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Introduction

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.

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Introduction

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  1. 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 A2Copenhagen, Denmark

  2. 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 • Berg T, et al. Gastroenterology. 2006;130:1086-1097. • Sanchez-Tapias JM, et al. Gastroenterology. 2006;131:451-460. • Pearlman BL, et al. Hepatology. 2007;46:1688-1694.

  3. 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

  4. Study Design • Enrolled 1,428 treatment-naive patients with chronic HCV G1 Week 12 Week 24 Week 72 Week 48 HCV-RNA (+) and <2 log10 ↓ Stop therapy Stop therapy HCV-RNA (+) PEG-IFN alfa-2b + RBV 12 weeks Tx PEG-IFN alfa-2b 1.5 µg/kg/wk + RBV 0.8 1.4mg/d 12 weeks Tx PEG-IFN alfa-2b + RBV :24 weeks Tx Group A HCV-RNA (+) and ≥2 log10 HCV-RNA (-) 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.

  5. 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

  6. Patient Disposition • Enrolled 1,428 treatment-naive patients with chronic HCV G1 Week 12 Week 24 Week 72 Week 48 HCV-RNA (+) and <2 log10 ↓ Stop therapy Nonrespondersn = 444 (31.3%) Stop therapy HCV-RNA (+) PEG-IFN alfa-2b + RBV 12 weeks T HCV-RNA (+) and ≥2 log10 Group An = 86 PEG-IFN alfa-2b 1.5 RBV 0.8-1.4mg/d: 12 weeks TxN = 1419 PEG-IFN alfa-2b + RBV 24 weeks Tx HCV-RNA (-) 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 Cn = 816 (57.5%) HCV-RNA Central lab Roche TaqMan assay (LLQ = 30 IU/mL)

  7. Patient Demographics SD = standard deviation.

  8. Most Slow Responders Had High Baseline Viral Load

  9. Treatment Discontinuations

  10. P < .0001 P = .6445 SVR With 72-Week Treatment Was Not Statistically Superior to 48-Week Treatment in Slow Responders (ITT Analysis) 649/816 37/86 35/73 ———Slow Responders ——— Complete EVR

  11. P = .6341 SVR Was Not Statistically Different Between 72- and 48-Week Treatment Groups in Slow Responders (Per Protocol Analysis) 37/85 35/72 Slow Responders

  12. SVR was not statistically different between 72-week treatment and 48-week treatment among 80/80/80 Compliance* and Completers† P = 0.2802 P = 0.1952 n=56 n=79 n=78 n=56 *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

  13. P < .0001 37.0%† P = .1699 14.4%* Relapse Rates Were Not Statistically Different Between 72- and 48-Week Treatment Groups in Slow Responders Patients, % Relapse: 16/49 Relapse: 32/68 Relapse: 71/702 ——-Slow Responders —— Complete EVR *95% CI: 3.3%, 32.1%.†95% CI: 24.9%, 49.0%.

  14. 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)

  15. Rates of Adverse Events Were Similar Among Treatment Groups

  16. 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

  17. 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

  18. 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

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