P01. Direct acting antiviral therapy of chronic hepatitis C in Denmark: treatment response, virologic failure and resistance associated substitutions

Christina Sølund1,2, Sofie Hallager1, Henrik B. Krarup3, Birgit T. Røge4, Peer B. Christensen5, Alex L. Laursen6, Jan Gerstoft7, Jens Bukh1,2 Nina Weis1,8, The DANHEP group9
Affiliates: 1Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark 2Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark 3Aalborg University Hospital, Section of Molecular Diagnostics, Clinical Biochemistry and Department of Medical Gastroenterology, Denmark 4Department of Medicine, Kolding Hospital, Denmark 5Department of Infectious Diseases, Odense University Hospital, Denmark 6Department of Infectious Diseases, Aarhus University Hospital, Skejby, Denmark 7Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Denmark 8Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark 9

Appendix Appendix Additional members of the DANHEP group: Ulla Baslev Handest, Department of Infectious diseases, Copenhagen University Hospital, Herlev, Lena Hagelskjær Kristensen, Department of Microbiology, Viborg Regional Hospital, Mette Rye Clausen, Department of Hepatology, Copenhagen University Hospital, Rigshospitalet, Axel Møller, Department of Medicine, Kolding Hospital, Karin Grønbæk, Department of Gastroenterology, Copenhagen University Hospital, Hvidovre, Jens Lindberg, Department of Internal Medicine, Herning Hospital, Henrik Nielsen, Department of Infectious Diseases, Aalborg University Hospital, Poul Schlichting, Department of Gastroenterology, Copenhagen University Hospital, Herlev, Jesper Bach Hansen, Department of Gastroenterology, Aalborg University Hospital, Lone G. Madsen, Department of Gastroenterology, Køge Hospital, Suzanne Lunding, Department of Infectious diseases, Copenhagen University Hospital, Hillerød, Britta Tarp, Diagnostic Center, Silkeborg Regional Hospital. Lead author of the DANHEP group: Nina Weis; ninaweis@dadlnet.dk

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Background
In Denmark, the number of hepatitis C virus (HCV) infected individuals is app. 20.000 and the most prevalent HCV genotypes (GT) are 1a, 1b and 3a. New 2nd generation direct acting antivirals (DAAs) were approved in 2013/2014 for treatment of chronic HCV infection, GT 1-6, showing promising sustained virologic response (SVR) rates above 85%. For patients who experience DAA treatment failure, HCV can harbour DAA resistance associated substitutions (RASs), which are selected under pressure of antiviral treatment. Persistence and long-term clinical consequences of RASs are currently unknown.
The primary objectives of this study were to describe clinical outcomes of treatment with 2nd generation DAAs in Denmark and to compare baseline characteristics between patients with SVR and treatment failure. The secondary objective was to identify RASs in HCV isolated at baseline and post-treatment failure from patients who failed DAA treatment by next-generation sequencing.

Methods
This observational cohort study is based on prospectively collected data. Patients were identified in the Danish Database of Hepatitis B and C (DANHEP); a clinical database with ongoing enrollment of patients with chronic hepatitis B or C, seen in outpatient clinics in Denmark since 1 January 2002. Patients with chronic HCV infection, GT 1-6, who fulfilled the treatment criteria; liver biopsy (Metavir fibrosis score ≥F3), transient elastography median elasticity ≥ 12 kPa and/or clinical cirrhosis, and initiated DAA treatment from 1 January 2014 to 1 May 2015, were eligible. Data on baseline characteristics were extracted from DANHEP and the patient’s medical record. From patients with DAA treatment failure, HCV RNA was extracted from a blood sample taken at baseline and post-treatment. Samples were analyzed by next-generation sequencing to identify common known RASs. Here we present the clinical outcome after DAA treatment and RAS analysis post-treatment for 12 out of 26 patients with treatment failure.

Results
A total of 478 patients initiated DAA treatment during the study period; 26 (5 %) patients experienced treatment failure. In total 237 patients were infected with GT1, 185 with GT3, 34 with GT2, 20 with GT4, 1 with GT5 and 1 with GT6. The majority of the patients were ≥45 years (417/87 %), male (327/68 %), Caucasian (408/85 %), infected by intravenous drug use (216/69 %), had a baseline HCV RNA ≥600.000 IU/ml (297/64 %), an ALT above upper normal limit (286/61 %) and had liver cirrhosis (280/59 %). Patients with relapse were more likely to have failed previous treatment (15 out of 26 with relapse and 158 out of 450 with SVR; p= 0.019).
RASs were identified post-treatment in 11 out of 12 patients so far analyzed. The following RASs were detected in the NS3 region; Q80K/R, D168H, R123W, T54S, V36L and R155K. For the NS5A region, RASs at position F28L, M28L, A30K, L31M, Q30E/R, and S62A were identified; onlyV321I were detected in NS5B.

Conclusions
We found an SVR rate of 95 % which is similar to what has been reported in clinical studies. Previous treatment failure was more prevalent among patients with relapse indicating that a history of previous treatment failure should be taken into account when evaluating patients for DAA treatment. The majority of patients with treatment failure (11 out of 12/92 %) had common known RASs post-treatment and further investigation of the remaining non-SVR patients is ongoing.