1

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

This webcast is not sanctioned by the AASLD conference organizers,

nor is it an official part of the conference proceedings.

2

Poor Adherence to Hepatocellular Carcinoma

(HCC) Surveillance in a U.S. Cohort of 2376

Patients with Chronic Hepatitis C (CHC)

and Cirrhosis

Abstract #57

Sally A. Tran1,4, Joseph K. Hoang1, An K. Le1, Changqing Zhao1,2,

Lee Ann Yasukawa3, Susan C. Weber3, Mindie H. Nguyen1;

1. Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA;

2. Department of Cirrhosis, Shuguang Hospital, Shanghai, China;

3. Center for Clinical Informatics, Stanford University School of Medicine, Palo Alto, CA;

4. Stanford University, Palo Alto, CA

3

0

5

10

15

20

25

30

35

40

45

50

Optimal (Imaging every 6mo)

Fair (Imaging every 6-12mo)

Poor (Imaging every 12-24mo)

Very Poor (Imaging < every24 months/no screening)

Pati

en

ts (

%)

18.8% 16.9%

18.5%

45.8%

• 2376 patients monitored for at least 1 year

• Median follow-up = 45.4 months (range: 12-231)

• Mean age = 54+10 yo; 63% male

4

• No significant difference in surveillance between men and women.

• Patients >55 yo had higher rates of optimal surveillance (21.4% vs. 16.2%,

p<0.0001), as well as decompensated patients compared to compensated

patients (22.7% vs. 10.9%, p<0.0001) and Asian patients compared to non-

Asians (30.6% vs. 17.4%, p<0.0001).

• 435 patients developed HCC during follow-up

– 30.2% (90/298) Asians

– 13.2% (345/2619) non-Asians

• The 5-year cumulative incidences of HCC were greater in Asians

(15.2% vs. 28.6%, p<0.00001).

• HCC patients who had optimal/fair adherence to surveillance (imaging at least

every 12 months) had less portal vein thrombosis (6.7% vs. 21.3%, P<0.0001).

• HCC patients who have had optimal/fair surveillance were also more likely to

meet the Milan criteria for liver transplants (66.0% vs. 50.0%, p<0.037) and

UCSF criteria for liver transplants (81.9% vs. 67.9%, p<0.031).

5

The impact of sustained virological response to

HCV infection on long term risk of hepatocellular

carcinoma: The BC Hepatitis Testers Cohort

Abstract #175

Naveed Z. Janjua1,2, Mei Y. Chong1, Margot E. Kuo1,

Amanda Yu1, Hasina Samji1, Zahid Butt1,2, Maria Alvarez1, Darrel Cook1,

Jason Wong1,2, Ryan Woods3, Mark Tyndall1,2, Morris Sherman4,

Eric M. Yoshida2, Mel Krajden1,2;

1. BC Centre for Disease Control,Vancouver, BC, Canada;

2. University of British Columbia, Vancouver, BC, Canada;

3. BC Cancer Agency, Vancouver, BC, Canada;

4. Medicine, University of Toronto, Toronto, ON, Canada

6

• The risk of hepatocellular carcinoma(HCC) post HCV cure

is not well-established for the North American population.

• We assessed the effect of sustained virologic

response(SVR) on the risk of HCC among a large

population based cohort in Canada.

7

• The BC Hepatitis Testers Cohort includes ~1.5 million individuals

tested for HCV between 1990–2013, linked with data on medical

visits, hospitalizations, cancers, prescription drugs and mortality.

• Patients who received IFN based treatments were followed from

the end of last treatment to HCC occurrence, death or December

31, 2012.

• Examined HCC risk among those who did

and did not achieve SVR using cumulative

incidence function and multivariable Cox proportional

hazard models.

• 8147 patients initiated treatment and 57% achieved SVR.

• Median follow up: 5.6 yr (range: 0.5-12.9)

8

• HCC incidence rate (IR)

was 1.1/1000 person-yr

(PY) in the SVR and

7.2/1000 PY in the no-

SVR groups.

• The IR was higher among

those with cirrhosis at

treatment (SVR: 6.4, no-

SVR: 21.0/1000 PY).

• In those with SVR,

cirrhosis (HR=3.16), older

age (50-59 yr: HR=4.73;

60+yr: HR=5.44 vs. ≤49

yr), and being male

(HR=3.3) were associated

with higher HCC risk.

Cumulative HCC Incidence by SVR

Person years at risk

Cu

mu

lati

ve

In

cid

en

ce

0.0

0.0 2.5 5.0

No SVR SVRTreatment outcome

Gray’s Test p<.0001

7.5 10.0 12.5

0.1

0.2

0.3

9

Multi-center experience using Sofosbuvir &

Ribavirin with and without pegylated interferon to

treat hepatitis C patients with and without liver

cirrhosis (RESiP Study: Real-life Experience with

Sofosbuvir in Pakistan)

Abstract #1943

Javed I. Farooqi1, Muhammad Humayun2, Asad Chaudhry3,

Mohammad Sadik4, Zia Uddin1, Altaf Alam5, Zahid Y. Hashmi6,

Mohammad Umar7, Rukhsana J. Farooqi8, Farooq Ahmad1,

Atta M. Khan1, Wazir Mohammad2, Muhammad Soomroo4,

Arshad K. Butt5, Kashif Malik5, Tayyab Akhter7;

1. Medicine, Lady Reading Hospital, Peshawar, Pakistan;

2. Medicine, Khyber Teaching Hospital, Peshawar, Pakistan;

3. Gut and Liver Center, Gujranwala, Pakistan;

4. AIMS Hospital, Hyderabad, Pakistan;

5. Shaikh Zaid Hospital, Lahore, Pakistan;

6. Liver Center, Faisalabad, Pakistan;

7. Holy Family Hospital, Rawalpindi, Pakistan;

8. ACRC / KTH, Peshawar, Pakistan

10

• 8 centers in Pakistan

• Analysis based on 1486 patients who completed

treatment and 12 week follow up

– 58% men

– Mean age: 34.83 years

– 94% GT3

– 61% treatment naïve

– 57% non-cirrhotic

– 80% treated with SOF+RBV

11

94 97 95

100

86 89 89 91

0

20

40

60

80

100

SOF+RBV; treatment-experienced

SOF+RBV; treatment-naïve

SOF+RBV+PEG;treatment-experienced

SOF+RBV+PEG;treatment-naïve

No cirrhosis Cirrhois

SV

R12 (

%)

12

• The most frequent adverse events were fatigue, headache,

insomnia, and nausea.

• Serious adverse events were uncommon: 3% with the dual

regimen, and 4% with triple regimen.

• Treatment discontinuations due to adverse events were

rare and occurred with similar frequency (<1%) in both

treatment arms.

• Significant laboratory abnormalities were 10% in dual

therapy and 18% in triple therapy and included anemia,

hyperbilirubinemia & coagulopathy.

13

Efficacy and Safety of Elbasvir/Grazoprevir in

Treatment-Naïve Subjects with Chronic HCV GT 1,

GT 4 and GT 6 Infection (C-CORAL): A Phase III

Randomized Multinational Clinical Trial

Abstract #76

Jacob George1, Eduard Z. Burnevich2, I-Shyan Sheen3, Jeong Heo4, Kinh Nguyen Van5,

Tawesak Tanwandee6, Pin-Nan Cheng7, Do Young Kim8, Won Young Tak11,

Svetlana N. Kizhlo9, Li W. Liang10, Pauline A. Lindore10, Joy Ginanni10,

Bach-Yen T. Nguyen10, Janice Wahl10, Eliav Barr10, Michael Robertson10, Rohit Talwani10;

1. Westmead Hospital - Gastroenterology & Hepatology Dept,

Westmead, NSW, Australia;

2. City Clinical Hospital #24, Moscow, Russian Federation;

3. Chang Gung Memorial Hospital- Linkou, Taoyuan

County, Taiwan;

4. College of Medicine, Pusan National University and Medical

Research Institute Pusan National University Hospital, Bu san,

Korea (the Republic of);

5. National Hospital of Tropical Diseases, Ha Noi, Viet Nam;

6. Siriraj Hosp, Divison of Gastroenterology, Bangkok, Thailand;

7. National Cheng Kung University Hospital, Tainan, Taiwan;

8. Severance Hospital, Yonsei University Health System, Seoul,

Korea (the Republic of);

9. Saint-Petersburg Center for Prophylactic of AIDS and Inf.

Diseases, Saint Petersburg, Russian Federation;

10. Merck & Co., Inc., Kenilworth, NJ;

11. Kyunpook National University Hospital, Daegu,

Korea (the Republic of)

14

93 89

99 100

63

0

10

20

30

40

50

60

70

80

90

100

Overall GT1a GT1b GT4 GT6

Pa

tien

ts (

%)

232/

250

23/

26

185/

187

2/

2

22/

35

• 18 patients did not achieve SVR12: 11 relapses, 6 breakthrough/rebound

(all GT6) and 1 GT1b patient withdrew consent.

15

C-ISLE: Grazoprevir/Elbasvir plus Sofosbuvir in

Treatment-naïve and Treatment-experienced HCV

GT3 Cirrhotic Patients Treated for 8, 12 or 16 weeks

Abstract #74

Graham R. Foster1, Kosh Agarwal2, Matthew Cramp3,

Sulleman Moreea4, Stephen T. Barclay5, Jane Collier6, Ashley S. Brown7,

Stephen D. Ryder8, Andrew Ustianowski9, Daniel M. Forton10,

Ray Fox11, Fiona Gordon12, William M. Rosenberg13,

David J. Mutimer14, Jiejun Du15, Christopher L. Gilbert15, Janice Wahl15,

Eliav Barr15, Barbara Haber15;

1. The Royal London Hospital, London, United Kingdom;

2. Institute of Liver Studies, Kings College Hospital, London,

United Kingdom;

3. South West Liver Unit, Derriford Hospital and Peninsula School

of Medicine and Dentistry, Plymouth, United Kingdom;

4. Bradford Teaching Hospitals Foundation Trust, Bradford,

United Kingdom;

5. Glasgow Royal Campus, Glasgow, United Kingdom;

6. John Radcliffe Hospital, Oxford, United Kingdom;

7. Imperial College Healthcare, London, United Kingdom;

8. NIHR Biomedical Unit in Gastrointestinal and Liver Diseases at

Nottingham University Hopsitals NHS Trust and The University

of Nottingham, Nottingham, United Kingdom;

9. North Manchester General Hospital, Manchester,

United Kingdom;

10. St. Georges University of London, London, United Kingdom;

11. Gartnavel General Hospital, Glasgow, United Kingdom;

12. Hepatology Joint Clinical Research Unit, Bristol, United

Kingdom;

13. University College London, London, United Kingdom;

14. QE Hospital, Birmingham, United Kingdom;

15. Merck & Co., Inc., Kenilworth, NJ

16

• Current approved HCV GT3 therapies are limited in patients with

cirrhosis demonstrating suboptimal responses (<90% Sustained

Virologic Response) especially in treatment-experienced patients.

• In the UK, GT3 cirrhotic patients receive sofosbuvir (SOF)/peg-

interferon (P)/ribavirin(RBV) or daclatasvir/SOF/RBV for

12-24 weeks.

• Supported by preliminary data showing high efficacy in GT3

patients treated with elbasvir (EBR)/grazoprevir (GZR) + SOF for

8-12 weeks, C-ISLE was developed as a regional study of HC

GT3 compensated cirrhotic patients treated for 8-16 weeks with

EBR/GZR + SOF ± RBV.

17

EBR/GZR + SOF

SVR12

Tre

atm

en

t-

na

ive

EBR/GZR + SOF + RBV

TW4 TW8 TW12 TW0 FW12

EBR/GZR + SOF

EBR/GZR + SOF

EBR/GZR + SOF + RBV

TW16

SVR12

SVR12

SVR12

SVR12

Tre

atm

en

t-

exp

eri

en

ce

d

18

Cirrhotic GT3-Infected Patients

(n=100)

Male, n (%) 68 (68)

Race, n (%) Asian White Other

29 (29)

69 (69)

2 (2)

Cirrhosis diagnosis method Liver biopsy, n (%) FibroScan®, n (%) Mean FibroScan® score, kPa (SD)

16 (16)

84 (84)

25.4 (12.1)

Prior treatment history, n (%) Naïve PR-Experienced

47 (47)

53 (53)

Albumin, g/dL, mean (SD) 3.6 (1.2)

Total bilirubin, mg/dL, mean (SD) 0.7 (0.4)

Platelets x 103 cells/μl, mean (range) Platelet count <100 x 103 cells/μl, n (%)

148 (46-396)

24 (24)

19

21

23

22

22

17

17

17

17

17

17

Treatment-naive Treatment-experienced

Relapse 2 0 0 0 0

91 100 100 100 100

mFAS excluded patients who discontinued treatment for reasons unrelated to study medication.

EBR/GZR

+ SOF + RBV

(8 weeks)

EBR/GZR

+ SOF

(12 weeks)

EBR/GZR

+ SOF

(12 weeks)

EBR/GZR

+ SOF + RBV

(12 weeks)

EBR/GZR

+ SOF

(16 weeks)

0

25

50

75

100

SV

R, %

20

Transmission Rates And Outcomes in

Hepatitis C Virus Positive Donor to Hepatitis C

Virus Negative Kidney Transplant Recipients:

Analysis of National Data

Abstract #178

Gaurav Gupta, Le Kang, Victoria Garcia, Dipankar Bandopadhyay,

Ashley Limkemann, Dhiren Kumar, Anne King, Marlon Levy,

Adrian Collerell, Chandra Bhati, Amit Sharma, Richard K. Sterling;

1. Virginia Commonwealth University, Richmond, VA

21

• The use of kidneys from deceased donors who

are HCV positive (D+) to HCV negative recipients

(R-) represents a strategy to increase the limited

donor pool.

• It is unknown whether HCV R- patients who receive HCV

D+ kidneys (HCV D+/R-) can derive the long-term benefits

of kidney transplant due to the possible risks of donor-

derived HCV disease and subsequent mortality.

• Analysis of the national Organ Procurement and Transplant

Network (OPTN) database to compare the outcomes of

D+/R- to D-/R- kidney transplantation.

22

• Using the OPTN database, all D+/R- transplants performed

from 1994 to 2011 were compared to propensity matched

D-/R- recipients in a 1:5 distribution.

• Matching was performed using the following variables:

age, race, gender, pre-transplant dialysis, duration of

dialysis, diabetes, blood type, panel reactive antibody

(PRA), number of previous transplants and kidney donor

risk index (KDRI).

23

• A total of 416 D+/R- transplants were compared to 2080 D-/R-

matched-controls.

• HCV D+/R- recipients: 72% male, 49% African-American, and

36% diabetic

• Mean age at transplant: 54±13 years; mean duration of dialysis 3.1±2.8 years

pre-transplant.

• Both five-year graft survival (43% vs. 56% p<0.001) and five-year patient

survival (57% vs. 76%; p<0.001) were significantly worse in D+/R- kidney

transplant recipients than in matched controls.

• Post-transplant HCV RNA and/or serologic testing was available only for 126

D+/R- kidney transplant recipients.

– During the course of follow-up, 62/126 (49%) patients were confirmed to be HCV RNA+ (likely

donor-derived).

– Five-year graft and patient survivals among these 126 D+/R- patients were not significantly

different between those who were HCV RNA+ (n=62) vs HCV- (n=64) following kidney transplant

(p=0.3).

24

Safety of Sofosbuvir-Based Regimens for the

Treatment of Chronic HCV Infection in Patients with

Mild or Moderate Renal Impairment

Abstract #867

Francois Durand2, Stephen Pianko3, Liyun Ni1, Shampa De-Oertel1,

John McNally1, Diana M. Brainard1, John G. McHutchison1,

Eugene R. Schiff4, Massimo Colombo5;

1. Gilead Sciences, Inc, Foster City, CA;

2. AP-HP H.pital Beajon, Clichy, France;

3. Monash Medical Center, Clayton, VIC, Australia;

4. Schiff Center for Liver Disease, University of Miami, Miami, FL;

5. Gastroenterology, IRCCS Maggiore Hospital University of Milan, Milan, Italy

25

• The major metabolite of SOF, GS-331007,

is cleared renally and accumulates in severe renal

impairment or end stage renal disease.

• Although these populations were excluded

from most Phase 2 and 3 clinical trials, patients with mild

and moderate renal impairment were enrolled.

26

• Safety data from pts with or without compensated cirrhosis enrolled in 48 Phase

2 or 3 studies of SOF+RBV, LDV/SOF±RBV, and SOF/VEL±RBV were

assessed according to

– +/- RBV

– Degree of renal impairment

• Normal renal function (eGFR >80 ml/min)

• Mild renal impairment (eGFR 50-80 mL/min)

• Moderate renal impairment (eGFR 30-49 mL/min)

• 11,111 pts included; 2,186 (20%) had mild or moderate renal impairment at

baseline.

• Mean eGFR was 119, 69, and 44 mL/min for pts with normal renal function

(n=8925), mild (n=2043), or moderate (n=143) renal impairment, respectively.

• Baseline characteristics were generally similar across groups,

except pts with impaired renal function were older.

27

• Pts receiving RBV had higher rates of Gr 3-4 AEs, SAEs, and discons compared to pts not

receiving RBV; more pronounced in those with renal impairment.

• In pts not receiving RBV, similar rates of Gr 3-4 AEs and discons due to AE across groups.

• Pts with moderate renal impairment had higher rates of SAEs but most were not

treatment-related.

Subjects

Experiencing

Adverse Events

N (%)

Normal

Renal

Function

+RBV

n=5863

Normal

Renal

Function –

RBV

N=3062

Mild Renal

Impairment

+RBV

N=1239

Mild Renal

Impairment

–RBV

N=804

Moderate

Renal

Impairment

+RBV

N=93

Moderate

Renal

Impairment

–RBV

N=50

Gr 3-4 AE 401 (7) 109 (4) 125 (10) 25 (3) 30 (32) 3 (6)

SAE 232 (4) 96 (3) 79 (6) 23 (3) 24 (26) 6 (12)

Treatment-Related SAE 37 (0.6) 8 (0.3) 13 (1) 1 (0.1) 9 (10) 1 (2)

Treatment Discontinuation due to AE

112 (2) 12 (0.4) 46 (4) 0 16 (17) 0

Death 17 (0.3) 5 (0.2) 7 (0.6) 3 (0.4) 4 (4) 0

28

RUBY-I: Safety and Efficacy of

Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir with

or without Ribavirin in Adults with Genotype 1 Chronic

Hepatitis C Virus (HCV) Infection with Severe Renal

Impairment or End-Stage Renal Disease

Abstract #886

John M. Vierling1, Eric Lawitz2, K. Rajender Reddy3, Eric Cohen4,

Nyingi Kemmer5, Giuseppe Morelli6, Philippe J. Zamor7, Michael Bennett8,

David E. Bernstein9, Kris V. Kowdley10, Parvez S. Mantry11,

Paul J. Pockros12, David L. Wyles13, Sonal Kumar14, Kalyan R. Bhamidimarri15, Daniel E. Cohen4,

Tami Pilot-Matias4, Wangang Xie4, Thomas Podsadecki4, Tarek I. Hassanein16;

1. Baylor-St. Luke’s Medical Center/St. Luke’s Advanced Liver

Therapies, Houston, TX;

2. The Texas Liver Institute, University of Texas Health Science

Center, San Antonio, TX;

3. University of Pennsylvania, Philadelphia, PA;

4. AbbVie Inc., North Chicago, IL;

5. Tampa General Medical Group, Tampa, FL;

6. University of Florida Health Science Center, Gainesville, FL;

7. Carolinas Medical Center, Charlotte, NC;

8. Medical Associates Research Group, San Diego, CA;

9. North Shore University Hospital, Manhasset, NY;

10. Swedish Medical Center, Seattle, WA;

11. The Liver Institute at Methodist Dallas, Dallas, TX;

12. Scripps Clinic, Scripps Clinic, LaJolla, CA;

13. University of California San Diego, LaJolla, CA;

14. Weill Cornell Medical College, New York, NY;

15. University of Miami, Miami, FL;

16. Southern California GI and Liver Centers and Southern

California Research Center, Coronado, CA

29

• 48 GT1 patients enrolled

• Treatment-naïve (79%) or treatment-experienced

(IFN/PEG ± RBV)

• eGFR<30 mL/min/1.73 m2

• Noncirrhotic or compensated cirrhotics (31%)

• CKD: 17% Stage 4, 83% Stage 5, 69% on hemodialysis

100

80

60

40

20

0Arm C

27___

28

11___

11

46___

48

8___

9

% P

ati

en

ts

Arm D Arm E Overall

96% 96%89% 100%

Arm C:

GT1a, F0-F3

N = 28

Arm D:

GT1a, F4

N = 9

Arm E:

GT1b, F0-F4

N = 11

SVR12

SVR12

SVR12

12 24 weeks 36 weeks 48 weeks

OBV/PTV/r +

DSV + RBV

OBV/PTV/r + DSV

OBV/PTV/r + DSV

+RBV

24-week post-treatment period

24-week post-treatment period

24-week post-treatment period

30

• A large proportion of patients on RBV required RBV

dose modifications for anemia

– 7 patients received erythropoietin and 2 patients required

blood transfusion

• Most AEs were mild or moderate in severity

31

Retreatment of Patients Who Failed

Direct-acting Antiviral (DAA) Therapies:

Real World Experience from a Large European

Hepatitis C Resistance Database

Abstract #894

Johannes Vermehren1, Julia Dietz1, Simone Susser1, Thomas von Hahn2,

Joerg Petersen3, Holger Hinrichsen4, Ulrich Spengler5, Stefan Mauss6,

Christoph P. Berg7, Stefan Zeuzem1, Christoph Sarrazin1;

1. Medizinische Klinik 1, Universit.tsklinikum Frankfurt,

Frankfurt am Main, Germany;

2. Medizinische Hochschule Hannover, Hannover, Germany;

3. ifi-Institut fur Interdisziplin.re Medizin, Hamburg, Germany;

4. Gastroenterologische Gemeinschaftspraxis, Kiel, Germany;

5. Universit.tsklinikum Bonn, Bonn, Germany;

6. Medizinisches Versorgungszentrum, Dusseldorf, Germany;

7. Universit.tsklinikum Tubingen, Tubingen, Germany

32

• Treatment with direct antiviral agents (DAAs) achieved

high sustained virologic response (SVR) rates across a broad

range of patients with chronic hepatitis C virus

(HCV) infection.

• Presence of baseline resistance-associated variants (RAVs) has

been associated with reduced SVR rates depending on the DAA

regimen.

• There are few data on retreatment after DAA failure.

• However, AASLD guidelines recommend a switch to another DAA

drug class, the addition of ribavirin and treatment extension to 24

weeks.

• In addition, testing for RAVs is recommended prior to initiating

retreatment.

33

• Patients with failure to currently approved DAA

combination therapies were drawn from a large

resistance database comprising more than

3900 patients.

• Post failure serum samples were analyzed for the

presence of RAVs by direct sequencing of the NS3,

NS5A and NS4B genes.

• Patients with urgent reasons were retreated

based on the RAV analysis and guideline

recommendations.

34

• In total, 456 patients with failure to different DAA combinations

were analyzed.

• All currently approved DAA therapies were affected by treatment failure.

• These include ledipasvir/sofosbuvir ±ribavirin (RBV) (n=178), simeprevir/sofosbuvir ±RBV

(n=63), daclatasvir/sofosbuvir ±RBV (n=70), sofosbuvir/RBV (n=93; genotypes 2/3 only),

and paritaprevir/ombitasvir and dasabuvir ±RBV (3D; n=52).

• RAVs were detected in 90% of genotype (GT) 1 failures and 39% of patients with GT3,

including 3 patients with the NS5B RAV S282T (GT1b: n=1;

GT3: n=2).

• Retreatment was initiated in 73 (16%) of GT1/3 patients of whom 74%

had cirrhosis.

• The majority of retreated patients had failed simeprevir/sofosbuvir.

• For retreatment, either ledipasvir/sofosbuvir or the 3D regimen were chosen.

• So far, 43 of GT1/ GT3 patients have completed follow-up and 89% of these patients

achieved SVR.

35

Virological failures to direct acting antivirals (DAA)

regimens in a real life setting show frequent resistance

associated variants and may require

re-treatment with unconventional strategies

Abstract #1944

Velia Chiara Di Maio1, Valeria Cento1, Ilaria Lenci2, Marianna Aragri1, Silvia Barbaliscia1, Simona Francioso2, Stefania Paolucci3, Michela

Melis4, Gabriella Verucchi5, Nicola Coppola6, Carlo F. Magni7, Francesco Santopaolo2, Simona Landonio7, Valeria Ghisetti8, Mario Starace6,

Cecilia D’Ambrosio9, Vincenza Calvaruso10, Nicola Caporaso11, Caterina Pasquazzi12, Ivana Maida4, Antonino Picciotto13, Antonio Di Biagio14,

Laura Sticchi15, Raffaele Cozzolongo16, Dante Romagnoli17, Marco Biolato18, Jacopo Vecchiet19, Gabriella D’Ettorre20, Manuela Merli21,

Giovanni B. Gaeta22, Alessia Ciancio23, Letizia Marinaro8, Pietro Andreone24, Giorgio -. Barbarini25, Roberto Gulminetti26, Valeria Pace Palitti27,

Perluigi Tarquini28, Massimo Puoti29, Vincenzo Sangiovanni30, Maurizio Paoloni31, Sergio Babudieri4, Giuliano Rizzardini7,

Savino Bruno32, Massimo Andreoni33, Adriano M. Pellicelli9, Giustino Parruti34, Antonio Crax.10, Mario Angelico2,

Carlo F. Perno1, Francesca Ceccherini-Silberstein1;

1. Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy;

2. Hepatology Unit, University Hospital of Rome Tor Vergata,

Rome, Italy;

3. Virologia Molecolare, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy;

4. Infectious Diseases Unit, University of Sassari, Sassari, Italy;

5. Policlinico S. Orsola-Malpighi, Bologna, Italy;

6. Infectious Diseases, Second University of Naples, Naples, Italy;

7. Division of Infectious Disease, Hospital Sacco of Milan, Milan, Italy;

8. Infectious Diseases, “Amedeo di Savoia” Hospital, Turin, Italy;

9. Hepatology Unit, San Camillo Forlanini Hospital, Rome, Italy;

10. Gastroenterology, “P. Giaccone” University Hospital, Palermo, Italy;

11. Department of Clinical Medicine and Surgery, University “Federico II” of Naples, Naples, Italy;

12. Infectious Diseases, Sant’Andrea Hospital – “La Sapienza” University, Rome, Italy;

13. Division of Hepatology, IRCCS San Martino, IST Genova,

Genova, Italy;

14. Infectious Disease, IRCCS AOU San Martino - IST, Genova, Italy;

15. Hygiene Unit, IRCCS AOU San Martino-IST, Genova, Italy;

16. Department of Gastroenterology, Scientific Institute for Digestive Disease “Saverio de Bellis”

Hospital, Castellana Grotte, Bari, Italy;

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

Emilia, Modena, Italy;

18. Liver Transplant Unit, Catholic University of Rome, Rome, Italy;

19. Infectious Disease Clinic, Hospital of Chieti, Chieti, Italy;

20. Policlinico Umberto I Roma, Rome, Italy;

21. Gastroenterology, “La Sapienza” University of Rome, Rome, Italy;

22. Viral Hepatitis Unit, Second University, Naples, Italy;

23. Unit of Gastroenterology, University of Turin, Department of Medical Sciences, Citt. della salute e

della scienza di Torino Molinette Hospital, Turin, Italy;

24. Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy;

25. Division of Infectious and Tropical Diseases,, Fondazione IRCCS Policlinico San Matteo, Pavia,

Italy;

26. Institute of Infectious Diseases, University of Pavia, Pavia, Italy;

27. Hepatology Unit, Ospedale San Massimo, Penne, Italy;

28. Infectious Disease, Hospital “G. Mazzini”, Teramo, Italy;

29. Hospital Niguarda Ca’Granda, Milan, Italy;

30. Hospital Cotugno, Naples, Italy;

31. Infectious Disease Unit, Avezzano General Hospital, Avezzano, Italy;

32. Internal Medicine,, Humanitas University, Rozzano, Milan, Italy;

33. Infectious Diseases, University Hospital of Rome Tor Vergata,

Rome, Italy;

34. Infectious Disease Unit, Pescara General Hospital, Pescara, Italy

36

• Analysis of 182 patients who failed a DAA regimen

– GT1a: 21%, GT1b: 33%, GT2c: 5%, GT3a: 23% and

GT4a/d/n/r: 18%

– 65% treatment-experienced (9% with prior NS3 protease inhibitor)

– 81% cirrhotic

– 81% relapsed, 12% had on-treatment breakthrough and 7%

were nonresponders

• 49% failed a regimen now known to be suboptimal/not recommended

37

• Overall, 53% of pts showed >1 RAV related to the DAA-failure; RAVs prevalence was

higher in breakthrough/non responders than in relapsers (94% vs 43%,p<0.001).

• RAVs related to the DAA-class at failure varied in prevalence according to the inhibitors

used:

– 92% NS5A-RAVs in NS5A-failing pts (N=51)

– 77% NS3-RAVs in NS3-failures (N=82)

– 20% NS5B-RAVs in SOF-failures (N=152)

– 23% NS5B-RAVs in dasabuvir-failures (N=17)

• 46% of pts treated with >2 DAA classes showed RAVs on >2 DAA-targets, including 13/13

NS3-NS5A-failures, and 10/17 (59%) in 3D-failures.

• Overall, 13% of pts showed resistance to a class different than the DAAs class used,

probably due to natural resistance.

• 50% (5/10) SOF breakthrough/non-responders showed the SOF S282T RAV

(3 GT4: SMV/LDV+SOF+RBV; 1 GT1b: SOF+SIM; 1 GT3: SOF alone).

• SOF RAV L159F detected in 14% (20/142) of SOF relapsers (35% GT1b,

9% GT3).

38

• Due to natural RAVs, HCV resistance test at

failure should be recommended for all 3 genes

(NS3/NS5A/NS5B).

• In a real life setting, RAVs prevalence at failure was

remarkably high in all genes tested (with a partial exception

for NS5B, whose limited resistance is still higher than

previously reported).

• Must consider appropriate retreatment regimens,

sometimes based upon unconventional, more

aggressive/prolonged regimens able to overcome

the natural/acquired resistance and to warrant high

success rates.

39

40

VOX

NS3/4A

Protease

inhibitor

VOX

NS3/4A

Protease

inhibitor

VEL

NS5A

inhibitor

Background

Sofosbuvir (SOF)/Velpatasvir (VEL)

• SOF: Nucleoside polymerase inhibator with

activity against HCV GT 1-6

• VEL: Potent pangenotypic NS5A inhibitor

Voxilaprevir (VOX)

• HCV NS3/4A PI with potent antiviral activity

against GT 1-6, including most RASs

SOF/VEL/VOX

• Once daily, oral, fixed-dose combination

(400/100/100 mg) for GT 1-6

SOF

Nucleotide

Polymerase

inhibitor

VEL

NS5A

inhibitor

SOF

Nucleotide

Polymerase

inhibitor

H

H

H

HH

F F

F

F

41

POLARIS-1

SOF/VEL

SOF/VEL/GS-9857

Placebon=100

n=100

n=100

n=205

n=175

n=405

n=375

n=280

SOF/VEL/GS-9857

SOF/VEL/GS-9857

SOF/VEL/GS-9857

SOF/VEL

SOF/VEL

NS5A DAA

Experienced

DAA Naive,

GT 3 with

Cirrhosis

DAA Naive,

GT 1-6

Wk 0 8 12 20 24

SVR 12

SVR 12

Non-NS5A DAA

Experienced

POLARIS-2

POLARIS-3

POLARIS-4

42

0

20

40

60

80

100

POLARIS-1 (GT1-6) (Placebocontrol) (NS5A inhibitor

experienced; 41% cirrhotic)

POLARIS-2 (GT1-6) (DAA-naïve; 18% cirrhotic)

POLARIS-3 (GT-3) (DAA-naïve; 100% cirrhotic)

POLARIS-4 (GT1-4) (DAA-experienced, no NS5Ainhibitor; 46% cirrhotic)

SOF/VEL/VOX SOF/VEL

SV

R1

2 (

%)

96% 96% 96% 95% 98% 97%

90%

0%

(pbo)

253/

263 476/

501

432/

440 106/

110

105/

109

177/

182

136/

151

8

wk

8

wk 12

wk

12

wk

12

wk

12

wk 12

wk

43

44

In vitro:1,2

• Additive/synergistic antiviral activity

• 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)

Clinical PK &

metabolism:

• Once-daily oral dosing

• Minimal metabolism and primary biliary excretion

• Negligible renal excretion (<1%)

45

ENDURANCE Trials

GT1 non-cirrhotic including

HIV co-infection: 8 vs 12 weeks

GT2 placebo-controlled: 12 weeks

GT3 active comparator: 12 weeks

GT4-6 non-cirrhotic: 12 weeks

SURVEYOR Trials

GT2, 4-6 non-cirrhotic: 8 weeks

GT3 cirrhotic: 12 vs 16 weeks

MAGELLAN Trials

GT1, 4-6 prior DAA failures:

12 vs 16 weeks

EXPEDITION Trials

GT1, 2, 4-6 cirrhotic

GT1-6 all stages of renal impairment

46

Study Name Patient Population Duration SVR12 Rate

ENDURANCE-1 (#253)

GT1 without cirrhosis, new to treatment

or not cured with previous IFN-based

treatments (pegIFN +/- RBV or

SOF/RBV +/- pegIFN), and patients co-

infected with HIV-1

8 Weeks 99%

(n=348/351)

ENDURANCE-2 (#73)

GT2 without cirrhosis, new to treatment

or not cured with previous IFN-based

treatments (pegIFN +/- RBV or

SOF/RBV +/- pegIFN)

12 Weeks 99%

(n=195/196)

ENDURANCE-3 GT3 without cirrhosis,

new to treatment 8 Weeks

95%

(n=149/157)

ENDURANCE-4 (#114)

GT4, 5 or 6 without cirrhosis, new to

treatment or not cured with previous

IFN-based treatments (pegIFN +/- RBV

or SOF/RBV +/- pegIFN)

12 Weeks

100% (mITT)

GT4 (120/120)

GT5 (26/26)

GT6 (19/19)

47

Study Name Patient Population Duration SVR12 Rate

SURVEYOR-2 (Part 3) (#113)

GT3, with or without cirrhosis, new to

treatment or not cured with previous

IFN-based treatments (pegIFN,

SOF/RBV or pegIFN/SOF)

12-16 Weeks

TE noncirrhotic

91% (20/22) (12 weeks)

96% (21/22) (16 weeks)

TN cirrhotic

98% (39/40)

TE cirrhotic

96% (45/47)

SURVEYOR-2 (Part 4) (#LB-15)

GT2, 4, 5, 6 without cirrhosis, new to

treatment or not cured with previous

IFN-based treatments (pegIFN,

SOF/RBV or pegIFN/SOF)

8 Weeks 97%

(n=196/203)

EXPEDITION-IV

(#LB-11)

GT1-6; renal impairment, with or without

cirrhosis, new to treatment or not cured

with previous IFN-based treatments

(pegIFN, SOF/RBV or pegIFN/SOF)

12 Weeks SVR4

99% (N-103/104)

48

This enduring activity is supported by educational grants from

AbbVie & Gilead Sciences, Inc.