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Background & Aims Coronavirus disease 2019 (COVID-19) pandemic lockdown and restrictions had significant disruption to patient care. We aimed to evaluate the impact of COVID-19 restrictions on hospitalizations of patients with alcoholic and nonalcoholic cirrhosis as well as alcoholic hepatitis (AH) in Alberta, Canada. Methods We used validated International Classification of Diseases (ICD-9 and ICD-10) coding algorithms to identify liver-related hospitalizations for nonalcoholic cirrhosis, alcoholic cirrhosis, and AH in the province of Alberta between March 2018 and September 2020. We used the provincial inpatient discharge and laboratory databases to identify our cohorts. We used elevated alanine aminotransferase or aspartate aminotransferase, elevated international normalized ratio, or bilirubin to identify AH patients. We compared COVID-19 restrictions (April–September 2020) with prior study periods. Joinpoint regression was used to evaluate the temporal trends among the 3 cohorts. Results We identified 2916 hospitalizations for nonalcoholic cirrhosis, 2318 hospitalizations for alcoholic cirrhosis, and 1408 AH hospitalizations during our study time. The in-hospital mortality rate was stable in relation to the pandemic for alcoholic cirrhosis and AH. However, nonalcoholic cirrhosis patients had lower in-hospital mortality rate after March 2020 (8.5% vs 11.5%; P = .033). There was a significant increase in average monthly admissions in the AH cohort (22.1/10,000 admissions during the pandemic vs 11.6/10,000 admissions before March 2020; P Conclusions Before and during COVID-19 monthly admission rates were stable for nonalcoholic and alcoholic cirrhosis; however, there was a significant increase in AH admissions. Because alcohol sales surged during the pandemic, future impact on alcoholic liver disease could be detrimental.

Supplemental Digital Content is available in the text., Background Acute-on-chronic liver failure (ACLF) is divided into three types according to the underlying liver disease: non-cirrhosis (type A), compensated cirrhosis (type B) and decompensated cirrhosis (type C). However, whether the underlying chronic liver diseases impact the ACLF prognosis is not clear. The present study aimed to compare the characteristics and outcomes of type A and type B hepatitis B virus (HBV)-ACLF patients. Methods According to the European Association for the Study of Liver-Chronic Liver Failure (EASL-CLIF) diagnostic criteria, 86 type A HBV-ACLF and 71 type B HBV-ACLF were prospectively enrolled. The demography and laboratory data, organ failures, ACLF grades and prognosis were evaluated. Univariate and multivariate Cox regression analyses were performed to analyze the prognostic factors. Results The 28-day and 90-day mortality rates of type A and type B ACLF were 20.9 vs. 60.6% and 34.9 vs. 73.2%, respectively (both P

Nonselective beta-adrenergic blocker (NSBB) therapy for the prevention of initial and recurrent gastrointestinal bleeding in cirrhotic patients with gastroesophageal varices has been used for the past four decades. NSBB therapy is considered the cornerstone of treatment for varices, and has become the standard of care. However, a 2010 study from the group that pioneered β-blocker therapy suggested a detrimental effect of NSBBs in decompensated cirrhosis, especially in patients with refractory ascites. Since then, numerous additional studies have incompletely resolved whether NSBBs are deleterious, although more recent evidence weighs against a harmful effect. The possibility of a “therapeutic window” has also been raised. We aimed to review the literature to analyze the pros and cons of using NSBBs in patients with cirrhosis, not only with respect to bleeding or mortality but also to other potential benefits and risks. β-blockers are highly effective in preventing first bleeding and recurrent bleeding. Furthermore, NSBBs improve congestion/ischemia of the gut mucosa, decrease intestinal permeability, and therefore indirectly alleviate systemic inflammation. β-blockers shorten the electrocardiographic prolonged QTc interval and may also decrease the incidence of hepatocellular carcinoma. On the other hand, the possibility of deleterious effects in cirrhosis has not been completely eliminated. NSBBs may be associated with an increased risk of portal vein thrombosis, although this could be correlational artifact. Overall, we conclude that β-blockers in cirrhosis are much more of a friend than enemy. (Clin Mol Hepatol 2021;27:425-436)

Purpose of review Cirrhotic cardiomyopathy (CCM) is a well-recognized entity. When patients with CCM encounter challenges such as liver transplantation, overt cardiac dysfunction manifests, leading to morbidity and mortality. Although revised diagnostic criteria for CCM have recently been proposed, these still need to be validated. Recent findings Previous reviews have summarized the mechanisms of CCM, such as abnormalities of the β-adrenergic pathway, cardiac plasma membrane biophysical and biochemical properties, and electrophysiological changes. Cardiomyocyte apoptosis, inflammation, and oxidative stress also play important roles. The present review details further mechanisms of CCM, which include myosin heavy chain isoform shifts and abnormalities in cellular calcium transients. Additionally, we review recent studies on therapeutic strategies. Recent work underscores the importance of CCM in the natural history of the immediate and medium-term postoperative period after liver transplantation. Appropriate management strategies for CCM remain the area of greatest unmet need, requiring much further research. Summary CCM is a clinically relevant syndrome affecting patients with cirrhosis, leading to increased morbidity and mortality. New diagnostic criteria have been recently proposed by an expert working group. The pathogenic mechanisms remain incompletely clarified and optimal management strategies need much further study.

Background & Aims Hepatitis C virus (HCV) has high genetic diversity with six major genotypes (GT) GT1‐6 and global distribution. HCV GT5 and 6 are rare with

Background The current use of ribavirin in difficult-to-cure chronic hepatitis C patients (HCV) and patients with severe respiratory infections is constrained by the issue of ribavirin-induced hemolytic anemia that affects 30% of treated patients, requiring dosage modification or discontinuation. Though some genetic variants have been identified predicting this adverse effect, known clinical and genetic factors do not entirely explain the risk of ribavirin-induced anemia. Methods We assessed the associations of previously identified variants in inosine triphosphatase (ITPA), solute carrier 28A2 (SLC28A2) and vitamin D receptor (VDR) genes with ribavirin-induced anemia defined as hemoglobin decline of ≥30 g/L on treatment, followed by a staged discovery (n = 114), replication (n = 74), and combined (n = 188) genome-wide association study to uncover potential new predictive variants. Results We identified a novel association in the gene coding glycophorin C (rs6741425; OR:0.12, 95%CI:0.04–0.34, P = 2.94 × 10-6) that predicts protection against ribavirin-induced anemia. We also replicated the associations of ITPA and VDR genetic variants with the development of ribavirin-induced anemia (rs1127354; OR:0.13, 95%CI:0.04–0.41, P = 8.66 ×10-5; and rs1544410; OR:1.65, 95%CI:1.01–2.70, P = 0.0437). Conclusions GYPC variation affecting erythrocyte membrane strength is important in predicting risk for developing ribavirin-induced anemia. ITPA and VDR genetic variants are also important predictors of this adverse reaction.

BACKGROUND: Indigenous populations experience higher rates of hepatitis C virus (HCV) infections in Canada. The Extension for Community Health Outcomes+ (ECHO+) telehealth model was implemented in Alberta to support HCV screening and treatment, using Zoom technology to support Indigenous patient access to specialist care closer to home. Our goal was to expand this program to more Indigenous communities in Alberta, using various Indigenous-led or co-designed methods. METHODS: The ECHO+ team implemented a Two-Eyed Seeing framework, incorporating Indigenous wholistic approaches alongside Western treatment. This approach works with principles of respect, reciprocity, and relationality. The ECHO+ team identified Indigenous-specific challenges, including access to liver specialist care, HCV awareness, stigma, barriers to screening and lack of culturally relevant approaches. RESULTS: Access to HCV care via this program significantly increased HCV antiviral use in the past 5 years. Key lessons learned include Indigenous-led relationship building and development of project outputs in response to community needs influences impact and increases relevant changes increasing access to HCV care. Implementation of ECHO+ was carried out through biweekly telehealth sessions, problem solving in partnership with Indigenous communities, increased HCV awareness, and flexibility resulting from the impacts of COVID-19. CONCLUSION: Improving Indigenous patient lives and reducing inequity requires supporting local primary health care providers to create and sustain integrated HCV prevention, diagnosis, treatment, and support services within a culturally safe and reciprocal model. ECHO+ uses telehealth and culturally appropriate methodology and interventions alongside multiple stakeholder collaborations to improve health outcomes for HCV.

PURPOSE OF REVIEW: Cardiovascular disease (CVD) is a common cause of mortality after liver transplantation. The transplant community is focused on improving long-term survival. Understanding the prevalence of CVD in liver transplant recipients, precipitating factors as well as prevention and management strategies is essential to achieving this goal. RECENT FINDINGS: CVD is the leading cause of death within the first year after transplant. Arrhythmia and heart failure are the most often cardiovascular morbidities in the first year after transplant which could be related to pretransplant diastolic dysfunction. Pretransplant diastolic dysfunction is reflective of presence of cirrhotic cardiomyopathy which is not as harmless as it was thought. Multiple cardiovascular risk prediction models have become available to aid management in liver transplant recipients. SUMMARY: A comprehensive prevention and treatment strategy is critical to minimize cardiovascular morbidity and mortality after liver transplant. Weight management and metabolic syndrome control are cornerstones to any prevention and management strategy. Bariatric surgery is an underutilized tool in liver transplant recipients. Awareness of ‘metabolic-friendly’ immunosuppressive regimens should be sought. Strict adherence to the cardiology and endocrine society guidelines with regard to managing metabolic derangements post liver transplantation is instrumental for CVD prevention until transplant specific recommendations can be made.

Background and aim: Cirrhotic cardiomyopathy (CCM) is a recognized complication of cirrhosis and is associated with poor outcomes, especially under challenges such as surgery/liver transplantation. However, the mechanism is not clear, and the treatment is not specific. The present study aimed to evaluate the role of anti-β1-adrenergic receptor antibodies (anti-β1-AR) in CCM.Methods: We enrolled 3 groups: healthy controls, cirrhotic patients without CCM and patients with CCM. The serum anti-β1-AR and N-terminal (NT)-pro hormone brain natriuretic peptide (NT-proBNP) were detected by enzyme-linked immunosorbent assay (ELISA). Left ventricular ejection fraction (LVEF), fractional shortening (FS), the ratio of peak early (E wave) and atrial (A wave) flow velocities (E/A) and left ventricular posterior wall minor motion amplitude were measured by echocardiography. Results: The anti-β1-AR levels in the CCM group were significantly higher than that in the non-CCM group (0.97±0.37 vs 0.74±0.37 ng/mL, PP < 0.05), negatively correlated to LVEF (r = - 0.466, P < 0.05), FS (r = - 0.488, P < 0.05) and E/A (r=-0.475, P < 0.05) in CCM patients. The area under the receiver-operating-characteristic (AUROC) of serum anti-β1-AR on CCM was 0.678 (95% CI 0.515-0.768). At a cutoff value of 0.669 ng/mL, the sensitivity of anti-β1-AR to diagnose CCM was 89.5%, and the specificity was 57%. Conclusion: The anti-β1-AR level in the CCM group was significantly elevated compared with that in the non-CCM group, and this increase was correlated with cardiac function. Anti-β1-AR is a useful predictive biomarker for the presence of CCM and eventually may also have therapeutic implications.

Background: Canada was the first country to approve elbasvir/grazoprevir (EBR/GZR) for the treatment of chronic HCV infection for genotypes 1 and 4 with or without ribavirin and genotype 3 with sofosbuvir, with no recommendation for baseline resistance testing. The aim of this study was to describe the effectiveness of EBR/GZR and the profile of patients selected for treatment in a Canadian real-world setting. Methods: This multicenter retrospective study of HCV-infected patients treated with EBR/GZR took place among selected Canadian health care providers, with no exclusion criteria. Primary outcome measures included parameters associated with patient profile and sustained virologic response at 12 weeks (SVR12) and 24 weeks after treatment. Results: A total of 408 patients were included; 244 had available SVR12 information (per-protocol population [PP]). Genotype distribution included 1a (54.7%), 1b (17.2%), 3 (11.8%), 4 (10.0%), and other (6.4%). The majority (88.7%) of participants were treated for 12 weeks without ribavirin. Fifty-nine (14.5%) participants, predominantly with genotype 1a (49/59) infection, were tested for baseline resistance-associated substitutions (bRAS). SVR12 was achieved by 95.9% of the PP. In an exploratory analysis assessing potential predictors of SVR12, participants who had undergone bRAS testing (OR 0.14, 95% CI 0.03–0.64) and participants who had undergone liver transplant (OR 0.05, 95% CI 0.00–0.68) had significantly lower odds of achieving SVR12. Conclusions: This study supports the real-world effectiveness of EBR/GZR—including a broad range of genotypes and diverse fibrosis stages—in the absence of bRAS testing and in special populations.

The challenges of managing varices during the COVID-19 pandemic are reviewed, and a treatment algorithm is presented to best manage patients with advanced liver disease during periods of limited access to endoscopy.

Introduction. Quantitative hepatitis B surface antigen (qHBsAg) combined with HBV DNA may be useful for predicting chronic hepatitis B (CHB) activity and nucleoside analogue (NA) response.Material and methods. In this retrospective cohort study we evaluated qHBsAg levels according to CHB disease phase and among patients on treatment. Random effect logistic regression analysis was used to analyze qHBsAg change with time in the NA-treated cohort.Results. 545 CHB carriers [56% M, median age 48 y (IQR 38-59), 73% Asian] had qHBsAg testing. In the untreated group (44%), 8% were classified as immune tolerant, 10% immune clearance, 40% inactive, and 43% had HBeAg- CHB and the median HBsAg levels were 4.6 (IQR 3.4-4.9), 4.0 (IQR 3.4-4.5), 2.9 (IQR 1.4-3.8), and 3.2 log IU/mL (IQR 2.6-4.0), respectively; p < 0.001. In the NA-treated group (28% entecavir, 68% tenofovir, 4% lamivudine), no significant change in qHBsAg levels occured with time. However, 19% of patients on long-term NA had sustained qHBsAg < 2 log10 IU/mL.Conclusion. qHBsAg titers were associated with CHB phase and remained stable in those on long-term NA. A significant number of treated patients had low-level qHBsAg, of which some may be eligible for treatment discontinuation without risk of flare.

Background Hepatitis B virus (HBV) variants are associated with nucleos/tide analogue (NA) response and liver disease but it is unknown whether NA influences extrahepatic HBV persistence. Objectives To investigate HBV replication and genetic evolution in hepatic and extrahepatic sites of chronic hepatitis B (CHB) before and after NA therapy. Study Design A total of 13 paired plasma, peripheral blood mononuclear cells (PBMC), were collected from chronic HBV carriers at baseline and after a median 53 weeks NA therapy as well as liver biopsy (N = 7 baseline, N = 5 follow-up). HBV covalently closed circular DNA (cccDNA) and messenger (m) RNA in liver and PBMC were analyzed. HBV polymerase (P)/surface (S), basal core promoter (BCP)/pre-core (PC)/C gene clonal sequencing was done in plasma, peripheral blood mononuclear cells (PBMC), and liver. Results Compare to baseline, at ∼53 weeks follow-up, there was no significant change in HBV cccDNA levels in liver (0.2–0.08 copies/hepatocyte, p > 0.05 ) or in PBMC 0.003–0.02 copies/PBMC, p > 0.05 ), and HBV mRNA remained detectable in both sites. At baseline, BCP variants were higher in PBMC vs. liver and plasma. After therapy, drug resistant (DR) and immune escape (IE) variants increased in liver but IE and PC variants were more frequent in PBMC. HBV P/S diversity was significantly higher in PBMC compared to plasma. Conclusion Continuous HBV replication occurs in liver and PBMC and shows compartmentalized evolution under selective pressure of potent NA therapy.

The majority of patients on a waiting list for liver transplantation have end-stage liver disease. Because of the marked peripheral vasodilatation of end-stage cirrhosis that masks a latent myocardial dysfunction, cardiac abnormalities in the resting state are usually subclinical and escape the attention of physicians. However, when challenged, the systolic and diastolic contractile responses are attenuated. In addition to these contractile abnormalities, morphological changes, such as enlargement or hypertrophy of cardiac chambers, and electrophysiological repolarization changes, including a prolonged QT interval, can be observed. The constellation of these cardiac abnormalities is termed cirrhotic cardiomyopathy. Liver transplantation induces significant cardiovascular stress. Clamping of the inferior vena cava and portal vein, hemorrhage and blood/volume infusion, and ischemia/reperfusion all cause hemodynamic fluctuation. The changing cardiac preload and afterload status increases the cardiac workload, and thus, the previously subclinical ventricular dysfunction may manifest as overt heart failure during the operative and perioperative periods. Cardiac dysfunction contributes to morbidity and mortality associated with liver transplantation. Cardiovascular events are the third leading cause of death in liver recipients. However, because liver transplantation is the only definitive treatment for end-stage liver failure and also appears to reverse cardiac abnormalities, it is important to understand the challenges of the heart in liver transplantation. This review focuses on cardiac status before, during, and after liver transplantation. Liver Transplantation 23 826-835 2017 AASLD.

BACKGROUND: Most recent major treatment guidelines recommend considering the patient profile and baseline prognostic factors (genotype, fibrosis level, treatment history) in the management of chronic hepatitis C virus (HCV) infections (CHC). There is, therefore, a need to better characterize clinician decision-making in real-life CHC management in Canada. AIMS: To describe the patient profile, prognostic factors and treatment strategies used in Canadian real-life CHC management. METHODS: Multicenter chart review of CHC patients diagnosed from 2005 to 2012. Patient data were extracted for a minimum of 2 years after CHC diagnosis. RESULTS: 250 patients were included with a mean (SD) follow-up after diagnosis of 5.9 (2.3) years. Table1 summarizes the patient/disease characteristics at CHC diagnosis and the mode of management. A majority of patients (70.4%) received some antiviral treatment, with a lower proportion of treated G1 patients vs. non-G1 patients (64% vs. 76.7%). The most common initial treatments were IFN/RBV dual therapy (68.4%) and NS3/4-containing IFN/RBV therapy (19.3%); Among non-G1 patients, 92.4% were treated with IFN/RBV dual therapy. SVR was achieved by 51.5% of patients (G1: 44.7%; non-G1: 62.2%), 19.3% relapsed and 11.1% were non-responders with initial treatment. The majority of treated patients (72.2%) experienced AEs, the most common ones being fatigue (33%), anemia (27.3%), insomnia (21.6%), neutropenia (18.8%). Two deaths were reported. CONCLUSIONS: Despite the majority of HCV patients having mild fibrosis and being treated, most frequently with dual IFN/RBV therapy, SVR rates were low prior to the all-oral DAA era, highlighting the need for more efficacious treatments and suggesting that recommendations to still use IFN are not justifiable. FUNDING AGENCIES: Abbvie corporation

Cirrhotic cardiomyopathy (CCM) is cardiac dysfunction in patients with end-stage liver disease in the absence of prior heart disease. First defined in 2005 during the World Congress of Gastroenterology, CCM criteria consisted of echo- cardiographic parameters to identify subclinical cardiac dysfunction in the absence of overt structural abnormalities. Significant advancements in cardiovascular imaging over the past 14 years, including the integration of myocardial deformation imaging into routine clinical practice to identify subclinical cardiovascular dysfunction, have rendered the 2005 CCM criteria obsolete. Therefore, new criteria based on contemporary cardiovascular imaging parameters are needed. In this guidance document, assembled by a group of multidisciplinary experts in the field, new core criteria based on contemporary cardiovascular imaging parameters are proposed for the assessment of CCM. This document provides a critical assessment of the diagnosis of CCM and ongoing assessment aimed at improving clinical outcomes, particularly surrounding liver transplantation. Key points and practice-based recommendations for the diagnosis of CCM are provided to offer guidance for clinicians and identify gaps in knowledge for future investigations.

Background The pangenotypic direct-acting antivirals (DAAs) glecaprevir (identified by AbbVie and Enanta) coformulated with pibrentasvir (G/P) are approved for the treatment of chronic HCV genotype (GT) 1–6 infection. However, the efficacy and safety data of G/P are limited in patients infected with HCV GT5 and GT6. Methods The data analysis integrated data from 10 Phase 2b, 3a (registrational) and 3b (post-registrational) studies. The patient population comprised adults with chronic HCV GT5 or GT6 infection and compensated liver disease (with or without cirrhosis) who were treatment-naive or experienced with regimens containing interferon (IFN) or pegylated IFN (pegIFN) ± ribavirin or sofosbuvir + ribavirin ± pegIFN. Patients received 8 or 12 weeks of G/P (300 mg/120 mg) depending on the design of the original study. Efficacy was evaluated as the rate of sustained virologic response (SVR) at post-treatment week (PTW) 12 (SVR12). HCV subtype was identified by phylogenetic analysis. Results Data from 181 patients were included in this integrated analysis, including 56 (30.9%) with HCV GT5 and 125 (69.1%) with HCV GT6 infection. Overall, 102 (56.4%) patients were treated for 8 weeks and 79 (43.6%) for 12 weeks, irrespective of the presence of cirrhosis. Most patients were male (54.1%), Asian (64.6%), Conclusions HCV GT5- and GT6-infected patients without cirrhosis or with compensated cirrhosis treated with G/P for 8 or 12 weeks achieved high rates of SVR12. There were no added efficacy benefits when treatment was extended from 8 to 12 weeks, even in patients with compensated cirrhosis. The G/P regimen was well-tolerated.

Background & Aims Tenofovir disoproxil fumarate (TDF) is a first‐line treatment for chronic hepatitis B (CHB). We aimed to describe the efficacy and safety profiles of TDF treatment for up to 10 years in a well‐described cohort of CHB patients. Methods Hepatitis B e antigen (HBeAg)‐negative and HBeAg‐positive patients from two randomised, double‐blind trials (ClinicalTrials. gov: NCT00117676 and NCT00116805) completed 48 weeks of randomised treatment with TDF or adefovir dipivoxil. A subset of these patients was then eligible to receive open‐label TDF treatment for up to 10 years. At Year 10, patients were assessed for virological suppression, alanine aminotransferase (ALT) normalisation, serological response, safety, and tolerability. Results Of 641 randomised and treated patients, 585 (91%) entered the open‐label extension phase with 203 (32%) patients completing Year 10 of the study. At Year 10, 118/118 (100%) of HBeAg‐negative patients and 78/80 (98%) of HBeAg‐positive patients with available data achieved hepatitis B virus (HBV) DNA

The pangenotypic direct-acting antiviral regimen of glecaprevir coformulated with pibrentasvir is approved to treat chronic hepatitis C virus (HCV) genotype 1-6 infection in adults. In registrational studies, 84 (99%) of 85 patients with HCV genotype 5 or 6 infection achieved a sustained virological response (SVR) with glecaprevir/pibrentasvir, with no virological failures. To increase the body of data for these less prevalent genotypes, ENDURANCE-5,6 evaluated the efficacy and safety of glecaprevir/pibrentasvir exclusively in patients infected with HCV genotype 5 or 6.ENDURANCE-5,6 was a phase 3b, single-arm, open-label, multicentre trial done in 24 hospitals or clinics in Europe, Oceania, North America, South Africa, and southeast Asia. Adults with chronic HCV genotype 5 or 6 infection who were previously untreated or treatment-experienced were eligible to be enrolled. Glecaprevir/pibrentasvir (300 mg/120 mg) was given orally once daily for 8 weeks (for patients without cirrhosis) or 12 weeks (for patients with compensated cirrhosis). The primary efficacy endpoint was SVR12 (ie, HCV RNA15 IU/mL at 12 weeks post-treatment), assessed within each HCV genotype, and analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02966795.Between Feb 9, 2017, and Aug 28, 2018, 84 patients were enrolled: 23 with genotype 5 infection and 61 with genotype 6 infection. Overall, 82 (97·6%, 95% CI 94·4-100·0) of the 84 patients achieved SVR12. 22 (95·7%, 95% CI 87·3-100·0) of 23 patients with genotype 5 infection achieved SVR12, as did 60 (98·4%, CI 95·2-100·0) of 61 with genotype 6 infection. One patient with an HCV genotype 6f infection and cirrhosis had on-treatment virological failure at treatment week 12, and one patient with HCV genotype 5a without cirrhosis who had achieved SVR at post-treatment week 4 relapsed at post-treatment week 12. Five (6%) patients had serious adverse events, none of which were deemed related to glecaprevir/pibrentsavir or led to discontinuation. Fatigue (11 [13%] patients) and headache (11 [13%]) were the only adverse events that occurred in 10% or more of patients. No post-baseline grade 3 or higher increases in aminotransferase concentrations were reported.Glecaprevir/pibrentasvir achieved high SVR12 rates, comparable with data reported in registrational studies, and was well tolerated in patients with HCV genotype 5 or 6 infection with compensated liver disease.AbbVie.

Background Cirrhotic cardiomyopathy is characterized by an attenuated contractile response to stress. Long-term exposure of β-adrenergic receptors to persistently high levels of catecholamines has been implicated in its pathogenesis. We hypothesized that β-blockade with metoprolol could reverse the changes in heart function and morphology in cirrhotic cardiomyopathy. Patients and methods In this prospective randomized trial, we included 78 patients aged between 18 and 60 years with abnormal cardiac output response under dobutamine stress echocardiography, without primary cardiac disease or a history of alcohol intake. Patients were assigned randomly to receive metoprolol or placebo for 6 months. The primary endpoint was the improvement in cardiac output response to stress, measured by an increase in the left ventricle stroke volume more than 30%. Results Three (7.3%) patients in the metoprolol group and nine (24.3%) patients in the placebo group showed improved stroke volume (P=0.057). Diastolic dysfunction was found in two (4.8%) patients before and in five (15.6%) patients after therapy in the metoprolol group, and in 10 (27%) patients before and nine (31%) patients after therapy in the placebo group (P=0.67). After treatment, no echocardiography parameter of morphology was significantly different between metoprolol or placebo groups. No significant differences were observed in noradrenaline, plasma renin activity, and troponin levels between groups. Cirrhosis-related clinical events, including hospitalizations and mortality, were not significantly different between the two groups. Six months of therapy with β-blocker did not ameliorate heart function and morphology in patients with cirrhotic cardiomyopathy.

Background The pangenotypic direct-acting antivirals (DAAs) glecaprevir (developed by AbbVie and Enanta)/pibrentasvir (G/P) are approved to treat chronic HCV genotype (GT)1–6 infection. In Phase 2 and 3 studies, G/P achieved high SVR12 rates with no virologic failures in 80 patients with GT5 or 6 infection. To increase the body of data for these genotypes, ENDURANCE-5,6 evaluates patients from countries where GT5 and GT6 are endemic, such as South Africa (GT5), Myanmar and Vietnam (GT6). This study evaluates the efficacy and safety of G/P in patients with chronic HCV GT5 or GT6 infection. Methods ENDURANCE-5,6 is an ongoing phase 3b, non-randomised, open-label, multicenter study conducted in adults with chronic HCV GT 5 or 6 infections with or without compensated cirrhosis who are HCV treatment-naive or experienced with interferon (IFN) or pegIFN with or without ribavirin (RBV) or sofosbuvir and RBV with or without pegIFN. G/P (300 mg/120 mg) was orally dosed once-daily for 8 or 12 weeks in patients without or with compensated cirrhosis, respectively. The primary efficacy endpoint was SVR12. Secondary endpoints were on-treatment virologic failure or relapse. Adverse events and clinical laboratory abnormalities were monitored in all patients. Results Seventy patients have enrolled to date, 61 and 9 in the 8- and 12 week treatment arms, respectively; 66 have completed treatment. Baseline demographics are shown in table 1. The SVR4 among patients with available data is 61/62 (98%). One HCV GT6c-l-infected patient with compensated cirrhosis experienced virologic breakthrough at treatment week 12, and one HCV GT5a-infected patient without compensated cirrhosis who achieved SVR4 relapsed at post-treatment week 12. To date, three patients (4%) have experienced treatment-emergent serious adverse events, none of which were related to G/P or led to discontinuation; no Grade 3 alanine aminotransferase elevations have occurred. Conclusions In this ongoing dedicated study, HCV genotype 5- and 6-infected patients without and with compensated cirrhosis treated with G/P for 8 and 12 weeks, respectively, achieved high rates of SVR4. Complete SVR4 and available SVR12 data will be presented.

Introduction and aim Accurately predicting the prognosis of individual patient is crucial in the management of ACLF. We aimed to establish a specific prognostic model for HBV-related ACLF patients treated with nucleoside analog (NA). Material and methods We prospectively collected 205 ACLF cases diagnosed according to the APASL criteria. A dynamic prognostic model based on APASL criteria was established and validated. To demonstrate that the model is also applicable to those within EASL criteria, we divided the patients into two groups: met APASL criteria only (group A, n = 123); met both APASL and EASL criteria (group B, n = 82). Its prognostic accuracy was also compared with chronic liver failure-sequential organ failure assessment (CLIF-SOFA) score in group B. Results The model is: R = 0.94 x Bilirubin + 0.53 x evolution of Bilirubin - 0.45 x PT-A - 0.22 x evolution in PT-A -0.1 x PLT + 10 x anti-HBe. The area under receiver operating characteristic curve (AUC) of the model for predicting 90-day mortality was 0.86, which was significantly higher than that of model for end stage liver disease(MELD), MELD-Na, CLIF-SOFA, ΔMELD (7d) and ΔMELD-Na (7d), ΔCLIF- SOFA(7d) (all p l 0.01). The AUC of our model in the validation group was 0.79 which was superior to MELD (0.45) CLIF-SOFA (0.53) score in group B patients (p l 0.01). Conclusion In conclusion, the model was superior to the conventional methods in predicting the outcomes of patients with HBV related ACLF treated with NA. It is the first description of a novel prognostic model using consecutive data in patients with HBV-induced acute-on-chronic liver failure (ACLF) treated by nucleoside analogs.

BACKGROUND: The 3-direct-acting antiviral regimen of ombitasvir/paritaprevir/ritonavir + dasabuvir (3D) +/- ribavirin (RBV) has been shown to be safe and effective for the treatment of chronic hepatitis C (CHC) in randomized controlled trials. However, data on real world treatment experience is limited. In Canada, the 3D regimen is approved to treat patients with CHC genotype (GT) 1 including compensated cirrhosis. AIMS: The aim of this non-interventional study is to provide evidence of the effectiveness of the 3D regimen in a real world setting across broader clinical practice patient populations. METHODS: The Canadian AMBER study is an ongoing, prospective, multi-center, observational cohort study aiming at enrolling 600 treatment-naïve and -experienced GT1 patients with and without compensated cirrhosis. The treatment course was at the discretion of the treating physician, according to the standard of care of the institution. All patients who started therapy from October 2015 up to March 31st, 2016 and for whom a treatment duration of 12 weeks was intended were included in this interim analysis. Effectiveness was defined as having achieved sustained virological response 12 weeks post-treatment (SVR12). RESULTS: The inclusion criteria for this analysis were met by 115 patients. Demographics: 70% male, mean age 55 (SD 10.7), 81% Caucasian, 7% Asian. Disease characteristics: Mode of HCV infection was i.v. drug use in 41%, blood transfusion in 17%, contaminated medical device in 6% and unknown in 28% of patients; GT1a 54%, GT1b 43%, GT1 subtype unknown 3%; 12% had failed previous therapy; 23% had cirrhosis, 8% transition to cirrhosis, Child Pugh B was present in 2 patients. Treatment: 74 (64%) patients had RBV added to their 12 week 3D regimen (96% of GT1a), 41 (36%) patients did not receive RBV (78% of GT1b). See table for co-morbidities. CONCLUSIONS: The data from this study may aid in better describing the medical profile of patients seeking care for CHC in real world. In contrast to development trials a broader population including patients with psychoactive substance dependency was enrolled. The effectiveness of new interferon-free regimens in such subpopulations is of particular interest. SVR12 data will be detailed in the poster. FUNDING AGENCIES: Abbvie corporation

BACKGROUND: PEG-IFN is first-line therapy for CHB offering the advantage of a finite treatment, but is rarely used due to concerns about tolerability and efficacy. Nucleot(s)ide analogues (NUC) therapy are well tolerated but require prolonged therapy, with significant cost as well as potential for long-term adverse effects. AIMS: We aim to assess tolerability and long term outcomes in treatment-naive patients who received PEG-IFN for CHB. The primary outcome assessed was durability of off-treatment response (i.e. HBV DNA

AIMS: The advent of direct acting antivirals is expected to improve the management of Chronic Hepatitis – C (c-HCV). METHODS: MOSAIC an observational study conducted in 30 countries describes the profile of c-HCV patients and the impact of Interferon (IFN) treatment on Patient Reported Outcomes and outpatient consultations (Table). Consecutive c-HCV patients initiated on IFN-based treatment were followed for 48 weeks. RESULTS: Of 346 invited patients 279 participated; (189 treatment-naïve and 90 treatment-experienced). IFN-treatment was initiated for 55 (20%): DAA+peg-IFN+RBV: 5, peg-IFN+RBV: 19, IFN+RBV: 1, other: 30. Main reasons for not initiating IFN for physicians were: waiting for new options (32%, 13%); tolerability (15%, 7%); contraindications (9%, NA); costs (7%, 1%) and for patients inconvenience (2%); impact on social/family life and work (9%). Demographic characteristics {Mean (SD) [Range]} of the 55 treated patients: Age: 52.1 (10.39) [31–74] yrs; Duration since HCV diagnosis: 10.8 (10.1) [0 – 46] yrs; and 69.1% male. Baseline cirrhosis status was: minimal/no fibrosis: 20(36.4%), bridging fibrosis: 16(29.1%), cirrhosis: 11(20.0%), portal fibrosis: 4(7.3%) and NA: 4(7.3%). Genotype was G1: 34(61.8%), G3: 11(20.0%), G2: 6(10.9%), G6: 2(3.6%) and n = 1 (1.9%) each for G4, G5. Baseline HCV-RNA level was 800,000 IU/ml: 26(47%) x IU/mL, positive by qualitative assay: 5 (9%), NA: 4(7%). Employment decreased from 46% to 33%. Outpatient consultation during treatment was none: 64%; 1: 11%. >=4: 20%. CONCLUSIONS: IFN use in c-HCV patients in MOSAIC is low. Patients treated with IFN-containing regimens experience a substantial negative impact on QoL and productivity. Anticipated availability of new IFN-free regimens is the main reason for not initiating treatment with IFN. FUNDING AGENCIES: Abbvie Corporation

Background High hepatitis C cure rates have been observed in registration trials with second-generation direct-acting antivirals. Real-world data also indicate high sustained viral response (SVR) rates. Our objective was to determine real-world SVR rates for patients infected with hepatitis C virus (HCV) who were treated with second-generation direct-acting antivirals in the first 18 months of their availability in Canada. Methods Four centres in Calgary contributed their treatment data for a diverse patient population including those who had or had not undergone liver transplantation, those coinfected with HIV and vulnerable populations. We included all patients documented to have started hepatitis C treatment with direct-acting antivirals between October 2014 and April 2016, with follow-up through October 2016. We used multivariate analysis to determine independent predictors of treatment failure. Results Outcome data were available for 351 patients, of whom 326 (92.9%) achieved an SVR (193/206 [93.7%], 57/59 [96.6%] and 44/51 [86.3%] for genotypes 1a, 1b and 3, respectively, p = 0.2). Independent predictors of not achieving SVR were older age (adjusted odds ratio [OR] 0.95 [95% confidence interval (CI) 0.90-1.00]), male sex (adjusted OR 0.30 [95% CI 0.10-0.89]) and, in patients with genotype 1a infection, history of hepatocellular carcinoma (adjusted OR 0.13 [95% CI 0.03-0.53]). In the entire cohort, the presence of cirrhosis, genotype and hepatocellular carcinoma were not associated with a lower SVR rate. There were no differences in SVR rate according to treatment centre, HIV coinfection or liver transplantation. Among patients with genotype 3 infection, a significantly lower SVR rate was observed for those treated outside of standard of care than for those treated within standard of care (33.3% v. 89.6%, p = 0.04). De novo hepatocellular carcinoma developed in 12 patients (3.4%) despite successful direct-acting antiviral therapy. Interpretation We report high SVR rates in a real-world diverse cohort of HCV-infected patients treated with second-generation direct-acting antivirals. The results highlight the importance of conducting real-world analyses to elucidate clinical factors associated with poorer outcomes that may not be identified in registration trials.

This study assessed the efficacy and safety of ribavirin-free coformulated glecaprevir/pibrentasvir (G/P) in patients with hepatitis C virus genotype 3 infection with prior treatment experience and/or compensated cirrhosis, a patient population with limited treatment options. SURVEYOR-II, Part 3 was a partially randomized, open-label, multicenter, phase 3 study. Treatment-experienced (prior interferon or pegylated interferon ± ribavirin or sofosbuvir plus ribavirin ± pegylated interferon therapy) patients without cirrhosis were randomized 1:1 to receive 12 or 16 weeks of G/P (300 mg/120 mg) once daily. Treatment-naive or treatment-experienced patients with compensated cirrhosis were treated with G/P for 12 or 16 weeks, respectively. The primary efficacy endpoint was the percentage of patients with sustained virologic response at posttreatment week 12 (SVR12). Safety was evaluated throughout the study. There were 131 patients enrolled and treated. Among treatment-experienced patients without cirrhosis, SVR12 was achieved by 91% (20/22; 95% confidence interval [CI], 72-97) and 95% (21/22; 95% CI, 78-99) of patients treated with G/P for 12 or 16 weeks, respectively. Among those with cirrhosis, SVR12 was achieved by 98% (39/40; 95% CI, 87-99) of treatment-naive patients treated for 12 weeks and 96% (45/47; 95% CI, 86-99) of patients with prior treatment experience treated for 16 weeks. No adverse events led to discontinuation of study drug, and no serious adverse events were related to study drug. Conclusion: Patients with hepatitis C virus genotype 3 infection with prior treatment experience and/or compensated cirrhosis achieved high SVR12 rates following 12 or 16 weeks of treatment with G/P. The regimen was well tolerated. (Hepatology 2018;67:514-523).

Background & Aims The need for further histological subclassification of cirrhosis has been increasingly recognized because of the heterogeneity of severity within cirrhosis. We sought to identify evidence in the literature regarding the histological subclassification of cirrhosis using the Laennec stage. Methods We conducted a systematic review and meta-analysis by searching databases, including MEDLINE, EMBASE and the COCHRANE library, for relevant studies. Results Of 208 studies identified, 16 were eligible according to the inclusion criteria. With higher grades of the Laennec stage, clinical stages of cirrhosis and Child–Pugh scores/Model for end-stage liver disease scores increased (P

Introduction: Management of hepatitis C virus (HCV) is rapidly changing as a result of new direct-acting antivirals (DAA). Sources of data: Several peer-reviewed papers featuring new DAAs are now available. Additionally, as new data are emerging so quickly, we also reviewed recent presentations at international congresses, published in abstract form. Areas of agreement: New DAAs are efficacious and superior to prior treat- ment regimens, with minimal side effects. Shorter interferon-free regimens will soon be the mainstay of HCV treatment. Areas of controversy: Access to new DAAs is variable across global regions. One approach to treating HCV may be to assess early viral kinetics of treat- ment to identify who may be cured with standard peg-interferon/ribavirin therapy as opposed to using a DAA in all patients. Growing points: Newer studies with combination of DAAs are being con- ducted. The ideal interferon-free regimen has yet to be determined. Areas timely for developing research: HCV genotype 3 is the new difficult- to-treat genotype. More efficacious regimens for treating HCV genotype 3 are needed. Subgroups of patients who only require even shorter regimens of 6-8 weeks need to be identified. There is still very little data on interferon- free regimens in patients with decompensated cirrhosis and certain other

Background Despite universal vaccination, chronic hepatitis B virus (HBV) infection remains a public health concern in North America owing to immigration. We aimed to characterize the number of people with a positive result of testing for HBV surface antigen (HBsAg) in Calgary, a large urban Canadian health care region, and to assess whether recommended laboratory tests and specialist consultation were done for those identified as HBsAg-positive. Methods Based on laboratory and Alberta Health Services administrative data, we identified all adults (age > 18 yr) with a positive HBsAg test result from Jan. 1 to Dec. 31, 2014 within the Calgary Zone. Demographic and relevant laboratory data were extracted within 6 months of a positive HBsAg test result, and referral to hepatology (2011-2014) was identified from data on referral to a centralized clinic. Parametric and nonparametric statistical methods were used for analyses. Results We identified 1214 HBsAg-positive people (584 women [48.1%]; median age 44 [interquartile range (IQR) 36-55] yr). A total of 1192 people (98.2%) had alanine aminotransferase testing (median level 23 [IQR 16-34] U/L; 117 [9.8%] with elevated levels), 682 (56.2%) had testing for HBV DNA (median level 2.8 [IQR 2.1-3.8] logIU/mL), 630 (51.9%) had HBV e antigen testing (negative result in 548 [87.0%]), and 145 (11.9%) had HBV e antibody testing (positive result in 111 [76.6%]). Overall, 144 people (11.9%) received anti-HBV treatment, and 390 (32.1%) were referred to a hepatologist. Interpretation Many HBsAg-positive people in Calgary did not receive the recommended laboratory assessments. The results highlight the necessity of continual public health efforts to screen for chronic HBV infection in Canada and to ensure adequate follow-up in order to reach the World Health Organization's goal of viral hepatitis elimination by 2030.

Background The once-daily, ribavirin-free, pangenotypic, direct-acting antiviral regimen, glecaprevir coformulated with pibrentasvir, has shown high rates of sustained virological response in phase 2 and 3 studies. We aimed to assess the efficacy and safety of 12 weeks of coformulated glecaprevir and pibrentasvir in patients with hepatitis C virus (HCV) infection and compensated cirrhosis. Methods We did this single-arm, open-label, multicentre phase 3 study at 40 sites in Belgium, Canada, Germany, South Africa, Spain, and the USA. We enrolled patients aged 18 years or older with HCV genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. Patients were either HCV treatment-naive or had not responded to treatment with interferon or pegylated interferon with or without ribavirin, or sofosbuvir plus ribavirin with or without pegylated interferon. Oral glecaprevir (300 mg) coformulated with pibrentasvir (120 mg) was administered once daily for 12 weeks. The primary efficacy endpoint was sustained virological response at post-treatment week 12 (HCV RNA

Chronic hepatitis B (CHB) is a major public health concern, particularly in endemic areas like Asia–Pacific. Sustained virologic suppression correlates with regression of histologic fibrosis and cirrhosis. This study evaluated efficacy and safety of tenofovir disoproxil fumarate (TDF) in Asian patients through 240 weeks of treatment. Post hoc analysis of the Asian subpopulation from two phase 3 clinical studies was performed. Following a 48-week randomized, double-blind evaluation of once-daily TDF versus once-daily adefovir dipivoxil, open-label TDF for up to 240 weeks was evaluated. Patients with both baseline and week 240 liver biopsies were evaluated for histologic changes. At baseline, 189/641 (29 %) patients randomized were Asian. Sixty-eight percent of Asian patients were male; 50 % were hepatitis B e antigen (HBeAg)-positive. At week 240, similar proportions of Asian (88 %) and non-Asian (87 %) patients demonstrated improvement in liver histology, and 19/22 (86 %) Asian patients with baseline cirrhosis were no longer cirrhotic. By modified intent-to-treat analysis, 74 % of Asian patients and 76 % of non-Asian patients had HBV DNA

Rituximab, an anti-CD20 monoclonal antibody that selectively depletes B cells, has shown promise in autoantibody-associated, immune-mediated disorders. As ursodeoxycholic acid (UDCA) is not successful in all patients with primary biliary cirrhosis (PBC), additional treatment options are necessary. The objective of this study was to assess the safety and efficacy of rituximab in patients with PBC refractory to UDCA.Fourteen PBC patients refractory to UDCA received two rituximab infusions (1,000 mg) 2 weeks apart. The primary efficacy outcome was normalization and/or 25% improvement in serum alkaline phosphatase (ALP) concentration at 6 months.The median age was 53 years, and 92% were female and antimitochondrial antibody (AMA) positive. The median UDCA dosage was 15.3 mg/kg/day (interquartile range 14.5-17.8). Although rituximab was well tolerated, one patient withdrew due to an asthma exacerbation during the first infusion. Effective B-cell depletion was observed in the remaining 13 patients, including three that developed human anti-chimeric antibodies. ALP normalization and/or ≥ 25% improvement was observed in three patients (23%) at 6, 12, and 18 months. Significant reductions in median ALP (from 259 U/l at baseline to 213 U/l at 6 months; median decrease 16%), and serum IgM and AMA levels were observed at 6 months. Although fatigue was stable, pruritus improved in 60% of patients at 12 months (vs. 8% with worsening pruritus).Selective B-cell depletion with rituximab was safe and associated with a significant decrease in autoantibody production, but had limited biochemical efficacy in PBC patients with an incomplete response to UDCA.

Antiviral therapy for chronic hepatitis C has dramatically changed with the advent of triple therapy incorporating direct-acting antivirals (DAAs) such as the protease inhibitors (PI) boceprevir and telaprevir. Such triple-therapy is associated with a new spectrum of side-effects which can hamper quality of life. These may lead to dosage reduction and sometimes discontinuation of therapy. This review presents practical tips to help manage adverse effects appropriately and efficiently. The main adverse effects causing discontinuation of therapy are varied. Although the most common adverse effects are the 'flu'-like symptoms of fatigue, myalgia, fever and lassitude, these are usually easily managed and do not lead to treatment discontinuation. Cytopaenia, particularly anaemia, has emerged as perhaps the most troublesome side-effect. Cirrhotic patients are especially prone to moderate or severe anaemia with boceprevir and telaprevir triple-therapy regimens. Aggressive ribavirin dosage reductions, erythropoietin and blood transfusions are effective for managing anaemia. Skin rash can be controlled with moisturization and corticosteroid ointment. Rarely, dermatology consultation is required for further management. Anal discomfort, with or without diarrhoea, sometimes responds to barrier creams and haemorrhoidal ointments. Dysgeusia is treated by sipping water frequently, oral ointments and mouth washes to maintain salivary flow and oral hygiene. Successful adherence to treatment can be enhanced by a strong support network for the patient, including specially-trained hepatitis nurses and a multidisciplinary team incorporating pharmacists, counsellors and social workers.

BACKGROUND: Although most patients with autoimmune hepatitis (AIH) respond to treatment with prednisone and/or azathioprine, some patients are intolerant or refractory to standard therapy. Rituximab is an anti-CD20 monoclonal antibody that depletes B cells and has demonstrated efficacy in other autoimmune conditions.AIMS: To evaluate the safety and efficacy of rituximab in patients with refractory AIH in an open-label, single-centre pilot study.METHODS: Six patients with definite, biopsy-proven AIH who failed prednisone and azathioprine treatment received two infusions of rituximab 1000 mg two weeks apart and were followed for 72 weeks.RESULTS: Rituximab was well tolerated with no serious adverse events. By week 24, mean (± SD) aspartate aminotransferase (AST) levels had significantly improved (90.0±23.3 U/L versus 31.3±4.2 U/L; P=0.03) and mean immunoglobulin G levels had fallen (16.4±2.0 g/L versus 11.5±1.1 g/L; P=0.056). The prednisone dose was weaned in three of four subjects, with one subject flaring after steroid withdrawal. Inflammation grade improved in all four subjects who underwent repeat liver biopsy at week 48. Regulatory T cell levels examined by FoxP3 immunohistochemistry paralleled inflammatory activity and did not increase on follow-up biopsies. There was no significant change in serum chemokine or cytokine levels from baseline to week 24 (n=5), although interferon-gamma-induced protein 10 levels improved in three of five subjects.CONCLUSIONS: Rituximab was safe, well tolerated and resulted in biochemical improvement in subjects with refractory AIH. These results support further investigation of rituximab as a treatment for AIH.

Erythropoietin exerts cardioprotective effects. The present study aimed to investigate the therapeutic effects of erythropoietin on cirrhotic cardiomyopathy.Rats were divided into 5 groups: sham control; sham+ erythropoietin; bile duct ligation; bile duct ligation+erythropoietin; bile duct ligation+erythropoietin+anti-tumour necrosis factor alpha (TNFα) antibody and were studied 4 wk after surgery. Erythropoietin was administrated for 10 days before the study date. TNFα, erythropoietin receptor-1 expression and oxidative stress-related parameters were measured. In separate groups, isolated cardiomyocytes were subjected to contractile and relaxation studies. Cardiomyocyte cell line was used to test the direct effect of erythropoietin on nuclear factor (erythroid-derived 2)-like 2(Nrf2).Erythropoietin receptor-1, TNFα and oxidative modified proteins were significantly increased (p0.01), and the antioxidant regulator Nrf2 transcription decreased in cirrhotic hearts (p0.01). Erythropoietin reversed these parameters. Maximal cardiac contractile and relaxation velocity was significantly decreased in cirrhotic cardiomyocytes. Erythropoietin significantly reversed these inhibitions. Anti-TNFα antibody significantly decreased cardiac TNFα content but did not further increase contractility.TNFα and oxidative stress are involved in cardiac dysfunction in the cirrhotic heart. Erythropoietin significantly decreased TNFα and oxidative stress and reversed the impaired cardiac function.

Malnutrition is prevalent among cirrhotic patients and is an important prognostic factor. Etiologic factors include hypermetabolism, malabsorption, altered nutrient metabolism, and anorexia. It is a challenge to manage nutrition in cirrhotic patients because of alterations to metabolic and storage functions of the liver; use of traditional assessment tools, such as anthropometric and biometric measures, is difficult because of complications such as ascites and inflammation. In addition to meeting macro- and micronutrient requirements, the composition and timing of supplements have been proposed to affect efficacy of nutrition support. Studies have indicated that branched chain aromatic acid can be given as therapeutic nutrients, and that probiotics and nocturnal feeding improve patient outcomes.

Ascites is a frequent complication of cirrhosis and portal hypertension, because of the increase of the sinusoidal hydrostatic pressure. Cirrhosis accounts for over 75% of episodes of ascites. Cirrhotic patients with ascites have marked alterations in the splanchnic and systemic haemodynamics, causing central hypovolaemia and arterial hypotension with consequent activation of the vasoconstrictor systems, renin-angiotensin and sympathetic systems, and with increased renal sodium re-absorption. One of the most serious complications in cirrhotic patients with ascites is the occurrence of refractoriness, that is the inability to resolve ascites by the standard medical treatment with low sodium diet and diuretic doses up to 160 mg/day of furosemide and 400 mg/day of spironolactone. Many patients with refractory ascites also have a chronic renal insufficiency that is called hepatorenal syndrome type-2. In these patients ascites may be treated with periodic paracentesis or with transjugular intrahepatic portosystemic shunt. However, only liver transplantation may improve the survival of such patients.

Background/Aims VCH-759 is a non-nucleoside inhibitor of HCV RNA-dependent polymerase with sub-micromolar IC 50 values versus genotype 1a/1b replicons. Methods The antiviral activity, pharmacokinetics and tolerability of VCH-759 administered as monotherapy for 10 days with a 14 day follow-up period were evaluated in 31 treatment-nai¨ve genotype 1 participants. Three cohorts received: 400mg thrice (t.i.d.), 800mg twice (b.i.d.), 800mg t.i.d or placebo. Results VCH-759 was well tolerated with the most frequent adverse event being gastrointestinal upset in both the active and placebo groups attributable, in part, to the dosing vehicle. VCH-759 was rapidly absorbed and trough plasma levels were at or above the IC 90 (non protein-adjusted) for all dosing regimens. The mean maximal decrease in HCV RNA log 10 (IU/mL) was 1.97, 2.30 and 2.46 for 400mg t.i.d., 800mg b.i.d. and 800mg t.i.d. doses. Viral polymerase genotypic sequencing revealed emergence of HCV variants in a majority of participants that coincided with on-treatment viral rebound. Conclusions VCH-759 was well tolerated and achieved a⩾2 log 10 decline in HCV RNA with 800mg b.i.d. and t.i.d doses. In a subset of participants, viral rebound was observed and associated with resistant variants. This data supports further evaluation of VCH-759 in combination with interferon–ribavirin treatment.

The two main goals of hepatitis B therapy are durable viral suppression and avoidance of antiviral resistance. Recent treatment guidelines now recognize the importance of these treatment endpoints in the prevention of end-stage liver disease and hepatocellular carcinoma rather then other surrogate markers such as HBeAg seroconversion and serum alanine aminotransferase normalization, especially in patients who acquired hepatitis B virus infection early in life. A variety of therapeutic options are now available for the treatment of chronic hepatitis B infection, including four nucleos/tide analogues (i.e lamivudine, adefovir, entecavir and telbivudine), along with standard and pegylated interferon. Newer oral nucleos/tide analogues that include tenofovir, emtricitabine and clevudine are soon likely to be approved worldwide. Given the wide array of choices and the complex nature of chronic hepatitis B infection, selection of the appropriate therapeutic agent can be challenging for clinicians. Effective treatment decisions require an understanding of the natural history of hepatitis B and knowledge of its life cycle and molecular biology. This review includes the range of treatment options and criteria for determining when and how to most effectively intervene with antiviral therapy for chronically infected patients positive for the HBeAg.

BACKGROUND: Pegylated interferon (pegIFN) and ribavirin combination therapy remains the first-line treatment for chronic hepatitis C virus (HCV) infection. In contrast to the wealth of studies in treatment-naive patients, the effectiveness of retreatment in patients who have previously failed pegIFN-based therapy is largely unreported.AIM: To assess the effectiveness of the retreatment of patients who have previously failed an initial course of pegIFN-based therapy with pegIFNα-2a and ribavirin.METHODS: A post-hoc analysis of a multicentre open-label study was performed. Patients received pegIFNα-2a and ribavirin at a dose of 800 mg/day and later 1000 mg/day to 1200 mg/day for 24 to 48 weeks at the discretion of the investigator. Outcomes at week 12 (early virological response [EVR]) and week 24 (sustained virological response [SVR]) were analyzed.RESULTS: Eighty-seven patients who had relapsed after previous pegIFN-based therapy (n=28; 78% genotype 1) or were nonresponders (n=59; 71% genotype 1) were analyzed. Of the relapsers, 86% achieved an EVR and 68% achieved an SVR. In relapsers to pegIFN monotherapy (n=15) or pegIFN plus ribavirin (n=13), 60% and 77% achieved an SVR, respectively. Fibrosis and genotype did not affect the likelihood of SVR in relapsers although this may be the result of the relatively small number of patients. In previous nonresponders, an EVR was achieved in 53% but an SVR occurred in only 17%. In nonresponders to pegIFN monotherapy (n=9) and pegIFN plus ribavirin (n=50), 33% and 14% achieved an SVR, respectively. Genotype did not affect SVR in nonresponders. Only 10% with a METAVIR score of F3 or F4 on liver biopsy achieved an SVR.CONCLUSIONS: Relapse after previous pegIFN-based therapy is associated with a strong probability of treatment success whereas retreatment of those with previous nonresponse does not.