Upload
others
View
3
Download
0
Embed Size (px)
Citation preview
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.