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Chapter 2.5 116 hepatocellular carcinoma. 30-32 Furthermore, this HBV DNA threshold and the duration of follow-up correspond with the defi nition of response to peginterferon therapy according to the recent European guidelines and the pivotal studies on peginterferon in chronic hepatitis B, respectively. 10, 20, 33 The large majority of our patients were of Caucasian origin and infected with HBV genotypes A and D. Responsiveness to interferon-based therapy appears to be lower in genotype D compared to other genotypes, which may explain the limited effi cacy of peginterferon in our study population. 9-10, 26, 34 A recent retrospective analysis of 264 HBeAg-negative patients treated with peginterferon alfa-2a alone or in combination with lamivudine reported that pretreatment HBsAg levels varied according to genotype. The highest concentrations were found in patients infected with genotypes A and D. Although serum HBsAg levels decreased during the treatment phase in all genotypes, HBsAg decline was least pronounced in genotype D. 35 Therefore, our data on HBsAg decline need to be confi rmed in genotypes B and C. In summary, the current study shows that a combination of early quantitative serum HBsAg and HBV DNA levels allows the best selection of patients with HBeAg-negative CHB who will not respond to a 48-week course of peginterferon alfa-2a therapy. Discontinuation of peginterferon therapy and a switch to alternative treatment appears to be indicated in patients without a decline in HBsAg level combined with less than 2 log copies/mL decline in HBV DNA level at week 12.
References Early on-treatment prediction of response to PEG 117 1. Dienstag JL. Hepatitis B virus infection. N Engl J Med 2008;359:1486-500. 2. Funk ML, Rosenberg DM, Lok AS. World-wide epidemiology of HBeAg-negative chronic hepatitis B and associated precore and core promoter variants. J Viral Hepat 2002;9:52-61. 3. Hadziyannis SJ, Vassilopoulos D. Hepatitis B e antigen-negative chronic hepatitis B. Hepatology 2001;34:617-24. 4. Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, DeHertogh D, Wilber R, Zink RC, Cross A, Colonno R, Fernandes L. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2006;354:1011-20. 5. Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OO, Shiffman ML, Trinh H, Washington MK, Sorbel J, Anderson J, Snow-Lampart A, Mondou E, Quinn J, Rousseau F. Tenofovir Disoproxil Fumarate versus Adefovir Dipivoxil for Chronic Hepatitis B. N Engl J Med 2008;359:2442-2455. 6. Shouval D, Lai CL, Chang TT, Cheinquer H, Martin P, Carosi G, Han S, Kaymakoglu S, Tamez R, Yang J, Tenney D, Brett-Smith H. Relapse of hepatitis B in HBeAg-negative chronic hepatitis B patients who discontinued successful entecavir treatment: The case for continuous antiviral therapy. J Hepatol 2009;50:289-95. 7. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, Marcellin P, Lim SG, Goodman Z, Ma J, Arterburn S, Xiong S, Currie G, Brosgart CL. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N Engl J Med 2005;352:2673-81. 8. Santantonio T, Mazzola M, Iacovazzi T, Miglietta A, Guastadisegni A, Pastore G. Long-term follow-up of patients with anti-HBe/HBV DNA-positive chronic hepatitis B treated for 12 months with lamivudine. J Hepatol 2000;32:300-6. 9. Rijckborst V, Ter Borg MJ, Cakaloglu Y, Ferenci P, Tabak F, Akdogan M, Simon K, Raptopoulou-Gigi M, Örmeci N, Zondervan PE, Verhey E, Van Vuuren AJ, Hansen BE, Janssen HL. A randomized trial of peginterferon alfa-2a with or without ribavirin for HBeAg-negative chronic hepatitis B. Am J Gastroenterol 2010. 10. Marcellin P, Lau GK, Bonino F, Farci P, Hadziyannis S, Jin R, Lu ZM, Piratvisuth T, Germanidis G, Yurdaydin C, Diago M, Gurel S, Lai MY, Button P, Pluck N. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004;351:1206-17. 11. Farci P, Marcellin P, Lu ZM, Diago M, Lai MY, Gurel S. On-treatment predictors of sustained biochemical and virological response in patients with HBeAg-negative chronic hepatitis B (CHB) treated with peginterferon alpha-2a (40kDa) (Pegasys(R)). J Hepatol 2005;42:S175. 12. ter Borg MJ, van Zonneveld M, Zeuzem S, Senturk H, Akarca US, Simon C, Hansen BE, Haagmans BL, de Man RA, Schalm SW, Janssen HL. Patterns of viral decline during PEGinterferon alpha-2b therapy in HBeAg-positive chronic hepatitis B: relation to treatment response. Hepatology 2006;44:721-7.
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Statistical Models of Treatment Eff
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ISBN: 978-90-8559-069-9 © Bettina
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PROMOTIECOMMISSIE Promotor: Prof.dr
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CONTENTS Chapter 1. Introduction 11
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Cha pter 1 Introduction
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Chapter 1 14 Epidemiology Worldwide
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Chapter 1 16 Prediction models with
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Chapter 1 18 standard method fails
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Chapter 1 20 The extended non-linea
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Chapter 1 22 References 1. Blumberg
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Cha pter 2 Prediction of response t
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Chapter 2.1 28 ABSTRACT The aim of
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Chapter 2.1 30 been hepatitis B sur
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Chapter 2.1 32 HBV DNA decline The
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Chapter 2.1 34 Figure 2 continued.
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Chapter 2.1 36 Figure 4. Estimated
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Chapter 2.1 38 DNA was observed in
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Chapter 2.1 40 15. Kao JH. Role of
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Chapter 2.2 44 ABSTRACT Background:
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Chapter 2.2 46 low baseline HBV DNA
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Chapter 2.2 48 patient subgroups wa
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Chapter 2.2 50 p=0.002). Previous I
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Chapter 2.2 52 Application of the m
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Chapter 2.2 54 PEG-IFN, the proport
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Chapter 2.2 56 References 1. Lavanc
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Chapter 2.2 58 26. Bonino F, Lau GK
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Chap ter 2.3 Prediction of the resp
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INTRODUCTION Dynamic prediction of
Page 67 and 68: Statistical analysis Dynamic predic
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Page 77 and 78: References Dynamic prediction of re
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Page 83 and 84: INTRODUCTION Dynamic prediction of
Page 85 and 86: For the indirect approach we rewrit
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Page 89 and 90: Dynamic prediction of response usin
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Page 108 and 109: Chapter 2.5 106 ABSTRACT Peginterfe
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Page 120 and 121: Chapter 2.5 118 13. Werle-Lapostoll
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Page 127 and 128: Chap ter 3.1 Long-term clinical out
Page 129 and 130: INTRODUCTION Glycyrrhizin for IFN-n
Page 131 and 132: Statistics Glycyrrhizin for IFN-non
Page 133 and 134: Glycyrrhizin for IFN-non responders
Page 135 and 136: Table 2. Time dependent Cox regress
Page 143 and 144: Cha pter 3.2 Discriminant analysis
Page 145 and 146: Introduction Discriminant analysis
Page 147 and 148: Discriminant analysis using a MLMM
Page 149 and 150: Estimation Discriminant analysis us
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Discriminant analysis using a MLMM
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Appendix Discriminant analysis usin
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Cha pter 4 Statistical models of ea
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Chapter 4.1 176 ABSTRACT Nucleoside
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Chapter 4.1 178 at day 1 at t =0 an
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Chapter 4.1 180 Table 1. Baseline c
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Chapter 4.1 182 Figure 1.
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Chapter 4.1 184 Figure 1. Viral dec
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Chapter 4.1 186 suppression in seru
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Chapter 4.1 188 13. Seifer M, Hamat
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Cha pter 4.2 Viral dynamics during
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INTRODUCTION Viral dynamics during
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Viral dynamics during tenofovir the
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log HBV DNA (copies/mL) 10.0 9.0 8.
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Chap ter 4.3 Modelling of early vir
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INTRODUCTION HBV viral kinetics dur
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HBV viral kinetics during PEG-IFN 2
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SUMMARY AND CONCLUSION Summary and
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Summary and conclusion 233 The mode
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Summary and conclusion 235 The infe
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Summary and conclusion 237 Early st
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SAMENVATTING EN CONCLUSIE Samenvatt
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Samenvatting en conclusie 243 Er we
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Samenvatting en conclusie 245 Data
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Samenvatting en conclusie 247 Behan
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Dan kwoord
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Dankwoord 254 Lieve Marion en Margr
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BIBLI OGRAPHY Bibliography 257 1. K
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Bibliography 259 Interferon-ribavir
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Bibliography 261 Long term clinical
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Bibliography 263 Flares in chronic
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Bibliography 265 Genetic characteri
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Bibliography 267 106. Reijnders JG,
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