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Chapter 2.5 106 ABSTRACT Peginterferon alfa-2a results in a sustained response (SR) in a minority of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients. This study investigated the role of early on-treatment serum hepatitis B surface antigen (HBsAg) levels in the prediction of SR in HBeAg-negative patients receiving peginterferon alfa-2a. HBsAg (Abbott ARCHITECT) was quantifi ed at baseline, during treatment (weeks 4, 8, 12, 24, 36 and 48) and follow-up (weeks 60 and 72) in the sera from 107 patients who participated in an international multicenter trial (peginterferon alfa-2a, n=53 versus peginterferon alfa-2a and ribavirin, n=54). Overall, 24 (22%) patients achieved SR (serum hepatitis B virus (HBV DNA)
INTRODUCTION Early on-treatment prediction of response to PEG 107 Chronic hepatitis B virus (HBV) infection affects 350 to 400 million people worldwide and is responsible for 1 million deaths every year. 1 Hepatitis B e antigen (HBeAg-)negative chronic hepatitis B (CHB) represents a late phase in the course of the infection, which is recognized worldwide with an increasing prevalence. 2 Therapeutic intervention is often indicated for HBeAg-negative patients, because spontaneous remission rarely occurs and patients have more advanced liver disease in comparison with HBeAg-positive patients. 3 In the last decade great strides have been made in the treatment of CHB, but the management of the HBeAg-negative type remains diffi cult. Nucleos(t)ide analogues are able to maintain suppression of viral replication in the majority of HBeAg-negative patients and are well tolerated, 4-5 but it is highly uncertain whether oral antiviral therapy can be discontinued. 6-8 In contrast to nucleos(t)ide analogues, one year of peginterferon therapy can result in an off-treatment sustained response (SR) in HBeAg-negative patients. 9-10 However, treatment with peginterferon is often complicated by the occurrence of side effects and a minority of patients with HBeAg-negative disease achieve SR. It is therefore a major challenge to identify patients who are likely to benefi t from peginterferon therapy as early as possible during the treatment course. HBV DNA quantifi cation is widely used as a marker of viral replication to assess response to nucleos(t)ide analogues, but prediction of response to peginterferon by means of serum HBV DNA levels is diffi cult. 11-12 Advances in technology have enabled the development of a quantitative assay for hepatitis B surface antigen (HBsAg). The serum concentration of HBsAg appears to refl ect the amount of covalently closed circular DNA (cccDNA) in the liver, which acts as a template for the transcription of viral genes. 13-14 Recently, several studies have suggested that serum HBsAg levels may be indicative of the likelihood of response to interferon-based therapy. 15-17 The aim of this study was to clarify the role of early on-treatment quantitative serum HBsAg in the prediction of SR in HBeAg-negative CHB patients treated with peginterferon alfa-2a. PATIENTS AND METHODS Patients HBsAg levels were measured in sera from a total of 107 of 133 HBeAg-negative chronic hepatitis B patients who participated in an investigator-initiated, multicenter, randomized, double-blind, controlled trial. 9 Patients were randomly assigned in a one-to-one ratio to receive 180 μg peginterferon alfa-2a weekly and ribavirin 1000 mg (body weight
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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
Page 58 and 59: Chapter 2.2 56 References 1. Lavanc
Page 60 and 61: Chapter 2.2 58 26. Bonino F, Lau GK
Page 63 and 64: Chap ter 2.3 Prediction of the resp
Page 65 and 66: INTRODUCTION Dynamic prediction of
Page 67 and 68: Statistical analysis Dynamic predic
Page 69 and 70: Dynamic prediction of response to P
Page 77 and 78: References Dynamic prediction of re
Page 81 and 82: Cha pter 2.4 Dynamic prediction of
Page 83 and 84: INTRODUCTION Dynamic prediction of
Page 85 and 86: For the indirect approach we rewrit
Page 87 and 88: logit pi,j = logit Pr(Ri =1|visit =
Page 89 and 90: Dynamic prediction of response usin
Page 101 and 102: Table 1. Results of different stopp
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Page 110 and 111: Chapter 2.5 108 and placebo daily.
Page 112 and 113: Chapter 2.5 110 for patients with a
Page 114 and 115: Chapter 2.5 112 Mean HBV DNA declin
Page 116 and 117: Chapter 2.5 114 peginterferon and n
Page 118 and 119: Chapter 2.5 116 hepatocellular carc
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
Page 153 and 154: where wi,k(y i, θ) = (k =1,...,K).
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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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