jasmohan bajaj, md rajender reddy, md - ic-hep.com · ckd stage 4-5 ckd no hiv had hiv 1,556 1,628...

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Expert Presentation Delivered by: Jasmohan Bajaj, MD Virginia Commonwealth University and McGuire VA Medical Center Richmond, VA, USA

Rajender Reddy, MD University of Philadelphia Philadelphia, PA, USA

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-095

Real World Experience with Elbasvir/Grazoprevir in the Veterans Affairs

Healthcare System Jennifer R. Kramer1, 2, Amy Puenpatom* 3, Kevin Erickson1, 2, Yumei Cao2, Hashem El-Serag1, 2, Fasiha Kanwal1, 2

1.  Department of Medicine, Baylor College of Medicine 2.  Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey VA Medical Center, Houston, TX 3.  Center for Observational and Real-World Evidence, Merck Sharp & Dohme Corp., Kenilworth, NJ, United States

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Methods

•  Nationwide retrospective observational cohort study of HCV patients seen at the US Department of Veterans Affairs (VA) using the VA Corporate Data Warehouse (includes laboratory, pharmacy, hospitalizations, and clinical diagnoses).

•  The study population included patients with positive HCV RNA who received EBR/GRZ from January-July 2016.

Kramer Jennifer R., et al. Abstract #PS-095, EASL 2017.

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Characteristics EBR/GZR

REGIMENS N = 2,436

Age, mean (S.D) 63.5 (5.9) Male, n (%) 2350 (96.5) Race/ethnicity, n (%) African American 1400 (57.5) White 824 (33.8) Hispanic 81 (3.3)

Other 35 (1.4) Genotype, n (%)

GT1 (all)** 2324 (95.4) GT1a 844 (36.3) GT1b 1428 (61.5)

GT2, GT3 6 (0.3) GT4 64 (2.6)

BVL >800,000 IU/ml, n (%)* 1560 (67.9)

Characteristics EBR/GZR

REGIMENS N = 2,436

Comorbidities, n (%) Cirrhosis 808 (33.2) CKD (stage 3-5) 800 (32.8) Depression 1394 (57.2) Diabetes 1295 (53.2) History of drug abuse † 1313 (53.9) History of alcohol abuse† 1473 (60.5) HIV 74 (3.0)

Prior Treatment, n (%) Treatment naïve 1988 (81.6) Previous treatment

prior PEG+/- RBV 316 (13.0) prior BOC/TEL 6 (0.3) prior SOF/SIM+SOF 9 (0.4) prior LDV/SOF 82 (3.4) prior PrOD 35 (1.4)

Patient Characteristics (EP)

GT: Genotype; Other = Asian/Pacific Islander/American Indian/Alaska Native; BVL: Baseline viral load; EP: Evaluable population *Denominator of BVL = 2,326 (missing = 110) ; **missing GT1 subtypes not displayed ; † Chronic conditions including history of drug abuse or alcohol abuse data were captured through ICD-9 codes at any time prior to HCV treatment Kramer Jennifer R., et al. Abstract #PS-095, EASL 2017.

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257*)

EBR/GZR vs. EBR/GZR+RBV

12 weeks vs. 16 weeks

* Exclude 173 patients who did not complete their treatment course Kramer Jennifer R., et al. Abstract #PS-095, EASL 2017.

Patient Characteristics (EP)

EBR/GZR, 93.2%

EBR/GZR+ RBV, 6.8% 12

weeks, 93.5% 16

weeks, 6.5%

6

Overall SVR

97.0% 95.6%

0%

20%

40%

60%

80%

100%

Per Protocol population Evaluable population

2,190 2,257

2,328 2,436


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SVR (EP) by Baseline Characteristics

Other = Asian/Pacific Islander/American Indian/Alaska Native Kramer Jennifer R., et al. Abstract #PS-095, EASL 2017.

95.5% 96.5% 95.9% 95.1% 95.0% 94.3% 96.9%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90%

100%

Male Female African American

Hispanic White Other Unknown

2245 2350

83 86

1342 1400

77 81

783 824

33 35

93 96

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Baseline Viral Load Genotype

SVR (EP) by Baseline Characteristics

BVL = baseline viral load; 110 patients did not have BVL data Kramer Jennifer R., et al. Abstract #PS-095, EASL 2017.

95.4% 93.4% 96.6% 100% 96.9% 100%

0%

20%

40%

60%

80%

100%

GT 1 GT 1a GT 1b GT 2 or 3 GT 4 Unknown GT

94.7% 97.3%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90%

100%

BVL >800,000 IU/ml

BVL ≤800,000 IU/ml

2,218 2,324

788 844

1,379 1,428

6 6

62 64

42 42 1,497

1,580 726 746

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History of Alcohol Abuse

History of Drug Abuse

SVR (EP) in Alcohol and Drug Abuse Subgroups

95.1% 95.9% 95.9% 95.3%

0%

20%

40%

60%

80%

100%

No alcohol abuse

History of alcohol abuse

No drug abuse

History of drug abuse

916 963

1,412 1,473

1,077 1,123

1,251 1,313


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Cirrhosis Status

CKD Stages HIV Co-infection Status

SVR (EP) in Cirrhosis, CKD, and HIV Subgroups

95.6% 95.5% 95.2% 96.7% 96.3% 95.5% 98.6%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90%

100%

No cirrhosis Cirrhosis eGRF >=60ml

Stage 3 CKD

Stage 4-5 CKD

No HIV Had HIV

1,556 1,628

772 808

1,533 1,611

380 393

392 407

2,255 2,362

73 74


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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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Background and Aims

•  High prices of branded DAAs prevent universal access to treatment in most countries. However, 12-weeks of generic sofosbuvir/daclatasvir (SOF/DCV) can be purchased for US$450 in India or Bangladesh.

•  Several generic DAAs have been approved by international donor agencies, meeting quality control standards.

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

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Methods

•  Generic versions of sofosbuvir (SOF), ledipasvir (LDV), daclatasvir (DCV) and velpatasvir were sourced from generic suppliers in India, Bangladesh, Egypt and China.

•  Four treatment access programmes in Russia, South East Asia and Australia were included in the analysis.

•  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.


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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.


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 GS-006

EXPEDITION-I: Efficacy and Safety of Glecaprevir/Pibrentasvir in Adults with Chronic

Hepatitis C Virus Genotype 1, 2, 3, 4, 5 or 6 Infection and Compensated Cirrhosis

Xavier Forns* 1, Sam Lee2, Joaquin Valdes3, Sabela Lens1, Reem Ghalib4, Humberto Aguilar5, Franco Felizarta6, Tarek Hassanein7, Holger Hinrichsen8, Diego Rincon9, Rosa Morillas10, Stefan Zeuzem11, Yves Horsmans12, David Nelson13, Yao Yu3, Tami Pilot-Matias3,

Chih-Wei Lin3, Federico Mensa3

1.  Liver Unit, Hospital Clinic, CIBEREHD, IDIBAPS, Barcelona, Spain 2.  University of Calgary, Calgary, Canada 3.  ABBVIE, North Chicago 4.  Texas Digestive Disease Consultants, Arllington 5.  Louisiana Research Center, LLC, Shreveport 6.  Private Practice, Bakersfield 7.  Southern California Liver Centers and Southern California Research

Center, Coronado, United States 8.  Gastroenterology-Hepatology Center Kiel, Kiel, Germany 9.  Liver Unit, Hospital General Universitario Gregorio Marañón, Madrid 10.  Liver Section and CIBERehd, Department of Gastroenterology, Hospital

Universitari Germans Trias i Pujol, Badalona, Spain 11.  J.W. Goethe University, Frankfurt, Germany 12.  Cliniques Universitaires Saint-Luc, Université Catholique de Louvain,

Brussels, Belgium 13.  Division of Gastroenterology, Hepatology and Nutrition,

Department of Medicine, College of Medicine, University of Florida, Gainesville, United States

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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. Forns Xavier, et al. Abstract #GS-006, EASL 2017.

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EXPEDITION-1: Objective and Study Design

Objective Evaluate the efficacy and safety of G/P for 12 weeks in patients with HCV GT1, 2, 4, 5 or 6 infection and compensated cirrhosis * Open-Label Treatment G/P is coformulated and dosed once daily as three 100 mg/40 mg plus for a total dose of 300 mg/120 mg.

G/P 300 mg/120 mg N=146

0 Week 12 Week 24 Week 36

SVR12 assessment Patients were enrolled at 40 study sites in Belgium, Canada, Germany, South Africa, Spain, and the United States

* GT3 patients with compensated cirrhosis enrolled in a separate study (SURVEYOR-II, part 3; n=40, 98% SVR12) Forns Xavier, et al. Abstract #GS-006, EASL 2017.

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Baseline Demographics and Clinical Characteristics

Characteristic 12-Week G/P N = 146

Male, n (%) 90 (62) Age, median (range), years 60 (26-88) White race,* n (%) 120 (82) BMI, median (range), kg/m2 29 (18-55) HCV genotype, n (%)†

1a 48 (33) 1b 39 (27) 2 34 (23) 4 16 (11) 5 2 (1) 6 7 (5)

G/P, glecaprevir/pibrentasvir; BMI, body mass index * Race and ethnicity are self-reported †Genotype determined by the Versant HCV Genotype Inno-LiPA Assay Version 2.0. Forns Xavier, et al. Abstract #GS-006, EASL 2017.

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12-Week G/P N = 146

HCV RNA, median (range) log10 IU/mL 6.1 (3.1–7.4) Treatment-naïve 110 (75) Treatment-experienced 36 (25) IFN-based (IFN/pegIFN ± RBV) 25 (69) SOF-based (SOF + RBV ± pegIFN) 11 (31) Platelet count <100,000, 109/L 29 (20) INR <1.7 144 (99) Total bilirubin ≥2, mg/dL 5 (3) Albumin ≥ LLN 145 (99) Child-Pugh score at screening 5 133 (91) 6 13 (9)

IFN, interferon; SOF, sofosbuvir; INR, international normalized ratio; LLN, lower limit of normal (33) Forns Xavier, et al. Abstract #GS-006, EASL 2017.

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SVR12 by Intent-to-Treat (ITT) Analysis

99 100 100 100 100 99

0

20

40

60

80

100

GT1 GT2 GT4 GT5 GT6 Total

% P

atie

nts

with

SVR

12

•  No treatment-emergent substitutions were present in NS3

•  In NS5A, Y93N was present at baseline; Y93N, Q30R and H58D were present at the time of failure

*Patient with HCV GT1a infection relapsed at PTW8 Forns Xavier, et al. Abstract #GS-006, EASL 2017.

89 90

31 31

16 16

2 2

7 7

145 146

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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

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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.

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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)

*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.

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SVR12 by Intent-to-Treat (ITT) Analysis

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

89 91

0

20

40

60

80

100

12 Weeks 16 Weeks

SVR

12 (%

Pat

ient

s)

Duration

Breakthrough Relapse

1 4

4 0

39/44 43/47


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SVR12 by DAA Class in Prior Therapy

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)

Prior Inhibitor Failure

12 weeks Duration 16 weeks

14/14 14/16 11/14 13/13 17/18 13/16


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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


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Abstract PS-159 (MS)

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

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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.

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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.

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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.

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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 with the following inclusion criteria were enrolled in 35 French centres between 2006 and 2012:

–  biopsy-proven HCV cirrhosis

–  Child-Pugh A

–  positive viremia (B or C)

–  no prior liver complication

•  All patients received HCV treatment after inclusion.

•  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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The ANRS CO12 CirVir Cohort: Inclusion Criteria – Design •  Biopsy-proven, Child-Pugh A cirrhosis •  HCV- or HBV-related cirrhosis

–  Anti-HCV+ or Ag HBs + •  Absence of previous decompensation or hepatocellular carcinoma (HCC)

Design •  Prospective multicenter study (35 French hospitals) •  Visits: every 6 months (HCC screening) •  Biobanks: at inclusion and every year

Inclusions n=1822

FOLLOW-UP Median: 51.5 months

March 2006

June 2012

January 2015 End Point


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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)

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


36

Compensated HCV-Related Cirrhotic Patients with SVR Showed Lower Incidence of Major Adverse Cardiovascular Events (MACE)


37

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

38

Background

Author Journal, Year

Recurrence or

Occurrence? Country, Setting Sample

Frequency of HCC

Occurrence/Recurrence

Control Group

Reig, et al J Hepatol, 2016 Recurrence

4 referral hospitals,

Spain

Treated with IFN-free regimen after

successfully treated HCC,

N=59

28% after median

follow-up of 5.7 months

None

Conti, et al J Hepatol, 2016 Recurrence

Liver clinics in Bologna,

Italy

Treated with IFN-free regimen after

successfully treated HCC,

N=58

29% by 24 weeks post-treatment follow-up

None

Conti, et al J Hepatol, 2016 Occurrence

Liver clinics in Bologna,

Italy

Cirrhotic patients treated with IFN-

free therapy, N=285

3.2% HCC occurrence

by 24 weeks post

treatment follow-up

None

Cardoso, et al

J Hepatol, 2016 Occurrence One clinic in

Portugal

Cirrhotic patients achieving SVR via IFN-free therapy,

N=54

7.4% after median 12

months follow-up

None

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

39

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


40

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.


41

Results: Baseline Description of the Cohort (N=857)

Characteristic % of Cohort (N=857)

Demographics Average age Mean: 49 years (sd: 8) White ethnicity 92% Male gender 75%

Health Behaviours

History of heavy alcohol use 44% Current tobacco smoker 73% History of intravenous drug use 70%

Clinical

Thrombocytopenia (<100/ 109 /L) 28%

Child Pugh B/C 15% Diabetes 9%

Treatment Treatment experienced 35%

IFN-free regimen 32%


42

Key Differences in Characteristics IFN-Containing Patients and IFN-Free Patients

Characteristic

Regimen

P-Value IFN-containing

(N=585)

IFN-free (N=272)

Mean age 48.1 years 52.1 years <0.001

Thrombocytopenic (<100 per 109/L) 22% 39% <0.001

Child Pugh B or C 9% 30% <0.001

Number of prior failed treatment episodes

0 73% 48% <0.001 1 21% 35%

≥2 7% 17% Innes Hamish, et al. Abstract #PS-035, EASL 2017.

43

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


44

Patient Characteristics Associated with HCC Occurrence in Univariate Analysis


45

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.

46

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


47

PS-037

No Increase in the Occurrence Rate of Hepatocellular Carcinoma in Chinese Treated by

Direct-Acting Antivirals Compared to Interferon After Eradication of Hepatitis C Virus:

A Long-Term Follow-up Dong Ji* 1, 2, 3, Cheng Wang3, 4, 5, Qing Shao1, 3, Fan Li1, 3, Bing Li1, 3, Vanessa Wu3, 4, April Wong4, Yu D. Wang3, 4,

Jing Chen3, 4, Guo F. Chen1, 3, George Lau3, 4, 6

1.  Second Liver Cirrhosis Diagnosis and Treatment Center 2.  Liver Failure Treatment and Research Center 3.  Beijing 302-Hong Kong Humanity and Health Hepatitis C Diagnosis and

Treatment Centre, Beijing 302 Hospital, Beijing, China 4.  Division of Gastroenterology & Hepatology, Humanity & Health Medical

Centre, Hong Kong, Hong Kong, China 5.  State Key Laboratory of Organ Failure Research, Guangdong Provincial

Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou

6.  Institute of Translational Hepatology, Beijing 302 Hospital, Beijing, China

48

Methods

•  Included 407 HCC-naïve patients treated with DAAs between 7/2013-4/2016 –  Mean age 51, 51% male, 82.2% genotype 1b, mean BMI 23.8, 48%

cirrhotic CHC)

–  All achieved SVR12 and were followed up for a median of 14 months (range 3-35 mo)

•  Matched controls (1:1) previously treated with PEG/RBV were included based on age, sex, HCV genotype and cirrhosis status.

Ji Dong, et al. Abstract #PS-037, EASL 2017.

49

Results •  After matching, 330 patients and 165 patients in each

treatment group were included in the final analysis.

•  No significant difference in most clinical characteristics at baseline (BMI, p = 0.13; HCV RNA level, p = 0.50; PLT level, p = 0.37; ALB level, p = 0.40) between two groups.

•  The cumulative HCC rate was not different in patients treated with PEG/RBV and treated with DAAs (log-rank test, p = 0.26).

•  Multivariate cox regression showed that the risk of developing HCC did not differ by treatment group (Hazard Ratio [HR] = 0.67, p = 0.56), after adjustment of age, sex and baseline cirrhosis status.

Ji Dong, et al. Abstract #PS-037, EASL 2017.

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

51

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.

52

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.


53

Results (Cont.)

•  During the observation (mean 34.2 weeks, 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).


54

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

55

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.

56

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.

57

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.

58

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.

59

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


60

Conclusions

•  Unexpected high recurrence rate temporally associated with DAA therapy.

•  More aggressive pattern of recurrence and faster tumor evolution.


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

jasmohan bajaj, md rajender reddy, md - ic-hep.com · ckd stage 4-5 ckd no hiv had hiv 1,556 1,628...

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