA)-IR.Paired HOMA-IR measurements were available in 1038 non-diabetic patients (497 with genotype 1; 541 with genotype 2/3). At baseline the prevalence of HOMA-IR3 was greater in patients with genotype 1 than 2/3 (33% vs 27%; p=0.048). There was a significant reduction in the prevalence of IR in patients with genotype 1 achieving SVR (δ 10%; p0.001), but not in genotype 1 non-responders or those with genotype 2/3. Multivariate analysis indicated that SVR was associated with a significant reduction in mean HOMA-IR in patients with genotype 1 (p=0.004), but not in those with genotype 2/3, which was independent of body mass index, alanine transaminase, γ-glutamyl transpeptidase and lipid level changes.SVR is associated with a reduction in HOMA-IR in patients with HCV genotype 1 but not in those with genotype 2/3. Genotype 1 may have a direct effect on the development of IR, independent of host metabolic factors, and may be partially reversed by viral eradication.

The World Health Organization estimates that approximately 350 million people are infected with the hepatitis B virus (HBV)1 and that over 170 million individuals are chronically infected with the hepatitis C virus (HCV).2 The majority of those who are infected live in the developing world and, although the incidence of these infections is declining in many Western countries,3 these viruses continue to spread in many countries. For example in Egypt, parenteral therapy for schistosomiasis administered between 1961 and 1986 led to an epidemic of chronic hepatitis C4 and recent reports suggest that the incidence is increasing once again in Egypt due to the reuse of needles for medical injections and other iatrogenic causes.5 6 It is therefore probable that the current discrepancy between disease burden in developed and developing nations will continue to widen and here we argue that the reduction in disease burden in the developed world should not lead to a reduction in engagement with these viruses. Migration is one of the defining issues of our times. For example, more than 5 million Canadians were born outside the country and approximately 250 000 new immigrants arrive in Canada each year. With an increasingly interconnected world due to travel and migration, health trends in one location have both local and global implications since infectious diseases do not remain geographically isolated. There is a paucity of data on many migration related health issues but there is a growing body of data demonstrating an increase in the burden of migration-related chronic viral hepatitis in Western societies. The UK Hepatitis Foundation estimated in 2007 that the number of hepatitis B cases in the UK doubled in the previous 6 years chiefly due to migration of infected people,7 many from the new member states of the European Union where …

The effects of hepatitis C virus genotype and viraemia on disease outcome in patients with chronic hepatitis C virus infection were studied. Patients infected with genotype 1 tended to develop more severe disease, and to respond less well to interferon (IFN) treatment, but no pretreatment variable successfully predicted either the severity of the disease or the response to IFN. Failure to eliminate the virus during the first three months of therapy, however, predicted a failure to derive long term benefit from the current IFN regime. Hence pretreatment variables cannot be used to determine whether individual patients will respond to IFN, but observations during the first three months of therapy can be used to decide which patients will not respond to prolonged therapy. In these patients consideration should be given to changing the IFN dosing regime or using alternative treatments.

Introduction HPC3014 is a Phase 3, open-label study to assess if response to SMV+Peg-IFN/RBV at Week 2 can allow shortening of treatment to 12 weeks, irrespective of baseline and on-treatment factors. Method Treatment-naive chronic HCV G1-infected patients with no-to-moderate fibrosis (METAVIR F0–F2) were recruited. In patients with HCV-RNA ® Taqman ® lower limit of quantification: 25 IU/mL, lower limit of detection: 15 IU/mL]) at Week 2 and undetectable at Weeks 4 and 8, all treatments were stopped at Week 12 (12-week group). If these criteria were not met, Peg-IFN/RBV was continued to Week 24 (in one case extended to Week 48). Results 123/163 (76%) patients treated were eligible for the 12-week group (53% male, 92% white, 40%G1a/60%G1b, 76% METAVIR F0/1 and 26/59/15% IL28B CC/CT/TT). Treatment was well tolerated in the 12-week group; all patients completed therapy and none failed on treatment; 33% (41/123) of patients relapsed and 3% (4/123) were lost to follow-up. Grade 3 AEs at least possibly related to SMV were experienced by 5% (6/123) of patients. No grade 4 AEs were considered related to SMV; 3% (4/123) of patients experienced an SAE (considered not related to SMV). AEs of special interest in >10% of patients were pruritus (36%), rash (any type, 17%), neutropenia (20%), dyspnoea (15%) and anaemia (11%). Overall SVR12 in the 12-week group was 66% (81/123) but was higher in patients with IL28B CC genotype (94%), patients with baseline viral load ≤800,000 IU/mL (82%), those with mild fibrosis (F0–F1) (74%), and those with undetectable HCV-RNA at Week 2 (77%). Amongst patients with undetectable HCV-RNA at Week 2, SVR12 rates still varied based on baseline factors. Conclusion Week 2 response alone did not predict treatment outcomes as other baseline factors such as IL28B genotype, baseline viral load and fibrosis score seemed to influence SVR rates. Multivariate analyses are ongoing using factors associated with higher SVR rates shown in this analysis in order to create a strong model to select patients with a good chance of SVR after 12 weeks of therapy. Disclosure of interest G. Foster Conflict with: BMS, Gilead, Janssen, GSK, Roche, Springbank, Tekmira, T. Asselah Conflict with: AbbVie, Janssen, Gilead, BMS, Merck, Roche, C. Moreno Conflict with: AbbVie, Astellas, BMS, Gilead, Janssen, MSD, Roche, C. Sarrazin Conflict with: Abbott, Abbvie, BMS, Gilead, Janssen, Merck/MSD, Qiagen, Roche, Siemens, M. Gschwantler Conflict with: AbbVie, BMS, Gilead, Janssen, MSD, Roche, A. Craxi: None Declared, P. Buggisch Conflict with: AbbVie, BMS, Gilead, Janssen, MSD, Roche, R. Ryan Conflict with: Janssen, O. Lenz Conflict with: Janssen, G. Van Dooren Conflict with: Janssen, I. Lonjon-Domanec Conflict with: Janssen, M. Schlag Conflict with: Janssen, M. Buti Conflict with: Gilead, Janssen, MSD.

Introduction Tenofovir and Entecavir are potent nucleots (t)ide analogues (NUCs) and are the standard of care in the treatment of Chronic Hepatitis B (CHB). Despite this, they have limited ability to reduce HBsAg, thus indefinite or life-long therapy is mandated in the majority of patients. Pegylated-Interferon-Alpha (PegIFNa) is associated with better rates of HBsAg decline, but its effect is limited to a small proportion of patients. In isolation, these therapies are inadequate. By optimising the use of these therapies, delivered in combination or sequentially, better treatment outcomes may be achievable. We report on the treatment response in a cohort of patients treated with sequential NUC therapy. Method 31 patients (male = 25); median age 32 (range 18–55), HBeAg positive (n = 20), were treated with PegIFNa; deemed non-responders and treated sequentially with a NUC analogue. Treatment response in this cohort was compared with 58 patients (male = 50); median age 45 (range 21–72), HBeAg positive (n = 25) who were treated with do-novo NUC therapy without previous PegIFNa exposure. Patients in both cohorts were virally suppressed at the time of analysis. Serum ALT, HBV DNA and HBsAg were quantified at baseline and longitudinally in the cohorts. Results In the sequential NUC therapy group, baseline median ALT was 102 IU/L (range 24–420) and median HBV DNA 6.93 logIU/ml compared with 43 IU/L and 4.48 logIU/ml respectively for the de-novo NUC group. ALT normalisation and reduction in HBV DNA to undetectable levels was similar in both groups over follow-up (p = n.s). At the time of viral suppression (9–12 months in both cohorts) the decline in HBsAg in the de-novo NUC group overall was 0.02 logIU/ml compared to baseline (p = n.s). In patients receiving sequential NUC therapy there was a significant decline in HBsAg over follow-up compared to baseline (0.70 log IU/ml, p = 0.0001). Conclusion Sequential NUC therapy following treatment failure with PegIFNa is associated with greater reductions in HBsAg than PegIFNa alone or NUC monotherapy. This suggests PegIFNa may prime the immune response, even in the context of treatment failure, leading to better outcomes with sequential NUC therapy. We have identified an immune phenotype associated with HBsAg decline in sequential NUC therapy. Further studies are required to confirm this finding and the applicability of an immune marker to predict treatment response in clinical practice. Disclosure of interest None Declared.

Introduction Cirrhotic patients admitted to the intensive care unit (ICU) are reported to have poor outcomes with published one year mortality rates of up to 81%. 1 ICU mortality in cirrhotic patients has improved over recent years, but there is no recent data on one year outcomes. The aim of this study was to examine one year mortality, assess organ and liver scoring systems predictive value for one year mortality and to compare outcomes in patients with alcohol and non-alcohol related cirrhosis admitted to the ICU of a non-transplant tertiary Hepatology centre. Method This was a retrospective analysis of prospectively collected data on outcomes of consecutively admitted patients with liver cirrhosis to the Royal London Hospital, from Intensive Care National Audit and Research Centre records. Results Between 01/01/2006 and 31/12/2013, 253 cirrhotic patients were admitted to ICU. The most common reasons for admission were sepsis (33%), GI bleed (24%) and hepatic encephalopathy (11%). Aetiologies of cirrhosis included alcohol (68%), viral hepatitis (17%) and NASH (4%). There were significant differences in median age (53 vs 57), ethnicity (White/Black/Asian – 87/5/8% vs 56/13/31%) and admissions for sepsis (38% vs 21%) between those with alcohol and non-alcohol related aetiologies. One year, hospital and ICU mortality were 66%, 57% and 39% overall, 66%, 58% and 40% in alcohol, and 66%, 54% and 38% in non-alcohol aetiologies of cirrhosis respectively (p=ns.). 1 year mortality in patients requiring 1, 2, 3 and 4 organ support was 49%, 68%, 95% and 88%. Patients requiring renal replacement therapy (RRT) had more organs failing (3 vs 1 p The SAPS II score was a better predictor of one-year mortality than other organ failure scores. Conclusion One-year mortality in our series compares favourably with the 81% previously reported in a UK transplant centre, 1 and most patients who survive hospital admission will survive to one year. Patients with alcohol and non-alcohol aetiologies of cirrhosis have similar outcomes. The requirement for RRT bestows a poor prognosis. Organ failure scores, particularly the SAPS II, are better at predicting one year mortality than the MELD score, but their discriminatory power was relatively poor. Disclosure of interest None Declared. Reference Mackle IJ et al . One year outcome of intensive care patients with decompensated alcoholic liver disease. Critical Care 2006;97:49–8

Introduction Immune tolerant (IT) chronic hepatitis B (CHB) is a clinical definition based on normal serum ALT and high HBV DNA. NICE guidelines identify a need to improve knowledge of the natural history of eAg+ IT disease. Importantly, recent studies have reported an inverse relationship between quantitative HBsAg (qHBsAg) and the degree of liver fibrosis in eAg+ patients. 1 We aimed to explore the utility of qHBsAg in combination with clinical variables to more accurately define the IT disease phase in young patients. Method Children and young adults were followed in dedicated clinics. 155 consecutive treatment naive, eAg+ patients were included for analysis; female = 79, median age 22 (range 6–30). Data on longitudinal ALT, HBV DNA and Ishak fibrosis stage (FS) were recorded. HBsAg levels were quantified to elucidate its relationship with IT disease. Results There was no correlation between qHBsAg and age, HBV genotype or ALT levels (p = ns). High HBV DNA correlated with high qHBsAg; HBV DNA >8 log, (p = 0.016); HBV DNA >9 log (p = 8 log, FS 0–2), to denote the IT disease phase; we noted significantly higher qHBsAg levels in IT vs. non-IT eAg+ patients (p = 1,000,000 IU/ml (6 log) was only seen in patients who had the combined clinical parameters of ALT, HBV DNA and FS consistent with IT disease; thus representing a theoretical qHBsAg threshold to identify genuine IT patients. Conclusion Serum ALT and HBV DNA alone do not accurately define IT CHB. We demonstrate that high qHBsAg levels combined with these parameters can more accurately characterise IT disease, confirmed histologically with minimal or no fibrosis. We propose that qHBsAg used in combination with serum ALT and HBV DNA could obviate the need for liver biopsy in young patients. Disclosure of interest None Declared. Reference Marcellin P, Martinot-Peignoux M, Asselah T, et al . Serum levels of hepatitis B surface antigen predict severity of fibrosis in patients with E antigen-positive chronic hepatitis B. Clin Gastroenterol Hepatol. 2014

Introduction In patients with non-alcoholic fatty liver disease (NAFLD), liver inflammation is a key histological feature that distinguishes benign simple steatosis from progressive non-alcoholic steatohepatitis (NASH). The mechanisms that underlie this process are poorly understood. We recently showed that Stat2 plays a pivotal role in acute inflammation, independent of its role as an interferon mediator. The aim of the current study is to test the hypothesis that STAT2 is associated with hepatic inflammation in patients with NASH and in a murine model of liver injury. Method Expression of (phosphorylated, p) STAT2 and STAT1 was assessed by immunohistochemistry in anonymised sections of archived liver tissue taken from consenting patients with NASH at The Royal London and St Mary’s Hospitals (London, UK). STAT2 -/- and WT mice were injected with incremental doses of carbon tetrachloride (CCl4) for 4 or 6 weeks. Serum and liver tissue were harvested 24 or 72hrs after the last injection. Immunohistochemistry for activated stellate cells (anti-alpha smooth muscle actin, aSMA) and macrophage/Kupfer cells (anti-F4/80) was performed. Results Tissue from 62 patients was examined. Hepatocyte nuclear expression in NASH liver tissue was significantly greater for STAT1 (74% vs 10%, p Stat2 -/- mice were protected from CCl 4 -mediated liver injury with reduced serum alanine aminotransferase (ALT, 2165 vs 1090 iU/ml, p = 0.03), inflammation and necrosis histologically and fibrosis (Picrosirius red staining). There were no significant differences in the number of aSMA or F4/80-positive cells between WT and Stat2 -/- mice. Conclusion These data identify a novel role for STAT2 in the development of liver disease, with expression of STAT1 and STAT2 relating to disease grade. The protection afforded by Stat2 loss in murine models is unrelated to macrophage and stellate cell activation, and we hypothesise that the mechanism of protection is therefore reduced production of Stat2-mediated cytokine production. Disclosure of interest None Declared.

Introduction Sequential/combined therapeutic approaches comprising Pegylated-Interferon (Peg-IFNα) and nucleot (s)ide analogues (NUC) are being given greater consideration as treatment strategies for chronic hepatitis B (CHB) to achieve HBsAg loss. We demonstrated boosting of NK cells in eAg- patients treated with Peg-IFNα (Micco et al , J. Hepatol , 2013), and postulated this effect could be maintained with sequential NUC therapy. Differential NK cell responses in patients receiving sequential NUCs were analysed and correlated with HBsAg response, to elucidate a possible treatment advantage with Peg-IFNα exposure. Method PBMC from 18eAg+ patients during Peg-IFNα therapy were utlised. 9/18 patients considered Peg-IFNα non-responders after 48-weeks therapy progressed to sequential NUCs and were followed until virally suppressed. Phenotypic and functional analysis of NK cell subsets was performed by multicolour flow-cytometry and findings correlated with on-therapy HBsAg changes. Results Peg-IFNα expanded CD56 bright NK cells by 3-fold (p = 0.0001) which was maintained on sequential therapy. NK cell receptor expression was analysed. All receptors, except NKG2C, were maintained on sequential NUCs, with marked augmentation in the expression of NKp30 and NKp46 on CD56 bright NK cells (p = 0.5 log 10 IU/ml) on sequential NUCs. We noted that only these patients showed the ability to increase the proportion of functional NK cells (IFNγ+&CD107 + ) on sequential NUCs. Additionally only these responders demonstrated a reduction in TRAIL expression on sequential NUCs, compared to those without HBsAg decline, who showed the reverse. Conclusion Restoration of NK cell cytotoxic/effector functions is seen on sequential therapy, but only in those patients with HBsAg decline. Lower expression of TRAIL also correlates with treatment response, in line with our finding that TRAIL+ NK cells can delete antiviral T-cells ( Peppa et al , JEM 2013 ). IFNγ, CD107 and TRAIL expression on NK cells may predict those patients who are likely to demonstrate HBsAg decline on sequential therapy. Thus we have identified a phenotype of TRAIL low IFNγ/CD107 hi NK cells which may act as a biomarker in predicting treatment response in this setting. Given these findings, the TRAIL pathway may be a potential future target in order to improve treatment outcomes in CHB. Disclosure of interest None Declared.

Introduction Identifying chronic Hepatitis B virus (HBV) patients in whom nucleos (t)ide analogues (NUCs) can be safely discontinued with sustained immune control is a major unmet need of current treatment strategies. Predicting the onset of biochemical relapse or hepatic flares (HF) following NUC discontinuation is currently not possible. Through the utilisation of cytometry time of flight (CyTOF), a novel mass cytometry technology, in conjunction with traditional flow cytometry tools, the aim of this study was to establish an immune profile associated with the onset of HF upon withdrawal of NUC therapy. Method Cytokine and chemokine serum levels (IL-1β, IL-6, TNF-α, IL-10, CXCL-8, CXCL-10) were measured longitudinally using Luminex in chronic HBV patients who developed HF (n = 6) and in those who did not (n = 2) upon the discontinuation of NUCs. HBV-specific T cell responses were assessed after in vitro expansion of patient peripheral blood mononuclear cells with overlapping HBV peptide pools. An in-depth longitudinal analysis of the expression of 35 markers involved in the activation, differentiation, exhaustion and anti-viral effector function of T and NK cells was performed by CyTOF mass cytometry. Results The analysis of HBV-specific T cells using overlapping HBV peptides, shows that in patients with biochemical relapse after therapy withdrawal, there was no detection of functional antigen-specific T cells at all time points. The onset of HFs was, however, associated with a significant increase in the serum levels of CXCL-10 and IL-10. In contrast, a chronic HBV patient that controlled viral relapse without experiencing HF displayed functional circulating HBV-specific T cells. Preliminary analyses by CyTOF also revealed significant differences in terms of the frequency and functionality of the bulk of the T and NK cell populations both longitudinally (during and after discontinuation of therapy), as well as amongst patients characterised by relapse or immune control. Conclusion Consistent with previous studies, HFs are associated with an increase in the serum levels of CXCL10 and IL-10 while HBV-specific T cells remain undetectable in the periphery. The absence of circulating virus-specific CD8 + T cells during HFs suggests that hepatic inflammation after NUC withdrawal in chronic HBV patients is induced independent of virus-specific CD8 + T cells. CyTOF technology represents a major advance, allowing us to investigate multiple parameters, providing a unique insight into potential biomarkers associated with sustained immune control of HBV. Disclosure of interest None Declared.

Introduction Currently the predominant mode of transmission of hepatitis C virus (HCV) in the developed world is injection drug use (IDU) and HCV antibody prevalence rates reach 60–90% in those who have injected drugs. Treatment rates of injecting drug users (IDU's) with HCV are low at just 3–10% and although small studies indicate treatment of IDU's is safe and effective, data on outcomes of antiviral therapy in current injecting drug users is limited with the largest study published to date including just 31 active IDU's. It has been suggested that antiviral therapy for HCV use may reduce illicit drug use, but published data to support this is lacking Aim To assess the treatment outcomes and the impact of antiviral therapy on illicit drug use in injecting drug users (IDU's) treated with antiviral therapy for Hepatitis C virus (HCV) by nurses based in community addiction services in North East London. The outcomes of the first 81 patients to be treated are presented here, 48 of whom were using illicit drugs at the start of treatment making this the largest cohort of active IDU's with HCV treated with antiviral therapy that has been presented to date. Method Methods consisted of a retrospective database analysis. Illicit drug use was quantified as 3 (heavy/daily); 2 (weekly/moderate); 1 (monthly/occasional) and 0 (previous drug use). The Wilcoxon signed rank test was used for statistical analysis. Results 81 patients were treated over a 45-month period from September 2004 to January 2009. 50 (62%) were genotype 2/3, and 31 (38%) were genotype 1. The average age of infection with HCV was 23, of diagnosis was 39 and of treatment was 41. Compliance with treatment was 88%. 63% of patients had a sustained viral response, 18% were non-responders and 10% discontinued treatment early due to side effects. 5 patients (6%) relapsed after successful treatment. Only 1 patient (1%) has been re-infected post treatment. 48 patients (60%) were actively using illicit drugs when HCV treatment was initiated. Data on pre and post treatment intravenous heroin use, crack cocaine use and alcohol use was available in 74, 40 and 21 patients respectively. Intravenous heroin use reduced from 41/74 patients (55%) to 27/74 (36%) (p=0.0033) after treatment, with daily use reducing from 16/74 (22%) to 7/74 (9%) Crack cocaine use reduced from 32/40 (80%) to 21/40 (53%) (p=0.0103) Alcohol use reduced from 15/21 (71%) to 13/21 (62%) (p=0.5775). Conclusion Nurse led provision of antiviral therapy for HCV infected injecting drug users in community based clinics is effective, with sustained viral response (SVR) rates that compare favourably with published randomised controlled trials of pegylated interferon and ribavirin.[1][1] High rates of compliance are seen and re-infection rates are low, so concern over compliance and re-infection should not prevent treatment of injecting drug users. This study has shown for the first time that a significant reduction in illicit drug use occurs during and after antiviral therapy demonstrating a social benefit of treatment in addition to the known health benefits. [1]: #ref-1

Introduction Chronic Hepatitis B (HBV), a major cause of liver disease, is underdiagnosed in the UK with pockets of high prevalence in areas with large immigrant populations. Identifying individuals through a screening programme dedicated to high risk individuals would be beneficial if that target population could be defined. Our aims were to interrogate a Primary Care database (SystmOne) establishing the best way of identifying individuals suspected of having had a HBV test to exclude them from the target population. Methods We used four search terms: age (>18), ethnic code, birth place, language spoken. Read codes (RC) were applied to identify individuals previously tested/diagnosed with HBV. RC were identified by using ‘HBV’ as a broad search term. Results We identified 4256 individuals aged ≥18. 718 (18%) were excluded because of lack of demographic data; 3210 (75%) qualified as the target population. 81 RC pertaining to HBV were found and generated 413 ‘hits’, only 224 ‘hits’ (54%) satisfied our criteria. 206 individuals (6.4%) had HBV serology recorded, 9/3210 (0.28%) were coded for chronic HBV, a further 2 HBsAg positive patients (0.9%) had no RC. After reviewing individual notes electronically we established the following 8 RC to be the ‘most useful’: XaIq7, XaFuS, X306n, X306i, 43B4, XaMBL, XaG1R, XaPEy which would have identified the latter. Conclusion We have identified the 8 most useful RC to help with a potential screening programme. Using all available HBV RC would be too time consuming. This study highlights that very few high risk immigrants are currently tested for HBV. Disclosure of Interest None Declared.

Introduction Awareness of liver disease as a major cause of morbidity and mortality has led to an increase in liver function tests (LFTs) performed in primary care with abnormal results a common finding. However, we hypothesise that a large gap exists between numbers of patients with abnormal LFTs and those with recorded liver diagnoses. Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver injury. Metabolic syndrome, common in people from the Indian subcontinent, is an important risk factor for NAFLD. We hypothesise that NAFLD is more common among adults of South Asian ethnicities. Methods In a cross-sectional study of 690,683 adults, registered in co-terminus general practices in a region with high ethnic diversity, we extracted demographic information and clinical care data including LFTs in the previous two years, liver disease diagnoses and co-morbidites from the EMIS Web computerised medical records. The breakdown of age, gender, deprivation, BMI, smoking status, alcohol consumption, co-morbidities and cholesterol was described for the whole population and for the six main ethnic groups of Bangladeshi, Indian, Pakistani, White, African and Caribbean. STATA 12 was used to conduct multivariate logistic regression analyses. Results LFTs were performed on 218,032 patients, of whom 31,627 had elevated serum transaminases. Testing varied by age, ethnicity and the presence of co-morbidities. The prevalence of abnormal LFTs was highest among Bangladeshis and independent risk factors for abnormal LFTs included male gender, alcohol consumption and elements of the metabolic syndrome. The most commonly recorded liver diagnosis was NAFLD, followed by chronic viral infection and alcoholic liver disease. 88.4% (n = 27,985) of patients with abnormal LFTs did not have a coded liver diagnosis. The prevalence of recorded NAFLD was highest among patients of Bangladeshi ethnicity. In a multivariate analysis, independent risk factors for NAFLD included Bangladeshi ethnicity, diabetes, raised BMI, hypertension and hypercholesterolaemia. Conclusion Abnormal LFTs are common in the population, but are under-investigated and often remain undiagnosed. Bangladeshi ethnicity is an important independent risk factor for NAFLD. Among the group of patients with abnormal LFTs and no recorded liver diagnosis, many will have a liver disease that is amenable to further management, which may prevent complications. There is a need for evidence-based guidelines for the investigation, referral and management of patients with abnormal liver tests in the community in order to ensure early identification of treatable disease. Disclosure of Interest None Declared.

Introduction Identifying at-risk migrant groups for Hepatitis B and C (HBV and HCV) is well established. The UK Nepali community has grown rapidly since 2004, when settlement rights were given for ex-Gurkha servicemen and dependants. Given military associations, the Hampshire County now has the second largest Nepali population, with the Nepali now making up close to 10% of the population. Nepal sits between China and India, two countries with higher prevalence rates of HBV and HCV, but relatively little is known about prevalence in the Nepali community, with no published studies in the UK. Methods To help design a culturally sensitive testing strategy for HBV and HCV (as advocated by NICE) we conducted focus groups sessions in the Nepali community. Nepali moderators guided sessions to study the beliefs, understanding and perceptions towards liver disease. Results 32 Nepali members attended the focus group sessions, with groups divided by sex and age ( 30 yrs). A thematic analysis approach was used to analyse results. Perceptions of Liver disease: “It is not a communicable disease” “In Nepal water is the main cause of hepatitis” “Mainly alcoholic and smokers get this disease” “I do not think people hate the person….it would not be considered as bad as leprosy disease” Treatment options: “In Nepal herbal medicine is better for jaundice….necessary to drink lot of water and fruits” Knowledge and outreach: “We need to know the function of liver. Then we understand the issue.” “Newspaper for the people who can read but for us who cannot read, radio and TV is better” “What the doctor said, we trust on it” Conclusion NICE guidelines advocate testing at-risk migrant groups for HBV and HCV at an early (asymptomatic) stage. Here, all groups identified liver disease with jaundice or symptoms. Different viewpoints were expressed based on age; younger Nepali members associating a greater stigma to liver disease and hepatitis. All groups expressed a sincere wish to gain greater knowledge about liver disease and to interact with primary care. The study also identified the functional illteracy of many Nepali, and the potential need to modify approaches away from written media. Reference 1 NICE (National Institute for Health and Care Excellence), Hepatitis B and C, ways to promote and offer testing to people at increased risk of infection, 2012 Disclosure of Interest None Declared.

Introduction Patients undergoing major surgery are at risk of systemic inflammatory response syndrome (SIRS) and life-threatening post-operative sepsis. Early identification of high-risk patients would allow for tailored post-operative care. We tested the hypothesis that post-operative SIRS could be predicted by differences in innate immune function in peripheral blood mononuclear cells (PBMC) taken from patients undergoing major abdominal surgery in the perioperative period. Methods Serial blood samples were taken from consenting, adult patients undergoing major hepatic or pancreatic surgery pre-operatively and on days one and two postoperatively. Patients with inflammatory co-morbidities, pre-operative sepsis and those taking anti-inflammatory or immunomodulatory medication were excluded. PBMCs were isolated, stimulated for 24 hours with lipopolysaccharide (LPS) or flagellin and cytokine production was quantified by ELISA. PBMC surface expression of CD14, TLR4 and TLR5 was assessed by flow cytometry. SIRS was defined by the American College of Chest Physicians/Society of Critical Care Medicine consensus criteria. Results We included 32 patients, nine of whom developed SIRS on day five or later. There were no significant pre-operative differences between the SIRS and the non-SIRS groups in TLR-induced IL-6 and TNFa production nor TLR4 and TLR5 expression. LPS- and flagellin- induced IL-6 concentrations were significantly greater in the SIRS group on day two (1532pg/µl vs 153pg/µl; p Conclusion Patients who develop SIRS show increased cytokine production in response to TLR stimulation in the early post-operative period. This is associated with elevated surface TLR4 and TLR5 expression in monocytes. These data indicate that there are early functional differences in innate immune responses in patients who develop SIRS compared to those who do not, and that these differences are detectable days before the onset of clinical symptoms. Such assays can help to identify at-risk patients in whom intensive therapy can be targeted. Disclosure of Interest None Declared

Introduction Tenofovir Disoproxil Fumarate (TDF) is an established oral antiviral (OAV) in the treatment of Chronic Hepatitis B (CHB). Bone Mineral Density (BMD) loss has been described in TDF treated HIV patients, but limited data exist in CHB. We have used DEXA scanning to determine BMD changes in TDF treated patients and have reported the possibility of BMD loss. DEXA scanning, however, is costly and requires longitudinal follow-up. We assessed the value of the FRAX® score and of bone biochemistry to evaluate their utility in TDF treated patients. Methods The FRAX score is a WHO web-based tool, used to calculate 10-year fracture risk and the need for lifestyle modification, DEXA scanning or preventative treatment. CHB patients treated with TDF for a minimum of 12-months and a control group not exposed to TDF were studied. 122 TDF exposed patients (male = 89), median age 45 (range = 26–64) and 48 patients (male = 31), median age 36 (range = 20–62) not exposed to TDF were DEXA scanned and included in the study. We calculated FRAX scores and recorded bone biochemical markers, comprising serum Alkaline Phosphatase (sALP), Calcium (sCa) and Phosphate (sPO). Results TDF treated patients had lower hip T-scores compared to controls (p = 0.02). On univariate analysis factors associated with a hip T-score Conclusion Our results demonstrate the FRAX score alone can accurately predict the risk of developing an osteoporotic fracture in TDF treated CHB patients. This potentially obviates the need for DEXA scanning and the associated costs. The relationship between sALP and TDF is noteworthy, but bone parameters are of limited use in predicting BMD changes. Although BMD loss in TDF treated CHB patients remains unproven, we demonstrate the use of the FRAX score may determine those at risk of osteoporotic fractures in CHB. Disclosure of Interest None Declared.

Introduction Tenofovir and Entecavir are potent oral antivirals (OAV’s) and leading agents in the treatment of Chronic Hepatitis B (CHB). Despite this, they have limited ability to reduce HBsAg, thus indefinite or life-long therapy is mandated as these drugs rarely achieve immunological control. Pegylated-Interferon-Alpha (PEG-IFNα) is associated with better rates of HBsAg decline, but only a minority of patients achieve sustained immune control. New strategies to reduce HBsAg and achieve immune control, including combination PEG-IFNα & OAV are under investigation at present. Here we report data on treatment response in a cohort receiving sequential OAV therapy following PEG-IFNα failure. Methods 55 patients (male = 41), median age 31 (range 18–55) were treated with PEG-IFNα over the course of the study. 13 patients remain on therapy and 5 patients discontinued due to poor response or intolerance. 37 patients, HBeAg positive (n = 29), completed 48 weeks PEG-IFNα and were included in the analysis. 23/37 patients (HBeAg positive = 18), following treatment with PEG-IFNα were considered non-responders and treated with sequential OAV therapy. Treatment response in this cohort was compared with 60 patients, (male = 54), median age 45 (range 21–70) receiving OAV monotherapy over a 12-month period. Serum ALT, HBV DNA and HBsAg were quantified at baseline and longitudinally in both cohorts. Results In the sequential therapy group, baseline median ALT was 60 IU/L (range 31–194) and median HBV DNA 5.15 logIU/ml compared with 43 IU/L and 3.43 logIU/ml respectively for the OAV monotherapy group. ALT normalisation and reduction in HBV DNA to undetectable levels was similar in both groups over follow-up (p- = n.s). Following 12-months of OAV monotherapy the decline in HBsAg in this group overall was 0.06 logIU/ml compared to baseline (p = n.s). In patients receiving sequential OAV therapy there was a significant decline in HBsAg over follow-up compared to baseline (0.65 log IU/ml, p = 0.0001). In addition 4/18 HBeAg positive patients seroconverted on sequential therapy and 1 patient cleared HBsAg. Conclusion Sequential OAV therapy following treatment failure with PEG-IFNα is associated with greater reductions of HBsAg than PEG-IFNα alone or OAV monotherapy. This suggests PEG-IFNα may prime the immune response, even in the context of treatment failure, leading to better responses with sequential OAV therapy. Further studies are needed to confirm this finding and determine whether a similar priming effect is observed with shorter courses of PEG-IFNα in line with current PEG-IFNα stopping rules. Disclosure of Interest None Declared.

Introduction Chronic Hepatitis B Virus (HBV) infection in persons attending drug addiction services has not been studied as thoroughly as infection with Hepatitis C Virus (HCV). The aim of this audit was to assess the number of service users chronically infected with HBV and their relevant co-infections, co-morbidities and access to treatment. Methods The Tower Hamlets Specialist Addiction Unit serves the London Borough of Tower Hamlets with a population of more than 200,000. Its Blood Borne Virus Team (BBVT) provides harm reduction healthcare in more than 10 drug and alcohol addiction facilities including outreach sites and neighbouring boroughs. Data on service users chronically infected with HBV was extracted from the service database. Results Of 2577 people currently registered with the BBVT 49 (1.9%) have chronic HBV infection with detectable HBs-Antigen. 88% are male, the average age is 40 years and the majority is of non-British origin with large groups of Baltic (18%) and Black/African/Caribbean (20%) ethnicity. 16 patients (33%) are currently injecting drug users (IDU), 13 (27%) formerly IDU. Other reasons for referral are non-injecting drug and alcohol use. 14/49 patients (29%) have psychiatric comorbidities other than drug/alcohol abuse. 22 patients (45%) knew about their infection when they entered the service. 12 patients (24%) have HBe-Antigen-positive and 37 (76%) HBe-Antigen-negative disease. 12/49 patients (24%) have detectable HCV-RNA and can be regarded as co-infected. 3/49 patients (6%) have detectable Hepatitis D Virus (HDV)-RNA. Two patients (4%) are infected with HBV, HCV and HDV. Two patients (4%) have active syphilis co-infection and HIV-co-infection, respectively. 10/49 patients (20%) have been diagnosed with cirrhosis. One patient has undergone resection for HBV-associated hepatocellular carcinoma and has been followed up for 9 years without recurrence. Two patients were infected after documented vaccination against HBV. 7/49 patients (14%) are currently undergoing treatment with a regimen that is effective against HBV. Three patients have cleared HBV, one through treatment and two spontaneously. Conclusion Even in a difficult setting where care can be interrupted by incarceration or psychiatric deterioration, successful health care for patients with chronic HBV infection is possible by using outreach facilities and appointment reminders. The community attending drug addiction services has overlapping risk factors and in East London, only a minority of patients chronically infected with HBV are currently injecting drug users. Vaccination against HBV has no 100% protection rate and service users should repeatedly undergo testing for blood borne viruses. Disclosure of Interest None Declared.

Introduction Tenofovir Disoproxil Fumarate (TDF) is a potent and effective oral antiviral used to treat Chronic Hepatitis B (CHB), but concerns remain about possible long-term toxicity and the costs of indefinite use. An induction-maintenance treatment strategy may allow the use of combination Lamivudine (LAM) and TDF, to avert the development of resistance, followed by maintenance of viral suppression with LAM. To date, there are no data on such a step-down strategy in HBeAg negative CHB. Here we report on patients in whom we safely discontinued TDF, while maintaining viral suppression and normal liver biochemistry. Methods We selected patients who were had received combination therapy for a minimum of 18 months. Selection criteria included HBeAg negative disease, fibrosis score of Results 21 patients (13 male), median age 47, (range 39–62) discontinued TDF. Median follow-up was 3 months (range 1–10 months). During monthly follow-up biochemical and serological data have been measured. All patients had undetectable HBV DNA prior to step-down therapy to LAM and this remained undetectable during follow-up. Pre-discontinuation of TDF the median ALT was 27 (range 15–38) and during follow-up, on LAM monotherapy, was 22 (range 15–45), (p=NS). Median HBsAg level pre-discontinuation of TDF was log 3.48 (range 1.55–4.49) and 3.49 (range 1.55–4.55), (p=NS) on LAM monotherapy. Conclusion We demonstrate no viral breakthroughs or biochemical flares on discontinuing TDF. These data suggest that an induction-maintenance strategy may be pursued in selected CHB patients to avoid long-term exposure to TDF and reduce the burden on healthcare budgets in the context of lifelong oral antiviral therapy. Competing interests None declared.

Introduction Current guidelines do not recommend treatment of Chronic Hepatitis B (CHB) in young adults as they are believed to be immune tolerant with minimal liver damage. Recently we demonstrated that young CHB patients have evidence of immune activity comparable to older patients. Therefore, a proportion of young patients will develop fibrosis as a consequence of immune mediated liver injury. Despite this, the most appropriate modality to assess liver fibrosis remains controversial. We compare the utility of liver biopsy and digital image analysis with FibroScan for assessment of CHB in young adults. Methods Young adult CHB patients were followed in a dedicated clinic and seen 3-monthly. Liver biopsy was performed where indicated and compared with FibroScan scores. Digital image analysis was performed on a selected number of Sirius red stained sections to evaluate percentage fibrosis. 167 patients were assessed; 101/167 (male=63); median age 26 (range 16–30) underwent liver biopsy and were included for analysis. Results 47/101 patients were eAg+. Overall median ALT was 41IU/L (range 14–426) & HBV DNA was 5.22 logIU/ml (range 1.4–9.3). Median Ishak fibrosis score was 1 (range 0–6); median FibroScan score was 5.95 kPa (range 2.6–35.2). There was no difference in the FibroScan score in patients with advanced (F5/6) and minimal fibrosis (F0/1); median FibroScan scores were 6 and 5.95 respectively, (p=ns). The correlation co-efficient between fibrosis and FibroScan was not statistically significant (p=0.46). FibroScan scores were confounded by ALT; using Prati criteria to define normal ALT (female Conclusion A proportion of young adult patients with CHB have significant liver disease on biopsy. This study highlights the limitations of FibroScan in assessing liver fibrosis in this cohort. Our data demonstrates the utility of digital image analysis in benchmarking fibrosis in young patients, potentially providing a more accurate methodology to assess progression of fibrosis over time. Competing interests None declared.

Introduction The innate immune response is an important determinant of progression in chronic inflammatory liver diseases such as alcoholic (ALD) and non-alcoholic fatty liver disease (NAFLD). Sepsis is a frequent cause of hepatic decompensation and some authors suggest a role for toll-like receptor (TLR) sensing of gut-derived pathogens (motile and gram-negative organisms) in disease progression. Paresis of the innate immune system has been described in patients with decompensated liver disease, but the function of TLRs in compensated disease has received scant attention. Our aim was to assess TLR responsiveness in patients with compensated ALD and NAFLD using a combinatorial experimental design, measuring LPS- and flagellin-induced TNFα and IL-6 production. Methods Consenting adult outpatients with compensated ALD or NAFLD were recruited. Diagnoses were confirmed by casenote review. Exclusion criteria included alternative aetiologies, decompensated disease, other systemic immune-related illnesses, and immunosuppression (including steroids). Normal healthy volunteers without liver disease were also recruited. Monocytes isolated from peripheral blood mononuclear cells were stimulated with low dose LPS and flagellin. The production of TNF-α and IL-6 was assayed in supernatants and in patient sera by ELISA. Results We included 28 patients and six normal controls. Patients with compensated cirrhosis have a selective defect in flagellin-induced IL-6 production (330±117 pg/ml) compared to patients with non-cirrhotic ALD or NAFLD (896±146 pg/ml; p=0.01) or healthy controls (764±96 pg/ml). There were no differences in flagellin-induced TNFα nor in LPS-induced cytokine production. There were no differences between the three groups in serum concentrations of TNF, IL-6 and RANTES. Conclusion Paresis of the innate immune response is not universal; there is selective impairment of TLR5-mediated IL-6 production in patients with compensated cirrhosis compared to non-cirrhotic patients. These data identify potential signalling pathways that may be involved in the progression of liver disease or in the susceptibility of patients with cirrhosis to bacterial infections. Competing interests None declared.

Introduction HCV replicates poorly in vitro, so testing of novel antiviral therapies currently relies on modified viral replicons, based on genotype (G)1, or the G2 JFH-1 virus. A model allowing patient virions to be cultured would facilitate drug discovery and allow direct sensitivity testing. Here we describe the development of a novel HCV replication assay, its validation using the antiviral agents alisporivir and telaprevir and its value in identifying responses to interferon and ribavirin. Methods CD14 (+) monocytes derived from patients with chronic HCV infection, or pre-stimulated THP-1 cells infected with serum from G1 and G3 HCV infected donors, were fused with HuH7 cells and treated with antiviral agents at various concentrations. The fused cells were maintained in tissue culture for up to 5 days, before extraction of HCV RNA and quantification by PCR. p Values were derived using the Mann–Whitney U test for comparison of non-parametric data. Results are expressed as mean±SEM. Results Replicating HCV from patients infected with diverse genotypes could be successfully transferred to HuH7 cells using the monocyte “capture-fusion” approach. RNA increased fivefold in fused cells and viral protein production as well as viral release could be demonstrated, confirming the presence of complete viral replication cycles in this new model. Treatment of G1 and G3 fused/infected Huh7 cells with escalating concentrations of alisporivir showed greater drug efficacy in cells infected with G3 than G1 (IC 50 0.026±0.008 μM vs 0.109±0.02 μM, p=0.0286). Conversely, telaprevir showed greater efficacy in fused/infected cells with G1 than fused/infected cells with G3 HCV. Treatment with 0.1 μM telaprevir, which approximates its IC 50 in replicon cells, resulted in a reduction of HCV RNA by 66.15±10.43% in G1 cells vs 21.56±3.16% in G3 infected cells (p=0.016). We examined sensitivity to interferon and ribavirin in samples from patients who did (N=3), or did not (N=4), respond to therapy. We found no significant difference in the viral sensitivity, suggesting that for interferon based therapies host factors play a more important role than virological response. Conclusion These data confirm the value of a capture-fusion model for HCV replication in studying the replication of patient-derived HCV and demonstrate that for interferon and ribavirin based treatments, host factors dominate the response. However viral response determines the clinical response to direct acting anti-viral agents. This technique may be useful in identifying the most appropriate treatment strategies for patients with HCV planning therapy with the new direct acting antiviral agents. Competing interests M Cunningham: None declared, A Javaid: None declared, J Waters: None declared, G Foster grant/research support from: Roche, Janssen, Tibotec, Novartis, Consultant for: Abbott, BI, BMS, Chughai, Janssen, Merck, Novartis, Roche, Tibotec.

Introduction Infection is common in patients with severe alcoholic hepatitis (AH) and a significant contributor to mortality. Monocytes play an important role in bacterial elimination by phagocytosis, using intracellular oxidative killing and antigen presentation. Our study sought to evaluate monocyte phagocytosis and scavenger receptor expression in AH. Methods Monocytes were collected from 14 patients with AH (DF >31, prior to treatment) and 22 healthy controls (HC). Using FACS, monoclonal antibodies to scavenger receptors (CD36, -64, -163, -206, DCIR) and HLA-DR were used for immunophenotyping. Subsequently, ex-vivo monocyte phagocytosis and oxidative burst activity was assessed using FITC-labelled opsonised and non-opsonised Escherichia coli . Results The expression of scavenger receptors was deranged. In CD14+CD16- (classical) monocytes, CD163 MFI was reduced in AH compared to controls (587 vs 403; p=0.05). CD36, -206 and DCIR expression was similar between HC and AH patients but CD64 MFI was raised (6002 vs 12599; p E coli was lower in AH compared to HC (77% vs 87%; p E coli was markedly reduced (84% vs 47%; p Conclusion It appears that there are a number of functional defects in circulating monocytes in patients with AH. The marked impairment of phagocytosis and intracellular killing may contribute to the increased susceptibility to infection in this group of patients. Competing interests None declared.

Introduction Stopping rules have been proposed for the early discontinuation of Pegylated-Interferon-α (PEG-IFN-α) therapy in those patients who are considered unlikely to respond. Recent studies have shown that no reduction in quantitative HBsAg and the absence of >2 log decline in HBV DNA at 12 weeks therapy can predict non-response. However, these data are almost exclusively from genotype A and D cohorts. Here we test how robust this strategy would be in clinical practice and whether this rule could be applied to a UK population of diverse HBV genotypes. Methods 49 patients (male=35) were treated with PEG-IFNα for CHB over the course of the study. Ten patients remain on therapy and eight patients discontinued due to poor compliance or intolerance. 31 patients (male=20), HBeAg positive (n=24), median age 31 (range 18–55) completed 48 weeks PEG-IFNα and were included in the analysis. HBV genotype was recorded for all patients (A=6, B=5, C=10, D=9, E=1). ALT, HBV DNA and HBsAg was quantified at baseline and longitudinally at 12-week intervals. Results Of the 31 patients, 10 were considered responders; seven were HBeAg positive and seroconverted on therapy and three were HBeAg negative pre-therapy and considered responders with sustained immune control off treatment. The decline in HBV DNA and qHBsAg by 12 weeks was 3.99 log, 0.17 log (HBeAg positive group) and 2.9 log, 0.5 log (HBeAg negative group) respectively. 16/31 patients were non-genotype A or D. Of the responders from this group there was a decline in HBV DNA and qHBsAg of 4.10 log and 0.58 log respectively by 12 weeks. On sub-group analysis by genotype, there was no statistically significant difference in HBV DNA and qHBsAg decline at 12 weeks across all genotypes, when comparing HBV DNA and qHBsAg between genotype A and D and non A and D patients (p=0.40 and 1.0 respectively). More over adopting the rule of >2 log decline in HBV DNA and no decline in qHBsAg by 12 weeks, reveals we would not exclude those likely to respond; as all responders achieve the outlined viral response by 12 weeks therapy. Conclusion These data highlight the utility of this stopping rule for PEG-IFNα across all genotypes. The absence of >2 log decline in HBV DNA and reduction in qHBsAg at 12 weeks therapy makes a favourable response unlikely. This rule should be adopted in clinical practice to avoid poorly tolerated side effects and the cost of completing 48 weeks therapy. Furthermore, this 12-week milestone would allow the early switch to an oral antiviral in PEG-IFNα non-responders. Competing interests None declared.

Introduction Chronic Viral Hepatitis (CVH) affects ˜0.5% of native UK population. However, endemicity varies world wide & previous studies show that ethnic minorities are likely to preserve the higher rates of their region of origin. The estimated prevalence of chronic HBV & HCV in Pakistan is >5% & the current UK Pakistani population is >1.2 million. The study aimed to (1) characterise HBV & HCV prevalence in a local Pakistani community within Surrey using DBS testing (2) test the hypothesis that 2nd generation immigrants (ie, those born in UK) retain this higher prevalence (3) promote awareness of viral hepatitis within this population. Methods We approached community leaders of three Woking (Surrey, UK) mosques & prospectively arranged testing sessions over 10 months (2011–2012), which were advertised during religious gatherings. Following approval by the Local Ethical Board & formal consent, finger prick DBS were tested for HBsAg, HBcore antibody, antiHCV Ab, HCV (Genotype & RNA quantification). Volunteers filled out a questionnaire outlining risk factors for CVH. Subjects who were HBsAg and/or AntiHCV Ab were invited back to the Mosques for focused counselling & offered outpatient confirmatory testing including specialist Hepatology assessment & treatment as necessary. Results A total of 219 subjects were tested (164M, 55F), age 18–81 yrs, mean age 45 yrs, median 44 yrs & modal age range 30–39 yrs. The mean total duration of stay in the UK prior to testing was 24 yrs; 195 cases (89%) were of Pakistani origin of which there were 176 1st & 19 2nd gen immigrants. Of those tested, 4(2F & 2M) were HBSAg+ve and four (all M) were antiHCV+ve with 3HCV RNA+ve (2Genotype 3a and 1, 3k). Definite risk factors for CVH transmission were not identified. Mean duration of stay in the UK for +ve cases was 13 yrs, all were 1st generation Pakistani (fibroscan score Conclusion DBS testing confirms that our local Pakistani community has retained CVH prevalence rates atleast seven times greater than that of the native UK population. Primary & secondary physicians need better awareness to engage & identify individuals in susceptible ethnic populations. This study has not picked up any cases of viral hepatitis in 2nd generation immigrants & further work is required to conclusively analyse this subset of the community. Our results suggest inequalities in health related to viral hepatitis in the Pakistani population & provide evidence for a wider UK study in this vulnerable group. Places of worship may act as focal testing points to improve screening uptake, management & potential treatment of viral hepatitis in at risk populations. Competing interests None declared.

Introduction Patients with liver cirrhosis admitted to ICU have a poor prognosis with reported ICU, in-hospital and 1-year mortality rates of 37%>65%, 49–74% and 69–81% respectively. Prognostic models may enable accurate discrimination at admission of those who will benefit from ICU admission. Organ failure scoring models have been shown to be good predictors of ICU mortality, but there are few reports of their utility in non-transplant centres in Europe. We aimed to describe mortality and the prognostic value of commonly used predictors in patients with cirrhosis admitted to the ICU of a tertiary non-transplant London teaching hospital ICU. Methods Retrospective analysis of the Intensive Care National Audit and Research Centre database of all patients with cirrhosis admitted to ICU from January 2006 to November 2010. Statistical analysis was performed with SPSS V. 19. The area under receiver operating curve (AUROC) was used to assess the prognostic accuracy of the scoring models. Results 135 out of 4890 (2.8%) admissions had diagnosed cirrhosis. Mean age was 53. 77% were white, 16% were Asian, and 7% were black. 74% were male. Cause of cirrhosis was alcohol in 70.4%, HCV in 9.6%, HBV in 4.4% and NASH in 5.2%. Admission was for sepsis in 34% of patients, GI bleeding in 24%, and encephalopathy in 12%. Mortality was 39% in ICU, 55% at 30 days and 59% at 1 year. 30-day mortality in those who required renal replacement therapy (RRT), advanced cardiovascular support, mechanical ventilation or CPR was 75%, 65%, 58% and 70% respectively. Overall all-cause ICU mortality was 19.4% for this period. Conclusion Mortality in this series compares favourably with published rates, particularly at 1 year. Mortality in patients who require CPR or RRT is high at 70% and 75%, but is appreciably better than the 100% and 89% mortality previously reported. SOFA score has the best predictive value for mortality, but is not strongly predictive. All predictive scores have a worse AUROC for mortality than previously seen suggesting a reduced prognostic validity in the non-transplant UK setting. Competing interests None declared.

Introduction Although genotype (G)3 HCV is generally regarded as “easy to treat”, based on clinical trial data showing response rates of up to 80%, real world studies have shown substantially lower rates of treatment response (45%), particularly in patients with advanced fibrosis or cirrhosis. Most patients who fail treatment for G3 HCV initially respond to antiviral therapy, but relapse after the end of treatment. HCV RNA has been demonstrated in peripheral blood mononuclear cells from patients with chronic HCV, but whether viral replication occurs in these cells remains controversial. This study tests the hypothesis that viable HCV in monocytes at the end of treatment predicts relapse in patients with G3 HCV. Methods CD14 (+) monocytes from patients at the end of treatment for G3 HCV were isolated and fused with HuH7 cells. The fused cells were maintained in tissue culture for up to 5 days, before extraction of HCV RNA and quantification by PCR. p Values were derived using the Mann–Whitney U test for comparison of non-parametric data. Results are expressed as mean ± SEM. Results HCV RNA increased up to fivefold in fused compared to unfused monocytes. Viral protein production was demonstrated in fused cells by indirect immunofluorescence, confirming that viral replication occurs in the fused cells. Fused monocytes from patients who relapsed after treatment showed a significantly greater increase in HCV RNA than those from patients with a sustained virological response (246.8±103.9%, compared to 5±33.9%, p=0.02). Conclusion These data demonstrate that the presence of replication-competent HCV in monocytes at the end of treatment predicts relapse in patients with G3 HCV. Monocytes may act as a sanctuary site for HCV virions during interferon-based treatment, facilitating relapse after withdrawal of therapy. Competing interests M Cunningham: None declared, A Javaid: None declared, J Waters: None declared, G Foster Grant/Research Support from: Roche, Janssen, Tibotec, Novartis, Consultant for: Abbott, BI, BMS, Chughai, Janssen, Merck, Novartis, Roche, Tibotec.

Introduction Background: Hepatitis C virus (HCV) infection has been identified by the MRC and Department of Health MRC as a priority area for research and development to meet the clinical challenges posed by the scale of the infection in the UK. There has been a perceived lack of connection between clinicians and basic scientists working on HCV in the UK to address this problem. Aims: To create a multi-disciplinary consortium comprising clinicians and non-clinical scientists to encourage translational research. To establish a cohort of 10 000 patients with HCV infection across the UK, together with clinical database and biorepository—“HCV Research UK”. To make this resource available to researchers, both academic/commercial, UK-based and abroad. Methods Aims: Our objective has been to create a multi-disciplinary consortium comprising clinicians and non-clinical scientists to encourage translational research into the factors that determine outcome of infection, treatment response and disease progression. We aim to establish a cohort of 10 000 patients with HCV infection from across the UK that is supported by the necessary systems to make clinical data and specimens available to academic and commercial researchers, both in the UK and abroad. Results Progress: HCV Research UK has been funded by the Medical Research Foundation (£1.92 million) to establish an infrastructure that connects 18 clinical centres who will recruit 10 000 HCV-infected patients. The key elements of the infrastructure are a bespoke clinical research database, which is linked to a biorepository of samples that will hold serum, PBMCs and DNA from patients. Access to data and samples is managed by a Tissue and Data Access Committee who have the authority to grant ethical approval for research using the resource. The study has been given CLRN portfolio status. Conclusion Future plans: Recruitment of patients will begin in early 2012 and grant applications have been submitted to (1) Wellcome/Department of Health Innovation Challenge fund (2) MRC call for Stratified Medicine (3) BLT Research call (4) NIHR Programme Development award schemes for research using the resource. It is hoped that portfolio support will provide a mechanism for new centres to join the consortium. Competing interests None declared.

Introduction The direct-acting HCV protease inhibitor telaprevir has recently been licensed for treatment of chronic genotype 1 HCV infection, and promises significant improvements in sustained virological response for these patients. However the patients who may benefit most from novel HCV therapies, namely those with advanced fibrosis or cirrhosis who have previously failed to respond to pegylated interferon (pegIFN) and ribavirin treatment, are relatively poorly represented in the telaprevir clinical trials. Efficacy, safety and tolerability were assessed in patients with genotype 1 HCV and advanced fibrosis/cirrhosis who have received telaprevir-containing treatment at the Royal London Hospital. Methods Laboratory results and case notes were reviewed for all patients treated with pegIFN, ribavirin and telaprevir at the Royal London Hospital between September 2011 and January 2012. Results Eight patients with genotype 1 HCV had commenced telaprevir-containing treatment. All had advanced fibrosis/cirrhosis (median Ishak score 5, range 4–6). One was treatment-naive, three had previously failed to respond to pegIFN/ribavirin and four had relapsed after therapy. All patients had completed at least 4 weeks of telaprevir-containing therapy. With one exception, all patients achieved undetectable HCV RNA at week 4 of treatment; the patient who did not had a viral load of 168 IU/ml at week 4 and undetectable HCV RNA at week 8. One patient had completed 12 weeks of therapy, with undetectable HCV RNA. The most common side effects were fatigue (8/8), pruritis (4/8), rash (3/8), anal pain (3/8), depression (3/8), nausea (3/8), gastrointestinal disturbance (2/8) and oral candidiasis (2/8). Most side effects were successfully managed, although telaprevir was stopped in two patients at week 8 due to worsening rash and one patient withdrew from all therapy at week 4 due to tolerability. The most common laboratory abnormality was an early, transient rise in bilirubin (3/8). Significant anaemia (Hb). Conclusion Telaprevir in combination with pegIFN and ribavirin appears efficacious in patients with advanced fibrosis or cirrhosis, who have previously failed treatment with pegIFN and ribavirin alone. However, the incidence of significant side effects in this subgroup of patients is high and necessitates frequent follow-up with medical support. Side effects, particularly rash, may limit duration of telaprevir treatment. Whether this impacts on sustained virological response remains to be seen. Competing interests M Cunningham: None declared, J Schulz: None declared, L Payaniandy: None declared, Y Kallis: None declared, P Kennedy: None declared, P Kooner: None declared, R Marley: None declared, G Foster grant/research Support from: Roche, Janssen, Tibotec, Novartis, Consultant for: Abbott, BI, BMS, Chughai, Janssen, Merck, Novartis, Roche, Tibotec.

Introduction Hepatitis C virus (HCV) is common in injecting drug users (IDU9s), but Methods A retrospective notes analysis was performed of all patients treated between September 2006 and June 2011. Data were collected on demographics, HCV treatment, health and social outcomes. Minitab 16 and Prism 5 were used to perform statistical analysis. The Wilcoxon signed rank test, unpaired T test, and Mann–Whitney test were used to analyse drug and alcohol and demographic outcomes. Results 152 patients were treated. 77 were active IDU9s and 75 were ex-IDU9s. 80% were male. 45% were genotype 1, 54% were genotype 2 or 3. 81% of patients were compliant with treatment. 105 patients (69%) achieved an end of treatment response (ETR) Sustained viral response (SVR) rate was 58%. Overall survival post SVR was 100% and HCV free survival was 98%. Two patients were re-infected at 14 and 51 months after treatment (See Abstract PMO-151 figure 1) five deaths occurred 21, 32, 35, 37 and 44 months after treatment finished. All deaths were in non-responders. No deaths were attributable to treatment. There was no significant difference in demographics or treatment outcomes between active and ex-IDU9s. Full data on heroin injection use was available in 133 patients, crack use in 58 patients and alcohol in 72 patients. Overall heroin injection use pre- and post-treatment reduced from 51% of patients to 38% (p Conclusion This is the largest study published to-date examining the impact of antiviral therapy in patients actively using illicit drugs. Of importance long term follow-up data showing low re-infection rates, a significant reduction in illicit drug use after therapy and excellent disease free and overall survival in patients who achieve SVR is presented. Our findings confirm previous, small scale studies showing that effective treatment for injectors is possible within the appropriate clinical setting. Competing interests None declared.

Introduction Injecting drug use is the main risk of HCV transmission in most developed countries. Hepatitis C virus antiviral treatment (peginterferon + ribavirin) is cost-effective for patients with no reinfection risk. Concerns about reinfection and non-compliance may discourage clinicians from treating injecting drug users (IDUs), despite the potential use of treatment as prevention in this population. Aim Using a cost-utility analysis, we examined the cost-effectiveness of providing antiviral treatment for IDUs as compared to treating ex/non-IDUs or no treatment. Method A dynamic model of hepatitis C transmission and disease progression among IDUs and ex-/non-IDUs was developed, incorporating: a fixed number of antiviral treatments allocated at the mild HCV stage over 10 years, no retreatment after initial treatment failure, and potential re-infection for cured IDUs. We performed a probabilistic cost-utility analysis estimating long-term costs and outcomes (measured in QALYs) and calculating the incremental cost-effectiveness ratio (ICER) to determine the cost-effectiveness of treating IDUs as compared to treating ex/non-IDUs or no treatment for three baseline IDU HCV prevalence scenarios (20%, 40%, and 60%). Results Antiviral treatment of IDUs is the most cost-effective option in both the 20% and 40% baseline chronic prevalence settings, with ICERs as compared to no treatment (best supportive care) of £521 and £2539 per QALY saved, respectively. Treatment of ex/non-IDUs is dominated in these scenarios. At 60% baseline prevalence, treatment of ex/non-IDUs or IDUs is roughly equally cost-effective; treating ex/non-IDUs is more likely to be the most cost-effective option (with an ICER as compared to no treatment of £6803), and treating IDUs is dominated due to the high re-infection at this prevalence. A sensitivity analysis indicates that these rankings hold even when IDU SVR rates as compared to ex/non-IDUs are halved. Conclusion Despite the possibility of re-infection, the model projections suggest that providing antiviral treatment to IDUs is the most cost-effective policy option in chronic prevalence scenarios

Introduction The prevalence of chronic viral hepatitis in people born in Pakistan living in the UK is 5% (2.7% Hepatitis C Virus (HCV) and 1.8% Hepatitis B Virus (HBV). Studies from the HPA show an increased risk of end stage liver disease from HCV in people from Pakistan living in the UK. Screening migrants from high prevalence regions (>2%) for HBV is cost effective if screening of 35% of a population is achieved. Given that screening for viral hepatitis in migrants will reduce morbidity, mortality and onward transmission of chronic viral hepatitis, the outstanding question is how should this be done? Aim The aim of this observational study was to evaluate community, and general practice (GP) based approaches to screening migrants for viral hepatitis. Method We distributed 5000 testing cards in Mosques, following an awareness campaign, encouraging people from Pakistan to attend their GP surgery for viral hepatitis testing. In primary care practices we studied two approaches targeting registered Pakistani/British Pakistani patients: an opportunistic approach, whereby patients attending the practice were offered screening for HBV and HCV, and an ‘opt out’ approach, where patients were contacted by letter and invited to opt out of screening. Those who did not ‘opt out’ were telephoned and asked to attend screening clinics. Results 5000 leaflets were distributed to Mosques but no patients presented to their GP for testing. In the primary care study there were 1163 Pakistani/British Pakistani patients in the ‘opportunistic’ arm. Of these 17 (1.5%) were screened and all were uninfected. In the ‘opt out’ arm there were 1134 eligible patients. It was not possible to screen 524 patients (46%) due to inadequate contact details (38%), previous screening (4%) or incorrectly recorded ethnicity (4%). Of those who could be contacted and were eligible for screening, 37% (223/600) have been screened. 75% of those who made a screening appointment were born in Pakistan, and 25% were British Pakistani patients. 1% of those screened were found to be HBsAg positive and 2.4% were HCV antibody positive. Conclusion Community awareness campaigns and leaflets do not directly lead to testing for viral hepatitis in at risk immigrant groups. A direct screening approach is more effective than an opportunistic screening approach in primary care. Inaccurate GP records reduce the efficiency of screening but GP based testing is easy to implement, popular with patients and effective. First generation migrants are more likely to comply with screening which may improve the cost-effectiveness of this approach.

Introduction Patients persistently infected with genotype 3 HCV are more likely to have a sustained viral response (SVR) to interferon and ribavirin therapy than patients infected with genotype 1. However many patients with advanced fibrosis infected with genotype 3 HCV relapse following therapy. The mechanisms underlying relapse are not known. Aim To examine the speed of relapse and compare quasispecies prior to and immediately following relapse. Method 30 chronically infected patients with advanced fibrosis (fibrosis score >F3/6) were treated for 24–48 weeks with Peg IFN α 2a and ribavirin. Plasma samples were taken pre-treatment, during treatment and weekly post treatment. The HCV quasispecies in the pre-treatment sample and the first HCV-RNA positive post-treatment samples of the relapsed patients were assessed. Results All of the patients responded with loss of virus on treatment. 18 had a sustained viral response and 12 patients relapsed post-treatment. All of the patients that relapsed did so within 4–6 weeks of treatment cessation. HCV-RNA was extracted from the pre- and post samples of relapsed patients. 10–15 clones from both samples were successfully prepared and sequenced over the E2 region, including the HVR1, 2 and 3 regions and the PKR-eIF2α region in five patients. Construction of phylogenetic trees showed that in two patients the quasispecies that emerged post-treatment were similar to those seen pre-treatment but in three patients a dramatic shift in populations occurred. Conclusion Relapse post therapy is very rapid and two distinct patterns of relapse were seen. These data suggest that there may be different mechanisms of relapse following treatment withdrawal in patients with genotype 3 HCV.

Introduction Establishing disease phase in chronic HBV is a critical step in long-term disease management. This classification has even more significance at a younger age, where a proportion of eAg positive patients are labelled ‘immune tolerant’ and treatment is deferred. However, disease phase is diagnosed on clinical phenotype only with little insight into immunological activity. Aim The aim of this study was to investigate the immunological profile in HBV infected children and young adults across different phases of disease and to compare the HBV-specific responses detected with those of older HBV infected patients. Method 45 children and young adults (median age 19, range 12–30) were recruited and followed longitudinally for a minimum of 12 months. Clinical profile included ALT, HBV DNA, quantitative HBsAg and, where available, biopsy fibrosis stage and NI scores. This was compared with the immunological analysis for each subject comprising: global T cell cytokine profile (frequency of T cells producing IFNα, IL-2, IL-4, TNFα and the ILs; 17, 8, 21, 22 and MIP-1a after PMA stimulation), quantity of T cells (CD4 and CD8) expressing exhaustion markers (PD-1, Lag-3, CTTL-4) and the presence of functional HBV-specific T cells (PBMC stimulated with overlapping HBV peptides covering envelope, core and E proteins). Results Frequency of T cells producing immunosuppressive or Th2 cytokines (IL-10, IL-4) and (IL-8, IL-21) is similar between age matched HBV infected and non-infected young adults, while T cells with pro-inflammatory cytokines (IFNα, TNFα, IL-17) were increased in the HBV infected group (p≤0.05). In addition, IL-22 producing cells were present in HBV infected young adults while almost absent in age matched uninfected controls. T cells expressing exhaustion markers were increased in HBV infected patients irrespective of age and correlated with ALT activity. Contrary to predictions HBV-specific T cells were detected with greater frequency in younger HBV-infected subjects when compared with those found in older infected patients (p≤0.05). The HBV-specific T cell response in younger patients show a classical Th1/Tc1 cytokine production profile and expands more vigorously than that seen in older HBV patients. Conclusion HBV infection in young patients did not induce a generic immune tolerant T cell cytokine profile. On the contrary, disease activity in chronic HBV appears to be independent of age. Furthermore, the detection of HBV-specific T cells and the presence of significant liver damage on biopsy in a proportion of our young adult patients underlines the dangers of labelling these patients as ‘immune tolerant’. Our findings highlight the dynamic nature of chronic HBV and stress the importance of more formal disease assessment in children and young adults with early therapeutic intervention where indicated.

Introduction Hepatitis C Virus (HCV) is a major cause of liver disease worldwide. Innate and adaptive cellular immune responses play a critical role in resolving acute HCV infection. However, the majority of infections are not cleared, resulting in a progressive chronic liver disease consistent with inadequate immune control. Evidence from human and animal models suggest that T cells play a critical role in controlling acute HCV infection, yet the mechanism(s) behind their failure to control chronic HCV replication are unknown. HCV replicates predominantly in the liver and virus specific immune cells need to target infected hepatocytes to control virus replication. HCV specific effector cells have been reported to home to the liver, however, little is known on their subsequent trafficking and fate within the organ. Aim Our aim is to investigate the role of HCV infection on lymphocyte-hepatocyte interactions, migration and immune cell effector function. Method We used in vitro and ex vivo models to study the effect of HCV infection on lymphocyte–hepatocyte interactions. Primary lymphocytes and hepatocytes were used in combination with hepatoma cell lines and replication competent HCV clones. Ex vivo lymphocyte migration assays were performed using biopsy material and tissue from explanted liver. Results were confirmed by in vivo observations using tissue sections from patients with end stage liver disease of viral and non-viral origin. Experimental techniques included immunohistochemistry, flow cytometry, fixed and live cell time-lapse confocal microscopy. Results We demonstrate: (1) A role for hepatocyte ICAM-1 in mediating T-lymphocyte adhesion and migration; (2) T-lymphocytes migrate spontaneously through hepatocyte monolayers via cell-cell junctions; (3). HCV enhances T-cell transmigration and pro-inflammatory cytokine expression. Our data demonstrate the existence of novel interactions between T cells and hepatocytes that are modulated in HCV infection. The nature of the T cell-hepatocyte interactions may have an impact on T-cell effector function and the outcome of anti-viral immune responses. Conclusion Interaction with HCV-infected hepatocytes alters T-cell trafficking and cytokine expression, providing a novel mechanism for HCV to persist in the liver.

Introduction Engagement of Toll-like receptors (TLRs) is an important initiator of the innate immune response in inflammatory liver diseases and leads to release of a range of inflammatory cytokines. TLRs signal through divergent signal transduction pathways but the majority lead to activation of members of the NFκB family. STAT2 is an essential component of canonical signalling through the type I and type III interferon (IFN) receptor but, unlike other members of the Stat family, is not believed to be involved in other signal transduction pathways. Aim We examined the role of STAT2 on inflammatory signalling. Results Loss of STAT2 markedly reduced immortalised macrophages’ response to a range of TLR agonists (lipopolysaccharide (LPS), poly I:C and IL-1)—production of TNFα and RANTES proteins and a range of inflammatory mRNAs were decreased. The reduction in inflammatory cytokine production could be reversed by reconstitution with STAT2 but blockade of type I IFN signalling did not reproduce the phenotype. Restoration of the normal response to LPS could be achieved with tyrosine phosphorylation defective STAT2 indicating that STAT2 interacts with these signalling pathways without phosphorylation on Tyr690. The multiplicity of STAT2′s effect suggests a common defect to these signalling pathways. There were no abnormalities in the activation of early signalling components in the absence of STAT2, however, levels of phosphorylated IκB, although not total IκB, were reduced in STAT2 −/− cells. Phosphorylation of this inhibitor of NFκB leads to its degradation and release of NFκB proteins into the nucleus. We found that translocation of the NFκB protein p65 into the nucleus and its subsequent binding to DNA was impaired in STAT2 deficient cells. Conclusion These data suggest that STAT2 is a critical component of the TLR signalling response to early inflammatory stimuli, in particular through maintaining the normal phosphorylation of IκB.

Introduction Tenofovir Disoproxil Fumarate (TDF) is now established as a very potent oral antiviral (OAV) agent in the treatment of chronic hepatitis B (CHB). However, as treatment with this OAV is often indefinite and potentially lifelong, concerns remain about its long-term safety. Bone Mineral Density (BMD) loss has been described in TDF treated HIV patients, but limited data exist for HBV treated patients. Furthermore, BMD loss has also been described in chronic liver disease in addition to being reported with certain patient characteristics. Aim The aim of this study was to determine the impact of TDF on BMD in an ethnically diverse HBV infected population undergoing long-term treatment with this agent. Method CHB patients treated with TDF for a minimum of 12 months were recruited to this single centre study. Patients were prospectively offered a dual x-ray absorptiometry (DEXA) scan. Serum bone profile and Vitamin D levels were requested simultaneously. BMD loss was defined by WHO criteria; T-score Results BMD loss was present in 44% of the treatment group (osteopenia 81%, osteoporosis 19%) and in 44% of the control group (osteopenia 83%, osteoporosis 17%) (p=0.21). In the ethnically diverse population studied, there was more marked BMD loss in the non-white population (47%, treated group; 45%, controls) compared with the white population (30%, treated group; 40%, controls). By univariate analysis age, gender, ethnicity, fibrosis stage, BMI, co-morbidities and low Vitamin D level were all significant for reduced BMD (p≤0.05, all variables). On multivariate analysis gender, ethnicity, BMI, fibrosis, co-morbidities and Vitamin D all met statistical significance for a reduction in BMD, but Vitamin D deficiency only was significant for the presence of osteoporosis (p=0.0001). Conclusion Our results demonstrate the prevalence of reduced BMD in CHB patients of diverse ethnicity and identify Vitamin D deficiency and not TDF as the likely cause. This cross-sectional study does not exclude the potential for BMD loss with TDF and further longitudinal studies are required to determine its effect on BMD over time. Vitamin D deficiency should be appropriately treated to avoid any potential for BMD loss associated with TDF when considering treatment with this OAV agent.

Introduction Highly effective oral antivirals (OAV) have been licensed for use in Chronic Hepatitis B (CHB). Efficacy of Tenofovir (TDF) and Entecavir (ETV) monotherapy has been demonstrated in randomised controlled trials. However, there may be a role for de novo combination therapy to reduce the development of resistance. For this reason, the authors offer patients combination therapy with TDF and Lamivudine (LAM) irrespective of whether they are OAV-naive or experienced. In this study the authors test the hypothesis that combination therapy is superior to TDF monotherapy as assessed by viral suppression and ALT normalisation. Methods A retrospective prospective study of 185 patients (male=135), from a single centre, was performed. Viral suppression, was defined as Results Median age of patients was 45 (range 18–81). 74% were eAg negative prior to starting TDF and LAM. Median ALT at baseline was 46 (range 12–1141). 86 patients were treatment naive prior to commencing combination therapy. Of 99 patients previously exposed to OAV9s, 65 were partial responders and 34 virally suppressed when switching to TDF and LAM. 125/185 patients had completed 12 months and 84, 24 months of combination therapy. Overall viral suppression was recorded in 84% and 94% at 12 and 24 months respectively and ALT normalisation was seen in 67% and 74% at 12 and 24 months respectively. In the OAV-naive group viral suppression was 81% compared with 84% in the OAV-experienced and ALT normalisation was 56% and 72% respectively in these groups at 12 months. In the published meta-analysis, viral suppression was 91% and ALT normalisation 67% at 12 months in a treatment naive group. Comparing real life with published data showed no statistical significance for viral suppression and normalisation of ALT for combination versus monotherapy (p=0.12 and p=0.2 respectively). Conclusion These data highlight the efficacy of TDF in generating and sustaining viral suppression and ALT normalisation at 12 months and beyond. Combination OAV therapy versus TDF monotherapy does not show superiority. Furthermore, there is no reported resistance with TDF to date, but data are limited to 4-year follow-up. Given that OAV resistance may occur over many years, combination OAV may still have a role in the treatment of CHB, however larger randomised controlled trials are needed to determine this.

Introduction Bone Mineral Density (BMD) loss has been reported in chronic liver disease. In Chronic Hepatitis B (CHB) patients, Tenofovir Disoproxil Fumarate (TDF) is recommended as a first line therapy, in accordance with EASL guidelines. Concerns regarding the long-term safety of TDF have been raised, in particular changes in BMD in HIV patients, but limited data exist on similar changes in HBV treated patients. The aim of this study was to determine the impact of TDF on BMD in an ethnically diverse HBV infected population undergoing long-term treatment with this agent. Methods In a single centre, CHB patients treated with TDF for a minimum 12 months were prospectively offered a dual x-ray absorptiometry scan. BMD loss was defined by WHO criteria; T-score Results BMD loss was present in 45% of the treatment group (osteopenia 84%, osteoporosis 16%) and in 48% of the control group (osteopenia 85%, osteoporosis 15%). There was no difference in BMD loss when comparing both groups (p=0.45). In the ethnically diverse population studied, there was increased BMD loss in the non-White population (48%, treated group; 50%, controls) compared with the white population (33%, treated group; 40%, controls). By univariate analysis age, gender, fibrosis stage, comorbidities were all significant (p= Conclusion This results demonstrate the prevalence of reduced BMD in CHB patients of diverse ethnicity, independent of TDF treatment. This cross-sectional study does not exclude the potential for BMD loss with TDF and further longitudinal studies are required to determine its effect on bone over time. Other factors also contribute to BMD loss, namely ethnicity and BMI, and should be given due consideration when selecting a treatment option.

In a recent issue of Gut Feuchinger et al report a novel marker antibody for primary biliary cirrhosis (PBC) which may become useful in the diagnosis of PBC in the future.1 At present diagnosis is based on the presence of the M2 substrate of anti-mitochondrial antibody (AMA) in the sera and liver function tests. The American Association for the Study of Liver Disease (AASLD) recommend that a diagnosis of PBC can be made with a positive M2 antibody and cholestatic liver biochemistry (biopsy can be used to confirm) and that patients who are M2 positive only should be followed up with annual …

Introduction Historically pegylated-interferon (PEG-IFN) was reserved for HBeAg+ disease, where seroconversion represented a well defined treatment outcome with reported rates of up to 32%.1 It has recently been shown to benefit a small proportion of patients with HBeAg- disease although patient groups who will benefit remains unclear. The Royal London Hospital treats a large ethnically diverse HBV infected population, thus represents an ideal setting to evaluate the influence of ethnicity on response. Methods Chronic HBV patients completing treatment with PEG-IFN between 2005 and 2008 were included. A total of 34 patients received PEG-IFN alfa-2a (180 μg once weekly) for 48 weeks. ALT, HBeAg, anti-HBe and viral load (VL) were recorded at 24 and 48 weeks on treatment, 6 and 24 months post treatment. Patients were divided according to e antigen status; HBeAg+ (Group 1, n=25) and HBeAg-(Group 2, n=9). Treatment success was defined by HBeAg seroconversion for Group 1, and a viral load Results For HBeAg+ve patients (Group 1, n=25, 6 East Asian, 4 Bangladeshi, 5 African 6 other): 4 patients (17%) seroconverted, one of whom became anti-HBs+ on treatment. 28% of patients suppressed viral load and normalised ALT while on treatment. 50% of patients progressed to oral antivirals, 25% of whom then seroconverted. Hence 50% of patients either seroconverted or moved to a disease state where therapy was not required. All ethnic groups had a similar response and no pre-treatment factors influenced outcome. For HBeAg-ve disease (Group 2, n=9, 3 Bangladeshi 2 Pakistani 4 other): 3 patients (33%) met the criteria for treatment success at 48 weeks which was upheld over follow-up, one of whom underwent HBsAg seroconversion. Two patients had a sustained reduction in viraemia and inflammation that led to a decision to withhold further therapy. Four patients (44%) required oral antiviral therapy. Hence 56% of patients were managed by interferon alone. Success was most marked in patients from Bangladesh; all three had a full response. Conclusion This study highlights the benefit of PEG-IFN in HBeAg- disease and its potential advantage in certain ethnic groups. Nevertheless, we saw lower seroconversion rates in HBeAg+ patients than previously reported. Our data suggest that a high ALT is not a requisite for treatment success, while baseline VL, fibrosis stage and age were not determinants of treatment outcome. These data suggest that consideration should be given to PEG-IFN as a treatment option, as opposed to the early initiation of lifelong oral antivirals in treating chronic HBV.

Introduction The impact of ethnic background on response to antiviral therapy in patients with genotype 3 chronic hepatitis C infection remains unclear. Methods We performed a large retrospective analysis of 535 patients (268 Caucasian, 267 South Asian) treated with pegylated interferon and ribavirin at four UK centres. Results At baseline age, sex and proportions with cirrhosis were compared between the South Asians and Caucasians and cirrhosis was the only factor more common in people from South Asia 83/267(31%) vs Caucasian 56/268 (20.8%) and this was statistically significant (p= The overall sustained virological response rate (SVR) was 77.6%. In univariate analysis, age, diabetes, cirrhosis and need for dose reduction were associated with treatment failure. Ethnicity (Caucasian vs South Asian) did not affect SVR (proportions achieving SVR were 210/268=78.3%% in Caucasians and 209/267=78.2% in South Asians). In a multivariable analysis cirrhosis and presence of diabetes were the only factors significantly associated with a reduction in the proportion who achieved an SVR. Treatment failure was due to relapse in the majority of patients (70/535 patients relapsed (13.08%) while 46/535 (8.59%) had a breakthrough or no response. Relapse was inevitable in patients who did not achieve an early virological response (all 32 patients without an EVR relapsed) and was more common in those who did not have a rapid virological response (relapse occurred in18/96–18.7% who did not have an RVR compared to 8/153, 5.2% who did have a RVR, p= Conclusion The SVR in patients with genotype 3 chronic HCV infection is similar in patients from South Asia and Caucasians. The presence of cirrhosis significantly reduces the response to therapy and relapse is the most common mode of treatment failure.

Introduction A significant proportion of patients with chronic hepatitis C (HCV) progress to cirrhosis with its attendant complications. Most studies evaluating the natural history of HCV infection have taken development of cirrhosis as an endpoint. We therefore sought to establish, by means of a systematic review and analysis of the literature, the natural history of compensated HCV cirrhosis. Methods A systematic literature review was performed. Where studies compared treated vs untreated patients, or HCV vs hepatitis B infection, only data regarding untreated, HCV monoinfected patients were included. Weighted mean annual percentage rates for death or transplantation, complications of cirrhosis and development of hepatocellular carcinoma (HCC) were calculated from the raw data. Results Our search returned 12 papers which met the inclusion criteria. Despite some heterogeneity (inclusion of other causes of cirrhosis or HCV patients who had received antiviral therapy) we extracted data from these studies relating to 2138 patients. In compensated HCV cirrhosis the estimated rate of death or transplantation is 4.75% per annum, of decompensation is 5.61% per annum and of HCC is 3.76% per annum. Five studies reported combined outcomes for both treated and untreated patients. When considered together, these studies reported significantly lower annual percentage rates of HCC than those reporting untreated patients only (mean 2.51%±0.37 vs 5.20%±0.76, p=0.016), but not of decompensation (mean 5.34%±0.79 vs 9.58%±1.14, p=0.057) or death or transplantation (mean 3.84%±0.53 vs 4.76%±0.62, p=0.29). Conclusion The estimated annual percentage rates of death or transplantation, decompensation and HCC confirm the relatively slow progress of compensated HCV cirrhosis, but highlight the need for continued vigilance for the occurrence of HCC. Heterogeneity in reporting, particularly the lack of distinction of outcomes according to treatment status or sustained virological response, means that the summary data presented may underestimate rate of disease progression, particularly HCC development. It will be important to ensure a clear distinction is made between treatment responders, partial responders and non-responders in future studies on the outcome of HCV cirrhosis.

Edited by K D Lindor, J A Talwalkar. Published by Humana Press, New Jersey, 2008, pp 188, hardcover, $89.50. ISBN 978-1-588-29-838-6