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Extended Treatment Duration
in Chronic Hepatitis C
Genotype 1 Infected
Slow-Responders:
Final Results of the SUCCESS Study
M. Buti, Y. Lurie, N.G. Zakharova,
N.P. Blokhina, A. Horban, C. Sarrazin,
L. Balciuniene, R. Chen, X. Yu, R. Faruqi,
R. Esteban
44th Annual Meeting of the European Association for the Study of the Liver
Sunday April 26, 2009; 12:30-12:45, Hall A2
Copenhagen, Denmark
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Buti P, et al. Presented at the
44th
Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.
04/28/09
Introduction
 Some studies suggest that extending treatment from 48
to 72 weeks could increase SVR in G1 patients who are
slow responders1-3
 However, definition of slow response varies depending
on the study (non-RVR2, partial early virologic
response1-3). In addition, the ribavirin dose is
suboptimal in many1-2; both factors affect the SVR rate
1. Berg T, et al. Gastroenterology. 2006;130:1086-1097.
2. Sanchez-Tapias JM, et al. Gastroenterology. 2006;131:451-460.
3. Pearlman BL, et al. Hepatology. 2007;46:1688-1694.
Buti P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.
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Objectives
 Evaluate the efficacy and safety of extended treatment
with PEG-IFN alfa-2b plus weight-based RBV in G1 slow
responders
• Slow responders are patients with detectable HCV-RNA
with ≥2 log viral reduction at TW 12 and undetectable HCV
RNA at TW 24
 Primary Efficacy End Point
• SVR for slow responders treated for 48 or 72 weeks
 Secondary End Points
• Relapse rate
• Safety
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Buti P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.
04/28/09
Study Design

Enrolled 1,428 treatment-naive patients with chronic HCV G1
Week 12
HCV-RNA (+)
and <2 log10 ↓
Week 24
Stop therapy
Stop therapy
HCV-RNA (+)
PEG-IFN alfa-2b 1.5
µg/kg/wk + RBV 0.8
1.4mg/d 12 weeks
Tx
Week 72
Week 48
PEG-IFN alfa-2b
+ RBV 12 weeks Tx
HCV-RNA (+)
and ≥2 log10
PEG-IFN alfa-2b
+ RBV :24 weeks Tx
HCV-RNA (-)
Group A
Group B
PEG-IFN alfa-2b + RBV:48 weeks Tx
Slow Responders
HCV-RNA (-)
PEG-IFN alfa-2b + RBV :36 weeks Tx
Group C
118 centers in Europe, Canada, Puerto Rico, and Israel participated in this study.
Buti P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.
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Key Inclusion Criteria
 Age 18–70 years
 Treatment-naive
 Chronic HCV G1 infection
 Detectable HCV-RNA
 Elevated serum ALT levels
 Liver biopsy (within 18 months) consistent with
chronic hepatitis
 Compensated liver disease
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Buti P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.
04/28/09
Patient Disposition

Enrolled 1,428 treatment-naive patients with chronic HCV G1
Week 12
HCV-RNA (+)
and <2 log10 ↓
Week 24
Stop therapy
Nonresponders
n = 444 (31.3%)
HCV-RNA (+)
PEG-IFN alfa-2b 1.5
RBV 0.8-1.4mg/d: 12
weeks Tx
N = 1419
HCV-RNA (+)
and ≥2 log10
Week 72
Week 48
PEG-IFN alfa-2b
+ RBV 12 weeks T
Stop therapy
PEG-IFN alfa-2b
+ RBV 24 weeks Tx
HCV-RNA (-)
Group A
n = 86
Group B n = 73
PEG-IFN alfa-2b + RBV 48 weeks Tx
Slow Responders n=159 (11.2%)
HCV-RNA (-)
PEG-IFN alfa-2b+ RBV 36 weeks Tx
Group C
n = 816 (57.5%)
HCV-RNA Central lab Roche TaqMan assay (LLQ = 30 IU/mL)
Buti P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.
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Patient Demographics
Slow Responders
Complete
EVR
Group A
48 Weeks Tx
(n = 86)
Group B
72 Weeks Tx
(n = 73)
Group C
48 Weeks Tx
(n = 816)
Age, mean, y (±SD)
44.5 (9.9)
46.5 (11.6)
40.4 (11.4)
Caucasians, n (%)
86 (100)
70 (95.9)
783 (96.0)
Female, n (%)
34 (39.5)
27 (37.0)
309 (37.9)
Weight, mean, kg (±SD)
78.04 (15.20)
77.53 (16.60)
76.45 (14.67)
ALT level, mean, U/L (±SD)
75.88 (48.03)
84.64 (70.68)
99.86 (70.30)
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SD = standard deviation.
Buti P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.
04/28/09
Most Slow Responders Had
High Baseline Viral Load
Slow Responders
Baseline
Viral Load
(IU/mL), n (%)
Complete EVR
Group A
48 Weeks Tx
(n = 86)
Group B
72 Weeks Tx
(n = 73)
Group C
48 Weeks Tx
(n = 816)
6.54
6.64
6.42
≤400,000
3 (3.5)
1 (1.4)
132 (16.2)
400,000–800,000
8 (9.3)
4 (5.5)
90 (11)
75 (87.2)
68 (93.2)
594 (72.8)
Median log IU/mL
>800,000
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Buti P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.
04/28/09
Treatment Discontinuations
Group A
48 Weeks Tx
Group B
72 Weeks Tx
Group C
Complete EVR
86
73
816
78 (90.7)
56 (76.7)
716 (87.7)
Withdrew early
8 (9.3)
17(23.3)
100 (12.3)
Due to AE
3 (3.5)
6 (8.2)
39 (4.8)
Lost to FU
2 (2.3)
1 (1.4)
21 (2.6)
No wish to continue
1 (1.2)
6 (8.2)
16 (2.0)
Noncompliance
2 (2.3)
2 (2.7)
16 (2.0)
0
2 (2.7)
8 (1.0)
Patient, n (%)
n
Completed study
Others
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Buti P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.
04/28/09
SVR With 72-Week Treatment Was Not Statistically
Superior to 48-Week Treatment in Slow Responders
(ITT Analysis)
100
P < .0001
Patients, %
80
79.5
P = .6445
60
47.9
43.0
40
20
0
37/86
35/73
649/816
Group A (48 Weeks)
Group B (72 Weeks)
Group C (48 Weeks)
———Slow Responders ———
Complete EVR
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Buti P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.
04/28/09
SVR Was Not Statistically Different Between 72- and 48Week Treatment Groups in Slow Responders
(Per Protocol Analysis)
100
Patients, %
80
P = .6341
60
48.6
43.5
40
20
0
37/85
35/72
Group A (48 Weeks)
Group B (72 Weeks)
Slow Responders
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Buti P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.
04/28/09
SVR was not statistically different between 72week treatment and 48-week treatment among
80/80/80 Compliance* and Completers†
Group A (48 wks)
Group B (72 wks)
Patients, %
100
80
60
P = 0.2802
P = 0.1952
57,1
57,1
44,3
46,2
n=79 n=56
n=78 n=56
80/80/80
Completers
40
20
0
*The subsets of all treated subjects meeting the criteria for fast or slow response and who took at least 80%of the planned
dose of each of the study medications (peginterferon and ribavirin) for at least 80% of the assigned treatment duration
†The subsets of all treated population meeting the criteria for fast or slow response and who completed the planned course
of treatment as per the Case Report Form Subject Status section
Buti P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.
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Relapse Rates Were Not Statistically Different Between
72- and 48-Week Treatment Groups in Slow Responders
P < .0001
 37.0%†
100
P = .1699
 14.4%*
Patients, %
80
60
47.1
32.7
40
20
10.1
0
Group A (48 Weeks)
Relapse: 32/68
Group B (72 Weeks)
Group C (48 Weeks)
Relapse: 16/49
Relapse: 71/702
——-Slow Responders ——
Complete EVR
*95% CI: 3.3%, 32.1%.
†95% CI: 24.9%, 49.0%.
Buti P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.
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Logistic Regression Analysis
 Weight
• <75 vs >75 kg
 Age
• 40–60 vs >60 y
• <40 vs >60 y
 Week 12 HCV-RNA
• 50–5000 vs >5000 IU/mL
• 50 vs >5000 IU/mL
 Baseline Viral Load
• ≤ vs > 800,000 IU/mL
 Treatment Arm
• A vs B
All Analyses NS except for Age <40 vs > 60 y (p = 0.0149)
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Buti P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.
04/28/09
Rates of Adverse Events Were Similar
Among Treatment Groups
Slow Responders
Complete
EVR
Group A
48 Weeks Tx
(n = 86)
Group B
72 Weeks Tx
(n = 73)
Group C
48 Weeks Tx
(n = 816)
At least one
83 (96.5)
71 (97.3)
792 (97.1)
Treatment-related
82 (95.3)
69 (94.5)
787 (96.4)
Serious
6 (7.0)
6 (8.2)
57 (7.0)
Leading to early withdrawal
3 (3.5)
6 (8.2)
41 (5.0)
Adverse Event, n (%)
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Buti P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.
04/28/09
Summary
 This, the largest prospective study among
naïve G1 slow responders, demonstrated no
statistically significant differences in SVR or
relapse rates between 48 and 72 weeks of
treatment when ribavirin is adjusted according
to body weight
 However there is a numerical trend toward
improved SVR and reduced relapse rates for the
72 wks therapy
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Buti P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.
04/28/09
Summary
 No unexpected safety concerns were reported
 Higher discontinuation rates may be associated
with extended treatment period
 Among Complete EVR patients, 80% achieved
SVR similar to those observed in the IDEAL
study
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Buti P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.
04/28/09
Study Investigators
Frank H Anderson
Jose D Pedreira Andrade
Joachim C Arnold
Ligita Balciuniene
Simon Bar-Meir
Harry P Bassaris
Manuel Garcia Bengoechea
Thomas Berg
Frieder Berr
Marc Bilodeau
Natalia P Blokhina
Danielle Botta-Fridlund
Marc Bourliere
Peter Buggisch
Mads R Buhl
Patrice Cacoub
Jose Luis Calleja
Andreas Cerny
Janusz Cianciara
Matthew Cramp
Antonio Craxi
Jens Encke
Lajos Dalmi
Jean Delwaide
Dimitrios Dimitroulopoulos
Halyna Dubynska
Martti Farkkila
Saya Victor Feinman
Jon Florholmen
Manuel Rodriguez Garcia
Cornelia Gelbmann
Guido Gerken
Judit Gervain
Andrzej Gietka
Andrzej Gladysz
Tobias Goeser
Olga A Golubovska
Jean-Jacques Gonvers
Michael Gschwantler
Natalya B Gubergrits
Rainer Gunther
Dominique Guyader
Waldemar Halota
Markus H Heim
Vaclav Hejda
Borys A Herasun
Christophe Hezode
Nir Hilzenrat
Andrzej Horban
Dominika Ipatova
Algimantas Irnius
Viktor Jancsik
Jacek Juszczyk
Kelly Kaita
Lars N Karlsen
Natalya V Kharchenko
Hartwig Klinker
John Koskinas
Tomas Krechler
Dominique Larrey
Mark Levstik
Alfredo Juan Lopez-Morante
Yoav Lurie
Spilios Manolakopoulos
Jose Maria
Oscar Nunez Martinez
Rafael Barcena Marugan
Philippe Mathurin
Leopoldo Matos
Stefan Mauss
Ehud Melzer
Larysa V Moroz
Viatcheslav G Morozov
Beat Mullhaupt
Rafael Esteban Mur
Frederik Nevens
Assy Nimer
Blai Dalmau Obrador
Ricardo Moreno Otero
Denis Ouzan
Court Pedersen
Giovambattista Pinzello
Viver Pi-Suner
Vladimir V Rafalsky
Maria Raptopoulou-Gigi
Jens Rasenack
Jose Aguilar Reina
Helmer Ring-Larsen
Mario Rizzetto
Federico Rodriguez-Perez
Jose Such Ronda
Fernando Pons Romero
Siegbert Rossol
Stephen Ryder
Jose Sanchez-Tapias
Rui Sarmento e Castro
Christoph Sarrazin
Jordi Ortiz Seuma
Stephen Shafran
Daniel Shouval
Emanuel Sikuler
Manfred V Singer
Jan Sperl
Zilvinas Sukys
Jolanta Sumskiene
Gerlinde Teuber
Valentyn Topolnytskyy
Albert Tran
Christian Trepo
Petr Urbanek
Jose M Zozaya Urmenata
Ola R Weiland
Johan Westin
Karl H Wiedemann
Florence Wong
Cristina Valente
Jean-Pierre Vinel
Zhanna I Vozianova
Eric Yoshida
Reinhart Zachoval
Natalia G Zakharova
Jean-Pierre Zarski
Eli Zuckerman
Buti P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.
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