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Chapter 2.2 44 ABSTRACT Background: In order to develop a model for the prediction of sustained response to PEG-IFN in all HBV genotypes, individual patient data from the 2 largest global trials in HBeAg-positive chronic hepatitis B were combined. Methods: Five-hundred-forty-two patients treated with PEG-IFN α-2a (180 μg/week, 48 weeks) and 266 patients treated with PEG-IFN α-2b (100 μg/week, 52 weeks) were included. Sustained response was defi ned as HBeAg loss and HBV DNA 30%) are genotype A patients with either high ALT or low HBV DNA, and genotype C patients with both high ALT and low HBV DNA. Genotype D patients have a rather low chance of sustained response. All remaining patients are moderate candidates for PEG-IFN therapy.
INTRODUCTION Factors that predict response to PEG-IFN 45 Hepatitis B is a major global health problem. The World Health Organization reported that there are more than 350 million carriers in the world, approximately 75% of whom reside in Asia and the Western Pacifi c. 1 In this part of the world, HBV infection is usually acquired perinatally or in early childhood. Most patients from these areas typically have HBeAg-positive chronic hepatitis B with high HBV DNA levels and they develop moderate to severe hepatic infl ammation with elevated alanine aminotransferase (ALT) levels after 10–30 years of infection. 2 In contrast, patients infected in late childhood, adolescence or adulthood present with elevated aminotransferases after a shorter duration of infection. Although spontaneous HBeAg seroconversion occurs in the majority of HBeAg-positive patients, the duration of hepatic infl ammation can be prolonged and severe, and may result in liver cirrhosis. Therefore, antiviral treatment is indicated in patients who remain HBeAg positive with high HBV DNA levels after a 3-6 month period of elevated ALT levels. 3 Successful treatment of chronic hepatitis B virus (HBV) infection with loss of hepatitis B e antigen (HBeAg), decline in serum HBV DNA and normalization of ALT is associated with favorable long-term outcome, independent of the antiviral drug used. 4, 5 In HBeAg-positive patients, sustained clearance of HBeAg from serum is associated with a higher likelihood of losing hepatitis B surface antigen (HBsAg), reduced incidence of cirrhosis and hepatocellular carcinoma (HCC), and improved survival. 5-8 Of currently available drugs for the treatment of chronic hepatitis B, pegylated interferon (PEG-IFN) still results in the highest rate of off-treatment sustained response after a one-year course of therapy. 9-12 Furthermore, responders to IFN-based therapy have a considerable chance of losing HBsAg, which has been observed in 12-65% of patients within 5 years after HBeAg loss. 7, 8, 13-18 Treatment with PEG-IFN is however often complicated by the occurrence of side-effects such as fl u-like symptoms, cytopenia and depression. 19 Nucleos(t)ide analogues such as lamivudine, adefovir, entecavir and tenofovir on the other hand are well tolerated, but because of the modest seroconversion rate and the high risk of post-treatment relapse, prolonged therapy is usually required. 20 Nowadays, maintenance of virological response over prolonged periods is feasible, 21 but may still pose a considerable risk for resistance in the long-term. 22-24 Since both treatment with PEG-IFN and nucleos(t)ide analogues has proven effective, but also have their advantages and limitations, the question arises what treatment regimen should be used as fi rst-line therapy in which patients. Both the chance of achieving response and specifi c patient characteristics play a role in the decision on what type of antiviral therapy should be started. Recently performed studies with one year of PEG- IFN in HBeAg-positive patients identifi ed high baseline alanine aminotransferase (ALT),
Page 1: Statistical Models of Treatment Eff
Page 4 and 5: ISBN: 978-90-8559-069-9 © Bettina
Page 6 and 7: PROMOTIECOMMISSIE Promotor: Prof.dr
Page 9 and 10: CONTENTS Chapter 1. Introduction 11
Page 13: Cha pter 1 Introduction
Page 16 and 17: Chapter 1 14 Epidemiology Worldwide
Page 18 and 19: Chapter 1 16 Prediction models with
Page 20 and 21: Chapter 1 18 standard method fails
Page 22 and 23: Chapter 1 20 The extended non-linea
Page 24 and 25: Chapter 1 22 References 1. Blumberg
Page 27: Cha pter 2 Prediction of response t
Page 30 and 31: Chapter 2.1 28 ABSTRACT The aim of
Page 32 and 33: Chapter 2.1 30 been hepatitis B sur
Page 34 and 35: Chapter 2.1 32 HBV DNA decline The
Page 36 and 37: Chapter 2.1 34 Figure 2 continued.
Page 38 and 39: Chapter 2.1 36 Figure 4. Estimated
Page 40 and 41: Chapter 2.1 38 DNA was observed in
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Page 48 and 49: Chapter 2.2 46 low baseline HBV DNA
Page 50 and 51: Chapter 2.2 48 patient subgroups wa
Page 52 and 53: Chapter 2.2 50 p=0.002). Previous I
Page 54 and 55: Chapter 2.2 52 Application of the m
Page 56 and 57: 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
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Dynamic prediction of response usin
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Table 1. Results of different stopp
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Chapter 2.5 106 ABSTRACT Peginterfe
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Chapter 2.5 108 and placebo daily.
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Chapter 2.5 110 for patients with a
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Chapter 2.5 112 Mean HBV DNA declin
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Chapter 2.5 114 peginterferon and n
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Chapter 2.5 116 hepatocellular carc
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Chapter 2.5 118 13. Werle-Lapostoll
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Chapter 2.5 120 Greece - G Germanid
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Chap ter 3.1 Long-term clinical out
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INTRODUCTION Glycyrrhizin for IFN-n
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Statistics Glycyrrhizin for IFN-non
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Glycyrrhizin for IFN-non responders
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Table 2. Time dependent Cox regress
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Cha pter 3.2 Discriminant analysis
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Introduction Discriminant analysis
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Discriminant analysis using a MLMM
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Estimation Discriminant analysis us
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where wi,k(y i, θ) = (k =1,...,K).
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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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