Publications by authors named "Bettina E Hansen"

239 Publications

A Comparison of Prognostic Scores (Mayo, UK-PBC, and GLOBE) in Primary Biliary Cholangitis.

Am J Gastroenterol 2021 May 4. Epub 2021 May 4.

Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands; Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada; Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy; Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany; Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany; Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium; Arizona State University, Phoenix, Arizona, USA; Liver Unit, Hospital Cli[Combining Acute Accent]nic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain; Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy; Department of Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada.

Introduction: Comparative data on scores that predict outcome in primary biliary cholangitis (PBC) are scarce. We aimed to assess and compare the prognostic value of the Mayo Risk Score (MRS, 1989 and 1994), UK-PBC score, and GLOBE score in a large international cohort of patients with PBC.

Methods: Ursodeoxycholic acid-treated patients from 7 centers participating in the GLOBAL PBC Study Group were included. The discriminatory performance of the scores was assessed with concordance statistics at yearly intervals up to 5 years. Model for End-stage Liver Disease was included for comparison. Prediction accuracy was assessed by comparing predicted survival and actual survival in Kaplan-Meier analyses.

Results: A total of 1,100 ursodeoxycholic acid-treated patients with PBC were included, with a mean (SD) age of 53.6 (12.0) years, of whom 1,003 (91%) were female. During a median follow-up of 7.6 (interquartile range 4.1-11.7) years, 42 patients underwent liver transplantation, and 127 patients died. At 1 year, the concordance statistic for Model for End-stage Liver Disease was 0.68 (95% confidence interval [CI] 0.64-0.72), 0.74 (95% CI 0.67-0.80) for the UK-PBC score, 0.76 (95% CI 0.72-0.81) for the MRS (1989 and 1994), and 0.80 (95% CI 0.76-0.84) for the GLOBE score. The GLOBE score showed superior discriminatory performance, but differences were not statistically different. For all scores, discriminatory performance increased in those with bilirubin >0.6 × ULN and advanced fibrosis estimated with Fibrosis-4. The predicted (median) minus observed 5-year transplant-free survival was +0.4% and +2.5% for the MRS (1989) and GLOBE score, respectively.

Discussion: All prognostic scores developed for PBC (GLOBE, UK-PBC, and MRS) demonstrated comparable discriminating performance for liver transplantation or death as well as good prediction accuracy.
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http://dx.doi.org/10.14309/ajg.0000000000001285DOI Listing
May 2021

Association of bezafibrate with transplant-free survival in patients with primary biliary cholangitis.

J Hepatol 2021 Apr 18. Epub 2021 Apr 18.

Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis (MIVB-H), Saint-Antoine Hospital, European Reference (ERN) Network Rare-Liver, Saint-Antoine Research Center (CRSA), Assistance Publique - Hôpitaux de Paris (APHP), Sorbonne University, Paris, France. Electronic address:

Background & Aims: Beneficial effect of bezafibrate (BZF) on symptoms and biochemical features of primary biliary cholangitis (PBC) with incomplete response to ursodeoxycholic acid (UDCA) has been reported but long-term efficacy on survival remains unknown. In Japan, BZF has been used as a de facto second-line therapy for PBC since 2000. Herein, we compared the survival rates between patients treated with and those without BZF in a large nationwide Japanese PBC cohort.

Methods: All consecutively-registered patients of this cohort who started UDCA therapy from 2000 onwards and had a follow-up ≥ 1 year were included. Association between BZF exposure and mortality or need for liver transplantation (LT) was assessed using time-dependent, multivariable-and propensity score-adjusted Cox proportional hazards models. Clinical benefit was quantified using the number needed to treat (NNT).

Results: Of 3908 eligible patients, 3162 (81%) received UDCA only and 746 (19%) UDCA and BZF over 17360 and 3932 patient-years, respectively. During follow-up, 183 deaths (89 liver-related) and 21 L T were registered. Exposure to combination therapy was associated with a significant decrease in all-cause and liver-related mortality or need for LT (adjusted hazard ratios: 0.3253, 95% CI 0.1936 - 0.5466 and 0.2748, 95% CI 0.1336 - 0.5655, respectively; p<0.001 for both). This association was consistent across various risk groups at baseline. The NNTs with combination therapy to prevent one additional death or LT in 5, 10, and 15 years were 29 (95% CI 22 - 46), 14 (10 - 22), and 8 (6 - 15), respectively.

Conclusions: In a large retrospective cohort study of treatment effects in patients with PBC, the addition of BZF to UDCA was associated with improved prognosis.

Lay Summary: The long-term efficacy of bezafibrate (BZF) on liver transplantation (LT) - free survival of patients with PBC with an incomplete response to ursodeoxycholic acid (UDCA) remains to be determined. In this Japanese nationwide retrospective cohort study, the use of UDCA-BZF combination therapy, compared to UDCA alone, was associated with lower risk in all-cause and liver-related mortality or need for LT. These results indicate that BZF is so far the only drug in PBC to have demonstrated efficacy in improving symptoms, biochemical markers, and long-term outcomes.
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http://dx.doi.org/10.1016/j.jhep.2021.04.010DOI Listing
April 2021

Biomarkers of coagulation, endothelial function, and fibrinolysis in critically ill patients with COVID-19: A single-center prospective longitudinal study.

J Thromb Haemost 2021 Apr 7. Epub 2021 Apr 7.

Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada.

Background: Immunothrombosis and coagulopathy in the lung microvasculature may lead to lung injury and disease progression in coronavirus disease 2019 (COVID-19). We aim to identify biomarkers of coagulation, endothelial function, and fibrinolysis that are associated with disease severity and may have prognostic potential.

Methods: We performed a single-center prospective study of 14 adult COVID-19(+) intensive care unit patients who were age- and sex-matched to 14 COVID-19(-) intensive care unit patients, and healthy controls. Daily blood draws, clinical data, and patient characteristics were collected. Baseline values for 10 biomarkers of interest were compared between the three groups, and visualized using Fisher's linear discriminant function. Linear repeated-measures mixed models were used to screen biomarkers for associations with mortality. Selected biomarkers were further explored and entered into an unsupervised longitudinal clustering machine learning algorithm to identify trends and targets that may be used for future predictive modelling efforts.

Results: Elevated D-dimer was the strongest contributor in distinguishing COVID-19 status; however, D-dimer was not associated with survival. Variable selection identified clot lysis time, and antigen levels of soluble thrombomodulin (sTM), plasminogen activator inhibitor-1 (PAI-1), and plasminogen as biomarkers associated with death. Longitudinal multivariate k-means clustering on these biomarkers alone identified two clusters of COVID-19(+) patients: low (30%) and high (100%) mortality groups. Biomarker trajectories that characterized the high mortality cluster were higher clot lysis times (inhibited fibrinolysis), higher sTM and PAI-1 levels, and lower plasminogen levels.

Conclusions: Longitudinal trajectories of clot lysis time, sTM, PAI-1, and plasminogen may have predictive ability for mortality in COVID-19.
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http://dx.doi.org/10.1111/jth.15327DOI Listing
April 2021

Blood Cell Salvage and Autotransfusion Does Not Worsen Oncologic Outcomes Following Liver Transplantation with Incidental Hepatocellular Carcinoma: A Propensity Score-Matched Analysis.

Ann Surg Oncol 2021 Mar 28. Epub 2021 Mar 28.

HBP and Multi Organ Transplant Program, Division of General Surgery, University Health Network, University of Toronto, Toronto, ON, Canada.

Background: Intraoperative blood cell salvage and autotransfusion (IBSA) during liver transplantation (LT) for hepatocellular carcinoma (HCC) is controversial for concern regarding adversely impacting oncologic outcomes.

Objective: We aimed to evaluate the long-term oncologic outcomes of patients who underwent LT with incidentally discovered HCC who received IBSA compared with those who did not receive IBSA.

Methods: Patients undergoing LT (January 2001-October 2018) with incidental HCC on explant pathology were retrospectively identified. A 1:1 propensity score matching (PSM) was performed. HCC recurrence and patient survival were compared. Kaplan-Meier survival analyses were performed, and univariable Cox proportional hazard analyses were performed for risks of recurrence and death.

Results: Overall, 110 patients were identified (IBSA, n = 76 [69.1%]; non-IBSA, n = 34 [30.9%]). Before matching, the groups were similar in terms of demographics, transplant, and tumor characteristics. Overall survival was similar for IBSA and non-IBSA at 1, 3, and 5 years (96.0%, 88.4%, 83.0% vs. 97.1%, 91.1%, 87.8%, respectively; p = 0.79). Similarly, the recurrence rate at 1, 3, and 5 years was not statistically different (IBSA 0%, 1.8%, 1.8% vs. non-IBSA 0%, 3.2%, 3.2%, respectively; p = 0.55). After 1:1 matching (26 IBSA, 26 non-IBSA), Cox proportional hazard analysis demonstrated similar risk of death and recurrence between the groups (IBSA hazard ratio [HR] of death 1.26, 95% confidence interval [CI] 0.52-3.05, p = 0.61; and HR of recurrence 2.64, 95% CI 0.28-25.30, p = 0.40).

Conclusions: IBSA does not appear to adversely impact oncologic outcomes in patients undergoing LT with incidental HCC. This evidence further supports the need for randomized trials evaluating the impact of IBSA use in LT for HCC.
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http://dx.doi.org/10.1245/s10434-021-09863-6DOI Listing
March 2021

Effectiveness and Renal Safety of Tenofovir Alafenamide Fumarate among Chronic Hepatitis B Patients: Real-World Study.

J Viral Hepat 2021 Mar 22. Epub 2021 Mar 22.

Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada.

Tenofovir alafenamide fumarate (TAF) has high plasma stability resulting in fewer renal adverse events compared to tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB) patients. We aimed to study the effectiveness and renal safety of TAF in a real-world setting, in patients with or without compromised kidney function. CHB patients (Nucleos(t)ide Analogue [NA]-naïve or experienced) who received TAF >1 year from 11 academic institutions as part of the Canadian Hepatitis B Network (CanHepB) were included. Kidney function was measured by estimated glomerular filtration rate (eGFR) as per Cockcroft-Gault. Patients were followed for up to 160 weeks. Of 176 patients receiving TAF, 143 switched from NA (88% TDF), and 33(19%) were NA naïve. Majority of NA-naïve patients (75%) achieved undetectable HBV DNA after one year of TAF treatment. Majority of patients with eGFR <60 mL/min who had renal deterioration during TDF (76%) reversed to eGFR increase after one year of TAF (p=0.009). Among patients with stage 2 chronic kidney disease (CKD) (eGFR 60-89), the estimated eGFR decline during TDF was halted after switching to TAF (p=0.09). NA-experienced patients with abnormal ALT before TAF showed a significant decline after switching to TAF: -0.005 [-0.006 - -0.004] log ULN U/L/month, p<0.001). In CHB patients, TAF was safe, well-tolerated and effective in this real-world cohort. Switching to TAF led to improved kidney function, particularly in those with stage 2 CKD, which suggests that the indication for TAF in the guidelines could be extended to patients with an eGFR higher than 60 mL/min.
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http://dx.doi.org/10.1111/jvh.13500DOI Listing
March 2021

Incidence of Hepatitis C Virus Infections Among Users of Human Immunodeficiency Virus Pre-exposure Prophylaxis.

Clin Gastroenterol Hepatol 2021 Mar 16. Epub 2021 Mar 16.

Toronto Centre for Liver Disease. Electronic address:

Background & Aims: Sexual transmission of hepatitis C virus (HCV) is well documented among human immunodeficiency virus (HIV)-uninfected individuals. The use of HIV pre-exposure prophylaxis (PrEP) may be associated with engagement in activities that facilitate the transmission of sexually transmitted infections (STIs) and possibly HCV among PrEP users.

Methods: Between 2012 and 2019, the incidence of HCV and bacterial STIs were calculated among HIV-negative patients receiving PrEP at the University Health Network HIV Prevention Clinic. Mucosal, anal, and blood samples were taken to test for HIV, syphilis, and anti-HCV antibodies.

Results: Among 344 HIV-uninfected patients receiving PrEP, 86% were men having sex with men (MSM). Five individuals were HCV-antibody positive at the time of PrEP initiation. Serologic and virologic follow-up data were available for 109 HCV-negative individuals over 282 patient-years (PY). Two new infections were recorded, yielding an incidence of primary HCV infection of 0.7 per 100 PY. In contrast with HCV, the incidence rates of chlamydia, gonorrhea, and syphilis were 49.2 per 100 PY, 36.3 per 100 PY, and 5.2 per 100 PY, respectively. Both individuals with new HCV diagnoses reported being MSM with a history of unprotected intercourse and 1 individual also reported recreational drug use. Both individuals were asymptomatic at the time of diagnosis and were detected by routine laboratory monitoring.

Conclusions: The low incidence of HCV infections despite significantly higher rates of other STIs suggests that sexual transmission of HCV is uncommon in HIV-negative MSM PrEP users in this community. Performing routine risk-based HCV surveillance among PrEP users should be evaluated. The high incidence of STIs in this population indicates a vital role for periodic STI monitoring in those receiving PrEP.
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http://dx.doi.org/10.1016/j.cgh.2021.03.006DOI Listing
March 2021

Peginterferon lambda for the treatment of outpatients with COVID-19: a phase 2, placebo-controlled randomised trial.

Lancet Respir Med 2021 05 5;9(5):498-510. Epub 2021 Feb 5.

The Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada.

Background: To date, only monoclonal antibodies have been shown to be effective for outpatients with COVID-19. Interferon lambda-1 is a type III interferon involved in innate antiviral responses with activity against respiratory pathogens. We aimed to investigate the safety and efficacy of peginterferon lambda in the treatment of outpatients with mild-to-moderate COVID-19.

Methods: In this double-blind, placebo-controlled trial, outpatients with laboratory-confirmed COVID-19 were randomly assigned to a single subcutaneous injection of peginterferon lambda 180 μg or placebo within 7 days of symptom onset or first positive swab if asymptomatic. Participants were randomly assigned (1:1) using a computer-generated randomisation list created with a randomisation schedule in blocks of four. At the time of administration, study nurses received a sealed opaque envelope with the treatment allocation number. The primary endpoint was the proportion of patients who were negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA on day 7 after the injection, analysed by a χ test following an intention-to-treat principle. Prespecified analysis of the primary endpoint, adjusted for baseline viral load, using bivariate logistic regression was done. The trial is now complete. This trial is registered with ClinicalTrials.gov, NCT04354259.

Findings: Between May 18, and Sept 4, 2020, we recruited 30 patients per group. The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon lambda than placebo from day 3 onwards, with a difference of 2·42 log copies per mL at day 7 (p=0·0041). By day 7, 24 (80%) participants in the peginterferon lambda group had an undetectable viral load, compared with 19 (63%) in the placebo group (p=0·15). After controlling for baseline viral load, patients in the peginterferon lambda group were more likely to have undetectable virus by day 7 than were those in the placebo group (odds ratio [OR] 4·12 [95% CI 1·15-16·73; p=0·029). Of those with baseline viral load above 10 copies per mL, 15 (79%) of 19 patients in the peginterferon lambda group had undetectable virus on day 7, compared with six (38%) of 16 in the placebo group (OR 6·25 [95% CI 1·49-31·06]; p=0·012). Peginterferon lambda was well tolerated, and adverse events were similar between groups with mild and transient aminotransferase, concentration increases more frequently observed in the peginterferon lambda group. Two individuals met the threshold of grade 3 increase, one in each group, and no other grade 3 or 4 laboratory adverse events were reported.

Interpretation: Peginterferon lambda accelerated viral decline in outpatients with COVID-19, increasing the proportion of patients with viral clearance by day 7, particularly in those with high baseline viral load. Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding.

Funding: The Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.
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http://dx.doi.org/10.1016/S2213-2600(20)30566-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906707PMC
May 2021

Simplified care-pathway selection for nonspecialist practice: the GLOBAL Primary Biliary Cholangitis Study Group Age, Bilirubin, Alkaline phosphatase risk assessment tool.

Eur J Gastroenterol Hepatol 2020 Dec 14. Epub 2020 Dec 14.

Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.

Background: Opportunity to redefine the care journeys for those living with primary biliary cholangitis (PBC) includes facilitating access to enhanced (PBC-dedicated) programmes by nonspecialist risk 'flagging' of patients.

Objective: To develop a nonexpert PBC stratification tool to help care pathway choices (standard vs. enhanced) choices in PBC.

Methods: We included ursodeoxycholic acid-treated patients with PBC from the Global PBC Study Group. The performance of baseline and 1-year clinical markers with transplant-free survival was assessed to develop the 'ABA' tool using Age (A), Bilirubin (B), and Alkaline phosphatase (A). Added value of fibrosis estimation was assessed.

Results: 'ABA' classification mapped three risk groups (n = 2226): low [Age > 50 years, bilirubin ≤ 1 × ULN, alkaline phosphatase (ALP) ≤ 3 × ULN], high (Age ≤ 50 years, bilirubin > 1 × ULN, ALP > 3 × ULN), and intermediate (other). Transplant-free survival at 10 years in the low-, intermediate-, and high-risk groups were 89, 77, and 59% at baseline and 86, 76, and 40% at 1 year, respectively. We propose that high-risk patients at baseline be directly triaged to enhanced (PBC-dedicated) care and the remaining be reassessed at 1 year. Modelling showed after 1 year 46% patients were proposed to enhanced care and 54% to standard care. The 'ABA' mapped pathways facilitated identification of patients at risk based on a young age, as compared to traditional liver biochemical stratification. In patients proposed to standard care, estimated fibrosis stage had ongoing prognostic value.

Conclusion: Nonspecialist use of the 'ABA' risk tool could prioritize care journey choices for patients with PBC.
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http://dx.doi.org/10.1097/MEG.0000000000002029DOI Listing
December 2020

Obeticholic acid is associated with improvements in AST-to-platelet ratio index and GLOBE score in patients with primary biliary cholangitis.

JHEP Rep 2021 Feb 29;3(1):100191. Epub 2020 Sep 29.

Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, ON, Canada.

Background & Aims: Biochemical markers, including GLOBE score and aspartate aminotransferase-to-platelet ratio index (APRI), are used to stratify risk in patients with primary biliary cholangitis (PBC). This study aimed to evaluate the effects of obeticholic acid (OCA) on categorical shifts in GLOBE score, APRI, and both combined, based on data from POISE, a phase III placebo-controlled trial in patients with PBC who had an incomplete response or were intolerant to ursodeoxycholic acid.

Methods: In a analysis, baseline and Month 12 data from POISE were used to calculate the APRI and GLOBE score. Patients were stratified into 3 risk groups based on a combination of APRI (0.54) and GLOBE (0.3 or age-specific) thresholds.

Results: The analysis included 215 patients (47 low risk; 79 moderate risk; 89 high risk). Using the combined GLOBE score (threshold of 0.3) and APRI thresholds, there was improvement in ≥1 risk stage in 37% and 35% of patients in the OCA 5-10 mg and 10 mg groups, respectively, 12% in the placebo group (both <0.05). Progression occurred in 10% and 0% in the 5-10 mg and 10 mg groups 37% in the placebo group. Results with GLOBE age-specific thresholds were similar.

Conclusions: Based on change in APRI and GLOBE score at 12 months, OCA treatment is associated with reduction in the predicted risk of liver-related complications in patients with PBC.

Lay Summary: Primary biliary cholangitis (PBC) is a chronic disease affecting the liver. People who suffer from PBC are at risk of serious long-term complications. Information from certain blood tests can be used to estimate the likelihood of experiencing long-term complications. The results of this study showed that based on blood test results, people taking obeticholic acid, with or without ursodeoxycholic acid, for PBC were predicted to have a better outcome than those taking placebo.

Clinical Trials Registration: NCT01473524.
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http://dx.doi.org/10.1016/j.jhepr.2020.100191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724188PMC
February 2021

Clinical outcomes following DAA therapy in patients with HCV-related cirrhosis depend on disease severity.

J Hepatol 2021 May 23;74(5):1053-1063. Epub 2020 Nov 23.

Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands. Electronic address:

Background & Aims: HCV-infected patients with cirrhosis achieve high sustained virological response (SVR) rates with direct-acting antivirals (DAAs) even after hepatic decompensation. We aimed to assess the clinical outcome following DAAs among patients with compensated and decompensated cirrhosis in relation to SVR and changes in model for end-stage liver disease (MELD) score.

Methods: Consecutive DAA-treated chronic HCV-infected patients with cirrhosis from 4 hepatology clinics were included. The primary endpoint in survival analyses was clinical disease progression, defined as liver failure, hepatocellular carcinoma, liver transplantation or death.

Results: In total, 868 patients were included with a median age of 59 (IQR 54-65) years; 719 (83%) with Child-Pugh A cirrhosis and 149 (17%) with Child-Pugh B/C cirrhosis. SVR was attained by 647 (90%) Child-Pugh A patients and 120 (81%) Child-Pugh B/C patients. During a median follow-up of 28 (IQR 20-36) months, 102 (14%) Child-Pugh A patients and 96 (64%) Child-Pugh B/C patients experienced clinical disease progression. SVR was independently associated with an improved event-free survival in patients with Child-Pugh A cirrhosis (adjusted hazard ratio [HR] 0.47; 95% CI 0.27-0.82, p = 0.007), but not in patients with Child-Pugh B/C cirrhosis (adjusted HR 1.23; 95% CI 0.67-2.26; p = 0.51). Twelve weeks post-DAAs, 28 (19%) patients with Child-Pugh B/C cirrhosis had ≥2-point MELD decline, but their 2-year event-free survival did not differ from those with a stable MELD (47.9%; 95% CI 28.7-67.1 vs. 48.9%; 95% CI 38.1-59.7, respectively, p = 0.99).

Conclusions: Among patients with chronic HCV infection, DAA-induced SVR was associated with a reduced risk of clinical disease progression in patients with Child-Pugh A cirrhosis but not in patients with Child-Pugh B/C cirrhosis. In Child-Pugh B/C cirrhosis, a ≥2-point MELD decline did not translate into improved clinical outcome.

Lay Summary: Chronic HCV infection can be cured with antiviral therapy. In this study, we evaluated the long-term effects of antiviral therapy on liver-related complications in patients with cirrhosis. Our results suggest that patients with compensated cirrhosis who were cured of their HCV infection have a lower rate of complications. In contrast, the rate of complications was not related to virological cure among those with decompensated cirrhosis. While these patients seem to remain in need of liver transplantation, antiviral therapy may lower their priority on the liver transplantation waiting list.
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http://dx.doi.org/10.1016/j.jhep.2020.11.021DOI Listing
May 2021

Hepatitis B virus RNA decline without concomitant viral antigen decrease is associated with a low probability of sustained response and hepatitis B surface antigen loss.

Aliment Pharmacol Ther 2021 01 21;53(2):314-320. Epub 2020 Nov 21.

Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

Background: Serum hepatitis B virus (HBV) RNA may reflect intrahepatic HBV replication. Novel anti-viral drugs have shown potent HBV RNA decline without concomitant hepatitis B surface antigen (HBsAg) decrease. How this relates to off-treatment response is yet unclear.

Aim: To study the degree of on-treatment viral antigen decline among patients with pronounced HBV RNA decrease in relation to off-treatment sustained response and HBsAg loss.

Methods: HBV RNA, HBsAg and hepatitis B core-related antigen (HBcrAg) were quantified in patients with chronic hepatitis B who participated in two randomised controlled trials of peginterferon-based therapy. Sustained response (HBV DNA <2000 IU/mL) and/or HBsAg loss were assessed in patients with and without on-treatment HBV RNA response (either >2 log HBV RNA decline or >1 log decline resulting in an undetectable value at on-treatment week 24), stratified by concomitant HBsAg decline (<0.5/0.5-1/>1 log).

Results: We enrolled 279 patients; 176 were hepatitis B e antigen (HBeAg)-positive, and 103 were HBeAg-negative. Sustained response was achieved in 20.4% of patients. At on-treatment week 24, HBV RNA response was associated with higher sustained response rates (27.4% vs 13.0% in non-responders, P =  0.004). However, among patients with an HBV RNA response (n = 135), 56.4% did not experience >0.5 log HBsAg decline. Among HBV RNA responders, sustained response was achieved in 47.6% of those with >1 log HBsAg decline (n = 20/42), vs 16.0% with <0.5 log decline (n = 12/75, P = 0.001). Similar results were obtained with HBcrAg and when response was defined as HBsAg loss.

Conclusions: In this cohort, many patients with HBV RNA response during peginterferon-based treatment did not experience HBsAg and/or HBcrAg decline. The absence of concomitant decline in these viral antigens was associated with low rates of treatment response and HBsAg loss. Future trials should therefore consider kinetics of combined biomarkers to assess anti-viral efficacy. Trial registration, ClinicalTrials.gov: NCT00114361, NCT00146705.
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http://dx.doi.org/10.1111/apt.16172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839551PMC
January 2021

Identification of prosthetic hip and knee joint infections using administrative databases-A validation study.

Infect Control Hosp Epidemiol 2021 Mar 30;42(3):325-330. Epub 2020 Sep 30.

Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada.

Objective: To determine whether combinations of diagnosis and procedures codes can improve the detection of prosthetic hip and knee joint infections from administrative databases.

Design: We performed a validation study of all readmissions from January 1, 2010, until December 31, 2016, following primary arthroplasty comparing the diagnosis and procedure codes obtained from an administrative database based upon the International Classification of Disease, Tenth Revision (ICD-10) to the reference standard of chart review.

Setting: Four tertiary-care hospitals in Toronto, Canada, from 2010 to 2016.

Participants: Individuals who had a primary arthroplasty were identified using procedure codes.

Intervention: Chart review of readmissions identified the presence of a prosthetic joint infection and, if present, the surgical procedure performed.

Results: Overall, 27,802 primary arthroplasties were performed. Among 8,844 readmissions over a median follow-up of 669 days (interquartile range, 256-1,249 days), a PJI was responsible for or present in 586 of 8,844 (6.6%). Diagnosis codes alone exhibited a sensitivity of 0.88 (95% CI, 0.85-0.92) and positive predictive value (PPV) of 0.78 (95% CI, 0.74-0.82) for detecting a PJI. Combining a PJI diagnosis code with procedure codes for an arthroplasty and the insertion of a peripherally inserted central catheter improved detection: sensitivity was 0.92 (95% CI, 0.88-0.94) and PPV was 0.78 (95% CI, 0.74-0.82). However, procedure codes were unable to identify the specific surgical approach to PJI treatment.

Conclusions: Compared to PJI diagnosis codes, combinations of diagnosis and procedure codes improve the detection of a PJI in administrative databases.
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http://dx.doi.org/10.1017/ice.2020.449DOI Listing
March 2021

Real-World Effectiveness of Obeticholic Acid in Patients with Primary Biliary Cholangitis.

Hepatol Commun 2020 Sep 6;4(9):1332-1345. Epub 2020 Jul 6.

Toronto Centre for Liver Disease Toronto General Hospital University Health Network Toronto ON Canada.

Patients with primary biliary cholangitis (PBC) with incomplete response to ursodeoxycholic acid are at risk of disease progression and need additional therapy. Obeticholic acid (OCA) was approved in Canada in May 2017, but its effectiveness in a real-world setting has not been described. We sought to describe our experience with OCA in a Canadian cohort. OCA-naive patients treated at two Canadian centers were included. Clinical and biochemical data were collected at OCA initiation and during follow-up. Primary outcomes were changes in serum alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and total bilirubin (TB) over the duration of therapy. Secondary outcomes were changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), immunoglobulin M (IgM), platelets, and albumin; and achievement of the primary endpoint of the original phase 3 study that led to OCA approval (A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis [POISE]), dose reductions, discontinuations, and tolerability. Repeated-measures models were used to assess changes in biochemistry over time. Sixty-four patients were included; 4 carried a diagnosis of overlap with autoimmune hepatitis. Mean age was 54.6 years, median ALP was 250 U/L, TB was 13 µmol/L, platelet count was 225 × 10/L, and 24% had liver stiffness measurements ≥16.9 kPa. There was a significant reduction in mean ALP of 55 U/L ( < 0.001), GGT of 138 U/L ( < 0.001), ALT of 11.9 U/L ( < 0.001), AST of 5.7 U/L ( < 0.05), and IgM of 0.70 g/L ( < 0.001) over 12 months; TB remained stable ( = 0.98). Forty-four patients met POISE-inclusion criteria, 39% (n = 17) of whom had 12-month biochemical measurements. In this subset, 18% (n = 3/17) met the 12-month POISE primary endpoint, but considering follow-up to 19 months, 43% achieved this target (n = 9/21). Pruritus was the most commonly reported complaint. : Use of OCA was associated with improvement in biochemical surrogates of outcome in PBC in a real-world setting.
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http://dx.doi.org/10.1002/hep4.1518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471421PMC
September 2020

Maintained virological suppression and renal function with reduced dose tenofovir disoproxil fumarate in renally impaired chronic hepatitis B patients.

J Viral Hepat 2021 01 4;28(1):51-60. Epub 2020 Oct 4.

Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, ON, Canada.

Tenofovir disoproxil fumarate (TDF) effectively suppresses viral replication in chronic hepatitis B (CHB), but occasionally leads to renal impairment. We evaluated the prevalence of viral and biochemical breakthrough and renal function kinetics in renally impaired patients with CHB on reduced and on full-dose TDF. This clinic-based longitudinal cohort study included patients receiving full and reduced dose TDF (due to eGFR [Cockcroft-Gault] <60 mL/min/1.73 m ). Viral and biochemical breakthroughs were assessed 1 month after starting full and reduced TDF dose until the end-of-follow-up. Breakthroughs were studied in full and reduced dose TDF, and renal function (MDRD) longitudinally before and after dose reduction within patients starting on full-dose TDF. Of 750 patients on TDF, 78 (10%) had reduced dose and 672 (90%) full dose. At the time of dose reduction, 36 (46%) patients had chronic kidney disease stage G3B. A viral breakthrough occurred in one cirrhotic dialysis-dependent patient (dosed 300 mg weekly) which resolved without signs of decompensation, and in one patient on full dose which resolved spontaneously. One biochemical breakthrough occurred during dose reduction and resolved naturally without viral breakthrough. The MDRD improved within the first year of dose reduction (+3.0 [2.5] mL/min per year; P < .005) and remained stable thereafter. Fifty-three (79%) patients reached an MDRD >50 mL/min during dose reduction. Low dose TDF maintains renal function and viral suppression in most renally impaired patients with CHB, even in those with advanced liver disease. This useful, yet simple strategy could be particularly viable in resource-constrained settings.
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http://dx.doi.org/10.1111/jvh.13401DOI Listing
January 2021

Ultra-Long-term Follow-up of Interferon Alfa Treatment for HBeAg-Positive Chronic Hepatitis B Virus Infection.

Clin Gastroenterol Hepatol 2020 Sep 3. Epub 2020 Sep 3.

Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada. Electronic address:

Background And Aims: Interferon-alpha (IFN-α) treatment for chronic hepatitis B (CHB) virus infection is finite and leads to relatively higher functional cure rates (HBsAg loss) than nucleo(s)tide analogue (NA) therapy. Effects of pegylated (PEG)/conventional IFN-α treatment on clinical outcomes were evaluated in an ultra-long-term follow-up of CHB patients.

Methods: HBeAg-positive patients treated with (PEG)IFN-α at a tertiary referral centre between 1977-2014 were included. We reviewed medical charts and consulted the municipal registry for patient information. Patients were invited for a single visit at the outpatient clinic in the case of missing follow-up data. The endpoints included serum HBeAg/HBsAg loss and incidence of clinical events, using life table methods and person-years to analyze the incidence of events. Patients were censored upon retreatment.

Results: The study cohort included 267 patients, 67% male, 58% Caucasian, with a median age of 32 years. The median follow-up duration was 11.5 years. The 5 and 10-year cumulative incidence of HBsAg loss were 14% and 32%, respectively. Baseline factors associated with a higher rate of HBsAg loss were male sex, Caucasian race, genotype A, age ≥40 years, and cirrhosis. HBsAg loss rates did not differ significantly between those who received short-term (≤24 weeks) vs long-term (>24 weeks) therapy. Both HBeAg and HBsAg loss were significantly associated with improved clinical outcomes. Early response (HBeAg loss) was associated with more HBsAg loss and better patient outcomes.

Conclusions: During long-term follow-up, high rates of HBsAg loss were observed from a single (PEG)IFN-α course. Its persistent effects suggest that a role for IFN-α remains, potentially in novel combination therapies in search of a functional cure.
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http://dx.doi.org/10.1016/j.cgh.2020.09.004DOI Listing
September 2020

Very low probability of significant liver inflammation in chronic hepatitis B patients with low ALT levels in the absence of liver fibrosis.

Aliment Pharmacol Ther 2020 10 4;52(8):1399-1406. Epub 2020 Sep 4.

Rotterdam, The Netherlands.

Background: Guidelines recommend liver biopsy to rule out significant inflammatory activity in chronic hepatitis B (CHB) patients with elevated hepatitis B virus (HBV) DNA but without other indications for treatment.

Aim: To study rates and determinants of clinically significant liver inflammation.

Methods: We selected patients with HBV DNA > 2000 IU/mL from the SONIC-B database. The presence of significant inflammation (METAVIR ≥ A2 or HAI ≥ 9) was assessed by liver biopsy and correlated with alanine aminotransferase (ALT) levels (according to AASLD upper limits of normal [ULN]) and stratified by the presence of significant liver fibrosis (Ishak ≥ 3 or METAVIR ≥ F2).

Results: The cohort included 2991 patients; 1672 were HBeAg-positive. ALT was < ULN in 270 (9%), 1-2 times ULN in 852 (29%) and > 2 times ULN in 1869 (63%). Significant fibrosis was found in 1419 (47%) and significant inflammatory activity in 630 (21%). Significant inflammatory activity was found in 34% of patients with liver fibrosis, compared to 9.5% of those without (P < 0.001). Among patients without fibrosis, significant inflammatory activity was detected in 3.6% of those with normal ALT, 5.0% of those with ALT 1-2 times ULN and in 13% of those with ALT > 2 times ULN (P < 0.001). ALT < 2 times ULN had a negative predictive value of 95% for ruling out significant inflammatory activity among patients without liver fibrosis.

Conclusions: Among patients without significant fibrosis, an ALT level < 2 times ULN is associated with < 5% probability of significant inflammatory activity. If fibrosis can be ruled out using non-invasive methods, liver biopsy solely to assess inflammatory activity should be discouraged.
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http://dx.doi.org/10.1111/apt.16067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540526PMC
October 2020

Novel biomarker for hepatocellular carcinoma: high tumoral PLK-4 expression is associated with better prognosis in patients without microvascular invasion.

HPB (Oxford) 2021 Mar 12;23(3):359-366. Epub 2020 Aug 12.

Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Division of General Surgery, University Health Network, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background: Hepatocellular carcinoma (HCC) recurrence after liver resection (LR) adversely affects prognosis but is difficult to predict. Aberrant expression of Polo-Like Kinase 4 (PLK-4) is implicated in several adult malignancies. We sought to evaluate the prognostic value of PLK-4 expression in HCC after curative-intent LR.

Methods: Patients undergoing LR for HCC between July-2015 and November-2017 at our centre were retrospectively identified. PLK-4 expression was measured in tumour and adjacent non-tumour liver tissue using quantitative RT-PCR. Disease-free survival (DFS) was evaluated by Kaplan-Meier and Cox proportional hazard models.

Results: A total of 145 patients were identified. Patients were divided according to PLK-4 expression (high: n = 58, low: n = 87) by generating a receiver operating characteristic curve for recurrence with an area under the curve of 0.72 (95% CI: 0.6-0.8). Recurrence and death rates were similar between groups. In patients without mVI, low PLK-4 expression was associated with worse actuarial DFS (low 1-, 3-, 5-year 83%, 60%, 47% vs. high 91%, 81%, 81%; p = 0.02). In patients without mVI, high PLK-4 expression was an independent predictor of survival (HR 0.3, 95% CI: 0.1-1.0; p = 0.04).

Conclusion: PLK-4 represents a biomarker for good prognosis in patients with HCC who do not have mVI. This could aid clinical decision making for adjuvant clinical trials.
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http://dx.doi.org/10.1016/j.hpb.2020.07.003DOI Listing
March 2021

Measurement of Gamma Glutamyl Transferase to Determine Risk of Liver Transplantation or Death in Patients With Primary Biliary Cholangitis.

Clin Gastroenterol Hepatol 2020 Aug 7. Epub 2020 Aug 7.

Bicocca Bioinformatics Biostatistics and Bioimaging Centre - B4, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.

Background & Aims: Gamma-glutamyltransferase (GGT) is a serum marker of cholestasis. We investigated whether serum level of GGT is a prognostic marker for patients with primary biliary cholangitis (PBC).

Methods: We analyzed data from patients with PBC from the Global PBC Study Group, comprising 14 centers in Europe and North America. We obtained measurements of serum GGT at baseline and time points after treatment. We used Cox model hazard ratios to evaluate the association between GGT and clinical outcomes, including liver transplantation and liver-related death.

Results: Of the 2129 patients included in our analysis, 281 (13%) had a liver-related clinical endpoint. Mean age at diagnosis was 53 years and 91% of patients were female patients. We found a correlation between serum levels of GGT and alkaline phosphatase (ALP) (r = 0.71). Based on data collected at baseline and yearly for up to 5 years, higher serum levels of GGT were associated with lower hazard for transplant-free survival. Serum level of GGT at 12 months after treatment higher than 3.2-fold the upper limit of normal (ULN) identified patients who required liver transplantation or with liver-related death at 10 years with an area under the receiver operating characteristic curve of 0.70. The risk of liver transplantation or liver-related death in patients with serum level of GGT above 3.2-fold the ULN, despite level of ALP lower than 1.5-fold the ULN, was higher compared to patients with level of GGT lower than 3.2-fold the ULN and level of ALP lower than 1.5-fold the ULN (P < .05). Including information on level of GGT increased the prognostic value of the Globe score.

Conclusions: Serum level of GGT can be used to identify patients with PBC at risk for liver transplantation or death, and increase the prognostic value of ALP measurement. Our findings support the use of GGT as primary clinical endpoint in clinical trials. In patients with low serum level of ALP, a high level of GGT identifies those who might require treatment of metabolic disorders or PBC treatment escalation.
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http://dx.doi.org/10.1016/j.cgh.2020.08.006DOI Listing
August 2020

Reducing Read Time of Point-of-Care Test Does Not Affect Detection of Hepatitis C Virus and Reduces Need for Reflex RNA.

Clin Gastroenterol Hepatol 2020 Aug 4. Epub 2020 Aug 4.

Viral Hepatitis Care Network (VIRCAN), Toronto, Ontario, Canada; Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background & Aims: Global elimination of hepatitis C virus (HCV) will require increases in diagnosis. Point of care (POC) tests that detect antibodies against HCV can be useful for testing large and difficult to reach populations. The most accurate POC test requires a 20 min read time to identify antibody-positive samples. We investigated whether viremic patients could be identified using a shorter read time, to increase efficiency and reduce the need for reflex tests (a follow-up test for HCV RNA on the same specimen, to confirm viremia).

Methods: Patients with past or current HCV infections provided samples at 2 clinics in Canada for evaluation by the OraQuick HCV Rapid antibody POC test. A community HCV-screening program in Madrid, Spain (real-world cohort) invited people to be tested for HCV with the same OraQuick test. Patients provided samples of whole blood, via finger prick. Fingerprick samples were tested immediately after collection. In the clinical cohort, photographs of the developing test were taken at 15 second intervals, and blinded readers recorded the time to positivity. In the real-world cohort, readers recorded the OraQuick result each minute, from 5-10 minutes and then again at 20 minutes; viremia was then evaluated using a POC HCV RNA test (GeneXpert HCV Viral Load Assay). Sera from viremic and non-viremic clinic patients were used to quantify antibody titers to investigate the relationship between the time of band appearance and antibody concentration. Fisher's exact test and exact logistic regression were used to determine factors associated with a positive result at 5 minutes.

Results: Blood from all viremic patients produced a positive result in the antibody POC test by 5 min. Median time to a positive result for 171 viremic patients was 2.6 min (range, 1.8-4.6 min), vs 4.1 min (range, 2.3-14.4 min) for 108 patients with resolved infection (P < .001). The 5-min threshold identified all viremic cases among 176 HCV antibody-positive patients in the real-world cohort, confirmed by the test for HCV RNA. In the pooled cohorts, antibody positivity at 5 min identified viremic patients with 100% sensitivity (95% CI, 98.4%-100%); the negative predictive value was 100% (95% CI, 94.9%-100%). The positive predictive value at 5 min was 62.0% (95% CI, 56.7%-67.0%) and therefore insufficient alone to detect viremia; an HCV RNA test would still be necessary to confirm active infection.

Conclusions: The wait time for the OraQuick HCV Rapid antibody POC blood test can be reduced from 20 min to 5 min and continue to reliably identify patients with HCV infection. Shortening the test time could increase high-throughput screening, reduce loss to follow up, and reduce the need for reflex HCV RNA testing.
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http://dx.doi.org/10.1016/j.cgh.2020.07.058DOI Listing
August 2020

Spontaneous Clearance After Relapse Following Direct-Acting Antiviral Treatment for Chronic HCV Infection.

Clin Gastroenterol Hepatol 2020 Jul 3. Epub 2020 Jul 3.

Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; Toronto Viral Hepatitis Care Network, Toronto, Ontario, Canada. Electronic address:

Background & Aims: Direct-acting antivirals (DAAs) cure most cases of chronic hepatitis C virus (HCV) infections. However, a small percentage of patients relapse with reappearance of viremia after a full course of therapy. Although most who relapse require retreatment, some patients spontaneously clear HCV without additional therapy. We studied patients who relapsed with detectable HCV RNA after a full course of DAA therapy and then spontaneously cleared the HCV infection without retreatment.

Methods: We performed a case-control study of patients who spontaneously cleared chronic HCV infection following a documented relapse after DAA therapy at the Toronto Centre for Liver Disease, from January 2014 through December 2017. We collected clinical information at baseline, 12 weeks after treatment, and 6 months after relapse and compared data among spontaneous clearers, patients with persistent relapse, and patients who achieved a sustained virologic response to therapy 12 weeks after treatment (SVR12). The strength and breadth interferon gamma cytokine secretion by HCV-specific T cells from peripheral blood were quantified using the ELISPOT assay.

Results: Of the 1032 individuals with chronic HCV infection who were treated with DAAs, 93 patients had a documented relapse. Of these patients, 12 patients (13%) spontaneously cleared HCV within 6 months after the documented relapse without additional therapy. The spontaneous clearers had low levels of HCV RNA (<4 log IU/mL in 11 of 12) and normal levels of alanine aminotransferase at the time of relapse, much like patients with an SVR12. There was no significant difference between the spontaneous clearance group and the SVR12 group in magnitude and breadth of HCV-specific T cell responses.

Conclusions: In a case-control study of patients who spontaneously cleared chronic HCV infection following a relapse after DAA therapy, we found that it is important to confirm viremia prior to retreatment after the relapse-particularly for individuals with low levels of HCV RNA and normal or near-normal levels of alanine aminotransferase after treatment.
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http://dx.doi.org/10.1016/j.cgh.2020.06.061DOI Listing
July 2020

Goals of Treatment for Improved Survival in Primary Biliary Cholangitis: Treatment Target Should Be Bilirubin Within the Normal Range and Normalization of Alkaline Phosphatase.

Am J Gastroenterol 2020 07;115(7):1066-1074

Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.

Introduction: In primary biliary cholangitis (PBC), bilirubin and alkaline phosphatase (ALP) are widely established as independent predictors of prognosis. Current treatment goals do not aim for normalization of surrogate markers because their association with survival has not been defined.

Methods: The patient cohort from the GLOBAL PBC Study Group was used, comprising of long-term follow-up data from European and North American centers. Ursodeoxycholic acid-treated and untreated patients with bilirubin levels ≤1 × upper limit of normal (ULN) at baseline or 1 year were included. The association of normal ALP with transplant-free survival was assessed in a subgroup with ALP ≤1.67 × ULN at 1 year. Optimal thresholds of bilirubin and ALP to predict liver transplantation (LT) or death were evaluated.

Results: There were 2,281 patients included in the time zero cohort and 2,555 patients in the 1-year cohort. The bilirubin threshold with the highest ability to predict LT or death at 1 year was 0.6 × ULN (hazard ratio 2.12, 95% CI 1.69-2.66, P < 0.001). The 10-year survival rates of patients with bilirubin ≤0.6 × ULN and >0.6 × ULN were 91.3% and 79.2%, respectively (P < 0.001). The risk for LT or death was stable below the bilirubin levels of 0.6 × ULN, yet increased beyond this threshold. Ursodeoxycholic acid-induced reduction in bilirubin below this threshold was associated with an 11% improvement in 10-year survival. Furthermore, ALP normalization was optimal, with 10-year survival rates of 93.2% in patients with ALP ≤ 1 × ULN and 86.1% in those with ALP 1.0-1.67 × ULN.

Discussion: Attaining bilirubin levels ≤0.6 × ULN or normal ALP are associated with the lowest risk for LT or death in patients with PBC. This has important implications for treatment targets.
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http://dx.doi.org/10.14309/ajg.0000000000000557DOI Listing
July 2020

Similar risk of hepatocellular carcinoma during long-term entecavir or tenofovir therapy in Caucasian patients with chronic hepatitis B.

J Hepatol 2020 11 16;73(5):1037-1045. Epub 2020 Jun 16.

Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

Background & Aims: A recent study in Asian patients with chronic hepatitis B (CHB) reported that the incidence of hepatocellular carcinoma (HCC) was lower in patients treated with tenofovir disoproxil fumarate (TDF) than entecavir (ETV), but this finding remains controversial. We aimed to identify any differences in HCC incidence, or other patient outcomes, between patients receiving TDF or ETV in the well monitored, multicenter European PAGE-B cohort.

Methods: We included 1,935 Caucasians with CHB, with or without compensated cirrhosis, treated with ETV (n = 772) or TDF (n = 1,163) monotherapy. Mean follow-up was 7.1 ± 3.0 years from ETV/TDF onset.

Results: The 5-year cumulative HCC incidence was 5.4% in ETV- and 6.0% in TDF-treated patients (log-rank, p = 0.321), with no significant difference in any patient subgroup (with or without cirrhosis, naïve or experienced to oral antiviral(s) [total, with or without cirrhosis]). In multivariable Cox regression analyses, the hazard of HCC was similar between ETV- and TDF-treated patients after adjustment for several HCC risk factors. ETV- and TDF-treated patients had similar rates of on-therapy biochemical and virological remission, HBsAg loss, liver transplantation and/or death. Elastographic reversion of cirrhosis at year 5 (liver stiffness <12 kPa) was observed in 245/347 (70.6%) patients with pretreatment cirrhosis, being more frequent in TDF- than ETV- treated patients (73.8% vs. 61.5%, p = 0.038).

Conclusion: In Caucasian patients with CHB, with or without cirrhosis, long-term ETV or TDF monotherapy is associated with similar HCC risk, rates of biochemical/virological remission, HBsAg loss and liver transplantation or death, but elastographic reversion of cirrhosis at year 5 was more frequent with TDF.

Lay Summary: In a large cohort of Caucasians with chronic hepatitis B treated with entecavir (ETV) or tenofovir disoproxil fumarate (TDF) monotherapy, cumulative rates of hepatocellular carcinoma did not differ (up to 12 years). Nor did rates of biochemical/virological remission, HBsAg loss and liver transplantation or death. However, elastographic reversion of cirrhosis at year 5 was more frequent in TDF- than ETV-treated patients with pretreatment cirrhosis.
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http://dx.doi.org/10.1016/j.jhep.2020.06.011DOI Listing
November 2020

Pediatric Wilson Disease Presenting as Acute Liver Failure: An Individual Patient Data Meta-analysis.

J Pediatr Gastroenterol Nutr 2020 09;71(3):e90-e96

Division of Gastroenterology, Hepatology, and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Canada.

Objectives: Wilson disease (WD) presenting as acute liver failure (ALF) is rare and typically fatal without liver transplantation (LT). Its rarity has hindered comprehensive studies. We undertook an individual patient data meta-analysis to characterize a cohort of pediatric patients presenting with ALF whose final diagnosis was WD to examine outcomes and identify predictors of poor outcomes.

Methods: Database searches were conducted in PubMed, ScienceDirect, and Google Scholar, restricted to English-language articles published between January 1984 and May 2018. Articles were excluded if pediatric (<18 years old) data were not extractable or if LT was not readily available at reporting institutions. Extracted data included clinical and biochemical characteristics, genotype, treatment, and outcome.

Results: Data were available on 249 subjects from 52 articles, plus 7 additional subjects identified from our institution's WD database (N = 256). Females represented 69% (n = 170/245). Median age at presentation was 13.4 years (n = 204, range 4.0-17.9). Of the total 256 subjects, 87% underwent LT, 11% achieved spontaneous recovery and 2% died before LT. International normalized ratio >2.0 at presentation was a predictor of LT/death (odds ratio 7.6, 95% confidence interval 1.5-28), with a trend observed for hepatic encephalopathy (HE) (odds ratio 4.18, 95% confidence interval 0.99-18). Arithmetic diagnostic scores proved inferior in the pediatric age-bracket compared to adults.

Conclusions: This large international pediatric cohort has permitted an individual patient data analysis of WD presenting as ALF. Notably, 11% of subjects achieved spontaneous survival; the rest required LT. Coagulopathy (international normalized ratio >2:0) and HE at presentation heralded poor outcomes. Further prospective studies may identify additional early predictors of outcomes.
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http://dx.doi.org/10.1097/MPG.0000000000002777DOI Listing
September 2020

Association Between Seroclearance of Hepatitis B Surface Antigen and Long-term Clinical Outcomes of Patients With Chronic Hepatitis B Virus Infection: Systematic Review and Meta-analysis.

Clin Gastroenterol Hepatol 2021 Mar 27;19(3):463-472. Epub 2020 May 27.

Department of Biostatistics, Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background & Aims: Seroclearance of hepatitis B surface antigen (HBsAg) is the desired end point of treatment for chronic hepatitis B virus (HBV) infection, according to guidelines. We performed a systematic review and meta-analysis to evaluate the strength of the association between HBsAg seroclearance and long-term clinical outcomes.

Methods: We performed a systematic review of the PubMed, EMBASE, and Cochrane Library databases for articles that assessed HBsAg status and reported the incidence of hepatocellular carcinoma (HCC), liver decompensation, liver transplantation, and/or all-cause mortality during follow-up evaluation. We performed a meta-analysis of rate ratios (RR) using a random-effects model independently for each end point and for a composite end point.

Results: We analyzed data from 28 studies, comprising a total of 188,316 patients with chronic HBV infection (treated and untreated), and 1,486,081 person-years (PY) of follow-up evaluation; 26 reported data on HCC, 7 on liver decompensation, and 13 on liver transplantation and/or death. The composite event rates were 0.19/1000 PY for the HBsAg seroclearance group and 2.45/1000 PY for the HBsAg-persistent group. Pooled RRs for the HBsAg seroclearance group were 0.28 for liver decompensation (95% CI, 0.13-0.59; P = .001), 0.30 for HCC (95% CI, 0.20-0.44; P < .001), 0.22 for liver transplantation and/or death (95% CI, 0.13-0.39; P < .001), and 0.31 for the composite end point (95% CI, 0.23-0.43; P < .001). No differences in RR estimates were observed among subgroups of different study or patient characteristics.

Conclusions: In a systematic review and meta-analysis, we found seroclearance of HBsAg to be associated significantly with improved patient outcomes. The results are consistent among different types of studies, in all patient subpopulations examined, and support the use of HBsAg seroclearance as a primary end point of trials of patients with chronic HBV infection.
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http://dx.doi.org/10.1016/j.cgh.2020.05.041DOI Listing
March 2021

Short-course, direct-acting antivirals and ezetimibe to prevent HCV infection in recipients of organs from HCV-infected donors: a phase 3, single-centre, open-label study.

Lancet Gastroenterol Hepatol 2020 07 6;5(7):649-657. Epub 2020 May 6.

Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; Soham and Shaila Ajmera Family Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada.

Background: An increasing percentage of potential organ donors are infected with hepatitis C virus (HCV). After transplantation from an infected donor, establishment of HCV infection in uninfected recipients is near-universal, with the requirement for post-transplant antiviral treatment. The aim of this study was to determine if antiviral drugs combined with an HCV entry blocker given before and for 7 days after transplant would be safe and reduce the likelihood of HCV infection in recipients of organs from HCV-infected donors.

Methods: HCV-uninfected organ recipients without pre-existing liver disease were treated with ezetimibe (10 mg; an HCV entry inhibitor) and glecaprevir-pibrentasvir (300 mg/120 mg) before and after transplantation from HCV-infected donors aged younger than 70 years without co-infection with HIV, hepatitis B virus, or human T-cell leukaemia virus 1 or 2. Recipients received a single dose 6-12 h before transplant and once a day for 7 days after surgery (eight doses in total). HCV RNA was assessed once a day for 14 days and then once a week until 12 weeks post-transplant. The primary endpoint was prevention of chronic HCV infection, as evidenced by undetectable serum HCV RNA at 12 weeks after transplant, and assessed in the intention-to-treat population. Safety monitoring was according to routine post-transplant practice. 12-week data are reported for the first 30 patients. The trial is registered on ClinicalTrials.gov, NCT04017338. The trial is closed to recruitment but follow-up is ongoing.

Findings: 30 patients (23 men and seven women; median age 61 years (IQR 48-66) received transplants (13 lung, ten kidney, six heart, and one kidney-pancreas) from 18 HCV-infected donors. The median donor viral load was 5·11 logIU/mL (IQR 4·55-5·63) and at least three HCV genotypes were represented (nine [50%] donors with genotype 1, two [11%] with genotype 2, five [28%] with genotype 3, and two [11%] with unknown genotype). All 30 (100%) transplant recipients met the primary endpoint of undetectable HCV RNA at 12 weeks post-transplant, and were HCV RNA-negative at last follow-up (median 36 weeks post-transplant [IQR 25-47]). Low-level viraemia was transiently detectable in 21 (67%) of 30 recipients in the early post-transplant period but not after day 14. Treatment was well tolerated with no dose reductions or treatment discontinuations; 32 serious adverse events occurred in 20 (67%) recipients, with one grade 3 elevation in alanine aminotransferase (ALT) possibly related to treatment. Non-serious transient elevations in ALT and creatine kinase during the study dosing period resolved with treatment completion. Among the serious adverse events were two recipient deaths due to causes unrelated to study drug treatment (sepsis at 49 days and subarachnoid haemorrhage at 109 days post-transplant), with neither patient ever being viraemic for HCV.

Interpretation: Ezetimibe combined with glecaprevir-pibrentasvir given one dose before and for 7 days after transplant prevented the establishment of chronic HCV infection in recipients of different organs from HCV-infected donors. This study shows that an ultra-short course of direct-acting antivirals and ezetimibe can prevent the establishment of chronic HCV infection in the recipient, alleviating many of the concerns with transplanting organs from HCV-infected donors.

Funding: Canadian Institutes of Health Research; the Organ Transplant Program, University Health Network.
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http://dx.doi.org/10.1016/S2468-1253(20)30081-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391837PMC
July 2020

hbsag levels can be used to rule out cirrhosis in hbeag positive chronic hepatitis b: results from the sonic-b study.

J Infect Dis 2020 Apr 21. Epub 2020 Apr 21.

Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Background & Aims: Serum HBsAg levels correlate with the duration of chronic HBV infection and may predict the extent of hepatic fibrosis.

Methods: We analysed data from the SONIC-B database, which contains data from 8 global randomized trials and two large hepatology centers. Relationship between HBsAg levels and presence of significant fibrosis (Ishak 3-4) or cirrhosis (Ishak 5-6) were explored and clinically relevant cut-offs were identified to rule out cirrhosis.

Results: The dataset included 2779 patients; 1866 HBeAg-positive; 322 with cirrhosis. Among HBeAg-positive patients, lower HBsAg levels were associated with higher rates of significant fibrosis (Odds Ratio [OR] 0.419, P<0.001) and cirrhosis (OR 0.435, p<0.001). No relationship was observed among HBeAg-negative patients. Among HBeAg-positive patients, genotype specific HBsAg cut-offs had excellent NPVs (>97%) and low misclassification rates (≤7.1%) and may therefore have utility in ruling out cirrhosis. Diagnostic performance of the HBsAg cut-offs was comparable among patients in whom cirrhosis could not be ruled out with FIB-4.

Conclusions: HBV genotype specific HBsAg cut-offs may have utility in ruling out presence of cirrhosis in HBeAg-positive patients with genotypes B, C and D and can be an adjunct to FIB-4 to reduce the need for further testing.
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http://dx.doi.org/10.1093/infdis/jiaa192DOI Listing
April 2020

Renal Dysfunction After Liver Transplantation: Effect of Donor Type.

Liver Transpl 2020 06 23;26(6):799-810. Epub 2020 Apr 23.

Multi-Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada.

Recipients of donation after circulatory death (DCD) grafts are reportedly at higher risk of developing renal dysfunction after liver transplantation (LT). We compared the development of acute kidney injury (AKI) and chronic kidney disease (CKD) after LT in recipients of DCD versus donation after brain death (DBD) or living donor liver transplantation (LDLT) livers. Adult recipients of DBD, LDLT, and DCD between 2012 and 2016 at Toronto General Hospital were included. AKI was defined as a post-LT increase of serum creatinine (sCr) ≥26.5 µmol/L within 48 hours or a ≥50% increase from baseline, and CKD was defined as an estimated glomerular filtration rate <60 mL/minute for >3 months. A total of 681 patients (DCD, n = 57; DBD, n = 446; and LDLT, n = 178) with similar baseline comorbidities were included. Perioperative AKI (within the first 7 postoperative days) was observed more frequently in the DCD group (61%; DBD, 40%; and LDLT, 44%; P = 0.01) and was associated with significantly higher peak AST levels (P < 0.001). Additionally, patients in the DCD group had a significantly higher peak sCr (P < 0.001) and a trend toward higher rates of AKI stage 3 (DCD, 33%; DBD, 21%; LDLT, 21%; P = 0.11). The proportions of recovery from AKI (DCD, 77%; DBD, 72%; LDLT, 78%; P = 0.45) and patients developing CKD (DCD, 33%; DBD, 32%; LDLT, 32%; P = 0.99) were similar. Nevertheless, patients who received DCD or DBD LT and required perioperative renal replacement therapy showed significantly lower patient survival in multivariate analysis (hazard ratio, 7.90; 95% confidence interval, 4.51-13.83; P < 0.001). In conclusion, recipients of DCD liver grafts experience higher rates of short-term post-LT renal dysfunction compared with DBD or LDLT. Additional risk factors for the development of severe kidney injury, such as high Model for End-Stage Liver Disease score, massive transfusions, or donor age ≥60 years should be avoided.
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http://dx.doi.org/10.1002/lt.25755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317208PMC
June 2020

Alcohol, tobacco and coffee consumption and liver disease severity among individuals with Chronic Hepatitis B infection in North America.

Ann Hepatol 2020 Jul - Aug;19(4):437-445. Epub 2020 Feb 8.

Division of Gastroenterology, Toronto General Hospital, University Health Network, Toronto, Canada. Electronic address:

Introduction And Objectives: The prevalence of alcohol, tobacco, and coffee use and association with liver health among North Americans with Chronic Hepatitis B (CHB) infection has not been well described.

Materials And Methods: The Hepatitis B Research Network includes an observational study of untreated CHB adults enrolled at 21 sites in the United States and Canada. Alcohol use was categorized as none, moderate, and at-risk based on the definition from the National Institute on Alcohol Abuse and Alcoholism; tobacco use as never, current and former; coffee use as none, 1-2 cups/day, and ≥3 cups/day. Linear regression and linear mixed models were used to associate lifestyle behaviors with ALT and FIB-4 values.

Results: 1330 participants met eligibility: 53% males, 71% Asian and the median age was 42 years (IQR: 34-52). Median ALT was 33U/L (IQR: 22-50), 37% had HBV DNA <10IU/mL, 71% were HBeAg negative, and 65% had a FIB-4 <1.45. At baseline, 8% of participants were at-risk alcohol drinkers, 11% were current smokers and 92% drank <3 cups of coffee/day. Current tobacco and 'at-risk' alcohol use, were significantly associated with elevated ALT levels in univariable analyses, however, these associations were not statistically significant when controlling for sociodemographic and HBV characteristics.

Conclusions: In this large diverse cohort of untreated CHB participants, at-risk alcohol use, current tobacco use and limited coffee consumption did not have an association with high ALT and FIB-4 values. In contrast, significant associations were found between the frequency of these lifestyle behaviors and sociodemographic factors.
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http://dx.doi.org/10.1016/j.aohep.2020.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757603PMC
February 2020

Genotype correlates with the natural history of severe bile salt export pump deficiency.

J Hepatol 2020 07 20;73(1):84-93. Epub 2020 Feb 20.

European Reference Network on Hepatological Diseases (ERN RARE-LIVER); Pediatric Liver Service, La Paz University Hospital, Madrid, Spain.

Background & Aims: Mutations in ABCB11 can cause deficiency of the bile salt export pump (BSEP), leading to cholestasis and end-stage liver disease. Owing to the rarity of the disease, the associations between genotype and natural history, or outcomes following surgical biliary diversion (SBD), remain elusive. We aimed to determine these associations by assembling the largest genetically defined cohort of patients with severe BSEP deficiency to date.

Methods: This multicentre, retrospective cohort study included 264 patients with homozygous or compound heterozygous pathological ABCB11 mutations. Patients were categorized according to genotypic severity (BSEP1, BSEP2, BSEP3). The predicted residual BSEP transport function decreased with each category.

Results: Genotype severity was strongly associated with native liver survival (NLS, BSEP1 median 20.4 years; BSEP2, 7.0 years; BSEP3, 3.5 years; p <0.001). At 15 years of age, the proportion of patients with hepatocellular carcinoma was 4% in BSEP1, 7% in BSEP2 and 34% in BSEP3 (p = 0.001). SBD was associated with significantly increased NLS (hazard ratio 0.50; 95% CI 0.27-0.94: p = 0.03) in BSEP1 and BSEP2. A serum bile acid concentration below 102 μmol/L or a decrease of at least 75%, each shortly after SBD, reliably predicted NLS of ≥15 years following SBD (each p <0.001).

Conclusions: The genotype of severe BSEP deficiency strongly predicts long-term NLS, the risk of developing hepatocellular carcinoma, and the chance that SBD will increase NLS. Serum bile acid parameters shortly after SBD can predict long-term NLS.

Lay Summary: This study presents data from the largest genetically defined cohort of patients with severe bile salt export pump deficiency to date. The genotype of patients with severe bile salt export pump deficiency is associated with clinical outcomes and the success of therapeutic interventions. Therefore, genotypic data should be used to guide personalized clinical care throughout childhood and adulthood in patients with this disease.
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http://dx.doi.org/10.1016/j.jhep.2020.02.007DOI Listing
July 2020

Serum hepatitis B virus RNA predicts response to peginterferon treatment in HBeAg-positive chronic hepatitis B.

J Viral Hepat 2020 06 17;27(6):610-619. Epub 2020 Mar 17.

Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Hepatitis B virus (HBV) RNA in serum is a novel biomarker that reflects cccDNA activity. We investigated whether HBV RNA can predict serological response to peginterferon (PEG-IFN) treatment. Serum HBV RNA levels were retrospectively measured at weeks 0, 12, 24 and 52 of therapy and after treatment discontinuation (week 78) in 266 HBeAg-positive chronic HBV patients who had participated in a global randomized controlled trial (HBV99-01 study). Patients received 52 weeks PEG-IFN monotherapy (n = 136) or PEG-IFN and lamivudine (n = 130). The primary end point was HBeAg loss 24 weeks after PEG-IFN discontinuation. At baseline, the mean serum level of HBV RNA was 6.8 (SD 1.2) log c/mL. HBV RNA levels declined to 4.7 (1.7) log c/mL after one year of PEG-IFN therapy alone and to 3.3 (1.2)log c/mL after combination therapy. From week 12 onward, HBV RNA level was significantly lower in patients who achieved HBeAg loss at the end of follow-up as compared to those who did not, regardless of treatment allocation (week 12:4.4 vs 5.1 log c/mL, P = .01; week 24:3.7 vs 4.9 log c/mL, P < .001). The performance of a multivariable model based on HBV RNA level was comparable at week 12 (AUC 0.68) and 24 (AUC 0.72) of therapy. HBV RNA level above 5.5 log c/mL at week 12 showed negative predictive values of 93/67/90/64% for HBV genotypes A/B/C/D for the prediction of HBeAg loss. In conclusion, HBV RNA in serum declines profoundly during PEG-IFN treatment. Early on-treatment HBV RNA level may be used to predict nonresponse.
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http://dx.doi.org/10.1111/jvh.13272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383601PMC
June 2020