The Canadian Liver Meeting is a collaborative effort of the Canadian Association for the Study of the Liver (CASL), the Canadian Network on Hepatitis C (CanHepC), the Canadian Association of Hepatology Nurses (CAHN), and the Canadian NASH Network (CanNASH). The meeting program offers a forum for presentation and discussion of basic science, and translational and clinical aspects of liver disease. This is a unique opportunity to exchange ideas, promote collaboration, and foster knowledge translation among Canadian researchers, health care practitioners, and community-based groups with an interest in Hepatology.
F Cinque1,2,*, R Lombardi1,2, A Cespiati1,2, P Francione2, E Fatta2, C Bertelli2, G Oberti1,2, F Alletto1,2, P Dongiovanni2, M Meroni2, G Bozzi3, A Bandera1,3, AL Fracanzani1,2
1Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy,
2Unit of Internal Medicine and Metabolic Disease, Fondazione Ca’ Granda IRCCS Ospedale Maggiore Policlinico, Milan, Italy,
3Infectious Diseases Unit, Fondazione Ca’ Granda IRCCS Ospedale Maggiore Policlinico, Milan, Italy
Background: Due to the epidemic of metabolic conditions, NAFLD is the most frequent liver disease worldwide. People living with HIV (PLWH) seems to be at risk for NAFLD due to a more complex pathogenesis, including chronic HIV-related inflammation and lifelong exposure to antiretroviral therapy. Furthermore, PLWH present with frequent metabolic comorbidities and increased cardiovascular (CV) risk. However, there are limited data whether HIV-associated NAFLD differs in clinical presentation from primary NAFLD.
Purpose: To evaluate prevalence of metabolic alterations, liver and CV damage in PLWH presenting with hepatic steatosis and to compare them with primary NAFLD patients.
Method: In this cross-sectional case-control study 30 consecutive HIV mono-infected patients (mean age 46±12 years, male 81%; 90% with viral suppression) presenting with hepatic steatosis at hepatic ultrasound (US) examination, in absence of alcohol abuse, were compared to a sex and age matched primary NAFLD control group (1:2). For all enrolled subjects, anthropometric parameters (BMI, waist circumference), metabolic comorbidities, fat mass and sarcopenia by bioimpedance, liver damage by transaminases determination and FibroScan (advanced fibrosis diagnosed by liver stiffness measurement >8.9/7.2 kPa with M/XL probe), CV damage by carotid ultrasound (plaques, arterial stiffness by radiofrequency as pulse wave velocity) and heart ultrasound (systolic and diastolic function and epicardial adipose tissue) were assessed.
Result(s): PLWH presented lower BMI (27.1±4 vs 29.1±4.3 kg/m2, p=0.04), waist circumference (98±9 vs 103.1±10.3 cm, p=0.03) and trunk fat mass (9.8±3.3 vs 12.4±4.7 kg, p=0.02) compared to primary NAFLD patients. Nevertheless, the prevalence of metabolic alterations (type 2 diabetes 13% vs 13%; hypertension 47% vs 42%; dyslipidemia 83% vs 85%) and sarcopenia (40% vs 52%) was not significantly different among the two study groups, as well as liver damage, being the prevalence of increased transaminases (17% vs 20%, p=0.78) and advanced fibrosis (17% vs 12%) similar in the two groups. Similarly, PLWH with HIV-associated NAFLD and primary NAFLD patients showed the same prevalence of high CV risk (84% vs 83%), carotid plaques (39% vs 28%), increased epicardial adipose tissue (20% vs 17%), systolic (6% vs 5%) and diastolic dysfunction (7% vs 6%), as well as similar pulse wave velocity values (7.4±2 vs 6.9±1.4 m/s).
Conclusion(s): PLWH with HIV-associated NAFLD have lower BMI and lower visceral adiposity compared to primary NAFLD patients despite similar prevalence of metabolic, liver and CV damage. Therefore, screening and follow up for steatosis in HIV patients is mandatory independently of their body weight.
FUNDING: None
Disclosure of Interest: None Declared
A Szilagyi1,*, AS Abbas1,*
1Gastroenterology Medicine, McGill University, Montreal, Quebec, Canada
Background: By the beginning of the 21st century, obesity and the inflammatory bowel diseases (IBD) have become global afflictions. Both began in high socioeconomic regions, but now obesity also affects poorer populations, while IBD lags behind. The two share pathogenic features, raising the possibility that the former promotes the latter.
Purpose: In this ecological analysis, we examine socioeconomic developments and geo-epidemiological parameters as they relate to both diseases.
Method: National rates for obesity, Crohn‘s disease, ulcerative colitis, national latitudes and lactase non persistence (LNP) were sought on Pubmed and Google Scholar. Economic metrics of Gross Domestic product/capita (GDP/c) and the Human development index (HDI) were obtained from the internet. Pearson‘s Correlation coefficients were evaluated for regional and global correlations. Countries were arbitrarily divided into high ≥0.8 and low < 0.79 HDI. The means of IBD and Obesity rates were evaluated using students t-tests. Significance was at < 0.05, 2 tailed tests.
Result(s): Sixty-three countries were matched for variables (median year 2008). Globally, there were strong correlations among HDI, GDP/c, Latitude (r=0.61 to 0.75) and inverse correlation with LNP (r=-0.59 to -0.61). Latitude correlated with LNP (r= -0.72). Globally HDI, GDP/c, Latitude correlated weakly or moderately with both forms of IBD, but more so with CD. LNP correlated negatively with both forms of IBD (r= -0.52 to -0.68). Obesity correlated weakly with HDI (r= 0.32) and both forms of IBD (r= 0.35–0.46).Obesity correlated negligibly with latitude (r= 0.17) and LNP (r= -0.23). There were variations in associations in parts of the world. Europe resembled global patterns the most. While there was statistically more IBD in high HDI countries, obesity did not differ statistically.
Conclusion(s): Both Latitude and LNP status correlates moderately with socioeconomic metrics.Obesity appears to be more independent of socioeconomic metrics than IBD and is more weakly linked with IBD. Observed patterns supports a weaker benefit of sunshine /vitamin D on preventing obesity. Obesity appears to precede expansion of IBD, raising the possibility of mutual pathogenic factors with a significant time delay.
FUNDING: None
Disclosure of Interest: None Declared
JD Makuza1,2,3,*, D Jeong1,2, S Phyumar1, P Adu1,2, M Binka2, G Cua2, A Yu2, HA Velásquez García1,2, M Alvarez2, M Alvarez2, S Wong2, S Bartlett2, EM Yoshida4, A Ramji4, A Ramji4, NZ Janjua1,2,5
1School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada,
2Clinical Prevention Services, British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada,
3IHDPC, Rwanda Biomedical Center, Kigali, Rwanda,
4Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia, Canada,
5Centre for Health Evaluation and Outcome Sciences, St Paul’s Hospital, Vancouver, British Columbia, Canada
Background: HIV infection has a significant impact on the natural history of chronic HBV infection, with increased HBV DNA levels, accelerated liver disease progression, and increased liver-associated mortality compared to HBV mono-infection. Despite effective suppression of both HIV and HBV replication due to antiviral treatment, morbidity and mortality are significantly higher in patients with HIV-HBV coinfection than with HIV or HBV alone.
Purpose: To assess the HBV treatment success and associated factors among people diagnosed with HBV mono-infection and HIV co-infection
Method: We used data from the updated District Health Information System 2 (DHIS2), which included data on ∼1 million individuals screened for HBV in Rwanda, from January 2016 to December 2019. DHIS2 includes information on screening, diagnosis, treatment, follow-up, outcomes such as death, and various demographic and comorbidities. Patients were included if they had HBV therapy for at least 12 months. We defined HBV treatment success as HBV DNA undetectable at 12 months. All Rwandans with chronic HBV infection, age ≥ 15 years, who received oral tenofovir-based, entecavir-based, or other high potent anti-viral treatment during the study period, were considered in the analysis. We computed treatment success rates and used Cox proportional hazard regression to assess risk factors associated with HBV treatment success.
Result(s): Overall, 2,773 people received HBV treatment during the study period (1,837 HBV mono-infected and 936 co-infected HBV/HIV), and were followed for a median (IQR) of 26 (13-42) months. The majority were males (n=1,585, 57.15%), between 35-54 years old (n=1,273, 45.91%, median age= 42 years). Among all individuals, 227 mono-infected (12.3%) and 30(3.2%) co-infected HIV/HBV had cirrhosis. During the 6,082.4 person-years (PY), 2391 HBV treatment success occurred, yielding a treatment success rate of 393.12 per 1,000 PY (95% CI: 377.64-409.2). People with HBV mono-infection had a higher treatment success rate compared to HBV/HIV co-infection (455.28 per 1000, 95% CI: 432.96-478.8.40 vs. 317.28 per 1000PY, 95% CI: 296.88-339.12). In the multivariable model, HIV coinfection (adjusted hazard ratio [aHR]: 0.76; 95% CI: 0.68, 0.84), male sex (aHR: 0.79; 95% CI: 0.72, 0.86) and age 55 years and above (aHR: 0.84; 95% CI: 0.73, 0.98) was associated with a lower likelihood of HBV treatment success. People with a shorter duration of treatment (>1 to 2 years) (aHR: 5.82; 95% CI: 5.07, 6.70) compared to those with a longer treatment length (over 2 years) had a higher HBV treatment success.
Conclusion(s): These findings highlight the need for early diagnosis and treatment of HBV in people with HIV co-infection. This data also supports close follow-up of the individuals with co-infection HBV/HIV, aged people as well individuals with long-term therapy is needed for suppression of HBV.
FUNDING: CIHR
Disclosure of Interest: None Declared
Y Menhem1,*, G Moncayo2, J Gorospe3, G Macphail4,5
1University of Toronto, Toronto, Ontario, Canada,
2Women’s Health, CUPS, Calgary, Alberta, Canada,
3University of Calgary, Calgary, Alberta, Canada,
4Liver Clinic, CUPS, Calgary, Alberta, Canada,
5Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
Background: CUPS is a multi-disciplinary clinic serving the inner-city marginalized in Calgary which helps people living with the adversity of poverty and traumatic events to build resilence. The incidence of HCV is increasing in women of childbearing age in Alberta, which is a concern given the 5.8% risk of vertical transmission. The CUPS pre-natal clinic has historically offered universal HCV testing for all pregnant women, before the provinical pre-natal screening pilot project. However, linkage to the on-site Liver Clinic has usually been deferred until after the pregnancy, as the safety of intrapartum antiviral treatment has not yet been established.
Purpose: We sought to assess the uptake of maternal HCV screening at CUPS, determine the prevalence of HCV exposure and active infection, and assess whether infants were being appropriately tested for possible vertical transmission.
Method: As the prospectively collected pre-natal database did not include HCV testing and care, we retrospectively accessed the clinic electronic medical records (EMR) and provincial Netcare to ascertain HCV antibodies, PCR and treatment history. It was difficult to obtain data for the infants, as there is a high rate of infant apprehensions and children’s names are often not recorded in the mother’s EMR.
Result(s): Between April 2018 and June 2022, 455 women were seen. Average age was 29.8 years. 51% were Indigenous. 76% were deemed high medical risk and 88% were deemed high social risk. 41% were on opiate agonist therapy. 63% had unstable housing at time of presentation. Average gestational age at presentation was 17.9 weeks (range 1.2-39 weeks).
384 (86%) were screened for HCV antibodies. 42 (11%) were antibody positive and 2 (0.5%) were indeterminate. PCR was done for 41 of these 44 (93%) with 18 positive (44%). Thus, 5% of the tested cohort were known to be HCV PCR positive during their pregnany. Only 8 of the 18 (44%) are known to have been treated post-partum.
30% of the 207 infants born were apprehended. Only 3 children had documentation of HCV testing (17% of babies born to HCV positive mothers). Two were negative and the other record did not specifiy the result.
Conclusion(s): The prevalence of HCV in pregnant women at CUPS is high (11% antibody positivity, 5% PCR positivity). Linkage to care is suboptimal and testing of infants is low.
Based on our findings, we are changing the practice of waiting for connection with the on-site Liver Clinic until after the delivery. Rather, expectant HCV PCR positive women will be linked upon identification to increase engagement for themselves and their children. We are implementing Dried Blood Spot testing for the infants at well-baby checks to overcome some of the barriers in testing. An algorithm for follow-up of infants who are apprehended or adopted will also be developed. All women with HCV will be asked about the HCV status of their offspring.
FUNDING: None
Disclosure of Interest: Y Menhem: None Declared, G Moncayo: None Declared, J Gorospe: None Declared, G Macphail Grant / Research support from: CanHepC Network, AbbVie, Coverdale, Gilead, Consultant of: AbbVie, Gilead, Paid Instructor of: INHSU, University of Calgary
S Sasson1,*, D Kablawi1, F Aljohani1, C Saroli Palumbo2, S Restellini3, A Bitton1, G Wild1, W Afif1, PL Lakatos1,4, T Bessissow1, G Sebastiani1
1Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada,
2Division of Gastroenterology, Jewish General Hospital, Montreal, Quebec, Canada,
3University Hospital of Geneva, Geneva, Switzerland,
41st Department of Medicine, Semmelweis University, Budapest, Hungary
Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and seems more frequent in patients with inflammatory bowel disease (IBD). In the general population, NAFLD is a dysmetabolic disease with extensive extra-hepatic involvement, including cardiovascular disease, extra-hepatic cancer, hypothyroidism, chronic kidney disease.
Purpose: We aimed to determine the effect of NAFLD and associated liver fibrosis on multi-organ diseases in patients with IBD.
Method: We conducted a cross-sectional analysis of an ongoing prospective cohort of IBD patients undergoing a routine screening program for NAFLD by transient elastography (TE) and associated controlled attenuation parameter (CAP) at a single centre, between August 2015 and September 2022. NAFLD and significant liver fibrosis were defined as CAP≥ 275 dB/m and liver stiffness measurement LSM by TE ≥8 kPa, respectively. Extra-hepatic conditions included: extra-hepatic cancers, cardiovascular events, chronic kidney disease, hypothyroidism. The number of all-cause hospitalizations after the TE visit was also computed. Predictors of extra-hepatic conditions were investigated by multivariable logistic regression analysis.
Result(s): We included 430 patients with IBD (54% female; mean age 43±15 years; mean BMI 26±5 kg/m2; 64% with Crohn’s disease; 4% with diabetes; 11% with hypertension). Overall, the prevalence of extra-hepatic conditions was as follows: extra-hepatic cancers 4%, cardiovascular events 8%, chronic kidney disease 5%, hypothyroidism 7%. The median number of hospitalizations was 1 (interquartile range 0-2) and 44% of patients had more than 2 hospitalizations after the TE visit. NAFLD and significant liver fibrosis were found in 29% and 8% of patients, respectively. Patients with NAFLD had higher proportion of cardiovascular events, chronic kidney disease and hypothyroidism (see Figure). No difference was observed by significant liver fibrosis status. After adjusting for age (adjusted odds ratio [aOR] 1.00, 95% CI 0.99–1.00; p=0.39), male sex (aOR 1.58, 95% CI 1.02-2.45; p=0.04), diabetes (aOR 3.53, 95% CI 1.68-7.42; p=0.001), IBD disease activity (aOR 1.10, 95% CI 0.67-1.80; p=0.70) and Crohn’s disease IBD subtype (aOR 1.49, 95% CI 1.00-2.25; p=0.05), NAFLD remained an independent predictor of extra-hepatic comorbidities (aOR 1.79, 95% CI 1.15–2.78; p=0.01) on multivariable analysis. We did not observe a difference in hospitalizations by NAFLD or liver fibrosis status.
Conclusion(s): NAFLD is associated with extra-hepatic comorbidities in patients with IBD, regardless of liver fibrosis. A multi-organ approach to these cases may be considered to prevent adverse clinical outcomes.
FUNDING: None
Disclosure of Interest: None Declared
C Bera1,*, H Kosick1, M Fakhriyehasl1, K Jhaveri1, K Patel1
1Medicine, University of Toronto, Toronto, Ontario, Canada
Background: The presence of significant fibrosis (3stage 2) in patients with non-alcoholic fatty liver disease (NAFLD) is considered high risk for morbidity and mortality. MEFIB index (MRE3 3.3 kPa and FIB-43 1.6) has been proposed as an alternative to liver biopsy, particularly for selecting patients for potential therapy in the future. However, MR elastography (MRE) is not widely available.
Purpose: our aims were to compare the MEFIB index to other simple, non-invasive predictors including vibration-controlled transient elastography (VCTE) for significant fibrosis.
Method: This is a single-centre retrospective analysis of NAFLD patients with MRE and VCTE between March 2019 to June 2022. Demographic and laboratory data were collected to calculate NAFLD fibrosis score (NFS), Fibrosis-4 (FIB-4), AST platelet ratio index (APRI), and AST: ALT ratio. Oneway ANOVA and ordinal logistic regression model were used for the statistical analysis.
Result(s): Our cohort included 56 patients with (mean ± SD) age 53±13 years, 35/56 (62%) female, Body Mass Index 33.4±6, prevalence of Diabetes Mellitus 26/56 (46%), Hypertension 23/56 (41%), Dyslipidemia 23/56(41%). All subjects had MRE and VCTE for the assessment of fibrosis. Significant fibrosis based on the MEFIB index was significantly associated age >53 years (p=0.004), VCTE score >12 kPa (p=0.002), NFS Score >-1.27 (p <0.001) and APRI >0.72 (p <0.001), whereas no significant association were noted with sex, BMI (p=0.17) and AST/ALT ratio (p=0.72). A logistic regression model showed that age (p=0.016), APRI (p=0.005) and VCTE (p=0.032) were independently associated with the MEFIB index and predicted MEFIB F32 with AUROC of 0.935 (Figure)
Conclusion(s): Clinical and laboratory parameters associated with advanced-stage fibrosis based on the MEFIB index include age, APRI and VCTE. Further validation is required, but these parameters can be used to develop a model with high accuracy to determine the MEFIB index.
FUNDING: None
Disclosure of Interest: None Declared
L Ata1,2,*, M Kilany1, S Yousif1, H Mohamed3,4, A Sarowar1, K Patel1
1UHN Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Ontario, Canada,
2National Liver Institute, Menoufia University, Menoufia, Egypt,
3Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada,
4Faculty of Computers & Artificial Intelligence, Benha University, Qalyubia, Egypt
Background: Endoscopy remains the reference standard for the detection of gastroesophageal varices. Baveno VI criteria identifies compensated advanced chronic liver disease patients with liver stiffness measurement (LSM) <20 kPa and platelet count more than 150,000 × 109/L. as being at low risk of clinically significant varices.
Purpose: Our aim was (1) to validate performance of these criteria for predicting varices in patients with cirrhosis from Nonalcoholic fatty liver disease (NAFLD) and (2) Compare the diagnostic accuracy of Baveno VI with simple markers of advanced fibrosis.
Method: NAFLD patients with cirrhosis (stage F4) based on imaging, available FibroScan, screening upper endoscopy, and simple blood markers for fibrosis between 2014 to 2021 were included in this single center retrospective study. Grade 2 and Grade 3 esophageal varices (EV) were considered clinically significant esophageal varices (CSEV) for analysis.
Result(s): This study included 208 NAFLD cirrhosis patients, mean age 62 (SD 11) years, 113/208 (54%) Female, mean LSM was 16.6 kPa and mean platelet count was 188 x 109/L. For endoscopy 30 patients had grade 1 EV, 16 patients with G2, 15 patients with G3, 139 patients had no varices. For EV grade 2 or 3, sensitivity and specificity of Baveno VI were 48%, and 86% respectively, with Area under the curve (AUC) 0.67, and comparable to AUC 0.69 for FIB-4 ≥ 2.67. Adding FIB4 ≥2.67 to Baveno VI increased sensitivity to 82%and AUC to 0.75 for CSEV. AST/ALT ≥ 1 also increased sensitivity of Baveno VI to 82%.
Conclusion(s): In our NASH cirrhosis cohort Baveno VI criteria had poor sensitivity for noninvasive detection of CSEV. The addition of simple noninvasive parameters including FIB4≥2.67 or AST/ALT≥1 scores increased sensitivity for CSEV. Further validation in larger cohorts with NASH cirrhosis is required.
FUNDING: None
Disclosure of Interest: None Declared
A Bourgeois1,*, F Veillette2, M Oliveira2, K Dubois2, M Tremblay2, C Bémeur1,2, CF Rose2,3
1Nutrition Department, Université de Montréal, Montreal, Quebec, Canada,
2Hepato-neuro lab, CRCHUM, Montreal, Quebec, Canada,
3Medicine Department, Université de Montréal, Montréal, Quebec, Canada
Background: Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome arising from chronic liver disease (CLD). HE manifests with symptoms such as poor memory, impairment in motor coordination, lethargy and coma. The gut microbiota has been shown to influence neurological functions via various mediators such as cytokines or bacterial metabolites, many studies have demonstrated the gut-brain axis is altered in liver disease. Fecal matter transplantation (FMT) in patients with cirrhosis has revealed beneficial effects yet many limitations of these studies render the results inconclusive.
Purpose: The aim of this study is to explore the impact of FMT on gut microbiota and the beneficial effects on neuro behaviour in bile-duct ligated (BDL) rats.
Method: Male Sprague-Dawley rats were randomly assigned to one of three groups; SHAM, BDL-VEH (vehicle) and BDL-FMT (who received FMT daily from pooled feces from SHAM rats). After five weeks, behaviour tests were performed to evaluate short- and long-term memory (Novel Object Recognition), anxiety (Open Field and Elevated Plus Maze) and motor coordination (Rotarod). Plasmatic parameters such as cytokines, short chain fatty acids (SCFA) and liver impairment markers were measured by ELISA, LC-MS/MS and using Cobas respectively. Finally, feces were collected for bacterial sequencing and SCFA analysis.
Result(s): FMT did not alter degree of liver disease in BDL rats. BDL-VEH developed a loss of short/long term memory and motor coordination compared to SHAM rats. However, alterations in neurological dysfunction were prevented in the BDL-FMT group. FMT did not impact microbiota α-diversity in BDL rats and β-diversity of microbiota was significantly different between all groups. The genera Bifidobacterium, Lactobacillus and Akkermansia significantly increased in both BDL groups, while Provotellaceae UCO-001 significantly increased only in SHAM and BDL-FMT rats and Clostridium Senso Stricto 1 significantly increased only in BDL-VEH compared to SHAMs. Finally, Rombustia was only present in SHAM. Plasma pro-inflammatory cytokines (TNF-α & IL-1□) increase in both BDL groups compared to the control group and no difference for the anti-inflammatory cytokine IL-10 was noted. Analysis of short-chain fatty acids in feces and plasma showed a variation in propionate and butyrate between both BDL groups. Plasma propionate significantly positively correlated with behavioural results.
Conclusion(s): Our results demonstrate that FMT leads to improvement in memory and motor coordination in BDL rats. The microbiota profile was different between BDL-VEH and SHAM, and FMT lead to further alterations on microbiota. The fact that FMT did not normalize microbiota profile compared to SHAM, suggests BDL-FMT leads to a novel specific microbiota profile which in turn protects the brain. The protective effect of plasma propionate needs to be further explored to define its impact on the brain and possible therapeutic application.
FUNDING: CIHR
Disclosure of Interest: None Declared
E Charlebois1, C Fillebeen1, J Presley2, G Cagnone3, V Lisi3, V-P Lavallée3, J-S Joyal3, K Pantopoulos4,*
1Lady Davis Institute for Medical Research, Montreal, Quebec, Canada,
2Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada,
3Centre de Recherche du Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada,
4Lady Davis Institute for Medical Research/McGill University, Montreal, Quebec, Canada
Background: Homeostatic adaptation to systemic iron overload involves transcriptional induction of bone morphogenetic protein 6 (BMP6) in liver sinusoidal endothelial cells (LSECs). BMP6 is then secreted to activate signaling to the iron hormone hepcidin (HAMP) in neighboring hepatocytes.
Purpose: The purpose of the study is to explore the mechanism for iron sensing by LSECs.
Method: We generated TfrcTek-Cre mice with endothelial cell-specific ablation of transferrin receptor 1 (Tfr1). We also used control Tfrcfl/fl mice to characterize LSEC-specific molecular responses to iron by single-cell transcriptomics.
Result(s): TfrcTek-Cre animals tend to have modestly increased liver iron content (LIC) compared to Tfrcfl/fl controls but express physiological Bmp6 and Hamp mRNA. Despite a transient inability to upregulate Bmp6, they eventually respond to iron challenges with Bmp6 and Hamp induction, yet occasionally to levels slightly lower relative to LIC. High dietary iron intake triggered accumulation of serum non-transferrin bound iron (NTBI), which significantly correlated with liver Bmp6 and Hamp mRNA levels and elicited more profound alterations in the LSEC transcriptome compared to holo-transferrin injection. These culminated in robust induction of Bmp6 and other nuclear factor erythroid 2-related factor 2 (Nrf2) target genes, as well as Myc target genes involved in ribosomal biogenesis and protein synthesis. LSECs and midzonal hepatocytes were the most responsive liver cells to iron challenges and exhibited highest expression of Bmp6 and HampmRNAs, respectively.
Conclusion(s): Our data suggest that during systemic iron overload, LSECs internalize NTBI, which promotes oxidative stress and thereby transcriptionally induces Bmp6 via Nrf2. Tfr1 appears to contribute to iron sensing by LSECs mostly under low iron conditions.
FUNDING: CIHR; PJT-159730
Disclosure of Interest: None Declared
NH Patel1,*, A Vachon2, KE Doucette3, A Ramji4, L Sycuro1, T Patel5, G V Marle1, C Osiowy2, CS Coffin1,6
1Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada,
2National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada,
3Division of Infectious Diseases, University of Alberta, Edmonton, Alberta, Canada,
4Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia, Canada,
5Departments of Chemistry and Biochemistry, University of Lethbridge, Lethbridge, Alberta, Canada,
6Department of Medicine, University of Calgary, Calgary, Alberta, Canada
Background: Individuals living with chronic hepatitis B (CHB) and non-alcoholic fatty liver disease (NAFLD) are at an increased risk for hepatocellular carcinoma. Large cohort studies show a positive association between hepatic steatosis and reduced hepatitis B virus (HBV) replication. The mechanisms remain unknown.
Purpose: This study aims to determine the virological and immunological factors that lead to lower HBV replication in patients with CHB and NAFLD.
Method: In total, 55 patients with CHB and NAFLD were recruited from three Canadian liver clinics. Age and sex-matched NAFLD-only (n = 13) and healthy (n = 7) patient cohorts were also recruited. Blood samples and clinical and demographical information, including NAFLD risk factors were collected. Plasma, sera, and peripheral blood mononuclear cells (PBMCs) were isolated from blood. HBV biomarkers were quantified using in-house and/or standard clinic assays. Next-generation sequencing of HBV surface and core genes was performed using the Illumina MiSeq platform. A panel of 13 pro-and-anti-inflammatory cytokines and chemokines were measured using multiplex Luminex assay. Ex vivo HBV-specific T-cell responses to HBV core and surface antigens were characterized through IFN-γ ELISPOT.
Result(s): In 55 patients with CHB and NAFLD (35% female, mean age of 45 ± 10.6 years), 52 (95%) were HBeAg negative. The mean HBV DNA, qHBsAg, and HBV pgRNA levels were 3.2 ± 1.8 log10IU/mL, 2.9 ± 1.2 log10pg/mL, and 2.1 ± 1.3 log10copies/mL, respectively. CHB and NAFLD patients with dyslipidemia, hypertension, and metabolic syndrome had lower levels of qHBsAg (p <0.001). A greater frequency of immune escape mutations in the HBV surface gene (i.e., 1277L/T, M133L/I/T, and E164D/G) was detected in hepatitis B patients with severe hepatic steatosis (CAP score > 280 dB/m, p <0.05). Patients with severe hepatic steatosis, diabetes, and obesity had higher levels of IL-8 (p=0.002), TNF-α (p=0.004), IFN-γ (p=0.021), MCP-1 (p=0.045), and IL-10 (p=0.007). Functional HBV-specific T-cell responses were heightened in CHB and NAFLD patients with severe hepatic steatosis compared to control patient groups (p <0.05). Increased HBV-specific T-cell responses observed in CHB and NAFLD patients were linearly associated with lower HBV DNA (p=0.046) and qHBsAg levels (p=0.041).
Conclusion(s): Elevated functional HBV-specific T-cell responses observed in hepatitis B and NAFLD patients contribute towards suppression of HBV replication.
FUNDING: CIHR
Disclosure of Interest: None Declared
D Fernando1,*, E Yuzbashian2, C Chan2,3
1Cell Biology, Edmonton, Alberta, Canada,
2Agricultural, Food & Nutritional Science, Edmonton, Alberta, Canada,
3Physiology, University of Alberta, Edmonton, Alberta, Canada
Background: Non-alcoholic fatty liver disease (NAFLD) is characterized by excess lipid accumulation in the liver and is caused by westernized diets and sedentary lifestyles. Furthermore, NAFLD is considered the hepatic manifestation of metabolic syndrome. Currently, there are no pharmacological treatments available to treat NAFLD; thus, adherence to a healthy diet remains the prominent approach for the prevention of NAFLD. Recent studies show that dairy products, especially milk, can reduce hepatic lipid accumulation though the exact mechanism by which milk improves liver lipid metabolism remains unknown.
Purpose: To elucidate the mechanisms by which different types of dairy products, namely milk, cheese, and yogurt, act to improve the hepatic lipid profile of a pre-diabetes mouse model.
Method: 8-week male C57BL/6 mice (n=30) were randomly assigned to a 10% fat diet (LFD, n=6), and the remainder of the mice were assigned to a 45% fat high-fat diet (HFD, n=24) for 1 week. Then, mice from the HFD group were randomly assigned 6/group: HFD, HFD + milk, HFD + yogurt, and HFD + cheese. After 8 weeks, body weight was measured, the mice were euthanized, and liver tissues were harvested. Immunoblotting was used to quantify target proteins involved in fat metabolism. Histological analysis was performed on the liver tissues, and morphological information such as lipid droplet count and area was obtained following digital image analysis via ImageJ.
Result(s): Results showed a significant reduction of lipid droplet count in the HFD + yogurt group compared to the HFD group. The average area of lipid droplets observed in the HFD + milk, HFD + cheese, HFD + yogurt, and LFD groups was significantly lower compared to the HFD group. Furthermore, we observed a reduction in the percentage of area covered by lipid droplets in the HFD + milk, HFD + yogurt, HFD + cheese, and LFD groups compared to the HFD group. The protein abundance of long-chain acyl-coenzyme A synthetase 1 (ACSL1), an enzyme involved in the process of β-oxidation, was shown to be higher in HFD + milk and HFD + yogurt-fed mice compared to HFD-fed mice in both re-fed and fasting stages, as determined by immunoblotting. The levels of lipogenesis-related proteins were similar across all study groups.
Conclusion(s): We demonstrate that the inclusion of dairy products (milk, yogurt, and cheese) in diets high in fat, similar to westernized diets, can reduce hepatic lipid accumulation in a mouse model of pre-diabetes. Yogurt and milk ameliorated the detrimental effects of HFD on excess fat build-up in the hepatocytes via increasing lipid oxidation in the liver.
FUNDING: Alberta Diabetes Institute
Disclosure of Interest: None Declared
T Thomas1, J Burnside1, G Sebastiani2, S Saeed1,*
1Public Health Sciences, Queen’s University, Kingston, Ontario, Canada,
2McGill University Health Centre, Montreal, Quebec, Canada
Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and the second leading cause of liver transplant in Canada. People living with type 2 diabetes mellitus (T2DM) and obesity are at the greatest risk of NAFLD and more aggressive forms of liver disease, such as non-alcoholic steatosis (NASH) and cirrhosis. Driven largely by the increased incidence of T2DM and obesity, modelling studies predict that by 2030, the prevalence of NASH will increase by 35% and liver transplants by 100% in Canada.
Purpose: It is unknown if Canada has the necessary resources needed to monitor patients requiring specialized liver healthcare. Therefore we conducted a resource assessment of specialists and transient elastography devices (TE)) and evaluated regional disparities.
Method: Demographic data on licenced specialists (gastroenterologists and hepatologists) were obtained from Scott's Medical Directory as of October 2022. Rates of specialists per 100,000 people by province/territories and census division were calculated by linking primary work locations (via postal codes) to Statistics Canada. A list of operational TE (with Controlled Attenuation Parameter) was provided by the Canadian distributor, KNS Canada Inc.
Result(s): 853 specialists were identified, 33% female and 25% completed medical school before 1990. Rates of specialists/100,000 people ranged from zero in the territories to 2.9 in Quebec. The majority of the provinces (7/10) had less than 2.0 specialists per 100,000 people. The heat map illustrates the heterogeneity of specialists/100,000 people across Canada by census division (darker blue indicating higher rates). Specialists were concentrated in 24% (71/293) of census divisions with a median population of 166,128 (IQR 93,579, 439,219). Eighty-two TE were identified in nine provinces. TE per 1,000,000 people ranged from 1.4 in Manitoba to 3.4 in British Columbia.
Conclusion(s): We found significant geographic variations in resources across Canada. Given the unprecedented number of people expected to develop NAFLD in the next decade, now is the time to increase the number of specialists equipped to manage liver diseases, particularly in non-urban settings.
FUNDING: Queen’s Research Initiative Grants
Disclosure of Interest: T. Thomas: None Declared, J Burnside: None Declared, G Sebastiani Grant / Research support from: Unrestricted research funding from Theratecnologies Inc., Consultant of and served as an advisory board member for Merck, Gilead, Pfizer, Allergan, Novonordisk, Intercept., Speakers bureau of: Pfizer, Merck, Novonordisk, Novartis, Gilead, and AbbVie, S Saeed: None Declared
S Kaur1,*, C Coffin1, N Forbes1, M Raman1, AA Shaheen1
1University of Calgary, Calgary, Alberta, Canada
Background: While many differences in disease prevalence and clinical outcomes could be attributed to sex as a biological variable, there is recent evidence that gender could impact healthcare utilization and clinical outcomes. To our knowledge, the impact of gender-role related variables and fibrosis stage in liver disease has not been evaluated.
Purpose: In this pilot study, we studied the association between gender-role related variables and significant fibrosis in two liver disease cohorts (nonalcoholic fatty liver disease [NAFLD] and chronic hepatitis B [CHB]).
Method: We recruited 62 NAFLD and 60 CHB patients from the hepatology clinics in Calgary, Canada. A one-time self-administered questionnaire was administered to collect data on sex, self-reported gender identity, and postulated gender-role related variables (marital status, occupation, immigration, education, annual household income, primary earner of house, number of children, ethnicity, and responsibilities over the last 12 months). The Calgary NAFLD pathway and the hepatitis B network databases were used to collect data on demographics and fibrosis stage. The primary outcome was significant fibrosis (F2-4), and the secondary outcome was advanced fibrosis (F3-4) using transient elastography scores. Predictors of outcomes were estimated using univariable and multivariable-adjusted logistic regression models.
Result(s): A total of 59 NAFLD and 57 CHB patients completed our questionnaire. The mean age of NAFLD patients was 56.44 ± 12.85 years and for CHB patients was 49.72±12.72 years. Females were 47.46% and 56.14% in NAFLD and CHB cohorts, respectively. All males and females in both cohorts identified as cisgender. The gender-role related variables associated with advanced fibrosis in NAFLD cohort were no work/part-time compared to full-time (66.67% vs 37.93% p=0.038), number of children (1 child: 21.43%, 2: 58.06%, 3: 71.4% p=0.023), household work [y/n] (90.00% vs 44.90% p=0.013). In the CHB cohort, significant fibrosis was associated with being retired in comparison to non-retired (60.00% vs 4.26% p< 0.001). In a multivariable analysis, for the NAFLD cohort, no predictor was found for significant fibrosis, however, age (aOR: 1.16, 95% CI: 1.07-1.27), vigorous exercise (aOR: 0.04, 95% CI: 0.00-0.71), going to school (aOR: 892.24, 95% CI: 13.35-59615.06), caregiving responsibilities for children (aOR: 54.33, 95% CI: 2.27-1299.74) were predictors of advanced fibrosis. Age (aOR: 1.18, 95% CI: 1.06-1.31) and education level (aOR: 29.93, 95% CI: 1.45-617.79) were predictors of significant fibrosis in the CHB cohort. Neither sex nor gender was a predictor of fibrosis in both cohorts.
Conclusion(s): In this novel pilot study, certain gender-role related variables were associated with fibrosis stage among patients with CHB or NAFLD. Future studies with large samples are warranted to understand the impact of gender-role on clinical outcomes in chronic liver diseases.
FUNDING: None
Disclosure of Interest: None Declared
D Mager1,*, A Hager1, V Mazurak1, N Boule2, M Noga3, S Gilmour4
1Agricultural, Food & Nutritional Science, Edmonton, Alberta, Canada,
2Kinesiology, Sport, and Recreation, Edmonton, Alberta, Canada,
3Radiology & Diagnostic Imaging, Edmonton, Alberta, Canada,
4Pediatrics, University of Alberta, Edmonton, Alberta, Canada
Background: Sarcopenia, is a condition that is characterized by deficits in skeletal muscle mass (SMM) and physical performance and has been associated with adverse clinical outcomes in children with end-stage liver disease before and after liver transplantation (LTx). Resistance exercise (RE) training has been shown in adults with sarcopenia to exert positive influences on muscle tissue regeneration and synthesis.
Purpose: This pilot study examined the impact of a 12-week home-based RE program using video-based technology on SMM and physical performance in children after LTx at risk for sarcopenia.
Method: Children (6-18 years) were recruited from the Pediatric Liver Transplant Program at the Stollery Children’s Hospital and the community (healthy controls; CON). Primary outcome variables include changes in SMM measured by Magnetic Resonance Imaging (MRI), muscle strength (hand-grip (HG), sit-to-stand (STS), push-up (PU)) and muscle functionality (stair climb test (SC), 6-minute walk test(6MWT)). Additional variables collected included demographic, anthropometrics (weight-z, height-z, multiple skinfold measures) and lifestyle factors (physical activity, 3-day food intake records). The RE program consisted of a warm-up/cool down and exercises targeting five muscle groups (legs, chest, back, shoulders, and arms) performed 3 days/week with progressive intensity use elastic bands over 12 weeks. Training sessions lasted approximately 20-30 minutes with weekly follow-up (virtual, telephone). Statistical significance was determined at p<0.05.
Result(s): Six children post-LTx (3M/3F, 12.5 ± 3.1 yrs) and thirteen healthy controls [HC] 6/7F, 11.7 ± 4.0 y) were recruited (p=0.65). Liver disease diagnoses included Biliary Atresia (n=4), Alagilles (n=1) and Progressive Familial Intrahepatic Cholestasis (n=1). Age (median [IQR]) at LTx was 0.65 (0.62-0.75 months) and time since LTx was 10.5 ± 3.2 years. No significant differences in anthropometric (wt-z, height-z, BMI-z), demographic (age, sex) or body composition (fat-free mass, fat mass, SMM) between CON and LTx participants were observed at baseline (p>0.05). With the exception of HG, LTx children had significantly reduced performance in all physical performance tests including 6MWT distances (483 ± 51 [LTx] vs 560 ± 38 [HC] m; 0.03.) LTx children saw the greatest increases in stair climb (+15.1%), sit-to-stand (+11.5%) and push-up (+4.8%), but no differences in body composition when compared to the CON (p<0.05) after the intervention.
Conclusion(s): A video-based RE program in children may result in significant improvements in muscle performance, rather than body composition in post-LTx children at risk for sarcopenia.
FUNDING: Canadian Society of Transplantation
Disclosure of Interest: None Declared
V Tambay1,*, V-A Raymond1, C Goossens1, L Rousseau2, S Turcotte2,3, M Bilodeau1,4
1Laboratoire d’hépatologie cellulaire, Montréal, Quebec, Canada,
2Biobanque et base de données hépatopancréatobiliaires, Centre de recherche du CHUM, Montréal, Quebec, Canada,
3Département de chirurgie, Service de transplantation hépatique et de chirurgie hépatopancréatobiliaire, CHUM, Montréal, Quebec, Canada,
4Département de médecine, Université de Montréal, Montréal, Quebec, Canada
Background: Hepatocellular carcinoma (HCC) is the third cause of cancer-related mortality. The lack of appropriate diagnostic biomarkers and limited curative treatment options contribute to its poor survival rates. Dysregulated cell metabolism is a key feature of cancer but few studies have been performed to identify the specificities of metabolic reprogramming in HCC.
Purpose: This study aimed to identify signatures of HCC metabolism. We focused on a combined approach of non-targeted and targeted metabolomics to measure trends in metabolite abundance as well as quantify specific metabolites within non-tumoral adjacent liver and HCC specimens.
Method: Five patients undergoing surgical liver resection for HCC were enrolled with written and informed consent. Non-tumoral and tumoral specimens were collected, homogenized, followed by metabolite extraction. The abundance of all polar metabolites was measured using non-targeted 1H-Nuclear Magnetic Resonance (NMR). Twenty-six metabolites were quantified using targeted Liquid Chromatography/Mass Spectrometry (LC/MS).
Result(s): NMR profiling identified a distinct pattern of metabolites in HCC compared to non-tumor liver. Principal Component Analysis (PCA) revealed a principal component (PC1) of 53.3%: distinct clustering of both groups along the PC1 showed that tissue type was the major source of variability in liver metabolomics. Supervised Partial Least-Squares Discriminant Analysis (PLS-DA) also identified both tissue types as having distinct metabolic signatures (First component=53.2%). Through LC/MS quantification, the abundance of 26 metabolites revealed a PC1 of 45.2%, which was again due to tissue type, both groups being clustered separately along the PC1. PLS-DA of the LC/MS dataset also showed that tissue type was the primary factor (First component=44.6%) explaining metabolic variability between both groups. According to their attributed Variable Importance in Projection (VIP) scores, AMP, glycerol-3-phosphate (Gro3P)/dihydroxyacetone phosphate (DHAP) ratio, malate, succinate, Gro3P, glutathione (GSH), and GSH/oxidized GSH (GSSG) ratio were the main contributors to the PLS-DA model (all VIP >1.0). Twelve of 26 metabolites were significantly altered in HCC. Arginine was increased (53.0±30.1 from 12.5±1.2 pmol/mgtissue, p<0.05) whereas DHAP, Gro3P, succinate, fumarate, malate, NADH, NADP+, AMP, ADP, and ATP were decreased in HCC samples (all p<0.05). GSH was depleted in HCC (3.2±0.7 vs 0.2±0.1 nmol/mgtissue, p<0.01), contributing to decreased tissue GSH/GSSG ratio (p<0.01).
Conclusion(s): Together, NMR and LC/MS metabolomics revealed that HCC tumors can be distinguished from non-tumor liver according to their metabolic composition. The depletion of key metabolites in HCC suggests that the demand for energy and building blocks required for cell proliferation outpaces the reserves found in non-tumoral tissues. These findings highlight that major changes in metabolic landscape occur in HCC, which could help identifiy novel biomarkers for HCC detection.
FUNDING: Chaire de recherche en hépatologie Novartis - Fondation canadienne du foie de l’Université de Montréal
Disclosure of Interest: None Declared
N Tiwari1,*, C Bera1, F Wong1
1Division of Gastroenterology & Hepatology, University Health Network, University of Toronto, Toronto, Ontario, Canada
Background: Acute kidney injury (AKI) occurs in about 50% of admitted cirrhotic patients. Its prevalence in outpatients is unclear. Whether it occurs at the same rate across all severities of ascites is also unclear.
Purpose: To evaluate the prevalence of AKI and its severity across the spectrum of patients with decompensated cirrhosis and ascites.
Method: Retrospective chart review of all patients with cirrhosis and ascites who attended the liver unit from April 2020 to March 2021. Data were collected for demographics, laboratory results, baseline and follow-up renal function. AKI episodes were sought and diagnosed according to International Ascites Club’s diagnostic criteria and staged according to severity of AKI. Patients were followed for 6 months for hospital admissions and survival. Patients with ultrasound detectable and diuretic responsive ascites (Group A) were compared to those with recurrent or refractory ascites (Group B).
Result(s): 183 patients were enrolled, (Group A=82, Group B=101) with mean age 62±11 years, 63% males, MELD=15.3±6.3 in Group A, and 15.9±4.9 in Group B (p=0.99), with alcoholic liver disease (53%) and NASH (23%) as the main etiologies of cirrhosis. Group B had higher Child-Pugh score of 9.1±1.7 versus 8.3±1.7 in group A (p=0.0019) on account of the ascites, receiving 4.9±2.4 large volume paracentesis (LVP) in past 3 months and a mean ascites volume of 7±3 litres removed per LVP. The mean baseline serum creatinine (sCr) was 98±47 μmol/L, with 72% having a normal sCr (<110 μmol/L) at enrolment. Chronic kidney disease (CKD) was observed in 17% of both groups. AKI was diagnosed in 16 of 82 (19.5%) patients in Group A, versus 44 of 101 (43.6%) in Group B (p=0.0008). AKIs in Group A were mostly precipitated by excess diuretics, whereas the triggers in Group B were LVP and infections (p=0.05). AKI episodes in group A were diagnosed at a mean of 45±55 days, significantly longer than the 22±26 days in Group B (p=0.0025). The Table shows the renal parameters for the AKI episodes between the 2 groups. Group B patients had more hospital admissions (75 admissions in 67 patients) versus Group A (40 admissions in 30 patients) (p<0.0001) during 6 months of follow-up. Similar proportions of patients died in Group A (9.8%) versus Group B (13.9%) (p=0.49). However, Group A patients survived significantly longer at 174±34 days versus 159±47 days in Group B, p=0.015.
Conclusion(s): Patients with small ascites not requiring regular LVP are less susceptible to AKI development. Late AKI diagnoses are related to infrequent hospital visits, with resultant higher peak sCr and less patients receiving treatment. Despite this, clinical outcomes are more favorable than patients with refractory ascites. Regardless, patients with ascites, independent of its severity, need to be monitored frequently to reduce the risks of AKI development.
FUNDING: Mallinckrodt Pharmaceuticals
Disclosure of Interest: None Declared
Q J Zhao1,*, E Lee2,*, J J Feld2,3, H Shah2,4, M Cunningham2,4
1Toronto Rehabilitation Institute, University Health Network, Toronto, Ontario, Canada,
2Toronto Centre for Liver Disease – Francis Family Liver Clinic, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada,
3McLaughlin Rotman Centre for Global Health, University of Toronto and UHN, Toronto, Ontario, Canada,
4Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Background: Three types of nursing professionals practice in Ontario: nurse practitioners (NPs), registered nurses (RNs), and registered practical nurses (RPNs). Each practice with a different scope and clinical independence. Nursing professionals are well-positioned within team-based models of care to address gaps in liver disease management. In the 2016 World Health Organization report on global strategy to elimination of viral hepatitis, strengthening health human resources and community-based services were identified as two key priority areas. Nurse-led models were an essential part of this strategy.
The Extension for Community Healthcare Outcomes (ECHO) Model™ is a tele-mentoring education program that connects healthcare providers from rural, remote, and underserved areas to an interprofessional specialist team. Each weekly session includes didactics and a patient case. Recommendations are then provided for each patient. ECHO Ontario Liver launched in 2017, targeting healthcare providers’ knowledge and competence in treating and managing liver diseases.
Purpose: This study aims to explore the experience of the ECHO Liver program on nursing professionals and their perspective on the interprofessional management of liver diseases.
Method: We conducted a qualitative study with nursing professionals who attended ECHO Liver sessions from January 2017 to September 2022. Focus group discussions were conducted with nursing professionals to explore their experience in ECHO Liver, their role negotiation in in liver care management (interprofessional collaboration), and the impact of ECHO Liver on their practice. All focus groups were conducted virtually, recorded, and professionally transcribed. A qualitative descriptive method was used to analyze transcripts. Final themes were reach by consensus. This study was approved by UHN REB #20-5222.
Result(s): Six focus group discussions were conducted between November 2021 and October 2022. Out of 20 participants, 13 (65%) were NPs, 6 (30%) were RNs, and 1 (5%) was an RPN. All participants identified as female.
Nursing professionals who practiced at all levels of liver care management participated. They were responsible for the full spectrum of liver care and management from the coordination of patient appointments to the provision of relevant clinical tasks and wraparound services.
Nursing professional participants were highly satisfied with the ECHO Liver program. Interestingly, all but one nursing professional worked on a team-based model of care, and they were the only healthcare provider to attend ECHO Liver sessions from their team and receive advanced training. NPs worked to full scope, meaning these nursing professionals managed their patients with liver disease mostly independently. The ECHO Liver program was perceived to fill a need for these participants, as the intention for attending for many participants was a perceived gap in their clinical knowledge. Finally, of the participants who presented their patient case, some used ECHO recommendations as a means of advocating for new or different care on their clinical teams. The ECHO Liver program became a resource for knowledge, confidence, and support.
Conclusion(s): Nursing professionals play a critical role in liver disease treatment and management. Participants who attended the ECHO Liver gained specialty training and knowledge. They also used knowledge from ECHO sessions as a means of advocacy for new or different care on their clinical teams. Future research will aim to examine contextual factors regarding differences in ECHO uptake and liver disease care.
FUNDING: Ontario Ministry of Health
Disclosure of Interest: None Declared
A Trigui1,2,*, G Huard3, J Maxwell3, M Tremblay2, CF Rose1,2, C Bémeur1,2
1Nutrition, Université de Montréal, Montreal, Quebec, Canada,
2Hepato-neuro laboratory, CRCHUM, Montreal, Quebec, Canada,
3Liver Unit, CHUM, Montréal, Quebec, Canada
Background: In Canada, more than 400 liver transplantation (LT) are performed every year. However, organ availability continues to be a major issue in LT, as the waiting time for a deceased liver donor ranges from months to years. In patients with end-stage liver disease waiting for LT, protein-energy malnutrition is the most common complication (> 80%) and one of the main risk factors for the onset and progression of sarcopenia (loss of muscle mass and function or quality). Previous clinical studies have shown that sarcopenia and malnutrition are associated with a prolonged hospital stay, increased mortality and higher rate of infections as well as a decrease in quality of life. Pre-operative malnutrition could also impact negatively on the post-transplant outcomes. Screening for the nutritional risk for patients waiting for LT is the first step to address adequate nutritional therapy. However, since the delay to receive a new liver could be long, following the patients longitudinally could help to detect the deterioration in nutritional status and muscle function at an advanced stage as well as to identify factors that could lead to this deterioration.
Purpose: In patients with cirrhosis waiting for LT: 1) Assess longitudinal changes in nutritional risk, muscle function and quality of life. 2) Identify factors that could lead to deterioration of nutritional status, muscle function and quality of life.
Method: Patients with end-stage liver disease waiting for LT at the CHUM were included. Muscle function (Chair Stand Test), nutritional risk (Liver Disease Undernutrition Screening Tool), and quality of life (SF-36) are assessed every 3 months prior to LT. Biochemical and anthropometric data, medications as well as complications are collected at each follow-up.
Result(s): Currently, 36 patients awaiting LT have been included. The mean age is 51.3 ± 11.6 years. The most common etiology is alcohol (33%). At enrollment, 86% (31/36) of patients are at risk of malnutrition, which remain unchanged with follow-ups ranging to 18 months while on the LT waiting list. Among the 5 patients who were not at risk of malnutrition and enrollment, 60% were defined at risk with follow-ups. Based on the EWGSOP-2 diagnostic criteria, at enrollment, 73% (26/36) of patients had a low muscle strength with a mean score of 18.9 ± 7.8 s (vs 12.6 s in healthy patients; p < 0.001) which decreased with time while waiting for an LT. Regarding quality of life, the mean score of physical heath (44.6% ± 20.4) and mental health (53.5% ± 26.1) were below normal scores for healthy Canadian in the same age. The physical health score tended to further decrease over time.
Conclusion(s): A majority of patients with cirrhosis placed on the LT list are at risk of malnutrition, have an impaired muscle function which decreases with time. Moreover, quality of life is impacted, and the physical health component tended to decrease with time.
FUNDING: CDTRP
Disclosure of Interest: None Declared
M Sophasath1,2,*, M Tremblay1, CF Rose1,3, C Bémeur1,2
1Hepato-Neuro, CRCHUM, Montreal, Quebec, Canada,
2Nutrition Department, Université de Montréal, Montreal, Quebec, Canada,
3Medecine Department, Université de Montréal, Montreal, Quebec, Canada
Background: In Canada, liver disease affects 1 in 4 persons. One of the most common complications of cirrhosis is malnutrition, associated with an increased risk of mortality and a decrease in the quality of life of patients. Adherence to nutrition guidelines appears to be difficult. Very few studies have focused on the development and evaluation of nutritional education resources adapted to this population. Thus, the development and evaluation of such strategies is essential.
Purpose: The general objective of the study is to assess the potential impact of the evidence-based Nutrition in Cirrhosis Guide on cirrhotic patients followed at the CHUM’s liver outpatient clinic through a mixed-design study. The first specific objective is to quantitatively assess nutritional knowledge, quality of life and nutritional status and the second specific objective is to qualitatively assess the patients’ satisfaction of the Guide.
Method: A randomized controlled study including 100 cirrhotic patients divided in 2 groups: Intervention (Guide+, n=50) and Control (Guide-, n=50), is on-going. All patients are assessed for nutrition knowledge (literacy questionnaire), quality of life (Chronic Liver Disease Questionnaire) and presence of malnutrition (Liver Disease Undernutrition Screen Tool). The Guide is taught to Guide+ patients for 6 months. Guide- patients do not use the Guide. At times T=0, 3 and 6 months, the same evaluations are carried out. The qualitative part evaluates patients’ satisfaction of the Guide through 5 focus groups of 3 patients each to assess general appreciation, complexity and applicability of the Guide. A patient-partner participates in focus groups.
Result(s): 42 patients are included in the study so far: Guide+ (n=21) and Guide- (n=21). The groups are comparable in age (mean = 59.0 and 55.0 in Guide+ and Guide-, respectively; p=0.28). To date, 21 patients have completed the study: Guide+ (n=10) and Guide- (n=11). The preliminary results show a trend of improvement of nutrition knowledge for Guide+ patients (from 76.0% to 80.4%) after 3 months, which is not maintained at 6 months (down to 76.4%; p>0.05). The Guide- patients’ knowledge remains unchanged throughout the study (from 74.2% to 74.5% after 3 months, to 77.8% after 6 months; p>0.05). As for the presence of malnutrition, a trend of improvement is denoted in the group Guide+ (50% of patients were initially malnourished, 40% at 3 months and 20% at 6 months; p>0.05). Presence of malnutrition worsened in the group Guide- (from 36.4% to 56.5% at 3 months, to 45.5% at 6 months). Preliminary results from focus groups suggest an overall satisfaction towards the content, but a need to lighten and better divide the concepts.
Conclusion(s): The preliminary results demonstrate a trend of improvement in patients’ nutritional knowledge over 3 months, which is not maintained at 6 months, and a decrease in the presence of malnutrition after 6 months. The results of this project will help optimize the quality of care for people suffering from cirrhosis.
FUNDING: Canadian Foundation for Dietetic Research
Disclosure of Interest: None Declared
A Magony1,*, L Ata2, K Hueniken3, D Wong2, K Patel2, E Lee2
1Department of Medicine, University of Toronto, Toronto, Ontario, Canada,
2Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada,
3Department of Biostatistics, University Health Network, Toronto, Ontario, Canada
Background: Alcohol-associated liver disease (ALD) is a major cause of end-stage liver disease and is associated with significant health-care burden after initial hospitalization. For discharged ALD patients, there is limited data on predictors of hospital readmissions. This ongoing study plans to identify gaps in clinical management and assess the rate and impact of referral to ambulatory specialist care and psychosocial services on reducing inpatient readmission.
Purpose: To identify trends in ALD-related admissions in a large Canadian urban tertiary care centre from January 1, 2010 to December 31, 2019.
We will also examine for associations between readmission rates and clinical factors of interest, including referral rates to ambulatory specialist and psychosocial services, inpatient assessment by addictions, metabolic comorbidities, gender, social supports, age, length of stay, and MELD score.
Method: Retrospective cohort study from a tertiary centre (University Health Network) from 2010-2019 with case identification using ICD-10 codes and electronic chart review with consensus. Clinical and demographic variables were collected on ALD patients from their index hospitalization, including age, gender, social supports, metabolic comorbidities, assessment by inpatient addictions, and ambulatory referral to psychosocial care and General Hepatology. For patients with multiple admissions, the first captured encounter was treated as the primary admission. Admissions that resulted in death were excluded from analysis. Variables associated with readmissions within one year were evaluated using logistic regression models.
Result(s): Preliminary data from our initial n=129 ALD patients indicated that there was a significant association between readmission within one year and older age (p=0.041) as well as a borderline significant association between readmission within three months and higher initial admission MELD-Na score (p=0.053). 86% of ALD patients were referred to Hepatology clinic. In contrast, only 7.7% and 14.0% were referred to inpatient and outpatient Psychiatry, respectively. 25.6%, 14.0%, and 15.4% of patients were readmitted 1, 2, and more than 3 times, respectively. A logistic regression model (adjusted for age, gender, LOS, metabolic comorbidities, admission MELD, inpatient or outpatient psychiatry referral, social supports, and hepatology referral) demonstrated that any inpatient or outpatient psychiatry referral was independently associated with reduced readmissions within one year with borderline significance (p=0.04 unadjusted, 0.10 adjusted). Length of stay (p=0.03 adjusted) and, unexpectedly, outpatient hepatology referral (p=0.01 adjusted) were associated with greater odds of readmission.
Conclusion(s): Our preliminary findings from this retrospective Canadian tertiary centre cohort of hospitalized ALD patients indicate that the majority were referred to ambulatory Hepatology clinic following index admission whereas few were referred for psychosocial assessment, despite the assocation between psychosocial referral and reduced readmissions within one year. These observations suggest that ALD patients are referred primarily for liver disease management as opposed to treatment for underlying alcohol use disorder. Data abstraction is ongoing in a further 300 patients and other factors, including clinical outcomes, psychiatric comorbidities, active alcohol use, history of substance use, medical therapy for ALD, presentations of liver decompensation, and clinical outcomes will be evaluated in this ongoing study.
FUNDING: None
Disclosure of Interest: None Declared
M Saunders1,*, K Blonde2, P Zezos3
1Internal Medicine, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada,
2Critical Care Medicine, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada,
3Gastroenterology, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada
Background: Acute liver failure (ALF) can be a feature of hemophagocytic lymphohistiocytosis (HLH), which is an underdiagnosed syndrome of immune dysregulation and unopposed inflammation. HLH has many potential triggers including rheumatological disorders, immunodeficiency, malignancy, infection, and rarely trauma. HLH is associated with high mortality and early recognition is essential for administering definitive treatment and improving prognosis.
Purpose: We report a rare case of undifferentiated acute liver failure, HLH syndrome and TTP (thrombotic thrombocytopenic purpura) in a 33-year-old woman precipitated by a motor vehicle accident (MVA).
Method: A healthy 33-year-old female presented to hospital with acute complaints of fever, nausea, and chest pain seven days following an MVA with a bear. In addition to multiple left-sided rib fractures, investigations demonstrated a severe hepatocellular injury: ALT 2415 U/L, AST 3490 (U/L), ALP 208 (U/L), GGT 362 (U/L), a mildly elevated INR and ferritin >10,000 mg/L. Abdominal imaging revealed diffuse hepatic steatosis and hepatosplenomegaly, but multiple MRCPs showed no obstruction. On review, she had no personal history of liver disease, took no prescription or OTC medications, consumed minimal quantities of alcohol, and had no relevant family history. Extensive work-up was negative for any autoimmune, toxic, metabolic, or infectious aetiologies of acute liver failure. Her presumptive diagnosis was hepatocellular injury secondary to abdominal trauma. She developed ascites, encephalopathy, and AKI requiring dialysis within ten days of admission. She had an episode of bacteremia with respiratory failure requiring intubation. Although her synthetic liver function slowly improved, she had persistent, progressive and severe conjugated hyperbilirubinemia (>900 mmol/L), unexplained pancytopenia, hyperferritinemia, hypertriglyceridemia, and hypofibrinogenemia. Liver biopsy could not be performed due to severe coagulopathy. A bone marrow biopsy revealed hemophagocytosis, with positive immunological testing (CXCL9 and IL-2 RA) diagnostic for HLH. Testing also showed low ADAMTS13 levels and high circulating activity of autoantibodies, consistent with TTP. Despite initiation of steroids and etoposide for HLH, and therapeutic plasma exchange for TTP, the patient developed progressive MOF and died.
Result(s): This case report illustrates how ALF of unknown etiology was an early presentation of HLH and TTP following abdominal trauma. It is possible the patient had undiagnosed NAFLD prior to her trauma, as evidenced by steatosis on abdominal imaging. Inflammation related to abdominal trauma may have rendered the liver vulnerable to autoimmune activation, triggering HLH.
Conclusion(s): HLH is rare and difficult to diagnose due to non-specific biochemical findings including fever, hypertriglyceridemia, ferritinemia, and cytopenias. HLH is associated with high mortality and early diagnosis is crucial for initiating urgent management.
FUNDING: None
Disclosure of Interest: None Declared
V Navalhas Cipriano1,*, F Dilauro1, V-A Raymond1, C Vincent2, F Alvarez3, M Bilodeau1,2, P Lapierre1,2
1Laboratoire d’hépatologie cellulaire, Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, Canada,
2Département de médecine, Université de Montréal, Montreal, Quebec, Canada,
3Service de gastroentérologie, hépatologie et nutrition, CHU Sainte-Justine, Université de Montréal, Montréal, Quebec, Canada
Background: Current first-line treatment achieves an adequate response in 80%-90% of patients with autoimmune hepatitis (AIH). However, if liver inflammation is not controlled, 10%-20% of patients may progress to cirrhosis or liver transplantation. Currently, no clinical, biological, or histological parameters can predict the initial response to treatment or long-term remission. Therefore, there is a crying need for reliable biomarkers to predict disease activity and response to treatment.
Purpose: This study aimed to identify biomarker(s) of disease activity and treatment response in AIH patients.
Method: Using our biobank of biological samples and clinical data of AIH patients, a cross-sectional immunological profiling of cytokines linked to subtypes of CD4 T cells (IL-16, IL-23a, IL-17, IL-17f, IL-10, IL-2, IL-21, and IL-22) and flow cytometry analysis of CD4 T cells (CD4 effector and regulatory T cells) was performed on biological samples (plasma and PBMCs) at the time of diagnosis and during treatment to identify putative biomarkers associated with disease activity and/or a favorable response to treatment.
Result(s): Expression of the anti-inflammatory cytokine IL-10 by PBMCs increased significantly after treatment in AIH patients that respond to first-line treatment (13.64±2.84 Fold vs. 3.36±3.1, n=9, p=0.017) while plasma levels of IL-16 decreased (542.3±107.2 vs. 338.7±22.7 pg/mL after treatment, n=116, p=0.0099). AIH patients with elevated ALT levels (>40 IU/L) have significantly higher plasmatic levels of IL-16 than those with normal ALT levels (<40 IU/L) (71.34±33.85, n=243, p=0.0359). Patients that respond to first-line treatments also had higher CD3+CD4+FoxP3+CD25highCD127low regulatory T cells (Tregs) levels after treatment (5.38%±0.42%, n=6), similar to that of healthy controls (4.93%±0.55%, n=5), compared to patients before treatment that had significantly lower levels of Tregs (4.06%± 0.24%, n=3, p=0.038). A direct correlation between Tregs levels and IL-10 expression was also found in these patients (r2=0.6484, n=9, p=0.0088). A significant correlation was also found between Tregs levels and plasmatic levels of IL-16 (r2=0.1864, n=49, p=0.0020). Interestingly, a significant correlation was also found between plasmatic levels of IL-2 and IL-16 in these patients (r2=0.1475, n=302, p<0.0001) suggesting a possible link between Tregs and IL-16 since IL-2 is an essential factor for the survival and differentiation of Tregs. Interestingly, a significant correlation was also found between activated CD4 T cells and activated CD8 T cells and plasmatic levels of IL-16 (r2=0.1469, n=49, p=0.0066 and r2=0.08227, n=49, p=0.0457, respectively) suggesting that activated T cells, the main producers of IL-2, could also be linked with IL-16.
Conclusion(s): Expression and circulating levels of IL-10 and CD4 regulatory T cells are increased in AIH patients that respond to treatment while IL-16 levels are decreased. These results suggest that plasma levels of IL-10, IL-16, and CD4 regulatory T cells could be putative biomarkers for disease activity and treatment response in AIH patients. These results also suggest that IL-16 could affect both pro-inflammatory and anti-inflammatory pathways and thus influence AIH activity in these patients. The identification of reliable biomarkers could allow for the prediction of treatment response in treatment-naïve patients and the development of effective personalized therapy and could be a milestone achievement for the clinical management of difficult-to-treat AIH patients.
FUNDING: Autoimmune Hepatitis Pinnacle Research Award in Liver Disease of the American Association for the Study of Liver Disease (AASLD) to Pascal Lapierre and Chaire de recherche Novartis-Fondation canadienne du foie en hépatologie de l’Université de Montréal to Marc Bilodeau.
Disclosure of Interest: None Declared
D Camat1,*, C Perciani2, SW Chung1, Y Liu1, J Manuel2, AM Bartczak2, ML Cheng1, OI Pezzutti1, SM Jafari1, X-Z Ma2, ID McGilvray2, SA MacParland1,2
1University of Toronto, Toronto, Ontario, Canada,
2University Health Network, Toronto, Ontario, Canada
Background: The precision-cut liver slice (PCLS) model is a unique platform in that it allows for the culturing and modulating of parenchymal and non-parenchymal cell types in intact liver tissue. Although used mostly in drug metabolism and toxicity studies, PCLS holds great potential for the study of intrahepatic immune populations within microenvironment in health and disease.
Purpose: To expand the applicability of PCLS beyond drug screening assays, it is critical to standardize a protocol that allows slices to remain viable in culture for extended periods of time. We have established a reproducible workflow with a fixed endpoint that promotes the extended viability of tissue slices whilst allowing for the evaluation of introduced interventions, such as treatment with the pro-regenerative and hepatoprotective cytokine, interleukin 4 (IL-4).
Method: Liver slices with a thickness of 250 uM, and a diameter of 6 mm and 3 mm were cultured for 5 days. Immunohistochemistry (IHC) was used to examine the morphology, apoptosis, and proliferation of cells in the cultured slices, using hematoxylin & eosin (H&E), Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and ki-67 stains respectively. Slice viability was measured by the quantification of nucleation and ATP production. Slices were treated with IL-4 at 50ng/mL to assess the impact on hepatocyte viability and regeneration.
Result(s): H&E staining demonstrated consistent presence of viable hepatocytes across slices on Day 5. Slices of 6 mm diameter produced ATP in the 500-1000 nM/mg range, in comparison to slices of 3 mm diameter which produced a greater amount of ATP within the range of 1500-2500 nM/mg. Additionally, quantification of nuclei revealed that slices of 3 mm diameter presented with less apoptosis compared to slices of 6 mm diameter. This suggests that slices of 3 mm diameter are more viable than those of 6 mm diameter. Slices of 3 mm diameter further treated with IL-4 presented with higher levels of ATP (517-1453 nM) in comparison to untreated slices (358-970 nM) on Day 5 of culture, as well as exhibiting an increased number of viable nuclei throughout culture. Staining with Ki-67 revealed that on Day 3 of culture, slices treated with IL-4 showed more proliferating cells compared to untreated.
Conclusion(s): We established a robust PCLS workflow by determining appropriate viability indicators and standardizing replicate size. Additionally, we demonstrate that slices of 3 mm diameter are the optimal size due to increased viability and reduced variability across replicates, allowing for more uniform assessment of interventions. We further promoted viability and regeneration of hepatocyte-like and cholangiocyte-like cells by IL-4 administration. A long-term goal of this work is to employ PCLS to identify and test potential therapeutic modifiers of the liver microenvironment in vitro.
FUNDING: CIHR
Disclosure of Interest: None Declared
J Grondin1,2,3,4,*, W Gagnon1,2,3,4, J Chouinard1,3,4, M Verreault1,3,4, J Trottier1,3,4, A Caron2,5, O Barbier1,2,3,4
1Endocrinology and Nephrology Axis, CHU de Québec-Université Laval Research Center, Laboratory of Molecular Pharmacology, Québec City, Quebec, Canada,
2Laval University, Faculty of Pharmacy, Québec City, Quebec, Canada,
3Laval University, Centre Nutrition, santé et société (NUTRISS), Québec City, Quebec, Canada,
4Laval University, Institute of Nutrition and Functional Foods, Québec City, Quebec, Canada,
5Laval University, Quebec Heart and Lung Institute (IUCPQ) Research Center, Québec City, Quebec, Canada
Background: Glucuronidation, catalyzed by the UDP-glucuronosyltransferases (UGTs) enzymes, is a detoxification mechanism for numerous exo- and endogenous compounds like bile acids (BAs). Although essential for cholesterol homeostasis and intestinal absorption of liposoluble alimentary lipids and vitamins, BAs are cytotoxic at high concentrations and provoke cell death, as observed in cholestatic pathologies such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), where impaired bile flow causes BA accumulation in hepatocytes. Because BA-glucuronide (-G) are abundantly detected in human urine, glucuronidation is viewed as a rerouting mechanism allowing BA detoxification when bile flow is reduced. This suggests that stimulating hepatic glucuronidation could be used as a novel avenue for PBC and PSC treatment. However, little is known about BA glucuronidation in rodents, which limits the realization of in vivo experiments aimed at validating this hypothesis.
Purpose: The purpose of this study is to characterize the glucuronidation of bile acids in mice.
Method: Murine tissue homogenates (liver, duodenum, jejunum, ileum, caecum, colon, kidney) from 8-month-old SP1 Elite mice (n=4/sex) or microsomal Ugt2b (Ugt2b1, 2b5, 2b34, 2b35, 2b36, 2b37 and 2b38) were incubated with 100mM of BAs (cholic acid (CA), chenodeoxycholic acid (CDCA), α-, β-, ω-muricholic acid (α-, β-, ω-MCA), lithocholic acid (LCA), deoxycholic acid (DCA), hyocholic acid (HCA) or hyodeoxycholic acid (HDCA)) for 1h at 37°C. Kinetic assays were performed with concentrations ranging from 0 to 600mM. BA-glucuronides (BA-G) were quantified using LC-MS/MS.
Result(s): The highest glucuronidation reactions were observed with β-MCA in female and male livers (5.5±0.4 and 3.7±0.4 pmol b-MCA-G/min/mg proteins, respectively) and colon (3.1±0.4 and 2.1±0.4 pmol β-MCA-G/min/mg proteins, respectively). Screening assays with the seven Ugt2b isoforms identified Ugt2b34 as the most active enzymes for the conjugation of CDCA, LCA, DCA and HDCA (with maximal velocity of 10.2±1.3 pmol DCA-24G/min/mg proteins) and Ugt2b37 for CDCA, LCA, β-MCA and HDCA (with maximal velocity of 42.8±4.7 pmol b-MCA-G/min/mg proteins). Previous observations from the lab demonstrated that b-MCA is the most frequently detected BA-G in the murine gastrointestinal tract. The kinetic parameters Km and Vmax of b-MCA glucuronidation catalyzed by Ugt2b37 were 125.6±41.0 mM and 11.2±1.7 pmol b-MCA-G/min/mg proteins, respectively.
Conclusion(s): These observations reveal that the liver and colon are the major sites for bile acid glucuronidation, and that the Ugt2b34 and 2b37 isoforms are the major contributors for this process. Future in vivo investigations on the impact of potential anti-cholestatic drugs on bile acid detoxification, may look at Ugt2b34 and 2b37 expression and activity in the liver and colon.
FUNDING: CIHR
Disclosure of Interest: None Declared
A-A Lavoie1,2,*, M Verreault1,2, A Marette2,3,4, O Barbier1,2,5
1Laboratoire de pharmacologie moléculaire, Axe Endocrinologie-Néphrologie, Centre de recherche du CHU de Québec - Université Laval, Quebec City, Quebec, Canada,
2Centre de recherche Nutrition, Santé et Société (NUTRISS), INAF, Université Laval, Quebec City, Quebec, Canada,
3Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec City, Quebec, Canada,
4Faculté de médecine, Université Laval, Quebec City, Quebec, Canada,
5Faculté de pharmacie, Université Laval, Quebec City, Québec, Canada
Background: Bile acid (BA) accumulation in liver cells contributes to the pathogenesis of cholestatic autoimmune liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Reducing BA toxicity is therefore a major drug target for PBC and PSC treatments. Ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are the only FDA-approved treatments for these pathologies. However, these drugs have very limited therapeutic windows, which are associated with overdosing events. It is therefore essential to find new therapeutic alternatives. The FXR agonist cilofexor and the PPARs ligands such as fenofibrate, bezafibrate, elafibranor and seladelpar are currently evaluated in the context of PBC/PSC treatment. Our lab previously observed that adding n-3 polyunsaturated fatty acids (PUFA) to UDCA and OCA improves their ability to provide a more favorable transcriptomic profile for BA synthesis, metabolism, detoxification and signaling.
Purpose: The goal of the present study was to evaluate whether the addition of n-3 PUFAs, such as the eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, impacts the BA-related transcriptomic signature of PPAR and FXR agonists currently tested for PBC/PSC treatment.
Method: Human hepatoma HepG2 cells were treated for 24H with vehicle (DMSO; ethanol 0.01%; v/v), 1μM cilofexor, elafibranor or seladelpar, or 100μM fenofibric acid or bezafibrate in the absence or presence of EPA/DHA (50/50 μM). Total RNA was purified and the mRNA expression of 27 BA-related genes was analyzed through qRT-PCR.
Result(s): The presence of EPA/DHA significantly improved the ability of cilofexor to stimulate mRNA expression of UGT2B4 (p<0.05) and OSTα (p<0.001), 2 factors governing BA detoxification and export. In the same vein, n-3 PUFAs reinforced the ability of elafibranor to stimulate the expression of the apical BA export pump MRP2 (p<0.01) and to reduce transcripts levels of NTCP (p<0.01), a major factor for BA recapture from the portal circulation. When compared to the drug alone, the combinations EPA/DHA+fenofibrate or bezafibrate displayed higher capabilities to reduce BA synthesis through an improved down-regulation of the gene encoding for the rate-limiting BA synthesizing enzyme 7α-hydroxylase (i.e., CYP7A1). Interestingly, the presence of EPA/DHA only minimally changes the BA-related transcriptomic signature of seladelpar.
Conclusion(s): All together, these results reveal that N-3 PUFAs alter in a differential manner the BA-related transcriptomic signature of FXR and PPAR agonists. Whether these alterations provide additional therapeutic benefits will need careful in vivo investigations.
FUNDING: CASL ans NUTRISS
Disclosure of Interest: None Declared
S L’Ecuyer1,2,*, A Matesan2,3, F Tamnanloo2,4, M Oliveira2, M Tremblay2, E Charbonney4,5, CF Rose2,4
1Department of Pharmacology and Physiology, Université de Montréal, Montreal, Quebec, Canada,
2Hepato-neuro lab, Centre de Recherche du CHUM, Montreal, Quebec, Canada,
3Department of Microbiology, Infectology and Immunology, Calgary, Alberta, Canada,
4Department of Medicine, Université de Montréal, Montreal, Quebec, Canada,
5Intensive Care Unit, CHUM, Montréal, Quebec, Canada
Background: Hepatic encephalopathy (HE) is a debilitating complication of cirrhosis that affects over 40% of chronic liver disease (CLD) patients, leading to gross disorientation, asterixis, memory impairments, and death. An increase in blood ammonia has been coined the major factor in the pathogenesis of HE. However, the severity of symptoms does not always correlate with blood ammonia concentrations. This implies other factors may be involved. Hyperuricemia is associated with metabolic syndrome and chronic alcohol consumption which are known precipitating factors of CLD. Furthermore, uric acid (UA) has been reported to be involved in the induction of neuroinflammation and cell loss by apoptosis and pyroptosis, leading to anxiety-like behaviour and memory impairment.
Purpose: This study investigates the impact of hyperuricemia on cognitive impairment in a rat model of chronic liver disease.
Method: We used the bile-duct ligation (BDL) model; a well-characterized rat model of chronic liver disease and HE. Fifty-two male Sprague-Dawley rats (200-240 g) were randomly assigned to a control (SHAM) or a BDL surgery. To induce hyperuricemia, half of the animals were fed a high uric acid diet (HUAD) (3% uric acid), dividing our rats into 4 groups: (1) SHAM+regular diet (RD), (2) SHAM+HUAD, (3) BDL+RD and (4) BDL+HUAD. During 5 weeks, weekly plasma UA measurements were made and different behaviour tests were conducted (anxiety (open-field) and short and long-term memory (novel-object recognition)) during the 5th week. At the end of week 5, rats were sacrificed, their brains collected, and the frontal cortex, hippocampus, and amygdala were isolated to assess cell death (caspase-3 (apoptosis) and caspase-1 (pyroptosis) activity).
Result(s): HUAD significantly increased circulating UA in both SHAM and BDL rats. This was associated with a significant decrease in short-term memory without changes in anxiety-like behaviour for HUAD rats compared to their RD counterparts in both SHAMs and BDLs. For long-term memory, BDLs were shown to be significantly impaired compared to SHAMs. A significantly higher degree of impairment was seen in BDL+HUAD rats compared to BDL+RD. Cell death (apoptosis and pyroptosis) was then evaluated in the limbic system to explain some of the behavioural changes. In the frontal cortex, increased caspase-3 activity was measured in both SHAM+HUAD and BDL+HUAD rats in comparison to RD animals. In the hippocampus, caspase-1 activity was significantly increased in the BDL+HUAD rats compared to the BDL+RD rats and SHAM groups. In the amygdala, no significant changes in caspase activity were detected.
Conclusion(s): In SHAM rats, diet-induced hyperuricemia shows a significant increase in circulating uric acid concentration as well as short-term memory loss associated with apoptosis (caspase-3 activity) in the frontal cortex. In BDL rats, hyperuricemia induces long-term memory impairments and apoptosis in the frontal cortex as well as pyroptosis in the hippocampus. The results from this study show the merit of further investigating the role of uric acid in HE.
FUNDING: Fonds de recherche du Québec-Santé and Ferring Pharmaceuticals
Disclosure of Interest: None Declared
RD Edgar1,2,*, D Nakib1,3, J Atif1,2,3, D Camat1,2,3, S Chung1,2,3, M Xue-Zhong Ma2, J Manuel2, BA Sayed2,4, GD Bader5,6, ID McGilvray2, SA MacParland1,2,7,8
1University Health Network, Toronto, Ontario, Canada,
2Ajmera Transplant Centre, Toronto General Research Institute, Toronto, Ontario, Canada,
3University of Toronto, Toronto, Ontario, Canada,
4Sick Kids, Toronto, Ontario, Canada,
5Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada,
6The Donnelly Centre, Toronto, Ontario, Canada,
7Department of Immunology, University of Toronto, Toronto, Ontario, Canada,
8Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
Background: The liver is vital for metabolism and immune function. Although it is known that the liver is composed of a heterogeneous mix of cell types, how these cell types contribute individually, and in concert, toward liver function remains poorly understood. Mapping of the human liver transcriptomic profiles using single-cell RNA sequencing (scRNA-seq) has revealed previously unknown complexity, especially in the hepatic immune microenvironment. However, existing maps do not characterize enough healthy livers to explore natural variation between healthy individuals that might predict transplant outcomes.
Purpose: An expanded map that includes more individuals with linked transplant follow-up metadata will allow for investigation of the relationship between liver transplant outcomes and liver cell composition or transcriptomics. To better understand the cellular composition of the healthy human liver, gene expression within the liver, and how it varies between individuals basic clinical phenotyping data such as age and sex, can also be explored to better understand how such variables impact the liver.
Method: Here we integrated previously published scRNA-seq from healthy liver samples with additional novel scRNA-seq samples for a total of 36 profiled livers linked to transplant outcome metadata. Gene expression patterns, cell type composition and inferred cell type localization will be characterized to better define variability in healthy livers across individuals.
Result(s): This research will expand our understanding of the healthy human liver and how it varies between individuals. The resulting atlas will be a crucial resource as a baseline from which investigations into liver disorders and diseases can be compared. Furthermore, by characterizing the natural variation that occurs in healthy gene expression, studies into diseased livers can more easily identify dysregulated expression and provide targets for new therapeutics.
Conclusion(s): The map will serve as an essential healthy reference for future efforts to understand the characteristics of resident cells in the liver, and potential associations with healthy phenotypic differences.
FUNDING: CIHR, CanHepC and UHN Foundation
Disclosure of Interest: None Declared
Y Sachar1,*, E Wang1, CS Coffin2, A Manko2, SE Congly2, A Ramji3, S Fung4, C Cooper5, M Ma6, J Jeyaparan1, RJ Bailey7, GY Minuk8, A Wong9, KE Doucette10, M Elkhashab4, P Wong11, M Brahmania12
1Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada,
2Department of Medicine, Division of Gastroenterology and Hepatology, University of Calgary, Cumming School of Medicine, Calgary, Alberta, Canada,
3Department of Medicine, Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia, Canada,
4Department of Medicine, Division of Gastroenterology, Toronto Centre for Liver Disease, University of Toronto, Temerty School of Medicine, Toronto, Ontario, Canada,
5Department of Medicine, Division of Infectious Diseases, University of Ottawa, Ottawa, Ontario, Canada,
6Department of Medicine, Division of Gastroenterology & Liver Unit, University of Alberta, Edmonton, Alberta, Canada,
7Department of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada,
8Department of Medicine, Section of Hepatology, University of Manitoba, Winnipeg, Manitoba, Canada,
9Department of Medicine, Division of Infectious Diseases, University of Saskatchewan, Saskatoon, Saskatchewan, Canada,
10Department of Medicine, Division of Infectious Diseases, University of Alberta, Edmonton, Alberta, Canada,
11Division of Gastroenterology & Hepatology, McGill University, Montreal, Québec, Canada,
12Department of Medicine, Division of Gastroenterology and Multi-Organ Transplant Unit, Schulich School of Medicine, Western University, London, Ontario, Canada
Background: Chronic hepatitis B virus (CHB) infection is a leading cause of hepatocellular carcinoma (HCC) development. Numerous risk-scoring systems (ex. aMAP and PAGE-B) have been developed to stratify ‘high-risk’ patients into screening programs. We developed and assessed a random survival forest (RSF) machine learning model to identify patients with an elevated 5-year risk of developing HCC.
Purpose: The primary aim of this study is to evaluate the capacity of a machine learning model to assess patient risk of developing HCC in comparison to more traditional summative models
Method: Data was derived from the CanHepB Network, an ethnically heterogenous CHB patient cohort from 21 academic and community centers in Canada from January 1st, 2012 to December 31st, 2021. Inclusion criteria for model development included HBV mono-infection and having a minimum of 7/10 input features (race, age, sex, platelets, albumin, ALT, INR, AFP, HBV DNA, and bilirubin), with a known 5-year outcome data regarding diagnosis of HCC. HBeAg status and quantitative HBsAg were not included due to insufficient data. Missing feature data was imputed. A RSF model was created with 4-fold cross validation and patients in the testing set were divided into high and low risk based on the median risk score. Accuracy of 5-year HCC risk prediction was assessed through AUC and compared to a Cox proportional hazard model developed using the same dataset. For comparison, complete-case analysis of existing aMAP and PAGE-B was conducted.
Result(s): Of the 6243 patients with CHB, 1058 patients had 5-year longitudinal data. All variables were available in 555 patients with 19 HCC events. The imputed dataset consisted of 621 patients with 83 HCC events. In the RSF 4-fold cross validation process, AFP, HBV DNA status, platelets, and age were consistently weighed as the most statistically significant determinants of HCC risk while sex, race, INR, and ALT were determined to be less significant determinants. The 5-year AUC based on median cut-off for the RSF model was 0.89 when stratified into high and low-risk, vs. AUC of 0.77 for PAGE-B and 0.81 for aMAP. The Cox model generated using our dataset had an AUC of 0.78. The RSF model also had the highest values for other metrics of accuracy, including sensitivity (0.99), specificity (0.57), positive predictive value (0.25), and negative predictive value (1.00).
Conclusion(s): The RSF model had an improved predictive capacity for 5-year HCC risk in CHB patients compared to more traditional scoring models, as well as a Cox model developed with the same dataset. Further, it demonstrated appropriate ability to stratify patients as high and low risk without missing patients that would develop HCC within the 5 year interval, a crucial aspect of effective screening. With results supporting the efficacy of this model, next steps would include investigating the capability of RSF model to optimize resource allocation for HCC screening and attempting external validation with new datasets.
FUNDING: None
Disclosure of Interest: Y Sachar: None Declared, E Wang: None Declared, CS Coffin Grant / Research support from: Gilead Sciences, Janssen Pharmaceuticals, GSK, Consultant of: Altimmune Pharmaceuticals, Speakers bureau of: Gilead Sciences, A Manko: None Declared, SE Congly Grant / Research support from: Bristol-Myers Squibb Canada, Genfit, Allergan, Sequana Medical Inc, Axcella Health, Inc., Gilead Sciences Canada, Consultant of: Eisai Pharmaceuticals, AstraZeneca, Paladin Labs, Novo Nordisk, Speakers bureau of: Intercept Pharmaceuticals, A Ramji Grant / Research support from: AbbVie, Assembly, Galmed, Gilead, Intercept, Janssen, Merck, Novartis, Novo-Nordisc, Pfizer, Consultant of: AbbVie, Gilead, Novartis, Intercept, Janssen, Novo-Nordisc, Pfizer, Speakers bureau of: AbbVie, Gilead, Intercept, Novo-Nordisc, S Fung Grant / Research support from: Gilead Sciences, Assembly Biosciences, Janssen, Consultant of: Janssen, AbbVie, C Cooper: None Declared, M Ma: None Declared, J Jeyaparan: None Declared, RJ Bailey: None Declared, GY Minuk: None Declared, A Wong Grant / Research support from: Gilead, Merck, ViiV, AbbVie, Consultant of: Gilead, AbbVie, Merck, ViiV, Pfizer, Speakers bureau of: Gilead, Merck, ViiV, KE Doucette: None Declared, M Elkhashab Grant / Research support from: Altimune, Assembly Biosciences, Arbutus Biopharma, BMS, Boehringer, Sagimet, Intercept, Galmed, Gilead Sciences, Madrigal, NovoNordisk, Pfizer, Protagonist, Consultant of: AbbVie, NovoNordisk, Speakers bureau of: AbbVie, P Wong: None Declared, M Brahmania: None Declared
AA Shaheen1,*, F Yang1, M Swain1, M Brahmania1, J Gonzales Abraldes2
1University of Calgary, Calgary, Alberta, Canada,
2University of Alberta, Edmonton, Alberta, Canada
Background: Increased alcohol sales during the COVID-19 pandemic restrictions have led to a significant increase of alcoholic hepatitis (AH) admissions in Alberta early in the pandemic.
Purpose: We aimed to evaluate the impact of the COVID-19 pandemic on hospitalizations in patients with AH in Alberta, Canada.
Method: We used the definition of the National Institute of Alcohol Abuse and Alcoholism (NIAAA) to identify patients admitted with AH in the province of Alberta between March 2018 and March 2022. We divided admissions into three stages: pre-pandemic (March 2018- March 2020), first year of the pandemic (April 2020-March 2021), and second year of the pandemic (April 2021-March 2022). We calculated AH hospitalization monthly rates compared to overall hospitalizations. We compared demographic and clinical characteristics of AH admissions between the three pandemic stages.
Result(s): We identified 1,413 hospitalizations for AH (552 pre-pandemic, 462 during the first year, and 399 during the second year of the pandemic). Women admissions were similar during these stages (40.2%, 39.8%, and 45.1%, respectively, p=0.22). AH admissions were more likely in younger patients (median age: 48, 44, and 44 years old, respectively, p<0.001) and those living in rural areas (22.5%, 39.2%, and 31.8%, respectively, p<0.001). Average MELD-Na was similar between the three stages (24, 25, and 25, respectively, p=0.39). The hospitalization rates significantly increased during the first year of the pandemic (133/100,000 hospitalizations) and second year of the pandemic (102/100,000), compared to pre-pandemic (65/100,000) p<0.001, Figure.
Conclusion(s): Since the beginning of the COVID-19 pandemic, AH admissions have particularly involved younger patients living in rural areas. Furthermore, admissions for AH peaked during the first year of the pandemic but remained elevated during the second year compared to pre-pandemic rates.
Funding: Wider Impact of COVID CIHR grant, 2022
Disclosure of Interest: AA Shaheen Grant / Research support from: Gilead, F Yang: None Declared, M Swain: None Declared, M Brahmania: None Declared, J Gonzales Abraldes: None Declared
N Faisal1,*, L Kosowan2, H Zafari3, F Zulkernine3, L Lix4, E Renner1, H Singh1, A Mahar5, A Singer2
1Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada,
2Family Medicine, University of Manitoba, Winnipeg, Manitoba, Canada,
3Queen’s University, Kingston, Ontario, Canada,
4Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada,
5School of Nursing, Queen’s University, Kingston, Ontario, Canada
Background: Worldwide, more than 2 million deaths are attributed every year to liver cirrhosis and its complications including portal hypertension, liver failure and hepatocellular carcinoma (1-2). It is widely accepted that, due to ambiguities inherent to diagnostic coding systems, the morbidity, health care utilization and mortality of liver cirrhosis are underestimated, and the true disease burden is significantly higher than usually reported (3-4). Electronic medical records (EMRs) provide a potential source of clinical data and serve as an important and cost-effective tool for conducting clinical research and disease surveillance (5-7). While selection bias is inherent to any population seen and captured in the database of specialized referral centres, the primary care EMR based data from a large national network such as that of the Canadian Primary Care Sentinel Study Network (CPCSSN) can more closely reflect the entire population (8). Using EMR data to correctly identify patients with cirrhosis (or any other diagnostic entity) requires the development of a case definition and the validation of case-finding diagnostic algorithms.
Purpose: We aimed to develop and validate case definitions to identify patients with cirrhosis and alcohol related cirrhosis using data from pan-Canadian primary care EMRs to provide national cirrhosis prevalence and incidence estimates.
Method: We performed a retrospective cross-sectional study using EMRs in the Canadian Primary Care Sentential Surveillance Network (CPCSSN). Initial study population comprised of 1,493,516 individuals. A total of 689,301 adult patients were included who made at least one visit to a primary care provider between January 1, 2017, and December 31, 2018. A subsample of 17,440 patients was used to validate our case definitions. Sensitivity, specificity, negative (NPV) and positive predictive values (PPV) were calculated for each definition with their 95% confidence intervals (95% CIs). Prevalence and incidence were estimated for the overall population, along with their 95% CI.
Result(s): The most accurate case definition for cirrhosis included: ≥1 health condition (problem list entry), billing or encounter diagnosis for International Classification of Diseases, Ninth Revision (ICD-9) codes 571.2, 571.5, 789.59, or 571. The sensitivity was 85.6% (95% CI: 82.9-88.0%), specificity 99.9% (95% CI: 99.9-100.0%), PPV 98.6% (95% CI: 97.4-99.3%), and NPV 99.2% (95% CI: 99.1-99.4%). Application of this definition to the overall population resulted in a crude prevalence estimate of 0.46% (95% CI: 0.45-0.48%). Annual incidence of patients with a clinical diagnosis of cirrhosis nearly doubled between 2011 (0.05%, 95% CI: 0.04-0.06%) and 2019 to (0.09%, 95% CI: 0.08-0.09%). The figure provides annual incidence estimates by sex. Although male patients had a consistently higher incidence estimate of cirrhosis, the incidence rate among female patients increased significantly over the study period. Among men incidence rose from 0.08%, (95% CI: 0.07-0.1%) to 0.11% (95% CI: 0.1-0.13%) between 2011 and 2019, whereas incidence among female rose from 0.03% (95% CI: 0.02-0.04%) to 0.07% (95% CI: 0.06-0.07%) (p=0.02). The annual incidence of alcohol-related cirrhosis was stable over the study period (0.01% to 0.02%).
Conclusion(s): This study is the first to use primary care data to validate case definitions for cirrhosis in Canada. The EMR-based case definition developed in this study accurately captured patients diagnosed with cirrhosis. Future work to characterize patients with cirrhosis and their primary care experiences can support improvements in identification and management of this condition in primary care settings.
FUNDING: Advanced Analytics Grant from IBM and Canadian Institute for Military and Veteran Health Research.
Disclosure of Interest: None Declared
K Leung1,2,*, W Li3, M Ismail2, A Bal2, A Gulamhusein2,4, B Hansen1,2,5, J Flemming3,6, G Hirschfield2,4
1Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada,
2Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada,
3ICES, Kingston, Ontario, Canada,
4Medicine, Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Ontario, Canada,
5Epidemiology, Biostatistics, Erasmus MC, Rotterdam, South Holland, Netherlands,
6Medicine and Public Health Sciences, Queen’s University, Kingston, Ontario, Canada
Background: Primary sclerosing cholangitis (PSC) is a rare, chronic progressive liver disease; 70%-80% of patients also have inflammatory bowel disease (IBD). Understanding the total disease burden is important as part of efforts to improve outcomes.
Purpose: Herein, we compare PSC-IBD patients identified using healthcare administrative data housed at ICES in Ontario to patients in a clinical cohort followed at the Toronto Centre for Liver Disease (TCLD).
Method: Individuals with PSC-IBD were identified using ICES data holdings as (1) residents of Ontario with public provincial health insurance, (2) having IBD as defined by criteria for the Ontario Crohn’s and Colitis Cohort, and (3) with at least 1 diagnostic code use for cholangitis and/or PSC. Patients were excluded if liver transplant occurred before PSC diagnostic code use, or if diagnostic codes for autoimmune hepatitis, primary biliary cholangitis, hemochromatosis, alpha-1-antitrypsin deficiency, and/or Wilson disease were present. Sex, age, socioeconomic status, and area of residence were collected. Liver decompensation, liver transplant, and death events were recorded from 2002-2021. Annual incidence and prevalence rates were calculated for 2002-2018, adjusted for age and sex and standardized to the 2011 Canadian population. Changes in incidence and prevalence over time were evaluated using joinpoint regression. A retrospective clinical cohort of PSC-IBD patients followed at the TCLD (2000-2020) was reviewed in comparison.
Result(s): There were 888 incident cases of PSC-IBD identified in Ontario from 2002-2018. Median age at PSC diagnosis was 47 years (IQR 32-62 y); 546 (61.5%) were male. From 2002-2021, there were 173 (19.5%) who developed decompensation, 85 (9.6%) who underwent liver transplantation, and 280 (31.5%) who died during follow-up. The overall age and sex-adjusted incidence and prevalence rate of PSC-IBD in Ontario was 0.46 (95% CI 0.43-0.49) and 5.5 (95% CI 5.4-5.6) per 100,000 person-years respectively (Figure). Incidence increased at a 1.60 average annual percent change (APC) (95% CI 0.7-2.5 APC). Prevalence increased at a 4.84 average APC 2002-2015, then at a 2.44 APC on average from 2015-2018. PSC-IBD patients tended to be from higher income areas (25.6% in highest quintile vs. 14.3% in lowest quintile) and lesser material deprivation areas (24.8% in lowest quintile vs. 14.5% in highest quintile). In contrast, in the mixed secondary/tertiary clinic cohort of 435 patients with PSC-IBD followed at the TCLD, the median age of PSC diagnosis was 33 years (IQR 24-46 y.o.) and n=279 (64.1%) were male. There were 85 (19.5%) who developed decompensation, 49 (11.3%) who underwent liver transplantation, and 29 (6.7%) who died during follow-up.
Conclusion(s): Quantifying the total burden of PSC-IBD with greater accuracy will require a multimodal approach to case ascertainment. This is essential to effectively understand disease course in what appears to be a disease with rising incidence and prevalence with socio-economic distinctions.
FUNDING: None
Disclosure of Interest: None Declared
H Patel1,*, FT Yang2, MG Swain3, GM Hirschfield4, GG Kaplan3, BE Hansen4,5,6, AA Shaheen3,*
1Department of Medicine, University of Calgary, Calgary, Alberta, Canada,
2Centre for Health Informatics, University of Calgary, Calgary, Alberta, Canada,
3Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada,
4Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada,
5Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada,
6Department of Epidemiology, Erasmus University Medical Center, Rotterdam, South Holland, Netherlands
Background: Studies describing the epidemiology of primary sclerosing cholangitis (PSC) have been limited due to suboptimal case-finding and case-ascertainment in administrative healthcare databases. We integrated administrative and endoscopic databases to provide updated epidemiological data for PSC within a Canadian population.
Purpose: Our primary objective was to provide updated epideomological data for PSC within a Canadian population.
Method: We utilized population-based administrative databases and our validated novel method of integrating endoscopic databases to identify PSC patients in the Calgary Health Zone (CHZ, 1.4 million) between fiscal years 2005 and 2019. Confirmed PSC cases were defined based on radiologic and/or interventional evidence of definite bile duct changes (multifocal strictures, segmental dilatations) ± cholestatic liver biochemistry (elevated gamma glutamyl transpeptidase or alkaline phosphatase or bilirubin) within 3 years of diagnosis ± confirming liver biopsy. We used Poisson regression models and Cox proportional hazard regression to evaluate rates of incidence, prevalence and survival respectively. We used a 3-year washout period (2005-2007) to identify incident cases. Rates were adjusted to the Canadian population census of 2015.
Result(s): Between 2008 and 2019, we identified 305 patients with a confirmed diagnosis of PSC with an overall age/sex adjusted annual incidence rate 2.09 per 100,000. The majority (56.4%) were men, and median age at diagnosis was 41.3 years (IQR 29.3-53.3). Age-adjusted incidence rates were 1.85 per 100,000 in women versus 2.34 per 100,000 in men (incidence rate ratio [IRR] 0.78; 95% CI 0.61-1.01). The highest adjusted incidence was observed among 18 to 39-year-old patients (2.33 per 100,000), Table. Age/sex-adjusted point prevalence rate of PSC was 20.75 per 100,000 in 2019. Adjusted point prevalence rates were not different between women and men (18.56 versus 22.97 per 100,000; IRR 0.81 [95% CI 0.64-1.02]). After a median follow-up of 5.1 years (IQR 2.9-7.3), 15 patients underwent transplantation (4.9%) and 6 patients died (2.0%). No patients died after transplantation. Estimated 5-year survival was 94.9% (90.7-97.1%). Transplant free survival was not significantly different between men and women, p=0.40. Inflammatory bowel disease (IBD) was prevalent in 77.4% of confirmed PSC cases.
Conclusion(s): We report an increase in both the incidence and prevalence of PSC in our Canadian population. These findings may represent improved case-ascertainment and/or improved PSC management.
FUNDING: Gilead Sciences
Disclosure of Interest: H Patel: None Declared, FT Yang: None Declared, MG Swain Grant / Research support from: Gilead Sciences Investigator-Sponsored Research Grant Program, GM Hirschfield Grant / Research support from: Gilead Sciences Investigator-Sponsored Research Grant Program, GG Kaplan Grant / Research support from: Gilead Sciences Investigator-Sponsored Research Grant Program, BE Hansen Grant / Research support from: Gilead Sciences Investigator-Sponsored Research Grant Program, AA Shaheen Grant / Research support from: Gilead Sciences Investigator-Sponsored Research Grant Program
MM Sag1,*, C Camargo2, SM Sagan1,2
1Biochemistry, McGill University, Montreal, Québec, Canada,
2Microbiology and Immunology, McGill University, Montreal, Québec, Canada
Background: The HCV non-structural protein 5A (NS5A) is a phosphoprotein which has crucial roles in viral replication organelle (RO) biogenesis and virion assembly, although the precise mechanism(s) by which NS5A mediates these events remains elusive. Additionally, potent direct-acting antivirals, including daclatasvir and ledipasvir, are known to target NS5A, yet how they exert their antiviral effects are not yet clear. The NS5A protein functions as a dimer and contains an N-terminal amphipathic helix (AH) as well as three cytosolic domains (DI, DII, and DIII). DI is the dimerization and RNA binding domain, with a preference for poly(rU) sequences, while DII and DIII are intrinsically disordered regions implicated in viral replication and virion assembly. Ectopic expression of NS5A alone induces double-membrane vesicles, the sites of viral RNA replication, which indicates that NS5A is the main driver of RO biogenesis during HCV infection.
Purpose: Accumulating evidence suggests that phase separation underlies RO biogenesis in RNA viruses. We hypothesize that NS5A mediates RO biogenesis via phase separation with the viral RNA. This process is likely nucleated through high affinity, multivalent interactions with the polyU/UC-tract located in the 3’ untranslated region of the viral RNA, with further condensation mediated through low affinity interactions with rU-rich sequences across the HCV RNA. We are exploring the conditions required for NS5A-mediated LLPS in vitro and in live cells.
Method: To study NS5A-mediated phase separation, a soluble NS5A protein fused to monomeric enhanced green fluorescent protein (ΔAH-NS5A-meGFP) is used to perform electrophoretic mobility shift assays (EMSA) and standardized in vitro liquid-liquid phase separation (LLPS) assays. Using various substrate and HCV reporter RNAs, we will explore the effects of protein and RNA concentration, salt, and temperature on RNA binding and LLPS. To explore these interactions in the context of infection, we are performing co-immunoprecipitation (co-IP) and co-localization studies in infected cells, as well as trans-complementation assays.
Result(s): Our preliminary data suggests that the NS5A protein co-IPs HCV RNA during infection and can phase separate with polyU substrate RNA in vitro. Trans-complementation assays are underway to test if ectopic overexpression of NS5A improves the efficiency of RO biogenesis during infection. EMSAs will reveal the precise conditions necessary for RNA binding, and LLPS assays will be used to reveal the conditions necessary for phase separation with substrate RNAs.
Conclusion(s): We have verified that NS5A interacts with viral RNA during infection and that it is able to undergo LLPS in the presence of substrate RNA. Future research will focus on exploring the conditions required for LLPS in vitro and in live cells. We anticipate that this study will help reveal the mechanism of NS5A-mediated RO biogenesis and may help to explain the mechanism(s) of action of the potent NS5A inhibitors.
FUNDING: CIHR
Disclosure of Interest: None Declared
D Jeong1,2,*, S Wong2, J Wong2, JD Makuza1, G Mckee2, HA Velásquez García2, ZA Butt3, PA Adu2, M Binka2, S Bartlett2, A Yu2, M Alvarez2, M Krajden2, NZ Janjua1,2
1University of British Columbia, Vancouver, British Columbia, Canada,
2British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada,
3University of Waterloo, Waterloo, Ontario, Canada
Background: Thanks to modern HIV therapy, people living with HIV now have a far longer lifespan; however, people aging with HIV are more likely to develop chronic diseases, such as chronic kidney disease and end-stage renal disease (ESRD). Syndemic of chronic viral infections is also associated with an increased risk of ESRD. Additionally, hypertension and diabetes have been identified as important risk factors for ESRD.
Purpose: In a large population-based linked administrative health data, we assessed the impact of HBV, HCV and HIV mono-, co- and triple infections on incident ESRD, in people with and without hypertension or diabetes.
Method: All people who were tested in British Columbia (BC) between 1990 and 2015 for HBV, HCV, and HIV are included in the BC Hepatitis Testers Cohort and linked to administrative health databases. Individuals tested for all three infections were followed from the date of their last test until the earliest of: 1) incident ESRD 2) death or 3) end of study (2021/03/31). We adjusted for sex, birth year, ethnicity, material/social deprivation, alcohol use, drug dependence, major mental illness, opioid agonist therapy and injection drug use, and estimated subdistributional hazard ratios (sHRs) for incident ESRD with Fine-Gray competing risk models. The impact of infections on ESRD by baseline hypertension or diabetes status was examined.
Result(s): The study included 690,873 people after excluding those with prevalent ESRD. There were 5,552 incident ESRD (0.8%) and 49,752 deaths (7.2%) during a median follow-up of 6.3 years. The highest ESRD incidence rate (per 1,000 person-years) was in persons with triple HBV/HCV/HIV infection (23.23), followed by HBV/HIV (11.39), HCV/HIV (10.32), HBV/HCV (5.8) coinfections, and HIV (4.75), HCV (2.83) and HBV (1.58) monoinfections. In multivariable analysis, compared to those with no infection, people with triple infection had the greatest ESRD risk (asHR 16.9, 95% CI 14.4-19.9). In people with no baseline diabetes or hypertension, those with triple infection had the highest asHRs for ESRD (22.5, 95% CI 19.0-26.5, and 30.5, 95% CI 25.6-36.3, respectively). Among those with diabetes or hypertension, people with HBV/HIV coinfection had the highest asHRs (39.9, 95% CI 20.8-76.9, and 41.3, 95% CI 22.9-74.5, respectively), though 95% CIs overlapped with asHRs for those with triple infection (27.7, 95% CI 16.1-47.9, and 36.8, 95% CI 23.9-56.6, respectively).
Conclusion(s): Syndemic of HBV, HCV and HIV infections and chronic comorbidities significantly increased the risk of ESRD. Prevention and surveillance for ESRD is crucial for the aging population with viral infections, especially among those with hypertension or diabetes.
FUNDING: CIHR, CanHepC Network
Disclosure of Interest: None Declared
F Tian1, F Forouzannia1, M J Biondi2,3, AB Mendlowitz2, J Feld2, Z Feng4, WWL Wong1,*
1School of Phamacy, University of Waterloo, Kitchener, Ontario, Canada,
2Toronto Centre for Liver Disease/Viral Hepatitis Care Network (VIRCAN), University Health Network, Toronto, Ontario, Canada,
3School of Nursing, York University, Toronto, Ontario, Canada,
4Department of Mathematics and Statistics, University of Guelph, Guelph, Ontario, Canada
Background: Managing chronic hepatitis C (CHC) is challenging because the majority of those infected are asymptomatic. Despite the availability of highly effective direct-acting antiviral therapy, whether Canada will be able to meet the World Health Organization (WHO)’s elimination goals on schedule with the ongoing impact of the COVID-19 pandemic starting in 2020 is questionable.
Purpose: The goal of this study is to develop an agent-based model (ABM) incorporating the current hepatitis C virus (HCV) risk-based screening and treatment strategy together with the impact of COVID-19 to predict HCV incidence and prevalence in Ontario over the next decade.
Method: By combining multi-agent systems and complex networks, we developed an ABM to explain the Ontario HCV epidemic and simulate transmission risk networks that include people who inject drugs and men who have sex with men. We simulated the entire Ontario population, stratifying individuals by age, gender, sexual and injection behaviours, and immigration status. The model considered the negative impacts of COVID-19 on screening and treatment after 2019 and the potential effects of future immigration from regions where HCV is of high endemicity. We estimated parameters from literature-derived estimates regarding Ontario demographics, epidemiology, injection and sexual behaviours. HCV-related outcomes data derived from Ontario health administrative data were used for calibration, including the reported incidence of CHC, decompensated cirrhosis (DC), and hepatocellular carcinoma (HCC).The calibrated ABM was then used to predict the incidence and prevalence of CHC, DC, HCC, and liver-related deaths in Ontario from 2015 to 2030 for the current screening and treatment strategy.
Result(s): Our calibrated model demonstrated a good match between the simulation results with the historical reported CHC, DC and HCC cases. The ABM predicted that the total incidence and prevalence of CHC in Ontario would only fall by 2.4% and 18.7% in 2030, respectively. The total incidence of HCV-attributable DC, HCC, and liver-related deaths would decrease by 32.8%, 30.2%, and 19.7%, respectively, in 2030 compared to 2015, the time when the WHO established the elimination goals. In comparison with the original projection without the negative effect from COVID-19, the viral hepatitis C elimination effort was slowed down by 15.3%, 15.3%, and 16% in 2030 in terms of preventing new cases of DC, HCC, and liver-related deaths, respectively (Figure).
Conclusion(s): We have developed an ABM that reflects the dynamics of HCV transmission and the impact of COVID-19, which enables forecasting the epidemiology of HCV for policy-level decision making in Canada. Our projected results suggest that the current HCV screening and treatment strategy are insufficient in achieving the WHO elimination goals during this ongoing pandemic era.
FUNDING: CIHR
Disclosure of Interest: None Declared
K Dunn1,*
1Royal Roads University, Victoria, British Columbia, Canada
Background: Hepatitis C disproportionately impacts Indigenous communities. Nearly half of those infected are unaware of their infection or resulting liver damage. Inspiration for this research began with persistent requests from Indigenous community members for culturally relevant hepatitis C awareness resources to address rising rates.
Purpose: Many do not complete screening or treatment for hepatitis C, and in fact may not even be aware of its existence or relevance. This may be due to predominantly western biomedical approach to liver disease alongside current health inequities stemming from historical and continued trauma. Stigma, shame, fear and misinformation often accompany conversations around hepatitis, leading to continued missed opportunities for screening, treatment and cure. This led to an innovative approach incorporating Indigenous Knowledge Keepers in co-design of a culturally relevant awareness resource utilizing media to increase awareness in a storytelling approach.
Method: Wisdom Seeking in a transdisciplinary approach oriented this research to focus on respect, relevance, responsibility, reciprocity and relationship building through semi-structured conversational interviews with eight Indigenous Knowledge Keepers across Alberta. These conversations incorporated Indigenous traditional perspectives with the researcher’s nursing background to engage in a Two-Eyed Seeing approach. Incorporating traditional protocol and frequent feedback loops with participant-partners in a blending of oral tradition and storytelling with modern audio-visual media to co-create a culturally relevant DocuStory (short Documentary story style video) for hepatitis C awareness.
Result(s): Reciprocity and partnerships have been the focus in this project and frequent communication to verify respectful and appropriate intent in the script and visuals have resulted in a DocuStory that participant-partners have expressed pride in, and an eagerness to share with others. This audio-visual educational resource is a health promotion tool that sparks conversation and supports wholistic wellness approaches to liver disease while focusing on the importance of balance in the circle of wellness, inclusive of mental, spiritual, emotional and physical health.
Conclusion(s): The co-creation of this DocuStory incorporates wholistic wellness perspectives shared by Knowledge Holders/Elders, social influencers and young people with hepatitis C lived experience, and increases awareness while maintaining the interest of audiences of various ages. Demonstrating an innovative health promotion approach relevant to a wide range of health-related topics incorporating community member engagement in a media format useful in schools, harm-reduction, diagnostic screening events, and routine programming. Due to rising rates, pandemic impact on community and disparity in awareness and screening this wholistic wellness-based resource is timely to bring community together in a traditional way while sharing knowledge and learning about the liver.
FUNDING: CIHR
Disclosure of Interest: None Declared
SX Jiang1,*, J Farivar2, E Tam3, J MacIsaac3, HH Ko2,3,4, A Ramji2,3,4
1Medicine, University of British Columbia, Vancouver, British Columbia, Canada,
2Pacific Gastroenterology Research Institute, Vancouver, British Columbia, Canada,
3Pacific Gastroenterology Associates, Vancouver, British Columbia, Canada,
4Gastroenterology, University of British Columbia, Vancouver, British Columbia, Canada
Background: Hepatitis C (HCV) management has been impacted by the COVID-19 pandemic due to rapid changes in healthcare resources and infection prevention measures. This may result in more patients being lost to follow up (LTFU).
Purpose: We sought to characterize LTFU patients amongst those treated for HCV before and during the pandemic.
Method: HCV patients enrolled in the British Columbia Hepatitis C Network database who were prescribed direct acting antivirals from 09/17/2018-9/17/2021 were included. Pre-pandemic (pre-PG) and pandemic (PG) groups were defined by treatment before and after 3/17/2020, respectively. LTFU was defined as not filling prescriptions or not completing lab work for sustained virologic response (SVR).
Result(s): From 09/17/2018-9/17/2021, 339 HCV patients were planned for treatment, with 61 (16%) were LTFU. Patients LTFU were 25 pre-PG patients (out of 221, 11%) and 36 PG patients (out of 172, 21%). Patients LTFU were similar in gender (69% male in PG vs 68% pre-PG) and age (mean 52.2 years pre-PG vs 48.4 years PG, p=NS). In patients LTFU, active drug use and significant alcohol consumption was similar between both groups but more PG patients were on opioid agonist therapy (OAT), 53% (n=19) vs 24% (n=6) pre-PG (p=0.03). Baseline liver stiffness measurement (transient elastography), FIB-4 score, HCV RNA viral load, and prescribed HCV treatment regimen were similar between patients. Patients LTFU both before and during the pandemic had a similar number of total appointments. Compared to retained PG patients, LTFU PG patients were younger with mean age of 48.4 years (vs 57.0 years in those retained, p<0.01) and a higher proportion were on OAT at 53% (vs 21% in those retained, p<0.01).
Conclusion(s): The pandemic led to a higher rate of loss to follow-up in HCV patients who were started on treatment, particularly in those on opioid agonist therapy. While shifting to telehealth reduces resource utilization, identifying patient-specific risk factors for loss to follow-up can help providers optimize HCV care in the future.
FUNDING: None
Disclosure of Interest: S Jiang: None Declared, J Farivar: None Declared, E Tam Consultant of: AbbVie, Gilead, Intercept, and Merck, Speakers bureau of: AbbVie, Gilead, Intercept, and Merck, J MacIsaac: None Declared, HH Ko Grant / Research support from: AbbVie, Celgene, Gilead, Intercept, Madrigal, Merck, and Pilant, Consultant of: AbbVie, Gilead, Intercept, Lupin, and Merck, Speakers bureau of: AbbVie, Gilead, Intercept, Lupin, and Merck, A Ramji Grant / Research support from: AbbVie, Assembly Bio. Sci, Gilead, Jassen, Intercept, Galmed, Novartis, Novo-Nordisc, Merck, Pfizer, and Springbanks, Consultant of: AbbVie, Gilead, Intercept, Novo-Nordisc, and Merck, Speakers bureau of: Amgen, Gilead, Janssen, Intercept, Novartis, Novo-Nordisc, and Merck
NH Patel1,*, CS Coffin1,2, V Durkalski-Mauldin3, WM Lee4, CJ Karvellas5
1Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada,
2Department of Medicine, University of Calgary, Calgary, Alberta, Canada,
3Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA,
4Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas, USA,
5Division of Gastroenterology (Liver Unit) & Critical Care Medicine, University of Alberta, Edmonton, Alberta, Canada
Background: Acute liver failure (ALF) is the rare and sudden onset of severe liver dysfunction in patients without pre-existing liver disease. The hepatitis B virus (HBV) causes ALF in two forms, true acute (de novo) HBV infection and reactivation in those with chronic HBV. Approximately 25% of patients with HBV–related ALF (HBV–ALF) survive spontaneously. However, little is known about the immune determinants of spontaneous survival in HBV–ALF patients.
Purpose: This study aims to determine the epidemiological, clinical, virological, and immunological profile associated with transplant-free survival in HBV–ALF patients.
Method: We identified 36 patients adjudicated by a review committee as having acute HBV – ALF from the US Acute Liver Failure Study Group registry (>3400 patients). The inclusion criteria were age > 18 years, diagnosis of acute HBV – ALF with hepatic encephalopathy, onset of hepatic dysfunction < 26 weeks, evidence of moderately severe coagulopathy (INR > 1.5), elevated ALT (> 10 × ULN), and HBV surface antigen positivity. Clinical, biochemical, and virological data were collected at admission (baseline) through day 21. Serum samples were collected at baseline and days 3-5. A panel of 42 cytokines, chemokines, and growth factors were measured using multiplex Luminex assay. Transplant-free survival at day 21 was used as the primary outcome in statistical analysis.
Result(s): In the 36 acute HBV – ALF patient cohort (52.8% female, mean age of 39.5±13.3 years, ALT of 1738±1881 IU/L, and INR of 3.7±3.4), there were 15 transplant-free survivors at day 21 follow-up. At baseline, those who died/received required liver transplant had higher levels of pro-inflammatory cytokines such as IL-15 (p=0.001), IL-1α (p=0.011), and MCP-1 (p=0.020) compared to transplant-free survivors. Interestingly, transplant-free survivors had higher levels of growth factors VEGF-A (p=0.001) and PDGF-AA (p=0.003). From baseline to day 5 follow-up, transplant-free survivors had similar ALT levels, whereas those who died/received liver transplant had lower ALT levels (p=0.043). Despite the ALT decline, those who died/received liver transplant had an increase in inflammatory G-CSF (p<0.0001), TGF-α (p<0.0001), IL-6 (p=0.001), MCP-1 (p=0.007), and sCD40L (p=0.042, Figure 1) at day 5. An increase in tissue regenerating PDGF-AA (p=0.008) was only observed in transplant-free survivors. Univariate analysis showed PDGF-AA (aOR 1.001, 95% CI: 1.00-1.001, p=0.019) to be associated with transplant-free survival.
Conclusion(s): Upregulation of protein growth factors and reduced pro-inflammatory cytokines levels were associated with transplant-free survival of acute HBV – ALF patients.
FUNDING: NIDDK U01-DK-058369
Disclosure of Interest: None Declared
A Ramji1,2,*, HH Ko1, S Lewendon3, J-P Walalch4, N Widmer5, J Feizi Farivar2, E Tam2
1Medicine, University of British Columbia, Vancouver, British Columbia, Canada,
2GastroIntestinal Research Institute, Vancouver, British Columbia, Canada,
3Fraser Health, Surrey, British Columbia, Canada,
4Medicine, University of British Columbia, Nanaimo, British Columbia, Canada,
5Medicine, University of British Columbia, Salmon Arm, British Columbia, Canada
Background: Baseline fibrosis assessment is considered routine for patients with hepatitis C (HCV), and remains included in most simplified treatment algorithms. However, this may present a barrier to initiation of curative therapy, and increases resource utilization. Progression of hepatic fibrosis is variable. Younger patients, particularly those without other liver co-morbidities, are less likely to have extensive fibrosis.
Purpose: To compare the distribution of pre-treatment fibrosis stage in an HCV positive population by age < 40 years (younger cohort, YC) versus ≤40 years (older cohort, OC).
Method: Retrospective review of HCV RNA (+) persons in the BC HCV Network. Data collected included demographics, co-morbidities, risk factors and viral parameters. Patients with HBV or HIV co-infection, and primary platelet disorders were excluded. Fibrosis was determined by transient elastography (TE) (FibroScan®) and/or FIB-4. TE cut-offs utilized were < 8.0 kPa (stage 0-1), 8.0-10.2 kPa (stage 2), 10.2-12.5 kPa (stage 3) and >12.5 kPa (stage 4) fibrosis. FIB-4 limits at <1.45 for non-significant fibrosis and > 3.25 for cirrhosis. Chi-square and Lin correlation analysis was performed.
Result(s): A total of 4987 patients were included: 414 (8.3% < 40 years old (YC) and 4573 (91.6%) ≥40 years old (OC). There was a similar proportion of males in YC (n=249, 60%) and OC (n=2974, 65%) (p>0.05). Recent or active IDU was more likely in YC (n=195, 47%) than in OC (n=1463, 32%) (p<0.05).
Cirrhosis was present in 4/414 (1%) of YC by TE, of which 3 had heavy alcohol use with clinical decompensation in 1 patient. Stage 2 or 3 fibrosis was present in 8/400 (2%) in YC by TE. In the OC there was a significantly higher proportion of persons with stage 2 (35%), stage 3 (50%) and stage 4 fibrosis (15%) (p<0.05).
In YC only 14 (3%) had FIB-4 >1.45 with higher rates in the OC (n=2761, 60%) (p<0.05).
Fibrosis by FIB-4 >1.45 (n=401, 97%) and TE (kPa >8) (n=401, 97%) in YC was significantly correlated (r=0.96, p<0.05).
Conclusion(s): Younger patients (<40 years) have a low likelihood of having advanced fibrosis by either FIB4 or TE in a real-world cohort. In a simplified algorithm, incorporating an age cut-off for performing fibrosis evaluation may identify populations in whom fibrosis assessment is unnecessary, particularly if fibrosis staging is considered a barrier to therapy.
FUNDING: Gilead SCALE program
Disclosure of Interest: A Ramji Grant / Research support from: AbbVie, Assembly, Galmed, Gilead, Intercept, Janssen, Merck, Novartis, Novo-Nordisc, Pfizer, Consultant of: AbbVie, Gilead, Intercept, Janssen, Novo-Nordisc, Pfizer, Speakers bureau of: AbbVie, Gilead, Intercept, Novo-Nordisc, HH Ko: None Declared, S Lewendon: None Declared, J-P Walalch: None Declared, N. Widmer: None Declared, J Feizi Farivar: None Declared, E Tam: None Declared
S Bartlett1,2,*, J Santana Parrilla2, A Tiwana1, P Young3, M Korchinski3, A Ramji4, A Routley5, S Sharma6, B Conway6, C Fraser7, D Luster8, D Schmitz8, K Kerr9, R Elwood Martin2
1BC Centre for Disease Control, Vancouver, British Columbia, Canada,
2School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada,
3Unlocking the Gates Services Society, Maple Ridge, British Columbia, Canada,
4GI Research Institute, Vancouver, British Columbia, Canada,
5BC Mental Health & Substance Use Services, Vancouver, British Columbia, Canada,
6Vancouver Infectious Disease Centre, Vancouver, British Columbia, Canada,
7Cool Aid Clinic, Victoria, British Columbia, Canada,
8BC Hepatitis Network, Richmond, British Columbia, Canada,
9BCCDC Foundation for Public Health, Vancouver, British Columbia, Canada
Background: People who experience criminalization, including people experiencing unstable housing, people who use drugs, and people who are incarcerated, have high prevalence of hepatitis C virus (HCV) infection and low HCV treatment uptake in Canada. Many barriers to treatment and continuity of care have been identified previously. One such barrier is many patients not having access to reliable means to maintain contact with care providers, nor transit to appointments. ‘Social prescribing’, an approach whereby providers address the determinants of health by writing a prescription for non-clinical services, could address this.
Purpose: To test that idea, we launched ‘Test Link Call’ (TLC), a Continuous Quality Improvement (CQI) project where eligible individuals are “prescribed” a cell phone and a Peer Health Mentor to support them accessing HCV treatment. We report here a preliminary qualitative evaluation of TLC project.
Method: To evaluate the acceptability of social prescribing of TLC and its impact on engagement with HCV care, semi-structured interviews were conducted with stakeholders. Stakeholders invited to be interviewed were clients prescribed TLC, Peer Health Mentors (PHMs), and HCV care providers supporting these clients. Interviews were conducted over the phone, and all persons interviewed received a $25 honorarium payment to compensate them for their time. Interviews were recorded, transcribed verbatim, approached inductively, and analysed thematically.
Result(s): From October 1 2021, to September 30 2022, 141 clients have been prescribed TLC; connected with a PHM, and received a cell phone. Overall, eighteen interviews were conducted with stakeholders; 10 among clients, 3 among PHMs and 5 among HCV care providers. All stakeholders described TLC as highly acceptable and effective at engaging people who experience criminalization who have HCV infection. All stakeholders agreed that TLC is beneficial for supporting continuity of access to HCV care and treatment. Stakeholders described several benefits of TLC for clients: elevated sense of personal value, improved convenience in accessing HCV care and other services, enhanced communication and trust, and increased social connection. Stakeholders also reported disadvantages of cell phone prescribing: vulnerability of phones to theft among those who are unstably housed, and technology illiteracy preventing full use of devices. Stakeholders also identified other health conditions that could be addressed with this kind of intervention, including other blood-borne infections such as HIV/AIDS.
Conclusion(s): Thus far, this CQI project demonstrates that social prescribing of cell phones and connection to a PHMs is an effective strategy to enhance engagement in HCV care among people who experience criminalization. Importantly, many added benefits to individuals were reported, therefore social prescribing of cell phones and PHMs may improve other health outcomes as well as those related to HCV. Collection of quantitative data on outcomes of clients prescribed TLC is underway, in order to evaluate impact on connection to HCV care. Given the benefits of TLC, the prescription of cell phones and PHMs for other health conditions should be implemented and evaluated.
FUNDING: The TLC Project is supported by funding from BCCDC Foundation for Public Health, AbbVie Corp, and a CONNECT-C Grant from Gilead Sciences Canada Inc.
Disclosure of Interest: None Declared
G Hirode1,*, S Pi2, A Kim3, JJ Feld1, M Bhatt3, R Van Uum1, L Lilly3, BE Hansen4, N Selzner3, HL Janssen5
1Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada,
2Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia, Canada,
3Multi-Organ Transplant Porgram, Toronto General Hospital, Toronto, Ontario, Canada,
4Department of Epidemiology and Biostatistics, Erasmus MC University Medical Center, Rotterdam, Netherlands,
5Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, Netherlands
Background: Nucleos(t)ide analogues (NA) provide prolonged viral suppression with favorable clinical outcomes such as reversal of fibrosis in patients with chronic hepatitis B. Development of adverse hepatic events, such as flares and decompensations, after NA discontinuation have not been well characterized and may be vital to the understanding and improvement of post-discontinuation monitoring and safety considerations.
Purpose: To describe and analyze patients with chronic hepatitis B who were referred for liver transplantation due to NA discontinuation.
Method: Retrospective analysis of patients with HBV who were referred to the liver transplant centre in Toronto, Canada till October 2020. Patients with HCC or coinfection (HIV, HCV, HDV), and patients waitlisted before January 2000 were excluded from this analysis. Patients were then carefully examined by an expert hepatologist to identify those who developed hepatic decompensation as a result of NA discontinuation. Hepatic decompensation was defined as the appearance of clinical jaundice, ascites, variceal bleeding, or hepatic encephalopathy.
Result(s): Of the 705 patients with HBV referred for liver transplantation, 474 (67%) were excluded due to HCC (n=412), coinfection (n=56), or other reasons (n=6) (Figure). Among the remaining 231 patients, 103 (45%) patients were never waitlisted or had unavailable data. Among 128 patients waitlisted, 8 (6%) patients had been referred because of hepatic decompensation associated with NA cessation. Clinical jaundice appeared in 7 (88%) patients, 5 (63%) developed ascites, 3 (38%) developed hepatic encephalopathy, and 2 (25%) experienced variceal bleeding. Among the 8 identified patients, 4 (50%) underwent liver transplantation, 2 (25%) were delisted of which one patient died, and 2 (25%) died on the waiting list. Mean age at NA cessation was 54±11 years, 7 (88%) were male, 5 (63%) stopped Tenofovir, and 3 (38%) stopped Lamivudine therapy. Reasons for NA cessation included noncompliance (n=5), and physician discretion (n=3). Median time from NA cessation to a decompensating event was 3.0 (3.0–8.0) months, and median time from the decompensating event to listing was 2.1 (0.5-12.9) months.
Conclusion(s): With the use of NAs, the majority of referrals for liver transplantation among HBV patients are due to HCC. In this study, among patients who were referred for liver transplantation after NA cessation, most experienced the decompensating event soon after cessation. Our data reinforce that patients should not discontinue NA themselves and that physicians should very carefully select non-cirrhotic patients for NA withdrawal after which close monitoring and timely retreatment is crucial.
FUNDING: None
Disclosure of Interest: G Hirode: None Declared, S Pi: None Declared, A Kim: None Declared, JJ Feld Grant / Research support from: AbbVie, Alexion, Eiger, Enanta, Gilead, GSK, Janssen, Roche, Wako/Fujifilm, Consultant of: AbbVie, Antios, Arbutus, Blue Jay, Deep Genomics, Eiger, Finch, Gilead, GSK, Janssen, M Bhatt Grant / Research support from: Paladin, Novo Nordisk, Natera, Oncoustics, Lallemand, CareDx, Ipsen, Speakers bureau of: Novartis, Lupin, R Van Uum: None Declared, L Lilly: None Declared, BE Hansen Grant / Research support from: Intercept, CymaBay, Albireo, Mirum, Calliditas, Gliad, Consultant of: Intercept, CymaBay, Albireo, Mirum, Genfit, Calliditas, Eiger, ChemomAb, N Selzner: None Declared, HL Janssen Grant / Research support from: AbbVie, Gilead Sciences, Janssen, Roche, Consultant of: AbbVie, Bristol Myers Squibb, Gilead Sciences, Janssen, Merck, Roche, Arbutus, Vir Biotechnology Inc.
W Elgretli1,*, S Sasson2, M Shengir1, L Ramos Ballestreros2, M Deschenes2, P Wong2, T Chen2, G Sebastiani1,2
1Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec, Canada,
2Department of Medicine, Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Québec, Canada
Background: Metabolic dysfunction–associated fatty liver disease (MAFLD) is the most common cause of chronic liver disease worldwide, with a prevalence at 25%. Patients infected with hepatitis C virus (HCV) may be at higher risk for MAFLD, with reported prevalence at 45%–55%. Both MAFLD and HCV are linked with an increased risk of cardiovascular disease (CVD) due to the presence of shared risk factors. The presence of hepatic steatosis in HCV has a high predictive value for the development of atherosclerosis, independent of other conventional CVD risk factors. To our knowledge, no study has investigated the effect of hepatic steatosis and liver fibrosis on the CVD risk in HCV monoinfected patients.
Purpose: We aimed to assess whether hepatic steatosis and significant liver fibrosis are associated with high CVD risk in patients with HCV monoinfection.
Method: This was a retrospective study including HCV monoinfected patients consecutively screened for hepatic steatosis and fibrosis by transient elastography with associated controlled attenuation parameter (CAP) at McGill University Health Centre. Patients with other viral co-infections (Hepatitis B or Human Immunodeficiency Virus), evidence of other liver disease, significant alcohol intake, or an unreliable transient elastography examination were excluded. Hepatic steatosis and significant liver fibrosis were defined as CAP ≥275 dB/m and liver stiffness measurement (LSM) ≥8 kPa, respectively. CVD risk was assessed using an the 10-year atherosclerotic cardiovascular disease (ASCVD) risk score . Risk categories of ASCVD were defined as follows: low (<5%), borderline (5%–7.4%), intermediate (7.5%–19.9%) and high (≥20%) or if there were previous CVD events. The prevalence of intermediate-high ASCVD risk was estimated after stratifying our patients according to their steatosis and liver fibrosis statuses. Linear regression analysis adjusted for potential confounders was used to determine factors associated with ASCVD risk.
Result(s): We included 155 patients with HCV monoinfection (mean age 60 years, 44% male, 64% white, 30% with undetectable HCV viral load, 26% with diabetes, 41% with hypertension). Hepatic steatosis and significant liver fibrosis were found in 25% and 48% of patients, respectively. The prevalence of low, borderline, intermediate, and high ASCVD risk was 38%, 10%, 20%, and 32%, respectively. Prevalence of intermediate and high ASCVD risk categories was higher in patients with hepatic steatosis and with significant liver fibrosis (see Figure). On linear regression analysis, both CAP (regression coefficient 0.03, 95% CI 0.001-0.06) and LSM (regression coefficient 0.14, 95% CI 0.01-0.32) were independently associated with ASCVD risk score after adjusting for liver transaminases and BMI.
Conclusion(s): Hepatic steatosis and significant liver fibrosis are associated with increased cardiovascular risk assessed by ASCVD in patients monoinfected with HCV. Assessment of cardiovascular disease should be considered in patients with HCV with hepatic steatosis and/or significant liver fibrosis.
FUNDING: CanHepC
Disclosure of Interest: W Elgretli: None Declared, S Sasson: None Declared, M Shengir: None Declared, L Ramos Ballestreros: None Declared, M Deschenes: None Declared, P Wong: None Declared, T Chen: None Declared, G Sebastiani Grant / Research support from: GS has acted as speaker for Merck, Gilead, AbbVie and Novo Nordisk; served as an advisory board member for Merck, Novartis, Gilead and Intercept; and received unrestricted research funding from Theratec.
N Gale1,*, T Preece1, N Hibbert1, G Macphail1
1Liver Clinic, CUPS, Calgary, Alberta, Canada
Background: The CUPS Liver Clinic is a multi-disciplinary clinic in Calgary, Alberta that provides health services to people experiencing poverty, homelessness and substance use disorders. Despite being a low-threshold, low-barrier setting that prioritizes care for marginalized groups, many HCV-affected individuals do not seek out care and are frequently lost to follow-up when they do. Taking inspiration from the Blueprint to Inform Hepatitis C Elimination Efforts in Canada recommendations (CanHepC, 2019), we have shifted to moving our treatment model from a traditional clinical setting to spaces where priority populations live or are already accessing services and care. This has involved the hiring of a peer support worker and screening outreach clinics to shelters, supportive housing sites, street outreach organizations, a provincial drug court program, as well as collaboration with an in-patient specialty addiction consult team.
Purpose: Our project aims to expedite linkage to HCV care for priority populations, including people who use drugs, people experiencing homelessness, and people with a history of incarceration. This will be achieved through assertive community outreach to engage with priority populations and facilitate linkages to care between key points within the health and social care systems.
Method: We have developed a unique conjoint model of care that supports an integrated and decentralized approach to the screening, testing, and treatment of HCV for priority populations. To support this, we have formed collaborative partnerships with: (1) the Addiction Recovery and Community Health (ARCH) team, a hospital-based specialty consult service for patients with substance use disorders; (2) local supportive housing sites; (3) the Alberta Provincial Drug Court team, a comprehensive social support program aimed at breaking the cycle of crime driven by substance use; and (4) local shelters and street outreach teams. Lastly, a peer support worker was hired to support, inform, and co-lead this work.
Result(s): This conjoint model of care has been progressively developed since January 2021, with ongoing monitoring and evaluation. To date, 150 clients have been screened through shelter and outreach programs, with 25 clients started on curative treatment; 16 referrals to the Liver Clinic have been initiated through the in-patient addiction team, with 8 clients started on treatment and transitioned to community; 49 clients were screened at 5 supportive housing sites, with 4 clients started on treatment within their home. Screening outreach and education days are currently in development with the Alberta Provincial Drug Court team. Lastly, frontline staff including housing workers, case managers, and social workers were provided with educational seminars to support front-line knowledge translation of HCV care and referral pathways.
Conclusion(s): Novel models of care are needed to tackle the challenges of our times including achieving the 2030 targets for HCV elimination. We anticipate that a blended model of decentralized care and referral pathways paired with community outreach will improve health equity for priority populations and can be replicated elsewhere.
FUNDING: None
Disclosure of Interest: None Declared
T Barnett1,*, M Selfridge1,2, F Boothman1, A Drost1, K Guarasci1, K Lundgren1, C Fraser1,3
1Cool Aid Community Health Centre, Victoria, British Columbia, Canada,
2Canadian Institute of Substance Use Research, University of Victoria, Victoria, British Columbia, Canada,
3Department of Family Medicine, University of British Columbia, Vancouver, British Columbia, Canada
Background: Canada is currently on target to reach the 2030 WHO goal of hepatitis C virus (HCV) elimination. Continued high rates of treatment initiation are required to meet this goal. People who use drugs (PWUD), account for the majority of new HCV cases in BC and continue to have many barriers to accessing DAA therapies, despite demonstrated high SVR rates in clinical trials. Improved elimination efforts including innovative outreach testing and treatment with this population are essential. Novel models have proven successful to engage PWUD in HCV therapy with a simplified, task-shifted cascade of care. Peer-based testing and support models have been piloted in other communities and may help connect to marginalized populations. People with lived and living experience of HCV treatment and drug use (peers) are seen as trusted sources of knowledge. Peers can vouch for the efficacy, minimal side effects and ease of HCV treatment that now exist in the current DAA era.
Purpose: The Peer HCV Point of Care (POC) testing project developed within our long standing nurse-led HCV treatment program seeks to determine whether an outreach peer model of HCV POC testing can be successful in Victoria, BC. The peer program focuses on finding populations who use drugs without regular access to primary care still living with HCV. This task shifting approach is the next phase of local micro-elimination efforts and has not been attempted previously.
Method: Six peers have been trained to provide HCV POC antibody and dried blood spot RNA tests. Our goals are to pilot the program, learn from our experiences, specifically from the direct input of peers to develop effective and supportive testing and treatment strategies. Peers have worked with nursing and research staff in two-hour blocks and are paid $26 per hour for these shifts. They provide testing at local supportive housing, shelters, social service sites and special events. Each client tested is offered a $10 incentive. Our peers are able to offer both POC antibody testing and, for those who have been exposed to HCV (currently infected, treated or cleared), RNA testing by dried blood spot. Serology by nursing from our mobile outreach van is collected as needed.
Result(s): Within the first 4 months of the project peers and staff tested 304 people: 251 people with HCV POC antibody tests (227 negative and 24 positive results), 41 people with HCV dried blood spot RNA tests and 28 with nurse RNA serology. To date 12 people tested RNA+ (11 with previously unknown HCV have active RNA that require treatment), 7 people have been started on treatment.
Conclusion(s): This innovative and novel approach to HCV therapy in PWUD was able to successfully use a peer-based approach to find people with limited connection to primary health care to test and treat HCV. We still have much to learn from the valuable knowledge, established relationships and novel perspectives of peers in our efforts to reduce barriers and reach PWUD and others who remain untreated.
FUNDING: Merck, AbbVie, Gilead
Disclosure of Interest: T Barnett Grant / Research support from: AbbVie, Gilead, Merck, M Selfridge Grant / Research support from: AbbVie, Gilead, Merck, F. Boothman Grant / Research support from: AbbVie, Gilead, Merck, A. Drost Grant / Research support from: AbbVie, Gilead, Merck, K Guarasci Grant / Research support from: AbbVie, Gilead, Merck, K Lundgren Grant / Research support from: AbbVie, Gilead, Merck, C Fraser Grant / Research support from: AbbVie, Gilead, Merck, Kirby Institute
M Shengir1,*, W Elgretli1, S Sasson2, L Ramos2, P Wong2, T Chen2, M Deschenes2, G Sebastiani1,2
1Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec, Canada,
2Department of Medicine, Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Québec, Canada
Background: Chronic hepatitis C (CHC) infection caused by the hepatitis C virus (HCV) is associated with substantial morbidity and mortality in Canada. The introduction of direct-acting antivirals (DAAs) has dramatically changed the landscape of HCV treatment, with over 95% of patients achieving sustained virologic response (SVR). Although there is a large body of data showed a reduction in the risk of end-stage liver disease, the need for liver transplantation, and decrease in liver-related mortality, data on HCV-associated metabolic conditions, particularly metabolic dysfunction–associated fatty liver disease (MAFLD) after HCV eradication, is scarce.
Purpose: The objective of this study was to investigate if MAFLD and cardiovascular disease risk differ between HCV treated (cured and achieved SVR) and non-treated.
Method: This was a retrospective analysis of HCV mono-infected patients consecutively screened for hepatic steatosis and fibrosis by transient elastography (TE) with associated controlled attenuation parameter (CAP) at a single centre between August 2014 and May 2018. Patients with viral co-infection status, evidence of other liver disease, significant alcohol intake, or an unreliable TE examination were excluded. MAFLD was diagnosed based on the following criteria: the presence of hepatic steatosis defined as CAP ≥275 dB/m and any of the following three metabolic conditions: overweight/obesity, diabetes mellitus, or evidence of metabolic dysregulation in lean individuals. CVD risk was assessed using the 10-year atherosclerotic cardiovascular disease (ASCVD) risk estimator. Based on this score, intermediate-high risk patients were defined if ASCVD >7.5% or if there were previous CVD events. Differences between treated and non-treated patients were presented by descriptive statistics.
Result(s): We included 137 HCV mono-infected patients (mean age 60 years, 44% male, 64% white, 27% treated and achieved SVR, 26% with diabetes, 41% with hypertension). The prevalence of MAFLD was 24% and 13% in the treated and the non-treated group, respectively (p=0.108). The prevalence of intermediate-high ASCVD risk categories was also incomparable between HCV treated (43%) and non-treated (53%) (p=0.675). Compared to untreated patients with MAFLD, those with SVR and MAFLD were less frequently of male sex. had lower liver transaminases and had lower ASCVD risk (see Table).
Conclusion(s): Even though the effect of achieving SVR has led to a reduction in liver-related outcomes, its effect on MAFLD and CVD risk compared to pre-treatment stage is less evident. Larger prospective studies are needed to confirm our findings.
FUNDING: CanHepC fellowship program
Disclosure of Interest: M Shengir Grant / Research support from: Receiving funds from Canadian Network on Hepatitis C (CanHepC) under the PhD fellowship program, W. Elgretli: None Declared, S Sasson: None Declared, L Ramos: None Declared, P Wong: None Declared, T Chen: None Declared, M Deschenes: None Declared, G Sebastiani Grant / Research support from: Acted as speaker for Merck, Gilead, Abbvie and Novo Nordisk; served as an advisory board member for Merck, Novartis, Gilead and Intercept; and received unrestricted research funding from Theratec.
J-HC Hung1,2,*, A Patey1,2, J Presseau1,2, C Cooper2,3,4, J Grimshaw1,2,4
1School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada,
2Clinical Epidemiology Programme, The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada,
3Division of Infectious Diseases, The Ottawa Hospital, Ottawa, Ontario, Canada,
4Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
Background: Decentralization and task-shifting of hepatitis C virus (HCV) infection testing and management from specialty services to primary care are key to achieve global and Canadian HCV elimination targets. Primary care providers should be central to enabling more accessible and sustainable community-based HCV management. However, to date, primary care in Canada has had little involvement in HCV management. There is a need to understand primary care physicians’ current experiences of HCV management to build supports to enhance primary care involvement in HCV management and HCV elimination in Canada.
Purpose: We aim to identify barriers and enablers to optimizing primary care–directed HCV treatment perceived by primary care physicians and map the identified relevant domains to behaviour change strategies for intervention development.
Method: We will conduct semi-structured interviews with primary care physicians practicing in Ontario to identify barriers or enablers to optimizing primary care–directed HCV treatment. The interviews will be guided by the Theoretical Domains Framework (TDF), which incorporates 33 theories of behaviour change into 14 domains to systematically identify cognitive, affective, social, and environmental influences on health behaviours. We will conduct 10 interviews as the initial analysis sample informed by the complexity of the research questions, sampling strategy, and the nature of data analysis and continue data collection until no new themes are identified. All the interviews will be recorded, transcribed verbatim, and anonymized prior to analysis. We will perform a content analysis of physicians’ responses into the corresponding TDF domains. Themes will be identified by grouping similar responses of the interview participants. Relevant domains will be identified by noting presence of conflicting themes, perceived influence on the performance of the behaviour under investigation, and the frequencies of the reported beliefs. In addition, we will map the identified relevant TDF domains to Behaviour Change Techniques (BCT) Taxonomy to inform future implementation interventions.
Result(s): We will identify the key influences perceived by primary care physicians for optimizing primary care–directed HCV management and the Behaviour Change Techniques that may address the barriers and strengthen the enablers to inform future implementation intervention.
Conclusion(s): Our results will provide practical insights into barriers and enablers to better primary care-based HCV management. Future research will focus on developing implementation strategies to tackle the barriers and fortify the enablers to optimal HCV treatment in primary care.
FUNDING: Canadian Network on Hepatitis C
Disclosure of Interest: None Declared
N Lepore1,*, J Pernica2, EM Ratcliffe1
1Pediatric Gastroenterology, McMaster University, Hamilton, Ontario, Canada,
2Pediatric Infectious Disease, McMaster University, Hamilton, Ontario, Canada
Background: SARS-CoV-2 infection continues to be an important public health concern and the literature surrounding the effect on the liver is evolving. Abnormal liver chemistries with SARS-CoV-2 infection have been described. Suspected mechanisms include a systemic inflammatory response to the virus, direct cytotoxic effect, mitochondrial protein interactions, and endothelial dysfunction. There is a paucity of literature focusing on the role of SARS-CoV-2 in liver injury in pediatric patients, especially severe hepatic involvement.
Purpose: We report a case of a patient who presented with two episodes of acute severe hepatitis, one after presumed SARS-CoV-2 infection and one with PCR confirmed SARS-CoV-2 infection.
Method: The pediatric case is reviewed in the context of the broader literature concerning severe acute hepatitis secondary to SARS-CoV-2 infection.
Result(s): A 7-year-old male presented to hospital with unilateral parotitis on a background of a 10 day history of mild cough and rhinorrhea. He had been in contact with a confirmed SARS-CoV-2 positive family member. There were no concerns of fever, rash, conjunctivitis, or jaundice. While in hospital, investigations revealed hepatitis with an elevated ALT 1102 U/L and AST 278 U/L. Liver synthetic function remained normal. As per Public Health Ontario recommendations at the time, an extensive work-up for acute hepatitis of unknown origin in children was completed. Expanded viral work-up (PCR and serology) and autoimmune liver work-up was negative. Viral nasopharyngeal respiratory panel was negative including SARS-CoV-2, however SARS-CoV-2 antibodies were positive. Overall, the patient’s symptoms improved and his liver enzymes returned to normal limits.
The patient presented again 5 months later after another mild respiratory illness with new onset gastrointestinal symptoms and was found to have PCR confirmed SARS-CoV-2 infection. Once again, he was found to have severe acute hepatitis with ALT 1366 U/L and AST 317 U/L. He had a normal bilirubin, CRP, synthetic liver function, and an unremarkable CBC. Abdominal ultrasound demonstrated new mild hepatomegaly and was mildly echogenic suggestive of steatosis. He was monitored in hospital and another thorough work-up was completed which did not reveal another cause for his hepatitis. Clinically he was well and his liver enzymes improved at follow-up.
Conclusion(s): On review of the literature, there is evidence of severe hepatitis secondary SARS-CoV-2 infection, however the number of reported cases are limited and only in small case series. Our case helps to increase awareness and further support the connection between severe hepatitis and SARS-CoV-2 infection. This case also demonstrates that even with mild symptoms and in the absence of respiratory symptoms, liver enzymes can be significantly elevated. Patients may require monitoring of the progression of their symptoms and to ensure resolution of their liver enzymes. Next steps include further evaluation of the pathophysiology and evaluation of potential predisposing factors for liver injury.
FUNDING: None
Disclosure of Interest: None Declared
C Masterman1,*, M Biondi1,2,3, J Feld3,4, G Eastabrook5, C Elwood6, L Lyons7,8, H Atyeo7, K Lang9
1Arthur Labatt Family School of Nursing, Western University, London, Ontario, Canada,
2Faculty of Health, York University, Toronto, Ontario, Canada,
3Toronto Centre for Liver Disease, Toronto, Ontario, Canada,
4Sandra Rotman Centre for Global Health, University of Toronto, Toronto, Ontario, Canada,
5Maternal-Fetal Medicine, London Health Sciences Centre, London, Ontario, Canada,
6BC Women’s Hospital, Vancouver, British Columbia, Canada,
7St. Joseph’s Hospital, Toronto, Ontario, Canada,
8Western University, London, Ontario, Canada,
9Four Directions Community Health Centre, Regina, Saskatchewan, Canada
Background: The opioid crisis is shifting the HCV epidemic to impact younger individuals, including women of childbearing potential; data indicates that women of reproductive age are experiencing greater barriers to treatment initiation than older women. Canadian guidelines recommend treatment in the postpartum period; however, small centre-site studies demonstrate extremely poor treatment initiation rates before the next pregnancy. Therefore, engaging pregnant individuals in the HCV cascade of care whilst interacting with healthcare services for prenatal care may provide an ideal opportunity for the co-localization of health services. The decision not to treat during pregnancy may not reflect the wishes of the pregnant individuals, and the American Association for the Study of Liver Disease recommends treatment in pregnancy on a case-by-case basis, with small studies demonstrating that treatment in pregnancy prevents vertical transmission.
Purpose: Even if treatment in pregnancy is eventually approved in Canada, the experiences of pregnant persons with HCV are not well understood, nor whether persons want to be treated during pregnancy. The purpose of the proposed study is to better understand whether women want to be treated in pregnancy.
Method: Over a two-year period, 100 participants will be recruited from seven practice sites across Ontario, Saskatchewan, and British Columbia. Participants will complete a one-time questionnaire comprised of seven sections evaluating: 1) Demographic information; 2) HCV history; 3) HCV screening; 4) Understanding stigma in healthcare; 5) Pregnancy-related questions which capture medical history as it relates to past and the current pregnancy; 6) Questions about treatment desires and motivations; and 7) A single question related to clinical trial interest for treatment in pregnancy.
Result(s): We hypothesize that women/pregnant individuals will be interested in treatment for maternal health benefits. It is also expected that interest in treatment will increase with the co-localization of services. The recruitment process is currently underway.
Conclusion(s): Understanding treatment motivations of pregnant individuals with HCV can ultimately provide autonomy and decision-making regarding their own care and the care of their children. This data will provide information on whether women want to be treated and potentially provide insight into the stigma and experiences of pregnant individuals with HCV within the healthcare system. This information can be used to implement integrated HCV elimination strategies that incorporate the voices of individuals with lived or living experiences.
FUNDING: Canadian Institutes of Health Research
Disclosure of Interest: None Declared
K MacKay1, D Luster1,*, D Schmitz1
1BC Hepatitis Network, Richmond, British Columbia, Canada
Background: Testing and treatment for the hepatitis C virus (HCV) are both crucial aspects of HCV elimination. Since Winter 2019, the BC Hepatitis Network has been training community-based organization staff and peers to provide HCV education and antibody point-of-care testing (POCT) to clients across British Columbia through our Screening and Linking to Care (SLTC) program. HCV POCT is simple to administer but must occur within the context of linking-to-care (with client support through treatment as required) and pre- and post-testing counseling. Trained testers are primarily community and peer workers largely in, but not limited to, harm reduction sites, peer groups, and other community organizations in BC.
Community and peer workers are uniquely positioned to provide screening and linking to care, as they have established trust with clients who may be at higher risk for HCV.
Purpose: The aim of the Screening and Linking to Care program is to simplify the pathway to HCV diagnosis and care by increasing opportunities for community-based awareness and screening.
Method: Screening and Linking to Care program partners were identified by various means, including prior relationships, outreach to suitable organizations, and word-of-mouth.
While some quantitative data has been provided by community sites, reported data does not represent all sites participating in SLTC and is therefore incomplete. Anecdotal/observational information and published literature are included to supplement our findings qualitatively, despite quantitative data limitations.
Result(s): Approximately 315 testers across 54 sites have been trained to do POCT. 1073 kits were sent to community partners. Testers have been trained in all BC health regions.
The formal discontinuation or disengagement of trained partners has been low; however, constraints exist in community-based organizations that make sustaining testing difficult. Issues identified by community organizations include need for more HCV-specific funding, training, and need for enhanced opportunities to collaborate with others to create capacity to focus work on HCV elimination.
Conclusion(s): Streamlining care access following an HCV-antibody positive result is key to engaging clients in care, including rapid access to confirmatory blood work and treatment. Better leveraging virtual care options and emerging testing technologies may be key to increasing HCV testing and treatment uptake in many priority populations (ie. rural/remote; individuals identified as at risk for loss-to-care).
Community-based POCT is an underused opportunity to connect people affected by HCV to care. We have found communities to be enthusiastic to play a direct role in helping clients access needed HCV testing, treatment, and care in their community, empowering both community-based organizations and their clients.
FUNDING: BC Provincial Health Services Authority
Disclosure of Interest: K. MacKay Grant / Research support from: The BC Hepatitis Network acknowledges the support of Gilead for HCV point of care test kits provided for use by our community partners., D Luster Grant / Research support from: The BC Hepatitis Network acknowledges the support of Gilead for HCV point of care test kits provided for use by our community partners., D. Schmitz Grant / Research support from: The BC Hepatitis Network acknowledges the support of Gilead for HCV point of care test kits provided for use by our community partners.
S Gysel1,*, A Kanters2,*, M Swain2, R Tsuyuki1, Y Al Hamarneh1, C Egan3, K Mrklas3, C Hughes1, L Study Team1,2,3
1University of Alberta, Edmonton, Alberta, Canada,
2University of Calgary, Calgary, Alberta, Canada,
3Alberta Health Services, Calgary, Alberta, Canada
Background: Hepatitis C (HCV) is now a curable disease for most patients who can access treatment. However, priority populations (i.e., those experiencing homelessness or unstable housing, injection drug users, interacted with the corrections system, live rurally) commonly experience inequity-based barriers in navigating and accessing HCV screening and treatment through traditional referral-based systems.
Purpose: To design a novel patient-centred HCV test and treat model to build sustainable community-based capacity and low barrier access to HCV treatment wherein community-based prescribing pharmacists and opioid agonist therapy programs/not-for-profit organizations (CBOs) collaborate to form testing and treatment hubs.
Method: LiveRx is a multi-centre, mixed methods, before-after hybrid implementation study. Pharmacies (n=100) and CBOs will be recruited based on recent epidemiological prevalence mapped areas of high-HCV burden across Alberta. Adult patients (≥18 years of age) belonging to priority populations are eligible to participate. Patients will be recruited for HCV screening at community pharmacies, participating CBOs, and by outreach and peer support workers. Patients will be offered point-of-care HCV antibody (Ab) screening (OraQuick); HCV-Ab+ patients will be offered confirmatory testing (RNA) using dried blood spot (DBS) testing or traditional phlebotomy. If HCV RNA+, patients will use a shared decision-making aid to assess readiness for HCV treatment. If agreeable, treatment naïve patients without decompensated cirrhosis will be offered 8 or 12-week HCV treatment prescribed by a LiveRx trained community pharmacist; excluded patients will be referred for Specialist care. Pharmacists will undertake regular patient follow-up and monitoring and will collaborate with local CBOs, outreach, and peer support workers to provide wrap-around care for patients on treatment. Pharmacists will assess for HCV cure 12-weeks post-treatment using DBS testing or traditional phlebotomy. The study’s primary outcome will evaluate the effect of a community pharmacy-based case finding and intervention program on overall HCV cure rate. Secondary outcomes will include assessment of patient-reported quality of life (EQ-5D) and satisfaction with pharmacist-led HCV care (HPSQ).
Result(s): The LiveRx study was launched in May 2022 and is currently in the implementation phase.
Conclusion(s): To our knowledge this is the first large trial-based program evaluating the impact of a partnership model between community pharmacists and CBOs on HCV case finding and point of care testing, independent pharmacist prescribing and ordering lab tests, on testing uptake, treatment initiation and adherence, and cure rates in patients living with HCV representing underserved priority populations.
FUNDING: Alberta Innovates Partnership for Research and Innovation in the Health System (PRIHS) program; collaboration between the University of Calgary, the University of Alberta, and Alberta Health Services, with private industry partners.
Disclosure of Interest: None Declared
M Palmer1,*, J Wilson1
1Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
Background: Hepatitis C virus (HCV) is a bloodborne viral infection affecting millions worldwide. It is a positive sense, single-stranded RNA virus of approximately 9.6 kb in length, consisting of a single ORF which encodes for a polyprotein, flanked on either side by highly structured 5’ and 3’ untranslated regions (UTRs). A unique aspect of HCV is its reliance on a liver-specific microRNA, miR-122, to promote its replication. microRNAs (miRNAs) typically regulate protein expression by binding to the 3’ UTR of an mRNA transcript, leading to translation suppression and subsequent degradation. By contrast, miR-122 binds to two sites within the HCV 5’ UTR and promotes viral replication. While the mechanism of miR-122-directed replication promotion and the contribution of Argonaute proteins (Ago1-4) are unknown, we hypothesize that miR-122 annealing modifies the HCV 5’ UTR RNA structure and that Ago2 plays a role in delivering miR-122. Ago2 may also be implicated in RNA structure modification. During canonical miRNA suppression, Ago2 is thought to be involved in protein localization via interactions with host proteins such as the GW182 scaffolding proteins. Ago2 also has unwinding and cleavage activity which is thought to play a role in miRNA processing and delivery. Phosphorylation of Ago proteins is also thought to be implicated in protein localization and function.
Purpose: Our goal is to determine the role of Ago proteins in HCV replication promotion and to identify required biochemical functions. This information will aid further characterization of the viral life cycle and uncover potential therapeutic options for the treatment and prevention of chronic HCV infection.
Method: We aim to identify Ago2 functional domains that play a role in HCV replication promotion through the use of an Ago2 complementation assay. We found that Ago1/Ago2 double-knockout Huh-7.5 cells support only low levels of HCV replication and, importantly, transfection of exogenous Ago2 mRNA can rescue HCV replication in these cells. Using this complementation, we have begun testing Ago2 mutants deficient in specific functions to determine if they are required for promotion of HCV replication.
Phosphorylation of Ago2 plays a key role in the regulation of its function throughout the canonical suppression pathway, and we aim to determine if these phosphorylation events have any impact on HCV propagation. Several phosphomimetic mutants have been generated that simulate either constitutively phosphorylated or dephosphorylated amino acids, and these mutants will be tested through the same complementation system. We will also test if other Ago isoforms can rescue HCV replication in this system.
Result(s): Thus far we have found that mutations that affect Ago:GW182 complex formation have a negative impact on viral replication. Furthermore, mutation of amino acids involved in interaction with other host proteins, as well as the unwinding activity of Ago2, results in a less severe but still noticeable decrease. Also, mutation in the Ago2 active site, which is responsible for cleavage of mRNA targets, showed no impact on viral replication, which is expected due to the general lack of cleavage induced by miRNAs. Finally, the effects of the various phosphomimetic mutants on replication are diverse, indicating a possible role for phosphorylation in the HCV life cycle.
Conclusion(s): A key aspect of Ago2-mediated HCV replication promotion is the localization of specific pro-viral host proteins. Without these interactions, there is little-to-no observable viral replication. While the data indicate a role for phosphorylation in HCV replication, the mechanism of this process requires further study through localization and host-virus protein-RNA interaction analysis.
FUNDING: CIHR, University of Saskatchewan
Disclosure of Interest: None Declared
N Fadlelmawla1,2,*, M Zahoor2, A Mosa2, J Feld2,3
1Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada,
2Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada,
3Medicine, University of Toronto, Toronto, Ontario, Canada
Background: Recently, N6-methyladenosine (m6A) modification of viral RNA has been observed in HIV and flaviviruses, including Hepatitis C Virus (HCV). This post-transcriptional modification affects translation (5’UTR), viral particle production (E1) and innate immune recognition (NS5B). To date, HCV RNA methylation has only been detected in vitro using the HCV genotype 2a JFH-1 infectious clone in liver cancer cell lines (Huh7 and HepG2). Given its varied effect on HCV infection, studying methylation in clinical samples will help us determine if it actually occurs in natural infection and will shed light on the importance of methylation at specific sites. We analyzed the reported methylation sites in the 5’UTR, E1 and NS5B sites of HCV RNA from patient-derived plasma of different HCV genotypes (1-4).
Purpose: Detection of m6A modification in HCV RNA derived from patient samples
Comparison of HCV methylation across different regions of HCV genome
Comparison of HCV methylation across different HCV genotypes (1-4)
Method: Reverse Transcription enzymes BstI and MRT, were used for cDNA synthesis of HCV-RNA from plasma from patients with chronic HCV infection (genotypes 1-4) and JFH1, followed by quantitative PCR. BstI activity is hindered by the presence of m6A on RNA, whereas MRT is not. The ratio of BstI to MRT product can therefore be used to infer methylation, where the threshold value >0.5 suggests methylation. Genes with known methylation (SON) and no methylation sites (HPRTI1) were used as controls. Methylation of JFH-1 RNA was also analyzed by immunoprecipitation of methylated RNA using m6A-specific antibodies.
Result(s): The RT-PCR approach showed diverse patterns of methylation across different genotypes. Methylation at the E1 and NS5B sites was evident in all genotypes, whereas the 5’UTR was methylated in genotypes 1a, 3 and 4 but not 1b and 2 (Figure A). Methylation patterns in JFH1 were the opposite of those seen in genotype 2 from plasma (Figure B). E1 methylation was evident in intracellular but not extracellular JFH1 RNA (Figure B) which was validated using immunoprecipitation (Figure C). E1 methylation was not seen in plasma HCV RNA (equivalent to extracellular virus).
Conclusion(s): We were able to confirm the presence of HCV RNA methylation in clinical HCV samples, which largely mirrored results from the JFH1 model. However, E1 was methylated in plasma samples from G1-4, whereas results from JFH1 (RT-PCR and Me-RIP) showed methylation of only intracellular RNA, suggesting that E1 methylation prevents particle production. Further studies will focus on specific sites of methylation in E1 to understand the apparent discrepancy between results using JFH1 and clinical samples.
FUNDING: CIHR
Disclosure of Interest: None Declared
N Fadlelmawla1,2,*, M Zahoor2, A Mosa2, A Chowdhury2, A Gehring2, J Feld2,3
1Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada,
2Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada,
3Medicine, University of Toronto, Toronto, Ontario, Canada
Background: In contrast to the large diversity seen in chronic hepatitis C virus (HCV) infection, samples taken from acute HCV infection have shown only a small number of viral lineages, suggesting the presence of a limited number of Transmitted/Founder (T/F) variants that are able to efficiently expand and establish infection in a new host. Characterization of T/F variants in HCV infection has been limited due to the difficulty of obtaining samples from early HCV infection and in identification of the donor virus. Using samples from lung transplant recipients who received organs from HCV-infected donors, we evaluated the presence of T/F variants in observed HCV infection.
Purpose: Identification the dominant quasi-species in the recipient and analyze their frequency in the donor
- Characterization of T/F variants and their signature sequence patterns in recipients
Method: The HCV genomes of our donor and recipient pairs were amplified using Klentaq LA polymerase. Using next generation sequencing (Illumina MiSeq, 250 bp reads) we obtained the sequences of donors and their respective recipients from day 7 post-transplant. The short reads were then trimmed using Trimmomatic and assembled using miCall. The donor consensus sequence generated by miCall was then used to align the recipient and donor reads. Multiple sequence alignment (MSA) was used to extract alignments covering the Core-E2 region. ShoRAH, a bioinformatics tool used for haplotype reconstruction, was then used to identify haplotypes in the Core-E2 region and estimate their frequencies. We used maximum likelihood phylogenetic trees (PhyML) to compare frequencies of identical and/or nearest-neighbor haplotypes between two recipient/donor pairs from the trial.
Result(s): In the first Donor/Recipient pair (DA/RA), the number of haplotypes in the recipient in each region varied from 3-10 haplotypes compared 10-25 haplotypes in the Donors. Ranking of the haplotype frequency showed that in all regions covering Core-E2, the most common haplotypes in the Recipient were found at lower frequency in the Donor. As an example, one haplotype in E2 was prevalent at 5% in recipient but only 0.08% of the population in the Donor. The prevalence of the 2 most common haplotypes in the recipient differed from that in the identical or nearest-neighbor haplotypes in the donor in all regions (p<0.0001)(Figure). In addition, the dominant haplotype in the Donor was detected in 9 of 17 regions in the Recipient but in 7 of these 9 regions it was nearest neighbor to a low frequency haplotype in the Recipient. In contrast, in the other D/R pair, the dominant haplotypes in the Donor were also the most commonly identified haplotypes in the Recipient.
Conclusion(s): Our preliminary data showing that rare Donor variants emerge in the Recipient are supportive of the T/F concept in HCV. We will continue to analyze longitudinal samples from these and other D/R pairs, as well as characterizing the functional attributes of putative T/F variants.
FUNDING: CIHR
Disclosure of Interest: None Declared
D Lawton1,2,*, C Cooper3,4,5, A Crawley1,2,6,7
1Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario, Canada,
2Chronic Disease, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada,
3Medicine, University of Ottawa, Ottawa, Ontario, Canada,
4Ottawa Hospital and Regional Hepatitis Program, The Ottawa Hospital, Ottawa, Ontario, Canada,
5Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada,
6Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada,
7Biology, Carleton University, Ottawa, Ontario, Canada
Background: In response to pathogenic, inflammatory stimuli and metabolic cues, macrophages can differentiate into a pro-inflammatory (M1) phenotype, producing high concentrations of TNF-α, IL-12 and IL-6. The recent findings that human macrophages are an important source of interferon-gamma (IFN-γ) add some complexity to this picture. We have previously identified that IFN-γ secretion in M1 cells is regulated by the PI3k-mTOR activated p70S6K activated pathway. mTORC1 signalling has further been shown to regulate macrophage polarity and metabolism, making it a therapeutic target for regulating macrophage functions. It remains unclear how liver resident Kupffer cells and systemic bone marrow macrophages are impacted by the development of advanced fibrosis.
Purpose: We aim to determine the underlying mechanism of aberrant IFN-γ production by M1-like macrophages in HCV-mediated liver fibrosis and attempt to ameliorate their dysfunctional phenotype.
Method: Blood monocytes were differentiated into macrophages using M-CSF for 6 days, then polarized into M1 macrophages from healthy and treatment-naïve HCV RNA+ individuals with varying degrees of fibrosis (F0-2 < 8 KPa, F3-4 > 8.5 KPa). The expression of IFN-γ and cell surface markers was determined by ELISA and multi-parameter flow cytometry. Rapamycin and AMPK-agonist treatments were applied to M1 cells to impair mTORC1 signalling. mTORC1 signalling expression was evaluated using a methanol-based flow cytometry approach. Murine bone marrow-derived macrophages (BMDM) were isolated from tibia and femur bones and cultured with GM-CSF. Murine Kupffer cells (KC) were isolated from livers by Percoll-density gradient and selective adherence.
Result(s): M1 cells were confirmed to be the sole producer of IFN-γ in vitro, while M2 macrophages produced basal amounts. Furthermore, lipopolysaccharide (LPS)-stimulated M1 cells upregulated IFN-γ expression. Polarization and LPS stimulation further enhanced mTORC1 signalling in macrophages from healthy individuals. M1 surface markers CD80 CD86 expression and IFN-γ secretions were found to be impaired when cells were treated with rapamycin or AMPK-agonist ACAIR. In minimal fibrosis, we have observed a significant reduction of CD80, CD86 PD-L1, and IFN-γ production from M1 macrophages compared to healthy controls. In those with advanced liver fibrosis, M1 macrophages exhibit significant enhancement of CD80, CD163 and IFN-γ production. Early observations indicate that these M1 cells from HCV+ patients have enhanced mTORC1 signalling profiles. Similar to human MDMs, murine BMDMs and KCs produce significantly higher quantities of IFN-γ when treated with M1 polarizing stimuli relative to their non-polarized counterparts.
Conclusion(s): We have identified that monocyte-derived macrophage polarity in chronic HCV infection is dependent on liver disease severity. Expression of M1 immunostimulatory markers and IFN-γ in advanced liver disease is enhanced and may contribute to the overall dysfunction of the innate/adaptative immune systems. mTORC1 inhibitors or AMPK-agonists may be a potential therapeutic target to counteract inflammatory M1-polarization. We have confirmed that BMDMs and KC can be polarized in vitro towards an M1 phenotype, providing the opportunity for future translational studies of macrophages using animal models of liver disease.
FUNDING: CIHR, CanHepC, NSERC
Disclosure of Interest: None Declared
J Lin1,2,*, S Nkongolo3, Y Ghosheh1, J Feld1, A Gehring1,2
1Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada,
2Immunology, University of Toronto, Toronto, Ontario, Canada,
3Internal Medicine IV (Gastroenterology, Hepatology, Infectious Diseases), University Hospital Heidelberg, Heidelberg, Baden-Württemberg, Germany
Background: Persistent liver damage is the driver of disease progression in chronic hepatitis B (CHB). Based on animal models, liver damage is caused by non-specific activation of CD8 T cells. By analyzing longitudinal liver samples from CHB patients with single-cell RNA sequencing (scRNAseq), we identified an auto-aggressive CXCR6+ CD8 T cell population (Thx) driving non-specific hepatocyte killing via Fas ligand in the human liver, which was regulated by IL-2 and IL-12.
Purpose: The aims of this project were to characterize the precursors of Thx cells and define their activation and differentiation pathways.
Method: Longitudinal scRNAseq of liver fine-needle aspirates, including T cell receptor (TCR) clonotyping, were used to identify cell clusters with overlapping T cell composition and predict differentiation pathways. Predicted activation and differentiation pathways were functionally validated using immune cells from uninfected donor livers to define the Thx differentiation requirements.
Result(s): Tissue residency marker CXCR6, highly expressed on Thx cells, was used to select precursor populations for further analysis. Bioinformatics analysis revealed two potential CXCR6+ CD8 Thx precursors. One cluster was CXCR3Hi with marker gene expression associated with liver resident memory T cells (KLF2Lo/S1PR1Lo/ITGAE/ZNF683) while the other displayed high GZMKHi/PRF1Hi expression with marker genes associated with recirculating CD8 T cells (KLF2Hi/S1PR1Hi) and shared more TCR clonotypes with Thx. We tested requirements for Thx activation and observed a ∼90% decrease in activation in sorted Thx precursors compared to the unsorted controls, indicating intercellular communication is required. To pinpoint immune subsets required for Thx activation, we depleted CD4, CD14, or CD19 cells. No single population impacted Thx activation. Combined depletion of all three reduced Thx activation, suggesting redundant or complex intercellular communication.
Conclusion(s): Transcriptional profiles and TCR clonotypes predicted two CD8 T cell clusters as Thx precursors, which required complex intercellular interactions for activation and differentiation. Understanding regulation of cells causing liver damage opens opportunity to better manage liver diseases and potentially harness these cells for immunotherapy.
FUNDING: None
Disclosure of Interest: None Declared
CE Gallardo Flores1,*, CC Colpitts1
1Biomedical and Molecular Sciences, Queen’s University, Kingston, Ontario, Canada
Background: Chronic HCV infection affects 71 million people worldwide and increases the risk for developing hepatocellular carcinoma (HCC). Although direct-acting antivirals against HCV cure infection, they do not eliminate the risk of developing HCC. Therefore, chemopreventive strategies for HCC in patients with a history of HCV infection are needed.Protein kinase R (PKR), a multifaceted kinase, has been implicated in liver disease and cancer (1). While both pro-carcinogenic and anti-carcinogenic functions have been described for PKR (2-4), its regulation in the context of chronic HCV infection and HCC are poorly understood. In HCV-infected cells, PKR is activated by binding to viral double-stranded RNA (dsRNA). Studies have shown that PKR interacts with HCV non-structural protein 5A (NS5A) (4) and cyclophilin A (CypA) (5), an essential host factor for HCV replication. Formation of this ternary complex may regulate PKR function in HCV-infected cells. Interestingly, mutations in the PKR-binding domain of NS5A are associated with liver fibrosis and HCC (6). However, the molecular mechanisms remain unclear. Here, we explore the role of the CypA-NS5A interaction in regulating PKR. We hypothesize that CypA enables NS5A to modulate PKR activation during HCV infection.
Purpose: Determine how PKR is regulated during HCV infection to better understand the mechanisms of HCV pathogenesis and identify new therapeutic targets.
Method: Using Huh7 hepatoma cells, we modulated CypA activity through genetic depletion/modification or Cyp inhibitor (cyclosporine A; CsA) treatment. We assessed PKR activation by transfection of double-stranded RNA mimic poly(I:C), or by electroporation of HCV subgenomic replicon RNA. We analyzed PKR activation by western blot to assess its autophosphorylation.
Result(s): We first confirmed that CsA inhibits HCV replication in Huh7 cells, as previously demonstrated, and that the enzymatic activity of CypA is required for HCV replication. We showed that CsA inhibits PKR activation in poly(I:C)-transfected cells and in HCV-replicating cells. We are currently evaluating whether CypA enzymatic activity is required for PKR activation by repeating these experiments in CypA-depleted cells compared to cells reconstituted with wild type CypA or CypA enzymatic mutants. Furthermore, NS5A transfection experiments are ongoing to evaluate NS5A inhibition of PKR and assess the role of CypA.
Conclusion(s): We show that CypA modulates the activity of PKR, a finely regulated multifaceted kinase with pro- and anti-oncogenic roles. These findings contribute to understanding the role of NS5A and CypA in regulating PKR during HCV infection and may provide insight into new chemopreventive strategies for HCC.
FUNDING: CIHR, NSERC
Disclosure of Interest: None Declared
J Skoreyko1,*, E Kasinyabo1, H Le1, V Meier-Stephenson1
1University of Alberta, Edmonton, Alberta, Canada
Background: Hepatitis B virus (HBV), a partially double-stranded DNA virus and member of the Hepadnaviridae family of viruses, chronically infects over 300 million people worldwide, increasing an individual’s chance of developing cirrhosis and hepatocellular carcinoma. The virus remains chronic because of a form of the virus, the covalently closed circular DNA (cccDNA) that remains in the nucleus. Current nucleotide analogue therapies target steps downstream of the cccDNA and while they are very good at suppressing HBV DNA, viral rebound can occur if stopped. The key to a potential cure therefore lies within the capacity to target and eliminate the virus’s cccDNA. The recent discovery of a conserved G-quadruplex (GQ) structure in the pre-core promoter region of HBV provides a unique target in cccDNA against which small molecule therapeutics can be designed. Currently, there are several GQ-binding ligands, originally developed as anti-cancer agents, available that can be used to target HBV.
Purpose: To study the impact of known GQ-binding ligands on HBV replication.
Method: Drug viability assays were performed using Alamar blue to find a dose tolerable for the HepG2-NTCP cells. Using a HepG2-NTCP infection model, cells were treated on the first day post infection (dpi) with 10μM TMPyP4, Braco-19 or tenofovir (TDF) and harvested at dpi 1, 4 and 7. Cells and supernatant were used to analyze viral markers including pgRNA, total HBV DNA, and HBsAg. Data was corrected for beta-globin and baseline housekeeping genes were screened, including albumin, HPRT, and GAPDH. Further, as TMPyP4 can auto-fluoresce, imaging studies were performed to confirm cellular localization.
Result(s): Viability assays show cellular viability is maintained at concentrations under use. Preliminary data from the infection study show a decrease in viral RNA and DNA when treated with GQ-binding ligands. Confirmatory studies are ongoing with cellular background impacts. Cellular localization studies show that TMPyP4 can enter the HepG2-NTCP cell nucleus- the site of HBV cccDNA.
Conclusion(s): GQ-binding ligands appear to impact HBV replication. Through better understanding of GQ-binding and off-target effects, we may be able to employ these GQ-binders or variants thereof to target this conserved region more specifically, ultimately leading to a novel approach for targeting cccDNA.
FUNDING: Li Ka Shing Institute of Virology, Faculty of Medicine and Dentistry (U of A)
Disclosure of Interest: None Declared
K Jorritsma1,2,*, M Ardolino2,3, AM Crawley1,2,4
1Chronic Disease, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada,
2Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada,
3Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada,
4Biology, Carleton University, Ottawa, Ontario, Canada
Background: Hepatitis C virus (HCV) and non-alcoholic fatty liver disease (NAFLD) place a significant burden on healthcare systems worldwide, currently affecting approximately 1.5 billion people. Ensuing liver fibrosis, resulting from progressive tissue damage, has many downstream consequences on local and systemic immune function. Notably, CD8+T cells in chronic HCV infection display a higher proportion of cells expressing perforin, IFN-γ and PD-1, as well as a reduction in the expression of anti-apoptotic Bcl-2. We have also observed lasting CD8+ T cell hyperfunction long after viral clearance in chronic HCV infection with advanced liver fibrosis. However, the effect of host and cellular metabolism on mediating this dysfunction remains unknown.
Purpose: Evaluate CD8+ T cell function in animal models of hepatotoxin and diet-induced liver fibrosis and determine if this dysfunction is associated with an upregulation in cellular glycolysis and alterations in mitochondrial fitness.
Method: Progressive liver fibrosis will be generated in C57BL/6 mice through 12 weeks of carbon tetrachloride (CCl4) hepatotoxin treatment (i.p.) to induce advanced liver fibrosis and mimic liver pathology associated with HCV. To mimic pathology observed in NAFLD, another model will apply a high-fat, methionine and choline deficient diet. Peripheral blood mononuclear cells will be stained with fluorochrome-conjugated antibodies for flow cytometry, quantifying CD8+ T cell function, mitochondrial mass and reactive oxygen species. The OT-1 model will be used to evaluate the effect of fibrosis-induced CD8+ T cell dysfunction on the response to Listeria monocytogenes (LM) infection.
Result(s): We have found that, in murine models of advanced liver fibrosis, generated by hepatotoxin treatment, there is an elevated proportion of IFN-γ+ and granzyme B+ CD8+ T cells. This hyperfunction, similar to that observed in human HCV, also persists after hepatotoxin cessation and liver fibrosis reversal. We have also determined, that transferred naïve CD8+ T cells cannot be followed post-adoptive transfer, in the absence of antigen stimulation. Future studies will be adapted to permit the assessment of transferred cells.
Conclusion(s): Using the hepatotoxin model of advanced liver fibrosis, we can uncover mechanisms that drive CD8+ T cell dysfunction and impairments in infection control and other clinical outcomes. We expect to see significant alterations in cellular metabolism, notably in mitochondrial mass and reactive oxygen species, alongside the development of fibrosis. Future studies, using Seahorse analysis, will allow us to further characterize cellular metabolism, in terms of oxidative phosphorylation and glycolysis. Finally, while the OT-1 model did not permit the assessment of naïve CD8+ T cells post-adoptive transfer, an experimental approach with LM-OVA challenge will provide the opportunity to evaluate immune responses to a pathogen whose clearance depends on a strong CD8+ T cell response.
FUNDING: CIHR
Disclosure of Interest: None Declared
S D’souza1,*, MD Badmalia2, G Balderas Figueora2, CS Coffin3,4, TR Patel5,6
1Department of Microbiology and Infectious Diseases, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada,
2Department of Chemistry and Biochemistry, University of Lethbridge, Lethbridge, Alberta, Canada,
3Department of Medicine, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada,
4Department of Microbiology, Immunology, and Infectious Diseases, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada,
5Alberta RNA Research and Training Institute, Department of Chemistry and Biochemistry, University of Lethbridge, Lethbridge, Alberta, Canada,
6Department of Microbiology, Imminology, and Infectious Diseases, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
Background: Nucleic acids rich in guanine nucleotides can form a secondary structure known asa Guanine-quadruplexes (G-quadruplex or G4). These G-quadruplex structures are formedthrough Hoogsteen hydrogen bonded guanine bases which stack to create a stable structure. G4 structures are conserved across all three domains of life and have roles in transcription, translation, and replication. More recently, these G-quadruplexes have been identified in viruses as well; however, their functional role is yet to be deciphered. Using prediction algorithms, a highly conserved G-quadruplex sequence was identified in the 3’UTR of the negative strand in HCV. The location of this G-quadruplex is found on the stem-loop IIy’ region and is within the 1-154 nt sequence which is identified as the minimal region required for efficient HCV replication.
Purpose: We hypothesize that stem-loop IIy’ is flexible during HCV replication and can adopt aG-quadruplex formation to aid in efficient viral replication.
Method: Using G4-hunter, we have designed and ordered wild-type/mutant RNA oligos of theputative G-quadruplex forming sequence in the negative-strand 3’UTR of HCV. These oligos were folded into G-quadruplexes and purified using size exclusion chromatography. The G-quadruplex structure was characterized using circular dichroism spectroscopy and confirmed using MicroScale Thermophoresis binding experiments with a commercially available antibody (BG4), which binds exclusively to G-quadruplexes. We have also Small Angle X-ray Scattering (SAXS) of wild-type and mutant HCV G-quadruplexes to see if mutations disrupt these structural features. We will subsequently use in vitro cell culture models to investigate the functionality of these wild-type and mutant G-quadruplexes in viral-replication using luciferase assays and perform pull-down assays to determine if a functional HCV G-quadruplex exists.
Result(s): CD spectroscopy experiments confirmed that all oligos form G-quadruplexes, andstructure stability is buffer dependent KCl>NaCl>LiCl. The wild-type G4 appears to have the most quartets intact when compared to the single mutant and double mutant G4s. MST experiments showed that BG4 can recognize all four HCV constructs – indicating that they all form G-quadruplexes. MST experiments were consistent with CD spectroscopy where G4s are most stable in KCl and less stable in NaCl buffer.
Conclusion(s): Biophysical studies indicate that a 22nt HCV oligo can form a G-quadruplex structure. The identification of a functional role of these G-quadruplexes in HCV can give us insight into how nucleic acid sequence and structure can impact viral replication.
FUNDING: CASL, CIHR-CanHepC, CIHR-CGSM, CIHR-MSFSS, CanHepC-TRR179, Eyes High Doctoral Research Award, Cumming School of Medicine Graduate Student Scholarship, AIHS
Disclosure of Interest: None Declared
AM Passos-Castilho1,2,*, DG Murphy3, K Blouin4, M Klein5, J Bruneau6, D Panagiotoglou7, A Benedetti7, S Bartlett8,9, J Kwong10, B Sander11,12, NZ Janjua8,9, C Greenaway1,2,13
1Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montréal, Québec, Canada,
2Department of Medicine, McGill University, Montreal, Québec, Canada,
3Laboratoire de Santé Publique du Québec, Institut National de Santé Publique du Québec, Sainte-Anne-de-Bellevue, Quebec, Canada,
4Unité sur les Infections Transmissibles Sexuellement et par le Sang, Institut National de Santé Publique du Québec, Quebec, Canada,
5Research Institute of the McGill University Health Centre, Montréal, Québec, Canada,
6CHUM Research Centre, Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada,
7Department of Epidemiology, Biostatistics and Occupational Health, School of Population and Global Health, McGill University, Montreal, Québec, Canada,
8BC Centre for Disease Control, Vancouver, British Columbia, Canada,
9School of Population Public Health, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada,
10Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada,
11Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada,
12Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada,
13Division of Infectious Diseases, Jewish General Hospital, Montreal, Québec, Canada
Background: HCV rates among children ≤4 years have increased over the past 10 years in Canada, likely primarily due to vertical transmission. Identifying and treating HCV among child-bearing women before pregnancy is key, given DAAs cannot be given during pregnancy.
Purpose: We characterized the HCV care cascade at the time of delivery among pregnant women with a prior HCV diagnosis, focusing on the highest risk groups, such as people who inject drugs (PWID) and immigrants born in HCV endemic countries.
Method: A population-based cohort of all reported HCV cases in Quebec (1990-2018) was linked to several health administrative databases. Delivery (1990-2018) was identified in medical and hospital data using standard procedure and intervention codes. PWIDs were identified using published algorithms. Immigrant status was assigned through linkage to the landed immigrant database. HCV care cascade steps included: diagnosed (antibody positive), RNA tested, RNA positive, genotyped, initiated treatment, SVR. The number and proportion of pregnant women at the time of their first delivery at each stage of the care cascade were estimated overall and by study period: pre-DAA (1990-2013) and post-DAA (2014-2018). Data on subsequent deliveries and progression through the cascade post-delivery was obtained up to Dec. 2018. Missing data were addressed using multiple imputations. Multiple logistic regression adjusting for baseline characteristics and comorbidities was used to determine predictors of RNA testing/treatment initiation as of the time of delivery.
Result(s): Among 42,514 HCV diagnoses between 1990-2018, 1,033 women had a first delivery a median of 4.4 (IQR 1.3-9.3) years after HCV diagnosis; 577 (56%) were PWID, and 223 (22%) were immigrants. As of the date of their first delivery, 63% (n=648) had been HCV RNA tested, 67% (n=434) RNA positive, 78% (n=337) genotyped, 44% (n=147) had initiated treatment, and 97% (n=72) of those assessed post-treatment initiation achieved SVR. Comparing women at first deliveries post-DAA vs. pre-DAA, there was an increase in the proportion RNA tested (92% vs. 56%) and treatment initiation (52% vs. 39%) (Figure). Delivery post-DAA (2014-2018) [adjusted OR (95% CI); 2.80 (2.08-3.78)] and immigrant status [1.48 (1.19-1.84)] were positively associated with RNA testing, while younger age [0.96 (0.94-0.98)], material deprivation [0.73 (0.57-0.93)], and HBV coinfection [0.51 (0.36-0.72)] were negatively associated with RNA testing. Delivery post-DAA [1.36 (1.05-1.75)] but not immigrant status [1.01 (0.73-1.39)] was positively associated with treatment initiation. During follow-up after first delivery up to Dec. 2018, 88% (n=911/1033) of all women had been RNA tested, but still only 61% (n=368/605) of RNA positive had initiated treatment. Among these women, 533 second/third deliveries occurred during follow-up.
Conclusion(s): HCV care among pregnant women living with HCV improved in the DAA period, particularly for immigrant women, but progression through all steps in the care cascade must be further improved to prevent vertical transmission and HCV outcomes.
FUNDING: CIHR
Disclosure of Interest: None Declared
AB Mendlowitz1,2,3,*, KE Bremner3, J Walker2,4, WW Wong2,3,5, B Sander2,3,6,7, L Jones8, M Biondi1,9, N Mitsakakis3,10, W Isaranuwatchai11, MD Krahn3, J Feld1
1Toronto Centre for Liver Disease/Viral Hepatitis Care Network (VIRCAN), University Health Network, Toronto, Ontario, Canada,
2ICES, Burnaby, British Columbia, Canada,
3Toronto Health Economics and Technology Assessment Collaborative, University Health Network, Toronto, Ontario, Canada,
4Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada,
5School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada,
6Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada,
7Public Health Ontario, Toronto, Toronto, Ontario, Canada,
8Ontario First Nations HIV/AIDS Education Circle, London, Ontario, Canada,
9School of Nursing, York University, Toronto, Ontario, Canada,
10Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada,
11Unity Health, Toronto, Ontario, Canada
Background: First Nations Peoples are a priority for Canada’s commitment to the World Health Organization strategy to eliminate viral hepatitis as a public health threat by 2030. As a result of colonialization, residential schools, and intergenerational trauma, hepatitis C virus (HCV) disproportionately impacts First Nations Peoples in Canada. In Ontario, partnership with First Nations organizations has allowed linkage of First Nations identifiers to patient-level administrative health data and HCV antibody testing records. As testing is the gateway to HCV care, understanding testing trends among First Nations Peoples is critical to monitor progress towards HCV elimination.
Purpose: In partnership with the Ontario First Nations HIV/AIDS Education Circle (OFNHAEC), this study characterized rates and predictors of HCV antibody testing among First Nations individuals in Ontario.
Method: We performed a population-based retrospective cohort study among Status First Nations individuals using Public Health Ontario Laboratory HCV testing records (1999 to 2018) and health administrative data held at ICES. Rates of annual HCV antibody testing volume and testers were defined as the number of antibody testing episodes and number of people tested, respectively, divided by the number of First Nations individuals alive and residing in Ontario at midpoint of each year. Rates were stratified by sex, age, and residence within or outside First Nations communities (available after 2000) at testing date. In each year after 2000, individuals with their first HCV test during that year were matched 1:2 on birth year and sex to individuals who were alive for that year and never had a test record. Conditional logistic regression was used to identify variables associated with HCV antibody testing.
Result(s): From 1999 to 2018, 40,699 Status First Nations individuals (mean age 35.1 years, 55.0% female) underwent HCV antibody testing, with 84,899 testing episodes. Most individuals (55.4%) had one test. Annual testing volume increased from 5.2 (95% confidence interval: 4.9-5.6) testing episodes per 1000 people in 1999 to 55.8 (54.7-57.0) in 2018 (Figure). The annual number of testers increased from 4.8 (4.5-5.2) per 1000 people in 1999 to 48.7 (47.6-49.8) in 2018. For individuals residing within First Nations communities, testing volume increased from 10.5 (9.6-11.6) per 1000 people to 65.5 (63.3-67.7) and the number of testers increased from 9.7 (8.8-10.7) per 1000 people to 57.0 (54.9-59.1). Multivariable analysis showed comorbidity, rurality, First Nations community residence, and/or previous HIV or Hepatitis B virus infection were predictors of testing (p<0.0001).
Conclusion(s): HCV testing among Status First Nations Peoples in Ontario continued to increase after the improvements observed up to 2014 in our previous study. Efforts within First Nations communities may have translated to greater increases in testing among their residents than among those who reside outside.
FUNDING: Post-doctoral fellowship from the Canadian Network on Hepatitis C (CanHepC); CIHR Postdoctoral Fellowship; CIHR Project Grant (PJT 166039).
Disclosure of Interest: None Declared
S Bartlett1,2,*, A Yu1, M Alvarez1, S Wong2, H Velásquez García2, B Mawuena2, P Adu2, D Jeong2, J D Makuza2, M Krajden1,3, J Wong1,2, N Janjua1,2
1BC Centre for Disease Control, Vancouver, British Columbia, Canada,
2School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada,
3Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
Background: People experiencing unstable housing are more likely to acquire hepatitis C virus (HCV) infection, face more barriers to accessing healthcare and HCV treatment, and are less likely to finish HCV treatment or to be cured. Current methods to measure how many people are unstably housed often only capture visible homelessness, and many studies of HCV outcomes report difficulty engaging homeless or unstably housed people. Therefore, the true impact of housing instability on HCV outcomes may be underestimated.
Purpose: To address this, we developed an algorithm to identify people experiencing unstable housing using administrative health data, and determined the HCV prevalence among this group on a population level.
Method: We used the British Columbia (BC) Hepatitis Testers Cohort (HTC), which includes all individuals tested for or diagnosed with HCV in BC since January 1st, 1996 (∼1.7 million people), linked to prescription drugs, medical visits, hospitalizations, and mortality data until December 31st, 2015. International Classification of Diseases (ICD) versions 9 and 10 codes associated with unstable housing were identified in the literature. We defined unstable housing as having ≥2 encounters where an unstable housing-related ICD 9/10 code was present within a 12 month period, and estimated the number of people that met this criteria each year from 2010-2015. Among those experiencing unstable housing, we determined the proportion who were HCV antibody positive, aged over 55 years, and male.
Result(s): The number of people identified each year in BC experiencing unstable housing increased by 320% from 2010 (2,691) to 2015 (11,296). The proportion of males among those identified experiencing unstable housing each year remained relatively stable between 49%–56%. There was a 33% decrease in the proportion of people aged over 55 years among those identified as experiencing unstable housing between 2010 (57%) and 2015 (39%). HCV sero-prevalence among people experiencing unstable housing decreased from 19% in 2010 to 13% in 2015.
Conclusion(s): These findings indicate that the sero-prevalence of HCV infection is ten times higher among people experiencing unstable housing compared to the overall population in BC. Due to the high sero-prevalence of HCV infection among people experiencing unstable housing, additional supports, such as supportive housing and outreach programs, may be needed to achieve HCV elimination targets by 2030 in BC. Reasons for the increasing proportion of people under 55 years of age among those experiencing unstable housing are being investigated, along with further characterization of the profile of people experiencing unstable housing who are diagnosed with HCV infection in BC, including investigation of overlap with other factors such as injecting drug use and mental illness. Continued monitoring of the prevalence of HCV infection among people experiencing unstable housing will be important in order to determine if this health equity gap persists, despite HCV elimination efforts at the population level.
FUNDING: CIHR
Disclosure of Interest: None Declared
L Thompson1,2,*, S Plitt3,4, C Charlton1,2,5,6
1Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada,
2Women and Children’s Health Research Institute (WCHRI), Edmonton, Alberta, Canada,
3Public Health Agency of Canada, Ottawa, Ontario, Canada,
4School of Public Health, University of Alberta, Edmonton, Alberta, Canada,
5Alberta Precision Laboratories (ProvLab), Edmonton, Alberta, Canada,
6Li Ka Shing Institute of Virology, Edmonton, Alberta, Canada
Background: Canadian guidelines for Hepatitis C virus (HCV) screening currently recommend: 1) risk-based screening in pregnant individuals; and 2) testing for HCV RNA at 2 months of age and HCV antibodies at 18 months of age for infants born to HCV positive mothers.
Purpose: We aimed to evaluate the rate of prenatal HCV risk-based screening and estimate the prevalence of HCV among pregnant individuals in Alberta. Additionally, we investigated follow-up testing and adherence to screening guidelines in infants perinatally exposed to HCV in order to identify gaps in infant screening.
Method: Patients participating in the Alberta Prenatal Screening Program over a one-year interval were cross-referenced with provincial HCV test results to identify prenatal individuals risk-based screened for HCV. The rate of screening was calculated from the number of pregnant individuals screened for HCV over total number of pregnant individuals participating in the program. Prenatal HCV prevalence was estimated from individuals testing positive for HCV RNA plus 75% of individuals testing positive for HCV antibodies (with no further follow-up) over total number of pregnant individuals. Infants were linked to HCV positive mothers through the Perinatal Health Program and infant personal health numbers were used to identify follow-up testing in the provincial public health laboratory database.
Result(s): Of the 50,753 individuals participating in the Alberta Prenatal Screening Program, 6,033 (11.9%) received HCV risk-based screening during pregnancy. From those, 28 were positive for HCV RNA and 8 were positive for HCV antibodies with no further follow-up, equating 34 individuals estimated to have active infection (prenatal HCV prevalence=0.07%). Of the 28 individuals with confirmed active infections, 24 (85.7%) had viable singleton births and 12 of those infants (50.0%) had record of HCV follow-up testing, although only 6 (50.0%) received testing that completely adhered to screening guidelines (6 received HCV antibody testing before 18 months). HCV status was available for 11 infants (1 lost-to follow-up), and revealed no cases of vertical transmission.
Conclusion(s): The rate of HCV risk-based screening in pregnant individuals across Alberta is low, indicating the current risk-based program could be underdiagnosing prenatal patients infected with HCV. While half of perinatally exposed infants received follow-up testing, more work is needed to increase the number remaining engaged in care. For infants remaining in care, appropriate adherence to HCV antibody screening guidelines is another area for improvement to ensure accurate test results and to avoid unnecessary use of laboratory resources.
FUNDING: CIHR Vanier Scholarship (AT), Killam Trust Scholarship (AT), WCHRI Graduate Studentship (AT), University of Alberta Doctoral Recruitment Scholarship (AT), CIHR CGS-M (AT), M.S.I. Foundation (CC).
Disclosure of Interest: None Declared
D Jeong1,2,*, S Wong2, ME Karim1,3, A Manges1,2, HA Velásquez García2, M Binka2, S Bartlett2, M Darvishian4, PA Adu2, JD Makuza1, H Samji2,5, A Yu2, M Alvarez2, M Krajden1,2, NZ Janjua1,2,3
1University of British Columbia, Vancouver, British Columbia, Canada,
2British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada,
3Centre for Health Evaluation and Outcome Sciences, Vancouver, British Columbia, Canada,
4British Columbia Cancer Agency, Vancouver, British Columbia, Canada,
5Simon Fraser University, Burnaby, British Columbia, Canada
Background: During the course of chronic HCV infection, the majority of people develop one or more extrahepatic manifestations (EHMs). EHMs can include cardiovascular, cerebrovascular, renal, metabolic diseases, and neurocognitive disorders. Treatment-induced sustained virologic response (SVR) has been shown to reduce the risk of certain EHMs; however, the effect of interferon-free direct-acting antiviral (DAA) treatment has not been well studied.
Purpose: To estimate the effect of DAA treatment and SVR on the risk of developing EHMs in a large population-based data.
Method: We used data from the BC Hepatitis Testers Cohort, which includes 1.3 million people tested for or diagnosed with HCV from 1990 to 2015, linked with health administrative data including all DAA dispensations in the province. This study included people diagnosed with chronic HCV before March 31, 2020, who received at least one DAA treatment. We matched people who received treatment to those who never received treatment by the year of their first HCV RNA positive date (1:1 ratio). Follow-up started on the date of SVR for treated people and the same date was assigned to the matched untreated people. Participants were followed until the earliest of 1) incident EHM 2) death or 3) end of study (2021/03/31). We assessed five EHMs based on ICD-9/10 diagnostic codes: chronic kidney disease (CKD) and end-stage renal disease (ESRD), type 2 diabetes (DM), stroke, neurocognitive disorders and major adverse cardiac events (MACE). Persons with EHMs prior to baseline were excluded from analyses pertaining to that specific EHM. Inverse probability of treatment weights (IPTW) for the average effect were estimated to adjust for differences in baseline characteristics, and used in multivariable cause-specific hazards models adjusting for confounders and competing risk of mortality.
Result(s): There were 12,361 people treated with DAA matched to those who never received treatment. Among the treated, 387 had not achieved SVR (3.1%). The cumulative incidence rate (CIR) of neurocognitive disorders was higher among untreated people compared to those who were treated & SVR: 14.8 (95% CI 13.4, 16.4) vs. 10.2 (95% CI 9.2, 11.4) per 1,000 person-years (PY), respectively. CIR of DM was higher among people who were treated & SVR compared to those who were untreated; 9.1 (95% CI 8.1, 10.3) vs. 5.0 (95% CI 4.2, 6.0) per 1,000PY, respectively. For CKD & ESRD, stroke and MACE, CIRs were higher among untreated people compared to those treated & SVR, however, the 95% CIs overlapped. In IPTW-weighted multivariable models, those who were treated & SVR had lower risks of incident CKD & ESRD (adjusted cause-specific hazard ratio [aCSHR] 0.66, 95% CI 0.58, 0.76), stroke (aCSHR 0.81, 95% CI 0.66, 0.99), neurocognitive disorders (aCSHR 0.60, 95% CI 0.51, 0.70) and MACE (aCSHR 0.72, 95% CI 0.64, 0.82) compared to those who didn’t receive treatment. Conversely, those who were treated & SVR had a greater risk of being diagnosed with DM than untreated people (aCSHR 1.36, 95% CI 1.10, 1.68).
Conclusion(s): Successful HCV treatment with DAA was associated with lower risks of CKD & ESRD, stroke, neurocognitive disorders and MACE. However, people who received treatment had a higher risk of diabetes. Further investigations are needed to understand the impact of treatment on the risk of diabetes. These findings suggest that people living with HCV infection may benefit from counselling regarding the risk of EHMs related to HCV, especially if they are considering delaying HCV treatment initiation.
FUNDING: CIHR, CanHepC Network
Disclosure of Interest: None Declared
HH Ko1,*, C Cooper2, A Manko3, A Ramji1, K Doucette4, S Fung5, G Minuk6, M Elkhashab7, E Tam8, M Ma4, A Wong9, M Brahmania3, R Bailey10, P Wong11, B Conway1, K Tsoi12, C Nudo13, J Zhu14, C Osiowy15, S Congly3, AA Shaheen3, C Coffin3
1University of British Columbia, Vancouver, British Columbia, Canada,
2University of Ottawa, Ottawa, Ontario, Canada,
3University of Calgary, Calgary, Alberta, Canada,
4University of Alberta, Edmonton, Alberta, Canada,
5University of Toronto, Toronto, Ontario, Canada,
6University of Manitoba, Winnipeg, Manitoba, Canada,
7Toronto Liver Centre, Toronto, Ontario, Canada,
8Pacific Gastroenterology Associates, Vancouver, British Columbia, Canada,
9University of Saskatchewan, Saskatoon, Saskatchewan, Canada,
10Bailey Health Clinic, Edmonton, Alberta, Canada,
11McGill University, Montreal, Québec, Canada,
12McMaster University, Hamilton, Ontario, Canada,
13Cité-de- la- Santé de Laval, Laval, Québec, Canada,
14Dalhousie University, Halifax, Nova Scotia, Canada,
15National Microbiology Laboratory, Winnipeg, Manitoba, Canada
Background: Although Canada has a universal health care system, this does not include prescription drug benefits. There are systemic factors impacting access to treatment leading to poor outcomes. Previous studies have shown a significant proportion of non-treatment in patients with chronic hepatitis B who meet treatment guideline criteria.
Purpose: The goal of this study is to determine factors associated with non-treatment among those eligible.
Method: In this cross-sectional multi-centre retrospective study conducted by the Canadian Hepatitis B Network (CanHepB), we analysed demographic, clinical and virological data from adult patients diagnosed with CHB and seen at any time Jan 2012 - December, 2022. Patients were grouped based on their eligibility for treatment based on Canadian Association for the Study of the Liver (CASL) guidelines (HBV DNA >2000 IU/mL and ALT >25 U/L in females and >35 U/L males), and/or liver stiffness measurement (LSM), using transient elastography, indicating >Stage 2 fibrosis or higher (>7 kPa). Retrospective data were summarized using descriptive statistics and treatment eligible vs. total compared by unpaired t-test.
Result(s): Among 7202 patients in the CanHepB Network database, 2546 (35.3%) had received HBV treatment (median age 53.7 years (53.1-54.2), 66.4% male), with diverse background (87.6% born outside of Canada, 87.2% self-reported as Asian, 9.7% White and 8.8% Black). Among patients on treatment, there were 7.7% with cirrhosis and 4.2% with hepatocellular carcinoma (HCC). 21% (980/4656) of treatment eligible patients were untreated. Younger (48.2 years (47.4-49.0)), female (43.2% vs. 33.6% in the treated group), and African populations (13.7% vs. 8.8%) and those with lower LSM (7.17 kPa vs. 9.08 kPa) and HBeAg positivity (62.3% vs. 22.1%) were less likely to receive treatment. Compared to the treated group, the untreated group had statistically higher baseline HBV DNA level, but baseline ALT levels were similar in both groups.
Conclusion(s): In this cross-sectional, retrospective study of ethnically diverse CHB patients, 21% were untreated despite meeting treatment criteria. In majority, reason for not being treated is unknown but a fair number of treatment eligible individuals lack drug coverage. Compared to the treated cohort, the untreated individuals were more likely to be younger, female, black, HBeAg positive, and have lower LSM. Further prospective study including patient and specialist surveys are ongoing to identify, and to better understand and reduce potential barriers in people willing to accept treatment.
FUNDING: Gilead Sciences
Disclosure of Interest: None Declared
STP Udhesister1,2,*, N Minoyan1,3, S Hoj1, D Jutras-Aswad1,4, V Martel-Laferriere1,5, G Pagé1,6, S Larney1,7, J Bruneau1,8
1Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada,
2Faculté de médecine, Université de Montréal, Montréal, Québec, Canada,
3École de Santé Publique de l’Université de Montréal, Québec, Canada,
4Département de Psychiatrie et addictologie, Montréal, Québec, Canada,
5Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Québec, Canada,
6Département d’anesthésiologie et médecine de la douleur, Université de Montréal, Montréal, Québec, Canada,
7Université de Montréal, Montréal, Québec, Canada,
8Département de Médicine Familiale et Médecine d’Urgence, Université de Montréal, Montréal, Québec, Canada
Background: Estimates suggest up to 50% of people who inject drugs (PWID) live with chronic pain (intermittent or continuous pain lasting >3 months). However, we know very little about the chronic pain experience of PWID. Many PWID have limited access to medication to help manage their pain due to prescribers’ hesitancy and stigma, potentially increasing self-medication and drug-related harms. A better knowledge of access and use of pain medications by PWID for pain management can help address barriers in care and help develop tailored interventions.
Purpose: The purpose of this study was to describe access and use of pain medication, both opioid and non-opioid, among PWID living with chronic pain followed in a long-standing community-based cohort in Montreal.
Method: A cross-sectional investigation was conducted using data collected among PWID participating in the Hepatitis Cohort (HEPCO), a longitudinal cohort study of PWID in Montreal, Canada. Between February 2017 and March 2022, the Brief Pain Inventory (BPI) questionnaire was added to the main questionnaire for all participants reporting current chronic pain, at baseline and at 3-month follow-up intervals. Additional questions pertained to the type of medication, as well as the use of illicit/non-prescribed substances and the mode of consumption to manage pain in the past 3 months. Using each participant’s first visit during which the BPI and related questions were administered, we examined the prevalence of chronic pain and conducted descriptive analyses to examine physician visits related to chronic pain, the use of opioid and non-opioid medication, and of alcohol, cannabis, or illicit drugs to manage their chronic pain.
Result(s): A total of 543 participants (median age of 45 years, 13.7% women) were included. The prevalence of chronic pain was 46% (n=252). 108/252 (43%) noted using alcohol, cannabis, or an illegal drug to help manage their chronic pain. A total of 87/252 (35%) participants were prescribed opioid (n=41, 47%) and/or non-opioid medications (n=59, 68%). 24% (n= 21) of participants reported using their prescribed medication at an increased dose or frequency than that recommended; 23% (n=20) of participants consumed their prescribed medication by a route different from the recommended mode of consumption; 23% (n=20) of participants reported using medication that was not prescribed to them to help manage their pain. Overall, prescribed pain medication was misused in at least one of the above manners by 30% of the participants who reported chronic pain (n=75). Of the participants who received a chronic pain diagnosis (n=156, 62%), 32% (n=50) visited a physician in the last 3 months due to their pain, and 23/31 (74%) were prescribed pain medication when requested.
Conclusion(s): Access to physicians for the management of pain was low, and self-management of pain was frequent. Further investigation into polyuse of drugs and modes of consumption could provide insights into better care and reduce drug-related harms.
FUNDING: CIHR, CanHepC
Disclosure of Interest: None Declared
H Velásquez García1,2,*, PA Adu1,2, D Jeong1,2, JD Makuza1,2, J Wilton1, A Yu1, S Wong1, M Binka2, H Samji1,3, H Sbihi1, NZ Janjua1,2,4
1BC Centre for Disease Control, Vancouver, British Columbia, Canada,
2School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada,
3Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada,
4Centre for Health Evaluation & Outcomes, St. Paul’s Hospital, Vancouver, British Columbia, Canada
Background: Emerging evidence suggests that people living with cirrhosis are at higher risk of severe disease after COVID-19 infection. However, most of the published studies are small and based on selected hospital-based cohorts.
Purpose: We assessed the risk of COVID-19-related severe outcomes (hospitalization and intensive care unit [ICU] admission) among people with cirrhosis.
Method: We used data from the British Columbia (BC) COVID-19 Cohort, a population-based cohort that integrates data on all laboratory-confirmed COVID-19 cases with data on hospitalizations, medical visits, emergency room visits, prescription drugs, chronic conditions, and deaths in the province. We included all individuals, aged 18 or above who tested positive for SARS-CoV-2 by real-time reverse transcription-polymerase chain reaction, from January 01, 2021 (following the start of the vaccination program) to December 31, 2021. Multivariable logistic regression models were used to assess the associations between cirrhosis status and COVID-19 related hospitalization and ICU admission while adjusting for age, sex, variant of concern, comorbidities, income, geographic area, and vaccination status. Cirrhosis was identified with a validated algorithm using ICD-9/10 codes relevant for this disease in administrative databases. Hospitalization was defined as hospital admission in a BC acute care facility within 14 days after a positive SARS-CoV-2 test. ICU was defined as admittance to ICU during hospitalization.
Result(s): Of the 162, 509 individuals testing positive for SARS-CoV-2 included in the analysis, 768 (0.5%) had cirrhosis. Among people with cirrhosis, 230 (29.9%) required hospitalization and 98 (12.8%) required ICU admission compared with 8,316 (5.1%) and 2,413 (1.5%), respectively, among those without cirrhosis. In the adjusted models, cirrhosis was still associated with increased odds of hospitalization (aOR=2.55, 95% CI: 2.11, 3.08) and ICU admission (aOR=2.87, 95% CI: 2.23, 3.70). In the analyses stratified by age, we found that the increased odds of ICU admission and hospitalization among people with cirrhosis were present in all the assessed age-groups (18-49, 50-69 and ≥70 years).
Conclusion(s): Cirrhosis is associated with increased odds of hospitalization and ICU admission among COVID-19 patients. Prioritization of COVID-19 vaccination and early treatment for people with cirrhosis is needed to prevent and reduce severe COVID-19 outcomes.
FUNDING: This work was supported by the BC Centre for Disease Control and the Canadian Institutes of Health Research [Grant # VR5-172683 and OV4-170361].
Disclosure of Interest: None Declared
G Hirode1,*, RJ Wong2,3, C Brosgart4, SS Wong5, JJ Feld1, J Glenn2, S Hamid6, C Cohen7, B Zovich7, JW Ward8, H Wedemeyer9, C Yurdaydin10, RG Gish7
1Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada,
2Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA,
3Gastroenterology Section, Veterans Affairs Palo Alto Healthcare System, Palo Alto, Santa Clara, California, USA,
4Department of Medicine, Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA,
5S Wong Consulting, LLC, Mountain View, California, USA,
6Department of Medicine, Aga Khan University, Karachi, Sindh, Pakistan,
7Hepatitis B Foundation, Doylestown, Pennsylvania, USA,
8Coalition for Global Hepatitis Elimination, Task Force for Global Health, Decatur, Georgia, USA,
9Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Lower Saxony, Germany,
10Department of Gastroenterology, Ankara University School of Medicine, Ankara, Türkiye
Background: Foreign-born (FB) individuals contribute disproportionately to burden of chronic hepatitis B (CHB) in Canada. CHB prevalence in Canada has been estimated to range from 10 to 13 per 100,000 persons. However, CHB prevalence particularly among ethnic minority immigrants and underserved populations may be underestimated due to limitations of existing datasets and surveillance systems.
Purpose: The aim of this study was to provide an accurate estimate of CHB prevalence among FB individuals living in Canada in 2016.
Method: We performed a comprehensive systematic review and meta-analysis of HBsAg seroprevalence surveys published between from 117 countries from which FB individuals migrate to Canada. We combined country-specific CHB prevalence rates with the number of FB individuals living in Canada in 2016 by country of birth using data from Statistics Canada, the national statistical office that provides data from the Canadian Census conducted every 5 years. Random effects meta-analyses were performed to generate country-specific pooled prevalence rates for CHB and 95% confidence intervals (CI).
Result(s): In 2016, there were approximately 7.54 M FB individuals living in Canada, the majority of whom were from Asia (3.63 M) and Europe (2.09 M). Among FB individuals, the estimated pooled prevalence of CHB was 3.96% (95% CI 3.34–4.62), which translates to about 300,000 (95% CI 250,327–348,497) FB individuals with CHB in Canada in 2016 (Figure). Approximately 68% of FB individuals with CHB in Canada were from Asia (201,770), followed by 15% from Africa (45,986), 10% from Europe (29,824), 7% from the Americas (19,475), and <1% from Oceania (1,674). The top three countries from which FB Canadians with CHB immigrated from were China, including Hong Kong (∼73,000), Philippines (∼41,000), and Vietnam (∼20,000), which together represent 45% for FB individuals with CHB in Canada.
Conclusion(s): This comprehensive systematic review and meta-analysis estimated that there are approximately 300,000 FB individuals with CHB living in Canada. We hypothesize that this population will continue to grow with increased immigration into Canada. The burden of CHB is even greater when factoring in Canada-born CHB patients.
FUNDING: Gilead
Disclosure of Interest: G. Hirode: None Declared, RJ Wong Grant / Research support from: Gilead Sciences, Exact Sciences, Consultant of: Gilead Sciences, Intercept Pharmaceuticals, Salix Pharmaceuticals, C. Brosgart: None Declared, SS Wong: None Declared, JJ Feld Grant / Research support from: AbbVie, Alexion, Eiger, Enanta, Gilead, GSK, Janssen, Roche, Wako/Fujifilm, Consultant of: AbbVie, Antios, Arbutus, Blue Jay, Deep Genomics, Eiger, Finch, Gilead, GSK, Janssen, J Glenn: None Declared, S Hamid: None Declared, C Cohen: None Declared, B Zovich: None Declared, JW Ward: None Declared, H. Wedemeyer Grant / Research support from: AbbVie, Biotest, Gilead Sciences, Merck/MSD, Roche, Consultant of: AbbVie, Aligos, Altimmune, Biotest, BMS, BTG, Dicerna, Enanta, Janssen, MYR GmbH, Vir Biotechnology, Paid Instructor of: AbbVie, Biotest, Gilead Sciences, Merck/MSD, Speakers bureau of: AbbVie, Biotest, Gilead Sciences, Merck/MSD, C Yurdaydin: None Declared, RG Gish Shareholder of: Arrohead, CymaBay Therapeutics, Altimmune, Durect, Grant / Research support from: Gilead, Consultant of: Quest, Perspectum, Fibronostics, Fujifilm/Wako, Biocollections, Helios, Eli Lilly, Merck, Pfizer, Salix, Shionogi, Venatorx, Viking Therapeutics, Abbott, AbbVie, Intercept, HepQuant, Gilead Sciences Inc, HepaTX, Gerson Lehrman Group, Arrowhead, Bristol-Myers Squibb, Dova, Dynavax, Eiger, Enyo, eStudySite, Genentech, Genlantis, Altimmune, Antios, Janssen, Sonic Incytes, Precision BioSciences
AB Mendlowitz1,2,3,*, JA Flemming4,5, T Kushner6, WW Wong2,3,7, ZR Greenwald2,8,9, J Feld1, M Biondi1,10
1Toronto Centre for Liver Disease/Viral Hepatitis Care Network (VIRCAN), University Health Network, Toronto, Ontario, Canada,
2ICES, Burnaby, British Columbia, Canada,
3Toronto Health Economics and Technology Assessment Collaborative, University Health Network, Toronto, Ontario, Canada,
4Departments of Medicine and Public Health Sciences, Queen’s University, Kingston, Ontario, Canada,
5ICES, Kingston, Ontario, Canada,
6Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA,
7School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada,
8Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada,
9Centre on Drug Policy Evaluation, MAP Centre for Urban Health Solutions, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada,
10School of Nursing, York University, Toronto, Ontario, Canada
Background: The opioid epidemic has led to increasing numbers of hepatitis C virus (HCV) infections in younger populations and women of childbearing age. As a result, HCV among pregnant women has also increased. At present, HCV screening in Ontario is risk-based, yet prenatal care may be the only time when women engage in healthcare services, making it an opportune time to screen for and diagnose HCV, and link those infected to care. Currently, there is little known to describe trajectories of HCV care (including screening, diagnosis, and treatment) among pregnant or postpartum women in Canada or globally.
Purpose: Using health administrative data, we characterized engagement in HCV care among pregnant and postpartum individuals in Ontario, identifying gaps in engagement and healthcare service delivery.
Method: We performed a population-based retrospective cohort study linking individuals who delivered between 1999 and 2018 to Public Health Ontario Laboratory HCV testing records and health administrative datasets held at ICES. We identified individuals who were alive and in Ontario as of December 31, 2018, with record of testing HCV antibody (Ab) or RNA positive and inpatient admission records of a delivery (livebirth or stillbirth). We determined whether individuals were positive before, within the prenatal care period (from estimated start of pregnancy) or after their earliest delivery date; as well as whether individuals had subsequent RNA testing, HCV care, and frequency of treatment through the Ontario drug benefit (ODB) program.
Result(s): On December 31, 2018, we identified 8,389 individuals with record of an Ab or RNA positive test and a delivery between 1999 to 2018. Of these individuals, 2384 (28%) had record of their earliest positive test before or on their earliest delivery date, 682 (8.1%) had their earliest positive test reported during the prenatal care period or on their earliest delivery date, and 370 (4.4%) up to a year following delivery date. For individuals where their earliest positive corresponded to an Ab positive test result (N=8041 (96%)), 6759 (84%) had a subsequent RNA test, with a median time to testing of 13 (interquartile range [IQR]:3-75) weeks and average of 79 (standard deviation [SD]:149) weeks. Of these individuals, 4642 (69% of RNA tested) were RNA positive. Among all individuals with an RNA positive test result (N=5147 (61.4% of 8389), 1575 (30.6%) had a subsequent first ODB HCV treatment dispensation record with a median time from RNA positive to treatment of 104 (IQR:40-274) (approximately 2 years) and average of 192.1 (SD: 205.5) weeks (approximately 3.7 years).
Conclusion(s): Substantial delays exist between HCV testing and treatment among pregnant and postpartum individuals in Ontario. This data captures early access to direct acting antiviral (DAA) treatment regimens. As a next step, we intend to extend this work to investigate testing, linkage to care, and treatment uptake. This work will examine timing in the absence of reimbursement barriers and consider the expansion of low barrier treatment models in Ontario (2018-2021), as well as further analyses to describe demographics and clinical outcomes.
FUNDING: In addition to funding from the Postdoctoral Trainee Fellowship from CanHepC, I am also funded by a CIHR Fellowship
Disclosure of Interest: A Mendlowitz: None Declared, JA Flemming: None Declared, T Kushner Grant / Research support from: Gilead, Consultant of: Gilead, AbbVie, Bausch, WW Wong: None Declared, ZR Greenwald: None Declared, J Feld Grant / Research support from: AbbVie, Enanta Pharmaceuticals, Gilead Sciences and Janssen, M Biondi Grant / Research support from: AbbVie, Gilead Sciences, Cepheid, Speakers bureau of: Abbott and AbbVie
G Fontaine1,2,*, J Presseau1,3,4, J Bruneau5,6, AM Patey1,3,7, Z van Allen1,4, S Mortazhejri1,3, S Bordier HØj8, G Boyer-Legault9, C Jui-Hsia Hung1,3, J Grimshaw1,2,3
1Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada,
2Faculty of Medicine, University of Ottawa, Ontario, Ottawa, Canada,
3School of Epidemiology and Public Health, University of Ottawa, Ontario, Ottawa, Canada,
4School of Psychology, University of Ottawa, Ontario, Ottawa, Canada,
5Research Centre, Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada,
6Department of Family and Emergency Medicine, Université de Montréal, Montréal, Québec, Canada,
7School of Rehabilitation Therapy, Queen’s University, Kingston, Ontario, Canada,
8Research Centre, Université de Montréal, Montreal, Québec, Canada,
9Direction of Community Services, CACTUS Montréal, Montréal, Québec, Canada
Background: Improving access to hepatitis C virus (HCV) infection care in community organizations serving people who inject drugs is critical to ensure widespread to treatment and reach hepatitis C micro-elimination. However, we have a paucity of data regarding HCV cognitive and emotional illness representations among people who inject drugs (PWID) visiting these organizations in the direct-acting antiviral (DAA) era, and how these might influence treatment uptake in treatment-naïve and reinfected individuals.
Purpose: This theory-informed qualitative descriptive study aimed to explore HCV cognitive and illness representations and coping strategies among PWID visiting a large urban needle syringe program in Montreal, Canada.
Method: Semi-structured, individual qualitative interviews guided by the Common Sense Self-Regulation Model (CS-SRM) were conducted to explore cognitive and emotional illness representations regarding HCV infection, as well as coping strategies and sources of information regarding the disease. Eligible participants included individuals aged 18 years old or older, speaking French or English, with a recent history (<3 months) of injection drug use, and a recent visit (<3 months) to the needle syringe program. Interview data were transcribed verbatim, coded according to CS-SRM dimensions and thematic analysis was conducted.
Result(s): Eighteen participants (median age 44.5 years) were recruited between October 2021 and January 2022. Most participants self-identified as male (13/18) and as White (15/18), and only three reported having stable housing. Fourteen participants had one or more HCV infection(s), for a total of 18 HCV infections across the sample. Of those, nine were treated with DAAs, six were self-cured, and three were treated with interferon-based therapies. Cognitive illness representations were dominated by beliefs regarding the curability, controllability and treatment of HCV infection, and influenced individuals’ motivations and intentions in seeking treatment for (re)infection. Emotional illness representations of HCV infection evolved along the care cascade steps. Common concerns and knowledge gaps among PWID included uncertainty on transmission risks of HCV from sexual activity, previous adverse experiences with interferon-based therapies, confusion related to DAA treatment eligibility and access in Quebec, as well as enacted and anticipated stigma related to HCV infection and drug use in different social contexts.
Conclusion(s): Findings underscore several adaptations required to service delivery in harm reduction community organizations serving PWID to promote the uptake of DAAs among PWID (re)infected with HCV.
FUNDING: CIHR, Canadian Network on Hepatitis C
Disclosure of Interest: None Declared
J M Beghin1,*, V Meier-Stephenson2,3
1University of Alberta, Edmonton, Alberta, Canada,
2Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada,
3Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
Background: Hepatitis delta virus (HDV) is a defective virus that requires the surface proteins of Hepatitis B virus (HBV) to complete its replication. Approximately 5% of HBV-infected individuals also harbour HDV, giving estimates of about 12 million people worldwide.Those co-infected with HBV-HDV will often have a more rapid progression of liver disease, hepatocellular carcinoma compared to HBV-monoinfected. Understanding the interplay between these two viruses may provide insight into new strategies for treatment. HBV has 8 genotypes (A-H) as does HDV (genotypes 1-8), both which tend to have a specific epidemiology, linking the different genotypes to different geographical locations. It remains unclear whether HDV has a preference for a specific HBV genotype or whether the link is purely epidemiological coincidence.
Purpose: To determine which HBV genotype is most often linked with active HDV infection and speculate on whether this may represent a viral “preference”.
Method: Electronic databases associated with OVID Medline were comprehensively searched for studies published between 1977-2022 including keywords, including “genotype” and all permutations of “HDV” (hepatitis D virus, hepatitis delta, etc.). All studies with English indexing were searched, regardless of the language of the main text. Primary studies of patient samples reporting genotype data for either or both of HDV and HBV were included in the initial literature search. Articles were screened and cross-checked for relevance by both authors. Data from the primary studies, that reported on both HDV and HBV genotypes, were tabulated to include HBV and HDV genotypes, study size, and country.
Result(s): The initial literature search revealed 419 articles. After screening, 82 primary studies remained that incorporated genotype data for both HBV and HDV. We limited our search to cases with detectable HDV RNA, highlighting the persistence of HDV in the HBV-HDV viral dynamic. These represented over 3000 samples from over 45 countries. The most common pairing where both viral genotypes were known, was HDV genotype 1 (which is found worldwide) with HBV genotype D. The overall most common HBV genotype supporting HDV was HBV-D. There were no studies that reported an HDV co-infection with HBV-H. Further, certain genotype pairings were found to be more common in specific regions of the world as not all HDV genotypes are found ubiquitously around the world.
Conclusion(s): This review provides a thorough overview of the HBV and HDV genotype pairs available in the literature. While the most common pairing was HBV-D with HDV-1, it is unclear whether this remains a viral “preference” or mere endemicity of the two viruses. Determining if there is a virologic link between HBV and HDV genotypes may have important implications for emerging HDV and HBV research.
FUNDING: University of Alberta Li Ka Shing Institute of Virology and Faculty of Medicine and Dentistry
Disclosure of Interest: None Declared
S Mortazhejri1,2,*, C Cooper1,2, C Greenaway3,4, S Pakhale1,2, A Patey1,2, J Presseau1,2, G Fontaine1,2, J Grimshaw1,2
1Ottawa Hospital Research Institute, Ottawa, Ontario, Canada,
2University of Ottawa, Ottawa, Ontario, Canada,
3McGill University, Montréal, Québec, Canada,
4Jewish General Hospital, Montreal, Québec, Canada
Background: Canada is committed to elimination of Hepatitis C Virus (HCV) as a public health threat by 2030. Immigrants from countries with high rates of HCV infection make up 35% of all cases in Canada and are one of the priority target groups. These immigrants are not routinely screened upon arrival in Canada. Furthermore, they do not usually have the typical risk factors for HCV infection and since HCV screening in Canadian healthcare system is based on risk factors, they may be missed by the system. As such, there is an average 10-year delay in diagnosis, which results in poor health outcomes in those individuals and high costs to the healthcare system. To address this gap, we need to understand the barriers and enablers to HCV screening and treatment, faced by immigrant communities and their healthcare providers. Ottawa has a large Egyptian community, and Egypt has one of the highest rates of HCV infection. Therefore, we focused on the Egyptian community to understand the factors that impact access to care in this population.
Purpose: We will explore the barriers faced by immigrants in receiving HCV care, as well as the barriers faced by healthcare providers in offering HCV care to this population.
Method: We have established a Community Advisory Group (CAG) who will be involved throughout the whole project, ensuring that the project reflects the perspectives of the community members, and respects their values and beliefs. We will perform qualitative semi-structured interviews with immigrants to determine their understanding of HCV and its management by using the Common-Sense Self Regulation Model, as well as their perceived barriers to HCV care by using the Theoretical Domains Framework (TDF). Study participants will be adult English-speaking immigrants from Egypt, as well as the healthcare providers practising in Ottawa. Furthermore, we will conduct interviews with healthcare providers to identify the barriers to providing HCV care to immigrants by using the TDF. Thematic analysis will be applied to code the interviews and identify key views.
Result(s): We will identify the key barriers to HCV care from immigrants’ and healthcare providers’ points of views and address those by designing theory-informed interventions.
Conclusion(s): As immigrants from endemic countries constitute a large proportion of HCV cases in Canada, to eradicate HCV in Canada, we need to improve their access to care. This study is the first step to understand the current challenges in access to care in immigrants and to inform the development of interventions to improve this.
FUNDING: CanHepC
Disclosure of Interest: None Declared
N Chang1,*, K Tsoi1
1Department of Gastroenterology, McMaster University, Hamilton, Ontario, Canada
Background: The WHO goal of reaching viral elimination of Hepatitis B virus (HBV) by 2030 is primarily through reduction of transmission as a result of vaccination programs. Current Canadian guidelines do NOT recommend routine boosters or repeat vaccination series for immunocompetent individuals who have completed a 3-dose primary series of HBV vaccinations. Boosters may be considered in the context of hemodialysis or on a case-by-case basis for immunocompromised states or high-risk individuals such as healthcare workers. These guidelines are based on the premise that even after antibody titres decline, immune memory persists for decades, allowing mobilization of HBsAg-specific memory B and CD4+ T cells on re-exposure to HBsAg.
Purpose: We describe a case of HBV in a healthy 57-year-old male who had previously responded appropriately to three-dose HBV vaccine series (Twinrix) with HBs antibody titres (HBsAb) > 34.34 mUI/mL, and developed acute hepatitis B only three years later.
Method: Case Report and Literature Review
Result(s): In December 2018, the patient was confirmed not to have immunity against HBV with HBsAb <2.50 mIU/mL nor any previous exposure to or infection with HBV (HBsAg and anti-HBcoreAb total negative). He received the 3-dose Twinrix vaccination series in December 2018, January and July 2019. Post vaccination testing February 2020 confirmed a positive HBsAb titre of 34.34 mIU/mL, with subsequent serial HBsAb of 2.40 mIU/mL in June 2021, and <2.0 mIU/mL in December 2021. Throughout this period, the patient had continued to test negative for HBsAg, anti-HCV, syphilis and HIV.
In March 2022, he presented with a 2-week history of mild epigastric discomfort, jaundice as well as dark urine and pale stools without evidence of hepatic encephalopathy or coagulopathy (INR 1.3 max). He was found to have hyperbilirubinemia (Tbili max 331 umol/L) and elevated liver enzymes (ALT peaking at 3708 U/L, AST at 1407 U/L, ALP at 364 U/L and GGT at 422) with CT and ultrasound imaging negative for biliary obstruction. He was subsequently found to have positive HBsAg, Anti-HBc IgM and started on tenofovir. HBV DNA viral load was 2.01E + 6 IU/mL and liver biopsy pathology was consistent with acute hepatitis B infection. Liver enzymes including ALT and AST normalized by beginning of June, with HBsAg becoming undetectable about one week after this. However, he has yet to develop anti-HBs. Tenofovir was also continued throughout this time and planned to do so until at least six months after his HBsAg had become undetectable.
Conclusion(s): This case demonstrated that the patient contracted acute HBV hepatitis despite being vaccinated only about 3 years ago with a positive anti-HBs response. This raises the question of the need for serial HBsAb testing post vaccination, and whether recommendations of booster vaccines should be extended to immunocompetent patients who demonstrated an early decline in anti-HBs antibody titres. If adapted, this may lead to significant changes in public health strategies against HBV.
FUNDING: None
Disclosure of Interest: None Declared
G Costaguta1,*, S Dion1,2, M-È Chartier1,3, M Paganelli1,3, F Álvarez1,3
1Pediatric Gastroenterology, Hepatology and Nutrition, CHU Sainte-Justine, Montréal, Québec, Canada,
2Transplant Québec, Montréal, Québec, Canada,
3Pediatrics, University of Montréal, Montréal, Québec, Canada
Background: Liver transplantation is the treatment for several diseases, but it is not free of complications. Years ago, we observed a 16 years-old patient with elevated levels of serum IgA who developed kidney failure and a biopsy was compatible with IgA-nephropathy. This case prompt us to investigate the presence of abnormal IgA levels in our patients to try and find possible causes and its relationship with renal disease.
Purpose: Investigate the prevalence of elevated IgA levels in our liver transplant patients and the possible effects on renal function
Method: We conducted a retrospective study by reviewing the records of liver recipients at CHU Sainte-Justine. Demographic data included sex, age at transplantation, underlying disease, re-transplantation, allergic manifestations and portal hypertension. Biochemical data included urea, creatinine, liver tests, immunoglobulins, hematuria, proteinuria, glomerular filtration rate (GFR), EBV and CMV status. Patients were included with at least one IgA measured during the follow-up. Exclusion criteria were less than 2 years of follow-up, no GFR measured or previous renal disease. Two groups were established: hyper-IgA (Group A) and normal-IgA (Group B)
We reviewed records between 1985 and 2000 as those patients were initially treated with cyclosporin A (CsA).
Allergic manifestations were classified as food or dermatologic. Persistent portal hypertension was defined as splenomegaly more than two years after transplantation. GFR was measured by Technetium-99m and adjusted for surface.
Result(s): Of the 85 patients included, 56% had elevated IgA with no differences in sex, underlying disease and re-transplantation. Patients in group A were younger (mean age 28 vs 47 months, p=0.003). In group A 54% had eczema but only 5% in B (p<0.00001).
Splenomegaly was more common in group A (53% vs 22%, p=0.02) and Z-score of spleen size was different (2.23 vs 0.76, p=0.03).
We found higher levels of IgG in group A (p=0.0001).
Significant proteinuria was exclusive of group A (p=0.001) and all had some degree of hematuria (p=0.01). No differences were found in urea and creatinine.
Only 13% in the CsA group had abnormal IgA (p=0.002). We found no difference in spleen size.
GFR decreased in both groups, but the rate was different (p<0.0001) and was evident from year 7 and onwards (p=0.019). (Fig 1)
Conclusion(s): We propose that the abnormal levels of IgA are caused by an augmented intestinal permeability, secondary to persistent portal hypertension, causing antigens to encounter the immune system provoking a reaction, mainly Th2, which stimulates B-cells to produce antibodies. This would normally be countered by Th1 cytokines (IFN-γ) but tacrolimus inhibits this response perpetuating a Th1/Th2 disbalance.
We believe that circulating IgA over time causes a kidney injury like that of an IgA-glomerulopathy, and this may partly explain why some but not all patients develop kidney failure years after liver transplantation.
FUNDING: None
Disclosure of Interest: None Declared
T Afzaal1,*, D Hudson1, B Van2, MQ Khan3, K Qumosani3, A Teriaky3
1Medicine, Western University, London, Ontario, Canada,
2Western University, London, Ontario, Canada,
3Gastroenterology and Hepatology, Western University, London, Ontario, Canada
Background: It is estimated 1.5 billion people worldwide have some element of chronic liver disease (CLD) or cirrhosis.1 Non-alcoholic fatty liver disease (NAFLD) has become the most common cause of CLD, affecting up to 30% of the world population.1,2 It is well known cirrhosis is the strongest risk factor for the development of hepatocellular carcinoma. However, several studies have shown the association of NAFLD and the development of extra hepatic malignancies, specifically an increased risk of gastrointestinal malignancies.2-5
Purpose: The aim of this study was to determine the incidence of gastrointestinal malignancies (esophagus, gastric, colorectal, pancreatic) for patients with NAFLD compared to controls without NAFLD using an adult inpatient population.
Method: Using a population based retrospective study design, we analysed data from the United States Nationwide Inpatient Sample (NIS) database for 2013. Using validated International Classification of Diseases, Ninth Revision (ICD-9) codes we identified inpatients 18 years or older with NAFLD and a diagnosis of a gastrointestinal malignancy (esophagus, gastric, colorectal, pancreatic). We then compared that cohort to adult inpatients without NAFLD. We adjusted for multiple confounders (age, payer type, location, hypertension, dyslipidemia, obesity, type 2 diabetes mellitus, chronic kidney disease, smoking, alcohol and cirrhosis) and performed a multivariable logistic regression analysis to evaluate the impact of NAFLD on gastrointestinal related malignancies.
Result(s): Utilizing the NIS database we were able to identify 36,597,790 potential patients to include in the study. 235,035 patients had NAFLD and a gastrointestinal malignancy while 36,362,755 patients were in the control group. The average age of the NAFLD group was 54.91 and non-NAFLD was 57.37. The NAFLD group had 56.9% females while the non-NAFLD group had 59.1%. Majority of patients in both groups were white, 70.9% in the NAFLD group and 68.6% in the control group. Patients with NAFLD had a higher incidence of gastric cancer (odds ratio [OR]: 1.25, 95% CI: 1.01-1.55), colon cancer (OR: 1.14, 95% CI: 1.05-1.25), and pancreatic cancer (OR: 1.51, 95% CI: 1.30-1.77). There was no significant difference between the two groups for rectal cancer (OR: 0.94, 95% CI: 0.78-1.12), esophageal cancer (OR: 0.91, 95% CI: 0.69-1.18) and hepatic cancer (OR: 1.11, 95% CI: 0.97-1.27).
Conclusion(s): Using a large database, when compared to controls, patients with non-alcoholic fatty liver disease had an increased incidence of gastric, colonic and pancreatic malignancies but no difference in rectal, esophageal and hepatic malignancies.
FUNDING: None
Disclosure of Interest: None Declared
J Francheville1,2,*, K Tennankore1,2, T Kulai1,2
1Dalhousie University, Halifax, Nova Scotia, Canada,
2Multi-Organ Transplant Program, Halifax, Nova Scotia, Canada
Background: Frailty in advanced liver disease is increasingly recognized as a predictor of adverse outcomes before and after transplant. Incorporation of a measure of frailty into transplant evaluation has been shown to improve risk prediction for waitlist mortality. However, assessment of frailty has not been integrated into liver transplant evaluation in a standardized fashion across Canada. In 2021, the Liver Transplant Program within the Multi-Organ Transplant Program at the QEII Health Sciences Centre in Halifax, NS, implemented a systematic frailty screening and intervention protocol for liver transplant candidates.
Purpose: We evaluated preliminary outcomes after implementation of a frailty screening program, including the impact of frailty on patients being evaluated for liver transplant.
Method: As part of the frailty protocol implemented in September 2021, all new referrals undergoing evaluation for liver transplant underwent standardized assessment: Liver Frailty Index, 6-Minute Walk Test, Karnofsky Score, and Clinical Frailty Score. While physiotherapy had historically been involved in liver transplant care, this program has expanded access to facilitate use of these validated tools to characterize patients as robust, pre-frail or frail to target intervention.
Using a retrospective observational study design, all new outpatient transplant evaluations from September 1, 2021 to September 30, 2022 were identified for analysis. Primary analysis assessed the prevalence of patients identified as frail, and its association with waitlist outcomes. Secondary analysis examined program parameters including the proportion of new referrals evaluated by physiotherapy and with completed frailty assessments.
Result(s): Over 12-months, there were 48 new outpatient evaluations for liver transplant. The majority (40/48) were assessed by physiotherapy, but only 28/48 had completed frailty assessments. Reasons for incomplete frailty assessments included physiotherapy assessment done virtually (9/48), and discharge from transplant clinic before evaluation (5/48). Of those assessed, 8/28 were frail, 18/28 were pre-frail, and 2/28 were robust. There were no significant differences in the proportion of frail/pre-frail patients between Child-Pugh classes. Patients with hepatocellular carcinoma were significantly less likely to be frail (1/12, p = 0.04). Of the 8 patients identified as frail, 2/8 died during assessment, 2/8 were felt too early for transplant, 2/8 are still being evaluated, 1/8 remains waitlisted for transplant and 1/8 was transplanted.
Conclusion(s): We describe the preliminary results of a frailty screening program in outpatient liver transplant candidates. Although the program was feasible, not all patients were assessed, and challenges assessing patients virtually is a barrier. In those assessed, there was a significant burden of frailty. This work is the first of a longitudinal quality improvement strategy to evaluate the program, and next study the impact of intervention for frail patients.
FUNDING: None
Disclosure of Interest: None Declared