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Real World Data
REAL-WORLD SAFETY AND EFFECTIVENESS OF
OMBITASVIR/PARITAPREVIR/R ± DASABUVIR ±
RIBAVIRIN IN THE GERMAN HEPATITIS C
REGISTRY
Holger Hinrichsen1, Heiner Wedemeyer2, Stefan Christensen3, Christoph
Sarrazin4, Axel Baumgarten5, Stefan Mauss6, Jan Hettinger7, Henning Kleine7
Affiliations: 1Gastroenterology-Hepatology Center Kiel, Kiel, Germany; 2Gastroenterology, Hepatology and Endocrinology,
Hannover Medical School, Hannover, Germany; 3Center for Interdisciplinary Medicine, Muenster, Germany; 4J.W. Goethe
University, Frankfurt, Germany; 5Medical Center for Infectious Diseases, Berlin, Germany; 6MVZ, Düsseldorf, Germany;
7AbbVie GmbH & Co KG, Wiesbaden, Germany
51st Annual Meeting of the European Association for the Study of the Liver
• Barcelona, Spain •
16 April 2016
Methods
German Hepatitis C Registry (DHC-R): non-interventional, prospective
cohort study with 254 study sites in Germany
Data were collected between February 1, 2014 and December 7, 2015
Patients must have had HCV GT1 or GT4 infection and been treated
with 2D / 3D ± RBV; N = 1017 patients
Exclusion criteria: HCV GT 2/3/5/6 or mixed GT1/GT4 infection
Limitations:
• Choice of treatment and duration was at physician’s discretion and
may not be in agreement with the local label or guideline
recommendations
• Follow up and laboratory testing were at investigator’s discretion
Study Profile
¶
= Defined by treatment initiation after June 22, 2015
= Patient files not completed. Queries ongoing.
F/U, follow-up. Data presented as of December 7th 2015
*
Baseline Demographics
2D / 3D ± RBV; (N = 1017)
Male, n (%)
660 (65)
Age, mean years ± SD
54.3 ± 12.5
BMI, mean kg/m2 ± SD
26.2 ± 4.4
Caucasian, n (%)
963 (95)
HCV Genotype, n (%)
1
892 (88)
1a
261 (26)
1b
614 (60)
Other
4
HCV RNA, mean  106 IU/mL ± SD
Cirrhosis, n/N (%)
Compensated (Child-Pugh A)
17 (2)
125 (12)
2.8 ± 4.0 (n = 973)
228/1017 (22)
149/228 (65)
Decompensated (Child-Pugh B/C)
16/228 (7)
Data not available
63/228 (28)
Deviations in n-values for diagnostic parameters are due to missing documentation in the registry at the time point of analysis
Regimen Duration, n (%)
8W
12 W
24 W
Other
GT1a*
N = 137
w/o cirrhosis
1
(0.7)
130
(94.9)
1
(0.7)
5
(3.6)
GT1a*
with cirrhosis
N = 30
1
(3.3)
24†
(80.0)
4
(13.3)
1
(3.3)
GT1b
N = 284
w/o cirrhosis
3
(1.1)
271
(95.4)
0
10
(3.5)
GT1b
N = 104
with cirrhosis
0
96
(92.3)
1
(1.0)
7
(6.7)
GT4
w/o cirrhosis
N = 58
0
56
(96.6)
0
2
(3.4)
GT4
with cirrhosis
N=2
0
2
(100)
0
0
Data is available for patients that reached EOT only (N = 615)
Dark green shading indicates the label-recommended treatment duration according to cirrhosis and HCV-genotype at the time of data collection
* Includes patients with unspecified (GT1 subtype not determined) or mixed GT1-subtype (>1 GT1 subtypes)
† For GT1a-patients with cirrhosis, German guidelines recommend treatment shorting to 12 weeks for patients with defined positive predictors (Viekirax and Exviera SmPC)
Reasons for Non-SVR, n (%)
2D / 3D
(without RBV)
N = 269
2D / 3D
(with RBV)
N = 289
260 (97)
279 (97)
Did not achieve SVR12
9 (3)
10 (3)
Virological relapse
5 (2)
1 (0.4)
Early D/C (possibly) related to therapy*
2 (0.7)†
5 (2)†
Early D/C not related to therapy*
2 (0.7)
4 (1)
Achieved SVR12
* Discontinuation (possibly) related to therapy was defined as one or more of the following: on-treatment virologic failure,
discontinuation due to AE, patient’s request and inadequate compliance. Discontinuation not related to therapy was defined as
follows: loss to follow up before completion of treatment, move of patient, unplanned event (such as incarceration) and other
reason. † One patient discontinued, but achieved SVR.
Real-world data in co-infected
patients
Ledipasvir/Sofosbuvir+/-Ribavirin in Patients Co-infected with
HCV and HIV:
Real-world Heterogeneous Population from the TRIO Network
Douglas T. Dieterich1, Bruce Bacon2, Michael Curry3, Steven L. Flamm4, Lauren
Guest5, Kris Kowdley6, Yoori Lee5, Zobair Younossi7, NaokyTsai8, and Nezam Afdhal3
1Icahn School of Medicine at Mount Sinai, 2Saint Louis University School of Medicine,3Beth Israel Deaconess Medical Center, 4Northwestern University
Feinberg School of Medicine,5Trio Health Analytics,
6Liver Care Network, Swedish Medical Center, 7Center for Liver Diseases, Department of Medicine, InovaFairfax Hospital, and 8Queens Medical Center,
University of Hawaii
The Trio Network – HIV/HCV coinfection
Treating patients with cirrhosis –
benefits for all?
The evolution of portal pressure after viral
suppression with interferon-free therapies and
its correlation with the change in liver stiffness
Mattias MANDORFER1, 2, Karin KOZBIAL1, Philipp SCHWABL1, 2, Clarissa FREISSMUTH1, Rémy
SCHWARZER1, 2, Rafael STERN1, David CHROMY1, Thomas REIBERGER1, 2, Albert F.
STÄTTERMAYER1, Wolfgang SIEGHART1, 2, Sandra BEINHARDT1, Michael TRAUNER1, Harald
HOFER1, Arnulf FERLITSCH1, 2, Peter FERENCI1, Markus PECK-RADOSAVLJEVIC1, 2
1Division
of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University
of Vienna, Vienna, Austria
3Vienna Hepatic Hemodynamic Lab
Mattias Mandorfer and Karin Kozbial contributed equally to the work
Study flow chart
ACLD advanced chronic liver disease; TE transient elastography
Results
Δ HVPG: Pronounced portal hypertension at BL
• No patient resolved portal
hypertension
• Regression to subclinical
portal hypertension in 5%
(1/20)
• FU HVPG of 10-15 mmHg in
35% (7/20)
• Increase in HVPG in 20%
(4/20)
Real-world efficacy of generic
DAAs
High sustained virological response rates using
generic direct antiviral treatment for Hepatitis C
REDEMPTION-1
James Freeman1, Richard Sallie2, Adam Kennedy3, Pham Thi Ngoc Nieu1,
John Freeman4, Greg Jeffreys5, Andrew M. Hill6
1GP2U
Telehealth, Hobart, 2Hepatology, Nedlands, 3Kingswood Pharmacy, 4Nephrology, Sandy
Bay, 5University of Tasmania, Hobart, Australia, 6St Stephens AIDS Trust, Chelsea and
Westminster Hospital, London, United Kingdom
International Liver Congress 2016 13-18 April, Barcelona, Spain
LB03
31
The Deployment Problem Is Price
Source: Significant reductions in costs of generic production of sofosbuvir and daclatasvir for treatment of hepatitis C, Hill et al, EASL 2016
32
The Legal Basis Of Personal
Importation
• Patents provision monopoly rights, however…
• Article 60 of TRIPS - De Minimis Imports – states:
– Members may exclude from the application of the
above provisions small quantities of goods of a noncommercial nature contained in travellers' personal
luggage or sent in small consignments
• In line with Article 60 most countries allow some
form of personal medication importation
• http://fixhepc.com/ helps patients access
medication and discuss their treatment online
33
Methods
• Generic DAAs were first evaluated for quality
using HPLC, NMR and Mass Spectrometry
• Patients enrolled on an intention to treat basis via
the fixhepc.com website and were assisted in
making a personal importation of affordably
priced medication
• Patients were assessed pre-treatment, during
treatment, and then for SVR (cure) following
treatment using the gp2u.com.au Telemedicine
platform
• The objective of this analysis was to assess the
safety and effectiveness of the generic
medications legally imported by patients
34
Over 400 Patients Worldwide Enrolled
35
Baseline Characteristics
36
REDEMPTION-1 HCV RNA < LLOQ at
EOT and SVR4
37
REDEMPTION-1 Overall SVR4 Results by
Genotype
Note: Some small percentage loss of SVR is expected during the SVR4 to SVR12 period
38
Patient Safety
• No new or unknown side effects were reported
with headache, fatigue and insomnia being the
most common
• 3 patients with compensated cirrhosis
temporarily decompensated on treatment
initiation but continued
• 4 patients who enrolled died, all from HCC
– 1 patient died prior to treatment commencement
– 2 withdrew early in treatment and entered palliative
care
– 1 patient died prior to SVR4
39
Summary
• In this interim analysis, treatment with legally
imported generic DAAs led to high SVR rates
• These SVR rates are similar to those seen in
the Phase 3 trials of branded treatments
• Mass global treatment with generic DAAs is a
feasible alternative where high prices prevent
access to branded treatment
40
HCV Re-infection in HIV+ in
Europe
Hepatitis C virus reinfection incidence and
outcomes among HIV-positive MSM in
Western Europe
Thomas Martin MD
On behalf of: Ingiliz P, Martin TCS, Rodger A, Stellbrink HJ, Mauss S, Boesecke C,
Mandorfer M, Bottero J, Baumgarten A, Bhagani S, Lacombe K, Nelson M, Rockstroh
JK and the NEAT study group
Reinfection with HCV after treatment or
spontaneous clearance occurs often
• Reinfection with HCV
– Amsterdam 15.2/100py
– London 8.0/100py
• Reinfection is important for a number of reasons
– Could affect cost/benefit of treatment with expensive
DAAs
– Could demonstrate a need for additional
education/prevention interventions
– Supports ongoing screening for HCV after successful
treatment
– People with reinfection may be at greater risk of
transmission of infection including HIV
1. Lambers FAE et al. Alarming incidence of hepatitis C virus re-infection after treatment of sexually acquired acute hepa- titis C virus infection in HIV-infected MSM.
AIDS (London, England) 2011; 25:F21–F27.
2. Martin TCS et al. Hepatitis C virus reinfection incidence and treatment outcome among HIV-positive MSM. AIDS 2013, 27:2551-2557
HCV reinfection among HIV positive MSM in
Western Europe
• Aims:
– Primary: to calculate reinfection incidence
among the European AIDS Treatment Network
(NEAT) consortium centres in Western Europe
(UK, Germany, Austria and France)
– Secondary: to look for factors associated with
reinfection and spontaneous clearance of
reinfection
HCV reinfection among HIV positive MSM in
Western Europe
• Analysis:
– Reinfection definition: newly positive HCV PCR any time after
cure or earlier if HCV geno-/subtype switch occurred
– Start of from end of treatment for those treated and the first
negative HCV PCR for people who spontaneously clear
– Date of reinfection taken as first newly positive HCV PCR
– End of follow up - last negative HCV PCR
• Kaplan Meier survival methods.
• Comparison using log-rank and Cox proportional hazards
• Multiple logistic regression to assess factors associated
with spontaneous clearance of reinfection
Overall population
Incident infection
1st Reinfection
Number included
606
606
Number reinfected (%)
N/A
149 (24.6)
Median time (years) to reinfection (IQR)
N/A
1.8 (1.1-3.2)
Genotypes (%)
GT1:
GT2:
GT3:
GT4:
Genotype switches (%)
N/A
71/136 (52.2)
Median age at reinfection (IQR)
39 (34-44)
41 (37-45)
Median HIV duration at infection (only data for
patients that were reinfected) (IQR)
Median CD4 at reinfection
5 (2-11)
9 (6-14)
Proportion with suppressed HIV VL
SC proportion
376(70.5)
13(2.4)
46(8.6)
96 (18)
GT1:
GT2:
GT3:
GT4:
104(73.2)
1(0.7)
12(8.5)
25(17.6)
553 (412-760)
91/111 (82.0%)
111/605 (18.3%)
21/135 (15.6%)
(failed treatment not
in denominator)
113 treated with 87 achieving SVR (78%)
Overall population
2nd Reinfection
3rd reinfection
4th reinfection
Number included
69
13
2
Number reinfected (%)
29 (42.0)
4 (30.8)
1 (50)
Median time (years) to reinfection
(IQR)
1.7 (1.2-2.4)
Genotypes (%)
GT1:
GT2:
GT3:
GT4:
GT1:
GT2:
GT3:
GT4:
GT1:
GT2:
GT3:
GT4:
Genotype switches (%)
13/25 (52.0)
2/4 (50)
1/1 (100)
Median age at reinfection (IQR)
43 (40-49)
-
-
SC proportion
6/21 (28.6%)
1/3 (33.3%)
0/1 (0%)
22(84.6)
0
1(3.8)
3(11.5)
3(75)
0
0
1(25)
1 (100)
0
0
0
HCV reinfection incidence is high
Reinfection incidence of 7.6/100py (95% CI 6.3-9.1)
[1583 py f/u with 121 reinfections]
2nd Reinfection incidence is even higher than
1st reinfection
19.9/100py (95% CI 13.3-29.7)
HR 2.59 (95% CI 1.67- 4.03)
Reinfection following spontaneous clearance is
reduced compared to treatment
HR 0.55 (95% CI 0.32-0.95)
Reinfection incidence by location
Associations with spontaneous clearance of
reinfection
Variable
OR
95% CI
P-value
HCV VL ≥500000
0.5
0.1 – 1.9
0.28
CD4 ≥ 500 cells/ml
0.7
0.2 - 2.6
0.55
Max ALT reinfection ≥1000
IU/ml
19.6
3.6-105.8
0.001
Max ALT initial infection ≥ 1000
IU/ml
0.6
0.1 – 3.2
0.53
Spontaneous clearance of
initial infection
12.7
2.3 – 70.2
0.004
HIV VL detectable
0.3
0.4 – 1.4
0.11
Age ≥30
3.7
0.8 – 17.6
0.10
Conclusions
• Substantial HCV reinfection risk among HIV/HCV
coninfected MSM – 7.6/100 py with 25% reinfected at 3
years
• Failure of current prevention interventions
– Urgently need prevention strategies
• Importance of rapid identification and treatment to
prevent transmission of HCV or HIV
– Suggest 3-6 month testing with HCV RNA PCR after initial
infection
– And every 3 months after a HCV reinfection
• Spontaneous clearance associated with reduced risk of
reinfection (HR 0.55) and increased chance of
spontaneous clearance if reinfected (OR 12.7)
Can short-duration DAA-based
therapy be used for acute/early HCV
infection?
New drugs for G3? DAA failures?
High Efficacy of Sofosbuvir/Velpatasvir Plus GS9857 for 12 Weeks in Treatment-Experienced
Genotype 1–6 HCV-Infected Patients, Including
Those Previously Treated With Direct-Acting
Antivirals
Eric Lawitz1, Kris Kowdley2, Michael Curry3, Nancy Reau4, Mindie Nguyen5, Paul Kwo6, Ira Jacobson7, Tram
T. Tran8, Ronald Nahass9, Federico Hinestrosa10, Robert Herring Jr.11, Michael Bennet12, Jenny C. Yang13,
Luisa M. Stamm13, Di An13, Hadas Dvory-Sobol13, Diana M. Brainard13, John G. McHutchison13, Eugene
Schiff14, Mitchell Davis15, Kyle Etzkorn16, Raymond T. Chung17, David Pound18, Maribel Rodriguez-Torres19,
K. Rajender Reddy20, Ziad Younes21, Edward J.Gane22
1Texas
Liver Institute, San Antonio, Texas, USA; 2Swedish Medical, Seattle, Washington, USA; 3Beth Israel Deaconess Medical
Center, Boston, Massachusetts, USA; 4Rush University Medical Center, Chicago, Illinois, USA; 5Stanford University, Palo Alto,
California, USA; 6Indiana University School of Medicine, Indianapolis, USA; 7Mount Sinai Beth Israel, New York, USA; 8Cedars
Sinai Medical Center, Los Angeles, California; 9ID Care, Hillsborough, New Jersey, USA; 10Orlando Immunology Center, Florida,
USA; 11Nashville Gastrointestinal Specialists Inc., Tennessee, USA; 12Medical Associates Research Group, Inc., San Diego,
California; 13Gilead Sciences, Inc., Foster City, California; 14University of Miami, Florida, USA; 15Digestive CARE-South Florida
Center of Gastroenterology, Wellington, Florida, USA; 16Borland-Groover Clinic, Jacksonville, Florida, USA; 17Massachusetts
General Hospital, Boston, Massachusetts; 18Indianapolis Gastroenterology Research Foundation, Indianapolis, Indiana, USA;
19Fundación De Investigación De Diego, San Juan, Puerto Rico; 20University of Pennsylvania , Philadelphia, USA; 21Gastro One,
Germantown, Tennessee, USA; 22Auckland Clinical Studies, New Zealand
EASL 2016, Barcelona
Study Designs
GS-US-367-1168 and GS-US-367-1169
Week 0
12
N=128 SOF/VEL + GS-9857
24
SVR12
• Two Phase 2, multicenter, open-label studies (US, New Zealand)
– GS-US-367-1168: GT 1
– GS-US-367-1169: GT 2, 3, 4, 5, 6
• Broad inclusion criteria
– HCV treatment experienced, including DAA experienced
• GT 1: NS5A inhibitor or ≥2 DAA classes
• GT 2–6: Peg-IFN + RBV or any DAA
– 50% with compensated cirrhosis
71
Results: Demographics and Baseline
Characteristics
SOF/VEL + GS-9857 12 weeks
N=128
Mean age, y (range)
58 (37–77)
Male, n (%)
96 (75)
White, n (%)
105 (82)
Mean BMI, kg/m2 (range)
29 (18-53)
IL28B non-CC, n (%)
93 (73)
Cirrhosis, n (%)
61 (48)
Mean HCV RNA, log10 IU/mL (range)
6.3 (3.8–8.1)
HCV GT, n (%)
1
63 (49)
2
21 (16)
3
35 (27)
4, 6
9 (7)
DAA experience, n (%)
None (GT 2-6 only)
27 (21)
1 DAA class
36 (28)
≥2 DAA classes
65 (51)
72