Expert Presentation Delivered by: Milagros Davalos, MD ... · The analysis of heterogeneity of characteristics and outcome by center size (≤ 10 patients vs. > 10 patients enrolled)

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Expert Presentation Delivered by: Milagros Davalos, MD Peru

Marcelo Silva, MD Argentina

This enduring activity is supported by educational grants from AbbVie & Gilead Sciences, Inc.

This webcast is not sanctioned by the EASL conference organizers, nor is it an official part of the conference proceedings.

Endorsed by:

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Abstract PS-096

Long-Term Follow-up After IFN-Free Therapy of Advanced HCV-Associated Liver Cirrhosis: Continued Improvement of

Liver Function Parameters – Results from the German Hepatitis C-Registry (DHC-R)

Katja Deterding* 1, Stefan Mauss2, Anita Pathil3, Peter Buggisch4, Eckart Schott5, Markus Cornberg1, Tim Zimmermann6, Karl-Georg Simon7, Hartwig Klinker8, Rainer Günther9, Heike Pfeiffer-Vornkahl10, Dietrich Hueppe11, Christoph Sarrazin12,

Stefan Zeuzem13, Michael P. Manns1, Heiner Wedemeyer1, Thomas Berg14, German Hepatitis C-Registry15

1.  Hannover Medical School, Hannover 2.  Center for HIV and Hepatogastroenterology, Düsseldorf 3.  Internal Medicine IV, Gastroenterology and Hepatology,

University Clinic of Heidelberg, Heidelberg 4.  ifi-Institute for Interdisciplinary Medicine, Hamburg 5.  Charité Campus Virchow-Klinikum (CVK), Berlin 6.  Universiry Hospital Mainz, Mainz 7.  MVZ Dres. Eisenbach, Simon, Schwarz GbR, Leverkusen

8.  University Hospital Würzburg, Würzburg 9.  Department of Internal Medicine I, UK S-H, Campus Kiel, Kiel 10. e.factum GmbH, Butzbach 11. Center of Gastroenterology, Herne 12. St. Josef-Hospital, Wiesbaden 13. University Hospital Frankfurt, Frankfurt 14. University Hospital Leipzig, Leipzig 15. Leberstiftungs-GmbH Deutschland, Hannover, Germany

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Methods •  The DHC-R (German Hepatitis C-Registry):

–  national multicenter real-world cohort: ap.9,500 patient

–  more than 250 centers including specialists in private practice and academic centers.

•  Patients treated at the discretion of the physician.

•  Advanced liver cirrhosis:

–  presence of at least one of the following criteria:

•  FibroScan >20 kPa

•  thrombocytes <90,000/µl

•  albumin <35 g/l

•  signs of liver decompensation.

Deterding Katia, et al. Abstract #PS-096, EASL 2017.

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Results •  Advanced cirrhosis: 974 patients, follow-up data available for 863 patients.

•  CPT class 69.9% A (n = 680), 13.7% B (n = 133) and 1.7% C (n = 17).

•  HCV-genotype 1 (n = 743), different regimens with (n = 512) or without (n = 462) ribavirin.

•  SVR: 88.3%

•  96 serious adverse events were reported, 40 of these were liver related.

•  De novo HCC: 12 patients during treatment and follow-up.

•  9 patients died during treatment and follow-up (8 due to liver related events).

•  Liver function and portal hypertension parameters improved in most patients during and after antiviral therapy.

•  Factors associated with disease progression* were Child Pugh Score and non-response to antiviral treatment while exposure to HCV protease inhibitors or ribavirin were not associated with decompensation.

* Increase in MELD by 3 or more points, variceal bleeding, ascites, encephalopathy, liver transplantation or death. Deterding Katia, et al. Abstract #PS-096, EASL 2017.

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Conclusions •  This analysis of a large real-world-cohort of patients with clinically

advanced liver cirrhosis confirmed the efficacy of currently available antiviral treatment options in compensated and decompensated disease.

•  The continued improvement of liver function parameters and portal hypertension justifies antiviral therapy – even though parameters associated with clinical disease progression should be considered.

Deterding Katia, et al. Abstract #PS-096, EASL 2017.

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Abstract PS-032

HCV Eradication Reduces the Occurrence of Major Adverse Cardiovascular Events in

Hepatitis C Cirrhotic Patients: Data from the Prospective ANRS CO12 CirVir Cohort

Patrice Cacoub* 1, Pierre Nahon2, Richard Layese3, Valérie Bourcier2, Carole Cagnot4, Patrick Marcellin5, Dominique Guyader6, Stanislas Pol7, Dominique Larrey8, Françoise Roudot-Thoraval9, Etienne Audureau9and ANRS CO12 CirVir group

1.  Internal Medicine, CHU Pitié-Salepêtrière, Paris 2.  Hepatology, CHU Bondy, Bondy 3.  Sabnté Publique, CHU Henri Mondor, Crétiel 4.  ANRS, Paris 5.  Hepatology, CHU Beaujon, Ckichy 6.  CHU Rennes, Rennes 7.  CHU Cochin, Paris 8.  CHU Montpellier, Montpellier 9.  CHU Henri Mondor, Crétiel, France

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Methods •  878 patients were enrolled prospective multicenter study (35 French

sites) between 2006 and 2012 with the following inclusion criteria:

–  Biopsy-proven HCV cirrhosis

–  Child-Pugh A without HCC

•  All patients received HCV treatment after inclusion.

•  Mean follow up period: 51.5 months

•  Major adverse cardiovascular events (MACE) included stroke, myocardial infarction, ischemic heart disease, heart failure, peripheral arterial disease, cardiac arrest, and cardiovascular death.

Cacoub Patrice, et al. Abstract #PS-032, EASL 2017.

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SVR Reduces the Occurrence of MACE in Hepatitis C Cirrhotic Patients: Prospective ANRS CO12 CirVir Cohort

62 out of 878 (7.1%) patients presented with a total of 79 Major Adverse Cardiovascular Events

Cardiovascular Event Number •  Heart failure 23 •  Stroke 16 •  Ischemic heart disease 12 •  Peripheral arterial disease 9 •  Myocardial infarction 8 •  Cardiovascular deaths 7 •  Cardiac arrest 4

The analysis of heterogeneity of characteristics and outcome by center size (≤ 10 patients vs. > 10 patients enrolled) did not reveal any significant differences across centers. Cacoub Patrice, et al. Abstract #PS-032, EASL 2017.

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Predictors of Major Adverse Cardiovascular Events in patients with compensated HCV-related cirrhosis

(multivariate Cox proportional hazards model)

SVR Reduces the Occurrence of MACE in Hepatitis C Cirrhotic Patients: Prospective ANRS CO12 CirVir Cohort

Features HR 95% CI P-Value

Arterial hypertension 3.24 [1.78; 5.91] <0.001 Tobacco consumption <0.001 Never Ref Past 1.75 [0.76; 3.91] 0.18 Ongoing 4.20 [2.11; 8.64] <0.001 Ethnic Origin 7 <0.001 EUR Ref AFR 1.14 [0.36; 2.80] 0.80 EAS 9.20 [2.46; 24.95] 0.003 Serum Albumin ≤35 g/L 2.78 [1.30; 5.56] 0.009 SVR* 0.35 [0.09; 0.97] 0.044

Cacoub Patrice, et al. Abstract #PS-032, EASL 2017.

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PS-031

Tumour Recurrence after Interferon-Free Treatment for Hepatitis C in Patients with Previously Treated

Hepatocellular Carcinoma Discloses a More Aggressive Pattern and Faster Tumour Growth

Maria Reig* 1, Zoe Mariño2, Christie Perelló3, Mercedes Iñarrairaegui4, Sabela Lens2, Alba Díaz5, Ramón Vilana6, Anna Darnell6,

María Varela7, Bruno Sangro4, José Luis Calleja3, Xavier Forns2, Jordi Bruix1

1.  Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit , Hospital Clinic Barcelona, IDIBAPS, University of Barcelona. CIBERehd 2.  Liver Unit , Hospital Clinic, IDIBAPS, University of Barcelona. CIBERehd., Barcelona 3.  Liver Unit, Hospital Univesitario Puerta de Hierro.CIBERehd.IDIPHIM, Madrid 4.  Unidad de Hepatología, Clínica Universidad de Navarra, IDISNA, CIBERehd, Pamplona 5.  BCLC group. Department of Pathology, Hospital Clínic Barcelona, IDIBAPS, University of Barcelona 6.  BCLC group. Department of Radiology, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona. CIBERehd, Barcelona 7.  Hospital Universitario Central de Asturias, Oviedo, Spain

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Patients and Methods October 2014 – March 2016

Retrospective Inclusion/Exclusion Criteria

History of HCC before starting DAA (n=124)

HCC treated before starting DAA (n=119) HCC treatment within 1 to 7 days of DAA treatment (n=4);

Absence of complete response (n=9)

HCC under complete response before starting DAA (n=105) IFN as part of the antiviral regimen (n=11). Prior LT (n=2) treated in other center (n=2) Achieved complete response and presence of non-characterized nodules (n=16)

HCC with CR without “non-characterized nodules” before starting DAA (n=79)

Without follow-up (n=2)

Confirmed HCC radiological assessment after starting DAA (n=77)

HCC= hepatocellular carcinoma; DAA= direct antiviral agent treatment; CR= radiological complete response Reig Maria, et al. Abstract #PS-031, EASL 2017.

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Patients and Methods •  HCV treatment in accordance with the current international guidelines

•  The follow-up policy for HCC patients who achieve complete radiologic response after:

ü TACE is to perform imaging with a magnetic resonance (MR) or computed tomography (CT) every 6 months.

ü Ablation is to perform a contrast-ultrasound is done at months 1 and 3; a magnetic resonance or CT is at month 6 and then every 6 months

ü Resection is to perform a dynamic CT or MR every 6 months

•  The baseline characteristics, laboratory and radiologic tumor response were registered in all patients:

ü Before starting antiviral therapy

ü During the follow-up according to the clinical practice policy

Reig Maria, et al. Abstract #PS-031, EASL 2017.

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Results – Updated March 2017

Confirmed HCC radiological assessment after starting DAA Without confounding factors (n=77)

HCC recurrence

36/102=35.3%

HCC under complete response before starting DAA (n=105)

HCC-recurrence (n=24)

HCC-complete response (n=52)

1 patient with multiple liver nodules Prostatic cancer recurrence and PS2

HCC= hepatocellular carcinoma; DAA= direct antiviral agent treatment; CR= radiological complete response Reig Maria, et al. Abstract #PS-031, EASL 2017.

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Results – Whole Cohort (n=77)

Baseline Characteristics

Age (median-range) 67 (45-83)

Gender-M/F (n-%) 53/24 Cirrhosis – Yes/No (n) 73/4

Child-Pugh A/B/C (n) 66/5/2

BCLC 0/A/B (n) 20/55/2

AFP 9.84 (1-369)

HCV genotype (n) GT1a 11 GT1b 57

GT2 1

GT3 4 GT4 4

HVC Treatment

Naïve/Treatment Experienced (n) 43/34

HCV-RNA (Log10) median-range (UI/mL) 6.02 (3.11-6.99)

DAA combination (n)

SOF/LDV 29

3D 21

SOF/SMV 16

SOF/RBV 2 SOF/DCV 7 SMV/DCV 2

Use of RBV (n) 64

Treatment duration 12/16/20/24w (n) 56/1/1/18

HCC treatment before DAAs (n)

Resection 28 Ablation 41 Transarterial chemoembolization 8

M: male; F: female; BCLC: Barcelona Clinic Liver Cancer; AFP: alpha-feio protein; HCV: hepatitis C virus; GT: genotype. Reig Maria, et al. Abstract #PS-031, EASL 2017.

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Summary of the HCC Patients Under Complete Response Treated with DAA

Whole Cohort (n=77)

Median follow-up -months 12.4 (IQR: 8.4-18.7)

HCC progression N= 24 (31.2%) Death N=5 (6.5%)

HCC Recurrence (n=24) Median time between start DAA and 1st HCC recurrence -months

3.5 (IQR: 2-7.6)

2nd recurrence or progression n=10 Median time between 1st, 2nd HCC recurrence/ progression –months

6 (IQR: 3.2-8.2)

Recurrence/progression within the 6 month of 1st HCC recurrence 6/20 (30%)

Death n=5 (20.8%)

16.7% BSC

37.5% Ablation

Resection LT

45.8% TACE

Sorafenib Regorafenib

RE Clinical Trials


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Conclusions •  Unexpected high recurrence rate temporally associated with DAA

therapy.

•  More aggressive pattern of recurrence and faster tumor evolution.


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PS-035

Among Cirrhotic Patients with a Hepatitis C Sustained Viral Response, the Risk of De-Novo Hepatocellular Carcinoma Relates to Baseline

Factors and Not the Use of Direct Acting Antivirals: Results from a Nationwide Cohort

Hamish Innes* 1, Stephen T. Barclay2, Peter C. Hayes3, Andrew Fraser4, John F. Dillon5, Adrian Stanley2, Andy Bathgate3, Scott McDonald1, David Goldberg6, Heather Valerio1, Ray Fox7, Nick Kennedy8, Pete Bramley9, Sharon J. Hutchinson1

Email: [email protected]

1.  School of Health and Life Sciences, Glasgow Caledonian University 2.  Glasgow Royal Infirmary, Glasgow 3.  Royal Infirmary Edinburgh, Edinburgh 4.  Aberdeen Royal Infirmary, Aberdeen 5.  Ninewells Hospital and Medical School, Dundee 6.  Health Protection Scotland 7.  The Brownlee Centre, Glasgow 8.  Monklands Hospital, Lanarkshire 9.  Stirling Royal Infirmary, Stirling, United Kingdom

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Methods: Study Fundamentals

•  Retrospective cohort study using –  Scottish HCV clinical database (downloads @ April 2016)

–  Subsequent medical chart review (carried out February–March 2017)

•  Definition of study cohort –  Inclusion criteria

•  SVR attainment in 1997–2016

•  Liver cirrhosis at time of starting treatment

–  Exclusion criteria •  Diagnosis of HCC prior to treatment

•  HBV/HIV co-infection

•  Attendance at a clinic with incomplete database or otherwise not able to participate in medical chart review

Innes Hamish, et al. Abstract #PS-035, EASL 2017.

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Methods: Study Fundamentals •  Primary outcome event: first time diagnosis of HCC by cross-sectional

imaging or biopsy

•  Wide range of baseline patient characteristics extracted:

–  Age; gender ethnicity; postcode deprivation score; Child Pugh score; thrombocytopenia; alphafetoprotein; diabetes; alcohol history; smoking history; drug use history; prior genotype; clinic attended; number of prior treatment failures

•  Survival analysis approach adopted

–  Start time=commencement of treatment

–  Stop time=earliest of: HCC occurrence; death; or reaching 31 Jan 2017.

–  Used Cox regression to assess univariate and multivariate association between regimen (IFN-free Vs. IFN-containing) and HCC.


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Follow-up Time and Outcome Events, by Treatment Regimen

Regimen IFN-

containing (N-585)

IFN-free (N=272)

Follow-up, person years

Total 2697 475

Median per patient (IQR) 3.5 (2.2-5.6) 1.7 (1.4-2.0)

Outcome events (i.e. HCC occurrence)

Total # 34 12 # occurring <24 weeks post-treatment 6 5

# occurring ≥24 weeks post-treatment 28 7

Median time to event (min-max range)

2.5 yrs (0.3-8.5)

0.9 yrs (0.5-2.0)

Crude rate, per 100 persons years 1.26 2.52


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Patient Characteristics Associated with HCC Occurrence in Univariate Analysis


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Association Between IFN-Free Versus IFN-Containing Therapy and HCC Occurrence, in Univariate and Multivariate Analysis

* Multivariate analysis includes adjustment for: age, gender, ethnicity, Child Pugh score, thrombocytopenia, alphafetoprotein, genotype, treatmentexperience and clinic location Innes Hamish, et al. Abstract #PS-035, EASL 2017.

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Conclusions

1.  There is no evidence that IFN-free therapy increases the risk of HCC occurrence in patients achieving an SVR

2.  Baseline characteristics of patients treated with IFN-free regimens differ from those treated with IFN- containing regimens

3.  Multivariate analysis demonstrated that the risk of HCC occurrence was equivalent between these two groups of patients


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PS-036

Sustained Virologic Response by Ledipasvir/Sofosbuvir Reduces the Incidence of

Hepatocellular Carcinoma in Japanese Patients with HCV Genotype 1 Infection - Comparison with Simeprevir with Peginterferon Plus Ribavirin

Masaaki Korenaga* 1, Namiki Izumi2, Osamu Yokosuka3, Tetsuo Takehara4, Naoya Sakamoto5, Syuhei Nishiguchi6, Fusao Ikeda7, Mikio Yanase8, Hidenori Toyota9, Takuya Genda10, Takeji Umemura11, Hiroshi Yatsuhashi12, Tatsuya Ide13, Nobuo Toda14,

Kazushige Nirei15, Yoshiyuki Ueno16, Youichi Nishigaki17, Masao Omata18, Masashi Mizokami1

1.  Kohnodai Hospital, National Center for Global Health and Medicine, Chiba

2.  Musashino Red Cross Hospital, Tokyo 3.  Chiba University, Chiba 4.  Osaka University, Osaka 5.  Hokkaido University, Sapporo 6.  Hyogo College of Medicine, Hyogo 7.  Okayama University, Okayama 8.  National Center for Global Health and Medicine, Tokyo

9.  Ogaki Municipal Hospital, Gifu 10.  Juntendo University Shizuoka Hospital, Shizuoka 11.  Shinshu University, Nagano 12.  National Hospital Organization Nagasaki Medical Center, Nagasaki 13.  Kurume University, Kurume 14.  Mitsui Memorial Hospital 15.  Nihon University School of Medicine, Tokyo 16.  Yamagata University, Yamagata 17.  Gifu Municipal Hospital, Gifu 18.  Yamanashi Prefectural Hospital Organization, Yamanashi, Japan

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Methods •  315 Japanese patients with GT1 received LDV/SOF for 12 weeks at 18

hospitals as a multicenter Phase 3 clinical trial in 2013.

•  Controls: 336 GT1 patients who received simeprevir (SMV) with PegIFN plus RBV for 24 weeks.

•  To identify HCC, all patients underwent ultrasonography, contrast-enhanced CT or Gd-EOB-DTPA-enhanced MRI by the treatment before 4 months and prospectively followed 2 years after the treatment.

Korenaga Masaaki, et al. Abstract #PS-036, EASL 2017.

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Results •  All patients achieved SVR and had no history of HCC. There were no

difference in Age, Sex, BMI, ALT, PLT, HCVRNA and history of IFN treatment at baseline between LDV/SOF and PegIFN/RBV/SMV group.

•  However, AFP levels in LDV/SOF group were significantly higher than those in PegIFN/RBV/SMV group (11.2 and 7.4 ng/mL, P<0.05).

•  The number of patients with advanced fibrosis (Fibroscan® >12.5kPa or FibroTest® >0.75) were significantly increased LDV/SOF group compared with PegIFN/RBV/SMV group (69 [23%] and 50 [15%], P<0.05).


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Results (Cont.) •  11 patients with detected non-hypervascular hepatic nodules by CT or

MRI before treatment were excluded from the study.

–  8/11 (72%) (6 LDV/SOF and 2 PEG/RBV/SMV) of these excluded patients developed HCC within 1 year after treatment

•  One (0.3%) LDV/SOF-treated patient developed HCC at 2 years after the treatment.


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Conclusions •  The incidence of HCC improved following only 12-week LDV/SOF

regimen to a similar degree as achieved with PegIFN/RBV/SMV.

•  Unexpected development of HCC after SVR in patients without previous HCC might be predicted by CT or Gd-EOB-DTPA-enhanced MRI.


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PS-038

Occurrence of Hepatocellular Carcinoma in Patients with Hepatitis C Virus Related Liver Disease Treated

with Direct-acting Antivirals Vincenza Calvaruso* 1, Giuseppe Cabibbo1, Irene Cacciola2, Salvatore Petta1, Salvatore Madonia1, Alessandro Bellia3, Marco Di Stefano4, Lydia Giannitrapani1, Fabio Tinè1, Antonio Magro5, Antonio Davì6, Licia Larocca3, Annalisa Ardiri3,

Antonio Digiacomo7, Maria Gussio3, Luigi Guarneri8, Ignazio Scalisi9, Giovanni Mazzola1, Fabio Cartabellotta1, Francesca Savalli10, Maurizio Russello3, Gaetano Scifo4, Giovanni Squadrito2, Calogero Cammà1, Giovanni Raimondo2, Antonio Craxì1,

Vito Di Marco1 and RESIST-HCV (Rete Sicilia Selezione Terapia - HCV) Email: [email protected]

1.  RESIST-HCV, Palermo 2.  RESIST-HCV, Messina 3.  RESIST-HCV, Catania 4.  RESIST-HCV, Siracusa 5.  RESIST-HCV, Agrigento

6.  RESIST-HCV, Modica 7.  RESIST-HCV, Comiso 8.  RESIST-HCV, Enna 9.  RESIST-HCV, Castelvetrano 10.  RESIST-HCV, Trapani, Italy

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Methods •  Between 3/2015 and 10/2016, the RESIST-HCV database included

10,123 patients with HCV chronic liver disease of which 5,130 started treatment.

•  Each physician established DAA regimen and use of RBV and performed HCC surveillance as indicated by guidelines before and after treatment.

•  Evaluated HCC occurrence in 3,447 patients who concluded DAA treatment.

•  The primary endpoints of this analysis were the time to HCC occurrence from start of DAA and the pattern of HCC at the diagnosis.

Calvaruso Vincenza, et al. Abstract #PS-038, EASL 2017.

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Results •  Patients had a mean age of 64.3 years, 58% were males and 47%

were naïve to antiviral therapy.

•  2363 patients (68.6%) had Child-Pugh A cirrhosis and 320 patients (9.2%) had Child-Pugh B cirrhosis.

•  Diabetes was present in 802 patients (23%).

•  Ribavirin was used in 1577 patients (45.7%)

•  Treatment duration: 63.7% received 12 week DAA regimen and 36.3% received 24 week DAA regimen.


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Results (Cont.) •  During the observation period (mean 34.2 wks, range 8-72) 55 patients

developed HCC with an overall rate of 1.44%.

•  The occurrence of HCC was 0.13%, 1.69% and 4.37% in non-cirrhotics, Child-Pugh A cirrhosis and Child-Pugh B cirrhosis, respectively (p <0.001).

•  At the time of HCC diagnosis, 49 patients (89.1%) meet Milan criteria and 6 patients (10.9%) were Milan-out.

•  The rate of HCC occurrence was 1.48% (26/1752) in patients who achieved SVR and 4.0% (10/249) in patients who maintained HCV viremia (p = 0.0089).


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Abstract PS-097

Sustained Virological Response for 94% of People Treated with Low-Cost, Legally Imported Generic Direct Acting Antivirals for Hepatitis C: Analysis of

1087 Patients in 4 Treatment Programmes James Freeman* 1, Giten Khwairakpam2, Julia Dragunova3, Sergey Golovin3, James Wang4, Andrew Hill5, Vicky Houghton-Price6,

Rachel Smith6, Roxanna Korologou-Linden7, Greg Jefferys8

1.  GP2U Telehealth FixHepC, Hobart, Australia 2.  TREAT Asia/amfAR, Bangkok, Thailand 3.  International Treatment Preparedness Coalition Russia, St Petersburg, Russia 4.  Ci Run Health Information Consulting Co. Ltd, Kunming, China 5.  St Stephens AIDS Trust 6.  METAVIROLOGY LTD 7.  Faculty of Medicine, Imperial College London, London, United Kingdom 8.  University of Tasmania, Hobart, Australia

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Methods •  Generic versions of sofosbuvir (SOF), ledipasvir (LDV), daclatasvir

(DCV) and velpatasvir, they were sourced from suppliers in India, Bangladesh, Egypt and China.

•  The choice of DAAs and treatment length were determined from baseline HCV genotype and stage of fibrosis.

•  This analysis includes available data from 1087 patients being monitored in hospitals, private doctors and clinics in 42 countries worldwide.

Freeman James, et al. Abstract #PS-097, EASL 2017.

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Results •  1087 patients were treated; 524 received SOF/DCV, 462 SOF/LDV, 99 received

SOF/RBV, 1 received SOF/VEL and 1 received SOF/LDV/DCV. The median length of treatment was 12 weeks.

•  Overall, the patients were 60% male with a mean age of 43.7 years; 56% were Genotype 1 and the mean baseline HCV RNA was 6.9 log IU/mL.

Freeman James, et al. Abstract #PS-097, EASL 2017.

SOF/RBV SOF/LDV (+/- RBV) SOF/DCV (+/- RBV)

RVR 52/58 (90%) 208/252 (83%) 253/300 (84%)

EOT 42/42 (98%) 293/299 (98%) 298/302 (99%)

SVR4 31/31 (100%) 235/249 (94%) 224/241 (99%)

SVR12 21/23 (91%) 194/212 (92%) 184/213 (86%)

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Abstract PS-154

Multiclass Hepatitis C Virus Resistance to Direct Acting Antivirals in Real Life Interferon-Free

Regimens Failures Advocates for Tailored Second-Line Therapies

Velia Chiara Di Maio* 1, Valeria Cento1, Ilaria Lenci2, Marianna Aragri1, Silvia Barbaliscia1, Simona Francioso2, Stefania Paolucci3, Michela Melis4, Gabriella Verucchi5, Nicola Coppola6, Carlo Federico Magni7, Valeria Micheli8, Teresa Pollicino9, Tina Ruggiero10, Francesco Santopaolo2, Simona Landonio7, Alessandro Mancon8,

Mario Starace6, Ada Bertoli1, Francesco Paolo Antonucci1, Cecilia D'Ambrosio11, Vincenza Calvaruso12, Filomena Morisco13, Caterina Pasquazzi14, Ivana Maida4, Antonio Picciotto15, Antonio Di Biagio 16, Bianca Bruzzone17, Laura Sticchi17, Valeria Ghisetti10, Raffaele Cozzolongo18, Dante Romagnoli19, Vincenzo Boccaccio20, Antonio Grieco21, Jacopo Vecchiet22, Gabriella D’Ettorre23, Manuela Merli24, Giovanni Battista Gaeta25, Alessia Ciancio26, Letizia Marinaro 10, Pietro Andreone27,

Giorgio Barbarini28, Roberto Gulminetti29, Valeria Pace Palitti30, Pierluigi Tarquini31, Massimo Puoti32, Vincenzo Sangiovanni33, Giorgio De Stefano33, Alessia Giorgini34, Maurizio Paoloni35, Nicola Caporaso13, Sergio Babudieri4, Guido Gubertini7, Savino Bruno20, Massimo Andreoni36, Adriano Pellicelli11, Giustino Parruti37,

Giovanni Raimondo9, Fausto Baldanti3, Antonio Craxì12, Mario Angelico2, Carlo Federico Perno1, Francesca Ceccherini-Silberstein1 and HCV Virology Italian Resistance Network Group (Vironet C)

1.  Department of Experimental Medicine and Surgery, University of Rome Tor Vergata 2.  Hepatology Unit, University Hospital of Rome Tor Vergata, Rome 3.  Virologia Molecolare, Fondazione IRCCS Policlinico San Matteo, Pavia 4.  Infectious Diseases Unit, University of Sassari, Sassari 5.  Policlinico S. Orsola-Malpighi, Bologna 6.  Infectious Diseases, Second University of Naples, Naples 7.  Division of Infectious Disease, Hospital Sacco of Milan 8.  Clinical Microbiology,Virology and Bioemergencies, ASST Fatebenefratelli Sacco, Milan 9.  Department of Internal Medicine, University Hospital of Messina, Messina 10.  Infectious Diseases, “Amedeo di Savoia” Hospital, Turin 11.  Hepatology Unit, San Camillo Forlanini Hospital, Rome 12.  Gastroenterology, “P. Giaccone” University Hospital, Palermo 13.  Department of Clinical Medicine and Surgery, University "Federico II" of Naples, Naples 14.  Infectious Diseases, Sant’Andrea Hospital – “La Sapienza” University, Rome 15.  Division of Hepatology, IRCCS San Martino, IST Genova 16.  Infectious Disease, IRCCS AOU San Martino – IST 17.  Hygiene Unit, IRCCS AOU San Martino-IST, Genoa 18.  Department of Gastroenterology, Scientific Institute for Digestive Disease "Saverio de Bellis"

Hospital, Castellana Grotte, Bari

19.  Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena

20.  Internal Medicine, Humanitas University, Rozzano, Milan 21.  Liver Transplant Unit, Catholic University of Rome, Rome 22.  Infectious Disease Clinic, Hospital of Chieti, Chieti 23.  Department of Public Health and Infectious Diseases 24.  Gastroenterology, Sapienza University of Rome, Rome 25.  Infectious Diseases and Viral Hepatitis Unit, Second University, Naples 26.  Unit of Gastroenterology, University of Turin, Turin 27.  Department of Medical and Surgical Sciences, University of Bologna, Bologna 28.  Division of Infectious and Tropical Diseases, Fondazione IRCCS Policlinico San Matteo 29.  Institute of Infectious Diseases, University of Pavia, Pavia 30.  Hepatology Unit, Pescara General Hospital, Pescara 31.  Infectious Disease, Hospital "G. Mazzini", Teramo 32.  Department of Infectious Diseases, Hospital Niguarda Ca’Granda, Milan 33.  Hospital Cotugno, Naples 34.  General Medicin Unit, SST Santi Paolo e Carlo, Milan 35.  Infectious Disease Unit, Avezzano General Hospital, Avezzano 36.  Infectious Diseases, University Hospital of Rome Tor Vergata, Rome 37.  Infectious Disease Unit, Pescara General Hospital, Pescara, Italy

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Methods

•  Among 325 patients failing a DAA-IFN free regimen, 261 (GT1a-1b-2c-3a/h-4a/d/n/r=57-91-12-64-37; 79.4% cirrhotic; 70.6% treatment-experienced, 16 with DAA), with available resistance test at failure in NS3/NS5A/NS5B (by Sanger sequencing) were analyzed.

Di Maio Velia Chiara, et al. Abstract #PS-154, EASL 2017.

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Results •  Most patients experienced virological relapse (84.5%), and 59.0% failed a recommended regimen according to 2015

CPG: SIM + SOF ± RBV (N = 58), DCV/LDV + SOF ± RBV (N = 23/39), 3D/2D ± RBV (N = 23), SOF + RBV (GT2, N = 11).

•  4.2% of failures had a misclassified genotype: 7 previously classified as GT1, were GT3a failing 3D ± RBV.

•  Overall, 59.0% of patients showed at least one RAS related to the DAA-failure

•  RASs prevalence was higher in breakthrough/non-responders than in relapsers (92.3% vs 50.9%, p <0.001) and in patients with unfavourable IL28 CT/TT vs patients with IL28 CC (57.7% vs 12.5%, p = 0.024).

•  RASs prevalence varied according to the DAA-class used (92.4% NS5A-RASs [N = 105], 72.3% NS3-RASs [N = 101], 34.5% DSV-RASs [N = 29)], 20.6% SOF-RASs [N = 218]) and according to HCV-GT. In NS5A-failing patients, Y93H was the most frequent major NS5A-RAS (61.9%), though with different prevalence among genotypes (15.4% GT1a; 90.0% GT1b; 82.6% GT3a; 40.0% GT4).

•  Furthermore, 40.0% of patients presented >2 NS5A-RASs, with complex patterns more frequently in GT1b failures (67.5%, e.g. Y93H+L31M/I).

•  Failures to SOF regimens showed frequent presence of L159F ± C316N (14.7%), particularly in GT1b (37.3%), followed by S282T in 3.6% (higher in GT4).

•  42.9% of patients treated with >2 DAA classes showed multiclass-resistance, including 100% NS3-NS5A-failures, and 65.5% in 3D-failures.

•  Overall, 6.1% of patients showed RASs in all 3 targets and 13.0% of patients showed also extra-target-RASs, probably due to natural resistance.

•  Finally, 11 patients (cirrhotic) experienced at least 2 subsequent virologic failures to IFN-free DAA reg.


39

Conclusions •  In this real life setting, RASs prevalence at failure was remarkably high

in all genes tested (with a partial exception for NS5B).

•  This multiclass-resistance advocates for HCV resistance testing at failure in all 3 genes for the best second-line therapeutic tailoring.


40

Abstract PS-159

Safety and Efficacy of the Fixed-Dose Combination Regimen of Uprifosbuvir (MK-3682) / Grazoprevir / Ruzasvir in Cirrhotic or Non-Cirrhotic Patients with Chronic HCV GT1 Infection Who Previously Failed

a Direct-Acting Antiviral Regimen (C-SURGE) Heiner Wedemeyer1, David Wyles2, K. Rajender Reddy3, Anne Luetkemeyer4, Ira Jacobson5, John Vierling6, Stuart Gordon7, Ronald

Nahass8, Stefan Zeuzem9, Janice Wahl10, Eliav Barr10, Bach-Yen Nguyen10, Michael Robertson10, Hee-Koung Joeng10, Hong Liu10, Patricia Jumes10, Frank Dutko10, Elizabeth Martin10

1.  Hannover Medical School, Hannover, Germany 2.  Denver Health Medical Center, Denver, CO, US 3.  University of Pennsylvania, Philadelphia, PA, US 4.  University of California, San Francisco, CA, US 5.  Mount Sinai Beth Israel, New York, NY, US 6.  Baylor College of Medicine, Houston, TX, US 7.  Henry Ford Health System, Detroit, MI, US 8.  ID Care, Hillsborough, NJ, US 9.  Goethe University Hospital, Frankfurt, Germany 10. Merck & Co., Inc., Kenilworth, NJ, US

41

C-SURGE: Study Design

SVR12* 1° Endpoint

GZR + RZR + UPR + RBV† (16 weeks), n=45

TW8 TW16 TW24 FW12

GZR + RZR + UPR (24 weeks), n=49

D1

GZR: 100 mg once-daily; RZR: 60 mg once-daily; UPR: 450 mg once-daily; TW= treatment week; FW=follow-up week; LDV=ledipasvir; SOF=sofosbuvir. *SVR12 = HCV RNA <15 IU/mL at 12 weeks after end of treatment (COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0®). †RBV dose based on body weight (<65 kg=800 mg/d; 65-85 kg=1000 mg/d; >85-105 kg=1200 mg/d; >105 kg=1400 mg/d). Patients could be compensated cirrhotic (platelet cutoff=75,000/µL; excluded Child-Pugh B & C) or non-cirrhotic patients. Wedemever Heiner, et al. Abstract #PS-159, EASL 2017.

42

Baseline NS5A or NS3 RASs

•  RASs at NS3 position Q80K detected in 33 of 93 patients (35%) •  One patient in the 16 week + RBV treatment group had an NS3 RAS at the 168 position

–  No patients had NS3 RASs at the 156 position

84

41 39

4

65 55

0

20

40

60

80

100

At least one NS5A

One NS5A Two NS5A Three or more NS5A

At least 1 NS3

Dual NS5A & NS3

% o

f Pat

ient

s

Number of RASs per Patient

78 93

38 93

36 93

60 93

51 93

4/93

*RASs detected by next-generation sequencing with 15% sensitivity; NS5A RAS: any change from wild-type at 4 positions (28, 30, 31, or 93); NS3 RASs = any change from wild-type at 14 positions (36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170, or 175). Wedemever Heiner, et al. Abstract #PS-159, EASL 2017.

43

SVR12 (Full Analysis Set; Modified Full Analysis Set*)

98 100 100 100

0

20

40

60

80

100

Full Analysis Set Modified Full Analysis Set

SVR

12 (%

with

HC

V R

NA

<15

IU/m

L; 9

5% C

I)

16 weeks + RBV 24 weeks (no RBV)

SVR12 = % of patients with HCV RNA <15 IU/mL at 12 weeks after end of treatment. Full analysis set = all patients who received at least one dose of study medication; *Modified full analysis set excluded one patient from the 16-week + RBV arm who withdrew from the study after taking 3 doses of study medication. Wedemever Heiner, et al. Abstract #PS-159, EASL 2017.

44

Abstract PS-156

MAGELLAN-1, Part 2: GLE/PIB for 12 or 16 Weeks in Patients with CHC GT1 or 4 and Prior

DAA Treatment Failure Fred Poordad1, Stanislas Pol2, Armen Asatryan3, Maria Buti4, David Shaw5, Christophe Hézode6, Franco Felizarta7, Robert W

Reindollar8, Stuart C Gordon9, Stephen Pianko10, Michael W Fried11, David E Bernstein12, Joel Gallant13, Chih-Wei Lin3, Yang Lei3, Teresa I Ng3, Tami Pilot-Matias3, Jens Kort3, Federico Mensa3

1.  The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA

2.  Groupe Hospitalier Cochin-Saint Vincent De Paul, Paris, France 3.  AbbVie Inc., North Chicago, IL, USA 4.  Vall d’Hebron University Hospital, Barcelona, Spain 5.  Royal Adelaide Hospital, Adelaide, Australia 6.  Hôpital Henri Mondor, Université Paris-Est, Créteil, France 7.  Private Practice, Bakersfield, California, USA 8.  Piedmont Healthcare/Carolinas Center for Liver Disease,

Statesville, North Carolina, USA

9.  Henry Ford Health System, Detroit, Michigan, USA 10.  Caulfield Endoscopy, Caulfield South, Victoria, Australia 11.  University of North Carolina, Chapel Hill, North Carolina,

United States 12.  North Shore University Hospital, Manhasset, New York,

United States 13.  Southwest CARE Center, Santa Fe, New Mexico, United States

45

Next Generation Direct-Acting Antivirals

In vitro:1

•  High barrier to resistance •  Potent against common NS3 polymorphisms (eg, positions 80, 155, and

168) and NS5A polymorphisms (eg, positions 28, 30, 31 and 93) •  Synergistic antiviral activity

Clinical PK & metabolism:

•  Once-daily oral dosing •  Minimal metabolism and primary biliary excretion •  Negligible renal excretion (<1%)

Glecaprevir (formerly ABT-493)

pangenotypic NS3/4A protease inhibitor

Pibrentasvir (formerly ABT-530)

pangenotypic NS5A inhibitor

Coformulated: G/P

GLE PIB

G/P is coformulated and dosed once daily as three 100 mg/40 mg pills for a total dose of 300 mg/120 mg; Glecaprevir was identified by AbbVie and Enanta Ng TI, et al. Antimicrobial Agents and Chemotherapy, 2017. Poordad Fred, et al. Abstract #PS-156, EASL 2017.

46

Part 2 of MAGELLAN-1: Objective and Study Design

Objective •  Determine the efficacy and safety of G/P for 12 or 16 weeks in patients with

chronic HCV GT1 or GT4 infection and prior DAA failure, including those with compensated cirrhosis

G/P is coformulated and dosed once daily as three 100 mg/40 mg pills for a total dose of 300 mg/120 mg Weeks

SVR12

0 12 24

G/P

20

Treatment Period

N = 44 12 weeks

1:1

rand

omiz

ed

SVR12 G/P

16 28

N = 47 16 weeks

Poordad Fred, et al. Abstract #PS-156, EASL 2017.

47

Patient Criteria •  Key patient inclusion criteria

–  ≥18 years of age (no upper limit)

–  Chronic HCV GT1, 4, 5 or 6 infection (HCV RNA ≥1000 IU/mL)

–  History of virologic failure to at least one DAA-containing treatment •  NS3/4A protease inhibitors: PTV/r, SMV, ASV, TVR, or BOC

•  NS5A inhibitors: DCV, LDV, or OBV

–  Without cirrhosis or with compensated cirrhosis (Child-Pugh ≤6 at screening)

•  Key patient exclusion criteria –  Discontinuation of prior DAA treatment regimen for reasons other than virologic failure

–  HBV or HIV coinfection or infection with more than one HCV genotype

–  Alanine or aspartate aminotransferase >10 × ULN

–  Albumin <LLN or <2.8 g/dL for those with cirrhosis

–  Platelets < 90,000 or < 60,000 cells/mm3 for those with cirrhosis

–  Creatinine clearance < 50 mL/min


48

Baseline Demographics and Clinical Characteristics

*Genotype and subtype determined by phylogenetic analysis for samples with available sequences †One patient had GT1, based on LiPA analysis, but was not subtyped BMI, body mass index; G/P, coformulated glecaprevir/pibrentasvir; GT, genotype; HCV, hepatitis C virus Poordad Fred, et al. Abstract #PS-156, EASL 2017.

Characteristic G/P

12 weeks N = 44

G/P 16 weeks

N = 47 Male, n (%) 31 (70) 33 (70) White race, n (%) 34 (77) 35 (75) Black race, n (%) 9 (20) 11 (23) Age, median years (range) 57 (22 – 67) 56 (36 – 70) BMI, median kg/m2 (range) 28 (21 – 41) 29 (20 – 52) HCV RNA, median log10 IU/mL (range) 6.1 (4.7 – 7.2) 6.3 (4.7 – 7.1) Compensated cirrhosis, n (%) 15 (34) 12 (26) HCV subtype*, n (%) 1a 35 (80) 32 (71) 1b 8 (18) 10 (22) 1e 0 1 (2) 4 1 (2) 3 (6) 1 (not subtyped) 0 1† (2)

49

Clinical Characteristics

NS3 PIs included: PTV, SMV, ASV, TVR, or BOC; NS5A inhibitors included: DCV, LDV, or OBV *Sofosbuvir (NS5B inhibitor) could be included in any prior treatment regimen †Only 44 patients had sequencing data available in each arm; percentages are based on N = 44; substitutions detected by next generation sequencing using 15% detection threshold at positions 155, 156, and 168 in NS3, and 24, 28, 30, 31, 58, 92, and 93 in NS5A DAA, direct-acting antiviral; G/P, coformulated glecaprevir/pibrentasvir; GT, genotype; HCV, hepatitis C virus; NS, non-structural protein; PI, protease inhibitor Poordad Fred, et al. Abstract #PS-156, EASL 2017.

Characteristic , n (%) G/P

12 weeks N = 44

G/P 16 weeks

N = 47 Previous DAA regimen class* NS3/4A PI only (NS5A inhibitor-naïve) 14 (32) 13 (28) NS5A inhibitor only (PI-naïve) 16 (36) 18 (38) NS3/4A PI + NS5A inhibitor 14 (32) 16 (34) Prior DAA treatment response On-treatment failure 14 (32) 13 (28) Virologic relapse 30 (68) 34 (72) Presence of key baseline substitutions† None 13 (30) 13 (30) NS3 only 2 (5) 4 (9) NS5A only 24 (55) 23 (52) NS3 + NS5A 5 (11) 4 (9)

50

89 91

0

20

40

60

80

100

12 Weeks 16 Weeks

SVR

12 (%

Pat

ient

s)

SVR12 by Intent-to-Treat (ITT) Analysis

SVR12 rate by cirrhosis Cirrhosis: 85% (23/27) No Cirrhosis: 91% (58/64)

Duration

Breakthrough Relapse

1 4

4 0

39 44

43 47


51

100 88

79

100 94

81

0

20

40

60

80

100

PI Only NS5A Only PI + NS5A PI Only NS5A Only PI + NS5A

SVR

12 (%

Pat

ient

s)

SVR12 by DAA Class in Prior Therapy

Prior Inhibitor Failure

12 weeks Duration 16 weeks

14 14

14 16

11 14

13 13

17 18

13 16


52

SVR12 by Presence of NS3A or NS5A Substitutions

Y93H/N at baseline: 100% (13/13) SVR12 in patients with NS5A inhibitor experience (PI-naïve)

Key baseline NS3 and NS5A substitutions were only present in patients with prior failure to both PI and NS5A inhibitors

5/9 of these patients achieved SVR12

Key NS3 positions: 155, 156, 168 Key NS5A positions: 24, 28, 30, 31, 58, 92, 93 OTVF: on-treatment virologic failure Poordad Fred, et al. Abstract #PS-156, EASL 2017.

100 100 83 100 100 96

0

20

40

60

80

100

None NS3 Only

NS5A Only

None NS3 Only

NS5A Only

SVR

12 (%

Pat

ient

s)

Baseline Substitutions

G/P: 12 weeks Regimen G/P: 16 weeks

13 13

2 2

20 24

13 13

4 4

22 23

3 relapse 1 OTVF 1 OTVF

53

Summary: MAGELLAN-1, Part 2 •  Patients with prior failure to PI containing regimens

(NS5A inhibitor-naïve):

–  100% SVR12 with 12 or 16 weeks of G/P treatment

•  Patients with prior failure to both PI- and NS5A inhibitor-containing regimens had lower SVR12 rates

•  Patients with prior failure to NS5A inhibitors (i.e., LDV or DCV); NS3/4A PI-naïve:

–  94% SVR12 with 16 weeks of G/P treatment with no relapse

–  No impact of baseline NS5A substitutions on SVR12

•  G/P for 12 or 16 weeks was well tolerated; Grade 3 lab abnormalities were rare, with no discontinuations due to AEs, and no DAA-related serious AEs


54

Abstract LBO-03

MAGELLAN-2: Safety and Efficacy of Glecaprevir/Pibrentasvir in Liver or Renal Transplant Adults with Chronic Hepatitis C

Genotype 1-6 Infection Nancy Reau1, Paul Y. Kwo2, Susan Rhee3, Robert S. Brown, Jr.4, Kosh Agarwal5, Peter Angus6, Ed Gane7, Jia-Horng Kao8, Parvez S.

Mantry9, K. Rajender Reddy10, Tram T. Tran11, Yiran B. Hu3, Abhishek Gulati3, Preethi Krishnan3, Emily O. Dumas3, Nancy S. Shulman3, Roger Trinh3, Xavier Forns12

1.  Rush University Medical Center, Chicago, IL, USA 2.  Stanford University School of Medicine, Palo Alto, CA, USA 3.  AbbVie Inc., North Chicago, IL, USA 4.  Weill Cornell Medical College, Center for Liver Disease

and Transplantation, New York, NY, USA 5.  Institute of Liver Studies, King's College Hospital

NHS Foundation Trust, London, UK 6.  University of Melbourne, Melbourne Australia 7.  University of Auckland, Auckland, New Zealand

8.  National Taiwan University Hospital, Taipei, Taiwan 9.  The Liver Institute at Methodist Dallas, Dallas, TX, USA 10. University of Pennsylvania, Philadelphia, PA, USA 11. Cedars Sinai Medical Center, Los Angeles, CA, USA

12. Liver Unit, Hospital Clinic, CIBEREHD, IDIBAPS, Barcelona, Spain

55

MAGELLAN-2 Study Design MAGELLAN-2 is an open label, multicenter, phase 3 study investigating the safety and efficacy of 12-week G/P treatment in adults with chronic HCV GT1-6 infection without cirrhosis who have had liver or renal transplant

Conducted in Australia, Canada, Italy, New Zealand, Puerto Rico, Spain, Taiwan, the United Kingdom and the United States

G/P (300 mg/120mg) N=100

MAGELLAN-2

Open-Label Treatment

Day 0 Week 12 Week 24 Week 48

SVR12 assessment

G/P is co-formulated and dosed once daily as three 100 mg/40 mg pills for a total dose of 300 mg/120 mg Reau Nancy, et al. Abstract #LBO-03, EASL 2017.

56

SVR12: G/P x 12 Weeks, ITT and mITT Populations

One DAA-naïve 65 year old male with GT3a infection relapsed at PTW4; one patient LTFU

98 99

0

20

40

60

80

100

SVR12, ITT SVR12, mITT

% P

atie

nts

with

SVR

12

Sustained Virologic Response

Non-inferiority threshold

98/100 98/99

Reau Nancy, et al. Abstract #LBO-03, EASL 2017.

57

GS-007

ENDURANCE-3: Safety and Efficacy of Glecaprevir/Pibrentasvir Compared to Sofosbuvir

Plus Daclatasvir in Treatment-Naïve HCV Genotype 3-Infected Patients Without Cirrhosis

Graham R Foster1, Edward Gane2, Armen Asatryan3, Tarik Asselah4, Peter J Ruane5, Stanislas Pol6, Fred Poordad7, Catherine A Stedman8, Gregory Dore9, Stuart K Roberts10, Kelly Kaita11, John Vierling12, Hugo E Vargas13, Jens Kort3,

Chih-Wei Lin3, Ran Liu3, Teresa I Ng3, Federico J Mensa3

1.  Queen Mary University of London, Barts Health, London, United Kingdom

2.  Liver Unit, Auckland City Hospital, Auckland, New Zealand 3.  Abbvie Inc., North Chicago, IL, USA 4.  Centre de Recherche sur l’Inflammation, Inserm UMR 1149,

Université Paris Diderot, AP-HP Hôpital Beaujon, Clichy, France 5.  Ruane Medical & Liver Health Institute, Los Angeles, California,

United States 6.  Group Hospitalier Cochin-Saint Vincent De Paul, Paris, France 7.  The Texas Liver Institute, San Antonio, Texas, United States

8.  Christchurch Hospital and University of Otago, Christchurch, New Zealand

9.  Kirby Institute, UNSW Australia and St. Vincent’s Hospital, Sydney, Australia

10. Alfred Hospital, Melbourne Australia 11.  University of Manitoba, Winnipeg, Manitoba, Canada 12. Baylor College of Medicine, Houston, Texas, United States 13. Mayo Clinic, Phoenix, Arizona, United States

58

HCV Genotype 3 and Treatment Options •  Chronic hepatitis C Virus (HCV) genotype (GT) 3 infection is common

and progressive

–  Prevalent among people who inject drugs

•  In GT3, DAA therapies have shown lower rates of SVR

•  EASL-recommended treatments for treatment-naïve patients without cirrhosis are:

–  Sofosbuvir + daclatasvir (12 – 24 weeks)

–  Sofosbuvir/velpatasvir (12 weeks)

•  Shorter treatment duration could enhance patient adherence and access to treatment

59

ENDURANCE-3: Objective and Study Design

Arm C: 8-week treatment duration Per discussion with regulatory authorities after phase 2 treatment data became available, an 8 week treatment Arm of G/P was added to the study design

•  SVR12: Non-inferiority of 8 weeks of G/P compared to 12 weeks of G/P*

SVR12

SVR12

SVR12

Weeks 0 12 24

G/P

20

Treatment Period

SOF + DCV

G/P N = 157 Arm C

8

Post-treatment Period

N = 233 Arm A

N = 115 Arm B

2:1

rand

omiz

ed

(2) n

on-in

ferio

rity

(1) n

on-in

ferio

rity

*Endpoint was tested only after 12 weeks of G/P was determined non-inferior to 12 weeks of SOF + DCV

60

Baseline Demographics and Clinical Characteristics

Characteristic G/P

12 weeks N = 233

SOF + DCV 12 weeks N = 115

G/P 8 weeks N = 157

Male, n (%) 121 (52) 52 (45) 92 (59)

White race, n (%) 205 (88) 103 (90) 134 (85)

Age, median years (range) 48 (22 – 71) 49 (20 – 70) 47 (20 – 76)

BMI, median kg/m2 (range) 25 (17 – 49) 25 (18 – 42) 26 (18 – 44)

HCV RNA, median log10 IU/mL (range) 6.1 (3.5 – 7.5) 6.0 (3.8 – 7.4) 6.1 (1.2 – 7.6)

History of Injection drug use, n (%) 149 (64) 73 (63) 104 (66) Baseline fibrosis stage, n (%)

F0 – F1 201 (86) 97 (84) 122 (78)

F2 12 (5) 8 (7) 8 (5)

F3 20 (9) 10 (9) 27 (17)

Subtype GT3a, n/N (%) 226/229 (99) 113/113 (100) 154/155 (99)

2:1 randomized non-randomized

BMI, body mass index; DCV, daclatasvir; G/P, coformulated glecaprevir/pibrentasvir; GT, genotype; HCV, hepatitis C virus; SOF, sofosbuvir HCV subtype determined by phylogenetic analysis; N = total number of patients with sequence data available

61

ENDURANCE 3: SVR12

(1) -1.2% (95% CI -5.6 – 3.1)

(2) -0.4% (97.5% CI -5.4 – 4.6)

(1) non-inferior

Non-inferiority: Lower bound of the confidence interval (CI) of the difference in SVR12 must be above -6%*

Both G/P treatments met non-inferiority criteria for the primary endpoint

(2) non-inferior

95 97 95

0

20

40

60

80

100

G/P SOF + DCV G/P Treatment

12 weeks Duration 12 weeks

222 233

8 weeks

111 115

149 157

This enduring activity is supported by educational grants from AbbVie and Gilead Sciences, Inc.

Documents

Expert Presentation Delivered by: Milagros Davalos, MD ... · The analysis of heterogeneity of characteristics and outcome by center size (≤ 10 patients vs. > 10 patients enrolled)