Background: Although highly effective as part of direct-acting antivirals (DAAs), protease inhibitors (PI) have been associated with decompensation in people with cirrhosis. A simple tool to identify patients who can safely take PIs with very low or no risk of decompensation would be useful, particularly as treatment expands to primary care.

Purpose: To validate our previously developed score using only baseline albumin and platelets (plt) in the large HCV-TARGET real-world cohort.

Methods: All patients treated with PI-based therapy in the HCV-TARGET and PRIORITIZE studies were included. Incidence of decompensation (ascites, spontaneous bacterial peritonitis, variceal bleed or encephalopathy) from treatment start to SVR12 was determined in patients with normal baseline bilirubin. Patients were categorized by previously identified thresholds of baseline albumin ≥ 38 g/L and plt ≥ 130 × 10⁹/L.

Result(s): A total of 2894 patients were included, 2136 without cirrhosis, 590 with compensated cirrhosis and 168 with history of decompensation. Median (IQR) age was 59 (51-64) years, 1689 (58.3%) were male, 108 (3.7%) had Genotype 3 and 126 (4.4%) had prior liver transplantation. In patients with available virological outcomes, SVR was attained in 93.2% (94.5% CI 92.5–96.4) with compensated cirrhosis, 86.5% (95% CI 81.0-91.9) with decompensated cirrhosis and in 95.7% (95% CI 94.8–96.6) non-cirrhotic patients. Overall, 17 (0.6%) patients experienced decompensation during treatment, all of whom had cirrhosis (17/758, 2.2%). The most frequent symptom of decompensation was hepatic encephalopathy in 12 (70.6%) patients. No treatment-emergent decompensation occurred in 2136 patients without cirrhosis. In patients with compensated cirrhosis, no decompensation events occurred in patients with albumin ≥ 38 and plt ≥ 130 (0/219). Among patients with a history of prior decompensation, 31/168 (18.5%) had an albumin ≥ 38 and plt ≥ 130 at baseline, of whom 2 (6.5%) decompensated during treatment (See Figure).

O02 Homelessness, unstable housing and risk of HIV and hepatitis C virus acquisition among people who inject drugs – a systematic review and meta-analysis

C Arum¹, H Fraser¹, AA Artenie¹,^*, S Bivegete¹, A Trickey¹, M Alary², ³, ⁴, J Astemborski⁵, K Debeck⁶, ⁷, P Dietze⁸, ⁹, K Dumchev¹⁰, K Hayashi⁶, ⁷, M Hellard⁸, ¹¹, ¹², ¹³, M Hickman¹, V Hope¹⁴, J Iversen¹⁵, A Judd¹⁶, AE Kurth¹⁷, P Cherutich¹⁸, P Leclerc¹⁹, ²⁰, A Lim¹, L Maher^8,¹⁵, L Macgregor¹, SH Mehta⁵, M Morris²¹, JJ Ong¹, K Page²², L Platt²³, M Prins²⁴, ²⁵, R Sacks-Davis⁸, ¹¹, DK van Santen⁸, SS Solomon⁵, V Sypsa²⁶, CS Todd²⁷, J Valencia²⁸, W Van Den Boom⁹, SA Strathdee²⁹, JG Walker¹, Z Ward¹, J Stone¹, P Vickerman¹

¹Population Health Sciences, University of Bristol, Bristol, United Kingdom

²Centre de recherche du CHU de Québec

³Institut national de santé publique du Québec

⁴Département de médecine sociale et préventive, Université Laval, Québec, Canada

⁵Johns Hopkins University, Baltimore, United States

⁶British Columbia Centre on Substance Use

⁷Simon Fraser University, Vancouver, Canada

⁸Burnet Institute, Melbourne

⁹National Drug Research Institute, Curtin University, Perth, Australia

¹⁰Ukrainian Institute on Public Health Policy, Kyiv, Ukraine

¹¹Department of Epidemiology and Preventive Medicine, Monash University

¹²Doherty Institute and School of Population and Global Health, University of Melbourne

¹³Department of Infectious Diseases, The Alfred Hospital, Melbourne, Australia

¹⁴Liverpool John Moores University, Liverpool, United Kingdom

¹⁵Kirby Institute for Infection and Immunity, UNSW, Sydney, Australia

¹⁶University College London, London, United Kingdom

¹⁷Yale School of Nursing, Yale University, Connecticut, United States

¹⁸Ministry of Health, Nairobi, Kenya

¹⁹École de santé publique, Université de Montréal

²⁰Direction régionale de Santé Publique, CIUSSS du Centre-Sud-de-l’Île-de-Montréal, Montréal, Canada

²¹University of California San Francisco, San Francisco

²²University of New Mexico, Albuquerque, United States

²³London School of Hygiene and Tropical Medicine, London, United Kingdom

²⁴Department of Infectious Diseases, Public Health Service of Amsterdam

²⁵Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands

²⁶National and Kapodistrian University of Athens, Athens, Greece

²⁷Global Health, Population & Nutrition, FHI360, Durham, United States

²⁸Department of Addictions and Mental Health, Harm Reduction Unit “SMASD”, Madrid, Spain

²⁹Department of Medicine, University of California San Diego, La Jolla, United States

Background: People who inject drugs (PWID) are a central population to HIV and hepatitis C virus (HCV) prevention efforts. They also experience high levels of homelessness and unstable housing.

Purpose: We assessed whether homelessness or unstable housing is associated with HIV or HCV acquisition risk among PWID.

Methods: We searched MEDLINE, Embase and PsycINFO databases for studies published from January 2000 to September 2020 that estimated HIV and/or HCV incidence among community-recruited PWID, without language restriction. We contacted authors of studies that reported HIV or HCV incidence but did not report on an association with homelessness or unstable housing, to request data. We extracted and pooled data using random-effects meta-analyses to quantify the associations between recent (current or within last year) homelessness or unstable housing and HIV or HCV acquisition risk. We assessed risk of bias using the Newcastle-Ottawa Scale, and between-study heterogeneity using the I²-statistic and p-value for heterogeneity.

Result(s): We included 45 studies with 70 estimates (26 for HIV;44 for HCV). Studies originated from 16 countries including in North America, Europe, Australia, East Africa, and Asia. Pooling unadjusted estimates, recent homelessness or unstable housing was associated with an increased risk of acquiring HIV (crude relative risk[cRR] 1.55; 95% confidence interval [CI] 1.23–1.95; I² = 62.7%; p-value = 0.00018; n = 17) and HCV (cRR 1.65; 95% CI 1.44–1.90; I² = 44.8%; p-value < 0.0001; n = 27). Associations for both HIV (adjusted RR [aRR]:1.39; 95% CI:1.06–1.84; p-value = 0.019; n = 9) and HCV (aRR:1,64; 95% CI:1.43–1.89; p-value < 0.0001; n = 14) persisted when pooling adjusted estimates. For HIV, the association for unstable housing (cRR:1.82; 95% CI:1.13–2.95; p-value = 0.014; n = 5) was higher than for homelessness (cRR:1.44; 95% CI:1.12–1.85; p-value = 0.0044; n = 11).

Conclusion(s): Homelessness or unstable housing are associated with increased HIV and HCV acquisition risk among PWID. These findings frame housing instability as an important driver of HIV and HCV transmission among PWID and call for intensified efforts to evaluate and implement housing initiatives and targeted prevention services that are tailored to the needs of this population.

O03 Pathways to hepatitis C care in BC provincial corrections: Partnering with people in prison to co-create policies and guidelines

S Bartlett¹, ¹, ², ²,^*, T Buller-Taylor¹, ², T Teal³, S Hughes¹, B McMillan¹, T Marion³, J Buxton¹, ², N Sharifi⁴, M Fong⁴, A Beaumont⁴, L Jennings⁵, D Luster⁶, D Laird⁶, M Moher⁷, M Erickson⁸, R Elwood Martin², N Pick⁹, A Krüsi⁸, S Young¹, NZ Janjua¹, ²

¹BC Centre For Disease Control

²University of British Columbia, Vancouver

³AIDS Vancouver Island, Nanaimo

⁴Correctional Health Services, BC Mental Health and Substance Use Services, Vancouver

⁵PASAN, Toronto

⁶BC Hepatitis Network, Vancouver

⁷Cool Aid Clinic, Victoria

⁸Centre for Gender and Sexual Health Equity, University of British Columbia

⁹Oak Tree Clinic, BC Women’s Hospital, Vancouver, Canada

Background: Several studies have demonstrated that routinely offering screening for sexually transmitted and blood-borne infections (STBBIs), including hepatitis C virus (HCV), results in higher uptake of testing compared to ‘on-demand’ strategies in correctional and other health care settings. However, the increases in uptake reported are inconsistent across correctional centres and unintended harms and consequences from these policies have been reported. This suggests that there is a need to further optimise implementation of routine STBBI screening in correctional settings, and provide guidance on best practices.

Purpose: The overall purpose of this project is to incorporate experiences and preferences of key stakeholders into the development of STBBI screening policy and guidelines for British Columbia (BC) provincial correctional centres. Engaging stakeholders is to help ensure the policy and guidelines are person centred, trauma-informed and culturally safe. Key stakeholders include people who are or who have recently been incarcerated, health staff who work in correctional centres, and corrections officers/staff (the latter not yet surveyed).

Methods: To-date we have conducted STBBI-related workshops/surveys with people currently or recently incarcerated and correctional health care staff. Workshops/surveys were conducted with key stakeholders working or living in one of four correctional centres in BC. Original in-person workshop activities were altered to comply with provincial and corrections associated with coronavirus disease of 2019 (COVID-19) restrictions. Activities with key stakeholders included virtual workshops, online surveys (health staff) and paper-based surveys (people incarcerated).

Result(s): As of this writing, 14 corrections health care providers and 12 people currently incarcerated in men’s centres participated in virtual workshops. People who were incarcerated told us in the virtual workshop sessions that barriers to STBBI testing in prisons include: limited knowledge among people who are incarcerated with regards to their rights to confidentiality of health information, fear of information not being private, inconsistent offer of testing, ‘lost’ appointment requests, competing health priorities; and that STBBI testing at initial intake is not the best time to test (paper-based surveys are not yet available). Through an online survey, only 30% (4 of 13) of health staff reported using potentially stigmatizing behaviour/words with clients; but 57% (8/14) reported observing a colleague using stigmatizing behaviour/words with clients. Most health staff (91%; 10/11) reported the workshop increased their knowledge of STBBI testing and hepatitis C treatment and 81% (9/11) reported improved knowledge about barriers to STBBI testing in prisons.

Conclusion(s): These preliminary results indicate that to improve STBBI-related health outcomes in corrections, policy and guidelines should address: 1) the timing of testing 2) confidentiality/privacy 3) stigma 4) culturally-safe and trauma informed care; and 5) protocols that ensure consistent implementation. Early results also indicate that virtual education sessions can be effective for improving STBBI-related knowledge among corrections health staff. Ongoing workshops/surveys with key stakeholders will further explore these conclusions.

O04 CD8+ T cell hyperfunction in a murine model of liver fibrosis

J Madani¹, ²,^*, A Vranjkovic², MS Hasim^1,³, J Li¹, ², M Ardolino¹, ^3,⁴, A Crawley¹, ², ⁴, ⁵

¹Biochemistry, Microbiology, and Immunology, University of Ottawa

²Chronic Disease Program

³Cancer therapeutics program, Ottawa Hospital Research Institute

⁴Centre for Infection, Immunity and Inflammation, University of Ottawa

⁵Biology, Carleton University, Ottawa, Canada

Background: Individuals with advanced liver fibrosis and hepatitis C virus (HCV) infection are more at risk to developing hepatocellular carcinoma. Many immune cells are impaired in chronic HCV infection, including CD8+ T cells which are important for anti-viral and anti-tumor responses. Previously, we reported generalized systemic CD8+ T cell hyperfunction in HCV-infected individuals with advanced liver fibrosis that persisted after direct-acting antiviral therapy. The underlying mechanisms of this immune hyperfunction in the context of liver disease and their impact on host immune response are unknown.

Purpose: To evaluate the link between systemic CD8+ T cell hyperfunction and advanced liver fibrosis and the associated effects on immune response, we use an in vivo hepatotoxin animal model of liver fibrosis.

Methods: Mice (C57BL/6) were injected 2x/weekly with carbon tetrachloride (CCl4, 1mL/kg in 50% olive oil) for 12-16 weeks, while control mice received oil only. At this time, CD8+ T cell phenotype and function were evaluated ex vivo by flow cytometry. In addition, in vivo responses to an ectopic cancer challenge was assessed, with or without ongoing liver insult, and responses toanti-PD1 + anti-CTLA-4 immunotherapy were evaluated therein.

Result(s): We report robust generation of liver fibrosis in CCl4-treated mice marked by severe, diffuse fibrosis, inflammation, and focal necrosis after 12-weeks of CCl4 injections. The proportion of granzyme B+, IFN-γ+, and PD-1+ CD8+ T cells in blood in advanced liver disease was significantly higher compared to controls, and this may be more pronounced in male mice. The elevated proportion of IFN-γ + cells was driven by the effector cells, whereas increased granzyme B+ cells were observed across all subsets. In addition, this hyperfunction was sustained over time following the cessation of CCl4 injections. Time course studies identified that progressive liver fibrosis resulted in the acquiring of granzyme B and IFN-γ hyperfunction by week 8. Finally, ectopic tumor growth was greater in fibrotic mice and responses to immunotherapy were delayed.

Conclusion(s): We show for the first time that bulk CD8+ T cell are dysfunctional in chronic liver fibrosis in the murine CCl4 model and that this adversely affects tumor responses. The effect of liver fibrosis on circulating CD8+ T cell was profound, and not readily reversed by removing the hepatotoxin or immunotherapy, resembling our previous report in DAA-treated HCV infection in advanced liver disease. This suggests there is an impaired extrahepatic immune response, including CD8+ T cell hyperfunction, yet the underlying mechanism is unknown. This new knowledge of CCl4 model will contribute to identifying immunorestorative treatments for individuals with advanced liver fibrosis to minimize adverse long-term sequelae associated with liver damage.

Panel 2 – May 4, 2021

O05 Enriched plasma cell transcriptomic signatures and humoral responses during HCV reinfection and clearance

S Mazouz¹,^*, N Bédard¹, E Salinas², O Khedr¹, A Filali¹, J Bruneau³, A Grakoui⁴, N Shoukry¹

¹Immunology, CRCHUM, Montréal, Canada

²Immunology, Faculty of Medicine Emory University, Atlanta, United States

³Département de médecine familiale et de médecine d’urgence, CHUM, Montréal, Canada

⁴Immunology, Faculty of Medicine Emory University, Atlanta, United States

Background: Development of efficient vaccines against chronic viral infections, including hepatitis C virus (HCV), is hampered by our limited understanding of the cellular and molecular pathways that form a potent protective memory immune response. Transcriptomic analysis of the peripheral immune response during acute primary HCV infection revealed that spontaneous resolution is associated with rapid induction of pathways associated with innate immune activation, interferon signaling, altered monocyte differentiation, and perturbations in the B cell compartment¹. Transcriptomic signatures of HCV memory responses during viral re-exposure remain unknown.

Purpose: The goal of this study is to characterize the transcriptomic and functional signatures of immune responses to HCV reinfection and their contribution to long term protective immunity.

Methods: We selected eight subjects who had successfully resolved two successive episodes of HCV infection. Whole PBMC samples collected during the reinfection episode at baseline (Pre-reinfection), early acute (EA; ~ 4 weeks post estimated date of infection), late acute (LA; ~ 12 weeks) and follow-up phase (~48 weeks) to perform bulk RNA-seq (n = 7). Flow cytometry (n = 8) was used to evaluate the kinetics of circulating follicular helper T cells (cT_FH), E2-specific B cells and HCV-specific CD8+ T cells using E2² and MHC class I tetramers respectively. Plasma samples collected at each time-point were used to evaluate HCV-specific (E2 and NS3) antibody responses by ELISA.

Result(s): Using Gene Set Enrichment Analysis (FDR < 0.05), in contrast to our previously published results during primary infection, we observed a global downregulation of pathways associated with innate leukocytes¹. Pathways associated with memory B cells, plasma cells and follicular helper CD4 T cells (T_FH) were upregulated at EA. The enriched plasma cells signature was sustained at LA in subjects that remained HCV RNA positive. The frequency of E2-specific class-switched memory B cells (CD19+ CD27+ IgM–), increased at EA as compared to pre-reinfection (p = 0.068), reflecting a rapid expansion of MBCs after HCV reinfection More than half (57%) of MBCs had an activated phenotype (CD71+ CD20^hi CD38–) indicative of antigenic stimulation. HCV-specific antibodies (IgG) responses increased significantly in 4/8 (E2; p = 0.008) and 5/8 (NS3; p = 0.02) subjects at the EA time-point. The E2-specific antibody response correlated positively with the frequency of activated E2-specific MBCs (r = 0.7692; p = 0.0256). In subjects with increased anti-E2 antibody responses, we also observed increased frequency of activated (ICOS+) cT_FH cells (CXCR5+PD1+CD45RA–CD4+) at EA. Finally, comparison with published HCV vaccine (ChAd3-NSmut prime and MVA-NSmut boost) data in healthy subjects³ revealed similar T cell signatures as observed in re-infection samples. However, B cell signatures were absent in vaccinees, as only the HCV non-structural genes were used as part of this T cell-based vaccine approach.

Conclusion(s): We detected antibody responses during HCV reinfection and clearance where E2-specific responses correlate with frequency of E2-specific MBCs and are associated with expansion of cT_FH. Hence, humoral immunity may play a key role during HCV reinfection clearance and may be an important factor to be added to the T cell-based vaccine regimen.

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O06 The impact of small RNA binding on hepatitis C virus replication via structural changes within the 5’ untranslated region

M Palmer¹,^*, T Mrozowich², T Patel², J Wilson¹

¹Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon

²Biochemistry, University of Lethbridge, Lethbridge, Canada

Background: Hepatitis C virus (HCV) is a bloodborne viral infection affecting millions of people worldwide. The virus is a positive sense, single-stranded RNA virus of approximately 9.6kb 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) are typically involved in regulation of protein expression by binding to the 3’UTR of an mRNA transcript, leading to suppression of translation and subsequently degradation. By contrast, in the case of HCV, miR-122 binds to two sites within the 5’UTR and promotes viral replication. The exact mechanism of this RNA-RNA interaction has yet to be elucidated, but we hypothesize that small RNA binding promotes HCV replication by inducing RNA structural changes within the 5’UTR. These RNA structural changes could result in different outcomes, such as exposing or hiding protein binding sites, or allowing more efficient translation of the virus polyprotein.

Purpose: Our goal is to determine if RNA-RNA interactions induce structural changes and identify pro-viral RNA structures. Computational predictions of the HCV 5’UTR secondary structure indicate that in the absence of small RNA binding the RNA folds into a “closed,” non-canonical conformation, whereas when bound to a small RNA it adopts an “open” conformation identical to the canonical internal ribosome entry site (IRES) conformation presented in the literature.

Methods: All models were generated using small angle X-ray scattering (SAXS) in collaboration with the Patel lab at the University of Lethbridge. For SAXS we generated and purified high-quality, mono-dispersed RNAs in solution through in vitro transcription and size exclusion chromatography. The purified RNA was then subjected to high-energy, monochromatic X-rays and the scattering pattern produced by the molecule was measured. The scattering pattern was then processed and a low-resolution 3D envelope was produced through ab initio modeling. To obtain experimental confirmation of secondary structure, we have employed selective 2’hydroxyl acylation analyzed by primer extension (SHAPE).

Result(s): We have obtained low resolution structural envelopes for the wild type HCV as well as an assortment of mutants capable of miR-122-independent replication, both on their own as well as bound to miR-122. We have also obtained data for HCV bound to alternative short perfect match RNAs (siRNAs), which have been shown to promote viral replication to varying degrees. The SAXS data we obtained indicate that the RNA structure of the HCV 5’UTR alone differs somewhat from that of the 5’UTR bound to small RNAs. The structures of the mutants were significantly different when compared to that of the wild type RNA alone, with altered conformations being observed. We have generated high resolution models of the RNA structures and fitted them to their respective structural envelopes, but ultimately this relies on secondary structures that have not been experimentally confirmed. We are still in the preliminary stages of implementing SHAPE methodology, and as such optimization is required.

Conclusion(s): We hope that by determining the secondary structure and fitting it to our 3D structural envelopes, we will be able to observe small structural changes induced by small RNA binding or point-mutations. Overall, we believe our structural data will provide us with valuable information on the structure of the HCV 5’UTR, and how it is affected by small RNA binding.

O07 Higher seroprotection rates (SPRS) and higher anti-HBS concentrations in adults age 18+ achieved with 3-antigen hepatitis B vaccine (3a-HBV) compared to 1-antigen hepatitis B vaccine (1a-HBV): results from the pivotal, double-blind, randomized phase 3 study (PROTECT)

F Diaz-Mitoma¹,^*, T Vesikari², J Langley³, N Machluf⁴, J Spaans⁴, B Yassin-Rajkumar⁴, D Anderson⁴, V Popovic⁴

¹VBI Vaccines Inc., Ottawa, Canada

²Nordic Research Network, Tampere, Finland

³Pediatrics and Community Health and Epidemiology, Canadian Center for Vaccinology, Halifax, Canada

⁴VBI Vaccines Inc, Cambridge, United States

Background: Hepatitis B virus (HBV) infection among adults continues to be a major global public health concern. Prophylactic vaccination is a critical measure to prevent the spread of HBV. Sci-B-Vac, a 3-antigen hepatitis B vaccine (3A-HBV) containing S (short), pre-S2 (medium) and pre-S1 (large) hepatitis B surface antigens, is produced in mammalian cells and adjuvanted with aluminum hydroxide. Currently available single-antigen hepatitis B vaccines such as Engerix-B (1A-HBV) contain only the S (short) hepatitis B surface antigen and are manufactured in yeast. Efficacy of 1A-HBV has been shown to decrease with age and with the presence of comorbidities or activities associated with impaired immune response to vaccination, such as diabetes, obesity, smoking and alcohol use. In previous non-comparative studies, strong immune responses to 3A-HBV immunization have been observed in individuals with a variety of chronic comorbid conditions.

Purpose: The PROTECT study was one of two pivotal Phase 3 studies conducted to support regulatory approval for licensure in Canada, the U.S., and Europe.

Methods: PROTECT was a double-blind, phase 3 study, which enrolled 1607 adults ≥ 18 years, (80% ≥ 45 years) in stable health, including those with controlled chronic conditions, randomized (1:1) to receive 3A-HBV (10 μg) or 1A-HBV (20 μg), on Days 0, 28, and 168. Immunogenicity, measured by seroprotection rate (SPR; % participants with anti-HBs ≥ 10 mIU/mL) and geometric mean concentration (GMC) of anti-HBs in serum, and safety outcomes were evaluated for 12 months. The co-primary immunogenicity endpoints of 3A-HBV compared to 1A-HBV were 1) non-inferiority in adults ≥ 18 years, and 2) superiority in adults ≥ 45 years, based on the SPR 4 weeks after the third vaccination (Study Day 196).

Result(s): At baseline, mean age was 56.6 years, > 80% were age ≥ 45 years, and 37% were age ≥ 65 years. Mean BMI was 29.3 kg/m² and 36.7% of participants had BMI > 30 kg/m²; 8% had well-controlled type-2 diabetes, 14% were current smokers and 27% former smokers; 8% consumed ≥ 2 alcoholic drinks/day; 42% were enrolled in the US, 16% in Canada, and 42% in Europe. Both co-primary endpoints were achieved. 3A-HBV was non-inferior to 1A-HBV in adults ≥ 18 years of age (SPR: 91.4% vs. 76.5%) and was superior to 1A-HBV in adults ≥ 45 years of age (SPR: 89.4% vs. 73.1%), based on the SPR at Study Day 196, 4 weeks after the third dose. SPR for 3A-HBV was consistently higher compared to 1A-HBV across all key subgroups, including by age, gender, race, ethnicity, BMI, diabetes status, current and non-smoking status, and alcohol use. Significantly higher GMCs of anti-HBs were noted for 3A-HBV compared with 1A-HBV in all subgroups analyzed (Figure). In all participants, markedly higher anti-HBs concentrations were achieved with 3A-HBV compared to 1A-HBV. Anti-HBs concentrations peaked at Study Day 196 in both vaccine arms with higher GMCs noted in the 3A-HBV arm as compared with the 1A-HBV arm (1148.31 mIU/mL vs. 192.65 mIU/mL) and remained high even at Study Day 336 (445.07 mIU/mL vs. 69.24 mIU/mL), highlighting the durability of antibody responses against HBV even in those with impaired immune response to vaccination. No new safety signals were found and safety profiles of 3A-HBV and 1A-HBV were consistent with previous studies.

Conclusion(s): SPR and anti-HBs concentrations were consistently higher for 3A-HBV compared to 1A-HBV across all adults, regardless of age, including key subgroups with comorbidities associated with reduced immune response to hepatitis B vaccination.

Panel 3 – May 5, 2021

O08 Younger age is associated with lower self-reported quality of life among patients with autoimmune liver disease during Canada’s response to the COVID-19 pandemic

CG Plagiannakos¹, ²,^*, SB Roberts¹, ², M Saini¹, C Vincent³, L Worobetz⁴, AL Mason⁵, JA Flemming⁶, C Tsien⁷, K Qumosani⁸, GM Hirschfield¹, ², HLA Janssen¹, ⁹, AF Gulamhusein¹, ², BE Hansen¹, ²

¹Toronto Centre for Liver Disease, Toronto Western and General Hospital, University Health Network

²Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto

³Department of Medicine, University of Montreal, Montreal

⁴Department of Medicine, University of Saskatchewan, Saskatoon

⁵Division of Gastroenterology and Liver, University of Alberta, Edmonton

⁶Department of Medicine, Queen’s University, Kingston

⁷Department of Medicine, University of Ottawa, Ottawa

⁸Schulich School of Medicine and Dentistry, Western University, London

⁹Department of Medicine, University of Toronto, Toronto, Canada

Background: On March 11^th 2020, COVID-19 was classified as a pandemic and a state of emergency (SoE) was declared across Canada. On September 23^rd 2020, the government of Canada announced a second wave of COVID-19.

Purpose: We leverage our national multisite registry of patients with autoimmune liver disease to investigate changes in self-reported quality of life (QoL) in a combined cohort of patients with Autoimmune Hepatitis (AIH) and Primary Biliary Cholangitis (PBC) during the COVID-19 pandemic.

Methods: We included patients with AIH or PBC who had completed at least 1 QoL survey between July 2019 and January 2021. Surveys completed prior to March 11^th 2020 were classified as Pre-SoE, after March 11^th as Wave 1, and surveys completed after September 23^rd as Wave 2. QoL surveys included the Short-Form 36 (SF-36) and the Itch Numeric Rating Scale (iNRS), for PBC patients only. Mixed effects linear and negative binomial regressions estimated mean QoL scores across time stratified by age and adjusted for diagnosis and disease duration.

Result(s): There were 570 participants from 7 tertiary liver clinics across Canada included in the analysis, of whom 62.1% (n = 354) had PBC and 37.9% (n = 216) had AIH. Females represented 87.4% (n = 498), and 78.6% (n = 448) were Caucasian. A total of 40.9% (n = 233) were 55 years of age or younger. Median duration of disease was 7.7 years [2.96-13.8]. A total of 385 assessments were completed before the SoE, 267 during Wave 1, and 241 during Wave 2.

We observed a significant decreasing trend in estimated mean SF-36 Mental Component scores in younger patients (p = 0.017), while older patient QoL remained stable (p = 0.123, figure 1a). Longer disease duration was associated with better scores, regardless of time (p = 0.011). For the SF-36 Physical Component, estimated mean scores were overall worse in younger PBC patients than older patients (p = 0.034). There was a non-significant weak decrease over time for all patients (p = 0.191, figure 1b).

For PBC patients, estimated mean iNRS scores worsened over time (p = 0.015), and older age was associated with lower reported itch (p = 0.007, figure 1c).

Conclusion(s): Younger patients reported worse mental and itch related QoL scores across time, suggesting that these patients are impacted differently than older patients during Canada’s response to the pandemic. More attention into this problem is required.

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O09 Hepatolithiasis is a frequent and prognostic finding in patients with primary sclerosing cholangitis

B Jubran¹,^*, M Ismail², M Stein³, D Little¹, B Hansen², A Gulamhusein², G Hirschfield²

¹Gastroenterology and Hepatology

²Toronto Centre for the Study of the Liver

³Internal Medicine, University of Toronto, Toronto, Canada

Background: Intrahepatic biliary stones (hepatolithiasis) is not well characterised clinically in patients with primary sclerosing cholangitis (PSC).

Purpose: To characterize the incidence of hepatolithiasis in PSC and describe its relationship to radiologic features of PSC, baseline patient characteristics and important clinical outcomes.

Methods: Chart reviews were conducted in patients with a histologic or radiographic diagnosis of PSC, followed at the Toronto Centre for Liver Disease. Radiographic data were collected between the years 2008-2018. Depending on frequency of testing, magnetic resonance imaging (MRI) and ultrasound (US) data was reviewed every 3-5 years. We assessed factors associated with hepatolithiasis based on sex, race, age and phenotype of PSC and inflammatory bowel disease (IBD). Qualitative radiographic findings on image report review, episodes of cholangitis, endoscopic retrograde cholangiopancreatography (ERCP) and occurrence of cholangiocarcinoma (CCA), death and transplant were documented. Data are reported with median and IQR and analyzed using chi-squared and Mann-Whitney U tests.

Result(s): 302 patients were reviewed. The median time to follow-up, defined as from date of diagnosis to last clinic visit or to transplantation date, was 98 months (IQR = 54.5–141.5). The mean age at diagnosis was 38 (SD = 15.1) years; 54% of patients were male. A total of 224 patients had IBD (74%). Of the 302 patients, 80 patients (26%) had evidence of hepatolithiasis on US or MRI. Patients with hepatolithiasis were more likely to be younger (37.4 vs 39.1, p = 0.025), male (65% vs. 50%, p = 0.021), and have large duct disease (99% vs. 88%, p = 0.004). Imaging report review revealed patients with hepatolithiasis were more likely to have intrahepatic biliary thickening (76% vs. 45%, p < 0.001), extrahepatic biliary thickening (69% vs. 50%, p = 0.003), focal biliary dilation (96% vs. 78%, p < 0.001) and disease characterised by more reported strictures on qualitative imaging report review (89% vs 69%, p < 0.001). Concomitant presence of cholelithiasis was greater in the hepatolithiasis vs. the non-hepatolithiasis group (45% vs. 19%, p < 0.001). Patients with hepatolithiasis were more likely to have experienced acute ascending cholangitis (50% vs. 20%, p < 0.001) and need for ERCP (50% vs. 35%, p = 0.020). CCA was numerically higher in the hepatolithiasis group (8.75% vs. 4%, p = 0.1). Patients with hepatolithiasis received transplant more frequently (26.3% vs 12.2%, p < 0.001) with no significant difference in mortality.

Conclusion(s): Hepatolithiasis is common in PSC and associated with increased clinical and radiologic disease burden.

Disclosure of Interest: None declared

O10 Machine learning approach to predict cardiovascular diseases in patients with NAFLD in the UK biobank cohort

D Sharma¹, NB Gotlieb¹,^*, M Farkouh³, K Patel⁴, M Bhat⁴

¹Department of Biostatistics, Princess Margaret Cancer Centre, UHN

²Division of Adult Gastroenterology, University of Toronto

³Heart and Stroke Richard Lewar Centre, Peter Munk Cardiac Centre

⁴Division of Gastroenterology, Toronto General Hospital, Toronto, Canada

Background: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide. It has become the main etiology for liver cirrhosis, hepatocellular carcinoma (HCC), and is predicted to soon become the leading indication for liver transplantation. Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with NAFLD. In fact, CVD dictates outcomes to a greater extent than does the progression of liver disease, resulting in ~ 40–45% of the total deaths in this population. The strong association between NAFLD and CVD is the result of shared metabolic risk factors. Additionally, NAFLD as an independent risk factor for CVD via accelerating the progression of subclinical atherosclerosis and promoting premature CVD events and mortality.

Purpose: The aim of this study was to develop a novel integrative machine learning (ML) algorithm that could identify NAFLD patients at high risk of CVD using the richly annotated clinical, demographic and laboratory data from the UK Biobank.

Methods: We created a cohort of patients with NAFLD from the UK Biobank, diagnosed according to proton density fat fraction (PDFF≥5) from MRI datasets after excluding other etiologies of liver disease. NAFLD patients with subclinical atherosclerosis as per carotid intima media thickness measurements (CIMT > 0.9 mm) or clinical CVD defined by disease codes, constituted cases. NAFLD cases with no CVD constituted as controls. We evaluated seven different supervised ML approaches on clinical, lifestyle, and genetic variables to distinguish NAFLD patients with versus without CVD.

Result(s): There were 1,007 NAFLD subjects of whom 474 had CVD. 220 cases had sub-clinical CVD detected through CIMT and 342 cases had CVD detected through disease codes specified in the UK biobank with 88 subjects common between both. The most significant clinical and lifestyle variables observed by the predictive modelling were older age (59 years), hypertension (145/85), high waist circumference (98 cm), alcohol consumption and sedentary life style defined as time spent watching TV > 4h/day. Red blood cell size distribution, arterial stiffness and diabetes were also significant to CVD prediction, however to a lesser extent. In the genetic data, SNPs in IL16 and ANKLE 1 gene were identified as most significant.

Of the 7 ML models applied, Random Forest model was the most robust for the prediction of CVD among patients with NAFLD, integrating clinical, lifestyle and genetic parameters with the highest AUC of 0.849 (82.7% sensitivity and 88.2% specificity).

Conclusion(s): We have developed a ML algorithm that can identify NAFLD patients with CVD through integration of significant clinical, lifestyle and genetic risk factors. These NAFLD patients at higher risk of CVD should be flagged for CVD screening and have aggressive treatment of their cardiometabolic risk factors to prevent cardiovascular morbidity and mortality.

O11 The Ontario alcohol-related liver disease pilot project: liver transplant for patients with less than six months of abstinence

J Quance¹, L Carrique¹,^*, A Tan¹, S Abbey¹, I Sales¹, L Lilly¹, M Bhat¹, Z Galvin¹, M-J Lynch¹, N Selzner¹

¹University Health Network, Toronto, Canada

Background: For patients with alcohol-related liver disease (ALD), six months of abstinence from alcohol is typically required prior to being listed for liver transplantation (LT). This policy has mixed empirical support¹, and disadvantages severely ill patients who cannot survive this timeframe².

Purpose: The Ontario ALD Pilot Program was initiated in 2018 to provide equitable access to LT for ALD patients through an in-depth examination of alcohol use history, social support and psychiatric comorbidity, as well as the provision of pre- and post-LT treatment of Alcohol Use Disorder (AUD) within the transplant program.

Methods: All referrals were triaged using pilot-specific inclusion criteria. Patients were assessed by a multidisciplinary team, including transplant hepatology, addiction and consultation-liaison psychiatry, social workers and a nurse practitioner. Random biomarker testing for alcohol with urine ethyl glucuronide (EtG) and carbohydrate-deficient transferrin (CDT) tests was utilized throughout the pre and post- transplant phases. Patients accepted into the pilot participated in ongoing relapse prevention therapy (RPT) and psychiatric follow-up. Statistical analyses were conducted to examine survival rates, return to alcohol use and the psychosocial profiles of the protocol patients.

Result(s): We reviewed 703 referrals from May 1, 2018 to October 31, 2020. From these, 264 referrals (39%) were declined upon initial triage (144 did not meet program criteria, 120 for other reasons). The remaining (n = 439) were assessed, including by the psychosocial team. Of this group, 146 (33%) did not meet ALD inclusion criteria for the following reasons: 124 met criteria for severe AUD likely to result in a return to problematic drinking, 25 provided a positive urine EtG, 16 had severe psychiatric comorbidity and 28 declined to participate in RPT. One-hundred and one patients (14%) were listed for transplant through the protocol. Forty-four (6.2%) were transplanted, five of whom expired. There were no significant differences in survival rates of the protocol patients compared to their non-protocol peers. After an average of 339 days post-discharge from hospital, three patients had returned to alcohol use as per positive biomarker tests or self-report. Older age and higher MELD scores at listing were associated with a decreased likelihood of a return to alcohol use. Length of abstinence was not a statistically significant predictor of return to alcohol use.

Conclusion(s): Our prospective protocol is the first of its kind to provide access to LT for those with less than six months of abstinence, while also directly providing assessment, monitoring and intervention of AUD through a multidisciplinary team. Transplanting patients in this way demonstrated comparable survival rates and low rates of return to alcohol use, and highlighted the importance of assessing suitability through the use of psychosocial criteria rather than the passage of time.

References

1.Addolorato G, Mirijello A, Leggio L, Ferrulli A, D’Angelo C, Vassallo G. … Gemelli OLT Group (2013) Liver transplantation in alcoholic patients: Impact of an alcohol addiction unit within a liver transplant center. Alcoholism: Clinical and Experimental Research, 37, 1601–1608.

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2.Im GY, Kim-Schluger L, Shenoy A, Schubert E, Goel A, Friedman SL, Florman S, & Schiano TD (2016). Early liver transplantation for severe alcoholic hepatitis in the United States – A single centre experience. American Journal of Transplantation, 16, 841, 849).

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Panel 4 – May 5, 2021

O12 The alarming impact of COVID-19 pandemic on alcohol-related liver disease: a population-based Canadian study

AA Shaheen¹,^*, S Congly¹, M Swain¹, K Kong², C Coffin¹, K Burak¹, S Lee¹, M Sadler¹, M Borman¹, J Abraldes³

¹Medicine, University of Calgary

²Alberta Health Services, Calgary

³Medicine, University of Alberta, Edmonton, Canada

Background: The COVID-19 pandemic has caused significant morbidity and mortality worldwide. During prolonged periods of global lockdown and disruption of clinical services, patients with alcoholic and non-alcoholic cirrhosis had to seek clinical care virtually and reduce their clinic visits. Furthermore, there has been significant increase in alcohol sales.

Purpose: In our study, we aimed to evaluate the impact of COVID-19 restrictions on patients with alcoholic and non-alcoholic cirrhosis as well as alcoholic hepatitis (AH) who were hospitalized.

Methods: We used validated international clinical classification (ICD-9 and ICD-10) coding algorithms to identify liver-related hospitalizations for non-alcoholic cirrhosis, alcoholic cirrhosis, and AH in the province of Alberta, Canada (population ~4.5 million) between March 2018 and September 2020. We used inpatient and ambulatory care administrative databases linked to the provincial laboratory database to identify our cohort. We defined the AH cohort as patients who had a diagnosis code of AH and possessed both of the following criteria: elevated ALT or AST, and elevated international normalized ratio (INR). We compared post COVID-19 restrictions (April-September 2020) to prior study periods. Joinpoint regression was used to evaluate inflection points in the temporal trends among the three cohorts.

Result(s): We identified 2,916 hospitalizations for non-alcoholic cirrhosis, 2,318 hospitalizations for alcoholic cirrhosis, and 1,408 AH hospitalizations during our study time. Pre- and post-COVID-19 admission characteristics and outcomes for the three cohorts are presented in Table 1. Among alcoholic and non-alcoholic cirrhosis cohorts, there were no significant changes between average monthly admission rate, demographics, LOS, ICU admissions, and in-hospital mortality (Table 1). AH patients had a significant increase in average monthly admission (69.5 vs. 39.6, P < 0.001) with April 2020 being the inflection point. Although AH patients admitted post COVID-19 restrictions were younger (median age 43 vs. 47, P = 0.02), there were no significant differences in admission outcomes pre- and post-COVID-19 among AH cohort.

Table O12: Pre-and post-COVID-19 admission characteristics and outcomes for our three cohorts

	Pre COVID-19 (n = 2,295)	Post COVID-19 (n = 621)	Pre COVID-19 (n = 1,821)	Post COVID-19 (n = 497)	Pre COVID-19 (n = 991)	Post COVID-19 (n = 417)
	Non-alcoholic cirrhosis		Alcoholic cirrhosis		Alcoholic hepatitis
Average admissions/ month	91.8	103.5	72.8	82.8	39.6	69.5*
Age, median (IQR)	64 (56–72)	63 (55–70)	56 (48–63)	55 (48–63)	47 (36–55)	43 (34–52)*
Female sex, n (%)	1,021 (45%)	271 (44%)	654 (36%)	170 (34%)	381 (38%)	144 (35%)
LOS, median (IQR)	5 (3-10)	5 (2-9)	6 (3-13)	6 (3-11)	6 (3-12)	5 (3-11)
ICU admission, n (%)	189 (8%)	50 (8%)	230 (13%)	74 (15%)	111 (11%)	47 (11%)
In-hospital mortality	265 (12%)	66 (11%)	224 (12%)	69 (14%)	76 (8%)	26 (6%)

* P value < 0.05 for pre- and post-COVID-19 among the respective cohort.

Conclusion(s): In this large population-based study, pre- and post-COVID-19 monthly admission rates were stable for non-alcoholic and alcoholic cirrhosis, however, there was a significant increase in AH admissions. As alcohol sales surged during the COVID-19 pandemic, future impact on alcoholic liver disease could be detrimental.

O13 Comparative analysis of the expression and significance of glutamine transporters in hepatocellular carcinoma and normal liver

V Tambay¹,^*, V-A Raymond¹, M Bilodeau¹, ²

¹Laboratoire d’hépatologie cellulaire, Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM)

²Département de médecine, Université de Montréal, Montreal, Canada

Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world and is associated with high morbidity and mortality. The proliferation of cancer cells requires an increased demand for nutrients such as glutamine (gln). To do this, cancer cells rely on a set of plasma membrane transporters.

Purpose: This study aims to analyze the effect of exogenous gln on murine HCC Dt81Hepa1-6 (Dt81). The polar nature of gln requires specific transporters. The objective was to provide a comprehensive and comparative analysis of gln transporters in normal (NL), peritumoral (PT) and tumor (LT) liver, hepatocytes in primary culture (NHc) and in cell pellets (NHp) as well as Dt81 and Hepa1-6 (H1-6) cell lines. Survival of HCC patients was then analyzed according to the level of expression of different gln transporters in tumoral tissue.

Methods: The viability and proliferation of Dt81 were evaluated at 24h with doses of gln [0 to 4mM]. mRNA expression was measured in cells cultured in DMEM for 24h; 7 gln transporters were analyzed. Kaplan-Meier survival analysis of 364 HCC patients was done using RNAseq data (1).

Result(s): Dt81 showed a dose-dependent increase in viability (p < 0.05) and proliferation (p < 0.01) with gln supply. Gln increased viability by 40±18% and cell doubling time by 90±6% from 0mM gln. The SLC1A5 transporter had the most upregulated expression in LT and HCC cell lines compared to normal tissues: its expression levels were 75±13 arbitrary units (AU) in LT, in comparison to 16±3AU in PT (p < 0.001) and 33±5AU in NL (p < 0.01). H1-6 (136±27AU) and Dt81 (157±11AU) exhibited higher SLC1A5 expression levels than NHp (1.5±0.4AU; p < 0.001) and NHc (2.5± 0.8AU; p < 0.001). Interestingly, SLC38A3 showed an opposite trend, with LT showing lower levels than NL (p < 0.05) and NHp higher levels than NHc, H1-6, and Dt81 (all p < 0.001). The expression of SLC7A6 was slightly higher in LT than PT and NL. Compared to NHc and NHp, greater expression of SLC7A6 was observed in H1-6 (p < 0.001) and Dt81 (p < 0.01). SLC38A2 levels were also higher in NL than PT (p < 0.001) and LT (p < 0.05). Compared to NHc, SLC38A2 levels were greater in NHp, H1-6 and Dt81 (all p < 0.05). Despite their weak expressions, SLC38A1 was higher in NL than PT and LT (all p < 0.001) and SLC38A5 higher in NHp than other cellular samples (all p < 0.05). SLC6A14 levels were negligible and showed no pattern of differential expression. Next, we studied the survival of patients from intratumoral expression of these 7 gln transporters. Patients with a high expression of SLC1A5 had a shorter median survival by 54mo compared to those with lower expression levels (p < 0.0001). Nearly 30% of patients exhibited high SLC1A5 expression. Similar, less striking observations were made with SLC7A6 (-25mo, p < 0.05) and SLC38A1 (-56mo, p < 0.0001). In contrast, survival of patients was higher in tumors showing high expression of SLC6A14 (p < 0.01) and SLC38A3 (p < 0.001). Median survival was no different between high or low expression levels of SLC38A2 and SLC38A5.

Conclusion(s): In Dt81, gln increases survival and proliferation based on a dose-response curve. HCC exhibits altered expression of gln transporters both in vivo and in vitro, with overexpressed SLC1A5 and downregulated SLC38A3. Finally, the expression profiles of gln transporters in HCC tissues are associated with significant differences in the median survival of patients. These results highlight the importance and significance of gln transporter reprogramming in tumorigenicity and pave the way to novel therapies targeting this metabolic pathway in HCC.

References

1.https://doi.org/10.1098/rsos.181006

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O14 Obeticholic acid improves transaminases in patients with non-alcoholic steatohepatitis: results from the 18-month interim analysis of the REGENERATE study

K Patel¹,^*, M Rinella², M Allison³, P Mathurin⁴, E Lawitz⁵, Q Anstee⁶, I Schiefke⁷, S Petta⁸, R Anty⁹, P Marotta¹⁰, JL Calleja¹¹, S Hussain¹², KV Kowdley¹³, MF Abdelmalek¹⁴, L Wang¹⁵, L MacConell¹⁵, A Trylesinki¹⁶, M Bonacci¹⁶, V Ratziu¹⁷, A Sanyal¹⁸, J-F Dufour¹⁹

¹Toronto Centre for Liver Disease, University Health Network, Toronto, Canada

²Feinberg School of Medicine, Northwestern University, Chicago, United States

³Cambridge University Hospitals Foundation, Trust-Addenbrooke’s Hospital, Cambridge, United Kingdom

⁴Hepato-Gastroenterology, CHU Lille, Lille, France

⁵Texas Liver Institute, University of Texas Health San Antonio, San Antonio, United States

⁶Newcastle University, Newcastle upon Tyne, United Kingdom

⁷Geschäftsführer/Zentrumsleiter, Leipzig, Germany

⁸Di.Bi.M.I.S, University of Palermo, Palermo, Italy

⁹Hôpital de l’Archet II, CHU Nice, Nice, France

¹⁰Western University, London, Canada

¹¹Hospital Universtario Puerta de Hierro, Madrid, Spain

¹²Royal Cornwall Hospital, Truto, United Kingdom

¹³Swedish Liver Center, Seattle, United States

¹⁴Duke University Medical Center, Durham, United States

¹⁵Intercept Pharma, San Diego, United States

¹⁶Intercept Pharma, London, United Kingdom

¹⁷Sorbonne Université, Hôpital Pitié–Salpêtrière, Paris, France

¹⁸Virginia Commonwealth University, Richmond, United States

¹⁹University of Bern, Bern, Switzerland

Background: The interim analysis of the REGENERATE study showed obeticholic acid (OCA) treatment significantly improved liver histology in patients with non-alcoholic steatohepatitis (NASH) and fibrosis. Patients with NASH often display elevated transaminase (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) levels and there is evidence that such elevations may be associated with progression of fibrosis and adverse liver-related outcomes.

Purpose: Here, we evaluate OCA-mediated improvement in transaminases and the potential utility of ALT and AST in monitoring treatment of NASH patients with fibrosis.

Methods: Changes in ALT and AST (upper limit of normal [ULN] = 55 U/L and 34 U/L, respectively, based on central lab values) were analyzed systematically throughout the study in 931 NASH patients with stage 2 or 3 fibrosis who were randomized 1:1:1 to placebo, OCA 10 mg, or OCA 25 mg in REGENERATE (intent-to-treat population).

Result(s): Baseline characteristics were well balanced across treatment groups: age (mean ± standard deviation) 55 ± 11 years; ALT 79 ± 53 U/L; AST 58 ± 36 U/L; 58% female; 44% F2, 56% F3. Baseline ALT was elevated (> ULN) in 60% of patients (8% > 3× ULN) and baseline AST in 73% of patients (9% > 3× ULN). OCA treatment resulted in rapid, sustained, dose-dependent improvements in transaminases as early as Month 1 and were sustained through Month 18. In subjects with ALT and AST > ULN at baseline, ALT normalized in 36%, 49%, and 66% of placebo, OCA 10-mg, and OCA 25-mg subjects and AST normalized in 28%, 42%, and 49% of subjects in the respective groups by Month 18. In patients with ALT and AST in the normal range at baseline, elevations to > ULN were more frequent in placebo (33%, 16%) than OCA 10 mg (16%, 15%) and least frequent in OCA 25 mg (9%, 5%). OCA-mediated ALT and AST improvements were greater in patients who achieved the REGENERATE primary endpoints than in those who did not (see Figure). However, transaminase improvements were also observed in subjects who did not achieve the primary endpoints.

Conclusion(s): OCA treatment resulted in rapid and sustained improvements in ALT and AST, suggesting these markers may be useful for monitoring treatment response. Compared with placebo, OCA-treated patients who did not achieve REGENERATE primary endpoints also had marked improvement in transaminases, suggesting OCA’s therapeutic benefit is not fully captured by the categorical histologic response at Month 18 and that continued longer term treatment may result in additional histologic improvement. The REGENERATE study remains ongoing and will continue through clinical outcomes for verification and description of clinical benefit.

O15 Omics approach towards understanding the etiology of primary sclerosing cholangitis

K Bashiri¹,^*, H Syed¹, B Dutra¹, AL Mason¹

¹Medicine, University of Alberta, Edmonton, Canada

Background: The pathogenesis of primary sclerosing cholangitis (PSC) is unknown and there is no effective treatment. Previously, we found evidence of serological reactivity to retroviral proteins, reverse transcriptase activity and upregulation of the viral restriction factor family of APOBEC3 deaminases in PSC patients.

Purpose: To investigate the hypothesis that PSC may be linked with viral infection, we searched for altered expression of pathways involved in host defense against viruses among PSC patients.

Methods: Peripheral blood samples from 21 PSC patients and 11 healthy controls were obtained and transcriptome signatures of the samples were profiled using RNA-seq. Proteomic studies were conducted using biliary epithelial cells (BEC) obtained from PSC patients and compared with patients with non-cholestatic liver disease.

Result(s): We found total of 296 overexpressed and 465 under-expressed transcripts among PSC patients compared to healthy controls. In a search for activity associated with a viral superantigen, we looked for T-cell receptor (TCR) Vβ subset skewing by comparing PSC with control mean +/- 3xSD and found several subsets to be skewed compared to healthy controls (TRBV10-1, TRBV10-3, TRBV5-5, TRBV28, TRBV7-1, TRBV7-1, TRBV7-3). In the pathway analysis, “Viral process” was among the top upregulated pathways (padj = 0.004). In addition, “mRNA splicing”, “capped intron-containing pre-mRNA processing” and “gene expression” were among the top dysregulated pathways enriched by BioPlanet (padj = 7.54E-9, padj = 5.27E-8 and padj = 8.12E-7 respectively). Proteomic studies of cholangiocytes showed decreased splicing and proteosomal degradation, confirming transcriptomics findings.

Conclusion(s): Upregulation of host defense mechanisms against viruses, and the disruption of cellular pathways linked with viral infection lend further weight on the hypothesis of infectious etiology for PSC. The frequent skewing of specific TCR-Vβ subsets may be indicative of an underlying superantigen activity. The dysregulation of splicing and proteasomal degradation found among PSC patients may be observed as a result of viral pathogenesis inhibiting cellular processes. Further studies are warranted to better identify the presence of virus infection in PSC.

References

1.Mason AL, et al., Detection of retroviral antibodies in primary biliary cirrhosis and other idiopathic biliarydisorders. Lancet, 1998. 351(9116): p. 1620-4.

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2.McDermid J, et al., Reverse transcriptase activity in patients with primary biliary cirrhosis and other autoimmune liverdisorders. Alimentary pharmacology & therapeutics, 2007. 26(4): p. 587–595.

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3.Bashiri K, Syed H, Mason AL, Retrovirus footprint in primary sclerosing cholangitis; APOBEC3 family expression, in Canadian Liver Meeting. 2020. p. 134.

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POSTER ABSTRACTS

P001 Human liver transcriptional mapping via single cell and single nucleus RNA sequencing reveals hepatic parenchymal cell identity

T Andrews^1,^*, J Atif¹, ², J Liu³, ⁴, C Perciani¹, ², ⁵, X-Z Ma¹, C Thoeni⁵, M Slyper⁶, G Eraslan⁶, A Segerstolpe⁶, J Manuel¹, S Chung¹, E Winter¹, I Cirlan⁷, N Khuu⁷, S Fischer⁵, O Rozenblatt-Rosen⁶, A Regev⁶, I McGilvray¹, G Bader³, ⁴, S MacParland¹, ², ⁵

¹Ajmera Transplant Centre, Toronto General Research Institute, University Health Network

²Department of Immunology

³Department of Molecular Genetics

⁴The Donnelly Centre

⁵Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

⁶Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, United States

⁷Princess Margaret Genome Centre, University Health Network, Toronto, Canada

Background: The critical functions of the human liver are coordinated through the interactions of hepatic parenchymal and non-parenchymal cells. Recent advances in single cell transcriptional approaches have enabled an examination of the human liver with unprecedented resolution. However, dissociation related perturbation can limit the ability to fully capture the human liver’s parenchymal cell fraction, which limits the ability to comprehensively profile this organ.

Purpose: To compare single-cell and single-nucleus RNAseq for their ability to recover the diverse cell-types of the liver, and reduce dissociation-related artefacts.

Methods: We sequenced 73,295 cells from the human liver using matched single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq), from four different individuals. Cell-types were identified through a combination of computational analysis and manual annotation, then validated using spatial transcriptomics and immunohistochemistry.

Result(s): We show that it is possible to fully integrate single-cell and single-nucleus sequencing of the liver to enable a more complete examination of liver cell populations. Cell-type frequencies varied by technology, with scRNA-seq exhibiting a higher proportion of immune cells and snRNA-seq exhibition a higher proportion of endothelial, stellate and chloangiocyte cells. SnRNA-seq also enabled a deeper examination of hepatocyte clusters and the detection of additional subtypes of hepatic stellate cells and cholangiocyte progenitors that are not observed with standard scRNA-seq. However, T and B lymphocytes and NK cells were only distinguishable using scRNA-seq. These novel populations had unique spatial distribution in the healthy liver as revealed by spatial transcriptomics and immunohistochemistry.

Conclusion(s): Single-nucleus RNAseq reduces dissociation related cell-type biases and enables a full examination of endothelial cells, stellate cells, and cholangiocytes. Whereas, single-cell RNAseq provides better resolution of lymphocyte populations including T, B, and NK cells. Combining both technologies together enabled a more complete examination of cell-types present in the liver than using either technology alone. Together, our study provides a systematic comparison of the recovered cell types and their associated transcriptome across scRNA-seq and snRNA-seq and delivers a high-resolution examination of the parenchymal cell populations in the healthy human liver.

P002 Spatio-temporal characterization of the immune landscape during acute liver injury uncovers a pathogenic role for Il-17A

M Flores Molina¹, ^2,*, MN Abdelnabi¹, ², S Muhammad³, S Mazouz², N Bédard¹, A Cleret-Buhot¹, NH Shoukry⁴, ⁵

¹Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)

²Microbiology, Infectology and Immunology, Universite de Montreal, Montréal, Canada

³Comsats University, Islamabad, Pakistan

⁴Medicine

⁵Microbiology, Infectology and Immunology, Université de Montréal, Montréal, Canada

Background: The wound healing response to acute liver injury is characterized by rapid changes in the composition, tissue positioning, phenotype, and function of the immune cell infiltrate. Although multiple studies examined the individual cellular and molecular components of this response, studies integrating all these components in the spatial and temporal dimensions are lacking.

Purpose: The goal of this study was to establish the kinetics and dynamics of the wound healing response during acute liver injury in the CCl4 model, while simultaneously mapping in situ the rapidly changing immune landscape during the different phases of acute liver injury.

Methods: Multiplex immunofluorescence (IF) immunohistochemistry (IHC), and H&E were used to visualize the hepatic tissue and cell populations of interest. VIS software was used for image analysis. qPCR was used for assessment of mRNA expression, and FACS was used for characterization of cell populations of interest.

Result(s): Tissue damage measured by serum ALT level peaked at 24h post CCl4 and was temporally associated with maximal expression of inflammatory cytokines, IL-17 induced genes, and infiltration of IL-17A+ neutrophils, followed by monocytes at 48h, consistent with the kinetics of expression of neutrophil vs. monocyte – specific chemokines. Transition to the tissue repair phase at 48h was characterized by transient expression of CX3CR1/CX3CL1, suggesting the emergence of monocyte derived macrophages (MoMF), and spatial overlap of macrophages, neutrophils, and HSCs in the necrotic tissue. Early tissue repair (48-72h) was characterized by activation of hepatic stellate cells (HSCs), proliferation of parenchymal and non-parenchymal cells as determined by Ki67 staining, and peak expression of fibrogenic genes. The late tissue repair phase (72-168h) was characterized by a return to baseline levels of ALT, increased expression of matrix metalloproteases, neutrophil clearance, repopulation of Kupffer cells (KCs), and restoration of normal liver histology. In vivo neutralization of IL-17A accelerated ALT return to baseline levels and the reduction of pro-fibrogenic/pro-inflammatory IL-13+/TNFα+ monocytes and MoMF, respectively.

Conclusion(s): We have established the kinetics and dynamics of the wound healing response and the immune landscape during the different phases of acute liver injury. Our results demonstrate early involvement of IL-17A producing neutrophils during the inflammatory phase, followed by monocytes and MoMF during the repair phase. Blocking IL-17A resulted in accelerated resolution suggesting a potential therapeutic value for acute liver injury.

P003 Characterizing the interplay between angiogenic and immunoactive factors of hepatocellular carcinoma

A Kapelanski-Lamoureux^1,*, F Kondrop¹, S Petrillo², T Mayer², A Lazaris², P Metrakos², ³

¹Anatomy & Cell Biology, McGill University

²Research Institute of the McGill University Health Centre

³Department of Surgery, McGill University, Montreal, Canada

Background: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death globally. It is considered a multistep process evolving from underlying liver cirrhosis most commonly due to hepatitis (B or C) virus infection or non-alcoholic steatohepatitis (NASH). Patients typically present at an advanced stage and less than 50% reach the maximum 1-year survival rate, when given as first-line treatment, Sorafenib. This highlights the need for novel therapeutic targets as well as predictive biomarkers to increase overall survival for patients with HCC. In this era of personalized therapy, immunotherapy is revolutionizing treatment of a variety of cancers, including HCC. Despite it’s promise, combinatorial approaches are required to extend benefits beyond a subset of patients. Given the important role of angiogenesis in HCC from its early stage and its rich immune composition, anti-angiogenic and immune checkpoint inhibitors (ICI), are two therapeutic approaches when combined have shown efficacy with response rate never observed before in patients with HCC. While combination of agents inhibiting angiogenesis and ICI have entered clinical trials for HCC, the interplay between angiogenic factors and immunity in the context of this approach remains poorly understood. We hypothesize that there is crosstalk between the vasculature and the immune system that can be exploited for therapeutic interventions in HCC.

Purpose: Here we focus on understanding the interplay between the vascular state of the tumor and the immune response in HCC. As a first step, we focus on characterizing the immune and vasculature landscape with a primary focus on the correlation to histopathological features and HCC subtypes.

Methods: Forty (40) formalin-fixed paraffin-embedded (FFPE) human liver tissue samples containing HCC tumors, obtained from the Liver Disease Biobank of the RI-MUHC will be used to perform immunohistochemistry (IHC) for angiogenic factors (CD31, CD34/Ki67, VEGF, Ang1, Ang2, and Tie2) and immune cell populations (CD4, CD8, elastase and CD68). Images will be viewed using the Aperio ImageScope software program for scoring analysis and assessment of signals. Next, to identify the immune populations present among HCC resected cases, we will use the NanoString Whole Transcriptome Atlas spatial profiler technology. Furthermore, we will also use immunofluorescence to validate angiogenic factors localization to immune cells and to determine the activation state of immune cells.

Result(s): In order to define the landscape, we quantitated the central tumor, peripheral tumor, adjacent liver to the tumor, and distal liver regions of each lesion by IHC. Preliminary results indicate that different immune cell populations infiltrate HCC subtypes specifically associated with an increase in angiogenic factors. This suggests that the angiogenic profile of these lesions can directly or indirectly mediate the immune response in HCC.

Conclusion(s): This project presents preliminary evidence for the interaction of vascular factors with immune cells, thus providing insight into the biological rationale of why 30% of patients responded to combined angiogenic and immunotherapy treatment. Moreover, as we further dissect the pathways differentially expressed this work may provide therapeutic avenues to treat other types of angiogenic driven cancers.

P004 Response to treatment by autoimmune hepatitis patients is associated with increased levels of Il-10 and circulating CD4+ regulatory T cells

F Dilauro¹, A Adhikari¹, 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)

²Département de médecine, Université de Montréal

³Service de gastroentérologie, hépatologie et nutrition, CHU Sainte-Justine, Université de Montréal, Montréal, Canada

Background: Current first-line treatment for autoimmune hepatitis is based on a combination of steroids and azathioprine and usually achieves an adequate response in 80% to 90% of patients. In case of no or partial response, second-line treatments are available, however, their use is based mainly on clinical experience since very little evidence-based data is available for the majority of these therapies. When control of liver inflammation is delayed, progression towards cirrhosis and end-stage liver disease can occur in 10 to 20% of patients, leading to liver transplantation for some of these patients. Currently, no clinical, laboratory or histological feature can accurately predict initial complete response or long-term remission of AIH. Therefore, there is a crying need for reliable biomarkers to help clinicians predict patient response to specific treatments or rapidly assess the effectiveness of these therapies in reverting the inflammatory process.

Purpose: This study aimed to identify biomarker(s) of treatment response in AIH patients to predict treatment outcomes and allow for personalized treatment.

Methods: Using our biobank of biological samples and clinical data from AIH patients, cross-sectional immunological profiling (IL-16, IL-23a, IL-17, IL-17f, IL-10, IL-2, IL-21 and IL-22 cytokine expression levels and CD3/CD4/CD8/CD39/CD127/FoxP3 Flow Cytometry analysis) of biological samples (plasma and PBMCs) was performed on unmatched samples at the time of diagnosis and during treatment to identify putative biomarkers associated with a favourable response to treatment as assessed by ALT levels.

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). Patients that respond to first-line treatments also had higher FoxP3⁺CD127^low Treg levels after treatment (5.38%±0.42%, n = 6), similar to the levels 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 CD3⁺CD4⁺FoxP3⁺CD127^low Treg levels and IL-10 expression was also found in these patients (r² = 0.6484, n = 9, p = 0.0088). When circulating plasma levels of IL-10 and ALT levels were assessed in patients at diagnosis and after treatment initiation, a clustering based on ALT levels and IL-10 levels was found; treated AIH patients under long-term remission (more than a year) had normal ALT and IL-10 levels (n = 60) compared to untreated AIH patients (high ALT and normal IL-10 levels, n = 5), recently treated AIH patients in remission (less than a year; normal ALT and elevated IL-10 levels, n = 24) or AIH patients in whom treatment was recently initiated and were not yet under remission (less than a year; elevated ALT and IL-10 levels, n = 8).

Conclusion(s): Expression and circulating levels of immunosuppressive IL-10 and CD4⁺ regulatory T cells are increased in AIH patients that respond to treatment. These results suggest that plasma levels of IL-10 and CD4⁺ regulatory T cells could be putative surrogate biomarkers for treatment response in AIH patients. The identification of reliable biomarkers could allow to predict treatment response in treatment-naïve patients and the development of effective personalized therapy. The identification of such biomarkers could be a milestone achievement for the clinical management of difficult-to-treat AIH patients.

P005 Dysregulation of sphingolipids in obese-cirrhotic rats aggravates hepatic encephalopathy

R Ochoa-Sanchez¹, ^2,*, M Tremblay¹, CF Rose¹, ²

¹Centre de Recherche du CHUM (CRCHUM)

²Medicine, Université de Montréal, Montreal, Canada

Background: Hepatic encephalopathy (HE) is a neuropsychiatric syndrome observed in chronic liver disease (CLD/cirrhosis). With an increasing prevalence of obesity-induced cirrhosis and evidence linking blood-derived lipids and brain lipid alterations to neurological impairment, we hypothesize that obese-induced brain lipid dysregulation increases the progression of HE in bile-duct ligated (BDL) rats.

Purpose: Study the impact of obesity on brain sphingolipids and the development of neurological impairment in a rat model of CLD and obesity.

Methods: CLD and HE model: 5-week BDL rats and sham-controls, were used. Groups: Obese-BDL (O-BDL) and obese-sham (O-Sham) received high-fat diet (HFD) for 25-days pre-BDL surgery and then proceeded with high-carbohydrate diet (HCD) for 5 weeks post-BDL; Lean-BDL (L-BDL) and lean-sham (L-Sham) received regular-diet (RD) pre-BDL surgery and then HCD post-BDL. Body weight (BW), fat-mass, behavior, plasma liver markers and brain hippocampal sphingolipids (sphingomyelin and ceramides) were measured at 0 (pre-BDL), 3 and 5 weeks post-BDL.

Result(s): Pre-BDL, HFD lead to increased BW and fat mass vs RD which was sustained with HCD in O-BDL vs L-BDL at 3 and 5 weeks. Ammonia, albumin, AST, ALT, ALP and bilirubin were impaired in O-BDL and L-BDL vs shams at 3 and 5 weeks. High-density (HDL) and low-density (LDL) lipoprotein levels were detected in pre-BDL rats which persisted in O-BDL and L-BDL vs controls at 3 and 5 weeks. LDL and total-cholesterol were higher in O-BDL vs L-BDL at 5 weeks. Short- and long-term (LTM) memory were impaired in both BDL groups at 5 weeks, whereas at 3 weeks, LTM impairment was found solely in O-BDL. Furthermore at 3 weeks, motor coordination was reduced in O-BDL, but not in L-BDL. At 5 weeks, motor coordination decreased in both BDL groups, with worse performance in O-BDL vs L-BDL. At 3 and 5 weeks, skill learning improved in L-Shams and L-BDL, but not in O-Shams and O-BDL. Muscle-strength was reduced in L-BDL but not in O-BDL vs Shams. Hippocampal sphingomyelin lipids were increased in O-BDL vs L-BDL rats at 0, 3 and 5 weeks, while ceramides were only reduced at 5 weeks.

Conclusion(s): CLD-obesity rat model is characterized by increased fat mass and hyperlipidemia pre- and post-BDL. Neurological decline in O-BDL rats developed earlier and was more severe vs L-BDL rats. In addition, different neurological impairments developed in O-BDL vs L-BDL. Brain sphingolipid alteration in obese-cirrhotic rats may contribute to accelerate/worsen HE.

P006 Sex disparity in the development of brain edema and hepatic encephalopathy severity in BDL rats

MM Oliveira^1,*, A Monnet-Aimard², M Tremblay¹, CF Rose¹

¹Medecine, CRCHUM, Montréal, Canada

²Neurosciences, Université Aix-Marseille, Marseille, France

Background: Hepatic encephalopathy (HE) is a neuropsychiatric syndrome with symptoms ranging from impaired reaction time, poor memory to asterixis, gross disorientation, lethargy and coma. HE is a major complication of chronic liver disease (CLD) and develops when the hepatic capacity to detoxify ammonia is decreased. During this condition, muscle plays a compensatory role removing ammonia, but muscle mass loss further reduces the capacity to metabolise ammonia and hyperammonemia prevails. HE is marked by an increase in brain water caused via the synergistic effect of ammonia and oxidative stress (reactive oxygen species (ROS)). Brain edema and ammonia-related cognitive impairments as well as muscle mass loss have been well described in male rats with CLD but have not been explored in female CLD rats.

Purpose: Therefore, our aim was to identify whether sex influences brain edema and ammonia-mediated cognitive impairments.

Methods: Five weeks after either bile-duct ligation (BDL) (n = 8) or sham (n = 8) surgery in male and female rats, we assessed markers of liver injury and function, body parameters (weight, composition (MRI), gastrocnemius muscle weight/circumference and grip strength), HE (open field test for anxiety, rota-rod test for motor coordination and night-time activity) and brain edema (by gravimetric density method). Finally, we assessed susceptibility to develop severe cognitive impairment (mild-moderate lethargy, ataxia and loss of righting reflex) in male and female BDL rats after an ammonia challenge (6 mmoles/kg of ammonium acetate injected subcutaneously). Both plasma ammonia (Randox kit) and ROS (2’,7’-dichlorodihydrofluorescein diacetate test (DCFDA)) were investigated.

Result(s): Female BDL rats, similar to male BDL rats, had CLD, with impaired liver markers (ALP (p < 0.001), AST (p < 0.001), bilirubin (p < 0.0001) and albumin (p < 0.001)) compared to respective sham controls. Male BDL rats experienced loss of lean mass (p < 0.001), muscle weight (p < 0.01) and strength (p < 0.01) while similar differences were not found in female BDL vs respective sham controls. Both female and male BDL developed HE (impaired motor-coordination (p < 0.05) and reduced night activity (p < 0.05)), compared to respective shams. However, contrary to male BDLs, female BDLs did not develop brain edema compared to respective sham controls. When compared to male BDL, baseline plasma ammonia levels did not differ to female BDL rats. However, plasma ROS levels were lower in females compared to males (p < 0.05). Following ammonia challenge, male BDL rats had progressive worsening of mental status, reaching ataxia and loss of righting reflex while female BDL were protected, reaching only moderate lethargy (p < 0.05). During the ammonia challenge, female BDL rats had similar ammonia levels but lower levels of ROS compared to male BDL rats (p < 0.01).

Conclusion(s): We demonstrated BDL surgery in females leads to hepatic and neurological impairment comparable to male BDL rats. Contrary to males, female BDL did not develop loss of muscle mass nor brain edema compared to respective controls. However, sustained muscle mass in females did not lead reduced blood ammonia therefore the protection versus brain edema in females in due to protection against systemic oxidative stress. Female BDLs did not developed severe HE following ammonia challenge. Whether brain edema or systemic oxidative stress renders the females resistant to ammonia insults remains to be determined.

P007 Deciphering the mechanisms involved in acute cellular rejection and tolerance following liver transplantation in rats

C Perciani¹, ^2,*, X Chen¹, S Chung¹, X Wang¹, ², M Sekhon¹, ³, C Thoeni³, J Manuel¹, M Ma⁴, S MacParland¹, ², ³, I McGilvray¹

¹Ajmera Transplant Centre, University Health Network

²Department of Immunology

³Department of Laboratory Medicine and Pathobiology, University of Toronto

⁴Ajmera Transplant Centre, University Health Network, Toronto, Canada

Background: Direct-acting antiviral (DAA) agents have revolutionized the treatment of hepatitis C virus (HCV) infection. However, despite significant reduction in HCV-related death worldwide, HCV cirrhosis and hepatocellular carcinoma (HCC) remain the leading indication for liver transplantation (LT) (1). Acute cellular rejection (ACR) is estimated to occur in 20-40% of LT patients and can impact graft function and recipient survival (2). Improving outcomes post-LT, including graft acceptance in the absence of immunosuppressive (IS) therapy remains a priority.

Purpose: Strategies able to modulate the liver microenvironment and skew the hepatic network towards graft acceptance would eliminate the need for is and restore immune competence. Macrophages are immune cells recognized as a key regulator of physiological processes, including homeostasis, tissue repair and regeneration and may play a key role in tissue rejection. Therefore, understanding the crosstalk of macrophages with hepatic cells during liver tolerance and rejection post-transplantation is warranted.

Methods: In this study, a revised orthotopic liver transplantation (OLT) procedure, which includes the hepatic artery (HA) reconstruction, was incorporated into in vivo rat models of ACR: Dark Agouti (DA) livers transplanted into Lewis (LEW) (DA-> LEW). Syngeneic (LEW-> LEW) and DA and LEW shams were used as controls. Liver function analysis and immunological profiling were performed at 1, 3, 7 and 9 postoperative days (PODs) to determine critical time-point to be further examined through single nucleus RNA-sequencing (snRNA-seq).

Result(s): Following transplantation, animals in the ACR and syngeneic groups showed increase in the rejection activity index (RAI) and in the concentration of ALT. AST and bilirubin levels were significantly elevated in the ACR group then in the syngeneic animals at PODs 7 and 9 (p = 0.05). Unlike all the animals in the syngeneic group which fully recovered after POD 7, the mean survival time of animals in the ACR group was 11 days (min 9 and max 12 days, n = 5). Immunological profiling showed sustained increase in CD45⁺ cells in the liver of ACR animals starting at POD3. Both flow cytometry and immunohistochemistry (IHC) analyses showed a shift towards T responses during ACR, predominance of CD8⁺ T cell and also marked presence of CD68⁺ cells at PODs 3, 7 and 9. The frequency of immune cells present in the liver (% CD45⁺ cells) were strongly correlated with the RAI (rs = 0.809, p < 0.0001). Based on this longitudinal characterization, we selected PODs 3 and 7 to be further examined using snRNA-seq.

Conclusion(s): By combining this relevant model with snRNA-seq, immunohistochemistry and flow cytometry, we will be able to describe the cellular landscape of the liver during ACR and tolerance.

References

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P008 A novel rat liver single-cell atlas aids understanding of liver transplant rejection

D Pouyabahar¹, ^2,*, C Perciani³, X-Z Ma³, C Jiang³, S Chung³, M Sekhon³, J Manuel³, X-C Chen³, I Mcgilvray³, S Macparland³, ⁴, G Bader¹, ⁵, ⁶

¹Department of Molecular Genetics, University of Toronto

²Terrence Donnelly Centre for Cellular & Biomolecular Research

³Ajmera Family Transplant Centre, Toronto General Hospital Research Institute

⁴Department of Immunology

⁵The Donnelly Centre

⁶Department of Computer Science, University of Toronto, Toronto, Canada

Background: Liver retransplantation is the only treatment option for patients diagnosed with acute cellular rejection following transplantation, and the development of therapeutics to treat and prevent acute cellular rejection is limited by our lack of comprehensive understanding of the cellular landscape of the liver 1. Laboratory rat (Rattus norvegicus) is a standard model animal used to study aspects of orthotopic liver transplantation 2,3. The degree of liver allograft rejection is known to be strain-specific, and while the transplantation is accepted without rejection in some strains, it leads to acute rejection in others 4. For instance, although Dark Agouti (DA) as donor and Lewis (LEW) as the recipient is used to model acute liver rejection, reversing the direction of transplantation leads to tolerance.

Purpose: To shed light on the hepatic cellular landscape and build the foundation for strain comparison, here, we present a comprehensive map of the healthy rat liver at a single-cell resolution. By comparing and contrasting the single-cell liver maps of the DA and LEW rat strains at baseline, we aim to unravel the cellular and molecular mechanisms that contribute to strain-specific rejection in rats. Methods: This study was focused on generating single-cell transcriptomic maps of the livers of DA and Lewis rat strains using single-cell RNA sequencing (10x Genomics platform). Six male rat samples have been included in this study, three from each of the strains. The single-cell map construction process can be affected by technical difficulties of the sample generation process. In this case, hepatocytes and cholangiocytes are known to be sensitive and are easily damaged through the dissociation process, leading to contamination of the input data. To overcome the challenges caused by such confounders, we utilized a matrix factorization method, called Varimax PCA, that is able to dissociate the biological and technical sources of variation and improves the interpretability of the data.

Result(s): The Varimax-based analysis pipeline guided the detailed annotation of the single-cell map of the rat liver and provided a foundation for strain comparison by detecting the factors which represent the variation between different samples. Interestingly, we were able to identify two factors that had clearly captured strain-specific variations. The first factor seemed to represent biological signatures which are not cell-type specific. Performing enrichment analysis on the genes corresponding to this factor indicated the enrichment of multiple nuclear receptors, such as PPARg and HNF4a. The second factor was able to capture the non-inflammatory KC-specific rat strain differences. Most of the top-hits of this factor, such as GATA1, SPL1, play a crucial role in macrophage differentiation.

Conclusion(s): We present the first single-cell RNAseq map of the rat liver which can be ultimately used to improve our understanding of the cellular basis of liver transplant rejection.

References

1Wang X, MacParland SA & Perciani CT. Immunological determinants of liver transplant outcomes uncovered by the rat model. Transplantation Publish Ahead of Print, (2021).

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P009 Oncogene-dependent genetic reprogramming of liver cancer cells induces glutamine-dependent mitochondrial metabolism

V Tambay^1,*, V-A Raymond¹, M Bilodeau¹, ²

¹Laboratoire d’hépatologie cellulaire, Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM)

²Département de médecine, Université de Montréal, Montreal, Canada

Background: Hepatocellular carcinoma (HCC) tumors are metabolically heterogeneous, such that liver tumors and specific subpopulations exhibit distinct metabolic programs. Indeed, metabolic reprogramming is a hallmark of cancer cells that have the capacity to scavenge a variety of nutrients, alternative to glucose, in order to maximize energy metabolism and mitochondrial activity. Among these alternative nutrients is glutamine (gln), an abundant non-essential amino acid. Interestingly, recent studies have proposed that the heterogeneity in cancer cell metabolism is the result of differential oncogenic driver activation.

Purpose: The purpose of this study was to understand the metabolic role of gln in murine HCC cells. Given that malignant transformation is associated with abnormal metabolism, gln can serve as a metabolic substrate for mitochondrial activity. The influence of gln on cellular respiration and oxidative phosphorylation was therefore of interest, alongside evaluating its traditional role in protein synthesis. Also, inherent differences in the expression of glutaminolysis-related genes between normal primary hepatocytes (NH) and Dt81Hepa1-6 (Dt81) HCC cells were investigated.

Methods: To measure protein synthesis, surface sensing of translation (SUnSET) was performed. Dt81 cells were cultured for 24h with 0 to 4mM gln, followed by a 30m incubation with puromycin, a tyrosyl-tRNA analog. Negative controls were treated with cycloheximide to block protein synthesis. Newly synthetized proteins, having incorporated puromycin, were quantified by Western Blot. To assess for mitochondrial respiration, Seahorse XF analysis measured oxygen consumption rate of Dt81 cells cultured with gln [0 to 4mM] or DMEM. For qPCR, mRNA was extracted from cells after a 48h culture at 4mM gln without glucose.

Result(s): Gln increased protein synthesis in a dose-dependent manner (p < 0.0001). At 4mM gln, the intensity of nascent proteins was 206243±17348 arbitrary units (AU), 2.7-fold higher than that of cells deprived of gln (76830±15301AU). Gln increased basal respiration and ATP production, 2 hallmarks of cellular respiration, although not to a statistically significant level. However, gln significantly increased, in a dose-dependent manner, maximal respiration from 4.8±0.9 to 36±3pmol_O2/m/μg_prot (p < 0.01) as well as mitochondrial matrix proton leak from 1.7±0.2 to 4.3±0.8pmol_O2/m/μg_prot (p < 0.01). Gln also increased spare capacity (p < 0.01). NH and Dt81 exhibited different mRNA expression profiles of several genes involved in gln metabolism: Gln synthetase was significantly higher in Dt81 (82±10AU) compared to NH (13±3AU; p < 0.001); kidney-type glutaminase was also higher by 2.2-fold in Dt81(78±12 vs 34±2AU; p < 0.01), gln–fructose-6-phosphate aminotransferase 7-fold higher in Dt81 (295±23 vs 42±21AU; p < 0.001) and phosphoserine aminotransferase was 3.6-fold higher (371±22 vs 104±38AU; p < 0.001). Liver-type glutaminase and glutamate dehydrogenase were vaguely decreased in Dt81, whereas mitochondrial aspartate transaminase was slightly increased. Interestingly, Dt81 cells exhibited a 4.5-fold higher level in the c-Myc oncogene in comparison to NH (211±13AU vs 47±13AU; p < 0.001).

Conclusion(s): In HCC Dt81 cells, the intracellular function of gln is not limited to being an amino acid important in protein synthesis. HCC cells can also rely on gln to maximize oxidative phosphorylation and meet energy demands. To do so, Dt81 overexpress key genes involved in the metabolism of gln. Moreover, this metabolic phenomenon could be explained by the overexpression of the c-Myc oncogene, known to target key genes in glutaminolysis.

P010 Repeated hyperammonemic insults leads to irreversible brain injury in bile-duct ligated rats

F Tamnanloo¹, ^2,*, R Ochoa-Sanchez¹, ², M Tremblay¹, CF Rose¹, ²

¹Centre de recherche du CHUM (CRCHUM)

²Medicine, Université de Montréal, Montréal, Canada

Background: Hepatic encephalopathy (HE) is a neuropsychiatric syndrome, a major complication of chronic liver disease (CLD). Defined as a metabolic disorder, HE is understood to be reversible following liver transplantation (LT). However, up to 47% of LT patients have been documented to have persisting neurological complications. Retrospective studies have revealed that patients with a history of overt HE are associated with a poor neurological outcome post-LT. However, the impact of HE episodes on neurological integrity is unknown. We hypothesize that episodes of HE will accelerate and/or exasperate neurological deterioration.

Purpose: Our goal was to characterize an animal model of episodic HE and to evaluate the impact of cumulative episodes induced by hyperammonemia on neurological status and brain injury in cirrhotic rats.

Methods: For animal model of CLD and HE, 5-week bile-duct ligation (BDL) rats, and sham-operated controls were used. Rats, both sham and BDL, were divided in two groups, episodic and non-episodic. Injection (ip) of ammonium acetate was used to induce episodes of overt HE (pre-coma; loss of righting reflex) every 4 days starting at 3-weeks post-BDL surgery (total 4 episodes). Saline was injected as vehicle for non-episodic group. Three days following the last episode of HE, neurological status was assessed. Upon sacrifice, plasma ammonia was measured, and brains were collected for western blot analysis; Neuronal nuclei (NeuN), caspase-3 (apoptotic marker) and GFAP (astrocyte marker) were measured to evaluate neurological integrity.

Result(s): BDL rats (vs sham) following ammonia insult developed overt HE (loss of righting reflex). Long-term memory (LTM) was impaired in both non-episodic and episodic BDL groups vs respective controls. However, LTM impairment was further aggravated in episodic BDL rats. Both GFAP and cleaved caspase-3 protein expression were significantly increased, whereas NeuN was significantly decreased in the hippocampus of episodic BDL rats vs non-episodic BDL rats. Blood ammonia levels were found to be higher in episodic vs non-episodic BDL rats.

Conclusion(s): HE episodes exasperate neurological impairments in BDL rats. LTM impairment was associated with an increase in the apoptotic marker (caspase-3) and a decrease in neuronal marker (NeuN) in the hippocampus, suggesting neuronal injury/loss. Elevated levels of GFAP in the hippocampus insinuates gliosis as a consequence of neuronal loss. These results suggest that multiple episodes of HE may cause permanent cell damage and therefore will less likely be reversible following LT justifying persisting neurological complications post-LT.

P011 End stage liver disease etiology and transplantation referral outcomes of major ethnic groups in British Columbia, Canada

DS Chahal^1,*, V Marquez¹, T Hussaini², P Kim³, S Chung³, M Segedi³, S Chartier-Plante³, C Scudamore³, S Erb¹, B Salh¹, EM Yoshida¹

¹Medicine

²Pharmacy

³Surgery, University of British Columbia, Vancouver, Canada

Background: British Columbia (BC) is home to a large multi-ethnic population, including persons of Asian (e.g. China, Korea, Japan, etc.), South Asian (e.g. India, Pakistan, Fiji, etc.) and First Nation (i.e. Indigenous) descent. Liver transplant indications and outcomes for these Canadian specific ethnic groups have not been well studied. Although it may be argued that this information can be extrapolated by reviewing liver disease studies arising from the originating countries of non-Indigenous ethnic groups, given that many liver diseases are not congenital or inborn and given that many members of the ethnic communities have lived in a Canadian environment for years, and possibly generations, this may not be a valid assumption.

Purpose: We aimed to profile the specific etiologies of ESLD in these ethnic communities and compare them to the larger Caucasian population using a Canadian specific provincial database. We also examined how ethnicity impacted decisions regarding eligibility and transplantation, and how ethnicity influenced graft survival and death whilst on the waitlist.

Methods: We retrospectively reviewed the provincial database for liver transplant referrals. We stratified cohorts by ethnicity and analyzed disease etiology and outcomes.

Result(s): 4916 referrals included 220 South Asians, 413 Asians, 235 First Nations (Indigenous) and 2725 Caucasians. Predominant etiologies by ethnicity included alcohol (27.4%) and PSC (8.8%) in South Asians, hepatitis B (45.5%) and malignancy (13.9%) in Asians, PBC (33.2%) and AIH (10.8%) in First Nations, and hepatitis C (35.9%) in Caucasians. First Nations had lowest rate of transplantation (30.6%, p = 0.01) and highest rate of waitlist death (10.6%, p = 0.03). Median time from referral to transplantation (268 days) did not differ between ethnicities (p = 0.47). Likelihood of transplantation increased with lower BMI (HR 0.99, p = 0.03), higher MELD (HR 1.02, p < 0.01), or fulminant liver failure (HR 9.47, p < 0.01). Median time from referral to ineligibility status was 170 days, and shorter time was associated with increased MELD (HR 1.01, p < 0.01), increased age (HR 1.01, p < 0.01), fulminant liver failure (HR 2.56, p < 0.01) or South Asian ethnicity (HR 2.54, p < 0.01). Competing risks analysis revealed no differences in time to transplant (p = 0.66) or time to ineligibility (p = 0.91) but confirmed increased waitlist death for First Nations (p = 0.04).

Conclusion(s): We have noted emerging trends such as alcohol related liver disease and PSC in South Asians. First Nations have increased autoimmune liver disease, lower transplantation rates and higher waitlist deaths. These data have significance for designing ethnicity specific interventions.

P012 Incidence of malignant neoplasms among liver transplant recipients and association with sociodemographic factors

M Haider^1,*, A Bapatla¹, R Ismail¹, A Chaudhary¹, S Iqbal¹

¹Department of Internal Medicine, Wayne State University/Detroit Medical Center, Detroit, United States

Background: Liver transplantation is the second most common organ transplant after kidney transplantation. In 2017, 8,000 liver transplants were performed; and as of 2016, 80,000 adults were living with functional liver grafts. With this growing number of people living with functional liver grafts, physicians need to be aware of associated complications. The most common complications post-liver transplantation are acute or chronic graft rejection, undesirable consequences associated with immunosuppressive medications, and primary liver disease recurrence.

Purpose: The purpose of this retrospective case-control study is to examine the incidence of de novo malignant neoplasms (excluding hepatocellular carcinoma-HCC) in hospitalized liver transplant recipients and to study the association of some relevant sociodemographic characteristics to the incidence of malignancies.

Methods: We used secondary data from the National Inpatient Sample database collected between January 2016 and December 2018 for all hospitalizations with a primary or secondary liver transplant (LT) status. This database is a part of the Healthcare Cost and Utilization Project (HCUP) and is maintained by the Agency of Healthcare Research Quality (AHRQ). All malignant neoplasms were identified and evaluated using the international classification of disease codes (ICD-10, code Z944). All hypothesis testing used a two-tailed P value with the significance level set at 0.05.

Result(s): Lymphomas were the most prevalent cancer among LT patients, followed by respiratory and gastrointestinal cancer (excluding HCC). Malignant neoplasms (MN) with LT were more frequent in older patients with a mean age of 61.21 years (SD ±15.08), more common in males (68.73% LT with MN vs. 59.20% LT) than females (31.27% LT with MN vs. 40.80% LT). Females had 34% less odds of developing cancers than males (OR, 0.660; 95% CI, 0.597–0.730; P < 0.001). Compared to patients aged 17 years or less, the odds of cancers in patients aged 65-84 were 2.7 times higher (OR, 2.739; 95% CI, 2.144–3.50; P < 0.001), and 1.9 times higher in patients aged 45-64 (OR, 1.894; 95% CI, 1.480–2.422; P < 0.001). In terms of race, as compared to white patients, Black patients had 34% lesser odds of MN (OR, 0.663; 95% CI, 0.550–0.798; P < 0.001), Hispanic patients also had 34% lesser odds of MN (OR, 0.668; 95% CI, 0.572–0.781; P < 0.001).

Table P012-1 Baseline patient demographics with liver transplant, with and without malignant neoplasms

Variables	No (n = 24316) 92.72%	Yes (n = 1909) 7.28%	P value
	Malignant Neoplasms
Sex			<0.01
Female	9922 (40.80%)	597 (31.27%)
Male	14394 (93.20%)	1312 (68.73%)
Age (y). mean (SD)	55.23 (18.99)	61.21 (15.08)	<0.01
Age groups (y)
≤17	1829 (7.52%)	72 (3.77%)
18-44	3069 (12.62%)	102 (5.34%)
45-64	10677 (43.91%)	796 (41.70%)
65-84	8587 (35.31%)	326 (46.51%)
≥85	154 (0.63%)	13 (0.68%)
Race/Ethnicity			<0.01
White	15885 (65.33%)	1356 (71.03%)
Black	2281 (9.38%)	129 (6.76%)
Hispanic	3366 (13.84%)	192 (10.06%)
Asian or Pacific Islander	652 (2.68%)	67 (3.51%)
Native American	182 (0.75%)	9 (0.47%)
Other	1950 (8.02%)	156 (8.17%)
Medan socioeconomic status by national quartiles			<0.01
0-25	6132 (25.22%)	401 (21.01%)
25-50	6158 (25.32%)	475 (24.88%)
50-75	6300 (25.91%)	565 (29.60%)
75-100	5303 (21.81%)	447 (23.42%)
Other	423 (1.74%)	21 (1.10%)

Table P012-2: Odds ratio of malignant neoplasms in hospitalized patients with liver transplant status in the United States, from 2016 to 2018

Malignant Neoplasms	Univariate logistic regression	P value
	OR (95%CI)
Sex. Female vs Mate	0.660 (0.597–0.730)	< .001
Age groups (y)
≤17	Reference	NA
18–44	0.845 (0.621–1.148)	NS
45–64	1.894 (1.480–2.422)	<.001
65–84	2.739 (2.144–3.50)	<.001
≥35	2.144 (1.161–3.959)	NS
Race/ethnicity
White	Reference	NA
Black	0.663 (0.550–0.798)	< .001
Hispanic	0.663 (0.572–0.731)	< .001
Asian or Pacific Islander	1.204 (0.931–1.557)	NS
Native American	0.937 (0.789–1.113)	NS

Conclusion(s): The number of liver graft patients with post liver transplantation complications is on the rise. Our study aimed to observe the incidence of malignancies in hospitalized liver transplant patients. Among these hospitalized patients, lymphoproliferative diseases followed by respiratory cancer were the most reported malignancies. Skin cancers are prevalent in post-transplant malignancy; they are usually localized and respond to local treatment, and do not require hospital admission.

References

1Dumortier J et al. (2018). Immunosuppressive regimen and risk for de novo malignancies after liver transplantation for alcoholic liver disease. Clin Res Hepatol Gastroenterol, 42(5):427-435. https://doi.org/10.1016/j.clinre.2018.04.011. Epub 2018 May 31. 29861393 https://doi.org/10.1016/j.clinre.2018.04.011

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P013 Implementing a cirrhosis order set: a qualitative analysis of provider-identified barriers and facilitators

E Johnson^1,*, M Carbonneau², D Campbell-Scherer³, P Tandon¹, A Hyde²

¹Medicine

²University of Alberta, Edmonton, Canada

³Family Medicine, University of Alberta, Edmonton, Canada

Background: Cirrhosis is the leading cause of mortality and morbidity in individuals with gastrointestinal disease. Multiple care gaps exist for hospitalized patients with cirrhosis, resulting in high rates of re-hospitalization (e.g. 44% at 90 days in Alberta). The Cirrhosis Care Alberta (CCAB) is a 4-year multi-component pragmatic trial with an aim to reduce acute-care utilization by implementing an electronic order set and supporting education across eight hospital sites in Alberta.

Purpose: As part of the pre-implementation evaluation, this qualitative study analyzed data from provider focus groups to identify barriers and facilitators to implementation.

Methods: We conducted focus groups at eight hospital sites with a total of 54 healthcare providers (3-12 per site). A semi-structured interview guide based upon constructs of the Consolidated Framework for Implementation Research (CFIR) and Normalization Process Theory (NPT) frameworks was used to guide the focus groups. Focus groups were recorded and transcribed verbatim. Data was analyzed thematically and inductively.

Result(s): Five major themes emerged across all eight sites: (i) understanding past implementation experiences, (ii) resource challenges, (iii) competing priorities among healthcare providers, (iv) system challenges, and (v) urban versus rural differences. Site-specific barriers included perceived lack of patient flow, time restraints, and concerns about the quality and quantity of past implementation interventions. Facilitators included passionate project champions, and an ample feedback process.

Conclusion(s): Focus groups were useful for identifying pre-implementation barriers and facilitators of an electronic orders set. Findings from this study are being refined to address the influence of COVID-19, and the data will be used to inform the intervention roll-out at each of the sites.

P014 Assessing the quality of preventative care in patients with chronic liver disease: trends in recommended vaccinations rates

A Lagrotteria^1,*, A Lagrotteria², K Tsoi³

¹McMaster University, Hamilton

²Faculty of Medicine, University of Toronto, Toronto

³Gastroenterology, McMaster University, Hamilton, Canada

Background: Vaccine-preventable infections in patients with chronic liver disease (CLD) are a major cause of morbidity and mortality, and immunization remains our best line of defence. The National Advisory Committee on Immunization Practices has recommended a comprehensive vaccination schedule to mitigate secondary decompensation by superinfection, including universal vaccination of patients with CLD against hepatitis A virus (HAV), hepatitis B virus (HBV), pneumococcal pneumonia, and influenza. Despite these recommendations, data suggests low adherence to vaccination guidelines in both primary care and specialty care settings in the United States. It is undocumented whether these trends prevail in Canada.

Purpose: To examine vaccination practices in an effort to mitigate potential disparities in coverage and the potential harm of vaccination delay. The aim of this quality assessment study was to assess the proportion of patients with CLD who were up to date with vaccinations.

Methods: Patients with CLD who received care at a large, primary care academic center in Ontario between January 1, 2010 and June 30, 2020 were identified using diagnostic codes. Demographics, etiology, and vaccination data pertaining to influenza, pneumococcus, HAV, and HBV were collected utilizing the electronic medical record and Canadian Primary Care Sentinel Surveillance Network database.

Result(s): Of 23, 021 patients registered,a total of 150 patients were identified to have CLD. The average age of the cohort was 55 and 25.3% (n = 38) were older than 65 at time of diagnosis. 58.7% (n = 88) were male. Overall, 32% (n = 48) of patients with CLD received at least 1 vaccination following their diagnosis.The rate of having at least 1 influenza vaccine after diagnosis was 28% (n = 42), of which 66.7% (n = 28) were vaccinated within 1 year after diagnosis. The rate of having at least 1 lifetime pneumococcal vaccine was 26% (n = 39), of which 12.8% (n = 5) were within 1 year after diagnosis. Analysis revealed that 6% (n = 9) of patients initiated vaccination against HAV, of which 44.4% (n = 4) initiated the series within 1 year after diagnosis. 55.6% (n = 5) completed the full schedule. 10% (n = 15) of the total cohort initiated vaccination against HBV, with 4.7% (n = 7) having initiated the series within 1 year after diagnosis. Only 2 patients completed the full schedule for HBV vaccine. Another 10 patients (6.7%) initiated dual-HepA/B vaccination, of which 3 patients (30%) did so within 1 year following diagnosis. Only 3 patients (30%) completed the full series.

Conclusion(s): We found that overall immunization rates against common vaccine-preventable infections were suboptimal among patients with CLD. There also appears to be significant delays in immunization from time of diagnosis. This data suggests a gap between recommendations and vaccine uptake in clinical practice amongst this high-risk population. These conclusions, based on a high-volume academic center, suggest that larger system redesign efforts are needed to improve the quality of preventative care in patients with CLD. Future studies are needed to identify how to implement interventions that standardize care delivery.

P015 Predictors of early and long-term initial readmission of patients following liver transplantation

N Simonian^1,*, M Brahmania², M Bhat², N Selzner², L Lilly², A Kim², H Janssen², K Patel², B Hansen³

¹Institute of Medical Sciences, University of Toronto

²Hepatology, UHN

³Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada

Background: Following liver transplant (LT), early hospital readmission within 30 days is associated with adverse post-operative outcomes. However, the long-term significance and factors associated with first readmission rates beyond 90 days post-LT have not been well-described.

Purpose: The aim of this current study is to examine the differences in risk factors associated with predictors of short term (30-day), mid-term (30-90 day) and long term (> 90 days to 5 years) first readmissions.

Methods: This is a retrospective observational study, investigating adult patients older than 18 years who underwent LT between January 1, 2010 and December 31, 2019 at Toronto General Hospital (TGH). Patients who received multiple organ transplants, and those residing outside of the GTA at time of transplant were excluded from the study. Readmission was defined as a hospital readmission for over 24 hours from home, clinic, emergency, or transfer from another hospital/rehabilitation center to TGH. Multiple donor, graft, pre- and post-operative recipient factors (including MELD, etiology of liver disease, post-LT length-of-stay (LOS), and distance from transplant center) were considered in the analysis. All statistical analyses were conducted using SPSS Statistics version 27. Time to first readmission was analyzed using Kaplan-Meier curves, and the predictors of short-term, mid-term, and long-term readmissions were analyzed using the Cox regression model and competing risk models.

Result(s): 1026 patients who received a LT between January 1, 2010 and December 31, 2019 fulfilled the inclusion criteria. Of those patients, 467 patients were readmitted (45.5%), with 176 being readmitted within 30 days post-transplant discharge (37.7%), 60 patients readmitted within the 30–90-day window (12.8%), and 231 readmitted for their first readmission 90 days post-LT (49.5%).

Multivariable analysis indicated that within 30-days post-LT, having autoimmune/cholestatic liver disease pre-LT (HR = 2.1, p = 0.015), and having a higher MELD at LT (HR = 1.02, p = 0.036) were predictors for readmission. Within the period of 30-90 days post-LT, increased post-transplant LOS is a predictor for a readmission (HR = 1.06, p < 0.0001), while patients having hepatocellular carcinoma (HCC) at time of transplant were less likely to be readmitted between 30 and 90 days (HR = 0.48, p = 0.022). After 90 days post-LT the predictors of readmission were having a living donor liver transplant (LDLT) (HR = 1.64, p = 0.002), and having a split donor transplantation (HR = 3.37, p = 0.004). In terms of survival, increased post-transplant LOS (HR = 1.07, p < 0.0001), having HCC (HR = 1.71, p = 0.001), and having increased time to first readmission (HR = 2.3, p < 0.0001) were all predictors of mortality, while having a LDLT was protective against mortality (HR = 0.54, p = 0.013).

Infection, followed by gastrointestinal events (including abdominal wall hematoma), and liver-related (including rejection) were the most frequent reason for first readmission for short-term and mid-term readmissions (Figure 1). For long-term readmissions, surgical events (such as incisional hernia) were the most frequent reason for readmission followed by infection, and gastrointestinal events.

Conclusion(s): This large single center study revealed that for short-term readmissions predictors are different from mid-term and long-term readmissions, with the former impacted more by pre-transplant etiology and MELD at LT, and the latter being impacted more by donor types. In our study infection, closely followed by surgical events, were the main reason for initial readmissions.

P016 Sex-dependent hepatoprotective role of Il-22 In NAFLD-related fibrosis

MN Abdelnabi^1,*, M Flores Molina¹, G Soucy², V Quoc-Huy Trinh², S Mazouz¹, N Bédard¹, S Tran¹, M. Bilodeau³, NH Shoukry³

¹Département de microbiologie, infectiologie et immunologie, Université de Montréal-CRCHUM

²Département de pathologie et biologie cellulaire, Université de Montréal-CHUM

³Département de médecine, Université de Montréal-CRCHUM, Montreal, Canada

Background: Due to the rise in obesity among adults, NAFLD-related liver fibrosis has become a major health challenge with a complex pathogenesis and limited therapies. Sex differences were reported in clinical and preclinical NAFLD studies but studies on sex differences in progression of NAFLD-related fibrosis are still lacking (Lonardo A. et al. 2019). Liver fibrosis occurs via the production of collagen by activated hepatic stellate cells in response to persistent tissue damage and inflammation. Intrahepatic leucocytes (IHL) can produce different cytokines such as IL-22 that can modulate liver fibrosis progression (Friedman S.L. et al. 2015). IL-22 is a pleiotropic cytokine that can play dual roles (protective or pathogenic) depending on the inflammatory context in the liver. We have demonstrated increased frequency of IL-22 producing cells in patients’ liver biopsies with advanced fibrosis irrespective of aetiology (Fabre T. et al. 2018). This finding was validated in vivo in chronic CCl4 injury model, where IL-22RA1 KO mice had less hepatic fibrosis compared to their wild-type (WT) littermates (Fabre T. et al. 2018). Here, we wanted to extend our findings to a more physiological model such as NAFLD.

Purpose: We hypothesize that intrahepatic IL-22 producing cells enhance NAFLD-related fibrosis

Methods: A cross-sectional analysis of 17 human NAFLD liver biopsies (males = 10, females = 7) was used to evaluate infiltration of IL-22+ cells. Also, we employed a mouse model of NAFLD (C57BL/6N) using IL-22RA1 KO mice and their WT littermates (age 6-8 weeks), including males and females, fed high fat diet (HFD, 40% Kcal fat+ 40% Kcal carbohydrate (including fructose) +2%cholesterol)) vs chow diet (18%Kcal fat+ 24%Kcal protein) for 30 weeks (Wk). IL-22+ cells were characterized in human biopsies and mice liver tissue using immunofluorescence (IF). ImageJ software was used for IF image analysis and quantification. Moreover, Picro Sirius Red (PSR) staining, TUNEL staining, IF, qPCR and H&E were used to evaluate liver fibrosis, injury and inflammation in the mice. NAFLD activity score (NAS) and fibrosis stage were blindly evaluated by two expert pathologists.

Result(s): Female patients had significantly higher density of IL-22+ cells in their livers compared to male patients (P = 0.0062), but this was not associated with liver fibrosis (Metavir score, r = 0.2286, P = 0.6603) or NAS score (r = -0.5426, P = 0.2286). This finding was validated using publicly available data from another cohort of NAFLD patients (males = 14 patients, females = 22), where IL-22 mRNA expression was significantly upregulated in the livers of female vs male patients (P = 0.0086) (Hass J.T. et al, 2019). Consistent with human data, livers of WT-female mice fed with HFD had significantly higher density of IL-22+ cells and upregulation of IL-22 mRNA level vs WT-male mice (P < 0.0001). Furthermore, livers from IL-22RA1 KO female mice on a HFD had higher degrees of fibrosis (PSR+ area), total NAS score, inflammation (MPO+ area) and apoptosis compared with control female mice (P = 0.0010, P = 0.0424, P < 0.0001, P < 0.00001, respectively). In contrast, WT and IL-22RA1 KO male mice on HFD had comparable levels of liver fibrosis, inflammation and apoptosis.

Conclusion(s): Our data suggest a sex-dependent hepatoprotective effect of IL-22 on NAFLD-related injury in females.

P017 Non-invasive diagnosis of non-alcoholic steatohepatitis in liver transplant recipients: a prospective study employing serum cytokeratin 18 and transient elastography (Fibroscan/CAP)

A Alhinai^1,*, A Qayyum Khan¹, X Zhang¹, P Samaha², M Deschenes², P Wong², T Chen², G Sebastiani²

¹McGill University Health Centre, Montreal, Canada

²Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Canada

Background: Non-alcoholic steatohepatitis (NASH), the progressive counterpart of Non-alcoholic fatty liver disease (NAFLD), is a major health concern in Canada. Previous studies have shown that NAFLD, NASH and liver fibrosis are common after liver transplant,however most of these studies were retrospective.

Purpose: We aimed to prospectively determine the incidence and predictors of NAFLD, NASH and liver fibrosis in liver transplant recipients using Fibroscan with CAP (Controlled Attenuation Parameter) and CK-18 (cytokeratin-18), and to evaluate the diagnostic performance of these tests compared to liver histology.

Methods: We performed a prospective study involving consecutive adult patients who received liver transplants between 2015 and 2018. Patients who received liver transplantation due to chronic hepatitis C, genotype 3; and/or failed Fibroscan with CAP assessment were excluded. Post-transplant, patients were followed for a total of 5 study visits over a period of 18 months. Serial measurements of Fibroscan/CAP and CK-18 were recorded. NAFLD and NASH were diagnosed non-invasively by CAP ≥ 270 dB/m, and by the combination of CAP ≥ 270 dB/m with CK-18 > 130.5 IU/l, respectively. We also described incidence of significant liver fibrosis diagnosed non-invasively using a cut-off value of Fibroscan ≥ 7.4 kPa. Multivariable Cox regression models were constructed to assess predictors of NAFLD and NASH. The performance of the non-invasive tests to diagnose NAFLD and NASH was compared to liver histology performed on the same patients using sensitivity, specificity, PPV, NPV, accuracy, and LR+ and LR-.

Result(s): Overall, 40 patients (mean age 57.3±8.5, 70% male, 80% Caucasian, and 30% transplanted due to NASH) were included. During a median follow-up of 16.8 months (IQR 15.6–18), 63% patients developed NAFLD (incidence rate: 71 per 100 PY, 95% CI 45–78), 48.5% patients developed NASH (incidence rate: 48.6 per 100 PY, 95% CI 31.4–66), and 60% patients developed significant liver fibrosis (incidence rate: 71 per 100 PY, 95% CI 42–76). On multivariate Cox regression analysis, BMI was an independent predictor of both NAFLD (adjusted HR 1.1, 95% 1.0–1.2) and NASH (adjusted HR 1.1, 95% CI 1.0–1.3). With the CAP cutoff of 270 dB/m, the diagnostic performance for NAFLD compared to liver histology was as follows: sensitivity 58%, specificity 86%, PPV 70%, NPV 79%, accuracy 76%, LR + 4.28, LR – 0.48. The diagnostic performance of a combination of CAP> 270 dB/m and CK-18 > 130.5 to diagnose NASH was as follows: sensitivity 75%, specificity 83%, PPV 37% and NPV 96%, accuracy 82%, LR + 4.50, LR- 0.3.

Conclusion(s): NAFLD and NASH are frequent occurrences in liver transplant recipients mainly driven by high BMI. CAP and CK-18 are useful tools for monitoring however the analysis must be replicated in a larger sample for further knowledge on their accuracy.

P018 Effect of probiotics on hepatic steatosis, inflammation and fibrosis in nonalcoholic fatty liver disease: a systematic review and meta-analysis

N Faisal^1,*, P Virdi¹, A Abou-Setta², N Askin³, GY Minuk¹, E Renner¹

¹Internal Medicine (section of Hepatology)

²Community Health Sciences

³Neil John Maclean Health Sciences Library, University of Manitoba, Winnipeg, Canada

Background: Preclinical evidence suggests that modulation of the gut microbiome might represent a therapeutic target in non-alcoholic fatty liver disease (NAFLD). Probiotics have been used to safely modulate the gut microbiome in humans. The aim of this systematic review and meta-analysis was therefore to evaluate the effects of probiotics on liver disease severity in patients with NAFLD.

Purpose: Multiple human clinical trials have been conducted to study the therapeutic effects of probiotics in patients with NAFLD in the past decade with equivocal clinical outcomes. Several meta-analyses have been published describing the impact of probiotics on metabolic outcomes but only a few focused on liver-related outcomes and then, only in a limited capacity (1-3). Additional limitations of these analyses include diverse patient populations and combination therapies (probiotics mixed with other active treatment) causing significant heterogeneity in the observations. Given the limitations in the current literature we aimed to conduct a systematic review and meta-analyses of randomized controlled trials (RCTs) assessing the effect of probiotics as only active treatment on liver disease severity in patients with NAFLD.

Methods: We searched multiple electronic databases for randomized controlled trials (RCTs) published before February 18, 2020 that enrolled persons with NAFLD to receive probiotics as sole active therapy. Outcome measures included serum aminotransferases activity, hepatic steatosis and fibrosis as assessed by MRI, elastography and/or liver biopsy, BMI, insulin resistance (HOMA), serum triglyceride and TNF-alpha levels. Outcomes were pooled with the use of random effects models and heterogeneity was assessed with the I² statistic.

Result(s): Twelve RCTs (556 participants) were included. Treatment duration ranged from 8 to 48 weeks. Probiotics were associated with a small, but statistically significant reduction in aminotransferases activity [ALT and AST, weighted mean difference (WMD: −7.74 U/L; 95% CI: −16.63, 1.16 U/L) and (WMD: –7.30 U/L; 95% CI: −13.55, −1.04 U/L) respectively] although analyses showed heterogeneity (I² = 73% in both). While hepatic steatosis and fibrosis were found not to be significantly affected, probiotics were associated with small, but statistically significant effects on BMI (WMD: −1.15 kg/m²; 95% CI: −2.22, −0.07g/m²), insulin resistance (WSMD: −1.31; 95% CI: –2.50, –0.11), serum triglycerides (WSMD: –0.36, 95% CI: [–0.69, –0.03, p = 0.03) and TNF α (WMD: –0.93, 95% CI: [–1.67, –0.20].

Conclusion(s): Treatment of NAFLD subjects with probiotics is associated with minor improvement in BMI, dyslipidemia, insulin resistance, and markers of hepatic inflammation, but not hepatic steatosis or fibrosis. Additional well-designed RCTs with longer follow ups are needed to determine the clinical significance of these effects.

References

1Sharpton SR, Maraj B, Harding-Theobald E, Vittinghoff E, Terrault NA. Gut microbiome-targeted therapies in nonalcoholic fatty liver disease: a systematic review, meta-analysis, and meta-regression. The American journal of clinical nutrition. 2019;110(1):139-49

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P019 Association between non-alcoholic steatohepatitis and fibrosis among non-alcoholic fatty liver disease patients

A Frolkis^1,*, M Swain¹, W Schaufert², J Jiang², AA Shaheen¹, ¹

¹Medicine, University of Calgary

²Alberta Health Services, Calgary, Canada

Background: Liver fibrosis stage is considered the main predictor of adverse non-alcoholic fatty liver disease (NAFLD) outcomes such as hepatocellular carcinoma (HCC), liver transplant, and mortality. However, non-alcoholic steatohepatitis (NASH) severity is considered a key driver of fibrosis development/progression. Therapeutic interventions aimed at preventing progressive NAFLD and poor clinical outcomes target patients with established NASH.

Purpose: Therefore, using a large primary care-based cohort, we assessed the association between NASH severity (NAFLD activity score [NAS]) and fibrosis stage among NAFLD patients.

Methods: Between 2018 and 2020, we used the Calgary NAFLD clinical care pathway database to identify patients evaluated in primary care (N = 6,923) with shearwave elastography (SWE) who had SWE ≥ 8.0 kPa (n = 437) or inconclusive results (n = 317), and were subsequently referred for further assessment in our high-risk NAFLD clinic. Among those patients assessed, 219 patients underwent a liver biopsy to stage their NAFLD disease. All liver biopsies were evaluated by a single liver pathology expert and Kleiner classification was used to determine NAS and fibrosis stage. The association between NAS and fibrosis stage was then determined. NAS score was classified as high (5-8) vs low (< 5). Logistic regression models were used to evaluate demographic, clinical, and laboratory as predictors of advanced fibrosis (≥ stage 3).

Result(s): NAFLD diagnosis was confirmed in 195 patients (89%). Distribution of fibrosis stages, NAS, and ALT are presented in Table 1. Prevalence of significant fibrosis (≥ F2), advanced fibrosis (≥ F3), and cirrhosis (F4) in our cohort were 81%, 61%, and 36%, respectively. Approximately half of our cohort had a high NAS score (n = 103, 53%). Patients with lower NAS had lower fibrosis stage (median 2, IQR: 1–4) compared to high NAS patients (median fibrosis stage 3, IQR: 2–4), p < 0.001. Patients with high NAS were of similar age (median: 60 vs. 62 yr, p = 0.19), sex (female prevalent at 58% vs. 53%, p = 0.48), and ALT level (median: 47 vs. 39 IU/mL, P = 0.20) compared to the low NAS cohort. However, high NAS patients had higher hemoglobin A1c levels (median 6.7 vs. 6.3, p = 0.003). In our adjusted models, age (adjusted OR 1.06, 95% CI 1.03–1.09), hemoglobin A1c (aOR 1.38, 95% CI 1.04–1.84), and high NAS (aOR 2.88: 95% CI 1.54–5.39) were independent predictors of advanced fibrosis.

Table O19: Distribution of fibrosis stages, NAS, and ALT in our cohort

	Stage 0 n=9, 5%	Stage 1 n=27, 14%	Stage 2 n=39, 20%	Stage 3 n=50 (26%)	Stage 4 N=69 (36%)
	Fibrosis stages in our cohort
NAS, median (IQR)	4 (1–4)	4 (4–5)	5 (4–6)	5 (4–6)	5 (4–6)
ALT lU/mL, median (IQR)	44 (25–64)	32 (20-49)	48 (32–61)	47 (33–78)	45 (33–70)

Conclusion(s): In this large primary care-based NAFLD study, only half of our cohort had high NAS indicative of significant NASH. However, NAS was associated with liver fibrosis stage and was a strong predictor of advanced fibrosis.

P020 Availability of a living donor optimizes timing of liver transplant in high-risk waitlisted NASH and non-NASH cirrhosis patients

FA Qazi Arisar^1,*, C Shiyi², C Chen¹, C Yang¹, NUS Shaikh¹, R Kiran², R Uchila¹, W Xu², S Asrani³, Z Galvin¹, N Selzner¹, K Patel⁴, M Cattral¹, L Lilly¹, M Bhat¹

¹Multi Organ Transplant Program

²Department of Biostatistics, University Health Network, Toronto, Canada

³Baylor University Medical Center, Dallas, United States

⁴Toronto Centre for Liver Disease, University Health Network, Toronto, Canada

Background: Liver transplantation (LT) has been offered to patients with end-stage liver disease with excellent overall survival. However, a growing waiting list has increased the demand for organs, while supply has not kept up. In the setting of scarce deceased donor organs, living donor liver transplantation (LDLT) represents a viable alternative.

Purpose: To identify the subgroups of waitlisted decompensated cirrhosis patients who particularly would be advantaged by having access to LDLT, specifically comparing NASH to non-NASH indications.

Methods: We retrospectively reviewed all adult patients listed for LT in our program from November 2012 to May 2019, and grouped them by NASH versus non-NASH indication. Patients with a potential living donor (pLD) available after listing were identified. We excluded patients with MELD exception points, fulminant liver failure, multi-organ transplant or retransplantation. All patients were followed from time of listing to LT or dropout. Survival analyses with Cox PH models and time to LT with Fine and Gray’s Competing risk models were performed.

Result(s): Out of 1290 listed patients, 860 met inclusion criteria. Mean age was 54.6 years; 505 (58.7%) were males. 360 (41.8%) patients had a pLD identified. 496 (57.6%) patients underwent LT, 170 (34.2%) were LDLT. Higher instantaneous rate of transplant was observed in patients with age < 60 (HR: 1.31 [95% CI:1.08–1.58], p = 0.018), MELD-Na > 20 (HR: 1.9 [95% CI:1.59–2.27], p < 0.0001), and less frailty (HR: 1.33 [95% CI:1.00–1.76], p = 0.05). High waitlist mortality/drop out was seen in patient with age > 60 (HR: 1.55 [95% CI:1.21–1.99], p = 0.0005), MELD-Na > 20 (HR: 3.48 [95% CI:2.68–4.51], p < 0.0001), eGFR < 60 (HR: 2.15 [95% CI:1.68–2.75], p < 0.0001), Height < 165 (HR: 1.32 [95% CI:1.02–1.7], p = 0.03), more frail (HR: 1.73 [95% CI:1.29–2.33], p = 0.0002) and diagnosis of NASH (HR: 1.46 [95% CI:1.08–1.97], p = 0.01).Benefit of pLD was evident for all patients, but patients with MELD-Na < 20 (p < 0.0001), GFR> 60 (p = 0.03), and more frail (p = 0.03) especially benefited. A trend was observed in patients with height < 165 (p = 0.079)

Conclusion(s): Both NASH and non-NASH cirrhosis patients on the waitlist benefit from access to a living donor, by optimizing the timing of transplant for subgroups at the highest risk for dropout (older age, MELD-NA < 20, frailty). Referral for LDLT should be encouraged especially in patients at highest risk of dropout.

P021 Impact of obesity on concordance of serum liver biomarkers and transient elastography in HIV

G Sebastiani^1,*, A Cervo², J Milic³, B Lebouche¹, M Klein¹, M Deschenes¹, A Cascio⁴, G Mazzola², G Guaraldi³

¹Medicine, McGill University Health Centre, Montreal, Canada

²Infectious Diseases, University Hospital of Palermo, Palermo

³Infectious Diseases, University of Modena and Reggio Emilia, Modena

⁴University Hospital of Palermo, Palermo, Italy

Background: Transient elastography (TE) with controlled attenuation parameter (CAP) is a feasible and accurate tool to assess both non-alcoholic fatty liver disease (NAFLD) and associated liver fibrosis in people with HIV (PWH), who are at high risk for the disease. However, it is not widely accessible. Serum liver biomarkers, including Fibrosis-4 (FIB-4) index, AST-to-platelet ratio index (APRI) and hepatic steatosis index (HSI), can be used for large scale studies and in limited resource settings. However, the concordance between TE with CAP and serum biomarkers in PWH is not known, particularly across the spectrum of body mass index (BMI).

Purpose: To investigate concordance between transient elastography and CAP with serum biomarkers in PWH across the BMI spectrum.

Methods: Consecutive HIV mono-infected patients from three prospective cohorts (LIVEHIV in Montreal, LHIVPA in Palermo, MHMC in Modena) underwent TE with CAP and serum liver biomarkers. Patients with viral hepatitis co-infection or alcohol abuse were excluded. NAFLD was defined as CAP ≥ 285 dB/m. Significant fibrosis and cirrhosis were defined as TE measurement ≥ 7.1 and > 13 kPa, respectively. A FIB-4 and APRI threshold < 1.3 and < 0.5, respectively, was used to categorize patients as absence of significant fibrosis. A HSI threshold < 30 was used to categorize patients as absence of NAFLD. Multivariable logistic regression analysis was used to identify predictors of discordance between serum liver biomarkers and TE, defined as FIB-4 < 1.3 with TE > 7.1, and as APRI < 0.5 with TE > 7.1.

Result(s): A total of 1510 PWH were included. Discordance between HSI < 30 and CAP > 285 for NAFLD was rare (1% in normoweight PWH, no discordance in overweight and obese PWH). For FIB-4 and APRI compared to TE, most of the discordance was observed in obese patients (see Figure). Of note, over 5% of PWH defined as cirrhotic by TE > 13 were missed by both FIB-4 < 1.3 and APRI < 0.5. After adjusting for sex, CD4 cell count and time since HIV diagnosis, BMI was an independent predictor of discordance for both FIB-4 < 1.30 with TE > 7.1 (Odds Ratio [OR] 1.13, 95% CI: 1.08-1.19, p < 0.001) and APRI < 0.5 with TE > 7.1 (OR 1.13, 95% CI 1.08-1.17, p < 0.001). In obese patients, the combination of HSI < 30 and APRI < 0.5 or HSI < 30 and FIB-4 < 1.3 had 100% negative predictive value to exclude presence of liver cirrhosis by TE.

Conclusion(s): Obese PWH have significantly less concordance between serum fibrosis biomarkers and TE for the diagnosis of significant fibrosis, leading to missed cirrhosis diagnosis. The combination of multiple serum biomarkers should be considered in obese PWH to minimize the risk of missed cirrhosis diagnosis.

P022 A Canadian survey on knowledge of non-alcoholic fatty liver disease among physicians

G Sebastiani^1,*, A Ramji², M Swain³, K Patel⁴

¹Medicine, McGill University Health Centre, Montreal

²University of British Columbia, Vancouver

³Medicine, University of Calgary, Calgary

⁴Medicine, University Health Network, Toronto, Canada

Background: In Canada, non-alcoholic fatty liver disease (NAFLD) is the most frequently occurring liver disease, affecting one in four Canadians. NAFLD can evolve to nonalcoholic steatohepatitis (NASH) and cirrhosis. As Canadian NASH Network, we have recently demonstrated that, in Canada, NAFLD frequency will increase by 20% through 2030 when there would be an estimated 9,305,000 cases. There will also be an increase of 65% in cases of liver cirrhosis and liver cancer related to NASH within the next decade. No study in Canada has investigated knowledge about NAFLD/NASH among physicians and nurses.

Purpose: We conducted a web-based survey aimed at investigating knowledge of NAFLD among Canadian physicians (primary care physicians and specialists) and nurses.

Methods: Primary care physicians (PCPs), specialists in internal medicine, gastroenterology and hepatology and hepatology nurses, either members of the Canadian Association for the Study of the Liver, Canadian Association of Hepatology Nurses or College of Family Physicians of Canada, were invited to participate in this web-based survey.

Result(s): Of 650 invited physicians and nurses, 214 (33%) responded and 171 (26%) completed the whole survey. Among respondents, 51% were PCPs, 38% were specialists, and 11% were nurses. Moreover, 71% dedicated more than 75% of their time to patient care, and 51% were based at a community practice. Overall, 58% of PCPs, 28% of specialists, and 39% of nurses declared that they were only somewhat familiar or unfamiliar with NAFLD (see Figure). Moreover, 53% of PCPs, 20% of specialists, and 35% of nurses thought the prevalence of NAFLD in Canada was 15% or less. Also, 42% of respondents thought that NASH could be diagnosed by imaging or blood tests. Interestingly, the main concerns about non-invasive markers to stage liver fibrosis in NAFLD were lack of updated guidelines for clinical practice (29%) and no treatment options after diagnosis (27%). With regard to the question about the most common cause of death among NAFLD patients, almost one-third of PCPs and half of nurses thought it was liver cirrhosis, whereas almost all gastroenterologists and hepatologists agreed that it was cardiovascular disease. Finally, more than 40% of PCPs, 22% of specialists, and 33% of nurses thought that metformin and statin were treatments for NASH.

Conclusion(s): This survey shows that a significant proportion of Canadian physicians and nurses managing patients with NAFLD are not very familiar with the disease. This study emphasizes the need for further provider education, national practice guidelines, and improved treatment options.

References

1Swain MG, Ramji A, Patel K, Sebastiani G, Shaheen AA, Tam E, Marotta P, Elkhashab M, Bajaj HS, Estes C, Razavi H. NAFLD Disease Burden – Canada, 2019-2030: a modeling study. CMAJ Open 2020 Jun 9;8(2)E429-436. https://doi.org/10.9778/cmajo.20190212.

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P023 Complication rates of liver biopsies in patients with nonalcoholic fatty liver disease

F Zhou^1,*, A Stueck¹, M McLeod¹

¹Dalhousie, Halifax, Canada

Background: Non-alcoholic fatty liver disease (NAFLD) is becoming the most common cause of liver disease as well as the most common indication for liver transplantation in Canada. Treatment options are limited as there are currently no approved medications to treat NAFLD, though many molecules are in development. If a treatment is approved for NAFLD, it will be important to risk stratify patients based on degree of fibrosis in order to allocate treatment to those who are at highest risk. While there are a number of non-invasive measures of fibrosis, the gold standard is the histopathological examination of a liver biopsy specimen. There have been no studies that have looked at the complication rates of liver biopsies in patients with NAFLD. If complication rates are higher in the NAFLD population, non-invasive approaches to risk stratify patients may be more appropriate.

Purpose: We conducted a retrospective chart review to determine the complication rate of outpatient elective percutaneous and transjugular liver biopsies in patients with NAFLD.

Methods: A retrospective chart review was performed on all patients with NAFLD who underwent outpatient elective percutaneous and transjugular liver biopsies at a tertiary hospital from 2010 to 2020. We excluded inpatient biopsies, surgical biopsies, allograft biopsies, and targeted liver biopsies. Ethics approval was obtained. We collected gender, age, and pre-biopsy platelets/INR/PTT. For each biopsy reviewed, we recorded the route used to obtain the biopsy (percutaneous or transjugular), indication for the liver biopsy, and the results of the biopsy. We recorded all complications up to one week post-procedure.

Result(s): Data collection is ongoing. 384 charts were reviewed, 43 were excluded. There were serious complications in 4 of the 341 (1.2%) biopsies included in the study.

Conclusion(s): The complication rate of liver biopsies in patients with NAFLD in our study is 1.2%. A previous study found a complication rate of 0.7% in a heterogenous population of patients (Boyum et al. 2016). Preliminary data suggests that consideration should be given to risk stratifying patients for future pharmacotherapies against NAFLD using non-invasive approaches, given their slightly higher risk of complications from invasive approaches.

References

1Boyum JH, Atwell TD, Schmit GD, Poterucha JJ, Schleck CD, Harmsen WS, Kamath PS. Incidence and Risk Factors for Adverse Events Related to Image-Guided Liver Biopsy. Mayo Clin Proc. 2016. 91(3):329.

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P024 Facebook is an informative source for NASH patient market research

M Betel^1,*, M Sherman²

¹NASHnet.ca

²Gastroenterology, University Health Network - Retired, Toronto, Canada

Background: An estimated 25% of the population in Canada have NAFLD. The prevalence may be even higher in the USA. Of those with NAFLD, 25% may have NASH and potentially progressive disease¹. There is a critical need to connect with this segment of the ‘at risk’ population and we need to understand both the patient journey and patient needs, and this is often assisted by market research.

Purpose: Currently fatty liver disease is under-diagnosed. Thus, there is a need for broad patient education. Digital channels for education can be an effective way to reach patients. Before developing educational programs there is a need to determine the current state of knowledge in the population in order to develop and target these programs.

Methods: Identical Facebook advertisements were placed in the Facebook feeds of two different target groups. The first posting (FB1, N = 102) was to random Facebook users in the US and Canada with no special interest criteria designated. The second group (FB2, N = 149) targeted Facebook users with an expressed interest in Diabetes Mellitus type 2 awareness or diet food or plus-size clothing. These criteria were chosen because they are indicators of conditions related to fatty liver disease. The third group (FB3, N = 102), receiving the survey, was a NASH support group.

Result(s): There were 353 Facebook users who responded to the 3 surveys over a 5-day period in October and November 2020. Of all respondents, 89% were female, 80% were over 55 years of age. In all, 88% self-identified as having been diagnosed with diabetes, obesity, cardiovascular disease or hyperlipidemia. Obesity was the most common metabolic disorder reported with a prevalence of 37%. Knowledge about risk factors for fatty liver disease varied between the 3 groups, with the highest awareness being in those with obesity (39% FB1, 37% FB2 and 46% FB3), and diabetes (28% FB1, 26.4% FB2 and 39% FB3). There were marked differences between the 3 arms to a question asking whether they understood what fatty liver disease was with 38% answering positively in FB1, 47% positive in FB2 and 94% in the NASH Support Group (FB3). Participants were less aware about the benefits of diet and exercise as treatment for fatty liver disease. FB3 was the most aware, with 61% acknowledging that diet and exercise was beneficial, versus the other two groups at 35% (FB1) and 32% (FB2). Very few survey participants had spoken with a physician about fatty liver disease, including those who have already been identified by a number of metabolic factors. In FB1, 26% had had a medical discussion about fatty liver disease, 31% in FB2, versus 95% in the NASH support group (FB3), even though 61% of FB1 and 57% in FB2 reported a previous diagnosis of diabetes, obesity, cardiovascular disease, hyperlipidemia, NAFLD, NASH or a combination of these.

Conclusion(s): Facebook users who belong to a NASH support group seem to be more likely aware of what fatty liver disease is, and indicated that diet and exercise are helpful. Most have never spoken to a physician about fatty liver disease even though they are at high risk. Encouraging patients to join online NASH/NAFLD support groups may help educate patients on disease state and disease treatment knowledge. These support groups could be an ideal target for future education.

References

1Burden of nonalcoholic fatty liver disease in Canada 2019-2030: a modelling study. CMAJOPEN June 9, 2020 vol. 8. no. 2 E429–E436

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P025 Non-alcoholic fatty liver disease in premenopausal women with polycystic ovary syndrome: systematic review and meta-analysis

M Shengir^1,*, T Chen², E Guadagno³, A Ramanakumar⁴, P Ghali², M Deschenes², P Wong², S Krishnamurthy⁵, G Sebastiani²

¹Medicine, McGill University

²Medicine

³Pediatric Surgery

⁴Research Institute

⁵Department of Obstetrics and Gynecology, McGill University Health Centre, Montreal, Canada

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Thus, identifying populations at risk is the first step toward implementing effective screening strategies that might help alleviating the burden of NAFLD-related outcomes and liver transplantation. NAFLD and polycystic ovary syndrome (PCOS) seem to be extremely relevant in clinical settings due to common pathogenic pathways such as obesity and insulin resistance.

Purpose: We performed a systematic review and meta-analysis to investigate the association between NAFLD and PCOS among premenopausal PCOS patients.

Methods: Studies that reported the association between NAFLD and PCOS or provided enough data to calculate it were systematically identified through various scientific databases. Study selection was performed using Rayyan QCRI, a web-based tool. Newcastle-Ottawa Scale (NOS) was used for quality appraisal. Statistically, we calculated pooled odds ratio using a random-effect model, and heterogeneity was addressed through I². Subgroup analyses stratified by geographic region, study design, applied PCOS criteria, NAFLD diagnostic tools, insulin resistance (IR), presence of metabolic syndrome, and body mass index (BMI) was performed. Frequently reported predictors were evaluated through meta-regression.

Result(s): Of the 1,833 studies retrieved in the search, twenty-nine reviews met the eligibility requirements to be selected for the systematic review. Of these, twenty-three studies with 7,148 participants were qualified for quantitative synthesis. The pooled result showed that women with PCOS had a 2.5-fold increase in NAFLD risk compared to controls (OR 2.49, 95% CI 2.20–2.82). In subgroup analyses comparing PCOS to controls, PCOS patients from South America and the Middle East had a greater risk of NAFLD (OR 3.55, 95% CI 2.27–5.55), compared to their Europe (OR 2.22, 95% CI 1.85–2.67) and Asia (OR 2.63, 95% CI 2.20–3.15) counterparts. IR and metabolic syndrome were also more frequent in PCOS group than in controls (OR 1.97, 95% CI 1.44–2.71 and OR 3.39, 95% CI 2.42–4.76), respectively. When we stratified by BMI, overweight/obese PCOS patients were at increased risk of NAFLD (OR 3.84, 95% CI 3.25–4.54) as opposed to weight matched controls, whereas lean PCOS showed no association with the outcome (OR 0.98, 95% CI .077–1.25). Although normal BMI showed no association with the outcome, IR and the occurrence of metabolic syndrome remained significantly higher in lean PCOS than controls. Additionally, study quality and BMI were the only covariates that showed a relationship with the outcome in the meta-regression, with a regression coefficient of –2.219 (95% CI –3.927 to –0.511) and –1.929 (95% CI –3.776 to –0.0826), respectively.

Conclusion(s): This meta-analysis suggests that premenopausal PCOS is associated with an increased risk of NAFLD, and among studied risk factors, BMI appears to be the primary modifier.

P026 Comparison of different definitions of metabolic syndrome and association with non-alcoholic fatty liver disease: a retrospective study

C Tse^1,*, N Lisanti², GY Minuk³, N Faisal³

¹Department of Internal Medicine

²Max Rady College of Medicine, Rady Faculty of Health Sciences

³Department of Internal Medicine, Section of Hepatology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada

Background: Metabolic syndrome (MetS) is considered an important risk factor for NAFLD and plays an important role in screening and diagnosing patients with NAFLD^1,2. Currently several criteria of MetS have been proposed including from the World Health Organization (WHO), the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP-III), the International Diabetes Federation (IDF), the American Association of Clinical Endocrinologists (AACE), the American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI), and most recently there was a joint interim statement from the IDF, AHA/NHLBI, World Heart Federation, International Atherosclerosis Society and International Association for the Study of Obesity for a “Harmonized” criteria. It remains unclear if certain definitions are more strongly associated with the diagnosis of NAFLD than the others. In addition, using different definitions of MetS can make comparison between studies difficult given the likely variations between them. And to date, prevalence of the metabolic features of MetS has not been studied in patients with NAFLD in Manitoba.

Purpose: To measure the prevalence of the MetS based on modified WHO (excluded microalbuminuria), NCEP/ATP-III, IDF, AACE and AHA/NHLBI in NAFLD cohort and to compare the association of different MetS definitions with NAFLD diagnosis. We will also estimate the prevalence of obesity, diabetes, hypertension, and dyslipidemia, in the NAFLD patient population in Manitoba.

Methods: A retrospective review of a clinical database containing demographic, laboratory, and histologic findings of adult NAFLD patients was undertaken. The diagnosis of NAFLD was made by hepatologists on the basis of liver imaging or biopsy compatible with fatty liver; the clinical presence of ≥ 1 feature of MetS with or without abnormal liver enzymes and chronic alcohol consumption ≤ 20 g/day. Those with concurrent liver diseases were excluded.

Result(s): A total of 463 patients were classified as NAFLD patients. The five components of metabolic syndrome were available in all subjects. The prevalence of the MetS as defined by modified WHO, NCEP/ATP-III, IDF, AACE, Harmonized criteria and AHA/NHLBI were 88% (407/463), 60% (277/463), 53% (244/463), 32% (148/463), 67% (310/463), 60% (277/463) respectively. MetS defined by modified WHO was closely associated with NAFLD as compared to other definitions in the study cohort (p < 0.001). The prevalence was higher in older adults and increased BMI ranging from 20% in normal weight subjects to 96% in obese patients. Fleiss’ kappa showed that there was fair agreement between the six MetS definition, κ = 0.367 (95% CI, 0.34–0.39), p < 0.005. The most prevalent MetS component was dyslipidemia (83%), followed by obesity (62%), hypertension (61%) and diabetes (57%) using the modified WHO criteria.

Conclusion(s): The level of agreement between the six MetS criteria in NAFLD patients appears to be low. The modified WHO criteria performed better than the other five definitions and is recommended for screening of the MetS in persons with NAFLD.

References

1Dietrich P, Hellerbrand C. Non-alcoholic fatty liver disease, obesity and the metabolic syndrome. Best Pract Res Clin Gastroenterol. 2014;28(4):637–653. https://doi.org/10.1016/j.bpg.2014.07.008

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2Yang S, Kwak S, Lee J-H, Kang S, Lee S-P. Nonalcoholic fatty liver disease is an early predictor of metabolic diseases in a metabolically healthy population. Vespasiani-Gentilucci U, ed. PLOS ONE. 2019;14(11):e0224626. https://doi.org/10.1371/journal.pone.0224626

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P027 Prospective study of non-alcoholic fatty liver disease in community-based First Nations and Caucasian populations

J Uhanova^1,*, B Beardy², GY Minuk¹, A Oketola¹, L Wood Ducharme², D Surina¹

¹Internal Medicine, University of Manitoba

²Four Arrows RHA, Winnipeg, Canada

Background: Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most common cause of chronic liver disease worldwide. NAFLD-cirrhosis or NAFLD-hepatocellular carcinoma (HCC) are now the second cause of liver transplantation in the USA. Although NAFLD is a significant contributor to liver-related morbidity and mortality, there are few studies describing its true prevalence. Thus far, no research has documented the community-based burden and severity of NAFLD in Canada or in the Canadian Indigenous populations. University of Manitoba, together with the Four Arrows Regional Health Authority (FARHA) is conducting a 5-yr. study of NAFLD in Anishininew communities of Island Lake and in a largely Caucasian community of Winkler MB.

Purpose: This study is designed to document the 5-year incidence, prevalence, severity and short-term outcomes of NAFLD in the community-based Indigenous and non-Indigenous populations in a Canadian province of Manitoba.

Methods: As the first stage of this research, the prevalence of NAFLD among adult populations (≥ 18 yrs.) was documented by conducting cross-sectional surveys of similarly sized Indigenous and non-Indigenous communities using portable ultrasound. Other/additional causes of liver disease were excluded. Clinical assessment of the severity at diagnosis included liver stiffness testing by FibroScan, risk factors for disease progression, and metabolic comorbidities.

Result(s): 1,708 participants are enrolled to date, 841 First Nations and 867 non-First Nations. The overall prevalence of NAFLD was 54%. The prevalence was 45% in a Caucasian and 65% in Anishininew communities.

The mean body mass index was 34.7±12.5 kg/m² among participants with NAFLD and 27.2±4.6 kg/m² among those without NAFLD. Most of the NAFLD patients were obese (74%) vs. 28% among those without steatosis on screening ultrasound, while 6% of persons with low or normal BMI had NAFLD.

Table P027: Baseline clinic-demographic characteristics of participants.

Characteristics	Anishininew participants		Caucasian participants
Characteristics	NAFLD	No NAFLD	NAFLD	No NAFLD
Females	63%	40%	66%	67%
NAFLD, Females	74%		44%
NAFLD, Males	54%		45%
Mean age, yrs.	44±15	35±14	55±15	51±12
Mean BMI	34.7±12.5	27.2±4.6	32.1±11.0	27.0±5
Waist/Hip Ratio	1.0±0.1	0.97±0.1	0.99±0.1	0.85±0.1
Obesity	76%	28%	75%	22%
Type 2 diabetes	35%	14%	16%	5.2%
Hypertension	32%	24%	36%	21%
Dyslipidemia	15%	11%	26%	13%
Sleep Apnea	7.1%	3.6%	16%	4.4%
Metabolic Syndrome	2.0%	1.1%	0.8%	--
Fibroscan score > F0-1	22%		16%
Elevated ALT	37%		27%
- ALT> 2xULN	9%		4%
Elevated AST	23%		10%
- AST> 2xULN	4.0%		0.7%
APRI ≤ 0.45	87%		91%
APRI≥ 1.5	2%		1%
FIB-4 < 1.45	89%		85%
FIB-4> 3.251.45	0.8%		2.3%

Conclusion(s): Overall, the majority of community-based participants had uncomplicated NAFLD. The risk profiles for NAFLD are somewhat different for Indigenous vs. Caucasian participants. The prevalence of NAFLD in Indigenous communities may be higher than expected due to higher prevalence of certain risk factors, such as diabetes.

References

1Younossi ZM, Marchesini G, Pinto-Cortez H, Petta S. Epidemiology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: Implications for Liver Transplantation. Transplantation 2019; 103 (1):22–27.

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P028 Deep learning algorithms for long-term risk stratification in liver transplant recipients

O Nitski¹, ², A Azhie^3,*, FA Qazi Arisar³, ⁴, X Wang¹, S Ma⁵, L Lilly³, ⁶, KD Watt⁷, J Levitsky⁸, S Asrani⁹, D Lee⁶, ¹⁰, ¹¹, ¹², B Rubin¹, ⁶, M Bhat³, ⁴, ⁶, ¹³, B Wang¹, ⁵, ¹⁴, ¹⁵

¹Peter Munk Cardiac Centre, University Health Network

²Faculty of Applied Science and Engineering, University of Toronto

³Multi Organ Transplant Program, University Health Network

⁴Division of Gastroenterology & Hepatology

⁵Department of Computer Science

⁶Faculty of Medicine, University of Toronto, Toronto, Canada

⁷Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester

⁸Northwestern University Feinberg School of Medicine, Chicago

⁹Baylor University Medical Center, Dallas, United States

¹⁰Peter Munk Cardiac Centre, University Health Network

¹¹Ted Rogers Centre for Heart Research

¹²Institute for Clinical Evaluative Sciences

¹³Institute of Medical Sciences, University of Toronto

¹⁴Vector Institute

¹⁵Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

Background: Despite improvements in short-term outcomes, long-term survival of liver transplant recipients beyond one year is significantly compromised by an increased risk of cancer, cardiovascular mortality, infection and graft failure. Transplant follow-ups provide a steady stream of information that may have predictive power in determining the probability and nature of approaching mortality. Recent advances in artificial intelligence (AI) make it possible to infer the patterns in massive amounts of longitudinal follow-up data that are most indicative of risk. The goal of our study was to develop interpretable and effective AI models to predict the risk of post-transplant mortality, broken down by the major causes of post-transplant mortality.

Purpose: To assess the ability of deep learning algorithms using longitudinal data to predict complications resulting in death after liver transplantation (LT) over multiple timeframes, in comparison to logistic regression (LR) models.

Methods: We trained and evaluated various AI architectures, on 42,146 liver transplant recipients from the Scientific Registry of Transplant Recipients (SRTR) database to make predictions of 1-year and 5-year outcome probability, at each follow-up, in 5 categories - graft failure, infection, cardiac related death, cancer, as well as survival. Transferability of the model was further evaluated by fine-tuning on local dataset from University Health Network, Canada, (N = 3,269 LT recipients) These AI architectures included recurrent Neural Network variations, Transformers, and Temporal Convolutional Networks. Hyper-parameter search was performed with cross-validation to improve the effectiveness of the AI models. We further developed a novel interpretable mechanism to automatically assign importance to each variable in the input data and therefore identify risk factors for post-liver transplant mortality.

Result(s): Best performance was achieved using a Temporal Convolutional Network, a novel AI model with temporal convolutions over longitudinal data, with an average AUC of 0.804, 99% CI [0.795, 0.854] for 1-year outlook and an average AUC of 0.733, 99% CI [0.729, 0.769] for 5 year outlook in the SRTR dataset. In the UHN dataset, the top deep learning AUROC was 0.807, 99% CI [0.795, 0.842] (1 year) and 0.722, 99% CI [0.705, 0.764] (5 years). AUROCs ranged from 0.695 for 5-year infection death to 0.859 for 1-year graft failure. Sensitivity analysis was performed on the model to determine the most which inputs lead to higher or lower probabilities of each of the outcome classes. The model is capable of producing a probability for each of the clinical outcomes within both timeframes to guide a clinician’s decision making. Moreover, the model was able to provide a list of ranked features including modifiable risk factors for the four major causes of post-transplant mortality.

Conclusion(s): Our machine learning models are able to effectively predict the risk of the major causes of post-liver transplant mortality (cardiovascular, cancer, graft failure and infection) in the largest liver transplant registry (SRTR) which was further validated in a local dataset (UHN). Such predictive models could serve as early warning systems, advising a clinician on performing further investigations and implementing preventive care strategies based on the ranked features for each outcome.

P029 Splenomegaly in HIV-monoinfected patients is a marker of significant chronic liver disease and is associated with endoscopic evidence of portal hypertension

A Benmassaoud^1,*, D Kablawi¹, AS Al Hinai¹, P Wong¹, M Deschenes¹, G Sebastiani¹

¹Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Canada

Background: Chronic liver disease is the second cause of morbidity and mortality in patients living with HIV (PLWH). Despite that, splenomegaly is often attributed to hematological, or infectious complications, especially in those without HCV or HBV co-infection.

Purpose: Given the changing landscape of the HIV epidemic, including a high frequency of nonalcoholic fatty liver disease, our aim was to evaluate the degree of liver disease and portal hypertension in those presenting with splenomegaly.

Methods: This is a cross-sectional retrospective analysis of a prospective cohort study assessing LIVEr disease in HIV (LIVEHIV) with baseline transient elastography (TE). We included all individuals from the LIVEHIV cohort with available abdominal imaging within 2 years of baseline TE. Those with unreliable TE were excluded. Cases were defined as presence of splenomegaly on abdominal imaging, while control had a normal spleen. Hepatic fibrosis was assessed using liver stiffness measurement (LSM). Endoscopic portal hypertension (PHTN) was defined as the presence of varices or portal hypertensive gastropathy on gastroscopy. HIV-monoinfected were analyzed separately. Two-tailed p-value below 0.05 was considered significant.

Result(s): 331 PLWH were included (mean age 51.3 years, 76.1% males, 32.6% HCV co-infected). Splenomegaly was present in 16.6% of patients. Patients with splenomegaly had longer HIV duration (20.1 vs 14.7 years, p < 0.001), were less likely to be mono-infected (29.1% vs 58.0%, p < 0.001), more likely to be Caucasian (80.0% vs 51.4%, p = 0.012), less likely to be dyslipidemic (16.4% vs 32.2%, p = 0.018), had lower CD4 count (467 vs 678, p = 0.003) and lower platelets (121 vs 202, p < 0.001). PLWH with splenomegaly had higher LSM values compared to those without (LSM> 10 kPa: 25.9% vs 9.3%, p = 0.009; LSM > 21kPa: 14.8% vs 1.8%, p < 0.001). This was also the case in HIV mono-infected patients (LSM > 10kPa: 27.3% vs 6.6%, p = 0.01, LSM> 21kPa: 18.2% vs 0.7%, p < 0.001). Patients with splenomegaly had also more frequent endoscopic findings of PHTN compared to those without splenomegaly (14.5% vs 2.4%, p = 0.031). This finding remained significant after adjusting for age and HCV co-infection status (OR 4.48, 95% CI 1.04–19.33).

Conclusion(s): Splenomegaly in PLWH suggests the presence of chronic liver disease and is associated with endoscopic evidence of portal hypertension independently of HCV co-infection status. Its presence should prompt TE examination and possibly referral to Hepatology for further assessment.

P030 Comparison of liver-related outcomes in PSC-IBD versus PSC alone

A Fetz^1,*, K Donaldson², D Chahal², H Bedi¹, B Salh², HH Ko²

¹Medicine

²Gastroenterology, University 0f British Columbia, Vancouver, Canada

Background: Inflammatory bowel disease associated with primary sclerosing cholangitis (PSC-IBD) has been characterized by an increased risk of colorectal cancer. However, evidence for its role in liver-related outcomes is conflicted.

Purpose: The objective of this study is to assess whether PSC-IBD patients had higher rates of liver transplantation, hepatobiliary (HPB) cancers, and all-cause mortality compared to those with primary sclerosing cholangitis (PSC) alone, and to examine factors that are associated with worst liver-related outcomes.

Methods: A retrospective analysis of patients with PSC-IBD and PSC at two large Canadian tertiary centres was completed. Baseline characteristics at initial assessment including demographics, clinical, laboratory, and imaging characteristics, along with liver-related outcomes and mortality, were collected. A composite outcome of liver transplants, hepatobiliary (HPB) cancers, and all-cause mortality was compared.

Result(s): 165 patients were included in this study. 70 patients were female (PSC-IBD 43, 38.7%; PSC 27, 50.0%; p = 0.170). The mean age of PSC diagnosis was 37.1 (range 10 to 79) and 43.6 (range 9 to 73) years in the PSC-IBD and PSC groups, respectively (p = 0.0234). The risk of liver transplants, HPB cancers, and all-cause mortality was greater in the PSC-IBD group compared to the PSC group (RR 1.61, 95% CI 1.17 to 2.17). The PSC-IBD group trended towards higher individual outcomes. Mean time to the composite outcome was 9.15 (SD 9.58) and 8.51 (SD 10.6) years in the PSC-IBD and PSC groups, respectively (p = 0.582). Death in the PSC group tended to occur closer to the time of PSC diagnosis compared to the PSC-IBD group (PSC-IBD 10.9 years, SD 12.8; PSC 4.50 years, SD 2.93; p = 0.0494). In the PSC-IBD group, higher rates of the composite outcome were seen in patients who were diagnosed with PSC after the age of 40 (p = 0.003), with undifferentiated IBD (p = 0.008), and higher bilirubin (p = 0.005) and lower platelets (p = 0.004) at their first visit.

Conclusion(s): PSC-IBD appears to be associated with increased rates of liver transplantation, hepatobiliary cancers, and all-cause mortality compared to PSC alone. Being diagnosed with PSC after age 40, having undifferentiated IBD, a higher bilirubin and lower platelet count at the initial visit may be associated with worst liver-related outcomes in PSC-IBD patients.

P031 Assessing the prevalence of risk factors for osteoporosis and rate of screening by DEXA scan in patients referred for liver transplant evaluation

A France^1,*, J Kirk², MK Dokus², B Al-Judaibi², M Laryea²

¹Internal Medicine

²Gastroenterology and Hepatology, University of Rochester Medical Center, Rochester, United States

Background: Osteoporosis (OP) and fragility fractures are well-known complications of both chronic liver disease (CLD) and transplant, with a significant increase in the prevalence of fractures in the first several months after liver transplant (LT).

Purpose: The objectives of this quality improvement project were to assess whether patients with CLD are appropriately screened for OP at the primary care level, to determine the prevalence of additional risk factors for bone loss in pre-liver transplant patients and to ascertain whether systematic screening for low bone mineral density (BMD) should be a routine component of LT evaluation.

Methods: A retrospective chart review was performed of patients referred for LT evaluation at a large academic medical center from July 20 - November 5, 2020. Baseline characteristics including etiology of CLD, risk factors for OP, history of fractures and prior screening for low BMD with DEXA scans were reviewed. Assessment of nutritional and lifestyle risk factors was conducted by the transplant dietician.

Result(s): The median age for our population was 59 years; 48% of the population was female, and the most common reason for liver transplant evaluation referral was alcoholic cirrhosis. Of 84 patients referred for LT evaluation, 17 (20.2%) had a DEXA scan to screen for low BMD. Among the 17 patients with DEXA scans, 5 had osteopenia and 2 had OP. Three of those 7 were prescribed Vitamin D. Seventy-six patients (90%) had at least one risk factor for OP other than CLD. In the 47 patients that had 2 or more risk factors, 13 (28%) had a DEXA scan. The median MELD-Na score was 17. Of the 24 patients with MELD < 15, 8 had a DEXA scan compared with 8/48 patients with MELD 15-25 and 1/12 patients with a MELD > 25.

Conclusion(s): The low rate of screening for OP in this high risk population highlights a gap in the care of patients with advanced CLD. Even patients with multiple other risk factors for OP have a low rate of screening. Given the known impact of LT on bone density and the morbidity associated with fragility fractures, there is need for increased education about the risks of low BMD in patients with CLD at the primary care level bone density, and BMD assessment should be a routine part of the transplant evaluation.

References

1Kanis JA, on behalf of the World Health Organization Scientific Group (2007) Assessment of osteoporosis at the primary health care level. Technical Report. World Health Organization Collaborating Center for Metabolic Bone Diseases. University of Sheffield, UK

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P032 Comparison of baseline characteristics and improvement in disease manifestations following treatment with sebelipase alfa in patients with lysosomal acid lipase deficiency with and without cirrhosis

M Francis^1,*, K Furuya², F Abel³, E Aigner⁴, Q Dong⁵, J Quintero Bernabeu⁶, V Ratziu⁷, M Zharkova⁸, R Kohli⁹

¹*Presenter, Medical Affairs, Alexion Pharma Canada, Vaughan, Canada

²Madison School of Medicine and Public Health, University of Wisconsin, Madison, United States

³Global Medical Affairs, Alexion Pharmaceuticals, Inc., Boston, United States

⁴Paracelsus Medical University Salzburg, Salzburg, Austria

⁵Alexion Pharmaceuticals, Inc., Boston, United States

⁶Vall d’Hebron Hospital, Barcelona, Spain

⁷Hospital Pitié-Salpêtrière, Institute of Cardiometabolism and Nutrition, Sorbonne Universités, Paris, France

⁸I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation

⁹Children’s Hospital Los Angeles and Keck School of Medicine at USC, Los Angeles, United States

Background: The efficacy and safety of sebelipase alfa (SA), the only approved treatment for lysosomal acid lipase deficiency (LAL-D), in cirrhotic patients is unknown.

Purpose: We compared demographic and disease characteristics before and after SA treatment in patients with LAL-D with vs without biopsy-proven cirrhosis at baseline.

Methods: Data were pooled from 4 cl inical trials of SA (CL01, NCT01307098; CL02, NCT01757184; CL04, NCT01488097; CL06, NCT02112994). Efficacy and safety were assessed by baseline cirrhosis status.

Result(s): Of 62 patients with Ishak stage determined on liver biopsy, 18 had cirrhosis. Median age at first LAL-D manifestation in patients with vs without cirrhosis was 3.4 vs 8.1 y (P < 0.05); median age at diagnosis was 7.1 vs 10.6 y. 50% of patients with and 11 % without cirrhosis were Hispanic/Latino (P < 0.05). 44% of patients with and 84% without cirrhosis had the c.894G> A or E8SJM (exon 8 splice junction mutation) LIPA mutation (P < 0.05). Median time to diagnosis from onset of first LAL-D manifestation was 3.1 vs 1.7 y for those with vs without cirrhosis. Median z scores for height, weight, and body mass index did not differ between groups. Baseline high-density lipoprotein cholesterol (HDL-C) levels were within the normal range for 17% of patients with vs 48% without cirrhosis (P < 0.05). Baseline spleen volume was significantly higher and liver fat content was significantly lower in those with cirrhosis (Table). SA generally led to similar improvements in liver and lipid parameters in patients with vs without cirrhosis (Table). Most treatment-emergent adverse events (TEAEs) were similar in the 2 groups; however, there was a higher rate of upper respiratory tract infections in those with vs without cirrhosis (94% vs 70%). No patient with and 1 patient without cirrhosis experienced treatment-related serious TEAEs (2 moderate-severity anaphylactic reactions, which resolved).

Conclusion(s): Patients with cirrhosis from LAL-D have more severe manifestations, are affected earlier in life, and are diagnosed at a younger age than those with LAL-D and without cirrhosis. Cirrhosis is associated with a greater spleen volume; however, SA decreases spleen volume, without changes in spleen fat content, suggesting an improvement in portal hypertension. Patients with cirrhosis who received SA also had significant improvements in alanine aminotransferase, HDL-C, and low-density lipoprotein cholesterol levels; thus, SA leads to physiologically meaningful improvements in patients with cirrhosis from LAL-D.

P033 Outcomes of liver transplantation with donation after circulatory death following medical assistance in dying: first report in Canada

J Glinka^1,*, A Skaro¹, M Brahmania², G Jada¹, A Teriaky², D Quan¹, K Qumosani², E Tang¹

¹General Surgery - Multi Organ Transplant Unit

²Department of Medicine; Division of Gastroenterology & Hepatology, Western University, London, Canada

Background: In 2016, Canadian federal legislation passed a regulatory framework for medical assistance in dying (MAiD) for individuals suffering from a medically intractable condition and foreseeable death. Patients eligible for MAiD began to initiate requests to become organ donors, prior to proceeding with MAiD. These requests created an unprecedented situation in the North American context to increase the donor pool in a manner that has only recently become acceptable in organ procurement programs.

Purpose: Study the results using DCD-MAiD liver grafts for transplantation.

Methods: The data for this retrospective study came from a prospectively collected database housed in the London Health Science Centre (LHSC) Multi-Organ Transplant Program (MOTP). The study population encompasses all patients that received a first LT from a MAiD Donor after Circulatory Death (DCD) at LHSC University Hospital since the legislation has been enacted. In our analysis, we considered the following: donor and recipient characteristics, perioperative outcomes, short and long-term graft function, and other transplant-related outcomes.

Result(s): A total of 6 patients with end-stage neuromuscular disorder were accepted as DCD donors following MAiD. The mean donor age was 47.6 years (25–59); time to arrest was < 6 minutes in all cases; warm ischemic time (WIT) of 11.8 minutes (11–14); and cold ischemic time (CIT) of 5 hrs (3.19–5:51). The recipient age was 46.6 years (19–66); MELD-Sodium was 21.5 (15–28); 50% had NASH cirrhosis. No reperfusion syndrome or perioperative vascular complications were observed. Trends for ALT, ALP, Bilirubin and INR within the first 7 days are illustrated in Figure 1. 50% (n = 3) patients met biochemical criteria for EAD, without immediate clinical implications. One patient developed a biliary anastomotic stricture 6 months after LT, with no cases of ischemic cholangiopathy. Patient and graft survival at 1 year were 100%.

Conclusion(s): Organ procurement after MAiD can safely augment organ availability. Minimizing warm and cold ischemia allowed for expansion into upper age strata previously associated with poor DCD outcomes. Consensus medical-ethical frameworks to facilitate the broader application of MAiD donation to other jurisdictions could help to address the challenge of organ scarcity.

References

1Downar J, Shemie SD, Gillrie C, Fortin M-C, Appleby A, Buchman DZ, et al. Deceased organ and tissue donation after medical assistance in dying and other conscious and competent donors: guidance for policy. CMAJ. 2019 Jun 3;191(22):E604–13.

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3Allard J, Fortin M-C. Organ donation after medical assistance in dying or cessation of life-sustaining treatment requested by conscious patients: the Canadian context. J Med Ethics. 2017 Sep;43(9):601–5.

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4Tun-Abraham ME, Wanis KN, Garcia-Ochoa C, Sela N, Sharma H, Al Hasan I, et al. Can we reduce ischemic cholangiopathy rates in donation after cardiac death liver transplantation after 10 years of practice? Canadian single-centre experience [Internet]. Vol. 62, Canadian Journal of Surgery. 2019. p. 44–51. https://doi.org/10.1503/cjs.012017

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P034 Durability of biochemical improvements through 6 years of open-label treatment with obeticholic acid in patients with primary biliary cholangitis who did not achieve the POISE criteria

G Hirschfield^1,*, M Carbone², DE Jones³, BE Hansen⁴, AE Kremer⁵, M Trauner⁶, E Smoot Malecha⁷, L MacConell⁷

¹Toronto Centre for Liver Disease, University Health Network, Toronto, Canada

²Center for Autoimmune Liver Disease, University of Milano Bicocca, Milan, Italy

³Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom

⁴HPME, University of Toronto, Ontario, Canada

⁵Department of Medicine I, Friedrich-Alexander-University, Erlangen, Germany

⁶Department of Medicine III, Medical University of Vienna, Vienna, Austria

⁷Intercept Pharma, San Diego, United States

Background: In various clinical studies and in daily clinical practice, response to primary biliary cholangitis (PBC) treatment has been assessed using dichotomous biochemical response criteria. Although achieving these response criteria may be associated with improved clinical outcomes, the benefit in patients who have an incomplete response to treatment may be underestimated.

Purpose: The objective of this analysis was to assess the extent and durability of obeticholic acid (OCA) in patients with PBC who did not achieve the dichotomous primary endpoint criteria in the phase 3 POISE study through 72 months of OCA treatment.

Methods: Key inclusion criteria included PBC diagnosis, alkaline phosphatase (ALP) ≥ 1.67× upper limit of normal (ULN) and/or total bilirubin > ULN to < 2× ULN, and on a stable dose of—or intolerant of—ursodeoxycholic acid. During the 12-month double-blind phase, 216 patients were randomized to daily placebo, OCA 5-10 mg, or OCA 10 mg. This analysis pooled double-blind placebo (OCA baseline was open-label extension [OLE] day 0) and double-blind OCA patients to evaluate the efficacy and safety of up to 72 months of OCA treatment. This analysis excludes patients who achieved the POISE primary endpoint (ALP < 1.67× ULN, with a reduction of ≥ 15% from baseline, and total bilirubin ≤ULN) 12 months from OCA baseline. Values shown are mean (standard deviation) unless otherwise specified. P values were based on paired t-tests.

Result(s): One hundred ninety-three patients enrolled in the OLE, of whom 107 patients (55%) did not achieve the POISE criteria after 12 months of OCA treatment. Patients were 93% female, 91% Caucasian, 56 (10) years of age at baseline, and 91% received ursodeoxycholic acid (15 [4] mg/kg/day). At baseline, ALP was 356 (138) U/L and total bilirubin was 13 (8) μmol/L (elevated above ULN in 18 patients [17%]). Despite not achieving the POISE criteria after 12 months of OCA, a significant and durable reduction was observed in ALP (p < 0.01 at all time points) through the duration of 72 months of treatment (Figure 1). Total bilirubin levels remained stable and near baseline values within the normal range through the duration of treatment. Throughout the 6-year study period, the most commonly occurring adverse events were pruritus (92 patients [86%]) and fatigue (33 patients [31%]), consistent with previous reports from POISE and expected PBC symptoms.

Conclusion(s): Despite the fact that these patients did not achieve the POISE primary endpoint, significant and sustained biochemical improvements were observed.

P035 Post hoc analysis in patients with unresectable hepatocellular carcinoma who progressed to Child-Pugh B liver function in the phase 3 REFLECT study of lenvatinib

J Huynh^1,*, MT Cho¹, E J-H. Kim¹, M Ren², C Robbins³, C Amaya-Chanaga², A Vogel⁴

¹University of California Davis Comprehensive Center, Sacramento

²Eisai Inc.

³Formerly of Eisai Inc., Woodcliff Lake, United States

⁴Hannover Medical School, Hannover, Germany

Background: The treatment landscape for patients (pts) with unresectable hepatocellular carcinoma (uHCC) has recently expanded. However, there is an unmet need for effective treatment options in Child-Pugh B (CPB) pts. Lenvatinib (LEN) is approved first-line in uHCC based on the REFLECT study (Child-Pugh A [CPA] pts were allowed, per inclusion criteria). In a prior analysis of REFLECT, pts treated with LEN benefited irrespective of baseline liver function (ALBI grade 1 or 2; Child-Pugh score 5 or 6).

Purpose: To determine outcomes in pts with reduced liver function, we report a post hoc analysis of key efficacy and safety results in LEN-treated pts from REFLECT who progressed to CPB and those who did not within the first 8 weeks of treatment.

Methods: In REFLECT, pts with uHCC were randomized 1:1 to LEN (per bodyweight: 12 mg/day for ≥ 60 kg; 8 mg/day for < 60 kg) or sorafenib (400 mg twice daily) in 28-day cycles. This analysis assessed ORR. Landmark analyses (starting at week 8) of PFS, time-to-progression (TTP), and OS in CPB pts and in pts who remained CPA at 8 weeks post-randomization were also conducted. Tumors were assessed by mRECIST by independent imaging review.Safety was also assessed from baseline.

Result(s): This subgroup analysis included LEN-treated pts (n = 60) who progressed to CPB within the first 8 weeks of treatment (CPB pts) and 413 pts who did not (CPA pts). At baseline, 26.7% and 73.1% of pts had an ALBI grade of 1 and 73.3% and 26.9% of pts had an ALBI grade of 2 in CPB and CPA pts, respectively. ORR was 28.3% (95% CI 16.9–39.7) for CPB pts and 42.9% (95% CI 38.1–47.6) for CPA pts. A landmark analysis showed a median PFS of 3.7 mos (95% CI 1.8–7.4) for CPB pts and 6.5 mos (95% CI 5.6–7.4) for CPA pts from the week 8 timepoint. Landmark analyses at week 8 also showed that the median TTP was 5.6 mos (95% CI 3.5–9.3) for CPB pts and 7.3 mos (95% CI 5.6–7.4) for CPA pts; the median OS was 6.8 mos (95% CI 2.6–10.3) for CPB pts and 13.3 mos (95% CI 11.6–16.1) for CPA pts per week 8 landmark analyses. As expected, efficacy appeared to be greater in CPA pts versus CPB pts; however, OS of 6.8 months in CPB pts after the week 8 landmark is notable. Moreover, median duration of treatment was 3.2 mos for CPB pts and 6.9 mos for CPA pts, thereby suggesting CPB pts can remain on LEN. The incidence of grade ≥ 3 treatment-related AEs (TRAEs) was 71.7% in CPB pts and 54.7% in CPA pts. TRAEs leading to discontinuation occurred in 18.3% of CPB pts and 7.5% of CPA pts.

Conclusion(s): In this post hoc analysis of pts in REFLECT, we examine the key efficacy and safety results for LEN-treated pts who progressed to CPB by week 8. This post hoc analysis is limited by its descriptive nature; however, the results indicate that further study of LEN in CPB pts with uHCC is warranted.

P036 Patterns of disease in patients with primary biliary cholangitis across the United States: the LabCorp experience

M Ismail^1,*, S Roberts¹, F Mittermayer², C Filozof³, B Hansen¹, G Hirschfield¹

¹TCLD, University of Toronto, Toronto, Canada

²Covance, Covance, Vienna, Austria

³Covance, Covance, Madrid, Spain

Background: Primary biliary cholangitis (PBC) is a progressive autoimmune liver disease. We sought insights into disease trends and severity over 8 years (November 2011 to March 2020), agnostic to treatment data, using lab values drawn across a large provider, LabCorp Labs, USA.

Purpose: To seek insights into disease trends and severity over 8 years from November 2011 to March 2020 in a US population.

Methods: Anonymised data was acquired from LabCorp Labs electronic records. PBC was defined by the presence of both an ICD-10 code (K74.3) and a positive anti-mitochondrial antibody test. Patients with impossible values or on tacrolimus or without an AMA positive test were excluded. Data are reported as mean and SD; analysis used the chi-square test and regression models.

Result(s): A cohort of 9721 patients with AMA positivity and an ICD-10 code of PBC was identified. The cohort was predominantly female (87.7%). The mean age at first AMA positive sample was 59.9 years (12.8). Mean alkaline phosphatase (ALP) was 221 IU/L (SD: 186; ULN = 117), with 39.4% of patients having an ALP > 1.67 x ULN; mean aspartate aminotransferase was 56 IU/L (SD:63; ULN = 40), mean alanine aminotransferase was 59.5 IU/L (SD:77; ULN: males = 45, females = 33), and mean platelets were 246 x10⁹/L (SD:94.8; LLN = 150). Overall, 11.8% of the cohort had moderately advanced-advanced PBC by Rotterdam criteria. 22.4% of men had moderately advanced-advanced stage disease compared to 10.4% of women (p < 0.0001). The majority (64%) of patients had a PBC globe score < 0.3; women had significantly lower globe scores compared to men (mean –0.0413 (SD:1.17) vs 0.352 (SD:1.22), p < 0.0001). Patients identified as from Northeastern USA had better lab values overall. Changes in age and sex at first AMA positive sample were observed over calendar years. The mean age in 2012 was 57(11.7) years compared to 61.9 (12.9) years in 2019 (p < 0.0001). The proportion of men increased from 9.2% in 2012 to 13.2% in 2019 (p < 0.0001) (Figure 1). In patients with repeated lab measurements (N = 9339, median follow-up time 32 months), there was a significant decline in mean ALP from 223 (187) to 159 (125) IU/L (p < 0.0001) and the percentage of patients with an ALP > 1.67x ULN declined to 20.7%.

Conclusion(s): Large agnostic laboratory datasets facilitate insights into patterns of disease severity for patients with PBC, and identify relevant changes in demographics (age and sex) over time. This supports previous findings in a European cohort.

P037 Dynamic risk profile of hepatocellular carcinoma recurrence after curative intent liver resection

T Ivanics¹, ^2,*, CF Murillo Perez¹, ¹, ³, ⁴, M Claasen¹, ⁵, M Patel¹, G Morgenshtern⁶, ⁷, ⁸, L Erdman⁶, L Rajendran⁹, G O’Kane¹⁰, B Hansen¹, ¹¹, S Cleary¹², G Sapisochin¹, ¹³

¹University Health Network, Toronto, Canada

²Henry Ford Hospital, Detroit, United States

³Toronto Centre for Liver Disease, Toronto Western & General Hospital, University Health Network

⁴Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada

⁵Department of Surgery, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, Netherlands

⁶Department of Computer Science, University of Toronto

⁷Genetics & Genome Biology, The Hospital for Sick Children

⁸Vector Institute, University of Toronto

⁹Division of General Surgery, University Health Network

¹⁰Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre

¹¹University of Toronto, Toronto, Canada

¹²Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, United States

¹³Department of Surgery, University Health Network, Toronto, Canada

Background: Following liver resection (LR) for hepatocellular carcinoma (HCC), the likelihood of survival is dynamic, in that multiple recurrences and/or metastases are possible, each having variable impact on outcomes.

Purpose: We sought to evaluate the natural progression, pattern, and timing of the various disease states after LR for HCC using multi-state modeling and to create a practical calculator to provide prognostic information for patients and clinicians.

Methods: Adult patients undergoing LR for HCC between Jan-2000 and Dec-2018 were retrospectively identified at a single center. Multistate data analysis was employed to model post-LR tumor progression by describing transitions between distinct disease states. In this model, the states included surgery, local recurrence(1^st,2^nd,3^rd,4^th,5^th), distant metastasis with or without local recurrence, and death.

Result(s): Of the 486 patients included, 169(34.8%) remained recurrence-free, 205(42.2%) developed local recurrence, 80(16.5%) developed distant metastasis, and 32(7%) died. For an average patient having undergone LR, there was a 33.1% chance of remaining disease-free,31.0% of at least one local recurrence,16.3% chance of distant metastasis, and 19.8% chance of death within the first 60-months post-LR. The transition probability from surgery to first local recurrence, without a subsequent state transition, increased from 3%(3-months), to 17.4%(30-months), and 17.2%(60-months). Factors that could modify these probabilities included tumor number, size, satellite lesions, and microvascular invasion.

Probability of making a transition and reaching each state over the first 5 years from the a) surgery state (post–curative intent surgery) b) first local recurrence state

Conclusion(s): In contrast to standard single time-to-event estimates, multistate modeling provides more realistic prognostication of outcomes after LR for HCC by taking into account many postoperative disease states and transitions between them. Our multistate modeling calculator can provide meaningful data to guide the management of patients undergoing postoperative surveillance and therapy.

P038 Outcomes of incidental cholangiocarcinoma in liver transplant patients with primary sclerosing cholangitis

LJ. James^1,*, T Kulai², M McLeod³, K Peltekian², EM Yoshida⁴, J Zhu²

¹Gastroenterology

²Gastroenterology/Hepatology

³IInternal Medicine/Hepatology, Dalhousie University, Halifax

⁴Gastroenterology/Hepatology, University of British Columbia, Vancouver, Canada

Background: Primary sclerosing cholangitis (PSC) is a predisposing factor for cholangiocarcinoma (CCA). Patients with CCA have poor outcomes post-transplant. Intrahepatic CCA is difficult to detect pre-operatively in cirrhosis. Few outcomes are reported among PSC transplant patients where CCA was incidental.

Purpose: To determine the incidence of incidental CCA (iCCA) in PSC liver explants and the impact of iCCA on post-transplant survival for patients with PSC.

Methods: This was a retrospective cohort study in which the medical records of PSC patients who underwent transplant at QEII Health Sciences Center in Halifax between January 1987 to March 2020 were reviewed. The incidence of iCCA was calculated. Survival analysis was performed to determine the mean time to survival among iCCA and non-iCCA groups.

Result(s): A total of 94 patients were transplanted for PSC during the study period. The mean age was 43 years. Twenty-six percent were women and 74% were men. Three were iCCA, one hilar and two intrahepatic CCA. All iCCAs occurred prior to 2008.

All iCCA patients had contrast enhanced CT, ERCP with cholangiogram and MRI. Two of the ERCPs reported CBD related strictures and the brushings had no evidence of malignancy. CA19-9 level was measured in one and reported as normal. Contrast enhanced MRI was not available prior to 2007.

The PSC patients had 1, 5, and 10-year survival rates of 93.8%, 88.6% and 81.9% respectively. One patient required re-transplant for graft failure and died within 3 months post-transplant due to complications. In all other cases the cause of death was not identified.

Among patients with iCCA, two deaths were due to metastatic cholangiocarcinoma and the other due to surgical complication in the immediate post-transplant period. None survived beyond 2 years.

Conclusion(s): Observed PSC survival in this cohort was above national average in the same period. The 3 iCCA cases identified occurred before the availability of contrast enhanced MRI. Patients with iCCA and liver transplant had poor survival at 1 and 2 years. There were no iCCA identified after 2007. These findings suggest incidental cholangiocarcinoma was effectively reduced by the advent of high-resolution imaging modality, and improvements in pre-transplant screening, including tumor marker CA19-9 and stringent patient selection. Further study involving multiple centres is necessary to draw a definite conclusion.

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1Song J, et al. “Cholangiocarcinoma in Patients with Primary Sclerosing Cholangitis (PSC): a comprehensive review.” Clinical reviews in allergy & immunology 58.1 (2020): 134–149.

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P039 Impact of the COVID-19 pandemic on the care, outcomes, and experiences of patients with chronic liver disease

SX Jiang^1,*, K Schwab², R Enns³, HH Ko³

¹Postgraduate Medical Education

²Undergraduate Medical Education

³Department of Gastroenterology, University of British Columbia, Vancouver, Canada

Background: The COVID-19 pandemic continues to have a secondary impact on health by disrupting systems and changing patient behaviours. Emerging literature suggests decreased hospitalizations and care-seeking by patients with chronic liver disease (CLD) [1]. Coupled with a shift toward telemedicine, outpatient care for CLD patients has been transformed, requiring evaluation of patient experiences and health outcomes.

Purpose: To understand how the COVID-19 pandemic has impacted care, outcomes, and preferences towards telemedicine in CLD outpatients.

Methods: CLD patients of Pacific Gastroenterology Clinic (Vancouver, Canada) who attended a telemedicine appointment from 03/17/2020 to 09/17/2020 were invited to complete an online survey. Survey items included demographic information, care delays resulting from the pandemic, medication adherence, care-seeking, and experience with telemedicine. To compare clinical outcomes during the pandemic with a control group, chart review was conducted on 400 randomly selected clinic patients: 200 patients were seen from 03/17/2020 to 09/17/2020; 200 patients were seen from 03/17/2019 to 09/17/2019. Data were extracted for demographics, clinical status, lab measures, and imaging.

Result(s): Of 399 patients invited to participate, 135 (34%) completed the online survey. Median age was 40-59 years, 60 (49%) were female, 67 (54%) were East Asian, and 53 (43%) had a university/college degree. Liver diagnoses included viral hepatitis (n = 63, 41%), NAFLD (n = 36, 24%), cirrhosis (n = 12, 8%), ALD (n = 6, 4%), and other CLD (n = 36, 24%). A total of 50 (39%) patients reported 83 care delays due to the COVID-19 pandemic, comprised of appointments (40%), imaging (33%), lab work (27%), and liver biopsy (1%). Across all reported care delays, the duration was > 2 months in 71% of cases and > 4 months in 41% of cases. Of 47 patients who reported avoiding healthcare, 57% experienced care delays. Most patients (75%) were satisfied with telemedicine appointments though 75% still preferred to be seen in-person.

Of 400 patient charts reviewed, mean age was 59 (SD 14.4) in 2019 and 57 (SD 14.6) in 2020. There were no differences in demographic factors, liver diagnosis, or treatment between the groups. The number of days between lab work and appointment was higher in the 2020 group (75 days) compared to 2019 group (53 days, p = 0.01). The 2020 group had numerically higher rates of cirrhosis decompensation (26 vs 22 in 2019, p = 0.64) and hospitalization (12 vs 5 in 2019, p = 0.13). Mean ALT and bilirubin levels were similar, but HBV level was significantly higher in 2020 (log 4.9 vs 3.4, p < 0.01). More new suspicious liver lesions were seen on ultrasound in 2020 (10 vs 6 in 2019, p = 0.31).

Conclusion(s): The pandemic has led to a high prevalence of care delays in CLD outpatients, with most delays on the scale of months. Most patients with delays also reported avoiding care, suggesting that patient decision-making is as important as healthcare availability. With a high rate of care delays, clinical outcomes trended towards higher rates of decompensation and hospitalization. These patient-reported experiences, with associated clinical observations, can direct initiatives to optimize telemedicine and patient care in the ongoing global pandemic.

References

1Mahmud N, Hubbard RA, Kaplan DE, Serper M. Declining Cirrhosis Hospitalizations in the Wake of the COVID-19 Pandemic: A National Cohort Study. Gastroenterology. 2020;159:1134–1136.e3.

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P040 Could baseline neutrophil-to-lymphocyte ratio predict outcomes in severe alcoholic hepatitis patients?

I Khan^1,*, F Ahmed¹, Z Zamani², U Akbar¹, Z Yukselen¹, ³, M-K Coronel¹, R Pakala¹, S Gara¹, J Okwundu⁴, A Thompson⁵, M Mouchli⁶, E Shahini⁷, F Pacha⁸, K Mohan⁸

¹Division of Clinical and Translational Research, Larkin Community Hospital, South Miami, United States

²School of Medicine, King Edward Medical University, Lahore, Pakistan

³University of Massachusetts, Amherst, United States

⁴HIV vaccine trials network, Desmond Tutu HIV centre University of Cape Town, Cape Town, South Africa

⁵Department of Family Medicine, Mississauga Health Centre, Mississauga, Canada

⁶Department of Gastroenterology, Cleveland Clinic, Cleveland, United States

⁷Gastroenterology Unit, Institute for Cancer Research and Treatment, Turin, Italy

⁸Department of Gastroenterology, Larkin Community Hospital, South Miami, United States

Background: Various studies proved the prognostic role of neutrophil-to-lymphocyte ratio (NLR) in different liver diseases, but very few in alcoholic hepatitis.

Purpose: Here, we perform a systematic review evaluating the potential prognostic use of NLR in severe alcoholic hepatitis (AH) patients.

Methods: A comprehensive literature search was performed in multiple databases until February 2021. We analyzed original studies reporting response to steroids, acute kidney injury (AKI), infections, change in Lille score, and 90-day mortality. Risk of bias was assessed using the Newcastle-Ottawa Scale (NOS).

Result(s): According to the results of STOPAH trial, a calculated baseline NLR was in 71% (n = 789). The area under receiver operating curve (AUROC) for overall pre-treatment NLR was 0.660 (95% CI: 0.626, 0.693), and the optimal cut-point for 90-day mortality was 5 (Youden index J = 0.247). Concerning the mean baseline NLR of 6.51 (6.14, 6.88), patients with an NLR < 5 had a 16% overall mortality rate compared to 33.6% with an NLR ≥ 5 (p < 0.0001). The optimal cut-point was 8 (J = 0.272) in patients with an NLR ≥ 5. Keeping track of this, treatment with prednisolone significantly reduced the 90-day mortality rate in 27.6% (n = 218) patients with an NLR 5–8 (21.0% cf. 34.5%; HR:0.52 (0.31, 0.86; p = 0.012). However, no such improvement was observed in the 90-day outcome in patients with NLR < 5 i.e., 47.1% (n = 372) or > 8 41.8% (cf.37.6%; P = 0.604). The risk for the development of treatment-associated infections and acute kidney injury (AKI) within 7 days of prednisolone treatment was found to be significantly greater among patients with a high NLR (> 8) compared to those with NLR < 8 (17.3% cf.7.4%: (P = 0.006), OR: 2.60 (1.32, 5.14) and 20.8% cf.7.0%: (P = 0.008), OR: 3.46 (1.39, 8.62), respectively. Similar difference in the incidental infection rate was observed until 28 days of treatment continuation with prednisolone, i.e., 30.6% cf.20.0%: (P = 0.031) OR:1.76 (1.05,2.96). The NLR was also higher in patients who initially presented with sepsis and AKI. Among 237 patients in the validation group, the mean baseline NLR was 8.56 (7.23, 9.84) for the prednisolone receiving group (n = 138). Results were consistent with the STOPAH trial, as patients initially presented with AKI and sepsis had high NLR (i.e., 10.22 cf.7.37; P = 0.014 (0.57, 5.14) and 10.06 cf.7.36: p = 0.023 (0.38, 5.01), respectively. Treatment strategy whereby treating patients with prednisolone achieved a 90-day survival of 85.5% in NLR < 5 and 67.3% in NLR ≥ 5 (p < 0.0001).

A significant 90-day mortality of 20.5% was noted in patients with NLR> 12.3 compared to 5.0% in the low NLR (p = 0.015). There was a strong correlation of NLR with Lille score (> 0.45: 31.2% vs. < 0.45: 2.8%, p < 0.00)

Table P040

Author	Ewan Forrest et al	Yazan Abu Omar et al	Sriram, PB et al
Year	2019	2019	2020
Country	UK	USA	India
Design	Retrospective	Retrospective	Retrospective
No. of subjects	789	104	200
Mortality at 90 days in association with NLR and treatment	NLR<5 : 16.1% NLR≥S : 33.36% (P < 0.0001; HR 2.39 [1.81, 3.15])	NLR > 12.3 : 20.5% Low LNR : 5.0% (P=0.015)	Day-4 NLR had an AUC of 0.786 with an optimal cut-off value of 11.5 (Sensitivity: 66.7%, specificity: 78.1%)
Response to steroids (or a change in Lille score)	NLR > Prednisolone increased the chance of Lille Response (56.5% cf. 41.1%: P = 0.01; OR 1.86)	High Lille score (> 0.45) group had 31.2% mortality, significantly higher than that of the low-Lillescore group (2.8%, p: <0.001)	Day-4 Lille score for the prediction of mortality revealed an AUC of 0.859 with an optimal cut-off value of 0.45 (sensitivity: 83.3%, specificity: 76.1%)
Misc.	Risk of Day 7 AKI after Prednisolone: NLR>8 vs. NLR<8: (20.8% cf. 7.0%: P = 0.0008; OR 3.46) Risk of Day 7 AKI without Prednisolone: NLR > 8 = 7.0% cf. 17.1%: P=0.005: OR 2.72 [1.35, 5.47] NLR > 8 = 20.8% cf. 20.0%: P = 0.913; OR 0.95[0.38] Infection risk after Prednisolone treatment: NLR > 8 vs. <8 7 days = (17.3% cf. 7.4%: p = 0.006; OR 2.60 (1.32, 5.14)) 28 days: (30.6% of cf. 20.0%: p = 0.031; OR 1.76 (1.05, 2.96)). AKI & Sepsis Associated With High NLR: 10.22 (cf. 7.37 P = 0.014) and 10.06 (cf. 7.36: P = 0.023 NLR and Response to Prednisolone: Rx group vs. Non-Rx group: bilirubin by (25%) from baseline in Rx group: 60.8% cf. 27.4% (P<0.0001) OR: 2.76 (1.72, 4.43).	N/A	N/A
Incorporated modified Glasgow alcoholic hepatitis Score (mGAHS)	Low GHS (< 9) had a mean NLR of 5.05(4.74, 5.37), high GAHS (≥ 9) had a mean NLR of 8.12 (7.47, 8.77): P<0.0001	N/A	N/A
Combined day NLR-Lille Model	N/A	The combined day-Lille-NLR model with a cut-off of 0.55 had an AUC of .899, which was higher than the day-4 Lille score and NLR independently	The combined day-Lille-NLR model with a cut-off of 0.55 had an AUC of .899, which was higher than the day-4 Lille score and NLR independently
Conclusion	High NLR is associated with both prevalent and incident AKI and infection in alcoholic hepatitis. A Lille response to Prednisolone is more likely if NLR ≥ 5, but the development of infection or AKI after Prednisolone treatment is greater if NLR>8. There was a significant correlation of NLR with Lille score (>0.45: 31.3% vs. <0.45: 2.8%, P>0.001)	In univariate logistic regression, both Day 4 NLR and Lille score is significantly predicted 90-day mortality (p=0.04, p<0.001, respectively)	Both Day-4 NLR and Lille score individually predicted 90-day mortality with a statistical significance (p: 0.0049, p<0.001, respectively)

Conclusion(s): We confirm a greater 90-day MR in severe alcoholic hepatitis cases with NLR ≥ 5 than those with NLR < 5. Corticosteroids significantly decreased mortality at NLR 5–8, despite higher rates of AKI and infections occurred for scores> 8. NLR and Lille scores were comparable for predicting 90-day survival outcomes. Nonetheless, prospective larger studies are needed to approve the regular use of NLR score in patients with severe alcoholic hepatitis.

P041 Real world management of Wilson disease in a North American cohort: a retrospective perspective

K Leung^1,*, G Burke¹, N Selzner¹, G Hirschfield¹, JJ Feld¹

¹Medicine, Gastroenterology & Hepatology, University of Toronto, Toronto, Canada

Background: Wilson disease (WD) is a rare genetic disorder characterized by dysfunctional copper metabolism that can lead to hepatic fibrosis, movement disorders, and neuropsychiatric changes. Copper chelators and zinc salts aim to reduce the excess total body copper through increased urinary excretion and decreased gut absorption.

Purpose: There are scarce data describing WD populations in North America. Here we examine a heterogenous population followed at the Toronto Centre for Liver Disease (TCLD), describe long-term outcomes, as well as identify characteristics of patients who develop hepatic or neurological dysfunction.

Methods: Retrospective data analysis was done for all patients with WD who regularly attended clinic at the TCLD from January 1, 2000 to December 31, 2019.

Result(s): Ninety-six patients median 17 yrs. after initial diagnosis (range 0-53 yrs.) were followed for a median of 7 yrs. (IQR 2–14 yrs.) of follow-up. At index visit, neurological symptoms were noted in 29 patients (30%), while hepatic decompensation was noted in 17 patients (22%). At time of data census, 32 patients had developed decompensated cirrhosis (33%), with 12 (13%) receiving a liver transplant. Five patients developed severe neurological dysfunction requiring higher level care to function, all of whom had cirrhosis. Sixty-eight (71%) patients were treated with zinc monotherapy during their course. Table 1 describes features of the cohort, as well as those successfully maintained on zinc monotherapy versus those who failed. In the 28 (41%) patients who failed zinc monotherapy (therapy duration range 0.5–10 years), 20 were exhibiting evidence of worsening disease: 9 (32%) had worsening liver enzymes, 8 (29%) had worsening neurological function, 8 (29%) had worsening copper parameters, and 9 (32%) had issues with tolerability or compliance. 3 developed new hepatic decompensation later in their disease course, while 2 developed significant neurological decompensation necessitating higher level of care despite chelator initiation.

Table P041: Wilson Disease Cohort Features and Zinc Monotherapy Response.

Parameter	Entire Cohort n = 96	Successful Zinc Monotherapy n = 40	Failed Zinc Monotherapy n = 28	p-value (t-test or Chi-square)
Male sex (n,%)	48 (50)	16 (40)	13 (46)	0.78
Age at diagnosis (median yrs., interquartile range)	15 (12-24)	16 (13-29)	14 (11-19)	*0.03
Race	42 (45)	18 (45)	14 (50)	0.56
Caucasian (n,%)	41 (44)	20 (50)	11 (39)
Asian (n,%)	2 (2)	0 (0)	1 (4)
Black (n,%)	9 (10)	2 (5)	2 (7)
Other (n,%)
Area of birth	53 (55)	25 (63)	18 (64)	0.32
North America (n,%)	31 (32)	12 (30)	7 (25)
Asia (n,%)	5 (5)	3 (8)	1 (4)
Europe (n,%)	4 (4)	0 (0)	2 (7)
Africa (n,%)
First degree relative with Wilson disease (n,%)	30 (33)	15 (38)	8 (29)	0.61
Initial disease presentation	22 (24)	9 (23)	6 (21)	0.84
Hepatic decompensation (n,%)	28 (31)	9 (23)	10 (36)
Neurological symptoms (n,%)	12 (13)	5 (13)	4 (14)
Asymptomatic enzyme elevation (n,%)	15 (17)	10 (25)	5 (18)
Family screening (n,%)	1 (1)	1 (3)	0 (0)
Psychiatric symptoms (n,%)	12 (13)	5 (13)	3 (11)
Other (non-liver, non-neuro) (n,%)
Presence of Kayser-Fleischer rings (n,%)	40 (42)	17 (43)	11 (39)	0.79
Leipzig score (median, interquartile range)	6 (4-7)	4 (4-6)	6 (4-7)	0.91

Conclusion(s): WD is a heterogenous disease with variable treatment strategies. Although zinc monotherapy can be an effective maintenance therapy, this approach is inadequate in a significant proportion. Aside from younger age at diagnosis, no clear factors were associated with zinc failure. Further longitudinal studies are needed to identify sub-populations at high risk for treatment failure and disease complications.

P042 From specialty guidelines to primary care practice: development of a primary care pathway for chronic abnormal liver enzymes (en-ABLE algorithm)

M McLeod^1,*, C Gallivan¹, C Chowdhury¹, M McLeod², T Kulai³, J Zhu³, S DeCoutere⁴, C Burgess⁴, K Peltekian³

¹General Internal Medicine, Dalhousie University, Halifax

²Family Medicine, University of Manitoba, Winnipeg

³Digestive Care and Endoscopy, Dalhousie University

⁴Digestive Care and Endoscopy, Nova Scotia Health, Halifax, Canada

Background: Chronic abnormal liver enzymes (ABLEs) are a frequent finding in primary care assessments. Current recommendations in this area are available through the 2016 American College of Gastroenterology (ACG) and 2018 British Society of Gastroenterology (BSG) guidelines. These guidelines advise extensive testing and are overly complex for primary care practitioners. The most common four causes of chronic ABLEs include non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease, viral hepatitis and drug-induced liver injury (DILI). These account for ~66% of all causes of ABLEs and most of these require limited laboratory testing. Chronic ABLEs are initially evaluated by primary care practitioners and subsequent management may be guided by following a simple algorithm. Specialty guidelines are important but do not readily translate into a primary care pathway.

Purpose: The objective of this exercise was to leverage clinical expertise to develop this practical translation of guidelines to a Primary Care Pathway.

Methods: One combined general internal medicine specialist/hepatologist, three hepatologists, two nurse practitioners, two general internal medicine specialists, and one family medicine practitioner convened with the aim of drafting a Primary Care Pathway to support primary care practitioners in the diagnosis and triage of patients with chronic ABLEs. The group discussed the information needs of primary care practitioners and the balance between accuracy, patient centric care (avoid unnecessary and/or harmful tests), and clinical knowledge in diagnosing ABLEs. It was concluded that the Primary Care Pathway should give practical advice on: initial laboratory and imaging tests, implicated medications to consider, and when to refer for specialist assessment. The group debated the assessments and criteria that should be included and formed a subsequent consensus.

Result(s): The working group of seven physicians and two nurse practitioners completed the Primary Care Pathway. They came to consensus using the most recent ACG and BSG guidelines and their clinical experience. This pathway includes 3 core algorithms: 1) diagnosis of chronic hepatocellular liver injury; 2) diagnosis of chronic cholestatic liver injury; and 3) NAFLD pathway. These algorithms detail the minimum amount of laboratory and imaging tests needed to accurately diagnose and triage most patients with ABLEs.

Conclusion(s): As an exemplar for all clinicians involved in the care of patients with ABLEs, this consensus Primary Care Pathway for the diagnosis and triage of ABLEs builds on recently published guidelines to support primary care. It provides an opportunity for more uniform practice, and for safe, economical and accurate care of patients. As ABLEs become more common and new therapies become available for liver diseases associated with ABLEs such as with NAFLD, this will be an important pathway for primary care practitioners to use on a provincial and national level.

References

1Newsome PN, Cramb R, Davison SM, et al. Guidelines on the management of abnormal liver blood tests. Gut 2018;67:6–19

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2Kwo P, Cohen SM, Lim JK. ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries, American Journal of Gastroenterology: January 2017 - Volume 112 - Issue 1 - p 18–35

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3Tapper EB, Lok ASF. Use of Liver Imaging and Biopsy in Clinical Practice. The New England Journal of Medicine. 2017 Dec;377(23):2296–2297.

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P043 Utility of Child-Pugh score in cirrhotic patients with primary biliary cholangitis

CF Murillo Perez^1,*, A Gulamhusein¹, P Trivedi², M Mayo³, A Lleo⁴, P Invernizzi⁵, M Carbone⁵, PM Battezzati⁶, T Bruns⁷, A van der Meer⁸, W Lammers⁸, C Ponsioen⁹, H Janssen¹, F Nevens¹⁰, G Dalekos¹¹, N Gatselis¹¹, C Corpechot¹², N Cazzagon¹³, A Floreani¹³, A Parés¹⁴, X Verhelst¹⁵, A Mason¹⁶, D Thorburn¹⁷, K Kowdley¹⁸, K Lindor¹⁹, G Hirschfield¹, B Hansen¹, ²⁰

¹Toronto General Hospital, Toronto, Canada

²University of Birmingham, Birmingham, United Kingdom

³UT Southwestern Medical Center, Dallas, United States

⁴Humanitas University, Milan

⁵University of Milano-Bicocca, Monza

⁶University of Milan, Milan, Italy

⁷University Hospital RWTH Aachen, Aachen, Germany

⁸Erasmus Medical Center, Rotterdam

⁹Academic Medical Center, Amsterdam, Netherlands

¹⁰University Hospitals Leuven, KU Leuven, Leuven, Belgium

¹¹General University Hospital of Larissa, Larissa, Greece

¹²Saint-Antoine Hospital, Paris, France

¹³University of Padua, Padua, Italy

¹⁴University of Barcelona, Barcelona, Spain

¹⁵Ghent University Hospital, Ghent, Belgium

¹⁶University of Alberta, Edmonton, Canada

¹⁷The Royal Free Hospital, London, United Kingdom

¹⁸Swedish Medical Center, Seattle

¹⁹Arizona State University, Phoenix, United States

²⁰University of Toronto, Toronto, Canada

Background: The Child-Pugh (CP) score is a prognostic tool that is implemented primarily in cirrhosis. The utility of CP-score for risk stratification in primary biliary cholangitis (PBC) and considerations for feasibility have not been extensively studied.

Purpose: To assess the CP-score in a cirrhotic population of patients with PBC.

Methods: We included cirrhotic patients from the Global PBC Study Group Database that were diagnosed with PBC from 1990 to 2011 and treated with ursodeoxycholic acid (UDCA) for at least 1 year. Cirrhosis was established through biopsy or by clinical diagnosis. Liver biochemistry was considered baseline if within 6 months of start of follow-up. A compensated and presumed CP-A population was selected by excluding those with biochemical criteria for CP-B/C (defined by 3 points in at least one or by 2 points in at least two of the following parameters: bilirubin, international normalized ratio [INR], albumin), history of decompensation, and CP-score greater than 6, if known. Transplant-free survival was estimated with a Kaplan-Meier curve and compared between presumed CP-A and CP-B/C and within CP-A with the log-rank test.

Result(s): We selected 573 patients with cirrhosis, of whom a CP-score at baseline could be calculated in 70 patients (12%) and 203 (35%) patients when assumed normal INR if missing. Within those with a calculated CP-A, the 5-year transplant-free survival was 88% for CP-5 (n = 125) and 59% for CP-6 (n = 34) (p < 0.001). A compensated and presumed CP-A population was selected (n = 419) after 154 patients were excluded (12 due to unknown decompensation status, 47 due to lab criteria for CP-B/C, and 95 due to prior decompensation). Their age at the start of follow-up after a cirrhosis diagnosis was 57.2 years (SD 11.4), as compared to 60.5 years (SD 11.1) in those excluded (presumed CP-B/C). The 5-year transplant-free survival of those with presumed CP-A was 82% compared to 37% in those with presumed CP-B/C (Figure, p < 0.001). Bilirubin can further risk stratify patients with presumed CP-A (Figure).

Conclusion(s): There are challenges in calculating a CP-score and there may be value in extending routine testing to include INR. The transplant-free survival of a compensated and presumed CP-A population is improved compared to CP-B/C. Within a CP-A population, patients with a CP score of 6 have worse transplant-free survival than those with a CP score of 5. Bilirubin can also aid to further risk stratify patients in the CP-A group.

P044 New therapies for patients with autoimmune hepatitis: challenges to finding patients for clinical trials

ML Ponta^1,*, C Plagiannakos¹, K Tirona¹, M Saini¹, S Roberts¹, B Hansen¹, A Gulamhusein¹, G Hirschfield¹

¹Toronto Centre for Liver Disease, University Health Network, Toronto, Canada

Background: Clinical trial recruitment in AIH is challenging in part due to patient heterogeneity.

Purpose: We reviewed our clinic practice to estimate the number of patients who might be suitable for trial inclusion.

Methods: Patients seen in clinic with AIH (overlap excluded) were identified. Subjects alive as of 31 December 2019 were included and data from 1 January 2017 to 31 December 2019 analysed. We abstracted laboratory tests, gender, age, and distance from clinic to patients’ home. Intra-patient variability of ALT, AST and IgG was assessed using the coefficient of variation (COV, 100 * SD/arithmetic mean). The proportion of subjects eligible for trials targeting remission and those with active disease was assessed based on latest labs, concomitant treatment, and classified: i) remission: ALT and IgG within normal range for 2 years, stable steroid treatment for 6 months, standard of care non-steroidal immunosuppression; ii) active disease: ALT 2-10xULN, AST < 10xULN, Total Bilirubin < 3xULN, Platelets> 100 × 10⁹, INR < 1.5, IgG> ULN, on first or second line treatment regimen with stable therapy for previous 4 weeks.

Result(s): 364 subjects were included (76% female; median age 56 yrs). 73% of patients live in Greater Toronto (54% outside downtown); 5% were more than 4 hours drive from clinic. Biopsy-proven cirrhosis was detected in 115 (37%) subjects. Median transaminases and IgG at latest bloodwork were: ALT 23 IU/L [IQR 15–44], AST 27 IU/L [IQR 21–41] and IgG 13.7 g/l [IQR 10.3–16.8], with normal ALT in 80%, normal IgG in 59%; 42% had both within normal range.The median COV, was 42.1 [IQR 18.8–94.7] for ALT with median ALT of 30IU/L [IQR 18–61]; 28.1 [IQR 13.8–73.0] for AST with median of 32 IU/L [IQR 23–54]; and 12.4 [IQR 5.5–26.3] for IgG with median IgG 14.8g/L [IQR 11.2–18.8]. Among reasons for exclusions for trials were history of cancer within 5 yrs (n = 65) and coexisting relevant non-autoimmune liver diseases (n = 85). Among 9 subjects (2%) who pre-qualify for active disease trials, 7 were on steroids (2 as monotherapy) and 7 were on second line treatments (2 on second line treatment only); among 46 (14%) subjects who pre-qualify for remission trials, 12 were on steroids (2 as monotherapy) and 36 were on second line treatments (26 on second line treatment only); only one was on third line treatment.

Conclusion(s): Clinical trials for AIH are challenged by limited numbers of patients suitable for recruitment based on a need for tightly defined criteria.

P045 Patterns of biochemical response during long-term UDCA treatment in patients with primary biliary cholangitis: association with liver transplant–free survival

SB Roberts¹, ^2,*, L Worobetz³, C Vincent⁴, J Flemming⁵, C Tsien⁶, K Qumosani⁷, M Swain⁸, D Grbic⁹, HH. Ko¹⁰, K Peltekian¹¹, N Selzner¹², L Abrahamyan², M Saini¹, K Tirona¹, B Aziz¹³, E Lytvyak¹³, A Montano-Loza¹³, G Hirschfield¹, ², H Janssen¹, A Gulamhusein¹, ², A Mason¹³, B Hansen¹, ²

¹Toronto Centre for Liver Disease, University Health Network

²Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto

³Medicine, University of Saskatchewan, Saskatoon

⁴Medicine, University of Montreal, Montreal

⁵Medicine, Queen’s University, Kingston

⁶Medicine, University of Ottawa, Ottawa

⁷Medicine, Western University, London

⁸Medicine, University of Calgary, Calgary

⁹Medicine, University of Sherbrooke, Sherbrooke

¹⁰Medicine, University of British Columbia, Vancouver

¹¹Medicine, Dalhousie University, Halifax

¹²Medicine, University of Toronto, Toronto

¹³Medicine, University of Alberta, Edmonton, Canada

Background: Sufficiency of UDCA response is dynamic in PBC, with varied patterns over time.

Purpose: We describe patterns of response and their association with liver transplant-free survival.

Methods: Patients with> 1 year of UDCA therapy from 8 Canadian sites were assessed; those with a clinical event within 6-months of diagnosis or without labs at 1-year (+/– 6mo) were excluded. We defined UDCA response as alkaline phosphatase (ALP) < 1.67xULN & total bilirubin (TB)≤1xULN. Multistate models estimated dynamic transition through biochemical response states over time, and from each state to transplantation or death (LTx/Death). We adjusted for sex, age, ALP, TB, and FIB-4 ≥ 4.03 at 1-year.

Result(s): Of 823 patients, median age at UDCA initiation was 53.6 years, 91.0% were female and 86.8% AMA positive. Median follow-up was 6.5 years and 7.0%/11.4%/13.5% had LTx/Death by 5/10/15 years. At 1-year, 67.4% of patients were responders. By 5-years, an estimated 6.4% never responded, 53.6% retained response, and 8.3% had LTx/Death. An estimated 31.8% fluctuated between response states: i) 15.5% lost response and were non-responders at 5-years; ii) 14.8% lost but then regained response and were responders at 5-years; iii) 1.5% had at least five state changes (Figure, dotted line). At any point, patients retaining initial response had significantly lower rates of LTx/Death than those who never responded (0.074-fold, 95% CI 0.015–0.359) or lost response (0.045-fold, 95% CI 0.009–0.219). At any point, regaining response was protective against LTx/Death (transition rates: < 0.001 vs 0.037; 0.005 vs 0.064). Older age at UDCA initiation was associated with increased hazard of responding (HR 1.03/year, 95% CI 1.01–1.04) and of regaining response after loss of initial response (HR 1.04/year 95% CI 1.03–1.05). Response patterns of patients≤40 years at UDCA initiation indicated high risk compared to patients aged 40–60 years: at 1-year, 56.2%/66.3% were responders. By 5-years an estimated 14.8%/6.7% never responded, 53.0%/57.8% retained response, and 4.2%/3.3% had LTx/Death. An estimated 28.0%/32.2% fluctuated between states: 17.9%/15.3% lost response by 5-years while 10.1%/17.0% lost then regained response. Age comparisons are for females, FIB-4 < 4.03, mean ALP and TB at 1-year.

Conclusion(s): Achievement of response at any time improves liver transplant-free survival regardless of prior non-response. New therapies will be important in improving response patterns, especially for younger patients.

P046 A case of IgG4-positive plasma cells on brush cytology of a common bile duct stricture in a patient with a presumed diagnosis of PSC

P Rutagarama^1,*, C Walker¹, SC Cheris², S Khotari¹, MA Laryea¹

¹Medicine

²Pathology, University of Rochester, Rochester, United States

Background: The diagnosis of IgG4-associated cholangiopathy (IAC) poses significant diagnostic challenges and often includes a trial of steroid as a criteria. IAC is a complex clinical entity that can mimic primary sclerosing cholangitis (PSC) but with a much more favorable prognosis due to its steroid-responsiveness.

Purpose: This case report illustrates the need for more broad use of bile duct biopsy in presumed PSC.

Methods: The authors present the case of a patient initially diagnosed with PSC and discovered to have finding of IgG4-positive plasma cells on brush cytology from a dominant stricture with no evidence of IgG4 disease on liver biopsy or serology.

Result(s): A 31-year-old male was referred to our Hepatology clinic for routine care following his PSC diagnosis in 2017. Throughout his disease course, he required serial stenting and brushing of dominant biliary strictures initially in the common hepatic duct (CHD) and later in the common bile duct (CBD). He had persistent unexplained elevation in alanine transaminase (ALT) and aspartate transaminase (AST) levels fluctuating from 268 U/L/130 U/L at his first visit to a peak of 590 U/L/380 U/L that did not improve with biliary endoscopic retrograde cholangiopancreatography (ERCP) therapeutic interventions. In 2018, initial serological markers for autoimmune hepatitis (AIH) and IAC were negative. In March 2020, autoimmune serology was repeated due to persistently elevated transaminases greater than 10x normal limits. F-actin was then minimally positive with an elevated IgG; however, IgG4 levels were normal. A liver biopsy was then performed and ruled out overlap with AIH or other chronic liver diseases. In 2020, an ERCP was performed to reassess a CBD stricture with brushings performed of CHD dominant stricture to rule out cholangiocarcinoma. Cytology demonstrated no atypical cells but did confirm the presence of many inflammatory cells, predominantly lymphocytes and plasma cells. Due to this unusual finding, the pathologist made the decision to stain the specimen for IgG4-plasma cells (Figure). Up to 40 IgG4-positive plasma cells/high power field were identified, highly suspicious for IAC[BK1]. The patient was subsequently started on steroids and repeat ERCP confirmed dramatic improvement in the stricture.

Conclusion(s): Based on our literature review, IgG4-positive plasma cells in specimens from brush cytology of a stricture at the time of ERCP have not been described and therefore are not sufficient to rule out IAC.This case illustrates how IAC can be present in patients with IBD and liver findings suspicious of PSC. This steroid-responsive entity should be sought with bile duct biopsy even when serology and liver biopsy may seem to exclude IAC.

P047 Post liver transplantation delirium assessment using CAM-ICU-7 scale: a retrospective cohort

FS Cardoso^1,*, A Ewasiuk², B Kok³, C Karvellas²

¹Intensive Care & Gastroenterology, Curry Cabral Hospital, Lisbon, Portugal

²Critical Care

³Liver Unit, University of Alberta, Edmonton, Canada

Background: Post liver transplantation (LT) delirium in the intensive care unit (ICU) has been associated with worse clinical outcomes. Validated tools to daily assess the presence of delirium are important but may be difficult to implement.

Purpose: We sought to study the application of previously derived Confusion Assessment Method (CAM)-ICU-7 delirium severity scale in patients who underwent LT.

Methods: Retrospective cohort including consecutive patients who underwent elective or semi-elective LT and were admitted to ICU within 24 hours of the operation from June 2013 to June 2016 at the University of Alberta Hospital, Edmonton, Canada. Delirium was assessed using the CAM-ICU-7 scale (0 to 7 points) twice daily on days one and 3 post ICU admission, with the highest score being considered. Primary endpoint was hospital mortality. Secondary endpoint was length of hospital stay.

Result(s): Among all patients, 135/199 (67.8%) were men and mean (SD) age was 53.0 (12.1) years. On days one and 3 post LT, mean (SD) Sequential Organ Failure Assessment (SOFA) scores were 9.8 (3.3) and 6.6 (4.3), respectively. On days one and 3 post LT, mean (SD) CAM-ICU-7 delirium scores were 1.9 (1.3) and 1.6 (1.8), respectively. Therefore, on days one and 3 post LT, 38/150 (25.3%) and 26/95 (27.4%) patients had delirium. While the presence of delirium on day 3 post LT was associated with higher hospital mortality (11.5% vs. 0%; P = 0.019), it was not associated with length of hospital stay (29.2 vs. 34.4 days; P = 0.36). Following adjustment for Glasgow Coma Scale and mechanical ventilation, serum creatinine level (mg/dL) on day 3 post LT was independently associated with higher odds of delirium (aOR = 1.01; P = 0.028).

Conclusion(s): Using CAM-ICU-7, delirium was diagnosed in about a fourth of patients who underwent LT. The presence of delirium on day 3 post LT was associated with higher hospital mortality.

References

1Khan BA, Perkins AJ, Gao S, et al. The CAM-ICU-7 Delirium Severity Scale: A Novel Delirium Severity Instrument for Use in the Intensive Care Unit. Crit Care Med 2017;45(5):851-7.

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P048 FIB-4 improves liver stiffness-based prediction of complications in overweight or obese patients with compensated advanced chronic liver disease

Y Mendoza¹, M Shengir², J Bosch¹, ³, G Sebastiani^4,*, A Berzigotti¹

¹Biomedical Research, University of Bern, Bern, Switzerland

²Division of Experimental Medicine, McGill University, Montreal, Canada

³Hospital Clinic-IDIBAPS and CIBERhed, University of Barcelona, Barcelona, Spain

⁴Medicine, McGill University Health Centre, Montreal, Canada

Background: Cirrhosis generates significant health burden in Canada and wordwide. Two distinctive stages with separate prognostic implications have been described: compensated advanced chronic liver disease (cACLD) and decompensated stage. Liver stiffness measurement (LSM) has an independent prognostic value in overweight/obese patients with cACLD. Whether the FIB-4 score predicts the onset of the first clinical complication and whether its use can improve the prognostic accuracy of LSM has not been well studied in this population.

Purpose: Our aim was to assess whether the FIB-4 score predicts first clinical complications in overweight/obesity patients with cACLD identified by LSM, and to evaluate whether its use in this population can improve the prognostic performance of LSM in this setting.

Methods: We analyzed the data of 233 overweight/obesity patients (mean age 60; median Child Pugh and MELD scores 5 and 6; 55% with nonalcoholic steatohepatitis) with cACLD identified by LSM (LSM ≥ 10 kPa measured by XL probe), recruited from two academic centers and followed-up for a median of 17 months. We assessed the performance of FIB-4 and LSM for clinical complications using the area under the receiver operating characteristics (AUROC) and according to a pre-defined LSM cut-off (21 kPa) and to the optimized FIB-4 cut-off. Clinical complications were defined as: 1) classical decompensation (portal hypertension bleeding, ascites, hepatic encephalopathy, or jaundice) or 2) sepsis or severe bacterial infections requiring hospitalization.

Result(s): Fourteen patients (6%) developed clinical complications during follow-up. FIB-4 score and LSM showed a good discriminative performance for clinical complications: AUROC FIB-4: 0.850 (95% confidence interval [CI] 0.766–0.933; p < 0.001); LSM: 0.767 (95% CI 0.652–0.883; p = 0.001; comparison: p = 0.187). A FIB-4> 2.67 had a sensitivity > 90% for clinical complications. Accordingly, patients could be classified noninvasively in 4 different risk categories: LSM> 21 kPa + FIB4> 2.67: high-risk, LSM < 21 kPa + FIB-4> 2.67: intermediate-risk, LSM> 21 kPa + FIB4≤2.67: intermediate-low Risk and LSM < 21 kPa + FIB-4≤2.67: low risk; actuarial rates of remaining free of any complication were 25%, 73%, 96% and 100%, respectively (Log Rank p < 0.001).

Conclusion(s): FIB-4 score helps refining the risk of developing clinical complications in overweight/obese patients diagnosed of cACLD based on LSM. Patients with FIB-4≤2.67 have an overall low risk of developing complications. Our data support the sequential use of LSM and FIB-4 score in this population.

P049 Liver-specific T-regulatory type 1 cells program local neutrophils to suppress hepatic autoimmunity via CRAMP

C Sokke Umeshappa^1,*, P Solé², BGJ Surewaard³, S Mohapatra¹, J Yamanouchi¹, M Myn Uddin¹, R Clarke¹, M Ortega⁴, SS Singha¹, D Mondal⁴, Y Yang⁶, DAA Vignali⁷, P Serra⁴, P Kubes³, P Santamaria¹, ⁴

¹Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Canada

²Institut D’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain

³Department of Physiology and Pharmacology, University of Calgary, Calgary, Canada

⁴Institut D’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain, University of Calgary, Calgary, Canada

⁶Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada

⁷Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, United States

Background: Neutrophils are known to actively contribute to the induction of tissue damage in various models of tissue injury, including chronic autoinflammatory disorders (1, 2). They can also have anti-inflammatory properties in many conditions, including cancer and sterile injuries (3, 4). However, the immunoregulatory properties of neutrophils have never been exploited in the treatment of inflammatory disorders.

Purpose: Previously, we have shown that systemic delivery of nanoparticles (NPs) coated with disease-relevant peptide-major histocompatibility complex class II (pMHCII) molecules (5) can resolve inflammation in various organ-specific autoimmune disease models in a disease-specific manner without impairing normal immunity (6-8). pMHCII-NP therapy functions by reprogramming cognate autoantigen-experienced CD4+ T-cells into regulatory 1-like T cells (TR1), followed by local suppression of autoantigen-loaded professional antigen-presenting cells (APCs).

Fortuitous inclusion of a neutrophil-specific label in liver imaging experiments revealed that pMHCII-NP therapy enhances the recruitment of neutrophils to the autoinflamed livers of these mice. Subsequent depletion experimentation led to the discovery that these cells play an active role in disease suppression. The purpose of this study is to understand how these neutrophils mediate the suppression of autoimmune progression in mice receiving pMHCII-NP therapy.

Methods: Various models of liver autoimmunity, including primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis, were treated with pMHCII-based nanomedicines in the presence or absence of neutrophils and then assessed the role of neutrophils in mediating suppression by scoring pathological lesions in the liver. To understand the mechanisms of actions of neutrophils, they were purified and subjected to various studies, including adoptive transfer, lymphocyte inhibition, receptors and cytokines blockading, and high-throughputomic’ RNAseq.

Result(s): Here we find that, in several models of liver autoimmunity, pharmacologically-induced autoantigen-specific T-regulatory-type-1 (TR1) cells and TR1 cell-induced B-regulatory (Breg) cells use five immunoregulatory cytokines (G-CSF, IL-10, IL-21, IL-35 and TGF-β) to coordinately recruit neutrophils into the liver and program their transcriptome to generate regulatory neutrophils. The liver-associated neutrophils of these mice, unlike their circulating counterparts or the liver neutrophils of sick mice lacking antigen-specific TR1 cells, are proliferative, can transfer disease protection to immunocompromised hosts engrafted with pathogenic effectors, and blunt antigen-presentation and local autoimmune responses via CRAMP, a cathelicidin, in a CRAMP receptor-dependent manner.

Conclusion(s): These results thus identify antigen-specific regulatory T-cells as drivers of tissue-restricted regulatory neutrophil formation and CRAMP as an effector of regulatory neutrophil-mediated immunoregulation.

References

1Bonder et al., J Immunol 2004. 172, 45–53

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P050 The nutrition in cirrhosis guide: a useful education tool for in people suffering from chronic liver disease and their caregivers?

M Sophasath^1,*, Y Mukaneza², M Tremblay³, G Huard⁴, CF Rose⁵, C Bémeur¹

¹Nutrition, Universite de Montreal/CRCHUM

²Nutrition

³CRCHUM

⁴Hepatology, CHUM

⁵Medecine, Universite de Montreal/CRCHUM, Montreal, Canada

Background: Liver disease affects over 9 million Canadians and kills 2 million people annually worldwide. One of the most prevalent complications of chronic liver disease (cirrhosis) is malnutrition, which greatly affects the quality of life of patients and their caregivers. In this context, several nutritional guidelines for cirrhotic patients have been developed. However, the application of these guidelines seems to have important shortcomings, such as the difficulty of achieving certain nutritional goals for the majority of patients. The Nutrition in Cirrhosis guide was developed by a national team of hepatology and nutrition experts.

Purpose: Objectives: 1) To assess the impact in cirrhotic patients, in the short and long term, of the Guide on: i) nutritional status; ii) nutrition knowledge; iii) quality of life; iv) liver function; and, in the long term, v) complications; vi) number and duration of hospitalization. 2) Determine the impact on the quality of life and the perceived burden of caregivers. 3) Survey the appreciation of the Guide by patients and their caregivers.

Methods: A randomized controlled study targeting 100 cirrhotic patients at the Centre Hospitalier de l’Université de Montréal (CHUM) divided into 2 groups: Intervention (Guide) and Control (without Guide). Nutritional status (Liver Disease Undernutrition Screening Tool), nutrition knowledge (homemade questionnaire), quality of life (Chronic Liver Disease Questionnaire) and liver function (from medical charts) are assessed at t = 0, 3 and 6 months, and hospitalizations after 6 months. For the second objective, the quality of life (Short-Form 36 Questionnaire) and perceived burden (Zarit Burden Interview) of caregivers is evaluated at t = 0 and 6 months. Three focus groups of 10 patients and their caregiver, randomly chosen from the intervention group, will be created to assess their appreciation of the Guide.

Result(s): Preliminary results: 26 patients completed the 3-month pilot study (67% men, mean age = 60 years and etiologies: 30% non-alcoholic hepatic steatosis, 25% alcoholic, 12.5% hepatitis C, hepatitis B and mixed etiologies, and 4% other etiologies). The results show that the patients in the intervention group (n = 20) have better knowledge of nutrition than the controls (n = 5) (79.5 ± 7.7% vs 68.4 ± 7.9%; p = 0.02) after 3 months. The control group also displayed an improvement in their quality of life after 3 months compared to t = 0 (5.10 ± 1.15 vs 5.61 ± 1.08, p < 0.0005).

Conclusion(s): The Nutrition in Cirrhosis Guide seems to offer a beneficial effect on the quality of life and nutrition knowledge of cirrhotic patients after 3 months. The long-term impact of this resource still needs to be established in order to develop implementation vehicles and eventually include it in cirrhotic patient care.

References

1Canadian Liver Foundation. Liver Disease in Canada - A Crisis in the Making. 2013

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2Plauth M et al. Clin Nutr. 2006

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3Bajaj et al. Am J Gastroenterol 2011

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P051 Emergency room care is essential in improving outcomes of decompensated cirrhosis patients: a Canadian experience

J Stach^1,*, K Burak², E Enns³, M Swain², S Congly², J Abraldes⁴, C Coffin², AA Shaheen²

¹University of Calgary, Calgary, Canada

²Medicine, University of Calgary

³Alberta Health Services, Calgary

⁴Medicine, University of Alberta, Edmonton, Canada

Background: Patients with decompensated cirrhosis suffer of poor clinical outcomes. Growing evidence highlights the importance of improved outpatient care. However, few studies have evaluated the role of emergency department (ED) care provided to cirrhosis patients and its impact on clinical outcomes.

Purpose: Therefore, we evaluated the implementation of standardized cirrhosis care practices in the ED and its impact on decompensated cirrhosis patient outcomes for those presenting with gastrointestinal bleeding (GIB).

Methods: We used the electronic medical record system implemented in the four acute care hospitals serving the Calgary Health Zone (CHZ; 1.4 million people), to identify decompensated cirrhosis patients with evidence of GIB who presented to the ED via reviewing ED triages notes between 2017-2019. We evaluated implementation of standardized care measures for patients with decompensated cirrhosis by assessing: antibiotic utilization, time to start antibiotics, administration of octreotide, time to start octreotide, proving endoscopy within 12 hours, consulting gastroenterology service, and performing a follow-up upper endoscopy for patients with banded varices. We then undertook a medical chart review to validate our findings in patients admitted in the last year of the study. Descriptive analysis methods were used.

Result(s): We identified 819 ED presentations for cirrhosis patients presenting with GIB over our study period. Among those identified, 88% were started on appropriate broad-spectrum antibiotics within a median time of 5.1 hours (IQR: 3.2–7.1) from ED presentation. Only 66% were started on octreotide infusion (median time from ED presentation 3.3 hours [IQR: 1.5–4.2]). Only 70% of this cohort were evaluated by the gastroenterology service (median time from ED presentation to consultation of 4.2 hours [IQR:3.0–5.3]). Urgent upper endoscopy within 12 hours of ED presentation was provided to 58% of our cohort. Of 185 patients who had esophageal variceal banding during hospitalization, only 81 (44%) patients had a follow-up upper endoscopy within 3 months. For our patient cohort, the median length of stay for decompensated cirrhosis patients with variceal bleeding was 7.5 days (IQ: 6.2–8.5), 30-day readmission rate was 20.3% (IQR: 17.7–22.1), and in-hospital mortality was 15.3% (IQR: 12.1–17.5). In our validation study, 74% (139/187) of patients had a history of esophageal, gastric varices, or portal hypertensive gastropathy on endoscopy, while 26% had other etiologies for GIB such as Mallory-Weiss tear, peptic ulcer disease, or unknown etiology.

Conclusion(s): In our cohort, we identified high rates of poor clinical outcomes among decompensated cirrhosis patients presenting to the ED with suspected variceal bleeding. Implementation of various standard of care measures in the ED was suboptimal. Improved integration of high-quality ED management of cirrhosis patient care is essential to lower readmission and in-hospital mortality rates.

P052 A systematic review on pharmacokinetics, cardiovascular outcomes and safety profiles of statins in cirrhosis

S Sung^1,*, M Al-Karaghouli¹, S Kalainy², L Cabrera Garcia³, JG Abraldes¹

¹Faculty of Medicine & Dentistry, University of Alberta

²Alberta Health Services, Edmonton, Canada

³Faculty of Medicine, Complutense University of Madrid, Madrid, Spain

Background: There is increased interest in the therapeutic use of statins in cirrhosis, but preferred statin and safety outcomes are still not well known.

Purpose: In this systematic review we aimed to address pharmacokinetics (PK), safety, and effects on cardiovascular (CV) outcomes of statins in cirrhosis.

Methods: Our systematic search in several electronic databases and repositories of two regulatory bodies up to 2020-06-11 yielded 22 articles and 2 drug monographs with relevant data.

Result(s): Rosuvastatin and pitavastatin showed minimal PK changes in Child-Pugh A cirrhosis. Only rosuvastatin was assessed in a repeated dosing PK study. Atorvastatin showed pronounced PK changes in cirrhosis. No PK data was found for simvastatin, the most commonly used statin in cirrhosis trials. There was insufficient data to assess CV effects of statins in cirrhosis. Clinical trials in cirrhosis were limited to simvastatin, atorvastatin, and pravastatin. In patients taking simvastatin 40mg, pooled frequency of rhabdomyolysis was 3.3%, an incidence 66-fold higher than that reported in non-cirrhosis patients, while this was no rhabdomyolysis observed in patients on simvastatin 20mg, atorvastatin 20mg, or pravastatin 40mg. Drug-induced liver injury was of difficult interpretation due to co-existence of muscle damage. No overt liver failure was reported.

Conclusion(s): Simvastatin 40mg should be avoided in decompensated cirrhosis. Safety data on simvastatin 20mg or other statins are based on small study sample size. This rarity of evidence combined with lack of data in dose adjustment methods in cirrhosis is a barrier for using statins for CV indications or for investigational use for liver indications.

P053 Trial in progress: adjuvant pembrolizumab for hepatocellular carcinoma and complete radiologic response after surgical resection or local ablation (KEYNOTE-937)

A Vogel^1,*, AX Zhu², A-L Cheng³, T Yau⁴, J Zhou⁵, RN Uppot², E Kim⁶, U Malhotra⁶, AB Siegel⁶, M Kudo⁷

¹Hannover Medical School, Hannover, Germany

²Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, United States

³National Taiwan University Cancer Center and National Taiwan University Hospital, Taipei, Taiwan, Province of China

⁴University of Hong Kong, Queen Mary Hospital, Hong Kong

⁵Zhongshan Hospital Fudan University, Shanghai, China

⁶Merck & Co., Inc., Kenilworth, NJ, United States

⁷School of Medicine, Kindai University, Osaka, Japan

Background: Surgical resection and local ablation are potentially curative options for patients with hepatocellular carcinoma (HCC); however, tumor recurrence is not uncommon. There is an unmet medical need for standard-of-care adjuvant therapy to prevent disease recurrence and improve overall survival. Pembrolizumab, a PD-1 inhibitor, has shown evidence of a favorable benefit-to-risk profile in the adjuvant setting in many tumor types but has not been investigated in HCC.

Purpose: To evaluate the safety and efficacy of pembrolizumab versus placebo as adjuvant therapy in patients with HCC who had a complete radiologic response after surgical resection or local ablation.

Methods: KEYNOTE-937 is a randomized, double-blind, phase 3 study. Adults with confirmed HCC, complete radiologic response after surgical resection or local ablation, Eastern Cooperative Oncology Group performance status of 0 or 1, and Child-Pugh liver class A are eligible. Patients with past or ongoing hepatitis C or controlled hepatitis B virus infection may be enrolled if they meet prespecified criteria. Patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg intravenously or placebo intravenously every 3 weeks for up to 17 cycles or until disease recurrence, unacceptable toxicity, or withdrawal, stratified by geographic region, prior local therapy (resection vs ablation), recurrence risk, and alpha-fetoprotein level at diagnosis. Coprimary end points are recurrence-free survival and overall survival; secondary end points are safety and tolerability (graded per National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0) and health-related quality of life; and exploratory end points include distant metastases-free survival; time to recurrence; and genomic, metabolic, and/or proteomic biomarkers. Tumor imaging will be assessed until recurrence, and adverse events will be recorded up to 30 days after the last dose (90 days for serious adverse events). The study protocol was approved by the relevant ethics committee or institutional review board at each participating center, and the study is being conducted in accordance with standards of Good Clinical Practice and the Declaration of Helsinki.

Result(s): Recruitment began in May 2019, and the planned sample size is 950 patients.

Conclusion(s): KEYNOTE-937 will elucidate the efficacy and safety of pembrolizumab as adjuvant treatment in patients with HCC who had a complete radiologic response after surgical resection or local ablation.

P054 Rxcirrhose.ca: development of an online tool on drug management for patients with liver impairment

V Ferreira¹, P Willems^2,*, A Mathieu¹, J Bissonnette³, R Coutu⁴

¹CHUM

²Universite de Montreal

³Hepatology, CHUM, Montreal

⁴CHUS, Sherbrooke, Canada

Background: The prevalence of liver disease and cirrhosis is on the rise in North America. Despite the significant impact of liver impairment on drug metabolism, there are very few validated and easy-to-use references to guide clinicians with their everyday prescriptions when managing patients with cirrhosis. Furthermore, none of the available references are translated in French, which can be problematic in the province of Quebec.

Purpose: To develop an online clinical tool to adjust drug prescriptions in the setting of liver impairment that is both evidenced-based and easy to consult.

Methods: Drug classes that are frequently used and that can be problematic in cirrhosis were identified. Literature reviews on all molecules of each the identified drug classes were conducted. Studies that evaluated adult patients with liver impairment were included. For each drug, the name, the dose, the recommended duration of use, the pharmacokinetics and pharmacodynamics parameters and reported adverse reactions were collected and analyzed by a group of pharmacists and physicians specialized in liver diseases from the CHUM in Montreal, Quebec. A website was then developed to share these data.

Result(s): Twenty-four drug classes, regrouping one hundred molecules, have been reviewed so far. A free website (www.rxcirrhose.ca) was launched gathering all the collected and analyzed data. Each drug class is presented on a separate web page. Every web page starts with a color-coded summary table offering an official recommendation (safe to use, use with caution or avoid use) for each molecule depending on the Child-Pugh class of the patient (see figure). Next, a section on pharmacodynamics and pharmacokinetics compares the effect of each molecule in healthy patients and those with hepatic impairment. Common adverse reactions are listed. Finally, a discussion justifying our recommendations and bibliographic references is presented. Since its launch in May of 2018, over 2 900 users have consulted the website. The website is exclusively in French for the moment.

Conclusion(s): Liver disease has a major impact on the metabolism of many drugs. Rxcirrhose.ca is, to our knowledge, the first Canadian online clinical tool aimed to help clinicians with drug management in the setting of liver impairment. An English version of the website will be undertaken soon.

P055 The frequency of use of head CT in patients presenting to emergency department with hepatic encephalopathy

DY Yang^1,*, M Ahmed², J Bowron², S Veldhuyzen van Zanten¹

¹Division of Gastroenterology, Department of Medicine

²Department of Medicine, University of Alberta, Edmonton, Canada

Background: Patients with decompensated liver disease often suffer from recurring episodes of hepatic encephalopathy (HE), resulting in frequent Emergency Department (ED) visits and hospital admissions.

CT head is often ordered in such presentations though studies have suggested the lack of clinic impact from this test (1). Furthermore, there are no disease specific findings for HE on CT head that would assist with diagnosis of the condition (2). Nevertheless, there are many cases of CT head ordered in EDs for patients with presumed HE in the absence of any risk factor for new intracranial abnormalities, such as intracranial hemorrhage, or focal neurologic deficits.

Purpose: The aims of this study were to analyze the pattern of CT head usage in the ED to identify which patient factors influence the decision to order CT head and whether the results of the CTs impacted management.

Methods: We conducted a single center, retrospective chart review, to assess the pattern of CT head usage for patients with cirrhosis presenting with hepatic encephalopathy. Potential patients were first identified based on their discharge ICD-10 codes (K72, K72.9, K74.6, K74.3, K74.4, K74.5, K70.3, K70.4, K71.1, K74.6). Charts for these patients were then manually screened for eligibility. Our inclusion criteria were: patients > age 18 with cirrhosis who present to the ED with altered mental status or cognition. Our exclusion criteria were patients with clinical history or suspicion for structural brain lesions, CNS infection or head trauma as their presenting complaint. Patients who met eligibility were divided into those who received CT head and those who did not. Clinical data, including timing of CT, imaging findings, demographics, laboratory parameters, outcome, were collected and compared between the two groups.

Result(s): A total of 529 charts were reviewed based on ICD-10 discharge diagnosis and 117 met eligibility criteria. Of the 117 patients, 64 (55%) received CT head in the ED and 53 (45%) did not. None of the 64 patients had significant new pathology on CT head. One patient who did not have CT head on admission had an intracranial hemorrhage diagnosed after a CT head was ordered for new onset seizure on day 8 of hospitalization.

The patients who received CT head on admission tend to be older while those who did not had higher INR and bilirubin (see Table). One possible explanation is that the ED providers were more likely to attribute a patient’s altered mental status to hepatic encephalopathy if the patient had worse liver disease, thus forgoing a CT head to rule out other pathologies.

The patients without CT scan did have longer hospitalization and higher mortality (see Table). However, this is likely due to worse liver disease as opposed to clinically significant findings on CT scan.

Table P055: Comparison of Patient Characteristics between Patients with and without CT head on Admission

Patient Characteristics	Patients with CT on Admission	Patients without CT on Admission	P value
Age	64	57	0.000121^
% female	43	46%	0.504 *
% EtOH cirrhosis	42%	51%	0.344 *
% with documented non-compliance	20%	25%	0.2981 *
Days to last hospital presentation for HE	80	37	0.0153^&
Days to pervious CT head	89	73	0.687^&
% on lactulose	63%	66%	0.347*
% on rifaximin	23%	36%	0.0712*
Average GCS	12.63	13.26	0.0865^
Hb (g/L)	111	98	0.00152^
WBC	6.46	8.17	0.0228^
Pit	95	126	0.002984^
Creatinine	116	142	0.0779^
Na	136	135	0.208^
INR	1.5	1.7	0.0124^
ALT	38	56	0.0533^
AST	69	106	0.0237^
Total Bilirubin	57	130	0.000237^
Albumin	31	29	0.100^
Ammonia	103	95	0.239^
Length of stay	10.65	15.6	0.0135^
% Died in hospital	1.6%	28.8%	0.000023*

Conclusion(s): CT head is frequently ordered in patients presenting with HE. The diagnostic yield is low in the absence of localizing findings. Patients presenting with HE who did not receive CT head tend to have worse liver function which likely resulted in their longer hospitalization and higher mortality.

References

1Rahimi RS, Rockey DC. Overuse of Head Computed Tomography in Cirrhosis With Altered Mental Status. Am J Med Sci. 2016 May;351(5):459–66.

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P056 The management of alcohol-use disorder during the COVID-19 pandemic: evaluating the efficacy of virtual care in patients with alcohol-related liver disease

MTK. Yau^1,*, L Bromley², K Treuil³, J Mong¹, C Tsien¹, ⁴

¹Faculty of Medicine, University of Ottawa

²Department of Family Medicine

³Department of Social Work, The Ottawa Hospital

⁴Ottawa Hospital Research Institute, Ottawa, Canada

Background: For patients with alcohol-related liver disease (ALD), the mainstay of treatment is alcohol abstinence. However, during the COVID-19 pandemic, surveys indicated a 10–25% increase in rates of alcohol consumption amongst Canadian adults, while many patients’ usual in-person recovery support systems closed (e.g. Alcoholics Anonymous).¹ This substantially increased patients’ risk of relapse. Therefore, since physical distancing restrictions were instituted in March 2020 due to COVID-19, we have been using virtual care to provide comprehensive pharmacotherapy and psychosocial treatment of alcohol-use disorder (AUD) in patients with ALD at the Ottawa Hospital, Ottawa, Ontario.

Purpose: Here we present a clinic audit of the accessibility and effectiveness of the virtual care format in our target patient population.

Methods: Our multidisciplinary clinic at the Ottawa Hospital includes visits with a hepatologist, an addictions medicine specialist, and a social worker. Patient visits are offered via OTN, Zoom-EPIC, or telephone. Our social worker performs an initial assessment of each patient, asking about their specific goals of care. We accept referrals only from the 4 practicing hepatologists at the Ottawa Hospital, who agreed to also provide us with numbers of patients who refused to participate in the clinic. We included all adult patients 18 or older, with any form of ALD. We excluded patients who already had community supports in place.

Result(s): Between April 1, 2020 and December 31, 2020, 61 patients were referred to the clinic. 3 patients refused referral to the clinic, citing an ability to stop drinking on their own. 58 patients (95.1%) agreed to be referred to the clinic. Despite initially agreeing, 4 patients (6.6%) declined a clinic appointment. 10 patients (16.4%) were refused by the clinic as they already had community supports in place. 4 patients (6.6%) were unreachable. Finally, 32 patients (52.5%) were assessed in clinic, and 20 patients (32.8%) had more than one visit with a mean follow-up of 130.2 +/- 72.1 days. However, an additional 4 patients were seen after this data was collected, giving a clinic retention rate of 75.0%. Only 4 patients were truly lost to follow-up – of these, 1 patient died and 1 patient did not have ALD. Mean patient age was 55 +/-10.1 years old, 75% (n = 15) were men, and 95% (n = 19) were cirrhotic. Mean Na-MELD was 15.7+/- 6.3. 70% of patients (n = 14) were treated with anti-craving medications, the most common being naltrexone (n = 5, 35.7%) and varenicline (n = 4, 28.6%). 1 patient on treatment stopped drinking completely (7.1%) vs. 0 patients not on treatment (p = 1.0). 9 patients (45.0%) remained abstinent for the duration of the follow-up. 1 patient on treatment was hospitalized for hepatic encephalopathy, vs 4 patients not on treatment (p = 0.0139). These patients were hospitalized for decompensated liver disease and/or consequences of alcohol misuse.

Conclusion(s): Using a novel format of virtual care, our multidisciplinary clinic was able to start anti-craving medications in 70% of patients with AUD and ALD. The clinic retention rate was 75%. There was no evidence of increased serious adverse events related to anti-craving medications. Patients not on treatment had a significantly higher rate of hospitalizations due to liver disease and alcohol misuse. This data strongly supports the development of multidisciplinary clinics for treatment of AUD in patients with ALD.

References

1Nanos Research, RDD dual frame hybrid telephone and online random survey, March 30th to April 2nd, 2020 (n = 972)

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P057 Canadian hepatology nurses identify and mitigate disparities in access to care during COVID-19 pandemic

D Zukowski^1,*, A DeWolff², E Lee³, S De Coutere⁴, L Gallagher⁵, C Yim³

¹President, Canadian Association of Hepatology Nurses, Trenton

²Board Member, Canadian Association of Hepatology Nurses, Salmon Arm

³Toronto Centre for Liver Disease, Toronto General Hospital/UHN, Toronto

⁴Nova Scotia Health, Halifax

⁵Vice President, Canadian Association of Hepatology Nurses, Vancouver, Canada

Background: The COVID-19 pandemic has presented unprecedented challenges to nurses in meeting patients’ health care needs. Hepatology nurses play a pivotal role in direct management of patients with liver disease. Challenges faced by hepatology nurses, with recent disruptions to health care delivery, are unknown.

Purpose: To gain insights from hepatology nurses across Canada on the impact COVID-19 has had on nursing care practices, the effect on personal stress levels, and the strategies hepatology nurses have employed in the delivery of care to their patients.

Methods: An online survey, with a mixed method design, consisting of 22 quantitative and 7 optional qualitative questions, was sent via email invitation and later posted on social media.Recipients were members of the Canadian Association of Hepatology Nurses. The study period was from July 23 to September 8, 2020. Quantitative responses were analysed with frequencies and percentages; the qualitative responses were analysed with constant comparative analysis.

Result(s): The overall response rate was 32% (41/129); of all respondents, 71% (29) replied to the optional qualitative questions. 76% of respondents worked in community-based health care settings, and 76% of all respondents reported working with people who have hepatitis C. Respondents had varying amounts of hepatology experience: 0-5 years (41%), and 6-15 years (41%). Moderate to severe negative impacts on practice settings were reported by 90% of respondents due to clinic closures, redeployment, and staffing shortages; and 68% reported Hepatitis C testing interruptions and treatment delays. 59% of respondents reported fear for personal self and family due to the pandemic, and 80% reported moderate to extreme levels of stress in their personal lives.

Six main themes were identified regarding the effect COVID-19 had on hepatology nursing care practices, separating into two broad themes: barriers in access to care, and strategies utilized by nurses to mitigate the identified barriers in delivery of care.

Barriers: 1) Insecurities – enforced isolation, patients prioritized the need for basic survival, toxic street drug supply, increased drug overdoses and deaths, displacement of individuals; 2) Limitations to health care – temporary lab closures, limited access to clinicians, health care providers redeployed, initial lack of PPE, decreased supports from outreach workers and volunteers; and 3) Fear of COVID-19 – patients’ fear of exposure prevented them accessing care, limited patient clinic attendance due to social distancing restrictions, no walk-in appointments.

Strategies (with recognized limitations): 1) Telephones – critical tool to maintain patient contact, increased access to rural patients, enabled nurses to work from home; 2) Outreach – increased use of outreach nurses for patient engagement and deliveries of medication and correspondence; and 3) Collaboration – increased collaboration between multidisciplinary team members, with pharmacists being an important point of patient contact within communities, increased access to care through virtual telehealth.

Conclusion(s): Canadian hepatology nurses identified COVID-19 had negative impacts on personal self and on delivery of health care to their patients. People who are marginalized were identified as the group most affected due to barriers and restrictions preventing access to care and treatment. Nurses developed strategies to mitigate these barriers, showing flexibility, dedication, and deep commitment to their patients.

P058 Development of high-throughput assays for hepatitis B virus detection in vitro

L Al-Yasiri^1,*, S D’souza¹, ², TR Patel¹, ², C Coffin¹

¹Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary

²Chemistry and Biochemistry, University of Lethbridge, Lethbridge, Canada

Background: The hepatitis B virus (HBV) is a non-cytopathic DNA virus which establishes persistent infection by forming an intranuclear covalently closed circular DNA mini chromosome (cccDNA) within infected cells. The approved anti-HBV treatments include nucleoside/nucleotide analogs that target the HBV reverse-transcriptase or pegylated-interferon-alpha therapy (Peg-IFN-α) which has non-specific antiviral and immunomodulatory effects. Both treatment options rarely achieve viral clearance and thus there is an urgent need for newer therapeutic strategies to clear or silence HBV cccDNA. In order to screen for potential anti-viral therapeutics, convenient and high-throughput infection systems are required. Hepatocyte cell lines such as HepAD38 cells are stably transfected with HBV and consistently express HBV proteins and nucleic acid but do not recapitulate the full HBV life cycle including cccDNA formation. HBV infection models include the HepG2-NTCP cell line, which express the functional HBV receptor (NTCP) and allow for the complete evaluation of the HBV life cycle.

Purpose: To develop a standardized and cost-effective high throughput HBV infection platforms and screening assays to assess viral protein and nucleic acid markers that will aid in the development of new therapeutics and further our understanding of HBV biology.

Methods: We established an HBV infection model using cultured supernatant derived from HepAD38 cells to infect HepG2-NTCP cells. The virus was precipitated and concentrated via the PEG-8000 method, which resulted in a 2-log increase in viral concentration. Infected cells were either left untreated (control) or treated with tenofovir disoproxil fumarate (TDF). Cellular and secreted proteins (HBsAg and HBeAg) were monitored using an in-house developed sandwich ELISA protocol. In addition, we evaluated the sensitivity of novel high-throughput systems to detect HBV DNA, HBV RNA, cellular cccDNA and pre-genomic RNA levels (pgRNA) without requiring the traditional and extensive nucleic acid extraction methods.

Result(s): Viral inoculum derived from HepAD38 cells was concentrated to ~10⁹ VGE/mL. To achieve high levels of infection (i.e., 80-90% of HepG2-NTCP cells be infected), we used an HBV inoculum multiplicity of infection (MOI) of 500 virus genome equivalents (VGE)/cell. Following infection in a 96-well plate format, we monitored markers of HBV infection over a 14-day time course. Our in-house sandwich ELISA was capable of detecting viral antigens in a 1.5-200 ng/mL range and at a fraction of the cost of commercially available kits: $15 vs $600 USD/plate. Additionally, using a novel high throughput extraction method we directly quantified secreted virions by quantitative PCR (10¹-10⁸ VGE/mL). The efficiency of this protocol was established as HBV DNA levels in cells treated with 1 μM TDF were detected to be ~2 log lower (10⁵ VGE/mL) compared to control/untreated cells (10⁷ VGE/mL).

Conclusion(s): HBV infection platforms and optimization of cost-effective, standardized virological assays is important for high-throughput anti-viral screening of drugs. These assays will be essential for future research involving development of novel agents targeting HBV.

P059 The growth and development of hepatocellular carcinoma (HCC) as induced in the woodchuck model of hepatitis B

ZA Clarke^1,*, L Liu², X-Z Ma³, J Manuel³, T Michalak⁴, I McGilvray⁵, ⁶, ⁷, S MacParland⁸, ⁹, ¹⁰, G Bader¹, ¹¹

¹Molecular Genetics

²University of Toronto

³Ajmera Transplant Centre, Toronto

⁴Medicine, Memorial University of Newfoundland, St. John’s

⁵Division of Experimental Therapeutics, Toronto General Research Institute

⁶Cancer Clinical Research Unit, Princess Margaret Cancer Centre

⁷Surgery

⁸Laboratory Medicine and Pathobiology, University of Toronto

⁹Toronto General Hospital Research Institute

¹⁰Immunology

¹¹Computer Science, University of Toronto, Toronto, Canada

Background: Natural experimental models of hepatocellular carcinoma (HCC) development from a hepatitis B virus (HBV) infection are limited due to the high host specificity of orthohepadnaviruses1. The woodchuck (Marmota monax) is an ideal experimental model for HCC caused by HBV, because most woodchucks naturally develop HCC as a result of chronic woodchuck hepatitis virus (WHV) infection on an intact immunological background2. Having a biologically relevant model to human disease is crucial to ensuring that therapeutics tested in these models will be safe and effective when translated to human research. However, the mechanisms by which WHV causes cancer are still unknown3, and the host immune response is very diverse and not fully understood4. This consequently limits our capacity to design treatments to fight human HBV and HCC. Incorporating single-cell RNA-sequencing (scRNA-seq) analysis further enables the study of the tumour microenvironment and cell-specific disease characteristics. This level of specificity can provide insight as to why and how HCC progresses from a chronic infection in certain cells and not others.

Purpose: Studying the response of individual cells to chronic WHV infection will help uncover the cell-type specific vulnerability to HCC and identify specific oncogenic mechanisms. Analyzing cellular transcriptomes across tumour spatial location and developmental time points will allow for detailed comparisons between chronically infected, non-cancerous tissue, and tissues in which cancer has recently developed. These comparisons can extend to characteristics including different tumour sizes or degrees of portal vein thrombosis, which both have been shown to independently predict HCC mortality5. Such comparisons may guide more specific therapies against hepatitis B viruses; the main global cause of HCC6.

Methods: Single-cell RNA sequencing will be performed on diseased tissue across varying tumour developmental time points and spatial locations in the tumor microenvironment. Magnetic resonance imaging (MRI) technology will enable early tumour detection in chronically infected woodchucks, and single-cell analysis of cells that have presumably just broken from their healthy stable state. A pipeline has been developed which can detect and analyze cell-associated viral integration sites and integration site motifs. This analysis will be performedin addition to gene enrichment analysis (including that of viral genes), cell cycle analysis, and mutation analysis to test the varying and contradicting hypotheses as to how this oncovirus causes cancer.

References

1Littlejohn et al. Cold Spring Harb. 2016.

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2Guo et al. Zool. Res. 2018.

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3Bruni et al. Virology. 2006.

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4Michalak. Front. Immunol. 2020.

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5Tandon & Garcia-Tsao. Liver Int. 2009.

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6Sayiner et al. Dig. Dis. Sci. 2019.

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P060 Beyond tags, antibodies and fluorescent proteins: a new way to visualize hepatitis C virus core protein using an unnatural amino acid system

LJF Curnew^1,*, K McNicholas¹, B Green¹, J Barry¹, H Wallace¹, L Wang¹, C Davidson¹, J Pezacki², R Russell¹

¹Division of Biomedical Sciences, Memorial University, St. John’s

²Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Canada

Background: The study of cellular localization of viral proteins is largely dependent on the ability to visualize those proteins by microscopy. Microscopic analysis requires using traditional protein labeling mechanisms, such as HA and HIS tags, antibodies and naturally fluorescent proteins (GFP; mCherry). Although these methods are powerful tools that have allowed for novel discoveries for numerous viral proteins, the presence and structure of these tags can affect protein function and topology, resulting in the appearance of artefactual results. To bypass the problems associated with traditional labeling mechanisms, we applied an unnatural amino acid (UAA) system to viral proteins using hepatitis C virus (HCV) as a model. UAAs are synthetic amino acids that share the same basic structure as proteinogenic amino acids but differ with regards to R group composition. These differing UAA R groups provide additional reactivity, function and application. Recent UAA applications include using autofluorescent UAAs to label proteins. Labelling viruses and viral proteins with autofluorescent UAAs eliminates the requirement for antibodies or tags, allowing for the visualization of viruses and viral proteins for which no antibodies or tags are available.

Purpose: To visualize the HCV Core protein using the autofluorescent UAA Anap (3-[(6-acetyl-2-naphthalenyl)amino]-L-alanine).

Methods: Huh-7.5 cells were co-transfected with HCV Core plasmids containing amber stop codons at various positions throughout the coding sequence, and a second plasmid encoding the orthogonal tRNA/synthetase pair that facilitates Anap incorporation. Three days post-transfection, cells were fixed and stained for Core protein and cellular lipid droplets (LDs), followed by immunofluorescence or confocal microscopy for visualization. In this system, Core protein can then be observed through conventional indirect immunofluorescence, as well as direct fluorescence from the incorporated Anap.

Result(s): We have optimized transient transfection protocols for efficient expression of the tRNA/synthetase pair required for Anap incorporation and are able to visualize our Core mutant proteins containing Anap. We have successfully substituted Anap into 11 different positions within Core, including substitutions for tryptophan, tyrosine and phenylalanine residues. In addition, we have shown that our core mutants associate with cellular LDs suggesting that the incorporation of the UAA did not disrupt Core protein expression, stability or cellular localization.

Conclusion(s): HCV Core protein can be directly visualized using unnatural amino acid technology, without obvious impact on Core protein function or topology. The establishment of a UAA incorporation system for viral proteins allows for the visualization of viral proteins without the requirement of antibodies or tags. In summary, the UAA system is a useful method to study HCV proteins, and can potentially be used to label viruses for live cell and animal studies.

P061 Investigating the role of an RNA guanine-quadruplex in hepatitis C virus replication

S D’souza^1,*, M Badmalia², C Coffin³, TR Patel¹, ²

¹Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary

²Chemistry and Biochemistry, University of Lethbridge, Lethbridge

³Medicine, Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary, Canada

Background: Nucleic acids that are rich in guanine nucleotides can form a secondary structure known as a Guanine-quadruplex (G-quadruplex). These G-quadruplex structures are formed through the stacking interaction of two or more G-tetrads which are made up of four Hoogsteen hydrogen bonded guanine bases. These G-quadruplex secondary 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; however, their functional role in the viral life cycles have yet to be thoroughly investigated. 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 1-154nt sequence that has been 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 a G-quadruplex formation to aid in efficient viral replication.

Methods: Using G4-hunter, we have designed and ordered wild-type/mutant RNA oligos of the putative G-quadruplex forming sequence in the negative-strand 3’UTR of HCV. These oligos will be purified using size exclusion chromatography methods and characterized using circular dichroism spectroscopy to investigate RNA secondary structure. The formation of these G-quadruplexes will be further confirmed using MicroScale Thermophoresis to determine the binding affinity of a commercially available antibody (BG4) that binds to G-quadruplexes. We will subsequently use in-vitro cell culture models to test 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): One wild-type and three mutant G-quadruplex HCV RNA oligos were designed and ordered. We are in the process of purifying and characterizing these oligos, as well as performing binding studies to evaluate the affinity of the BG4 antibody to these HCV G-quadruplexes.

Conclusion(s): The identification of a functional role of these G-quadruplexes in HCV can give us insight into how nucleic acid structure is able to impact viral replication.

P062 Short chain fatty acids delay the development of hepatocellular carcinoma in HBX transgenic mice

M Feitelson^1,*, N McBrearty¹, A Arzumanyan¹, E Bichenkov¹

¹Temple University, Philadelphia, United States

Background: Chronic infection with hepatitis B virus (HBV) is a major risk factor for the development of hepatocellular carcinoma (HCC). The HBV encoded oncoprotein, HBx, alters the expression of host genes and the activity of multiple signal transduction pathways that contribute to the pathogenesis of HCC by multiple mechanisms independent of HBV replication. However, it is not clear which pathways are the most relevant therapeutic targets in hepatocarcinogenesis. Short chain fatty acids (SCFAs) have strong anti-inflammatory and anti-neoplastic properties, suggesting that they may block the progression of chronic liver disease (CLD) to HCC.

Purpose: This hypothesis was tested in HBx transgenic (HBxTg) mice fed SCFAs.

Methods: Groups of HBxTg mice were fed with SCFAs or vehicle from 6-9 months of age and then assessed for dysplasia, and from 9-12 months of age and then assessed for HCC. Livers from 12 mo. old mice were then analyzed for changes in gene expression by mass spectrometry-based proteomics.

Result(s): SCFA-fed mice had significantly fewer dysplastic and HCC nodules compared to controls at 9 and 12 months, respectively. Pathway analysis of SCFA-fed mice showed down-regulation of signaling pathways altered by HBx in human CLD and HCC, including those involved in inflammation, phosphatidylinositol 3-kinase (PI3K), epidermal growth factor, and Ras. SCFA treatment decreased Ras pathway activity, which is constitutively activated by HBx. SCFAs also reduced cell viability in HBx-transfected cell lines in a dose-dependent manner while the viability of primary human hepatocytes was unaffected.

Conclusion(s): These unique findings demonstrate that SCFAs delay the pathogenesis of CLD and development of HCC, and provide insight into some of the underlying mechanisms that are relevant to pathogenesis in that they are responsive to treatment.

P063 Understanding the mechanism of miR-122 dependent promotion of hepatitis C virus replication

RD Kunden^1,*, S Ghezelbash¹, JQ Khan¹, JA Wilson¹

¹Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, Canada

Background: The genome of Hepatitis C Virus (HCV) is a 9.6 kb positive-sense RNA that contains a polyprotein coding region, a 5’UTR and a 3’UTR. Its replication requires host miR-122 (small-RNA) annealing to two sites on its 5’UTR. The mechanism by which miR-122 promotes HCV replication is thought to involve viral genome stabilization and translation promotion but is poorly understood. We recently found that annealing of small perfect match RNAs like small interfering RNAs (siRNAs) to HCV 5’UTR can also promote HCV replication as efficiently as miR-122 when siRNA-mediated target cleavage was abolished using Ago2 knockout cells (Ago2KO).

Purpose: To map the locations on the HCV genome to which siRNA annealing can promote HCV replication and to determine the mechanism behind miR-122 and siRNA dependent HCV replication.

Methods: To identify regions where siRNAs annealing can promote HCV replication, several 19bp siRNAs targeting different sites on the HCV genome were tested for their ability to promote HCV replication. To gain insights into the mechanisms by which miR-122 and siRNAs induce the viral life cycle, we monitored translation stimulation and genome stabilization by siRNAs that do and do not promote the HCV life cycle. To assess translation stimulation, we used a non-replicative mutant of HCV RNA and siRNAs to measure protein production 4 hours post co-electroporation. To assess genome stabilization by miR-122 and the siRNAs, we used northern blot assays to determine the half-life of non-replicative HCV RNA in presence of miR-122 or siRNAs that do and that do not promote virus replication.

Result(s): From our replication assay, we found that siRNAs annealing between nucleotides 1 and 44 in HCV 5’UTR, promoted replication, and siRNAs annealing within IRES, NS5B and 3’UTR regions, including other predicted miR122 binding sites, did not. Replication promotion efficiency decreased as the siRNA target site moved away from the center of this region and was abolished if the siRNA target included nucleotide 45. This suggested that location-specific annealing of small RNAs is required to promote virus replication. Translation assays showed correlation between translation stimulation and replication promotion by individual siRNAs suggesting replication promotion and translation stimulation are linked functions. RNA structure predictions of HCV RNA in presence of siRNAs that promote virus replication showed the formation of canonical HCV IRES structure, required for virus translation. These data suggest that translation promotion by small RNAs is necessary to promote HCV lifecycle. We further sought to determine correlation between replication and genome stabilization by siRNAs. We observed that siRNAs stabilized HCV RNA whether they did or did not promote virus replication. This suggested that genome stabilization by siRNAs is not sufficient for promotion of HCV replication.

Conclusion(s): We present a model in which position-specific annealing of small RNAs induces the formation of the viral IRES RNA structures and promotes virus translation and replication. In addition, position-independent small RNA annealing stabilizes the viral genome but alone is insufficient to promote the virus life cycle. Future studies will characterize how RNA structures are modulated by small RNA annealing to better understand the mechanism by which miR-122 promotes HCV life cycle.

P064 M1 macrophage-derived interferon-γ dysfunction in chronic hepatitis C virus infection

DA Lawton^1,*, A Crawley², ³, ⁴, ⁵

¹Biochemistry, Microbiology and Immunology

²Biochemistry, Microbiology, Immunology, University of Ottawa

³Chronic Disease Program, Ottawa Hospital Research Institute

⁴Biology, Carleton University

⁵Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, Canada

Background: Bone marrow-derived monocytes augment the liver macrophage pool in association with the resident liver macrophages, including Kupffer cells. In response to pathogenic, inflammatory stimuli and metabolic cues, macrophages can differentiate into a pro-inflammatory (M1) phenotype. The recent findings that human macrophages are an important source of interferon-gamma (IFN-γ) adds some complexity to this picture. We reported dysfunctional M1 polarization in HCV infection with advanced liver fibrosis, characterized by reduced IFN-γ production by M1 cells, and impairment. Recently, we and our collaborators found that IFN-γ production by M1 macrophages is mediated through the PI3K/Akt/mTOR pathway. Furthermore, monocyte dysfunction is pronounced in HCV infection, and disproportionally affects CD16+ vs CD14+ subsets, yet their role in contributing to IFN-γ dysfunction M1 macrophages in advanced liver fibrosis is not known.

Purpose: This project aims to identify the mechanism underlying IFN-γ dysfunction in M1 macrophages in HCV+ individuals with advanced liver fibrosis, and to define the contribution of CD16+ and CD14+ monocyte-derived M1 cells to this activity.

Methods: To quantify IFN-γ production by M1 macrophages, CD14+ and CD16+ blood monocyte-derived M1 macrophages (MDM) will be generated from healthy individuals and treatment-naïve HCV-infected individuals with minimal and advanced liver fibrosis. Intracellular IFN-γ expression will be analyzed by flow cytometry while IFN-γ concentrations in culture supernatants will be quantified by ELISA and compared to M0/M2 subsets and between study groups. The activity of the PI3K/Akt/mTOR pathway in the production of IFN-γ these subsets will be assessed using agonists and inhibitors.

Result(s): We have successfully isolated monocytes from PBMCs and generated macrophages using M-CSF. Furthermore, M1 and M2 macrophage subsets have been generated using polarizing stimuli. Macrophage activation markers (e.g. CD80, CD86, HLA-DR) facilitate the distinction of subsets by flow cytometry and elevated levels of intracellular expression of IFN-γ in M1 macrophages have been confirmed. Experiments are ongoing to delineate the monocyte subset contributions to IFN-γ production by M1 macrophages in health and HCV disease.

Conclusion(s): We aim to gain important insights on understanding macrophage subset dysfunction in chronic liver disease with advanced fibrosis. Collectively these findings will be a first in the description of macrophage IFN-γ production in HCV-mediated liver disease with potential relevance for non-infectious liver disease. Our probing into the signalling pathway central in mediating IFN-γ within macrophages will narrow in on specific factors that can be modulated to rescue dysfunctional macrophage phenotypes. Understanding the immunological functioning of IFN-γ and the perturbations of M1 macrophages in chronic HCV infections will lead to the identification of therapeutic to modulate immune function in cirrhotic individuals, and aid in the mitigation of associated negative clinical outcomes.

References

1Kazutomo S, Takashi A, Tsutomu T, Shigeo K. In vivo role of IFN-γ produced by antigen- presenting cells in early host defense against intracellular pathogens. European Journal of Immunology 10, 2666 (2003)

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2Ahmed F, Ibrahim A, Cooper CL, Kumar A, Crawley AM. Chronic Hepatitis C Virus Infection Impairs M1 Macrophage Differentiation and Contributes to CD8+ T-Cell Dysfunction. Cells 8, 374 (2019).

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P065 Hedgehog signalling mediates interferon-gamma expression in CD8+ T cells confirming gene expression patterns in hepatitis C infection in advanced liver disease

J Li¹, ², ^3,*, A Vranjkovic², K Levesque³, D Read³, WL Stanford³, ⁴, ⁵, ⁶, ⁷, CL Cooper¹, ⁸, ⁹, ¹⁰, AM Crawley¹, ², ³, ¹¹

¹Centre for Infection, Immunity and Inflammation, University of Ottawa

²Chronic Disease Program, Ottawa Hospital Research Institute

³Department of Biochemistry, Microbiology and Immunology

⁴Department of Medicine

⁵Ottawa Institute of Systems Biology

⁶Department of Cellular and Molecular Medicine, University of Ottawa

⁷Sprott Centre for Stem Cell Research

⁸Clinical Epidemiology Program, Ottawa Hospital Research Institute

⁹School of Epidemiology and Public Health, University of Ottawa

¹⁰Division of Infectious Diseases, The Ottawa Hospital

¹¹Department of Biology, Carleton University, Ottawa, Canada

Background: Prolonged liver insult in chronic hepatitis C virus (HCV) infection results in liver fibrosis, which can progress to cirrhosis and high-risk of hepatocellular carcinoma. Both HCV-specific and bulk CD8+ T cells are significantly affected by chronic HCV infection. We previously reported long-lasting generalized CD8+ T cell hyperfunction in chronically infected individuals correlates with liver fibrosis severity¹. However, the specific mechanisms underlying this dysfunction remain unknown.

Purpose: To investigate the underlying molecular mechanisms of generalized CD8+ T cell hyperfunction in advanced liver fibrosis.

Methods: Peripheral blood CD8+ T cells were isolated from chronic HCV-infected treatment-naïve individuals with minimal (Metavir F0-F1 ≤ 7.0 kPa) or advanced (F4 ≥ 12.5 kPa) liver fibrosis, before and after curative direct-acting antiviral therapy. Cells were stimulated with PHA for 18h, RNA was extracted and subsequently sequenced and analysed with bioinformatics approaches. The role of Hedgehog (Hh) signalling in mediating IFN-γ and perforin expression was assessed by flow cytometry following 48h stimulation with anti CD3/28 antibodies, with or without chemical inhibitors or agonists of the Hh pathway. The effect of Fas-mediated apoptosis on IFN-γ production was also assessed in these cultures.

Result(s): Principal component analysis and fold-change analysis identified 444 differentially expressed genes in CD8+ T cells from HCV-infected individuals with advanced liver fibrosis compared to minimal fibrosis regardless of treatment stage. Gene Set Enrichment Analysis (GSEA) reveals higher expression of genes related to Hh signalling, IFN-α, -γ, and TGF-β responses, apical surface pathways, inflammatory responses and apoptosis, amongst others. GSEA also identified lower expression of genes related to c-Myc and E2F targets, oxidative phosphorylation, G2/M checkpoint, mTOR signalling, and others. Enrichment analysis for Gene Ontology classifications revealed higher expression of genes related to phospholipase, secondary messenger and GPCR signalling, phosphatidyl-choline/inositol activity, Hh signalling, and G1/S transition, in contrast with downregulated genes related to nuclear division, RNA trafficking, and actin nucleation. In CD8+ T cells from healthy individuals, dose-dependent inhibition of Hh signalling reduced IFN-γ and perforin expression, while induction of apoptosis reduced IFN-γ expression. Moreover, IFN-γ expression was not concomitant with apoptosis.

Conclusion(s): Taken together, in HCV infection with cirrhosis where there is CD8+ T cell hyperfunction, there are significant changes in genes expressed by CD8+ T cells. Specifically, Hh signalling may contribute to this dysfunction as it mediates IFN-γ and perforin production in CD8+ T cells. In contrast, inducing apoptosis decreases overall IFN-γ production, suggesting that apoptotic pathways do not directly lead to CD8+ T cell hyperfunction. In addition, the RNA-seq data hint that overall dysregulation of cell cycle and metabolic processes influences CD8+ T cell activation and function in advanced liver disease that will be investigated further. Understanding the mechanisms underlying chronic immune cell dysfunction will inform improved treatments for individuals affected by advanced liver disease to ameliorate long term clinical outcomes.

References

1Vranjkovic A, Deonarine F, Kaka S, Angel JB, Cooper CL and Crawley AM. Direct-acting antiviral treatment of HCV infection does not resolve the dysfunction of circulating CD8+ T-cells in advanced liver disease. Front Immunol (2019) 10:1926.

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P066 The use of oncolytic measles-based vectors for targeted treatment of hepatitis C virus-related hepatocellular carcinoma

C-H Liu¹, ^2,*, Y-C Pan³, CD Richardson¹, ⁴, L-T Lin², ³

¹Department of Microbiology & Immunology, Dalhousie University, Halifax, Canada

²Graduate Institute of Medical Sciences

³Department of Microbiology and Immunology, Taipei Medical University, Taipei, Taiwan

⁴Department of Pediatrics and Canadian Center for Vaccinology, Izaak Walton Killam Health Centre, Halifax, Canada

Background: While direct antiviral agents nowadays offer a cure for hepatitis C, therapeutic options for HCV-related hepatocellular carcinoma (HCC) remain limited. Current management of HCC includes surgical resection, radiofrequency ablation, embolization, liver transplantation, and chemotherapy, etc.; however, these therapies are ineffective in advanced HCC stage, and situations such as contraindications, lack of donor livers, risk of recurrence, and the varied responses lead to the poor prognosis of the disease. These issues highlight the importance of developing novel therapies for the treatment of HCV-related HCC. Recently, the tumor marker nectin-4, which is found on many epithelial-derived malignancies including HCC, was identified as one of the receptors for measles virus (MV). This discovery highlighted the potential of using oncolytic MV-based vectors for treating liver cancers, including in the context of HCV-related HCC.

Purpose: To explore the use of MV-based oncolytic viruses to target the tumor marker nectin-4 on HCV-related HCC.

Methods: We first examine the level of nectin-4 expression in clinical HCC specimens from the Oncomine online microarray/gene expression database (https://www.oncomine.org). Commercially available HCC cell lines are evaluated for nectin-4 expression in vitro. The targeting and oncolytic abilities of a recombinant wild type (wt) MV (strain IC323) are validated in the HCC cell lines and their derivatives containing HCV subgenomic RNA. The role of HCV NS3/4A protease and cell innate immunity in the scenario of oncolytic virus treatment are also examined. We will subsequently determine the effect of MV-based vectors on tumor growth in HCC mouse tumor models.

Result(s): Oncomine online dataset analysis reveals that nectin-4 is upregulated in HCC specimens, including those with HCV infection, compared to normal liver tissue. Preliminary results indicate that HCC cell lines express nectin-4 and are susceptible to oncolytic MV infection. Additionally, Huh-7 cells harboring replicating HCV subgenomes (GT1b and GT2a) exhibit better MV infectivity and spread compared to the HCV-negative parental cells.

Conclusion(s): We have shown that nectin-4 is upregulated in HCC specimens, and that HCC cell lines expressing nectin-4 can be targeted by MV-based oncolytic vector. More importantly, enhanced MV infectivity and spread in the hepatoma cell lines with replicating HCV subgenomes suggest that suppressed cell innate immunity may have influenced the infectivity of oncolytic vector. We expect that oncolytic virus treatment will retard tumor growth, and a functional immune system should further enhance remission in these liver cancer models.

P067 Systemic cytokine levels and T cell responses in patients with chronic hepatitis B and comorbid non-alcoholic fatty liver disease

NH Patel^1,*, K Doucette², S Joshi³, S Haylock-Jacobs⁴, A Lucko⁵, A Ramji⁶, C Coffin¹

¹Medicine, Microbiology and Infectious Diseases, University of Calgary, Calgary

²Division of Infectious Diseases, University of Alberta, Edmonton

³ChipCare, Toronto

⁴Medicine, University of Calgary, Calgary, Canada

⁵Institute of Virology, Munich, Germany

⁶Division of Gastroenterology, University of British Columbia, Vancouver, Canada

Background: Despite the availability of an effective vaccine against the hepatitis B virus (HBV), over 257 million people worldwide are chronically infected. Individuals with chronic hepatitis B (CHB) and comorbid Non-Alcoholic Fatty Liver Disease (NAFLD) are at an increased risk for severe liver disease such as hepatocellular carcinoma. Recent studies show positive association between hepatic steatosis and HBV surface antigen seroclearance^1-3. However, the mechanisms remain unknown.

Purpose: To analyze systemic cytokine levels and HBV specific T cell responses in patients with CHB and comorbid NAFLD.

Methods: In total, 54 patients with CHB and NAFLD were prospectively recruited from 3 Canadian liver clinics. Clinical and demographical information including BMI, NAFLD risk factors, alanine aminotransferase levels, liver stiffness measurement (LSM), and controlled attenuation parameter (CAP) scores were collected. Whole blood samples were collected for isolation of plasma, sera, and peripheral blood mononuclear cells (PBMCs). HBV replicative markers were quantified using in-house and/or standard clinic assays. In age and sex matched patients with CHB and NAFLD (n = 30), NAFLD only (n = 13), CHB only (n = 10), and healthy (n = 6), 13 pro-and anti-inflammatory cytokines and chemokines were measured using multiplex Luminex assay. Ex vivo HBV specific CD4+ and CD8+ T cell responses were characterized using flow cytometry.

Result(s): In 54 patients with CHB and NAFLD (47% female, mean age of 45±10.2 years, 59% Asian, and LSM of 5.8±1.9 kPa), 51 (94%) were HBeAg negative. The median HBV DNA, quantitative HBV surface antigen, and HBV pre-genomic RNA levels were 3.2 log₁₀IU/mL, 3.0 log₁₀IU/mL, and 1.2 log₁₀copies/mL, respectively. The mean CAP score was 305.4±50.6 dB/m. Serum TNF-α and IL-8 levels remained similar despite differing levels of hepatic steatosis in patients with CHB and NAFLD (p> 0.999). However, serum TNF-α and IL-8 levels in patients with CHB and NAFLD were significantly lower compared to patients with NAFLD only (p < 0.0001 and p = 0.0114), but were similar to patients with CHB only and healthy (p> 0.999). No significant associations were observed when cytokines and chemokines levels were compared between CHB and NAFLD and the control groups based on stratifications by obesity, BMI, metabolic syndrome, dyslipidemia, and diabetes (p> 0.05). In CHB and NAFLD patients, T cell responses to HBV surface and core antigens stimulation were not associated with hepatic steatosis and obesity.

Conclusion(s): Pro-inflammatory cytokines and chemokines levels in patients with CHB and NAFLD are more similar to patients with CHB than patients with NAFLD. Further studies on HBV specific T cell responses due to NAFLD induced metabolic alterations may increase our understanding of HBV surface antigen seroclearance in patients with CHB and NAFLD.

References

1Mak LY, Hui RWH, Fung J, Liu F, Wong DKH, Cheung KS, Yuen MF, Seto WK. Diverse effects of hepatic steatosis on fibrosis progression and functional cure in virologically quiescent chronic hepatitis B. J Hepatol. 2020;73(4):800–06.

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2Zhang J, Lin S, Jiang D, Li M, Chen Y, Li J, Fan J. Chronic hepatitis B and non-alcoholic fatty liver disease: conspirators or competitors. Liver Int. 2020;40(3):496–508.

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3Hui RWH, Seto WK, Cheung KS, Mak LY, Liu KSH, Fung J, Wong DKH, Lai CL, Yuen MF. Inverse relationship between hepatic steatosis and hepatitis B viremia: results of a large case-control study. J Viral Hepat. 2018;25(1):97–104.

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P068 Quantifying the relative contributions of the three roles of miR-122 in the HCV life cycle

M Rheault^1,*, S Sagan¹, ²

¹Microbiology & Immunology

²Biochemistry, McGill University, Montreal, Canada

Background: The liver-specific microRNA, miR-122, is an essential host factor for efficient viral RNA accumulation of hepatitis C virus (HCV). miR-122 binds to two sites in the 5’ UTR of the viral genome termed Site 1 (S1) and Site 2 (S2); and has three established roles in the viral life cycle: 1) riboswitch activity to promote formation of the functional internal ribosomal entry site (IRES) structure; 2) stabilization of the viral genome by protecting it from pyrophosphatase activity and subsequent exoribonuclease-mediated decay; and 3) promotion of translation mediated by the S2-bound Argonaute (Ago) protein interacting with the IRES. Notably, recent studies have revealed several resistance associated variants (RAVs) of HCV that are able to accumulate in the absence of miR-122. Two of these, the U4C and G28A RAVs, are able to form the functional IRES even in the absence of miR-122.

Purpose: We hypothesize that the three roles miR-122 plays in the HCV life cycle have different relative contributions to the overall impact of the microRNA. We plan to quantify the relative contributions of these three functions in the HCV life cycle using viral RAVs and luciferase reporter assays.

Methods: To study the three roles of miR-122 in the HCV life cycle, we generated Renilla luciferase (RLuc) reporters whose translation is directed by the HCV IRES, including those with the complete 5’ UTR of wild-type, U4C and G28A. The reporters contain a S1:p3 (C26A) or S2:p3 (C41A) mutation which abolishes wild-type miR-122 binding, but can be complemented with miR-122 molecules containing compensatory mutations (i.e. miR-122p3U). This allows us to study miR-122 binding at either site independently by exogenous addition of wild-type and/or miR-122p3U in miR-122 knockout (KO) Huh-7.5 cells. Using luciferase assay to measure HCV IRES-mediated translation and Northern blotting to measure reporter RNA stability, we are quantifying the stabilization, riboswitch and translational promotion activities of miR-122.

Result(s): Our preliminary results, using the G28A reporter, suggest that the riboswitch activity accounts for an approximately 1.5-fold increase in luciferase activity when compared with wild-type. Additionally, with respect to the translational promotion effect, when complemented with miR-122 at Site 2 only, we observe an approximately 1.6-fold increase in luciferase activity.

Conclusion(s): Thus far, we have established a reporter assay system to quantify the relative contributions of each of the miR-122 activities in the HCV life cycle. Our preliminary data suggests a similar magnitude of the riboswitch and translational enhancement activities; however, this will need to be verified by Northern blot to assess the stability of the reporter RNAs. We anticipate that this study will help to reveal the importance of each of miR-122’s roles in the HCV life cycle and provide novel insight into this unique mechanism of RNA regulation that may be applicable to other cellular or pathogenic RNAs.

P069 Elucidating the mechanism of hepatitis C virus-induced bystander pyroptosis

HL Wallace^1,*, C Davidson¹, R Russell¹

¹Biomedical Sciences, Memorial University, St John’s, Canada

Background: Pyroptosis is an inflammatory form of cell death, mediated by a protein complex, referred to as an inflammasome, containing effector enzyme caspase-1. Pyroptosis ultimately results in lytic death of the cell and release of inflammatory cytokines. Our lab has previously shown that both HCV-infected and uninfected bystander cells undergo pyroptosis during infection of hepatocyte-like Huh-7.5 cells. It was previously shown that the mechanism by which bystander pyroptosis is induced is cell contact-independent and therefore likely mediated by a soluble factor (Kofahi et al., 2016). Some literature suggests that the inflammasome itself, after being released from lysed cells, triggers pyroptosis of nearby cells. However, the exact mechanism by which bystander pyroptosis occurs, specifically in the context of HCV infection, has yet to be elucidated.

Purpose: The purpose of this study is to determine the mechanism by which uninfected bystander cells undergo pyroptosis in the context of HCV infection.

Methods: A cell culture-adapted strain of HCV JFH-1 (JFH1_T) was cultured in Huh-7.5 cells and virus infection and cell death was monitored. To confirm HCV itself did not have a role in bystander-induced pyroptosis, S29 cells were utilized as a control (1000-fold less permissive to HCV than Huh-7.5 cells). THP-1 cells stimulated with LPS/Nigericin were utilized as a positive control. A previously published protocol for inflammasome isolation from cells was employed to obtain an inflammasome isolate that could be used as a treatment for naïve cells. FAM-FLICA probes and antibodies were used to visualize active caspase-1 and HCV core protein, respectively. Pyroptotic cell death was analyzed by Western blotting and fluorescence microscopy.

Result(s): Inflammasome isolates taken from HCV-infected and uninfected Huh-7.5 cells both induced caspase-1 activation in naïve Huh-7.5 cells. However, HCV itself was unable to be ruled out as the effector, as the inflammasome isolation protocol did not result in the removal of virus. When S29 cells were exposed to the same inflammasome isolates taken from HCV-infected and uninfected Huh-7.5 cells, we observed an increase in caspase-1 activation in the inflammasome-treated cells, independent of productive HCV-infection. This effect was not seen when cell-free culture supernatants were taken from uninfected Huh-7.5 cells and added to naïve Huh-7.5 cells.

Conclusion(s): These preliminary results suggest that the protein complex dubbed the inflammasome is involved in the induction of bystander pyroptosis during HCV infection. Research by other groups has shown that inflammatory markers are not completely reduced following DAA treatment, including those associated with pyroptosis. If bystander pyroptosis has a role in the continuous production of inflammatory markers, there may exist a mechanism to stop this process, potentially stopping the progression of liver disease. These findings, and further research into the phenomenon of bystander pyroptosis, will aid in understanding the mechanisms surrounding inflammation and liver pathology associated with chronic HCV infection.

References

1Kofahi HM, Taylor NGA, Hirasawa K, Grant MD, and Russell RS. (2016). Hepatitis C virus infection of cultured human hepatoma cells causes apoptosis and pyroptosis in both infected and bystander cells. Scientific Reports, 6(1), 1–14.

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P070 Cost-effectiveness of pegylated interferon for sustained virological response in chronic hepatitis B

S Congly^1,*, A Syed¹, S Haylock-Jacobs¹, H Israelson¹, J Pinto¹, S Lee¹, C Coffin²

¹Division of Gastroenterology and Hepatology, Department of Medicine

²Division of Gastoenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Canada

Background: First-line treatment for chronic e-antigen positive chronic hepatitis B (HBV) include pegylated interferon (PEG-IFN) as well as nucleos(t)ide analogue (NA) treatments. Although PEG-IFN offers a fixed treatment course, it is uncommonly used due to its significant side effects as compared to NA based therapies. NA therapy often is indefinite with significant ongoing costs lifelong.

Purpose: Given the potential long term economic implications with NA for patients and the possible advantage of a fixed treatment with PEG-IFN, we wished to model the cost-effectiveness of PEG-IFN as compared to NA therapy using real-life data.

Methods: In this retrospective study we modelled the cost-effectiveness of PEG-IFN vs. NA for CHB utilizing data collected by retrospective chart review of all patients followed in the Calgary Liver Unit who received Peg-IFN antiviral therapy from 01/2008-12/2020. The cost-effectiveness of Peg-IFN as compared to NA therapy was modelled using a Markov model with a 10-year time horizon with cost/patient with sustained virological response/viral suppression being the primary endpoint. Patients who did not respond to PEG-IFN/were intolerant of it were assumed to switch to a NA. Costs of drugs were based on the list price in Alberta. Costs and outcomes were discounted by 3% as per current guidelines.

Result(s): A total of 69 patients were treated with PEG-IFN with 14 patients stopping therapy early due to intolerance/lack of efficacy. 23/55 of the patients who completed therapy had a SVR. In the model, patients who received NA had a cost of $14,894 over 10 years time with a total of 8.79 years of sustained virological response. PEG-IFN cost $26,806 for a total of 8.12 years of sustained virological response and as such was considered dominated.

Conclusion(s): Based on a 10-year time horizon, the use of PEG-IFN did not appear to be cost-effective as compared to NA use. More careful selection of potential PEG-IFN treatment candidates may improve its cost effectiveness.

P071 Higher seroprotection rates (SPR) and higher anti-HBS concentrations in adults age 18–45 immunized with 3-antigen hepatitis B vaccine (3A-HBV) compared to 1-antigen hepatitis B vaccine (1A-HBV): results from the pivotal, double-blind, randomized phase 3 study (CONSTANT)

F Diaz-Mitoma^1,*, T Vesikari², A Finn³, P van Damme⁴, I Leroux-Roels⁵, G Leroux-Roels⁵, N Segall⁶, A Toma⁷, N Garg⁸, G Vallieres⁹, R Aronson¹⁰, D Reich¹¹, H Sah¹², S Arora¹³, P Ruane¹⁴, C Anderson¹⁵, C Cone¹⁶, M Manns¹⁷, C Cosgrove¹⁸, S Faust¹⁹, M Ramasamy²⁰, N Machluf²¹, J Spaans²¹, B Yassin-Rajkumar²¹, D Anderson²¹, V Popovic²¹

¹VBI Vaccines Inc., Ottawa, Canada

²Nordic Research Network Ltd, Tampere, Finland

³Bristol Royal Hospital for Childre, Bristol, United Kingdom

⁴University of Antwerp-Center for the Evaluation of Vaccination, Wilrijk

⁵Ghent University, Gent, Belgium

⁶Clinical Research Atlanta, Stockbridge, United States

⁷Manna Research, Toronto

⁸Manna Research, Montreal

⁹Manna Research, Quebec

¹⁰LMC Diabetes and Endocrinology, Toronto

¹¹Medicor Research Inc, Sudbury, Canada

¹²Care One, North Hollywood

¹³Aventiv Research, Columbus

¹⁴Ruane Clinical Research Group Inc, Los Angeles

¹⁵Clinical Research Consortium, Tempe

¹⁶Montana Medical Research Inc, Missoula, United States

¹⁷Medizinishe Hochschule, Hannover, Germany

¹⁸St. George’s University Hospital NHS Foundation Trust, London

¹⁹NIHR Southampton Clinical Research Facility, University Hospital Southampton NHS Foundation Trust; and Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton

²⁰Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital and University of Oxford, Oxford, United Kingdom

²¹VBI Vaccines Inc, Cambridge, United States

Background: Hepatitis B virus (HBV) infection among adults continue to be a major global public health concern. Prophylactic vaccination is a critical measure to prevent the spread of HBV. Sci-B-Vac®, a 3-antigen hepatitis B vaccine (3A-HBV), containing 10 μg of S (short), pre-S2 (medium) and pre-S1 (large) hepatitis B surface antigens is produced in mammalian cells and adjuvanted with aluminum hydroxide. The currently available 1-antigen hepatitis B vaccines, such as Engerix-B® (1A-HBV), contain 20 μg of S (short) hepatitis B surface antigen and are manufactured in yeast.

Purpose: Manufacturing consistency demonstrated by lot-to-lot comparison of vaccine immunogenicity and safety is required as part of the regulatory approval application, and was assessed in the pivotal Phase 3 study, CONSTANT, designed to support licensure in Canada, the U.S., and Europe.

Methods: CONSTANT was a double-blind 4-arm study designed to evaluate consistency of immune responses elicited by 3A-HBV from 3 consecutive manufacturing lots (A, B, C). Additionally, the pooled immunogenicity of 3A-HBV was compared to a comparator arm of 1A-HBV. Participants were randomized across 37 clinical study sites in Canada, USA, and Europe. The primary endpoint for manufacturing equivalence of 3 consecutive lots of 3A-HBV was defined as the 95% confidence intervals (CI) of each pairwise comparison of the ratios of geometric mean concentration (GMC) of anti-HBs being between 0.67 and 1.5. The secondary and exploratory objectives included demonstration of non-inferiority of SPR, defined as % participants with anti-HBs concentrations ≥ 10 mIU/mL, of 3A-HBV vs. 1A-HBV, kinetics of SPR, anti-HBs titers, safety and tolerability, including solicited adverse events (AEs) within 7 days and unsolicited AEs within 28-days after vaccination, serious AEs (SAEs), medically-attended AEs to end of 48 week-long study.

Result(s): 2,838 young (18–45 years old; mean age 33; females 57.8% and males 42.2%) and healthy adults were randomized across 4 arms: 1A-HBV (n = 712), 3A-HBV Lots A (n = 711), B (n = 709) and C (n = 706). The primary objective of lot-to-lot manufacturing consistency was met, with each pairwise comparison falling within the pre-defined 95% CI intervals for the GMC ratios. Compared to 1A-HBV, the pooled anti-HBs concentrations (GMC) of 3A-HBV were > 7 times higher after 2 doses and > 3 times higher after 3 doses (Fig. A). SPR of the pooled 3A-HBV was non-inferior and higher than 1A-HBV after 2 doses (90.4% vs. 51.5%) and 3 doses (99.3% vs. 94.8%) (Fig. B). Higher rates of mild or moderate injection site pain and tenderness were noted with 3A-HBV compared to 1A-HBV (75% vs. 54%). Unsolicited and medically-attended AEs were well-balanced across study arms. Rates of SAEs were low, 2.0% and 0.4%, for 3A-HBV and 1A-HBV, respectively. Vaccine discontinuations due to AEs were uncommon (0.4% and 0.2%) for 3A-HBV and 1A-HBV, respectively.

Conclusion(s): In the CONSTANT study, 3A-HBV demonstrated manufacturing consistency by lot-to-lot comparison of vaccine immunogenicity and safety. Pooled SPR and anti-HBs concentrations after 2 and 3 doses of 3A-HBV were consistently higher compared to 1A-HBV.

P072 Short course glecaprevir/pibrentasvir with ezetimibe prevents HCV transmission from HCV-positive donors to HCV-negative recipients: ongoing experience

W Aleyadeh¹, M Cypel², A Humar², I Bahinskay², JJ Feld^1,*

¹Toronto Centre for Liver Disease

²Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, Canada,

Background: The ongoing overdose crisis has led to an increasing number of potential organ donors with hepatitis C virus (HCV) infection. Multiple studies have shown that organs from individuals with HCV infection can safely be transplanted into HCV-uninfected individuals with post-transplant treatment. We previously showed that a very short course of therapy with glecaprevir/pibrentasvir combined with ezetimibe, to block HCV entry into hepatocytes, prevented chronic infection in organ recipients. Since completion of the initial trial, this protocol has been adopted as standard of care at University Hospital Network (UHN).

Purpose: To report extended follow-up on those in the initial trial and describe outcomes since adoption of the protocol as standard of care.

Methods: All patients who received an organ transplant from an HCV-infected donor and received the ultra-short protocol of glecaprevir (300mg)/pibrentasvir (120mg) plus ezetemibe (10mg oral tablet) as one pre-operative dose followed by daily dosing for 7 days after transplant were included. The primary endpoint was establishment of chronic HCV infection, defined as HCV RNA positivity 12-weeks post-transplant or the need for additional antiviral therapy after completion of the initial treatment protocol. Follow-up time was censored at last HCV RNA or death. Outcomes including graft and patient survival are described.

Result(s): The initial trial included 30 recipients from 18 donors. Median follow-up was 52 weeks (IQR 12–69), with a minimum of 12 weeks of follow-up. No patients developed chronic HCV infection. With extended follow-up to 88 months, no cases of late relapse have been reported. 6 patients died of causes unrelated to HCV infection, with 2 deaths attributed to sepsis (49 and 85 days post-transplant), 2 to cerebral hemorrhages (89 and 95 days), cardiac arrest (86 days), and respiratory failure (88 days). Since adoption of the protocol as standard of care, 15 additional patients have received organs from HCV-infected donors, with complete data on 11 to date. The cohort included 6 (55%) females and 5 (45%) males with a median age 47 years (range 20–66), including 6 (55%) White, 3 (27%) Asian, and 2 (18%) Hispanic recipients. There were 5 kidney, 4 heart, and 2 lung transplants from 10 donors. All patients completed the full treatment regimen before hospital discharge with no dose reductions or treatment discontinuations. All patients had undetectable levels of HCV RNA 2 weeks post-transplant. Four patients had positive HCV antibodies after the treatment period. Seven serious adverse events occurred in 3 (27%) recipients, with three grade 3 elevations in alanine aminotransferase (ALT) and one grade 3 elevation in total bilirubin, possibly related to treatment. Four additional transient elevations in ALT and bilirubin in three patients during the treatment period resolved with treatment completion. Three episodes of acute rejection requiring treatment were reported. One recipient died due to pneumo-sepsis (98 days post-transplant). No recipients developed chronic HCV infection. All patients were negative for HCV RNA at last follow-up visit (median 14 weeks, IQR 12–26). Data from the other 6 patients will be presented.

Conclusion(s): Ultra short-course treatment with glecaprevir/pibrentasvir plus ezetimibe prevents chronic HCV infection in recipients of organ transplants from HCV-infected organ donors with no late complications and excellent outcomes when adopted as standard of care. This short course approach is cost saving and avoids complications of delayed therapy.

P073 Higher hepatitis B surface antigen loss among whites compared to asians after stopping nucleos(t)ide analogue therapy in a large, global, multi-ethnic cohort of patients with chronic hepatitis B

G Hirode¹, ^2,*, BE Hansen¹, ², C-H Chen³, T-H Su⁴, W-K Seto⁵, G Wong⁶, S Van Hees⁷, M Papatheodoridi⁸, S Lens⁹, SM Brakenhoff¹⁰, HSJ Choi¹, R-N Chien¹¹, JJ Feld¹, ², M Sonneveld¹⁰, X Forns⁹, GV Papatheodoridis⁸, T Vanwolleghem⁷, HLY Chan⁶, M-F Yuen⁵, J-H Kao⁴, Y-C Hsu¹², M Cornberg¹³, W-J Jeng¹¹, HLA Janssen¹, ²

¹Toronto General Hospital, Toronto Center for Liver Disease

²The Toronto Viral Hepatitis Care Network (VIRCAN), University Health Network, Toronto, Canada

³Kaohsiung Chang Gung Memorial Hospital, Kaohsiung

⁴National Taiwan University Hospital, Taipei, Taiwan, Province of China

⁵The University of Hong Kong

⁶The Chinese University of Hong Kong, Hong Kong, Hong Kong

⁷Antwerp University Hospital, Antwerp, Belgium

⁸Medical School of National and Kapodistrian University of Athens, Athens, Greece

⁹Hospital Clinic Barcelona, IDIBAPS and CIBEREHD, Barcelona, Spain

¹⁰Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, Netherlands

¹¹Chang Gung Memorial Hospital, Taipei

¹²E-Da Hospital/I-Shou University, Kaohsiung, Taiwan, Province of China

¹³Hannover Medical School, Hanover, Germany

Background: While currently approved antiviral agents for the management and treatment of chronic hepatitis B (CHB) are highly effective, hepatitis B surface antigen (HBsAg) loss on therapy is rare. Despite several recent studies, the feasibility of finite nucleos(t)ide analogue (NA) therapy for CHB patients is controversial due to contradictory findings and inadequate sample sizes.

Purpose: We aim to establish and describe a global, multi-center cohort of CHB patients who discontinued NA therapy and evaluate outcomes following cessation of NA therapy.

Methods: Cohort study of virologically suppressed, end-of-therapy HBeAg negative patients with CHB who stopped NAs between 2001-2020 from 12 participating centers across North America, Europe and Asia. Patients co-infected with HIV, hepatitis C virus, hepatitis D virus, or those who received (peg)interferon treatment within a year prior to NA cessation were excluded. Cox regression models were used to analyze rates of HBsAg loss and rates of retreatment after NA cessation, and differences in rates by patient characteristics.

Result(s): Among 1528 CHB patients included (mean age 53±11 years, 72% male, 88% Asian, 10% White, 43% HBV genotype B) 85% were start-of-therapy (SOT) HBeAg negative, and 14% were SOT HBeAg positive. Majority were treated with entecavir (ETV [64%]) or tenofovir disoproxil fumarate (TDF [27%]) prior to NA cessation. Overall, 113 achieved off-treatment HBsAg loss and 717 were retreated. Total median off-treatment follow-up time was 17 (IQR: 7.2–35) months, median time to off-treatment HBsAg loss was 17 (IQR: 10–34) months, and median time to retreatment was 9.2 (IQR: 5.7–20) months. On unadjusted regression, rate of off-treatment HBsAg loss was higher among older patients (HR 1.02, p = 0.04), Whites (vs. Asians: HR 4.83, p < 0.001) and patients treated with TDF prior to NA cessation (vs. ETV: HR 1.58, p = 0.03). While not statistically significant, off-treatment HBsAg loss was higher among males (vs. females: HR 1.39, p = 0.15) and among SOT HBeAg negative patients (vs. SOT HBeAg positive: HR 1.42, p = 0.21). On adjusted regression, differences in off-treatment HBsAg loss by race/ethnicity remained significant (Whites vs. Asians [reference]: HR 4.68, p < 0.001). On unadjusted regression, rate of retreatment was higher among older patients (HR 1.02, p < 0.001) and SOT HBeAg negative patients (vs. SOT HBeAg positive: HR 1.29, p = 0.02). While not statistically significant, rate of retreatment was slightly higher among males (vs. females: HR 1.05, p = 0.58), Asians (vs. Whites: HR 1.10, p = 0.52) and those treated with ETV prior to NA cessation (vs. TDF: HR 1.11, p = 0.24). On adjusted regression, differences in retreatment by age remained significant (HR 1.02, p < 0.001).

Conclusion(s): Rate of HBsAg loss after NA cessation was nearly 5 times higher among Whites compared to Asians. There was also a trend towards higher off-treatment HBsAg loss among males, SOT HBeAg negative patients, and those treated with TDF prior to NA cessation compared to those treated with ETV.

P074 Mortality risk following HCV cure among people with HIV co-infection

NZ Janjua^1,*, S Wong¹, Y Abdia¹, S Bartlett¹, H Velasquez¹, MJ Damascene¹, H Samji¹, D Jeong¹, P Adu¹, M Pearce¹, J Wilton¹, M Alvarez¹, M Binka¹, T Buller-Taylor¹, M Krajden¹

¹BC Centre for Disease Control, Vancouver, Canada

Background: Co-infection with Human Immuno-deficiency Virus (HIV) is associated with higher morbidity and mortality compared to Hepatitis C Virus (HCV) mono-infection. Sustained virologic response (SVR) following HCV treatment is associated with reduced morbidity and mortality.

Purpose: We assessed all-cause, liver-, drug- and non-liver non-drug-related mortality following SVR among people with HIV co-infection (PWHI) compared to people with HCV mono-infection (PWHC) in a large population-based cohort in British Columbia (BC), Canada.

Methods: We used data from the BC Hepatitis Testers Cohort, which includes ~1.3 million people tested for HCV since 1990, linked with data on medical visits, hospitalizations, prescription drugs and mortality. We followed PWHC and PWHI who achieved SVR following DAA treatment to death or December 31, 2019. We computed mortality rates by HIV co-infection status and performed multivariable proportional hazard modeling to assess the effect of HIV co-infection on all-cause, liver, drug-related and non-liver and non-drug-related mortality.

Result(s): There were 10,101 people who achieved SVR following direct-acting antiviral treatment. PWHI: n = 811, person-years (PY) = 1,774.2, deaths = 78; PWHC: n = 9,290, PY = 19,464.8, deaths = 474. Median follow-up time was 1.9 years (interquartile range 0.9-3.3; maximum = 5.4). The all-cause, liver, drug and non-liver and non-drug-related mortality rate among PWHI and PWHC was 44.0 vs. 24.4/1,000PY, 5.1 vs. 9.1/1,000PY, 20.9 vs. 4.5/1,000PY, 18.0 vs. 11.9/1,000PY, respectively. In the multivariable model, HIV co-infection was associated with higher all-cause (adjusted hazards ratio (AHR): 1.54, 95% CI: 1.18–2.00), drug-related (AHR: 1.86, 95% CI: 1.20-2.90) and non-liver and non-drug related mortality (AHR: 1.57, 95% CI: 1.05–2.35), while risk of liver-related mortality (AHR: 0.78, 95% CI: 0.39–1.54) was not significant different compared to HCV mono-infection.

Conclusion(s): After successful treatment, people with HIV co-infection have similar liver-related mortality as people with HCV mono-infection, but have higher all cause, drug- and non-liver, non-drug-related mortality. Higher drug-related and non-liver, non-drug related mortality indicate tailoring services based on syndemic conditions co-occurring with HIV and HCV infections, such as substance use and mental health support and care for chronic non-communicable conditions.

P075 Beneficial effect of nucleos(t)ide analogue treatment interruption in HBeAG negative patients with chronic hepatitis B: 3 year follow up of the Toronto STOP study

A Sarowar^1,*, S Fung¹, D Wong¹, JJ Feld¹, ², S Noureldin¹, J Chen¹, C Yim¹, B Hansen¹, ³, H Janssen¹

¹Toronto Centre for Liver Disease

²McLaughlin-Rotman Centre, University Health Network

³Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada

Background: Studies have investigated the benefits of nucleos(t)ide analogues (NA) discontinuation in chronic hepatitis B (CHB) patients, however long-term follow-up (LTFU) and outcomes of those eventually retreated remain limited.

Purpose: Prospectively evaluate long term outcomes in HBeAg negative patients during NA discontinuation and retreatment.

Methods: Patients who stopped or continued NA therapy for 72 weeks in a single-center randomized controlled prospective trial were evaluated in this LTFU study. Patients were retreated according to a standardized protocol if they had HBV DNA > 20,000IU/mL, HBeAg seroreversion, or HBV DNA> 2000IU/mL with ALT> 5xULN. HBsAg loss and HBsAg decline were compared.

Result(s): Out of 66 patients eligible in this study, 45 patients stopped and 21 continued NA therapy at time of randomization. Mean duration of LTFU was 172 weeks. 23/45 stop patients required retreatment, with median time to retreatment being 23.1 weeks. HBsAg loss was achieved by 2/45 (4%) patients randomized to stop and 1/21 (5%) continue patient at LTFU. HBsAg decline > 1 log IU/mL at LTFU was achieved by 3/22 (14%) not-retreated stop patients, 1/23 (4%) retreated stop patients, and 1/21 (5%) continue treatment patients. HBsAg decline > 0.5 log IU/mL at LTFU was achieved by 9/22 (41%) not-retreated patients, 7/23 (30%) retreated stop patient, and 3/21 (14%) continue patients. During LTFU, stop patients that were retreated experienced no significant HBsAg decline before retreatment (–0.02 [–0.13 to 0.08] log IU/mL/year, P = 0.66), but experienced significant declines after retreatment (-0.10 [–0.16 to –0.03] log IU/mL/year, P < 0.01). Stop patients not retreated experienced significant HBsAg declines (–0.14 [–0.20 to –0.09] log IU/mL/year P < 0.01) while continue patients experienced no significant declines with (–0.07 [–0.14 to 0.00] log IU/mL/year, P = 0.07) No patients experienced adverse outcomes, liver decompensation, or death.

Conclusion(s): CHB patients that stop NA and are retreated have limited HBsAg declines before retreatment but higher HBsAg declines after retreatment. CHB patients after NA discontinuation, regardless of retreatment, show higher rates of HBsAg declines at LTFU compared to those that continued treatment, showing benefits not only for discontinuation but also for interruption of NA therapy.

P076 An investigation of novel hepatitis B virus quantitative serum biomarkers in hepatitis B–hepatitis D virus co-infected patients enrolled in the Canadian hepatitis B virus network

A Vachon¹, ^2,*, J Day², E Giles², S Poulin³, C Coffin⁴, S Haylock-Jacobs⁴, GY Minuk¹, K Doucette⁵, A Ramji⁶, S Fung⁷, C Cooper⁸, C Osiowy¹, ²

¹University of Manitoba

²National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg

³CISSS des Laurentides, St-Jérôme

⁴University of Calgary, Calgary

⁵University of Alberta, Edmonton

⁶University of British Columbia, Vancouver

⁷University of Toronto, Toronto

⁸University of Ottawa, Ottawa, Canada

Background: It is estimated that hepatitis D virus (HDV) affects 5% of people living with chronic hepatitis B worldwide. HBV-HDV co-infection results in severe liver disease, with a rapid progression to cirrhosis and hepatocellular carcinoma. During co-infection, HDV often suppresses HBV replication although HBV protein expression is not specifically decreased. Novel HBV biomarkers, such as quantitative measures of HBV serum RNA, HBsAg (qHBsAg), and anti-HBc antibody, (qAnti-HBc), and detection of Nucleic Acid-Related antigen (NRAg), consisting of PreS1 and core antigens, have shown utility in predicting infection progression and risk of HBV relapse or reactivation. However, these biomarkers have not been analyzed in the context of HDV co-infection for predictive value in disease phase or clinical outcome.

Purpose: The purpose of this study was to characterize the presence of novel HBV biomarkers in longitudinal serum samples from HBV-HDV co-infected individuals. Biomarkers were analyzed in association with virological and patient clinical information to elucidate their potential clinical utility in the context of HBV-HDV co-infection.

Methods: Longitudinal serum samples (n = 85) from 18 patients followed between 2010 and 2020 were retrospectively analyzed. All individuals were HDV antibody positive, with 14/18 HDV RNA positive throughout the follow-up period. Demographic and clinical information was available for all patients through the Canadian HBV Network or the treating physician. 50% of patients were treated with nucleos(t)ide analogue therapy during the follow up period, with one patient also treated with Hepcludex™ (bulevirtide). Active hepatitis was defined as ALT > 2xULN. HBV serum RNA was extracted from serum samples and measured by 3’ RACE RT-PCR methods. Serological biomarkers were measured by standard immunoassay methods. Differences between groups were determined using Fisher’s exact test for categorical variables and Mann-Whitney U-test for continuous variables. Correlations between markers were analysed using nonparametric Spearman’s rank test. Statistical significance was shown by P-values below 0.05.

Result(s): Of the 18 patients investigated (13 males, median age 43 [26-70] years, 14 HBeAg negative) the majority were non-Canadian born (72%, 13/18). Low HBV serum RNA levels (< 3 log copies/mL) were observed among most along with low to undetectable levels of HBV DNA (P < 0.0001). HBeAg positive patients with HBV DNA levels > 6 log IU/mL also had increased HBV serum RNA levels (mean 5.3 log copies/mL). Serum RNA correlated with qHBsAg (P < 0.001) and qAnti-HBc levels (P = 0.01), consistent with the active hepatitis observed in most patients (median ALT 76 U/L). Persistent detection of qHBsAg and qAnti-HBc was observed among patients, with a significant association noted between qHBsAg levels and mean elevated ALT (> 1xULN; P < 0.001). A lack of NRAg detection was observed in HDV RNA negative individuals having negligible (< 40 IU/mL) qHBsAg levels, suggesting reduced cccDNA transcriptional activity. However, positive NRAg was significantly associated with qHBsAg (P < 0.001) and elevated ALT levels (> 1xULN; P = 0.0213). Although Hepcludex™ successfully reduced HDV RNA levels over 48 weeks of treatment, all novel HBV biomarkers tested remained stable and persistent over time.

Conclusion(s): During HDV infection, novel HBV markers were observed to correlate with hepatitis and were consistent with molecular mechanisms affecting HBV and HDV activity. HBV biomarkers show potential for use in patient management of HDV co-infected patients.

P077 First case of successful viral suppression of hepatitis delta virus using low dose bulevirtide in a patient with compensated cirrhosis after failure of 1-year pegylated interferon alpha 2a therapy in canada

P Willems^1,*, B Willems¹, C Osiowy², K Swidinsky², E Huchet³, ⁴, M Poliquin⁵, S Poulin⁶, ⁷

¹Service d’hépatologie, Centre hospitalier de l’Université de Montréal, Montréal

²Viral Hepatitis and Bloodborne Pathogens Section, National microbiology laboratory, Winnipeg

³General medicine, Clinique L’Agora, Montréal

⁴General medicine, Clinique I.D., St-Jérôme

⁵Gastro-entérologie, Clinique L’Agora, Montréal

⁶Microbiologie-infectiologie, Clinique I.D., St-Jérôme

⁷Microbiologie-infectiologie, Clinique L’Agora, Montréal, Canada

Background: Bulevirtide (Hepcludex), an inhibitor of viral entry through the NTCP receptor, combined with pegylated interferon alpha-2a (PEG-IFN alpha 2a) has shown promising results in viral suppression and potential cure of hepatitis delta virus (HDV) infection in the MYR 203 study. However, this study only included a few patients with compensated cirrhosis and even fewer patients with previous therapy failure. Therefore, the efficacy of this regimen is mostly unknown when both situations are present.

Purpose: Describe the first Canadian case of viral suppression of hepatitis delta virus using low dose (2 mg) bulevirtide in a patient with compensated cirrhosis and previous pegylated interferon alpha 2a failure.

Methods: This is a report of a 38-year-old woman with biopsy-proven HDV-related compensated cirrhosis. She had previously failed a 1-year course of PEG-IFN alpha 2a therapy from 2017 to 2018 and developed portal hypertension and peri-esophageal varices while undergoing treatment. She was treated with tenofovir disoproxil fumarate (TDF) 300 mg/day, subcutaneous PEG-IFN alpha 2a 180 mcg/week and subcutaneous bulevirtide 2 mg/day as the first compassionate use in Canada. The patient was followed up every 1 to 4 weeks until week 48 for possible side effects and monitoring of HDV RNA, liver function tests and HBV biomarkers.

Result(s): Baseline liver function tests and virological parameters were as follows: ALT, 46 IU/L; total bilirubin, 10 umol/L; albumin, 38 g/L; creatinine, 63 umol/L; platelets, 170 x 10⁹/L; INR, 1.00; HDV RNA 647000 copies/mL; HDV genotype 5; HBV genotype E and quantitative HBsAg 17 715 IU/mL. After 16 weeks, HDV RNA was undetectable and liver function tests were normal. At week 35, the patient had to stop PEG-IFN alpha 2a after experiencing severe adverse effects: persistent fatigue and migraines. Bulevirtide was continued at the same dose. At week 48, HDV RNA was still undetectable and liver function tests remained normal. The bile acid levels increased from 3.0 to 248 umol/L, but the patient remained asymptomatic and did not suffer any notable adverse effects from bulevirtide therapy. There was no significant decrease in the quantitative HBsAg levels.

Conclusion(s): Low dose (2 mg) bulevirtide in combination with PEG-IFN alpha 2a was used to induce viral suppression of HDV in a patient with compensated cirrhosis, portal hypertension and previous 1-year PEG-IFN alpha 2a treatment failure. Viral suppression was successfully maintained through week 48 even after discontinuation of PEG-IFN alpha 2a. The current suppressive therapy with 2 mg bulevirtide and TDF is planned to be continued for at least a total of 96 weeks.

P078 Global real-world evidence of sofosbuvir/velpatasvir (SOF/VEL) as a highly effective treatment in underserved patient populations because of mental health disorders, incarceration or homelessness

L Barrett¹, S Rosati², M Garcia-Retortillo³, E Teti⁴, F Perez Hernández⁵, M Selfridge⁶, A Wong^7,*, S Rodriguez-Tajes⁸, L Morano⁹, C Brixko¹⁰, EJM Jiménez Mutiloa¹¹, J O’Loan¹², M Milella¹³, F Campanale¹⁴, G Macedo¹⁵, MF Guerra Veloz¹⁶, I Maida¹⁷, R Ranieri¹⁸, A Martins¹⁹, A Bascià²⁰, M Buti²¹, CM Fernandez-Rodriguez²², B Conway²³, J Foucher²⁴, S Fagiuoli²⁵, A Ramji²⁶, M Fenech²⁷, P Ryan²⁸, S Borgia²⁹, A Mangia³⁰, H Wedemeyer³¹, I Ntalla³², C Hernandez³³, M Mertens³³, K Vanstraelen³³, V. Calvaruso³⁴

¹Infectious Diseases, NSHA/Dalhousie University, Halifax, Canada

²INMI Lazzaro Spallanzani, IRCCS, Rome, Italy

³Gastroenterology Department, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain

⁴Infectious Diseases Clinic, Tor Vergata University, Rome, Italy

⁵Head of Digestive Disease Department, Complejo Hospitalario Nuestra Señora de Candelaria, Tenerife, Spain

⁶Cool Aid Community Health Centre, Cool Aid Community Health Centre, Victoria

⁷Department of Medicine, University of Saskatchewan, Regina, Canada

⁸Liver Unit, Hospital Clinic Barcelona, CIBEREHD

⁹Unit of Infectious Diseases, Alvaro Cunqueiro University Hospital, Vigo, Spain

¹⁰Dept Gatroenterol & Digest Oncol, CHR Citadelle, Liege, Belgium

¹¹Hospital Universitario Insular de Gran, Hospital Universitario Insular de Gran, Canaria, Spain

¹²Medeco Inala, Kombi Clinic, Brisbane, Australia

¹³Clinic of Infectious Diseases, University of Bari, Bari

¹⁴Local Health Department BAT, ASL BAT and Infectious Disease Consultant of Detention Center, Trani, Italy

¹⁵Dep of Gastroenterology and Hepatology, Centro Hospitalar S.João, Porto, Portugal

¹⁶Virgen Macarena University Hospital, Seville, Spain

¹⁷Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Sassari

¹⁸Chief of Penitentiary Health Service Region Lombardy, San Paolo Hospital University of Milano, Milano, Italy

¹⁹Hospital Prof Dr Fernando Fonseca, Amadora, Portugal

²⁰San Borgo San Nicola Detention Center, Lecce, Italy

²¹Department of Internal Medicine, Vall d’Hebron University Hospital, Barcelona

²²Hospital Universitario Fundacion Alcorcon, Madrid, Spain

²³Infectious Diseases, Vancouver Infectious Diseases Centre, Vancouver, Canada

²⁴Centre Hospitalier Universitaire Bordeaux, Bordeaux, France

²⁵Lombardia HCV Network, Lombardia, Italy

²⁶University of British Columbia, Vancouver, Canada

²⁷Better Access Medical Clinic, Brisbane, Australia

²⁸Infanta Leonor Hospital, Madrid, Spain

²⁹William Osler Health System, Brampton, Canada

³⁰IRCCS-Ospedale Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Italy

³¹Hannover Medical School, Hannover, Germany

³²Pharmacovigiliance and Epidemiology, Gilead Sciences Europe Ltd. UK

³³Medical Affairs, Gilead Sciences Europe Ltd. UK, Stockley Park, United Kingdom

³⁴University of Palermo, Palermo, Italy

Background: The treatment of vulnerable populations, must be prioritized to accomplish the WHO HCV elimination goals by 2030, including patients with mental health disorders, incarcerated patients or homeless patients. Simplification of the treatment cascade and rapid treatment start is key to achieve this goal, even more so in the COVID-19 era. Sofosbuvir/velpatasvir (SOF/VEL) is a protease inhibitor-free, pangenotypic, panfibrotic, single duration, single tablet regimen, to be taken without regards to food and with limited drug-drug interactions, allowing treatment simplification.

Purpose: This real-world data analysis evaluates the effectiveness and safety of SOF/VEL for 12 weeks in a heterogeneous HCV population who suffer a mental health disorder, are incarcerated or homeless.

Methods: 33 clinical cohorts across Australia, Canada, Europe & USA included 1,888 patients, 280 of them (from 6 clinical cohorts) were treated in Canada, and overall managed following local standards of care. Adults were included if SOF/VEL for 12 weeks was started before November 2019 and completed while suffering a mental health disorder, being incarcerated or homeless, irrespective of genotype (GT), presence of compensated cirrhosis (CC) or treatment experience. Exclusion criteria were history of decompensation, prior NS5A-inhibitor exposure, treatment duration > 12 weeks or addition of ribavirin. Sustained virological response (SVR; ≥ 12 weeks after end-of-treatment) and time to treatment initiation were assessed.

Result(s): Overall analysis includes 1,888 (71.3% male) patients (1,422 with a mental health disorder, 526 incarcerated, 153 homeless) aged 50 y. 24.4% were taking antipsychotic drugs and 52.2% of patients had former or current intravenous drug use. 43.2% patients had HCV GT1, 11.6% GT2, 36.3% GT3, 5.9% GT4-6, and 3.0% mixed/unknown GT. 19.0% patients had CC and 12.4% were treatment-experienced.

In 257 patients (13.6%) SVR was not evaluated, due to non-virological or unknown reason; 79.9% of those due to lost to follow-up. When SVR was measured, 98.0% (n = 1598/1631) achieved SVR, with 97.6%, 98.9% and 100% in patients with a mental health disorder, incarcerated or homeless patients respectively. SVR was 98.5% in non-cirrhotic and 95.4% in CC patients. SVR remained > 95% under antipsychotic use, or coexistence of two negative factors of non-response such as GT3 plus active drug use or psychiatric disorder. SVR was similar, irrespective of time from diagnosis to treatment. Detailed analysis of the Canadian cohort data will be presented at the conference.

Conclusion(s): A test-and-treat strategy, easily implemented with SOF/VEL, and supported by the AASLD/ALEH/APASL/EASL joint call to action, could further enhance the population-level efficacy of HCV therapy by reducing the rate of non-virologic failure due to LTFU and related factors.

P079 Non-invasive prediction of esophageal varices by transient elastography and platelet count in patients with hepatitis B and advanced chronic liver disease: validation of Baveno VI and extended Baveno VI criteria

A Zoughlami^1,*, J Serero¹, M Deschenes², P Wong¹, A Qayyum Khan¹, G Sebastiani²

¹Medicine, McGill University

²Medicine, McGill University Health Centre, Montreal, Canada

Background: Patients with compensated advanced chronic liver disease (cACLD) are at increased risk of developing complications from portal hypertension, including esophageal varices (EV). Baveno VI and extended Baveno VI criteria, based on the combination of liver stiffness measurement (LSM) by transient elastography with platelet count, have been proposed to avoid unnecessary esophagogastroduodenoscopy (EGD) screening for large esophageal varices needing treatment (EVNT). However, this approach has not been validated in patients with hepatitis B virus (HBV) chronic infection, who have etiology-specific cut-off of LSM for liver fibrosis.

Purpose: We aimed to validate the Baveno VI and extended Baveno VI criteria for EVNT in HBV patients with cACLD.

Methods: We performed a retrospective analysis of HBV patients who underwent LSM in 2014-2020. Inclusion criteria were: a) diagnosis of cACLD, defined as LSM> 9 kPa; b) availability of EGD and platelets within 1 year of LSM. Baveno VI (LSM < 20 kPa and platelets> 150,000) and extended Baveno VI criteria (LSM < 25 kPa and platelets> 110,000) were tested for EGD sparing. Diagnostic performance of these criteria against the gold standard (EGD) was computed and compared to patients with hepatitis C virus (HCV) infection and nonalcoholic steatohepatitis (NASH) etiologies, where these criteria have been widely validated. In these patients, the threshold for cACLD definition was > 10 kPa.

Result(s): A total of 287 patients (mean age 56, 95% Child A) were included, comprising of 43 HBV patients (58% on antiviral therapy), 134 HCV patients and 110 NASH patients. The prevalence of any grade EV and EVNT was 25% and 8%, in the whole cohort, while 19% and 5% in HBV patients, respectively. Table 1 reports the diagnostic performance, spared EGD and missed EVNT according to the non-invasive criteria and the etiology of cACLD. Both Baveno VI and extended Baveno VI criteria performed well in patients with HBV-related cACLD. There was no significant difference on diagnostic performance of these non-invasive criteria across the etiologies of cACLD.

Table P079

	Sensitivity (%)	Specificity (%)	NPV (%)	PPV (%)	Spared EGD (%)	EVNT missed (%)
HBV (n=43)
Baveno VI	100	44	100	8	42	0
Extended Baveno VI	100	78	100	18	74	0
HCV (n=134) Baveno VI	100	12	25	100	23	0
Extended Baveno VI	89	46	15	98	43	2.5
NASH (n=110) BavenoVI	97	37	15	99	34	1
Extended Baveno VI	78	62	19	96	58	3.8

Conclusion(s): These results support the use of non-invasive criteria based on LSM and platelets to spare unnecessary EGD in patients with HBV and cACLD. Baveno VI and extended Baveno VI criteria can ameliorate resource utilization and avoid invasive testing in context of screening EGD for patients with HBV-related cACLD.

P080 Policies for reimbursement of direct-acting antiviral treatment for hepatitis C virus infection in Canada: ‘a patchwork of obstruction’

S Bartlett¹, ^2,*, J Van Gennip³, AD Marshall⁴, ⁵, M Bonn⁶, D Fuchs⁷, G Yetman³, J Butler McPhee³, CL Cooper⁸, L Gallagher³, N Kronfli⁹, SA Williams¹⁰, J Bruneau¹¹, JJ Feld¹², NZ Janjua¹, ², M Klein⁹, J Grebely⁴

¹BC Centre for Disease Control

²University of British Columbia, Vancouver

³Action Hepatitis Canada, Toronto, Canada

⁴Kirby Institute

⁵Centre for Social Research in Health, UNSW Sydney, Sydney, Australia

⁶Canadian Association of People Who Use Drugs, Halifax

⁷Saskatchewan Health Authority, Regina

⁸Department of Medicine, University of Ottawa, Ottawa

⁹Department of Medicine, Division of Infectious Diseases and Chronic Viral Illness Service, McGill University Health Centre, Montreal

¹⁰Calgary Liver Unit, Alberta Health Services, Calgary

¹¹Centre Hospitalier de l’Université de Montréal Research Center, Montreal

¹²Toronto General Hospital, University Health Network, Toronto, Canada

Background: The first interferon-free direct-acting antiviral (DAA) hepatitis C virus (HCV) treatment regimens were approved for use by Health Canada in 2013. At that time, there were disease-stage restrictions on eligibility for reimbursement of DAAs through publicly-funded drug plans. Consistent with clinical guidelines, these reimbursement restrictions have all since been lifted. However, several other non-disease stage related restrictions persist, including the requirement to submit genotype results, even when pan-genotypic regimens are being prescribed to treatment-naïve patients, or needing two consecutive HCV RNA positive tests 6 months apart to qualify for HCV treatment. These policies prevent treatment providers from being able to implement ‘test and treat strategies’ which have been shown to accelerate HCV elimination.

Purpose: The objective of this study was to describe criteria for reimbursement of DAAs for HCV treatment in publicly-funded drug plans across Canada, and appraise them with respect to enabling or obstructing simplified or rapid HCV treatment initiation.

Methods: We reviewed the reimbursement criteria for DAAs in the 10 provincial, three territorial and three federal publicly funded drug plans including one in federal correctional facilities. Data were extracted from October to December 2020. The outcomes extracted were selected based on suggested activities put forward in the “Blueprint to Inform Hepatitis C Elimination Efforts in Canada,” released in 2019. The primary outcomes extracted were the requirement/availability of for: 1) rapid or point-of-care HCV RNA test results, 2) HCV genotype test, 3) fibrosis staging, 4) a minimum of six months between the first two positive HCV RNA test results for DAA approval; and 5) the time taken for DAA approval to be given.

Result(s): Overall, 94% (15/16) of Canadian publicly funded drug plans have at least one policy in place for DAA reimbursement approval that obstructs simplified or rapid HCV treatment initiation (Figure 1). Two plans (13%) restrict the treatment of HCV with DAAs to people with confirmed chronic infection, excluding people with unknown or acute infections until they have had two HCV RNA positive tests six months apart. Nine plans (56%) require faxed requests for treatment reimbursement approval, and five (31%) require fibrosis stage to be submitted with requests (APRI/FIB-4 or FibroScan). Six plans (38%) require genotype test results, despite the use of pan-genotypic HCV regimens for treatment-naïve patients. Only one plan (Prince Edward Island) accepts results from a finger stick HCV RNA test (e.g. Cepheid GeneXpert assay) as proof of infection only among key populations for reimbursement requests, which is through a Research Use Only exemption as the test is not Health Canada Approved.

Conclusion(s): This review of criteria for reimbursement of HCV DAAs in Canada shows substantial interjurisdictional heterogeneity in publicly-funded drug plans. These findings may inform health policy at the provincial, territorial and federal levels, allowing identification of specific policy changes that could facilitate HCV treatment uptake, particularly among priority populations. These findings further support the development and adoption of a national HCV strategy to reduce disparities in treatment access, as well as further support the rationale for a national Pharmacare program in Canada. Without the removal of these restrictions on treatment reimbursement eligibility, Canada’s progress towards elimination of HCV as a public health threat by 2030 may be jeopardized.

P081 Impact of COVID-19–related restrictions on HCV testing in British Columbia, Canada

M Binka^1,*, M Darvishian², H Velasquez¹, P Adu¹, S Bartlett¹, J Wilton¹, D Jeong¹, M Alvarez¹, A Yu¹, S Wong¹, M Pearce¹, Y Abdia¹, H Samji¹, J Wong¹, M Krajden¹, N Janjua¹

¹Clinical Prevention Services, BC Centre for Disease Control

²Cancer Control Research, BC Cancer Research Centre, Vancouver, Canada

Background: After the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19), in 2019, countries across the world including Canada implemented multiple public health measures to limit transmission of the virus. In British Columbia (BC), like many other places, these measures were first introduced in March 2020 and also resulted in the disruption of various healthcare services.

Purpose: To assess the impact of COVID-19-related public health measures on hepatitis C (HCV) testing and first-time HCV-positive diagnoses in BC.

Methods: HCV testing data for BC residents were obtained from the provincial Public Health Laboratory, which performs over 95% of screening and all confirmatory anti-HCV testing, as wells as all ribonucleic acid [RNA] and genotype testing in BC. Weekly changes in HCV testing episodes (anti-HCV, HCV RNA, and/or genotype tests performed on a unique individual within 1 day) and first-time HCV-positive diagnoses (first recorded HCV-positive test [anti-HCV/RNA/genotype] since the inception of the laboratory system) from January 2018 to December 2020 were assessed and associations determined using interrupted time series segmented regression models before versus after week 12 of 2020, when the COVID-19-related public health emergency was declared in BC. First-time RNA-negative testing following the first HCV-positive test result as a proportion of all RNA testing episodes was also assessed as a measure of progression towards viral clearance.

Result(s): Average weekly HCV testing and first-time HCV-positive diagnosis rates fell immediately following the imposition of public health measures by 62.1 and 2.9 episodes per 100,000, respectively (p < 0.0001 for both); recovering in subsequent weeks to near pre-March 2020 levels. Average weekly anti-HCV positivity rates decreased steadily pre-restrictions and this trend remained unchanged afterwards. In contrast, the average weekly proportion of first-time RNA-negative tests following first-time HCV-positive diagnoses declined steadily in the weeks after restrictions were implemented, reversing the trend observed in preceding weeks.

Conclusion(s): Decreases in HCV testing and first-time diagnoses, key barriers to progression along the HCV care cascade, occurred following the introduction of COVID-19-related restrictions. Further assessment of steps along the HCV care cascade and of HCV-related health care utilization, in addition to the monitoring of health outcomes, will be required to fully understand the impact of these disruptions. This information will support the development of strategies to re-engage people who may have been lost to care, as well as mitigate future impacts of COVID-19 pandemic-related disruptions to HCV care.

P082 Infant hepatitis B vaccination in Ontario is cost-saving: economic comparison of age-based strategies and disease impact from 2020-2050

M Biondi^1,*, C Estes², D Razavi-Shearer², K Sahdra³, N Lipton³, H Shah¹, C Capraru¹, H Janssen¹, H Razavi², JJ Feld¹

¹Viral Hepatitis Care Network (VIRCAN), University Health Network, Toronto, Canada

²Center for Disease Analysis, Lafayette, United States

³Toronto Centre for Liver Disease, University Health Network, Toronto, Canada

Background: The World Health Organization has prioritized HBV birth dose vaccination as a key tenet in the global strategy for HBV elimination. However, 30 years after the initiation of birth dose vaccination and adoption among 100+ countries, only 3 provinces/territories in Canada provide birth dose vaccination, 5 vaccinate in infancy, and 5 in adolescence; including Ontario where vaccination occurs in grade 7. We recently demonstrated that children born in Canada are acquiring HBV before vaccination, providing scientific and public health rationale for policy change.

Purpose: Here, we compared five different approaches (see Table) for vaccination timing based on direct and health outcomes to determine which approaches would be cost-effective or cost-saving compared to current adolescent vaccination from 2020 to 2050.

Methods: The PRoGReSs model was used to quantify the future disease and economic burden of chronic HBV infection in Ontario where the infected population, including the impact of immigration on the HBV disease burden from the top ten high-endemic source countries. Direct costs (healthcare, screening, prophylaxis, diagnostic, and treatment costs) and indirect costs (disability-adjusted life years and the value of a statistical life year) were calculated.

Result(s): The impact of four general population vaccination strategies were compared to a base scenario of adolescent vaccinations. All intervention scenarios involving infant vaccination were projected to prevent greater than 560 (37%) of acute and 160 (30%) of chronic cases. Vaccinating at birth with additional doses at 2 and 6 months only led to slightly higher cumulative direct medical costs of $3.34B compared to $3.33B with the adolescent strategy. However, incorporating HBV vaccination into the hexavalent approach at 2, 4, and 6 months, reduced costs to $3.31B. Perhaps more importantly, cumulative costs were 1% lower than the base scenario when given at 2, 4, 6 months as a part of the hexavalent: leading to an overall cost saving of $23M. In addition to taking into account the cost of preventing new HBV cases, and all that is required in terms of care and treatment, this scenario resulted in $428,000 cost saving per DALY averted (see Figure). Our model demonstrates no additional costs incurred at the time of switching from adolescent to infant vaccination, and ongoing cost-saving to 2050.

Table P082: HBV Age-Related Vaccination Strategies

Scenario	Vaccine Administration	Description
1	Base Scenario (current adolescent schedule)	Two pediatric HBV doses in Grade 7
2	3 individual doses (0, 1, 6 months)	Three pediatric HBV doses in the first year of life
3	2 individual, 1 combined (0, 1, 6 months)	Two pediatric HBV doses, final dose hexavalent on the same schedule as current pentavalent
4	1 individual, 2 combined (0, 2, 6 months)	One dose of pediatric HBV, two doses of hexavalent on the same schedule as current pentavalent
5	3 combined (2, 4, 6 months)	Three doses of hexavalent on the same schedule as current pentavalent

Conclusion(s): Revising the current vaccination strategy in Ontario from adolescent vaccination to vaccination at birth or in the first year of life would reduce new HBV infections. Specifically, birth dose vaccination would be cost-effective, while aligning vaccination with existing infant vaccinations would make the change cost-saving. Ontario should consider revising its current vaccination policy as part of a comprehensive plan to mitigate disease burden.

P083 Birth cohort hepatitis C antibody prevalence in real-world screening settings

M Biondi^1,*, G Hirode¹, C Capraru¹, B Wolfson-Stofko¹, A Vanderhoff¹, J Karkada¹, S Friedman², K Bates³, T Mazzulli⁴, J Juan⁵, H Shah¹, B Hansen¹, JJ Feld¹, H Janssen¹

¹Viral Hepatitis Care Network (VIRCAN)

²Department of Emergency Medicine, University Health Network

³Emergency Department, Toronto Western Hospital, University Health Network

⁴Department of Laboratory Medicine and Pathobiology, University of Toronto

⁵Albany Medical Clinic, Toronto, Canada

Background: Widespread screening and treatment of hepatitis C virus (HCV) will be required to decrease late-stage liver disease presentation and related complications. However, primary healthcare and community providers in Canada remain hesitant to implement one-time birth cohort screening among individuals born between 1945 and 1975 – potentially due to competing Task Force recommendations.

Purpose: To conduct a real-world analysis of HCV antibody (Ab) prevalence among a large number of individuals born between 1945 and 1975, categorized by screening site.

Methods: HCV Ab testing was conducted at multiple sites in Canada between January 2016-December 2020 through point-of-care or conventional testing. We analyzed trends in HCV Ab testing and prevalence among the 1945-1975 birth cohort. Multivariable logistic regression was used to analyze differences in HCV Ab prevalence by site. Sites were categorized as screening events, community outreach, addiction centres, primary care, hepatology department, emergency departments (ED)/walk-in clinics, or other.

Result(s): From 2016 to 2020, 20,488 HCV tests were conducted among birth cohort individuals (mean age at time of test 57.6±8.2 years, 48.6% male). Overall HCV Ab+ prevalence was 3.1%. HCV Ab+ prevalence was highest at addictions centres (27.3%), followed by community outreach (11.2%). Majority of testing occurred in primary care (9,884 tests), with a prevalence of 1.3%. Considerable testing also occurred at hepatology departments (4,293 tests) and ED/walk-in clinics (3,326 tests), with HCV Ab+ prevalence of 5.3% and 1.6%, respectively. Compared to screening events, odds of a HCV Ab+ test result was higher at addictions centres (OR 13.3, 95% CI 8.4–21.2, p < 0.001), during community outreach (OR 6.0, 95% CI 3.7–9.7, p < 0.001), and at hepatology departments (OR 3.0, 95% CI 1.9–4.6, p < 0.001). Odds of a HCV Ab+ test result was also higher among younger birth cohort individuals (OR 0.98, 95% CI 0.96–0.98, p < 0.001), and males (vs. females: OR 1.6, 95% CI 1.3–1.9, p < 0.001).

Conclusion(s): Although recommended in Canadian guidelines, birth cohort screening uptake by Canadian providers remains a challenge. Our data demonstrates that HCV Ab+ prevalence was very high in those seen in addictions centres – potentially individuals who may be less likely to access primary or community care. However, within the birth cohort screened in primary care, HCV Ab+ prevalence was higher than the national average. These data highlight the need to challenge existing Task Force recommendations, to incorporate birth cohort HCV screening into the primary care workflow as a preventative health indicator, and to increase training among primary care providers to treat HCV.

P084 Prevalence of chronic hepatitis B amongst a population-based prep program in British Columbia, Canada

G Blank^1,*, J Toy², D Moore², N Lachowsky³, N Bacani², W Zhang², P Sereda², V Lima², R Barrios², J Montaner², M Hull²

¹Faculty of Medicine, Undergraduate Program, University of British Columbia

²BC Centre for Excellence in HIV/AIDS, Providence Health Care, Vancouver

³School of Public Health & Social Policy, Faculty of Human & Social Development, University of Victoria, Victoria, Canada

Background: Pre-exposure prophylaxis (PrEP) for preventing HIV is standard of care among men who have sex with men (MSM) and other populations. Use of tenofovir/emtricitabine for HIV PrEP also serves as therapy for hepatitis B (HBV), and assessment of HBV status is recommended at PrEP start.

Purpose: Currently limited numbers of HBV-infected individuals were included in PrEP trials, and limited information is available regarding PrEP use in those living with HBV. We sought to characterize baseline HBV status and monitoring in individuals receiving PrEP in British Columbia (BC), Canada.

Methods: Enrollment in the BC PrEP program requires reporting of HBV status for medication approval. We evaluated the baseline prevalence of HBV defined based on physician-report or positive HBV surface antigen from 6 months prior to 3 months following PrEP start over the period of 1-Jan-2018 to 30-Jun-2019. We assessed the proportion of HBV positive individuals with evaluation of HBV DNA status as a measure for engagement in HBV care. We then compared baseline demographic characteristics including age, gender, PrEP-qualifying risk factors, and urban versus rural location between those with and without HBV using bivariate analyses.

Result(s): Overall, 4760 individuals (98% male) were enrolled in the PrEP cohort with median age 33 years (Q1-Q3: 27-43 years). For those with elevated HIRI-MSM scores as the PrEP-qualifying criterion, the median index score was 19 (Q1-Q3 15–24); 20% also reported prior rectal STI or syphilis as a PrEP-qualifying criterion. The HBV prevalence was 0.86%, including 19 laboratory-confirmed HBV cases (among n = 1826 with available results) and 22 physician-reported cases. Of those with HBV, the median baseline ALT was 44 IU/mL (Q1-Q3: 22-66 IU/mL), 70.7 % (n = 29/41) had at least one HBV DNA measured during the study period, and 53.7% (n = 22/41) had follow-up of HBV DNA with 95% (n = 21/22) achieving viral suppression over the study period. The prevalence of reported prior bacterial rectal STI or syphilis was lower in HBV-positive individuals (7.32% versus 20.17%, p = 0.048), however there was no statistically significant difference in age, gender, urban vs. rural location, HIRI-MSM score, or other PrEP-qualifying criteria.

Conclusion(s): Chronic HBV infection was seen in 0.89% of PrEP users in British Columbia, though a significant proportion did not undergo baseline or follow-up of HBV parameters. This underscores the need for further PrEP provider education.

P085 Hepatitis C prevalence in a population-based HIV-prep program in British Columbia, Canada

G Blank^1,*, J Toy², D Moore², N Lachowsky³, N Bacani², W Zhang², P Sereda², V Lima², R. Barrios², J Montaner², M Hull²

¹Faculty of Medicine, University of British Columbia

²BC Centre for Excellence in HIV/AIDS, Providence Health Care, Vancouver

³School of Public Health & Social Policy, Faculty of Human & Social Development, University of Victoria, Victoria, Canada

Background: Hepatitis C (HCV) is commonly acquired through injection drug use, and men who have sex with men (MSM) may be at increased risk for HCV through sexual transmission, intravenous or other methamphetamines use. Research from a France cohort has suggested a similar incidence of HCV in MSM using pre-exposure prophylaxis (PrEP) and patients with HIV (1). However, evidence for HCV infection in the context of PrEP use in North America is limited.

Purpose: To better understand HCV infection in a Canadian PrEP cohort, we sought to characterize baseline HCV prevalence, HCV incidence, and associated HCV risk factors in individuals receiving PrEP in British Columbia (BC). In turn, this information will allow providers to deliver more effective counseling and preventative care to PrEP users.

Methods: The study included individuals enrolled in the BC PrEP program from 1-Jan-2018 to 30-Jun-2019. We evaluated baseline prevalence of HCV, defined as either positive HCV antibody or HCV RNA drawn within 12 months prior to or 3 months following PrEP start. We conducted a multivariate logistic regression model of factors associated with HCV prevalence including age, gender, HIV risk factors, HIRI-MSM risk index, and reported prior STI in those with HCV laboratory results.

Result(s): Baseline HCV prevalence was 0.74% (n = 35 in the overall cohort of 4760 individuals), or 0.89% when restricted to those with available laboratory results (n = 3967). Of the 35 baseline HCV positive cases, 31 were MSM. In bivariate analysis, those with HCV were older (median age 41 vs. 32 years, p = 0.003), had elevated median HIRI-MSM (22 versus 19, p = 0.008), higher reported prior bacterial-rectal STI or syphilis infection (37.1% versus 20.1%, p = 0.006), and were more likely to have a partner with detectable HIV viral load or who is not on stable antiretroviral therapy (28.6% versus 5.4%, p < 0.001). Female PrEP users were also more likely to have HCV (7.8% vs. 0.79%, p < 0.001). In multivariate analysis, older age (aOR 1.60; 95% CI 1.20–2.14), having a HIV-positive partner with unsuppressed viral load (aOR 4.65; 95% CI 1.71–12.57), and higher HIRI-MSM risk score (aOR 1.09; 95% CI 1.04–1.14) remained associated with HCV status.

Conclusion(s): Baseline HCV prevalence was low amongst a population-based PrEP program in BC, Canada. HCV was more common among those with a higher HIRI-MSM score and who had partners with unsuppressed HIV viral loads. Routine HCV testing in those initiating PrEP should be considered, and longer-term follow-up for incident infections is required.

References

1Cotte L, Cua E, Reynes J, Raffi F, Rey D, Delobel P, Gagneux-Brunon A, Jacomet C, Palich R, Laroche H, Cabie A, Hoen B, Chidiac C, and Pradat P. (2018). Hepatitis C virus incidence in HIV-infected and in preexposure prophylaxis (PrEP)-using men having sex with men. Liver International, 38(10), 1736–1740. https://doi.org/10.1111/liv.13922

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P086 Comparison of clinical and virologic characteristics of chronic hepatitis B patients with hepatitis B surface antigen clearance or persistence of low-level quantitative hepatitis B surface antigen

C Coffin^1,*, S Haylock-Jacobs¹, K Doucette², A Ramji³, HH Ko³, C Cooper⁴, DK Wong⁵, M Elkhashab⁶, R Bailey⁷, GY Minuk⁸, K Tsoi⁹, A Wong¹⁰, M Ma², E Tam¹¹, M Brahmania¹², C Nudo¹³, J Zhu¹⁴, C Osiowy¹⁵, E Chan¹⁶, A Villasis Keever¹⁷, U Sbarigia¹⁸, S Fung⁵

¹Department of Medicine, University of Calgary, Calgary

²Department of Medicine, University of Alberta, Edmonton

³Division of Gastroenterology, University of British Columbia, Vancouver

⁴Division of Infectious Diseases, University of Ottawa, Ottawa

⁵Department of Medicine, University of Toronto

⁶Toronto Liver Centre, Toronto

⁷Bailey Health Clinic, Edmonton

⁸Department of Internal Medicine, University of Manitoba, Winnipeg

⁹McMaster University, Hamilton

¹⁰Department of Medicine, University of Saskatchewan, Regina

¹¹Pacific Gastroenterology Associates, Vancouver

¹²Division of Gastroenterology, Western University, London

¹³Hopital de la Cite-de-la-Sante, Laval

¹⁴Dalhousie University, Halifax

¹⁵National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Canada

¹⁶Janssen Pharmaceuticals, Raritan

¹⁷Janssen Pharmaceuticals, Titusville, United States

¹⁸Janssen Pharmaceuticals, Brussels, Belgium

Background: Chronic hepatitis B (CHB) functional cure is defined as a sustained loss of serum HBV surface antigen (HBsAg) but is rarely achieved by oral nucelos(t)ide analog therapies. In individuals with HBsAg loss and very low-level quantitative HBsAg (qHBsAg) (i.e., < 100 IU/mL), studies suggest potential for improved immune control and reduced liver disease. Most epidemiologic studies of CHB outcomes associated with qHBsAg levels were done in large Asian cohorts. A study by the Canadian Hepatitis B Network (CanHepB) of 9380 patients had shown a multi-ethnic, diverse cohort of individuals living with CHB¹.

Purpose: To compare clinical characteristics within a multi-ethnic cohort of patients who achieved HBsAg loss (-) to patients with persistence of low level qHBsAg (i.e., qHBsAg < or > 100 IU/mL).

Methods: In this cross-sectional multi-centre retrospective study, adult patients with CHB seen at any time from January 1, 2012 – January 30, 2021, with standard-of-care clinical and virological data within 1 year of HBsAg testing were analysed. HBsAg was tested using commercial qualitative and/or quantitative assays (i.e., Abbott Architect or Roche Elecsys) and patients were grouped based on HBsAg levels (negative, < 100, and > 100 IU/mL). Baseline data were summarized using descriptive statistics and groups compared by univariate/multivariate analysis.

Result(s): Among 6882 patients enrolled in the CanHepB network database, 781 patients with available qHBsAg data were included (HBsAg(−), n = 229; qHBsAg < 100 IU/mL, n = 135; qHBsAg > 100 IU/mL, n = 417) (Figure 1). The majority of patients were of Asian descent (n = 688 known, 77.3% Asian, 4.9% Caucasian, 14.4% Black). Median age was 49.6 years, individuals with higher HBsAg > 100 tended to be younger (i.e., HBsAg(−) 53.1 years; qHBsAg < 100 IU/mL 56.4 years; qHBsAg > 100 IU/mL 45.6 years, p < 0.001). HBsAg+ subjects with qHBsAg < 100 IU/mL were more likely to be of Asian ethnicity (83.3%) compared with HBsAg(−) group (72.5%, p = 0.032). In those who received NA (56.2%, 439/781), 61% (268/439) received tenofovir based therapy. The proportion and total duration of antiviral treatment for each group was: HBsAg loss - 39.7%, 86.1 months (95% CI 74.9–97.3), qHBsAg < 100 – 56.3%, 104.9 months (95% CI 90.5–119.2), and > 100 qHBsAg – 65.2%, 87.6 months (95% CI 75.4–99.7). The proportion with undetectable HBV DNA (viral load tested within 1 year of HBsAg test) was 74.5% HBsAg(−), 50% HBsAg < 100, 34.1% qHBsAg> 100 IU/mL, p < 0.001. There were no significant differences in comorbidities. Hepatocellular carcinoma was less likely to be reported in the HBsAg(−) group (0.9%) than qHBsAg < 100 IU/mL (10.4%) or qHBsAg > 100 IU/mL (4.8%) groups (p < 0.001). Cirrhosis was also less likely in HBsAg(−) patients (5.7%, 15.6%, 7.4%, respectively p = 0.003). Mean liver stiffness measurement by transient elastography was lower in the HBsAg(−) group (5.7 kPa [5.2–6.3]) compared to patients with qHBsAg < 100 IU/mL (8.5 kPa [6.5–10.4], p = 0.004), but not qHBsAg > 100 IU/mL patients (6.0 kPa [5.5–6.5]), based on one-way ANOVA.

Conclusion(s): In this real-world, cross-sectional, retrospective study, cirrhosis and HCC was less frequently diagnosed in Canadian CHB patients who achieved HBsAg loss. Individuals with very low-level HBsAg (< 100 IU/mL) were still at risk for advanced liver disease, highlighting the need for ongoing monitoring, improved biomarkers to predict liver disease risk, and therapies to achieve HBV functional cure.

References

1Coffin CS et al., CMAJ Open, 2019.

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P087 Interventions to enhance testing and treatment uptake for hepatitis C infection: a systematic review and meta-analysis

E Cunningham^1,*, A Wheeler², S Bajis², A Conway², L Degenhardt³, GJ Dore¹, C French⁴, G Fontaine⁵, B Hajarizadeh¹, M Hickman⁴, A Marshall¹, R Roche⁶, BM Valencia¹, P Vickerman⁴, J Ward⁷, J Grebely¹

¹Kirby Institute, UNSW Sydney, Sydney

²Kirby Institute, UNSW Sydney, Randwick

³National Drug and Alcohol Research Centre, UNSW Sydney, Sydney, Australia

⁴Health Protection Research Unit, Population Health Sciences, University of Bristol, Bristol, United Kingdom

⁵Research Center, Montreal Heart Institute, Montreal, Canada

⁶Public Health England, London, United Kingdom

⁷Program for Viral Hepatitis Elimination, Task Force for Global Health, Centers for Disease Control and Prevention, Atlanta, United States

Background: Hepatitis C virus (HCV) elimination efforts require evidence-based interventions to improve the HCV care cascade.

Purpose: We conducted a systematic review to assess the effect of interventions to enhance HCV testing, linkage to care, treatment uptake, treatment outcomes and post-treatment follow-up. This analysis focuses on interventions to enhance HCV testing and treatment uptake.

Methods: We searched bibliographic databases and conference abstracts for studies assessing interventions to improve stages of the HCV care cascade. To be included, studies needed to include a comparator. No restrictions on date or population were made. Meta-analysis was used to pool the effect of interventions on study outcomes.

Result(s): From 16,191 unique records assessed, 219 studies were included. Most studies (k = 210) were conducted in 22 high-income countries with nine studies occurring in seven middle-income countries. The most common study populations included general population (k = 66), birth cohort (k = 39), people receiving opioid agonist therapy (OAT; k = 15), people in prison (k = 14) and people who inject drugs (k = 13). Data from 94 studies revealed the interventions which improved HCV antibody testing uptake included medical chart reminders (n = 24; pooled odds ratio [OR] 6.75; 95% confidence interval [CI] 4.32–10.56), provider education (n = 11; OR 2.01; 95% CI 1.62–2.50), patient education (n = 6; OR 4.18; 95% CI 1.25–13.96), dried blood spot testing (n = 4; OR 4.26 95% CI 1.22–14.85), and point of care (POC) testing (n = 4; OR 23.43; 95% CI 8.20–66.98). Data from 48 studies revealed interventions which improved HCV treatment uptake (Interferon-therapy: n = 25, direct acting antiviral (DAA)-therapy: n = 23) included patient navigation (n = 4; OR 3.48; 95% CI 1.66–7.26), integrated care (n = 4; OR 5.74; 95% CI 1.04–31.54), and psychological therapy (n = 3; OR 2.20; 95% CI 1.47–3.28).

Conclusion(s): Several interventions were identified which improved HCV testing and treatment uptake. There remains limited data for several interventions, including POC testing for treatment uptake, particularly in low- and middle-income countries.

P088 Implementing opt-out hepatitis C virus screening in canadian provincial prisons: a model-based cost-effectiveness analysis

L Duchesne^1,*, C Dussault², A Godin³, M Maheu-Giroux³, N Kronfli⁴, ⁵

¹Universite de Nantes, Nantes, France

²Research Institute of the McGill University Health Centre

³Department of Epidemiology, Biostatistics, and Occupational Health, School of Population and Global Health, McGill University

⁴Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montreal

⁵Department of Medicine, Division of Infectious Disease and Chronic Viral Illness Service, McGill University Health Centre, Montreal, Canada

Background: People incarcerated in prison represent a key population for hepatitis C virus (HCV) micro-elimination. As most Canadian provincial prisons offer risk-based HCV screening, a minority of incarcerated individuals undergo testing. An essential first step towards micro-elimination is the implementation of systematic opt-out HCV screening. In provincial prisons, where short incarcerations, unplanned transfers, and high turnover rates exist, cost-effectiveness studies are needed to determine screening strategies that rapidly link incarcerated individuals to HCV care.

Purpose: We aimed to assess the cost-effectiveness of 14 opt-out screening strategies in Quebec’s largest provincial prison, l’Établissement de Détention de Montréal (EDM).

Methods: A Markov micro-simulation model using daily cycles was developed to model a prison cohort of 50,000 individuals and assess the cost-effectiveness of the strategies (compared to reference standard: venipuncture-based HCV-antibody and HCV-RNA). The model considered incarceration lengths, time to linkage to care, and tests’ performances, acceptability and turnaround times. Strategies included point-of-care (POC) testing, venipuncture, dried blood spot, and a 1 to 2-test sequence using different biomarkers (HCV-antibody, HCV-RNA, HCV-core antigen). Costs (tests and nursing) were estimated over a one-year time horizon in 2020 Canadian dollars (CAD), adopting a health-payer perspective. Using the number of true positives linked to care (TPs-L/10,000 incarcerations), incremental cost-effectiveness ratios (ICERs) were calculated (additional CAD$/additional TP-L) compared to the next best strategy. Base-case and sensitivity analyses (both deterministic and probabilistic) were performed.

Result(s): In the base-case analysis, combining venipuncture-based HCV-Ab and HCV-cAg was the least expensive strategy (204 TPs-L; CAD $16/incarcerated individual). Three strategies provided the best value for money: HCV-cAg testing via venipuncture (224 TPs-L; ICER = CAD $721), POC HCV-antibody and HCV-RNA (254 TPs-L; ICER = CAD $4,308), and POC HCV-RNA (256 TPs-L; ICER = CAD $199,374). Despite high diagnostic performances, these four strategies only linked 23%, 25%, 28% and 29% of viremic individuals to care, respectively. In the sensitivity analyses, reducing the time to either notification (of diagnosis) or post-diagnosis clinical appointment, or the likelihood of disengagement at every step of the cascade increased all strategies’ effectiveness. The main drivers of cost-effectiveness were prison-based HCV prevalence, proportion viremic, HCV-RNA POC test costs, tests’ performances, and time to linkage to care. Based on a cost-effectiveness acceptability curve exploring willingness-to-pay values up to CAD $150,000, two cost-effectiveness thresholds were identified. Venipuncture-based HCV-Ab and HCV-cAg had the highest probability of being the most cost-effective strategy (willingness-to-pay < CAD $1,250), followed by venipuncture-based cAg (CAD $1,250 < willingness-to-pay < CAD $2,800), and POC HCV-Ab and HCV RNA (willingness-to-pay> CAD $2,800).

Conclusion(s): Alternative HCV screening strategies are more cost-effective than standard of care if systematic opt-out screening was implemented in provincial prisons. Our findings also underscore the need to explore interventions that maximize linkage to care, both during incarceration and following release, and that reduce the time between cascade steps to minimize those who are lost to care.

P089 Resilience and creativity expanding hepatitis C awareness and access to care with Indigenous communities in Alberta

K Dunn^1,*, K Delina², S Lee³, M Potestio¹, K Williams¹

¹Indigenous Wellness Core, Alberta Health Services, Calgary

²Indigenous Wellness Core, Alberta Health Services, Edmonton

³Liver Unit, University of Calgary, Calgary, Canada

Background: Hepatitis C Virus (HCV) infections represent a major public health burden in Canada, leading to more life-years lost than any other infectious disease. Indigenous population (consisting of First Nation, Métis and Inuit) HCV incidence rates are higher compared to non-Indigenous Canadians. Extension for Community Health Outcomes (ECHO+) in Alberta aims to increase access to HCV treatment through a hepatologist-led hub and spoke model focusing effort working with Indigenous communities designing a model of care tailored to local needs.

Purpose: ECHO+ partners with Indigenous communities in co-designing an approach supporting local goals through building relationships and developing practical tools removing barriers while increasing awareness, screening for HCV, and access to specialist care within the community’s health infrastructure.

Methods: Embedding the 5 R’s of Indigenous Research Methodology into practice by building a predominantly Indigenous team, following local protocol for relationship and knowledge sharing, and incorporating Respect, Relationship, Relevance, Reciprocity, and Responsibility into all aspects is reflected in the iterative grounding of holistic knowledge. Building relationship while offering an opportunity to support local community; developing culturally safe relevant resources delivering scientifically sound messaging; building infrastructure facilitating sustainability; and supporting community directed implementation and expansion to include other health concerns. Although original plans included in person community visits and liver health events, the pandemic necessitated a shift in focus. Virtual invitations have been extended to every Indigenous community in the province, as well as taking time to interview practitioners utilizing the ECHO+ platform to identify barriers to local care pathways where the ECHO+ team can support minimizing or eliminating identified barriers. Virtual Presentations covering HCV awareness topics, and interactive technology implementation such as Menti, QR code embedded information, surveys, and e-technology monthly newsletters have increased community HCV awareness and facilitated ECHO+ support with culturally relevant resources, mailed resources packages, and sharing of lived experience stories from youth and Elders. Biweekly meetings with community health care teams utilizing Zoom technology have expanded during the pandemic to include infectious disease specialist’s taking questions regarding COVID as well as hepatologist case consults for HCV and other liver diseases. Shifting the annual ECHO+ liver conference to a virtual platform in 2020 allowed increased community representation attendance as well as community practitioner panel discussion and networking. Monthly multi-organizational and jurisdictional collaborative and community represented advisory committee meetings guide the community engagement approach, as well as advise and support project functioning and expansion.

Result(s): This approach has increased community communication and involvement while doubling the number of engaged communities, and increasing support treating HCV during the pandemic. NIHB data indicating an increase in HCV DAA prescriptions showing steady increase over the past five years likely resulting from implementation of ECHO+.

Conclusion(s): Creative technologically supported approaches alongside persistent team efforts to build and maintain relationship have supported the breakdown of barriers and the continuation of HCV screening, care and treatment in Indigenous communities in Alberta.

P090 Modelling the impact of direct-acting antiviral treatment uptake on hepatitis C transmission among people who inject drugs in Ontario

ZR Greenwald¹, ^2,*, AE Simmons¹, AR Tuite¹, DN Fisman¹, D Werb², ³, ⁴, JJ Feld⁵, NK Martin⁴, ⁶

¹Dalla Lana School of Public Health, University of Toronto

²Centre on Drug Policy Evaluation, Li Ka Shing Knowledge Institute, St. Michael’s Hospital

³Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada

⁴Division of Infectious Diseases and Global Public Health, University of California San Diego School of Medicine, La Jolla, United States

⁵Toronto Centre for Liver Disease, University Health Network, Toronto, Canada

⁶Population Health Sciences, University of Bristol, Bristol, United Kingdom

Background: Canada’s progress towards attaining the global hepatitis C virus (HCV) elimination target for reducing HCV incidence by 80% by 2030 will depend on successful treatment and prevention of HCV among people who inject drugs (PWID). Yet, direct-acting antiviral (DAA) treatment uptake rates remain low among PWID relative to other key populations. Mathematical modelling can project the effects of scaling up DAA treatment among PWID and inform treatment scenarios required to attain elimination targets.

Purpose: Develop and use a dynamic mathematical model to project the impact of DAA treatment scale-up on HCV incidence among PWID in Ontario, Canada from 2021-2035.

Methods: We developed a modified susceptible-infectious-susceptible (SIS) dynamic compartmental HCV transmission model which incorporates additional compartments to account for chronic infection, spontaneous clearance, and treatment-induced clearance (sustained virologic response [SVR]). We assumed a fixed population size of 76,700 current PWID in Ontario (i.e., injecting drug use cessation rate equals initiation rate) with an average duration of injection drug use of 11 years. The model was calibrated to align with HCV seroprevalence among current PWID in 2011 (66%) and estimated SVR attainment among ever-infected PWID by 2018 (14%). We used our model to project incident HCV cases among PWID in Ontario from 2015 to 2035 while varying DAA treatment uptake scenarios beginning in 2021. Harm reduction interventions were held stable at 2011 levels. Intervention scenarios include fixed DAA treatment uptake of 25/1,000 PWID (base-case estimate for current treatment uptake among PWID), 40/1,000 PWID, 50/1,000 PWID, 60/1,000 PWID, and 70/1,000 PWID treated per year.

Result(s): Following the base-case scenario of 25/1,000 PWID treated per year and stable access to harm reduction interventions, only 1% of new HCV infections will be averted in 2030 compared to 2015 (3,973 vs 4,031 infections in 2030 and 2015, respectively), falling far below the 80% reduction required to attain the HCV incidence reduction elimination target (figure 1). Scaling DAA treatment uptake up to 40/1,000, 50/1,000 PWID, or 60/1,000 PWID treated per year would avert an estimated 14%, 30%, or 55% of incident HCV infections in 2030, respectively. Treating 70/1,000 PWID per year would allow Ontario to meet the HCV incidence reduction elimination target in 2029.

Conclusion(s): These findings suggest that with a substantial increase in DAA treatment, HCV incidence can be driven below 2030 elimination targets among PWID in Ontario. A combination of harm reduction interventions including increased opioid agonist therapy, needle and syringe programs, and supervised consumption site access alongside DAA treatment scale-up will be the most efficient method to attain HCV elimination targets among PWID in Ontario. Our analysis will be expanded to project simultaneous scale-up of harm reduction and DAA treatment uptake.

P091 Distribution and management strategies to eliminate hepatitis C virus in the Asia-Pacific region

F Ahmed¹, P Guntipalli^1,*, R Pakala¹, S Gara¹, M-K Coronel¹, A Bhatnagar¹, Z Yukselen¹, J Okwundu², S Mishra¹, F Pacha³, E Shahini⁴, M Mouchli⁵

¹Division of Clinical and Translational Research, Larkin Community Hospital, South Miami, United States

²HIV vaccine trials network, Desmond Tutu HIV centre University of Cape Town, Cape Town, South Africa

³Department of Gastroenterology, Larkin Community Hospital, South Miami, United States

⁴Department of Gastroenterology, Institute for Cancer Research and Treatment, Turin, Italy

⁵Department of Gastroenterology, Cleveland Clinic, Cleveland, United States

Background: Hepatitis C virus (HCV) infection rates are unevenly distributed worldwide. The Asia-Pacific region displays the highest percentage of Hepatitis C–related deaths, with 74% of global deaths occurring from hepatocellular carcinoma. The 2016 World Health Assembly approved a global strategy to reduce new infections by 90% and deaths by 65% and ultimately eliminate the HCV public health threat by the year 2030.

Purpose: The study aims to describe the HCV prevalence, genotypic variance, treatment, and prevention strategies in the Asia-Pacific region.

Methods: A comprehensive literature search was done utilizing PubMed, Google Scholar, Cochrane, Science Direct, and Scopus databases. The study included 45 relevant articles using the following search terms: epidemiology, the HCV genotypes and subtypes, current HCV management, and the policies being implemented to eliminate HCV risk.

Result(s): Viremic prevalence rates for Japan, South Korea, China, Pakistan, India, Indonesia, Malaysia, Philippines, and Thailand were 0.7%, 0.5%, 0.7%, 3.8%, 0.5%, 0.5%, 1.2%, 0.6% and 0.7% respectively. Australia and New Zealand individually have a viremic prevalence rate of 1%. The most predominant genotype in Asia-Pacific countries is genotype (GT) 1, followed by GT2, GT3, GT4, and GT6 depending on the region. The countries of the Asia-Pacific region have employed national plans and preventative measures to control HCV rates, such as policy and advocacy, reliable data to manage implementation of policy, needle syringe programs (NSP) activities, peer education, community-based hepatitis support groups, and harm reduction strategies aimed at prisoners and people who inject drugs. Examples of this include Pakistan’s Hepatitis Education, Prevention, Advocacy, Information, Diagnosis (HEPAID), the Philippines’ “Yellow Warriors”, and Indonesia’s comprehensive 5-year plan to decrease the spread of viral hepatitis. Vaccines represent the most cost-effective strategy to prevent any infectious disease. Unfortunately, given the high sequence variation of HCV, vaccine development continues to be a challenge across the Asia-Pacific Region. The potential vaccine would need to be able to provide full protection from all seven HCV genotypes and most of the subtypes. The data infers that the HCV vaccine, even if only moderately efficacious, will play a key role in HCV elimination over the next 15–20 years.

Treatment modalities for HCV include antivirals and oral direct acting antivirals (DAAs) therapy (e.g. inhibitors of NS3/4A protease, the NS5A protein, and NS5B polymerase). There is, however, a wide variation in terms of access to DAAs from country to country. For instance, the treatment experience in Australia is notable, as it is one of the first and currently still one of the few countries that has allowed subsidized access to DAA therapy for the entire population. The same cannot be said for other countries in the region. Additionally, the cost of HCV drugs is usually not covered by either public or private health insurance providers in Asia. Many patients in the region are left to pay large out-of-pocket expenses.

Table P091: Genotype prevalence in the Asia-Pacific countries

Asia-Pacific Countries	Genotype (GT)
Japan	1b, 2
South Korea	1a, 1b, 2, 3, 4, & 6
China	1a, 1b, 2, 3, & 6
Pakistan	1a, 1b, 2a, 2b, 3a, 3b, 4, 5, & 6
India	1a, 1b, 3, 4, & 5
Indonesia	1a, 1b, 2, 3, & 4
Malaysia	1, 2, 3, 4, & 6
Philippines	1a, 1b, 2, 4, & 6
Thailand	1a, 1b, 3, & 6
Australia	1a, 1b, 2, 3, 4, & 6
New Zealand	1a, 1b, 2, 3, & 6

Conclusion(s): Globally, countries are implementing policies and measures to eliminate HCV risk, based on their distribution of genotypes and prevalence. To achieve this goal in the Asian-Pacific region, additional interventions and strategies are needed.

P092 Trends in amphetamine injection and determinants of initiation among people who inject drugs in Montreal, Canada, 2011-2019

SB Hoj^1,*, G Zang¹, N Minoyan¹, ², D Vlad¹, ², J Bruneau¹, ³

¹Centre de Recherche du CHUM

²École de Santé Publique

³Département de médecine de famille et de médecine d’urgence, Université de Montréal, Montréal, Canada

Background: Methamphetamine possession incidents in Canada rose nearly 600% from 2010-2017.¹ Meanwhile, attention to methamphetamine injection in the context of sex between men has also grown.² Among people who inject drugs (PWID), the primary group at risk of HCV infection in Canada, amphetamine injection has been associated with syringe sharing and may increase HCV risk.³ Though the practice remains uncommon in Montreal, shifting preferences for other substances suggest evolving local drug eras.⁴

Purpose: Applying a framework for the subcultural evolution of illicit drug use,⁵ this study sought to:

Examine trends in the annual prevalence of amphetamine injection among PWID in Montreal, Canada

Estimate the gender-specific incidence of amphetamine injection, with a focus on sexual identity as a potential risk factor

Methods: Data were drawn from HEPCO, an open prospective cohort study involving 3-monthly (HCV RNA- persons) or yearly (HCV RNA+) interviews with PWID in Montreal, Canada. Participants were aged ≥ 18 and had injected drugs in the 6 months preceding enrolment. Self-identified gender (male vs. female) and sexual identity (heterosexual vs. gay/bisexual), age, and lifetime amphetamine injection were recorded at enrolment. Questionnaires at each visit captured amphetamine injection (yes vs. no) and covariates in relation to the past three months, including other drug use (cocaine, heroin, prescription opioid injection; non-injection amphetamine, crack, alcohol, cannabis use) and social stability indicators (housing, income, incarceration, opioid agonist therapy, public injecting, sex work).

Annual prevalence of amphetamine injection (overall and stratified by gender) was estimated among all participants using the first questionnaire completed each year. Statistical significance of linear trends was assessed using generalized estimating equations with year of interview as the independent variable, adjusted for participant age. Incidence of amphetamine injection (overall and stratified by gender) was calculated in the subset of participants who did not inject amphetamine in the 6 months preceding enrolment, using the person-time method. Gender-stratified associations with sexual identity were estimated using Cox regression adjusted for age, lifetime amphetamine injection, and covariates associated with the outcome (p < 0.10) in bivariate analyses.

Result(s): 807 participants (145 female; 106 gay/bisexual; median age 41) were enrolled between 2011-2019 and included in the study. Prevalence of amphetamine injection increased from 5.41% in 2011 to 7.53% in 2019, with a mean linear increase of 0.48% per year (p = 0.022). 501 males and 100 females were included in incidence analyses. Incidence of amphetamine injection (per 100 person-years) was 3.67 [95% CI: 2.99–4.47] overall, 3.80 [3.04–4.68] among males, and 3.00 [1.63–5.11] among females. Gay/bisexual identity was positively associated with initiation in both genders, but estimates for females were imprecise (Crude Hazard Ratio [95% CI] among males: 2.173 [1.18–4.01], females: 3.86 [1.24–12.0]; Adjusted Hazard Ratio [95% CI] among males: 2.20 [1.17–4.14], females: 2.33 [0.55–9.85]).

Conclusion(s): Among PWID in Montreal, prevalence of amphetamine injecting increased roughly 0.5% per year from 2011 to 2019. Initiation was associated with gay or bisexual identity in both males and females.

References

1Canadian drug summary: Methamphetamine. Ottawa ON: CCSA, 2018

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4Bruneau et al. Addiction 2019; 114(2):366–73

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5Golub et al. Addict Res Theory 2005; 13(3):217–29

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P093 Impact of direct-acting antiviral treatment on mortality related to extrahepatic manifestations: findings from a large population-based cohort in British Columbia, Canada

D Jeong¹, ^2,*, S Wong², ME Karim¹, ³, S Bartlett², ⁴, J Wilton², MJ Damascene¹, ², H Velasquez², M Binka², P Adu¹, ², M Pearce², A Yu², M Alvarez², H Samji², ⁵, Y Abdia², M Krajden², ⁴, N Janjua¹, ²

¹School of Population and Public Health, University of British Columbia

²British Columbia Centre for Disease Control

³Centre for Health Evaluation and Outcome Sciences

⁴Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver

⁵Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada

Background: In addition to liver-related disease burden, chronic hepatitis C virus (HCV) infection is associated with high morbidity and mortality due to extrahepatic manifestations (EHM). Since the introduction of highly effective direct-acting antiviral (DAA) treatment, sustained virologic response (SVR) achieved with DAA treatment has been shown to decrease all-cause and liver-related mortality. However, analyses assessing the impact of DAA treatment on mortality due to EHM are lacking.

Purpose: This study assessed the impact of DAA treatment and SVR on reducing mortality related to EHM using large population-based linked administrative data.

Methods: The British Columbia (BC) Hepatitis Testers Cohort includes ~1.3 million people tested for HCV since 1990 and is linked with administrative health data, including medical visits, hospitalizations and chronic disease registry. Among individuals who were identified to have a chronic HCV infection by December 31, 2018, those who received at least one DAA treatment were matched to those who never received treatment. EHM mortality included deaths due to diabetes, cardiovascular diseases, cerebrovascular diseases, chronic kidney diseases, rheumatoid arthritis and neurocognitive disorders, and was assessed from BC Vital Statistics. Individuals were followed from index date to the earliest of: 1) death due to EHM; 2) any other death, or 3) end of study (2019/12/31). To assess the impact of DAA treatment and SVR, we compared three groups of individuals: treated & SVR, treated & no-SVR, and untreated. EHM mortality rates were computed and incidence curves were generated for each group. Then, we estimated the inverse probability of treatment weights (IPTW) for the average treatment effect (ATE) to adjust for differences in baseline characteristics of individuals. To assess the effect of DAA and SVR, we used a multivariable Fine-Gray subdistributional hazards model with weights, adjusting for competing mortality risk and confounders, including socio-demographic and clinical characteristics assessed at baseline.

Result(s): The study population included 10,254 individuals who were treated & SVR, 440 individuals who were treated & no-SVR and 10,694 untreated individuals. Treated & SVR group had 26,090.03 person-years of follow-up (PYFU), and EHM mortality rate of 5.86 per 1,000 PYFU (95% confidence interval [CI] 5.00–6.87). Treated & no-SVR group had 868.97 PYFU, and EHM mortality rate of 25.32 per 1,000 PYFU (95% CI 16.67–38.45). The untreated group had 21,839.35 PYFU and EHM of 24.61 per 1,000 PYFU (95% CI 22.78–26.59). Figure 1 shows the 5-year cumulative incidence curves for deaths related to EHM. In the multivariable model weighted with IPTW for ATE, the treated & SVR group had the greatest reduction in EHM mortality (adjusted hazard ratio [aHR] 0.15, 95% CI 0.13–0.17), followed by the treated & no-SVR group (aHR 0.44, 95% CI 0.32–0.62) compared to the untreated group. Older age and history of hypertension, cardiovascular diseases, cirrhosis, diabetes, end-stage renal disease, hepatocellular carcinoma, statin use and co-infection with HIV or HBV were all associated with higher EHM deaths.

Conclusion(s): In this analysis using a large, population-based dataset, the virologic cure of HCV following DAA treatment was associated with a significant reduction in mortality due to extrahepatic manifestations, with a 85% reduction in EHM mortality associated with SVR following treatment. This highlights the crucial need of providing diagnosis and treatment for people living with HCV infection to reduce extrahepatic mortality.

P094 Hepatitis C treatment capacity building during a pandemic: using a virtual classroom model to enhance primary care capacity to test and treat hepatitis C in Saskatchewan

S Kogilwaimath^1,*, A Galambos², S Ortynsky³, K Stewart⁴

¹Division of Infectious Diseases, Department of Medicine, University of Saskatchewan

²Saskatchewan Infectious Diseases Care Network (SIDCN)

³Johnson Shayama Graduate School of Public Policy

⁴Department of Medicine, University of Saskatchewan, Saskatoon, Canada

Background: The Hepatitis C Virtual Classroom (HCV VC) was launched in October 2020 using an online platform to deliver 4.0 hours of live accredited medical education. The HCV VC uses its own curriculum developed by Saskatchewan Infectious Disease Care Network (SIDCN) with content that is specific to HCV in Saskatchewan. Presentations are interactive and delivered by local HCV specialists to primary care providers located across Saskatchewan. Upon completing the course, participants are eligible to become approved HCV treatment prescribers.

Purpose: To address the demand for HCV medical education and enhance the primary care capacity to test, treat and cure HCV using a Virtual Classroom (VC) model.

Methods: The HCV VC was launched in October 2020 with one session and 13 primary care providers. Due to the high number of registrants, two additional sessions were offered in 2020 along with a previously planned session in January 2021. Over these four initial sessions, the VC was delivered to 58 primary care providers located in 17 different communities across Saskatchewan. A post-evaluation survey was developed and sent by email at the end of each session to all participants to determine whether their confidence increased in providing HCV treatment and care as a result of the VC. The data were analyzed using descriptive techniques.

Result(s): A total of 35 surveys (60% response rate) were collected. Of those surveyed, 98% of respondents (34/35) indicated an average of 4.87-point increase (scale:1-10) in confidence providing HCV treatment and 100% indicated they will use this education in their clinical practice. Participants indicated that effective components of the VC included: case-based approach, overview of treatment options, and online small-group delivery. As a result of the VC training, 88% of participants will offer treatment to patients with an HCV diagnosis; 94% are better aware of community resources available; 94% will likely discuss local harm reduction resources available in patients’ communities; and 100% will offer HCV testing to patients who present with risk factors. After completing the VC, 26% (15/58) of the participants chose to become approved HCV prescribers in Saskatchewan and are being mentored by local HCV care specialists.

Conclusion(s): Early findings suggest that despite an ongoing global pandemic the VC is a promising and effective model for educating increasing numbers of primary care providers and enrolling new HCV prescribers in Saskatchewan. Based on the positive response, four additional sessions will be offered as part of the 2020-22 grant funding this project.

P095 Examining the role of overdose prevention and supervised consumption sites in the provision of integrated HIV, HCV, and overdose care

G Kolla^1,*, B Pauly¹, A Guta², A Payne¹, M Gagnon¹

¹University of Victoria, Victoria

²University of Windsor, Windsor, Canada

Background: The emergence of illicitly manufactured fentanyl and fentanyl analogues in the North American drug supply has led to a staggering increase in overdose deaths; data from early 2020 in Canada indicates that fentanyl or fentanyl analogues were involved in 77% of all opioid overdose deaths. Shifts in patterns of drug use due to fentanyl and fentanyl analogue contamination in the drug supply have necessitated a re-orientation in harm reduction programming and service delivery to focus on emergency life-saving measures including overdose prevention and response. Overdose prevention and supervised consumption sites are one element of this response, and provide a supervised location for consumption of previously obtained drugs, where prompt intervention is available from trained staff should overdose occur.

Purpose: We examine the potential for overdose prevention or supervised consumption site in the provision of integrated care for HIV, HCV and overdose to people who use drugs in an era where fentanyl(s) dominate the drug market.

Methods: Drawing on a rapid scan of the literature, we use a syndemic framework to explore the potential for overdose prevention and supervised consumption sites as points of access for comprehensive, low-threshold HIV, HCV and overdose care.

Result(s): In the Canadian context, there has been a rapid increase in the number of overdose prevention and supervised consumption sites to address the rapid increase in fentanyl-related opioid overdose mortality. There was only 1 sanctioned overdose prevention or supervised consumption site in 2015, and there are currently over 60 sites in operation in 6 provinces. Several features of fentanyl injection have been identified that may have the potential to contribute to increased risk of bloodborne infection transmission, including how the short duration of action among fentanyl(s) may contribute to increasing injection frequency and concomitant potential for increased sharing of injection equipment and HIV/HCV transmission. While initial evidence shows that overdose prevention and supervised consumption sites may be contributing to a reduction in overdose-related deaths (when deployed in combination with measures such as opioid agonist treatment and naloxone distribution), we identified several structural impediments to the delivery of integrated harm reduction programming and care through OPS/SCS, including continued opposition to these services, increasing homelessness and displacement, challenges in maintaining low-threshold service delivery, and difficulties in maintaining service provision during the COVID-19 pandemic.

Conclusion(s): Overdose prevention and supervised consumption sites have emerged as a crucial part of the harm reduction response to overdose. Opportunities remain to better integrate the provision of low-threshold HIV and HCV care within the scope of services offered with these sites.

P096 Are HIV-HCV co-infected people who inject drugs accessing HCV prevention and care in Canada?

C Lanièce Delaunay¹, ^2,*, M Maheu-Giroux¹, G Marathe¹, ², S Saeed³, C Cooper⁴, S Walmsley⁵, J Cox¹, ², M Hull⁶, V Martel-Laferrière⁷, N Pick⁶, M-L Vachon⁸, MB Klein¹, ²

¹McGill University

²Research Institute of the McGill University Health Centre, Montréal, Canada

³Washington University, Saint-Louis, Missouri, United States

⁴University of Ottawa, Ottawa

⁵University of Toronto, Toronto

⁶University of British Columbia, Vancouver

⁷Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montréal

⁸Université Laval, Québec, Canada

Background: In Canada, 85% of new hepatitis C virus (HCV) infections occur among people who inject drugs (PWID), and co-infection with HIV can exacerbate disease severity. Quantifying unmet needs in HCV prevention and treatment among HIV-HCV co-infected PWID is key for developing appropriate interventions to eliminate HCV as a public health threat by 2030.

Purpose: We investigated temporal trends (2003-2019) in HCV treatment uptake and efficacy, injection behaviours, and access to harm reduction services among HIV-HCV co-infected PWID in four Canadian provinces to identify gaps that need to be addressed for reaching HCV elimination by 2030.

Methods: We used data from the Canadian Co-infection Cohort, a prospective study of 2,004 HIV-HCV co-infected people. We included 1,090 participants from Quebec, Ontario, Saskatchewan, and British Columbia who reported injecting at least once from 2003 to 2019. Trends were examined using three time periods based on HCV treatment guidelines: 2003–2010: interferon/ribavirin-based; 2011–2013: first-generation direct-acting antivirals (DAAs); 2014–2019: second-generation DAAs. The harm reduction services assessed include needle and syringe programs (NSP), opioid agonist therapy (OAT), and supervised injection sites (SIS), for which data were available from 2014 to 2019.

Result(s): The participants’ median age at cohort entry was 44 years; 69% were male and 33% were Indigenous. The overall HCV treatment uptake among HCV RNA positive people increased substantially from 7 per 100 person-years (95% CI: 5–9) in 2003–2010 to 20 per 100 person-years (95% CI: 18–22) in 2014-2019. We observed a higher treatment rate in the province of Quebec in the second-generation DAA era (31 per 100 person-years, 95% CI: 26–37). Treatment efficacy also increased over time, from 57% (95% CI: 49–65) in 2003–2010 to 94% (95% CI: 91–96) in 2014–2019.

The frequency of cocaine injection decreased across provinces from 84% (95% CI: 83–86) of visits in 2003–2010 to 57% (95% CI: 56–59) in 2014–2019, and opioid injection increased from 50% (95% CI: 47–52) to 60% (95% CI: 58–61). Cocaine remains the most frequently injected drug in Quebec and Ontario, whereas the consumption of opioids exceeds that of stimulants in Saskatchewan and British Columbia.

Needle/syringe sharing declined from 12% of visits (95% CI: 11–15) in 2003–2010 to 5% (95% CI: 4–6) in 2014–2019 and was reported less frequently in British Columbia (2%, 95% CI: 1–3) than in other provinces. Paradoxically, reported NSP use also decreased (from 90% (95% CI: 88–92) to 61% (95% CI: 59–63)), potentially reflecting fewer daily injections due to reduced cocaine use. OAT engagement among opioid users was low (around 20% across time periods), with a higher coverage in western provinces (23% (95% CI: 18–31) in Saskatchewan and 25% (95% CI: 22–29) in British Columbia in the second-generation DAA era). Only 9% (95% CI: 8–10) of participants accessed SIS over 2014–2019, although coverage was higher in British Columbia (16%, 95% CI: 14–19).

Conclusion(s): HCV treatment access and outcomes have greatly improved among co-infected PWID. Yet, exposure to injection-related risks continues and is increasingly related to opioid use. Injection behaviours and coverage of harm reduction programs vary across provinces, emphasizing the need to tailor prevention strategies to specific contexts. Overall, maximizing access to proven harm reduction strategies to prevent HCV re-infection and overdose, and ultimately achieve HCV elimination, is required.

P097 HCV elimination opportunities in Ontario identified by analysis of screening activity in correctional facilities

K Beck², Y Li^1,*, J Chan³, JJ Feld⁴, ⁵, ⁶, J Flemming⁷, ⁸, N Grewal¹, ⁸, P Ioudovski⁹, A Majury¹, ⁸, ¹⁰, ¹¹, T Mazzulli¹², ¹³, ¹⁴, C McClintock¹⁵, ¹⁶, W Wobeser¹

¹Department of Biomedical and Molecular Sciences

²Queen’s University, Kingston, Canada

³Division of Infectious Diseases & Immunology, NYU Grossman School of Medicine, New York City, United States

⁴Toronto Centre for Liver Disease

⁵Toronto General Hospital

⁶Universtity of Toronto, Toronto

⁷Department of Medicine

⁸Department of Public Health Sciences

⁹Public Health Sciences

¹⁰Department of Environmental Studies, Queen’s University

¹¹Public Health Ontario, Kingston

¹²Laboratory Medicine and Pathobiology, University of Toronto

¹³Public Health Ontario Laboratory

¹⁴Department of Microbiology, Sinai Health System/University Health Network

¹⁵Institute for Clinical Evaluative Sciences, Toronto

¹⁶Division of Cancer Care and Epidemiology, Queen’s Cancer Research Institute, Kingston, Canada

Background: Persons who are incarcerated (PWI) are more likely to have a positive test result when screened for HCV. Access to both screening and treatment is highly variable across jurisdictions both inside and outside Canada. We have identified that screening in short term incarceration settings such as jails and detention centres where, in Ontario, persons who may be in remand or have a sentence of less than two years may be house are less likely to have a test result in the public health lab system. PWI have been identified by the Blueprint to Inform Hepatitis C Elimination Efforts in Canada as a priority population.

Purpose: We undertook a geographically and correctional facility focused examination of screening for HCV efforts for the province of Ontario with specific focus on jails and detention centres. This work was done with a view to inform public health programming efforts to provide access to screening and care for PWI in Ontario.

Methods: We have retrospectively analyzed public health laboratory data for Ontario from 1990-2014 inclusive. Two administrative datasets were merged internally at Public Health Ontario to classify unique individuals. The merged datasets was deidentified. Data fields included gender, year of birth, date of test (antibody and RNA), location of testing laboratory, submitting institution or physician as well as test results. We classifed persons into community and incarcerated using the data field “submitter_name”. Analysis was stratified by federal vs. provincial institutions. PWI had at least one test from a correctional facility.

Result(s): A total of 44,355 (38,149 ab and 6,206 RNA) tests were performed on 25,502 PWI over the period of observation. Antibody tests were performed by public health labs across the province with the largest number being tested in Kingston (22,356 - 58.6%) followed by Central (10,997 - 28.8%). Orrillia, Ottawa and London each process 2,369, 867 and 784 respectively. The remain labs had relatively low test Ab volumes (Thunder Bay 314; Hamilton 258; Sudbury 86; Timmins 71; Sault Ste. Marie 42; Windsor 5; Peterborough 0). Federal correctional facilities submitted the majority of HCV tests (32,904 - 74.2%) with 11,451 - 25.8% from provincial facilities. Federal testing was concentrated in facilities where routine public health surveillance is performed on entry. Provincial testing volumes did not correlate with facility size. Figure 1 demonstrates testing by Ab vs. RNA for all provincial settings submitting at least 25 tests over period of observation. Many facilities only contributing Ab test. There was a clear increase in testing volume over the period of observation for Central North Correctional Centre only. Toronto Don Jail (capacity 550 closing in 2013) appear to contribute the lowest expected rate of testing.

Conclusion(s): We have demonstrated significant variability in testing activity both between and within federal and provincial facilities. Federal variability is driven in part by the HCV program in place with screening on entry into the system. Many provincial institutions appeared to contribute few tests to our dataset and may represent an opportunity to expand access to screening for persons at risk for HCV. Testing in the private lab system needs to be considered as a contributor to the variability seen between provincial institutions.

P098 Ultra L MK I: A genotype independent long RT-PCR method for obtaining near full-length hepatitis C virus genomes

LL Lin^1,*, R Penner¹, T Chestley², X HU¹, M Carpenter¹

¹National Microbiology Laboratory, Public Health Agency of Canada

²National Microbiology Laboratory, Canadian Food Inspection Agency, Winnipeg, Canada

Background: Introduction of highly effective direct-acting antiviral drugs has made the aim of eliminating hepatitis C virus (HCV) infection, as a public health concern, a reality. In support of this effort, viral genome sequencing is required to provide information on drug resistance mutations and support for virus transmission/epidemiology studies. However, sequencing of the 9.5 kb HCV genome is hampered by significant sequence diversity, with the eight major genotypes, differing by 30% at the nucleotide level. As such, current near full-length HCV genome amplification strategies require prior knowledge of the genotype and/or exclude a portion of the NS5B region, which often acts as a primer-annealing site. While metagenomics next generation sequencing (NGS) methods can also be genotype independent, low viral load samples, particularly in clinical specimens, remain problematic due to poor virus sequence representation in the final libraries.

Purpose: Develop a genotype independent HCV sequencing strategy producing near full-length (complete coding region) sequence that can be applied to viral genotyping, drug resistance and virus transmission/epidemiology studies.

Methods: Reverse transcription and reverse PCR primers were designed to anneal to highly conserved regions in the HCV 3’ untranslated (UTR) X-box while forward PCR primers were located in the 5’ UTR. cDNA synthesis was performed in the presence of betaine and was followed by nested PCR amplification. ~9.4 kb amplicons were purified and subjected to Nextera XT library preparation followed by sequencing on an Illumina MiSeq platform. Viral reads were filtered for quality and assembled to HCV reference sequences using Bowtie 2 (Geneious or Galaxy) software.

Result(s): Optimization of the protocol was achieved primarily through use of different primer sequences within the 3’UTR X-box, and testing different reverse-transcriptase and PCR polymerase enzymes and various PCR additives. Reverse transcription and nested PCR required the PCR additive betaine primarily for GT 1a due to a hairpin structure in NS4B. The length of the poly U stretch in the 3’ UTR negatively correlated with amplification efficiency. Amplification of complete coding regions was achieved for clinical samples with viral loads > 3.5log10 IU/mL for several genotypes and subgenotypes tested including 1a, 1b, 2a, 2b, 3a, and 6. Using this procedure a unique GT 2/1b recombinant was identified.

Conclusion(s): We demonstrate a simple genotype agnostic near full-length HCV genome method that captures the entire open reading frame of the HCV genome. The procedure will prove useful for drug resistance, transmission analysis and genotyping studies where additional sequence information can be informative. The ability to clone the resulting amplicons and maintain linkages for individual virus genomes may be of importance for low-level drug resistance analysis.

P099 Decreased hepatitis B and C testing in Ontario, Canada during the first wave of the COVID-19 pandemic

E Mandel^1,*, A Peci², K Cronin², ³, H Janssen¹, ⁴, V Tran², ⁵, M Biondi⁴, ⁶, JJ Feld⁴, ⁷, ⁸

¹University Health Network

²Public Health Ontario Laboratory

³National Microbiology Laboratory, Public Health Agency of Canada

⁴Viral Hepatitis Care Network (VIRCAN) Study Group, University Health Network

⁵Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto

⁶Arthur Labatt Family School of Nursing, Western University, London

⁷Toronto Centre for Liver Disease, University Health Network

⁸Institute of Medical Sciences, University of Toronto, Toronto, Canada

Background: The COVID-19 pandemic has significantly disrupted care across many clinical areas with particular impact on the screening for, and management of, chronic medical conditions.

Purpose: We examined trends in hepatitis B (HBV) and C (HCV) testing in Ontario to determine how the first wave of COVID-19 impacted management of these chronic conditions.

Methods: We extracted de-identified data from the Public Health Ontario Laboratory (PHOL) Information Management System for HBV and HCV testing from January 1, 2019 until August 31, 2020. Total and unique test volumes were evaluated for hepatitis B surface antigen (HBsAg), HBV DNA, HCV antibody (Ab) and HCV RNA, and were stratified by age, sex, region and test indication. Prenatal HBV screening was evaluated separately. Changes in testing volumes were analyzed by comparing percent and absolute changes over time.

Result(s): COVID-19 first emerged in Ontario in late January 2020 with near-immediate impact on health service provision. We compared testing volumes from February–August 2019 to those from February–August 2020. Compared to 2019, HCV Ab testing (screening) in 2020 decreased 30% and HCV RNA testing decreased 36%. Pre-treatment HCV RNA testing decreased by 43% and post-treatment sustained virologic response testing decreased by 36%. For HBV, HBsAg testing decreased 29% and HBV DNA testing by 33%. While pre-treatment HBV DNA decreased by 38%, on-treatment monitoring decreased by only 14%. Trends were consistent when testing volumes were stratified by age, region, and sex; however, prenatal HBV testing volumes remained stable. Test volumes for all tests were increasing prior to 2019 with increased awareness of viral hepatitis elimination targets. No non-prenatal test type returned to pre-pandemic levels by August 2020, recovering 75% for HCV Ab, 64% for HCV RNA, 77% for HBsAg and 82% for HBV DNA compared to tests in 2019.

Conclusion(s): Significant decreases in HBV and HCV testing occurred in Ontario during the first wave of the COVID-19 pandemic. Screening for HCV as well as pre- and post-treatment RNA testing were greatly affected and did not return to pre-pandemic testing levels by the end of the first wave. HBV screening and pre-treatment testing were similarly reduced, but HBV on-treatment monitoring was not as severely impacted. Strategies to maintain and ultimately increase screening, diagnosis and treatment initiation will be required to ensure the pandemic does not derail progress toward viral hepatitis elimination in Canada.

P100 Hepatitis C virus (HCV) treatment initiation and clinically relevant depressive symptoms in the HIV-HCV co-infected population

GJ Marathe¹, ^2,*, E Moodie¹, C Lanièce Delaunay¹, ², M-J Brouillette², J Cox¹, ², C Cooper³, M Hull⁴, J Gill⁵, S Walmsley⁶, N Pick⁷, M Klein¹, ²

¹Department of Epidemiology, Biostatistics and Occupational Health, McGill University

²Centre for Outcomes Research and Evaluation, McGill University Health Center-Research Institute, Montreal

³Department of Medicine, University of Ottawa, Ottawa

⁴Centre for Excellence in HIV/AIDS, St. Paul’s Hospital, Vancouver

⁵Department of Medicine, University of Calgary, Calgary

⁶Toronto General Hospital Research Institute, Toronto

⁷Oak Tree Clinic, BC Women’s Hospital, Vancouver, Canada

Background: The Hepatitis C virus (HCV) treatment has evolved from interferon (IFN)-based to IFN-free direct acting antiviral (DAA) regimens. Psychiatric illness was a major barrier for HCV treatment during the IFN era due to medication-related neuropsychiatric side effects (1). While DAAs are better tolerated, patient-level barriers to treatment initiation persist.

Purpose: We aimed to assess the effect of depressive symptoms on time to HCV treatment initiation among HIV-HCV co-infected persons in Canada during the IFN (2003-2010) and second-generation DAA eras (2013-2020).

Methods: We used data from a multicentre prospective cohort, the Canadian Co-infection Cohort and its associated food security sub-study (2, 3). Clinically relevant depressive symptoms were predicted by a random forest classifier derived using the Center for Epidemiologic Studies Depression Scale-10 (4). We developed marginal structural Cox proportional hazards models accounting for baseline and time varying confounders to assess effect of the predicted depressive symptoms on time to treatment initiation among HCV RNA+ participants (5). We accounted for death as a competing risk using inverse probability censoring weights. Exposure misclassification was addressed using predictive value-based record-level correction.

Result(s): In the IFN era, we included 535 predominantly male (78%) and white (82%) participants, with median age of 45 years (interquartile range (IQR), 41, 51) and 51% with depressive symptoms at baseline. In the DAA era, we included 1,127 predominantly male (70%) and white (65%) participants, with median age of 45 years (IQR, 38, 51) and 64% with depressive symptoms at baseline. There were 119 and 566 treatment initiations in the IFN and DAA era respectively, with overall treatment initiation rates increasing from 9 (95% CI: 8–11) to 21 (95% CI:19–22) per 100 person-years.Results indicate lower treatment initiation (Hazard ratio (HR): 0.61 (95% CI: 0.40–0.93)) among those with depressive symptoms compared to those without in the IFN era and higher initiation (1.32 (95% CI: 1.07–1.63)) among those with depressive symptoms in the DAA era. Effect attenuation was observed after misclassification correction; hazard ratio increased to 0.78 (95% CI: 0.66–0.90) in the IFN era and decreased to 1.15 (95% CI: 1.07–1.23) in the DAA era.

Conclusion(s): Depression may be a smaller barrier to HCV treatment in the DAA era. The relatively higher treatment initiation in patients with depressive symptoms suggests those previously unable to tolerate IFN are now accessing treatment.

References

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P101 Hepatitis C virus infection in First Nations populations in Ontario from 2006 to 2014: a population-based retrospective cohort analysis

AB Mendlowitz¹, ^2,*, K Bremner¹, J Walker³, ⁴, W Wong⁵, JJ Feld⁶, B Sander¹, ², ⁴, ⁷, L Jones⁸, W Isaranuwatchai², ⁹, M Krahn¹, ², ⁴

¹Toronto Health Economics and Technology Assessment (THETA) Collaborative, University Health Network

²Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto

³School of Rural and Northern Health, Laurentian University, Sudbury

⁴ICES, Toronto

⁵School of Pharmacy, University of Waterloo, Waterloo

⁶Toronto Centre for Liver Disease, Toronto General Hospital

⁷Public Health Ontario, Toronto

⁸Ontario First Nations HIV/AIDS Education Circle, London

⁹St. Michael’s Hospital, Toronto, Canada

Background: Colonization and marginalization have affected the risk for and experience of hepatitis C virus (HCV) infection for First Nations people in Canada. Although some studies have provided data on HCV infection in specific First Nations communities, many of these estimates have been limited in their scope and generalizability. As a part of Canada’s commitment to First Nations people and the World Health Organization (WHO) strategy for eliminating viral hepatitis by 2030, First Nations populations have been identified as a priority for the creation of policy and community action to reduce HCV infection. Generating province-wide evidence of the impact of HCV on the First Nations people is the necessary first step to understanding how infection affects First Nations populations in Canada.

Purpose: In partnership with the Ontario First Nations HIV/AIDS Education Circle (OFNHAEC), this study describes trends in HCV testing and diagnosis among First Nations individuals in Ontario.

Methods: We conducted a population-based retrospective cohort study linking those in Ontario with registered First Nations status to laboratory records from Public Health Ontario (PHO), and Ontario health administrative records held at ICES. From 2006 to 2014 we compared three cohorts: 1) individuals tested for HCV for the first time; 2) individuals who tested positive for HCV antibodies and/or RNA; 3) individuals with no HCV laboratory/testing records. We examined cohort characteristics, and annual prevalence and incidence of HCV testing and diagnoses. Outcomes were stratified by region, sex, and residence within or outside First Nations communities.

Result(s): From 2006 to 2014, 2,423 individuals were diagnosed with HCV; 20,481 received their first test; and 135,185 individuals had no test record. The point prevalence of an individual ever having been tested increased from 6.3 (95% CI, 6.2–6.5) per 100 people in 2006 to 16.2 (95% CI, 16.0–16.4) per 100 people in 2014. The point prevalence of diagnosed HCV increased from 0.9 (95% CI, 0.9–1.0) per 100 people in 2006 to 2.0 (95% CI, 1.9–2.0) per 100 people in 2014. From 2006 to 2014, the incidence of first test and incidence of diagnosis increased from 12.1 (95% CI, 11.5–12.6) to 21.3 (95% CI, 20.5–22.1) and 1.3 (95% CI, 1.1–1.5) to 2.3 (95% CI, 2.1–2.6) per 1,000 person-years, respectively. Testing and diagnoses of HCV were consistently higher among individuals living outside First Nations communities, but larger increases over time were observed among those living within.

Conclusion(s): Testing and diagnoses increased from 2006 to 2014 in First Nations people in Ontario. Our findings will serve as reference in beginning to understand the impact of HCV infection among the First Nations population in Ontario.

P102 Healthcare costs associated with hepatitis C virus infection in the First Nations populations in Ontario

AB Mendlowitz¹, ^2,*, K Bremner¹, J Walker³, ⁴, W Wong⁵, JJ Feld⁶, B Sander¹, ², ⁴, ⁷, L Jones⁸, W Isaranuwatchai², ⁹, M Krahn¹, ², ⁴

¹Toronto Health Economics and Technology Assessment (THETA) Collaborative, University Health Network

²Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto

³School of Rural and Northern Health, Laurentian University, Sudbury

⁴ICES, Toronto

⁵School of Pharmacy, University of Waterloo, Waterloo

⁶Toronto Centre for Liver Disease, Toronto General Hospital

⁷Public Health Ontario, Toronto

⁸Ontario First Nations HIV/AIDS Education Circle, London

⁹St. Michael’s Hospital, Toronto, Canada

Background: Canada’s complex history with First Nations people has left a significant portion of the First Nations population suffering from health and socioeconomic inequities. In addition, the healthcare costs associated with managing hepatitis C virus (HCV) infection create a substantial impact on the healthcare system in Canada. Despite this, in Ontario, where more than 200,000 First Nations people reside, there has been no study describing the population-specific economic impact of HCV infection. The Blueprint to Inform Hepatitis C Elimination Efforts in Canada emphasizes the need for culturally safe, First Nations-led, multidisciplinary approaches to address HCV infection.¹ Estimates of First Nations-specific costs of care associated with HCV infection will be essential to planning and evaluating effective and culturally safe approaches to reduce infection.

Purpose: In partnership with the Ontario First Nations HIV/AIDS Education Circle (OFNHAEC), we estimated the publicly-borne healthcare costs associated with HCV infection among First Nations populations in Ontario.

Methods: We conducted a population-based retrospective cohort study linking individuals in Ontario with registered First Nations status to HCV laboratory testing data from Public Health Ontario, and health administrative data held at ICES to estimate costs among case and control subjects. Case subjects consisted of First Nations individuals who tested positive for HCV antibodies and/or RNA between 2004 to 2014. The control group consisted of First Nations individuals who had no or negative HCV testing records. A phase-of-care costing approach was used where case observation time was assigned to the four following disease phases: pre-diagnosis (six months before HCV diagnosis), initial (after diagnosis), late (liver disease), and terminal (six months before death). Individuals were followed until death or December 31, 2017. In each phase, case subjects were matched to controls on age, sex, and propensity score. We estimated total and net costs (the difference between cases and matched controls) attributable to HCV and 95% confidence intervals (CI) associated with each phase of care. Costs were stratified by sex and residence within or outside of First Nations communities. All costs were measured in 2018 Canadian dollars.

Result(s): From 2004 to 2014, 2,197 individuals were diagnosed with HCV. The mean total costs per 30 days for HCV cases were: pre-diagnosis $637; initial $875; late $2,786; and terminal $8,896. Inpatient care was the most costly component in all phases. Net costs considerably varied in all phases between those who resided within or outside of First Nations communities. Net costs were higher for females than for males, except in the terminal phase.

Conclusion(s): The mean cost per 30 days for HCV cases among First Nations people in Ontario substantially increased with progression to advanced liver disease, and finally to death. These cost estimates will allow for planning and evaluation of population-specific HCV provincial/territorial control efforts.

References

1The Canadian Network on Hepatitis C Blueprint Writing Committee and Working Groups. Blueprint to inform hepatitis C elimination efforts in Canada. Montreal, QC: Available at: canhepc.ca/sites/default/files/media/documents/ blueprint_hcv_2019_05.pdf

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P103 Rapid assessment of the impact of the COVID-19 pandemic on people who inject drugs in Montreal

N Minoyan¹, ^2,*, S Høj¹, D Vlad¹, ², J Bruneau¹, ³, S Larney¹, ³

¹Health innovation and evaluation hub, CHUM Research Centre

²Department of social and preventive medicine, École de santé publique, Université de Montréal

³Department of family medicine and emergency medicine, Université de Montréal, Montreal, Canada

Background: The COVID-19 pandemic has had dramatic impacts on vulnerable populations including people who inject drugs (PWID).¹ In this group, high reliance on government services (e.g. shelters, harm reduction, healthcare services) and social contacts (e.g. for drug procurement, income generation) may place individuals at particularly high risk of experiencing: i) direct harms of the pandemic (i.e. SARS-CoV-2 infection) and ii) indirect harms of measures implemented to curb viral spread. These harms may include increased risk of HCV infection, as well as disruptions to the HCV care cascade.

Purpose: We sought to document acute impacts of the COVID-19 pandemic on active PWID in Montreal, with a focus on impacts relevant to HCV elimination; namely experiences and perceptions regarding changes in housing (a known determinant of HCV infection), traditional healthcare services, and harm reduction.

Methods: From May 21–Jun 23, 2020, existing members of a longstanding cohort of PWID in Montreal (HEPCO) were invited to complete a structured rapid assessment questionnaire. Given lockdown restrictions, only participants with contact information on file (e.g. telephone, email) were contacted for a remote telephone interview. To diversify the sample, a second wave of interviews was conducted from Sep 9–Dec 18, 2020, among individuals newly recruited via outreach. Both telephone and in-person interviews were permitted in this period. Analyses for the current aims were restricted to individuals reporting drug injection in the previous six months. Descriptive statistics were computed, pooling data from both interview waves.

Result(s): Of 229 interviewed individuals, 94 (41%) had injected drugs in the last six months and were included in analyses. 71% were male (median age 43), 91% were Caucasian, 5% were Indigenous. 27% reported a change in living situation during the pandemic. Of these, 60% reported housing improvements, while a quarter (24%) reported a change for the worse. 28% of the sample reported unstable housing in the 6 months prior to their interview. Of these, 81% reported increased difficulty finding shelter since the pandemic was declared a provincial public health emergency. 63% of PWID were receiving OAT at the time of their interview. 38% had discussed strategies to avoid treatment disruptions with providers. Seven (14%) had missed dose(s) due to service disruptions. Most respondents did not attempt to access traditional healthcare services or enrol in addiction treatment (including OAT) during the health emergency. Many were either unaware or perceived increased difficulty in accessing traditional healthcare. 79% of respondents tried to access needle-syringe programs during the health emergency. Of these, 93% obtained services. 45% tried to access supervised injection sites; 71% gained entry. Attempts to access services were higher among second-wave respondents.

Conclusion(s): This snapshot suggests mixed impacts of the COVID-19 pandemic on PWID. Restrictions appeared to have minimal impact on access to needle-syringe programs. Disruptions to housing may increase exposure to environments conducive to HCV infection, particularly among those unstably housed. Low levels of access to addiction treatment, as well as traditional healthcare services, may further undermine HCV elimination efforts. Findings should be interpreted in light of the over-representation of stable participants in wave 1. Drug-related harms will likely evolve alongside measures to curb COVID-19 spread; continued monitoring is warranted in this vulnerable group.

References

1Walters et al. Health Beh Policy Rev 2020; 7(5): 489–497.

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P104 A collaborative approach to community-wide hepatitis C testing in two First Nations in Ontario

D Smookler^1,*, A Beck², C Albany³, L Quoquat⁴, B Head⁴, C Capraru¹, JJ Feld⁵, H Shah⁵

¹VIRCAN/Toronto Centre for Liver Disease, University Health Network, Toronto

²First Nations and Inuit Health Branch, Health Canada

³Nursing, Lakehead University, Kitchenuhmaykoosib Inninuwug

⁴Health Services, Lac Seul First Nation, Lac Seul

⁵Toronto Centre for Liver Disease, University Health Network, Toronto, Canada

Background: Hepatitis C (HCV) is endemic in several Indigenous communities in Northwestern Ontario. With the ease and availability of new treatments, the barrier to HCV elimination is now testing and linkage to care. Testing in remote First Nation communities presents certain challenges and opportunities. We are working with some of these communities to develop culturally appropriate, collaborative approaches to wide-spread testing, followed by linkage to care. Here we present results in two such communities. Comparisons of similarities and differences in approaches used in each community could inform future initiatives.

Purpose: To evaluate widespread community testing for HCV in two remote indigenous communities, using dried blood spots (DBS) collected by health care workers and community members

Methods: Both communities were engaged as follows:presentations to Chief and Council regarding HCV and its suspected local prevalence; formation of a local team of planners and testers; development of community-specific approaches to testing; DBS training of team members; counselling of those testing positive, linking them to care.

Testing was advertised using flyers, radio, Facebook, and posters, highlighting endorsement by Chief and Council; incentives included coffee-cards, phone cards, food, and raffled gifts. While flyers were delivered house-to-house in Community 1, this was highly unacceptable in Community 2. Instead, Facebook was preferred, and a 15km walkathon was staged to raise awareness. In Community 1, DBS sample integrity was emphasized, and all samples were directly sent to the National Laboratory for HIV Reference Services (NLHRS) as soon as possible. In community 2, strict adherence to protocol was observed, ensuring samples were documented by standard protocol and sent to the NLHRS through Public Health Ontario.

Result(s): DBS for community-wide testing was piloted in Community 1 where 226 of a population of ~900 (~33% of the adult population) were tested in 3.5 days, averaging 65/day. Samples were collected for both HCV Ab and reflex RNA testing. Samples reached the NLHRS 8 days after the first test was completed. Community 2, was primarily tested in three week-long events over 5 months, resulting in 484 tested, of a population of ~1200 (~50% of the adult population). In community 2, relabelling samples with health card numbers and the requirement that samples reach the NLHRS from the Toronto Public Health Lab led to delays of up to 7 weeks for batches of DBS cards to arrive at the testing lab. In community 1 only one sample was HCV Ab positive. All samples were easily identified and deemed of high quality by the testing lab. Prevalence of false-positive HCV antibody tests was 0 in Community 1. In Community 2, 129 samples were either positive or indeterminate for HCV antibody (101 and 28 respectively). Of 97 samples retested by venipuncture, 22 (12 of the positive samples and 10 of the indeterminant) were found to be negative, for a sensitivity of 77%.

Feedback from both communities has been positive. A survey of Community 2 indicated that food and Facebook announcements were the two most important features attracting participants.

Conclusion(s): The strength of the community-based model was highlighted by the satisfaction expressed in both communities, the ease of training local non-medical staff to perform DBS, and the extraordinary turnout of people to be tested. The high percentage of indeterminate and false-positive tests in Community 2 underscores the necessity to make sample quality a priority when designing protocols for delivery of samples to the testing lab.

P105 Reaching out to our nation through a Métis-specific cultural response to hepatitis C

R St. Denys^1,*, K Olgivie¹, D Atkinson², C Lund³, R Landy², R Masching³, C Worthington², OBO DRUM & SASH Team³

¹Shining Mountains Living Community Services, Red Deer

²University of Victoria, Victoria

³Research Unit, Canadian Aboriginal AIDS Network, Fort Qu’Appelle, Canada

Background: HCV prevalence is much higher among most Priority populations; it is nearly five times higher among Indigenous peoples, especially women and youth, than among non-Indigenous people in Canada (1) (2) (3).

There is a lack of Métis-specific resources available for addressing prevention and care for HCV. Métis communities are often expected to use resources that are adapted from resources developed for, or by, First Nation communities who have different cultural beliefs and norms from Métis communities. This gap in resources has had a negative impact on Métis uptake of important HCV-related information.

Purpose: To develop a Métis-specific cultural response to HCV that includes developing a wide range of Métis-specific tools, resources, pathways for testing, linkage to culturally appropriate, wholistic care and increase community engagement in the cultural response development, monitoring and evaluation

Methods: The development of a community-led Métis cultural response to HCV has been grounded in community-based and Indigenous research methodologies that privilege Métis ways of knowing and doing. This cultural response is guided by Métis Elders, language and knowledge keepers, with the participation of our Métis Wellness Advisory Circle, staff, community members and DRUM & SASH team members.

Result(s): 1) community priorities and leaders have been identified; 2) Elders and other community members have developed a holistic conceptual model of Métis health that is grounded in Métis culture, identity, and imagery; 3) language keepers and community members have developed language in Cree-Michif to address wellbeing and HCV 4) Working with our provincial health services, we assisted in designing the pathway and pre-post testing scripts for Métis people to access Dried Blood Spot testing in Alberta, which included wrap around services for Métis individuals; 5) a Métis Wellness Advisory Circle has been formed to provide guidance for future initiatives, and 6) Métis-specific resources have been developed for community including an assessment tool for Métis wellbeing.

Conclusion(s): Creating a Métis-specific cultural response to HCV will improve cultural safety, uptake of HCV information and improve access to services, including access to testing and treatment, for Métis peoples.

The Métis Nation of Alberta (MNA), through Shining Mountains Living Community Services are partners in the DRUM & SASH implementation grant with direct access to all MNA regions in Alberta. The results of this study will address an MNA identified gap and raise awareness of HCV province-wide.

References

1Canada Communicable Disease Report (CCDR) Volume 44-7/8, July 5, 2018: Can we eliminate hepatitis C? Implementation science Hepatitis C virus infection in Saskatchewan First Nations communities: Challenges and innovations S Skinner¹, G Cote², I Khan³

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P106 Improving the efficiency of patient diagnosis with hepatitis C reflex testing and assessing affordability in Alberta, Canada

A Thompson^1,*, C Charlton¹, ²

¹Laboratory Medicine and Pathology, University of Alberta

²Alberta Precision Laboratories, Edmonton, Canada

Background: Hepatitis C (HCV) diagnosis typically requires a patient to submit two separate blood samples, one for antibody detection and the other for confirmatory RNA testing, creating extra steps in the cascade of care and relying on proper follow-up and patient engagement. As a result, many patients do not receive confirmatory RNA testing or diagnosis efficiently.

Purpose: HCV reflex testing allows diagnosis with a single blood sample, where an HCV antibody positive sample is directly reflexed to RNA testing for confirmation of active infection. We analyzed average diagnostic turnaround times and the proportion of patients able to be diagnosed with a single blood sample to evaluate the efficiency of diagnosis with reflex testing. We also estimated costs of reflex testing to evaluate affordability for public health laboratories.

Methods: HCV reflex testing was implemented in Alberta Precision Laboratories on December 12, 2019. Blood samples were tested for HCV antibodies on the Abbott ARCHITECT and, if positive, directly reflexed to the Roche Cobas 6800 for confirmatory testing. A viral load of 1000 IU/mL was used as the cutoff for a positive sample. Average diagnostic turnaround times for first-time HCV patients were analyzed from specimen submission to confirmed diagnosis and compared six months before and six months after reflex testing implementation. The proportion of patients with indeterminate specimens was calculated for six months of reflex testing by analyzing the number of specimens between 0 and 1000 IU/mL. Costs of reflex testing were estimated at $50/test times the number of reflex tests and compared to decreased HCV genotyping costs ($120/test) performed over six months to determine if decreased genotyping costs could cover funding for HCV reflex testing.

Result(s): Overall, reflex testing of a single blood sample significantly lowered average diagnostic turnaround times compared to when patients had to submit two blood samples (4 days vs 39 days, p < 0.0001). In the 6 months after implementation, 1,472 antibody positive samples underwent reflex testing and 46 (3.13%) samples were indeterminate. The total estimated costs for the 1,472 samples to be reflex tested was $73,600. In comparison, the number of HCV genotype tests decreased from 721 before reflex testing implementation ($86,520) to 252 after implementation ($30,240), equating a savings of $56,280 through decreased genotyping.

Conclusion(s): Reflex testing is significantly more efficient at diagnosing HCV compared to when patients had to submit two separate blood samples. Only a small proportion of patients were indeterminate and had to submit a second sample, highlighting the ability for the majority of patients to be diagnosed with a single specimen. Although the costs saved from decreased genotyping were less than costs of reflex testing, further reduction in total HCV genotyping would be sufficient to fund total costs of reflex testing in Alberta.

P107 Determinants of long-term retention in opioid agonist therapy among people who inject drugs in Montreal, Canada

D Vlad¹, ^2,*, SB Høj³, N Minoyan², ³, J Bruneau³, ⁴

¹Centre de recherche du CHUM, Montreal

²Département de médecine sociale et préventive, École de santé publique de l’Université de Montréal

³Centre de recherche du CHUM

⁴Département de médecine de famille et médecine d’urgence, Université de Montréal, Montréal, Canada

Background: Opioid agonist therapy (OAT) is a key intervention for addressing hepatitis C virus (HCV) infection in people who inject drugs (PWID). Longer-term engagement in OAT has been associated with better health and social outcomes, including reduced HCV incidence and increased HCV treatment uptake, but there is a need to better understand factors supporting retention in treatment.

Purpose: We sought to identify sociodemographic characteristics, drug use patterns, and treatment factors associated with retention in OAT among active PWID.

Methods: We conducted a cross-sectional analysis of baseline data collected within a longitudinal cohort study of PWID in Montreal (HEPCO). Eligible participants were aged ≥ 18 years and had injected drugs in the previous 6 months. We restricted the analysis to those eligible for OAT, inferred from self-reported illicit opioid use or OAT receipt in the past-six months. The outcome variable, retention in OAT, was defined as self-reported time spent in treatment at baseline, categorized as not on OAT, < 1 year, 1-3 years, ≥ 3 years according to previously used cut-offs. Multinomial logistic regression analyses were first used to identify factors associated with retention, comparing each retention category to a reference category composed of participants not on OAT. Similar analyses were then conducted in the subset receiving OAT, to examine treatment factors associated with retention.

Result(s): Of 805 cohort participants enrolled between March 2011 and January 2020, 546 (68%) were considered eligible for OAT (mean age: 37; 78% male) and included in analyses. Of those, 47% (n = 255) were currently enrolled in OAT (29% in treatment for < 1 year, 21% for 1–3 years, 50% for ≥ ≥ 3 years). In multivariable analyses in the overall sample, female gender (adjusted odds ratio (AOR) 1.90 [95% CI 1.02–3.53]), age (1.01 [1.00–1.03] per year), and stable housing (3.39 [1.91–6.02]) were positively associated with 3 years retention in OAT (vs. not enrolled), whereas inverse associations were observed for regular opioid, cocaine, and cannabis use (respective AORs: 0.42 [0.24–0.72], 0.47 [0.28–0.81], and 0.49 [0.30–0.80]). Only stable housing showed a graded response across retention categories: 1.71 [0.90–3.27] for < 1 year, 1.83 [0.89–3.79] for 1-3 years, and 3.39 [1.91–6.02] for ≥ 3 years (vs. not enrolled). Among participants receiving OAT, longer retention was positively associated with allowance for takeaway doses and inversely associated with regular urine screening. High-dose OAT (methadone ≥ 60 mg/day or buprenorphine/naloxone ≥ ≥ 16 mg/day) was associated with nearly four-fold odds (3.85 [1.40–10.56]) of engagement in OAT for 1–3 years, compared to low dose OAT. This association was not statistically significant for the ≥ 3 years category (1.73 [0.75–3.96]).

Conclusion(s): Half of participants likely to be eligible for OAT were enrolled in treatment. Among active PWID receiving OAT, high prevalence of long-term engagement in treatment was observed. In addition to sociodemographic factors, we identified treatment-related factors associated with greater treatment duration, suggesting the need for flexible implementation approaches in OAT programmes. Due to our cross-sectional design, however, reverse causation cannot be excluded; findings should be confirmed in longitudinal samples.

References

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P108 Screening persons who are incarcerated for HCV in the province of Ontario 1999-2014

W Wobeser^1,*, Y Li¹, K Beck², J Chan³, JJ Feld⁴, ⁵, ⁶, J Flemming⁷, ⁸, N Grewal¹, ⁸, P Ioudovski⁹, A Majury¹, ⁸, ¹⁰, ¹¹, T Mazzulli¹², ¹³, ¹⁴, C McClintock¹⁵, ¹⁶

¹Department of Biomedical and Molecular Sciences

²Queen’s University, Kingston, Canada

³Division of Infectious Diseases & Immunology, NYU Grossman School of Medicine, New York City, United States

⁴Toronto Centre for Liver Disease

⁵Toronto General Hospital

⁶Universtity of Toronto, Toronto

⁷Department of Medicine

⁸Department of Public Health Sciences

⁹Public Health Sciences

¹⁰Department of Environmental Studies, Queen’s University

¹¹Public Health Ontario, Kingston

¹²Laboratory Medicine and Pathobiology, University of Toronto

¹³Public Health Ontario Laboratory

¹⁴Department of Microbiology, Sinai Health System/University Health Network

¹⁵Institute for Clinical Evaluative Sciences, Toronto

¹⁶Division of Cancer Care and Epidemiology, Queen’s Cancer Research Institute, Kingston, Canada

Background: Persons who are incarcerated (PWI) are more likely to have a positive test result when screened for HCV. Access to both screening and treatment is highly variable across jurisdictions both inside and outside of Canada. Persons who are incarcerated have been identified as a priority population by the Blueprint to Inform Hepatitis C Elimination Efforts in Canada.

Purpose: In order to eliminate HCV in Ontario an effective public health system for all PWI will be required. We undertook an analysis of testing for HCV with specific focus on PWI in the province of Ontario in order to have a better understanding of barriers and possible opportunities for broadening elimination efforts.

Methods: We have retrospectively analyzed public health laboratory data for Ontario from 1999-2014. Two administrative datasets were merged internally to classify unique individuals. The merged dataset was deidentified. Data fields included gender, year of birth, date of test, type of test (antibody vs. RNA), location of testing laboratory, submitting institution/physician as well as test results. We classified persons into community and incarcerated using the data field “submitter_name”. PWI had at least one test submitted from a correctional facility.

Result(s): A total of 1,729,869 HCV tests for 1,055,073 unique individuals were analyzed. Of the total tests 44,355 originated from a correctional facility (25,502 unique PWI). The majority of testing for PWI came from the Federal system (32,073 –72%). Among PWI the rate of HCV positivity was 30.0% with the rate for the remainder being 8.9%. Among PWI testing positive by antibody 73.2% had at least one RNA test with 90.4% of remainder having.

Conclusion(s): It is known that persons who are incarcerated are more likely to be infected with HCV than those who are not. This was confirmed in the current study using the public health system data for Ontario. We also demonstrated that persons who were incarcerated were less likely to have viral RNA testing which is necessary before treatment can be considered. There are several limitations which will be discussed including the absence of private lab test results, the retrospective nature of this study and the time period of study ending in 2014 when the broad distribution of effective antivirals may have influenced screening behaviors.

References

1Blueprint to Inform Hepatitis C Elimination Efforts in Canada. https://www.canhepc.ca/sites/default/files/media/documents/blueprint_hcv_2019_05.pdf.

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P109 Improvements in quality of life and health utility for chronic hepatitis C patients after direct-acting antiviral treatment in a real-world setting

WWL Wong^1,*, J Wong², KE Bremner², Y Saeed³, K Mason⁴, A Phoon², J Bruneau⁵, JJ Feld⁶, Z Feng⁷, S Lee⁸, J Powis⁹, M Krahn²

¹School of Pharmacy, University of Waterloo, Kitchener

²Toronto Health Economics and Technology Assessment (THETA) Collaborative, University Health Network

³Leslie Dan Faculty of Pharmacy, University of Toronto

⁴Toronto Community Hepatitis C Program (TCHCP), Toronto

⁵Department of family medicine and emergency medicine, Université de Montréal, Montreal

⁶Toronto Centre for Liver Disease, University Health Network, Toronto

⁷Department of Mathematics and Statistics, University of Guelph, Guelph

⁸Liver Unit, University of Calgary, Calgary

⁹Michael Garron Hospital, Toronto, Canada

Background: Direct-acting antiviral agents (DAAs) have transformed hepatitis C virus (HCV) treatment, offering high cure rates with excellent tolerability. Health-related quality of life (HRQoL) is another outcome which is important to patients with chronic hepatitis C (CHC). Utility is a global preference-based measure of HRQoL which is used in cost-effectiveness analyses.

Purpose: To evaluate HRQoL and utilities in CHC patients and assess the impact of treatment with DAAs in a real-world setting.

Methods: We conducted a longitudinal study in CHC patients from two tertiary care centre clinics and four community clinics in Toronto, Calgary and Montreal. Criteria for inclusion were age ≥18 years, diagnosis of CHC, and scheduled to begin 8-12 weeks of DAA treatment with or without prior treatment.

Patients were assessed four times: 1) baseline, pre-treatment; 2) during treatment (four to six weeks after the start of DAA treatment); 3) 12 weeks after the end of DAA treatment; and 4) one year after the end of DAA treatment. At each assessment, patients completed two utility instruments (EuroQol-5D-5L (EQ5D-5L), Health Utilities Index Mark 2 (HUI2)), and a psychometric instrument (Short-Form 36 (SF-36v2)). Socio-demographic and clinical data were collected, including age, gender, education, co-morbidity, fibrosis stage, DAA type, sustained virologic response (SVR) status, and adverse events. We recorded the utility and HRQoL scores over time and estimated the differences between baseline and the other time points.

Result(s): Between April 2017 and June 2020, 83 and 126 patients were recruited from community and tertiary care clinics respectively. Fifty-one percent (N = 107) completed the 1 year post-treatment assessment before June 2020 and are reported here. The average age was 54 years, 51% were male, and 23% had previously failed PEG-interferon treatment. At 12-weeks post treatment, 96% of patients achieved SVR and 4% did not.

At baseline, the mean ± standard deviation EQ5D utility was 0.76±0.22, HUI2 utility was 0.73±0.21, SF-36v2 physical component score (PCS) was 45.00±10.13, and mental component score (MCS) was 46.24±12.32. Improvement in patient-reported HRQoL was observed for all measures at one year post-treatment (Figure 1). The mean changes from baseline in EQ5D, HUI2, SF-36v2 PCS and MCS were 0.03, 0.07, 3.70 and 3.42 respectively, representing improvements of 4%, 10%, 8% and 7% respectively from baseline scores.

Conclusion(s): This study suggests that improvement in HRQoL and utility occurred after DAA treatmen in CHC patients in a real-world setting. The utilities from our study are essential for valuing health outcomes in future HCV-related cost-effectiveness analyses.

P110 How far are we from viral hepatitis B elimination? A model-based analysis in Ontario

WWL Wong^1,*, F Tian¹, B Sander²

¹School of Pharmacy, University of Waterloo, Kitchener

²Toronto Health Economics and Technology Assessment (THETA) Collaborative, University Health Network, Toronto, Canada

Background: Hepatitis B virus (HBV) is one of the top five most burdensome infectious diseases in Ontario and chronic hepatitis B (CHB) is a major cause of morbidity and mortality. 47% of viral hepatitis complications can be attributed to HBV. Addressing hepatitis B is vital in meeting WHO hepatitis elimination goals.

Purpose: The objective of this study is to develop an agent-based model (ABM) predicting HBV prevalence and incidence over the next decade by integrating the current HBV interventions.

Methods: By combining multi-agent systems and complex networks, we developed an ABM that accommodates differential selectivity, behavior, and network properties to explain the HBV epidemic. We simulated the entire Ontario population, stratified by age, gender, and immigration status. Everyone has their own sexual behavior, characterized by the rate of sexual activity, the number of sexual partners, and the type of partnership. We estimated parameters from literature-derived estimates regarding Ontario demographics, epidemiology, and sexual behavior. Historical Ontario HBV data were used for calibration. The calibrated ABM was then used to predict the prevalence of CHB, the reported incidence of acute hepatitis B (AHB), and the incidence of CHB, decompensated cirrhosis (DC), hepatocellular carcinoma (HCC), and CHB liver-related deaths in Ontario from 2017 to 2030 for the current vaccination, screening, and treatment policy. One-way sensitivity analyses were performed on all the major assumptions to determine the impact of the assumptions on the model predictions.

Result(s): After extensive calibration and validation processes, our model results showed good match between the HBV natural history data as well as the historical reported cases, and was used to project new HBV infections for the future. Our model predicted that, between 2017 and 2030, the reported incidence of AHB and the number of new CHB cases in Ontario would only drop by 48.8% and 51.6%, respectively. This represent an 11.5% decline in the actual prevalence of CHB in Ontario. On the other hand, the model predicted that the incidence of DC and HCC in Ontario is expected to decrease only by 9.9% and 1.8% from 2017 to 2030, respectively. However, the actual number of liver-related deaths is expected to increase by approximately 12.4% from 2017 to 2030. The simulated HBV-related health outcomes were found to be sensitive to the number of immigrants, the number of newborns, and the prevalence of HBV in the immigrant-source regions.

Conclusion(s): We have developed an agent-based model that reflects the dynamics of HBV transmission, which enables forecasting of the epidemiology of HBV for policy-level decision making in Canada. The results suggest that the current vaccination, screening and treatment strategies do not play a significant role in achieving the WHO’s goals of eliminating new CHB cases and CHB deaths. More aggressive efforts may be required to improve HBV cares from vaccination to treatment in order to reach the target.

P111 Health utilities in people with hepatitis C virus infection in Ontario, Canada using a population-level health survey and linked healthcare administrative data: a proposal

Y Saeed^1,2,3,*, N Mitsakakis², JJ Feld⁴, J Kwong³, M Krahn^1,2,3, W Wong^3,5

¹Leslie Dan Faculty of Pharmacy, University of Toronto

²Toronto Health Economics and Technology Assessment (THETA) Collaborative, University Health Network

³ICES

⁴Toronto Centre for Liver Disease, University Health Network, Toronto

⁵School of Pharmacy, University of Waterloo, Kitchener, Canada

Background: There is debate surrounding the quality of life and health utility decrement associated with hepatitis C virus (HCV) infection. This debate revolves around the question of how much of the impairment in quality of life is associated with HCV infection itself versus commonly co-occurring patient characteristics including: substance use, mental health issues, low income, and other factors associated with socioeconomic marginalization. This is an important question as it can guide health policy relating to HCV.

Purpose: The primary objective of this study is to estimate and separate the effects of HCV infection status on health utility from other confounding factors such as comorbid mental health issues, substance use, and socioeconomic factors using real-world population-based survey and administrative data. A secondary objective is to analyze whether there is an interaction between HCV and socioeconomic status that modulates the impact of HCV on health utility.

Method: This is a retrospective cohort study of health utilities in people with and without HCV infection using linked survey and administrative data from Ontario, Canada.

Health utilities will be obtained from the Health Utilities Index (HUI) Mark 3 questionnaire administered as part of the Canadian Community Health Survey (CCHS). Respondents from Ontario who completed the 2000–2001, 2009–2010, and 2013–2014 cycles of the CCHS will be included as these are the years in which HUI data was collected.

HCV infection status will be determined using HCV antibody and HCV ribonucleic acid (RNA) test results recorded in the Public Health Ontario Laboratory (PHOL) database between January 1, 2003 and December 31, 2014.

Additionally, linkage to the following healthcare administration databases will be performed to identify comorbid health conditions: the Ontario Health Insurance Plan, Canadian Institute for Health Information Discharge Abstract Database, National Ambulatory Care Reporting System, and Ontario Drug Benefit.

The cohort will include all individuals in Ontario who completed the HUI component of the CCHS. Individuals with a missing or invalid health card number, age, or sex will be excluded. The HCV-infected cohort will include all individuals with a positive HCV antibody and/or HCV RNA test. The uninfected cohort will include all individuals with no evidence of HCV positivity.

Unadjusted mean HUI scores will be estimated and compared for the HCV-infected and uninfected cohorts. Propensity score matching will be used to match HCV-infected cases with uninfected controls; then, regression analysis will be used to estimate the effect of HCV infection on health utility while adjusting for age, sex, comorbidities, and other sociodemographic factors.

Result(s): In Ontario, a total of 99,107 respondents completed the CCHS in the relevant cycles.

After applying our exclusion criteria, the PHOL database contained a total of 5,002,892 HCV testing records.

These databases were linked, identifying 7,261 individuals who completed the CCHS during the relevant cycles and were tested for HCV. Of those, 550 tested positive and 6,711 tested negative.

At present, data linkages have been completed and analysis is underway. Preliminary results will be reported at the meeting.

Conclusion(s): This study will estimate population-level mean health utilities and utility decrements for Ontarians with and without HCV infection from 3 cycles of the CCHS and linked health administrative data. The findings from this study will form the basis for future HCV-related cost-effectiveness analyses, as health utility is a critical component in such analyses.

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Canadian Liver Journal

Volume 4 • Number 2 • Spring 2021

Pages: 125 - 254

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Published in print: Spring 2021

Published online: 29 April 2021

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Annual Meeting of the Canadian Association for the Study of the Liver (CASL), the Canadian Network on Hepatitis C (CANHEPC) and the Canadian Association of Hepatology Nurses (CAHN) 2021 Abstracts.

Canadian Liver Journal 2021 4:2, 125-254

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