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Predicting Early and Sustained Virological Responses in Prior Nonresponders to Pegylated Interferon alpha-2b Plus Ribavirin Retreated With Peginterferon alpha-2a Plus Ribavirin and the Benefit-Risk Ratio of Retreatment

Marcellin, Patrick MD, PhD*; Craxi, Antonio MD, PhD; Brandao-Mello, Carlos E. MD, PhD; Di Bisceglie, Adrian M. MD§; Andreone, Pietro MD; Freilich, Bradley MD; Rajender Reddy, K. MD#; Olveira Martín, Antonio PhD**; Teuber, Gerlinde MD††; Messinger, Diethelm MSc‡‡; Hooper, Greg PhD§§; Wat, Cynthia MBBS, MRCP, MFPM§§; Tatsch, Fernando MD∥∥; Jensen, Donald M. MD¶¶

Journal of Clinical Gastroenterology: October 2013 - Volume 47 - Issue 9 - p 786–793
doi: 10.1097/MCG.0b013e31827b9b45
LIVER, PANCREAS AND BILIARY TRACT: Original Articles

Goals: To evaluate the predictive value of complete early virological response (cEVR) on sustained virological response (SVR) following retreatment with peginterferon alpha-2a (40 kDa) plus ribavirin in previous nonresponders to peginterferon alpha-2b (12 kDa).

Background: In the randomized multinational retreatment with Pegasys in patients not responding to PegIntron therapy study, a 72-week regimen of peginterferon alpha-2a (40 kDa) plus ribavirin improved SVR rates over a standard 48-week regimen in previous nonresponders to peginterferon alpha-2b (12 kDa). cEVR, defined as hepatitis C virus RNA <50 IU/mL at treatment week 12, was an important predictor of SVR.

Study: We conducted an exploratory analysis of the retreatment with Pegasys in patients not responding to PegIntron therapy study data to better define the predictive value of cEVR for SVR in this patient population.

Results: In total, 157 of the 942 patients achieved a cEVR (16.7%). SVR rates were higher with 72 versus 48 weeks of retreatment in patients with a cEVR (57% vs. 35%), whereas SVR rates were <5% in patients without cEVR in both groups. The relative adverse event (AE) burden was lower with 72 weeks of treatment (8.1 vs. 10.1 AEs/y of treatment) as was the estimated number of AEs per SVR achieved (55 vs. 100). Cumulative treatment duration required to achieve 1 SVR was lower with 72 weeks of treatment (6.7 vs. 10.0 y/SVR) and lower still assuming that treatment was stopped at week 12 for non-cEVR patients (3.6 vs. 7.1 y/SVR).

Conclusions: cEVR is a reliable predictor of SVR in patients retreated with peginterferon alpha-2a (40 kDa) plus ribavirin. Seventy-two-week retreatment has a more favorable benefit-risk ratio than 48 weeks, especially when cEVR is used to identify patients most likely to be cured.

*Hôpital Beaujon, Boulevard du Général Leclerc, Clichy, France

Instituto Di Clinica Medica Policlinico, Palermo

Department of Clinical Medicine, University of Bologna, Bologna, BO, Italy

Internal Medicine Department, Hepatology Division, Gaffrèe e Güinle University Hospital, College of Medicine & Surgery, University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil

§Department of Internal Medicine, Saint Louis University School of Medicine, St Louis

Kansas City Gastroenterology and Hepatology, LLC, Kansas City, MO

#Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA

**Hospital La Paz de Madrid, Madrid, Spain

††Interdisziplinäres Facharztzentrum Sachsenhausen, MVZ-Sachsenhausen, Frankfurt

‡‡IST GmbH, Mannheim, Germany

§§Roche Products Ltd, Welwyn, UK

∥∥F. Hoffmann-La Roche Ltd, Basel, Switzerland

¶¶Center for Liver Diseases, University of Chicago Hospitals, Chicago, IL

Supported by F. Hoffmann-La Roche, Basel, Switzerland. Support for third-party writing assistance for this manuscript was provided by F. Hoffmann-La Roche Ltd.

ClinicalTrials.gov no.: NCT00087646.

P.M. has served as a speaker, a consultant or an advisory board member for Roche, Schering-Plough, Gilead, Bristol-Myers Squibb, Vertex, Novartis, Pharmasset, Tibotec, Merck Sharp & Dohme, Boehringer, Abbott, and Pfizer; and has received research funding from Roche, Schering-Plough, Gilead, and Echosens. A.C. has served as a speaker, a consultant, and an advisory board member for Roche, Merck, and Novartis and has received research funding from Roche, Merck, and Novartis. A.M.D.B. has served as a speaker, a consultant, or an advisory board member for Roche (now Genentech), Vertex, Bristol-Myers Squibb, Merck, Anadys, Bayer, GlobeImmune, Pharmasset, Salix, and Tibotec; and has received research funding from Roche (now Genentech), Gilead, Idenix, Vertex, Bristol-Myers Squibb, Abbott, Anadys, GlobeImmune, Pharmaset, Transgene, and Tibotec. P.A. has served as a speaker, a consultant, and an advisory board member for Janssen, Roche, and Merck Sharp & Dohme; and has received research funding from Gilead, Roche, and Bristol-Myers Squibb. B.F. has served as a speaker, a consultant, and an advisory board member for Roche, Merck, and Vertex and has received research funding from Roche, Merck, and Vertex. K.R.R. has served as a speaker, a consultant, and an advisory board member for Roche, Genentech, Merck, Tibotec, Vertex, and Gilead and has received research funding from Bristol-Myers Squibb, Roche, Genentech, Merck, Tibotec, Vertex, and Gilead. G.T. has received research funding from Essex Pharma, Gilead Sciences, Bristol Meyers Squibb, and Roche. G.H. is an employee of Roche and owns stocks and shares in Roche. C.W. is an employee of Roche and owns stocks and shares in Roche. F.T. is an employee of Roche and owns stocks and shares in Roche. D.M.J. has served as a consultant and an advisory board member for Abbott, Globeimmune, Roche, Merck, Pfizer, Pharmasset, Tibotec/Johnson & Johnson, Vertex, Bristol-Myers Squibb, Boehringer Ingelheim, and Genentech. The remaining authors declare that they have nothing to disclose.

Reprints: Patrick Marcellin, MD, PhD, Hôpital Beaujon, 100 Boulevard du Général Leclerc, Clichy 92110, France (e-mail: patrick.marcellin@bjn.aphp.fr).

Received July 9, 2012

Accepted October 29, 2012

© 2013 by Lippincott Williams & Wilkins