Epigenetic reprogramming in hepatitis C virus-induced liver fibrosis: DNA methylation as a biomarker to identify susceptibility

Epigenetic reprogramming in hepatitis C virus-induced liver fibrosis: DNA methylation as a biomarker to identify susceptibility

POSTER PRESENTATIONS alcohol. Etiologic profile is different between HIV− and HIV+ patients. There is an association with male sex and severity of liv...

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POSTER PRESENTATIONS alcohol. Etiologic profile is different between HIV− and HIV+ patients. There is an association with male sex and severity of liver damage and, in the case of HIV− patients, with genotype 3 infection. THU-192 Epigenetic reprogramming in hepatitis C virus-induced liver fibrosis: DNA methylation as a biomarker to identify susceptibility A. Vasanthakumar1, J.W. Davis1, K. Idler1, E. Dilmukhametova1, L. Hazelwood1, M. Abunimeh1, P. Dorr1, M. Charafeddine1, D.E. Cohen1, S. England1, J. Waring1. 1Abbvie, North Chicago, United States E-mail: [email protected] Background and Aims: Hepatitis C virus (HCV) causes acute and chronic infections, affecting ∼185 million people worldwide. Patients with chronic HCV infection are more likely to develop liver related complications including fatty liver and fibrosis, which result in increased susceptibility of progression to cirrhosis with subsequent need for liver transplantation. HCV-related liver disease can progress undiagnosed for several years, since there is lack of a reliable diagnostic or screening process for patients at risk for progression. DNA methylation, a dynamic epigenetic mark that can be modulated by environmental factors, has been associated with loss in liver homeostatic mechanisms and increased susceptibility to liver disease, and is differentially altered in early and late stages of fatty liver disease. Our aim is to determine if DNA methylation is a marker of liver fibrosis progression in long-term monitored HCV infected subjects, as assessed by transient elastography. Methods: To identify changes in DNA methylation in HCV-infected subjects who progressed to advanced stages of liver fibrosis, we analyzed DNA from subjects who achieved SVR12 in TOPAZ-1 (Phase 3 study of 3-DAA regimen [identified by AbbVie and Enanta] with or without ribavirin), which included long-term monitoring of enrolled subjects for liver disease using Fibroscan®. Illumina 450k arrays were used to compare methylation dynamics in subjects with no fibrosis at baseline (BL) and at Post-Treatment Week 24 (PTW24) (Group 1; n = 73) to subjects who had fibrosis at BL and improved by PTW24 (Group 2; n = 74) or maintained/progressed by PTW24 (Group 3; n = 45). As longer-term follow up data (up to PTW52) become available, patient stratification will be re-evaluated and data updated. Results: Comparison of subjects in Group 1 vs Group 2 yielded 14 differentially methylated regions (DMR), and Group 1 vs. Group 3 yielded 224 DMR. Many of the DMR were within promoter regions of, or adjacent to transcripts of genes associated with immune function and signaling pathways (e.g., NFκB and TGFβ). The correlation between BL fibrosis scores and methylation revealed several positively correlated markers, which are being validated in an independent cohort of subjects. Conclusions: This work supports the evidence that genomic DNA methylation can function as a novel non-invasive biomarker to distinguish HCV patients who progress to advanced stages of fibrosis, and will be studied in the context of changes in cytokine pathways to offer clues into disease etiology. THU-193 HCV-infected people who inject drugs (PWID): engagement in care and treatment, and prevention of reinfection A. Alimohammadi1, A. Singh1, R. Shahi1, T. Raycraft1,1, G. Kiani1, B. Conway1. 1Vancouver Infectious Diseases Centre, Vancouver, Canada E-mail: [email protected] Background and Aims: People who inject drugs (PWID) are disproportionately represented within the HCV-infected population of Canada. Unsafe injection practices and sharing of equipment favor viral infection and increase the risk of recurrent viremia (RV) after successful HCV therapy. Engagement of this vulnerable population within a multidisciplinary care program with enhanced long-term follow-up post-cure of HCV (achievement of a sustained virologic response, or SVR) is critical to reducing the prevalence and incidence

of HCV infection in the population. This study seeks to assess the efficacy of such a model in clinical practice. Methods: An observational, retrospective cohort study was conducted among HCV-infected patients. All individuals had access to multidisciplinary care to address medical, psychiatric, addictionrelated, and social needs prior to, during and after HCV therapy, with maintenance in long-term follow-up at our centre. Endpoints were achievement of SVR and occurrence of RV, based on systematic twice yearly evaluation post-SVR. Results: Among 339 HCV-infected PWID, 95 actively injected drugs during HCV treatment, and 50 received all-oral HCV regimens. Key demographics included: mean age 53 years, 85% male, 60% genotype 1, 57% HIV co-infected, 22% cirrhotic, 83% treatment-naïve, 63%/70% using heroin/stimulants, 58% on opiate substitution therapy. In the general PWID population, the SVR rate was 78%, 74% among active/ recent PWID, 86% among those receiving all-oral regimens. With a mean follow-up period of 5.5 years, there were 5 cases of RV, all in the active PWID cohort, giving a rate of 12.9 cases/1000 person years of follow-up (95% CI, 0.031–0.157%) within that group. No individuals that experienced RV were on all-oral HCV treatment regimens. Among the five cases of RV, we note: mean age 52 years, 100% male, 80% genotype 1, 60% cirrhotic, 100% HIV co-infected, 100%/80% using amphetamines/heroin. Conclusions: A multidisciplinary care model addressing medical, psychiatric, addiction-related, and social needs allows for high rates of HCV treatment and cure in a vulnerable PWID population, and rates of RV post-SVR 66% lower than reported in recent meta-analysis of this issue. Highly effective all-oral regimens paired with a model of care such as ours will be a powerful tool in the control of the HCV epidemic, expanding HCV treatment programs among PWID by promoting engagement in care and minimizing the risk of posttreatment reinfection. THU-194 Large-scale screening is not useful to identify individuals with hepatitis B or C virus infection: results of an interim analysis A. Marot1, A. Trabelsi1, C. André2, P. Deltenre1,3. 1Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne; 2Division of Immunology and allergology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland; 3Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium E-mail: [email protected] Background and Aims: Current treatments are able to control HBV replication and to eradicate HCV in almost all cases. Further improvements in the management of HBV and HCV infections will be possible by focusing on treatment impact at a population level for which screening is an essential step. As most patients with HBV or HCV infection are still undiagnosed, large-scale screening could be useful. Aim: To investigate whether large-scale screening for HBV or HCV infection (e.g. risk-based vs. age-based) could identify infected individuals. Methods: Individuals between 18 and 80 years attending the preoperative consultation prior to minor surgery in a general surgical outpatient clinic were tested for HBsAg, anti-HBc and anti-HCV since November 2014. The presence of anti-HCV was confirmed by an Immunodot test. HBV DNA and HCV RNA were determined in HBsAgand anti-HCV-positive individuals. Results: Among 1345 individuals tested so far, two were positive for HBsAg (0.2%) and one of these had detectable HBV DNA. Five individuals were positive for anti-HCV (0.4%). Two of these had detectable HCV RNA and 3 had undetectable HCV RNA (1 spontaneously and 2 after a successful antiviral treatment). When compared to those without, people with anti-HCV antibodies had already been screened more frequently for HCV (100% vs. 12%, p < 0.001) as well as for HBV (80% vs. 20%, p < 0.001), had more frequently anti-HBc

Journal of Hepatology 2017 vol. 66 | S95–S332