ABSTRACTChronic hepatitis B (CHB) is the leading cause of hepatocellular carcinoma (HCC) globally. We described and evaluated the outcomes of patients with CHB‐HCC in Canada. In this retrospective cross‐sectional cohort study, data were analysed from CHB mono‐infected subjects seen between 1 January 2012 and 31 December 2022, and entered the Canadian Hepatitis B Network Registry. Descriptive analysis and chi‐squared modelling were used to compare cohorts, followed by multivariable survival analysis regarding survival post‐diagnosis. Statistical analyses were completed in R version 2.2. Of the 6711 patients with CHB who met inclusion criteria, 232 (3.5%) developed HCC. Compared with the CHB cohort, the majority of CHB‐HCC cohort were male, SEA and HBeAg negative and born in endemic area (80% vs. 56%, 73% vs. 55%, 84% vs. 54%, 64% vs. 40% and all p < 0001). Overall, median HBV DNA level was log 2.54 (IQR: 0–4.04). Advanced liver disease, defined as minimum Fibrosis stage F3, was seen in 9.4% of overall cohort, but 92% of HCC cohort. At diagnosis, median tumour size was 2.5 cm (IQR: 1.7–4.0) and mean tumour number was 1.33 (SD: 1.33), with 81% of patients BCLC 0‐A. Fifty‐three per cent of patients were diagnosed with HCC as part of surveillance protocols. The survival rate after HCC diagnosis was 78.7%, during the median follow‐up of 52.9 months (IQR: 17–90). In multivariable analysis, survival was significantly correlated with diagnosis through the screening programme. In this large cohort of patients with CHB‐HCC, the majority of patients were detected with early‐stage HCC and received treatment with curative intent, resulting in strong survival rates.

BACKGROUND: Primary biliary cholangitis (PBC) is a rare, chronic autoimmune, cholestatic liver disease affecting approximately 318 per million Canadians. There is limited information regarding the characterization of this patient population in Canada. Consequently, we aim to describe a cohort of PBC patients managed across liver centres serving this type of population. METHODS: A cross-sectional examination of 1,125 PBC patient charts at 15 liver centres across Canada was conducted between January 2016 and September 2017. RESULTS: Data from 1,125 eligible patients were collected from 7 Canadian provinces. The patient population was largely female (90.2%), had a median overall age of 61.3 years, and a median overall time since diagnosis of 6.4 years. Of the patients included in the study, 89% were on ursodeoxycholic acid (UDCA) therapy at a median dose of 14.0 mg/kg/day and 4.4% were previously treated with UDCA, whereas 6.6% were never treated with UDCA. Of the patients with available data (n = 1067), 289 (27.1%) presented with alkaline phosphatase (ALP) levels ≥200 IU/L and/or total bilirubin levels ≥21 µmol/L. Assessment of UDCA treatment response revealed that 26.6% and 38.3% of patients were inadequate responders according to the Toronto and Paris-II criteria, respectively. Mortality occurred in 1.2% (14) of patients, with liver-related adverse outcomes being more commonly observed in patients who discontinued UDCA compared to those who are currently on treatment (36.3% and 19.6%, respectively). CONCLUSION: This study showed that Canadian PBC patients present with demographics and features commonly reported in the literature for this disease. Over one third of PBC patients had inadequate response to UDCA treatment or were not currently being treated with UDCA. Consequently, there is a significant unmet therapeutic need in this Canadian PBC population.

Abstract Background Chronic hepatitis B (CHB) is the most common cause of hepatocellular carcinoma (HCC) worldwide. Aims The primary aim of this study is to explore the degree of treatment adherence to the American Association For The Study of Liver Disease (AASLD) HCC treatment guidelines for patients with CHB-HCC. Methods This is a retrospective, cross-sectional study of available data (2005–2020) in patients mono-infected with CHB collected from the Canadian HBV Network; a national consortium across 8 Canadian provinces. We analyzed data using descriptive statistics along with parametric and nonparametric statistical methods with a significance level of p < 0.05. Results Of the 6500 patients, 132 (2.0%) patients met inclusion criteria. The median age was 64 (IQR: 53.5- 71.5) with 101 (76%) being male. The median ALT was 40 (IQR: 26–59.5) and the median tumor number was 1(IQR: 1- 2) with a median tumor size of 2.6 cm (IQR: 1.9- 4.5). 98 (74.5%) patients were HBeAg negative with a median viral load of 3.8 logs (IQR 1.9 – 5.8). 58 (43%) patients had cirrhosis at diagnosis. 36% of patients were diagnosed with HCC on their first screening imaging whereas 39% were found to have HCC on repeated surveillance imaging. 116 (87.9%) were on treatment at the time of diagnosis or after (70 (60.3%) NA and 46 (39%) Combination therapy with double NA or NA plus interferon). Out of the 132 patients, BCLC stage 0, A, B, and C represented 30 (23%), 42 (32%), 17 (13%), and 5 (4%) patients, respectively, with 38 (28%) patients with unknown BCLC stage. The overall adherence to AASLD guidelines was 61%. The HCC treatment adherence rate for patients with BCLC stage 0, A, B were 63%, 97.5%, and 23.5%, respectively. BCLC stages C and D did not have a sufficient sample size for analysis. The adherence rate ranged from 53% (Eastern Canada) to 71% (Western Canada) across Canada. Conclusions In this retrospective nationwide cohort study of patients with CHB-related HCC, the overall treatment adherence rate to AASLD guidelines was low with notable regional differences. Further analysis will determine the cause of regional differences. Funding Agencies None

OBJECTIVES: Patients with cirrhosis experience a worsened quality of life; this may be quantified by the use of health-related QoL (HRQoL) constructs, such as the chronic liver disease questionnaire (CLDQ) and EuroQoL Group—visual analog scale (EQ-VAS). In this multicenter prospective study, we aimed to evaluate HRQoL as a predictor of unplanned hospital admission/early mortality, identify HRQoL domains most affected in cirrhosis, and identify predictors of low HRQoL in patients with cirrhosis. METHODS: Multivariable logistic regression was used to determine independent association of HRQoL with primary outcome and identify predictors of low HRQoL. HRQoL was also compared with population norms. RESULTS: In this cohort of 402 patients with cirrhosis, mean model for end-stage liver disease was 12.5 (4.9). More than 50% of the cohort had low HRQoL, considerably lower than population norms. HRQoL (measured by either CLDQ or EQ-VAS) was independently associated with the primary outcome of short-term unplanned hospitalization/mortality. Every 1-point increase in the CLDQ and every 10-point increase in the EQ-VAS reduced the risk of reaching this outcome by 30% and 13%, respectively. Patients with cirrhosis had lower HRQoL scores than population norms across all domains of the CLDQ. Younger age, female sex, current smoker, lower serum albumin, frailty, and ascites were independently associated with low CLDQ. DISCUSSION: Patients with cirrhosis experience poor HRQoL. HRQoL is independently associated with increased mortality/unplanned hospitalizations in patients with cirrhosis and could be an easy-to-use prognostic screen that patients could complete in the waiting room before their appointment.

Impaired cognitive function is a key prognostic factor in patients with cirrhosis. This is often, but not always, attributable to hepatic encephalopathy (HE). The Montreal Cognitive assessment (MOCA) is a sensitive measure of mild cognitive impairment, yet has been sparingly reported in the literature in cirrhotic populations. In a cohort of stable cirrhosis outpatients without overt HE, we aimed to: i) characterize baseline MOCA scores, ii) determine the domains of MOCA that are most commonly affected and iii) determine the predictors of a low MOCA score (<26). Consecutive adults with cirrhosis assessed prospectively in one of two Edmonton cirrhosis clinics between May 2013 and June 2016 were screened for enrolment. Exclusion criteria included active malignancy, dementia, HCC outside of Alberta liver transplant criteria, end-stage renal disease and overt HE (as defined by lack of orientation (person, place, time) or asterixis). Multivariable logistic regression analysis was used to determine independent predictors of a MOCA <26. Fifty-three patients were excluded because they were disoriented to person, place or time. Of 390 included patients, the mean age was 55.6 ± 9.8, 62% were male and the etiology of cirrhosis was alcohol or hepatitis C in 54%. Thirty-two percent scored positive for depression. Forty-one percent had an abnormal handgrip as defined by BMI and sex cut-offs. The mean MOCA score was 25.2 ± 3.2 and 45% had a score of <26. Abnormalities were most commonly seen in the following MOCA subdomains – delayed recall (81%), visuospatial/executive (70%), attention (48%) and language (46%) and least commonly seen in abstraction (19%) and naming (7%). Depression was the only independent predictor of a MOCA <26, with increasing age trending to significance (Table 1). In a large cohort of stable cirrhosis outpatients, 45% of them have MOCA scores below the accepted lower limits of normal. Depression and low muscle strength are associated with lower cognitive function scores. These potentially modifiable variable needs to be screened for and treated to determine if they may positively impact cognitive function. Ongoing work will associate MOCA total scores and subdomains with clinical outcomes including unplanned hospitalization, death and HE related hospitalizations. None

Psychological distress is common in patients with cirrhosis. Depression has a significant effect on health-related quality of life (HRQoL), adaptive coping, functional status and mortality. The effect of anxiety on HRQoL and clinical outcomes is not as well understood. 1. Determine the prevalence of anxiety in cirrhosis and its association with clinical outcomes 2. Inform a rapid cirrhosis-specific anxiety screening tool by identifying multivariate predictors of anxiety using relevant clinical variables and subcomponents of the Hospital Anxiety and Depression Scale (HADS) Patients 18–80 years old with a diagnosis of cirrhosis were recruited consecutively from liver clinics at three tertiary care hospital sites in Alberta. Individuals were excluded if they: were disoriented to person, place, or time orhad overt hepatic encephalopathy; active malignancy or hepatocellular carcinoma outside of the Alberta liver transplant criteria; end-stage renal disease on dialysis; or were on antidepressants. Patient sociodemographic and cirrhosis characteristics were collected. Patients were identified as having anxiety using the Mini Neuropsychiatric Interview (MINI) modules for panic disorder, agoraphobia, social phobia, and generalized anxiety disorder. The HADS was also completed to assess anxiety. The chronic liver disease questionnaire (CLDQ) and EQ-VAS score were used to determine HRQoL and participants were followed up to 6 months to determine whether they had unplanned hospitalizations or deaths during that time. Of the 369 patients, 65 patients were excluded for being on anti-depressants, leaving a total of 304 patients. Of those, 17.1% had anxiety by the MINI. Multivariate analysis revealed active smoking and 3 HADS subcomponents as independent predictors of anxiety (Table 1). Anxious patients had lower HRQoL as assessed by CLDQ (P < 0.001) and EQ-VAS (P < 0.001) and were more frail by the Clinical Frailty score (P = 0.004). Although numerically higher, there were no statistically significant difference between anxious and non-anxious patients for hospitalizations or death within 6 months of testing (P = 0.14). The 8.2% of patients meeting diagnostic criteria for both anxiety and depression had worse CLDQ, EQ-VAS and Clinical Frailty scores than anxious-only or depressed-only patients. Anxiety is common in patients with cirrhosis and not routinely screened for. Anxiety has a significant impact on HRQoL and functional status, most pronounced in those patients with anxiety-depression overlap. Active smoking and three HADS subcomponents were identified as being independent predictors of anxiety. Multidisciplinary approaches targeting psychosocial and lifestyle factors as well as pharmacological therapies should be explored to treat anxiety in patients with cirrhosis. None

The purpose of this investigation was to assess the real-life effectiveness of pegylated interferon (peg-IFN) α-2b with ribavirin (RBV) in a cohort of treatment-naïve patients with chronic genotypes 2 (G2) or 3 (G3) hepatitis C virus (HCV) infection. A post-hoc pooled analysis of two Canadian multicenter, observational studies, RediPEN and PoWer, was carried out. A total of 1242 G2- or G3-infected patients were included. The primary outcome was sustained virologic response (SVR). Secondary endpoints included early virologic response (EVR), end-of-treatment (EOT) response, and relapse. Multivariate logistic regression was used to identify independent predictors of treatment response. SVR in G2 and G3 was 74.4 % and 63.6 %, respectively. Relapse occurred in 12.7 % and 19.1 % of G2- and G3-infected patients achieving EOT response, respectively. Overall, G3 was found to independently predict reduced SVR [odds ratio (OR) = 0.20; p = 0.007] and increased relapse (OR = 6.84; p = 0.022). Among G3-infected patients, increasing fibrosis score was the most important factor predicting reduced SVR [F2 vs. F0/F1 (OR = 0.41; p = 0.009); F3 vs. F0/F1 (OR = 0.72; p = 0.338); F4 vs. F0/F1 (OR = 0.27; p = 0.001)]. Male gender (OR = 13.16; p = 0.020) and higher fibrosis score [F2 vs. F0/F1 (OR = 9.72; p = 0.016); F3/F4 vs. F0/F1 (OR = 4.23; p = 0.113)] were associated with increased relapse in G3 patients. These results support the real-life effectiveness of peg-IFN α-2b plus ribavirin in HCV G2- and G3-infected patients. Overall, genotype was identified as the most significant predictor of treatment outcome. Fibrosis score and gender were key outcome predictors in the G3-infected population. In clinical settings, peg-INF/RBV offers an alternative for patients without access to all oral direct-acting antivirals.

BACKGROUND & AIMS:Treatment of hepatitis C virus (HCV) infection with boceprevir, peginterferon, and ribavirin can lead to anemia, which has been managed by reducing ribavirin dose and/or erythropoietin therapy. We assessed the effects of these anemia management strategies on rates of sustained virologic response (SVR) and safety.METHODS:Patients (n = 687) received 4 weeks of peginterferon and ribavirin followed by 24 or 44 weeks of boceprevir (800 mg, 3 times each day) plus peginterferon and ribavirin. Patients who became anemic (levels of hemoglobin approximately ≤10 g/dL) during the study treatment period (n = 500) were assigned to groups that were managed by ribavirin dosage reduction (n = 249) or erythropoietin therapy (n = 251).RESULTS:Rates of SVR were comparable between patients whose anemia was managed by ribavirin dosage reduction (71.5%) vs erythropoietin therapy (70.9%), regardless of the timing of the first intervention to manage anemia or the magnitude of ribavirin dosage reduction. There was a threshold for the effect on rate of SVR: patients who received <50% of the total milligrams of ribavirin assigned by the protocol had a significantly lower rate of SVR (P < .0001) than those who received ≥50%. Among patients who did not develop anemia, the rate of SVR was 40.1%. Eleven thromboembolic adverse events were reported in 9 of 295 patients who received erythropoietin, compared with 1 of 392 patients who did not receive erythropoietin.CONCLUSIONS:Reduction of ribavirin dosage can be the primary approach for management of anemia in patients receiving peginterferon, ribavirin, and boceprevir for HCV infection. Reduction in ribavirin dosage throughout the course of triple therapy does not affect rates of SVR. However, it is important that the patient receives at least 50% of the total amount (milligrams) of ribavirin assigned by response-guided therapy. ClinicalTrials.gov number, NCT01023035.

Boceprevir (BOC) added to peginterferon alfa-2b (PegIFN) and ribavirin (RBV) significantly increases sustained virologic response (SVR) rates over PegIFN/RBV alone in previously untreated adults with chronic hepatitis C genotype 1. We evaluate the relationship of incident anemia with triple therapy. A total of 1,097 patients received a 4-week lead-in of PegIFN/RBV followed by: (1) placebo plus PegIFN/RBV for 44 weeks (PR48); (2) BOC plus PegIFN/RBV using response-guided therapy (BOC/RGT); and (3) BOC plus PegIFN/RBV for 44 weeks (BOC/PR48). The management of anemia (hemoglobin [Hb] <10 g/dL) included RBV dose reduction and/or erythropoietin (EPO) use. A total of 1,080 patients had 1 Hb measurement during treatment. The incidence of anemia was 50% in the BOC arms combined (363/726) and 31% in the PR48 arm (108/354, P < 0.001). Among BOC recipients, lower baseline Hb and creatinine clearance were associated with incident anemia. In the BOC-containing arms, anemia was managed by the site investigators as follows: EPO without RBV dose reduction, 38%; RBV dose reduction without EPO, 8%; EPO with RBV dose reduction, 40%; and neither RBV dose reduction nor EPO, 14%. SVR rates were not significantly affected by management strategy (70%-74%), and overall patients with anemia had higher rates of SVR than those who did not develop anemia (58%). Serious and life-threatening adverse events (AEs) and discontinuations due to AEs among BOC-treated patients did not differ by EPO use. Conclusion: With BOC/PR therapy, SVR rates in patients with incident anemia were higher than nonanemic patients and did not vary significantly according to the investigator-selected approach for anemia management. Prospective studies are needed to confirm this observation. (HEPATOLOGY 2013)

BACKGROUND:Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies.METHODS:We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately.RESULTS:A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively.CONCLUSIONS:The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.).

BACKGROUND: The natural history of pancreatic cystic neoplasms remains poorly understood despite growing evidence on the subject. Pancreatic cysts display a wide spectrum of pathological phenotypes, each associated with a different prognostic implication. Many pancreatic cysts are of undetermined malignant potential at presentation and remain so until surgically resected. While the survival rates of patients with malignant cysts are known to be poor, survival rates in patients with undetermined pancreatic cysts are unknown. OBJECTIVE: To identify the factors associated with survival in a group of patients diagnosed with a pancreatic cyst(s). METHODS: The present study was a retrospective multicentre review of pancreatic cystic neoplasms. All patients with a diagnosis of a neoplastic pancreatic cyst from 1994 to 2003 were identified at five different institutions in Edmonton, Alberta. The data collected included patient age, sex, imaging modality, cyst location, cyst size, number of cysts, comorbid illnesses, history of upper abdominal surgery, previous cancer, previous or concurrent metastases, symptoms (pain, upper gastrointestinal bleeding, signs of biliary obstruction, nausea/vomiting), remarkable radiological features, elevated amylase or lipase, type of pancreatic surgery, final pathology (benign or malignant) and overall survival. Survival models were used to assess whether any covariates were predictors of the survival time. Patient data were plotted using the Kaplan-Meier method. The resulting plot was used to calculate survival in the cohort. RESULTS: In total, 64 patients were identified as having neoplastic pancreatic cysts from 1994 to 2003 at the five institutions. The median overall patient survival time was 86 months. The median age at diagnosis for the patient population was 73 years, with 40 patients being women. Univariate analysis revealed that the risk of death was associated with patient age, sex and history of major comorbid illness. Multivariate models identified increased patient age and male sex as the factors that correlated most strongly with decreased overall survival. CONCLUSION: Overall survival in patients with neoplastic pancreatic cysts is determined by patient factors (ie, age and sex) rather than factors descriptive of the cyst such as size and morphology. No conclusions could be made regarding the relationship between cyst pathology and patient survival.

SummaryBackground Budd–Chiari syndrome carries significant mortality, but factors predicting this outcome are uncertain.Aim To determine factors associated with 3‐month mortality and compare outcomes after surgical shunting or liver transplantation.Methods From 1985 to 2008, 51 patients with Budd–Chiari syndrome were identified.Results By logistic regression analysis, features associated with higher risk of 3‐month mortality were Rotterdam class III, Clichy >6.6, model for end‐stage liver disease (MELD) >20 and Child–Pugh C. Rotterdam class III had the best performance to discriminate 3‐month mortality with sensitivity of 0.89 and specificity of 0.63, whereas Clichy >6.60 had sensitivity of 0.78 and specificity of 0.69; MELD >20 had sensitivity of 0.78 and specificity of 0.75 and Child–Pugh C had sensitivity of 0.67 and specificity of 0.72. Eighteen patients underwent surgical shunts and 14 received liver transplantation with no significant differences in survival (median survival 10 ± 3 vs. 8 ± 2 years; log‐rank, P = 0.9).Conclusions Rotterdam score is the best discrimination index for 3‐month mortality in Budd–Chiari syndrome and should be used preferentially to determine treatment urgency. Surgical shunts constitute an important therapeutic modality that may help save liver grafts and prolong transplantation‐free survival in a selected group of patients with Budd–Chiari syndrome.

SummaryBackground The impact of reduced drug exposure on outcomes in patients with chronic hepatitis C has not been determined in routine clinical practice.Aim To examine the impact of exposure to peginterferon alfa‐2a and ribavirin on early virological response (EVR) and sustained virological response (SVR) in treatment‐naïve patients with HCV genotype 1 infection enrolled in a large expanded access programme.Methods Eight hundred and ninety‐one patients treated for 48 weeks with an initial ribavirin dose of 800 or 1000/1200 mg/day were evaluated. Ribavirin 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg) and peginterferon alfa‐2a 180 μg/week were considered optimal. The impact of reduced drug exposure (expressed as a percentage of optimal) on EVR and SVR was evaluated.Results Mean ribavirin exposure in week 0–12 was 70% and 96% in patients assigned to ribavirin 800 and 1000/1200 mg/day, respectively. EVR and SVR rates were lower in patients assigned to ribavirin 800 than 1000/1200 mg/day (EVR, 75% vs. 84%, respectively, P < 0.001; SVR, 45% vs. 54%, respectively, P = 0.011). Furthermore, there was a strong correlation between achievement of EVR and SVR and ribavirin dose over the first 12 weeks expressed either as absolute dose or proportion of optimal dose received (P < 0.001 for both).Conclusions Ribavirin exposure to week 12 is significantly associated with EVR and SVR in genotype 1 patients. Maintenance of an optimal ribavirin dose is the most important modifiable factor during combination therapy for chronic hepatitis C.