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Summary and conclusion 234 who developed sustained response. However, a substantial on-treatment HBV DNA decline was observed in non responders as well. At week 12, patients without a HBV DNA decline ≥2 log copies/mL combined with a HBsAg decline ≥0 log IU/mL from baseline were non responders (NPV 100%). Quantitative serum HBsAg in combination with HBV DNA may enable on-treatment adjustment of PEG-IFN therapy in HBeAg-negative chronic hepatitis B. A solid stopping rule at week 12 is suggested using a combination of declines in serum HBV DNA and HBsAg level from baseline. STATISTICAL MODELS OF LONG-TERM TREATMENT EFFECTS In Chapter 3.1 the long term effects of glycyrrhizin treatment on the incidence of hepatocellular carcinoma (HCC) in chronic hepatitis C patients not responding to interferon were studied. Data of all consecutive patients treated with interferon, who showed no sustained response after interferon treatment in 12 major Japanese hospitals between 1990 and 1995 were analysed. During a mean follow-up of 6.1±1.8 years, 107 of 1093 included patients developed HCC. Cox regression with time dependent variables showed that older age, male sex, higher ALT and higher fi brosis stage were signifi cantly associated with a higher risk for developing HCC. Response to glycyrrhizin, defi ned as ALT
Summary and conclusion 235 The inference is performed in the Bayesian framework using the Markov chain Monte Carlo methodology. The methodology is applied to data from the Dutch primary biliary cirrhosis study. STATISTICAL MODELS OF EARLY TREATMENT EFFECTS Viral dynamics during and after entecavir therapy in patients with chronic hepatitis B are described in Chapter 4.1. Nucleoside analogues inhibit HBV replication. Entecavir, a guanine nucleoside, has also been shown to reduce covalently closed circular DNA (cccDNA) to undetectable levels in wood chucks chronically infected with hepatitis virus. Mathematical description of changes in viral load during and after therapy may help to understand the process that takes place during nucleoside analogue treatment. Ten chronic hepatitis B patients were evaluated with a mathematical model during treatment with and after withdrawal of four doses of entecavir. Blood was drawn for HBV DNA measurement at frequent intervals. Decay and rebound of viral concentration during and after entecavir therapy, respectively, showed a bi phasic pattern. Non-linear modelling was used to fit individual patient data. The median effectiveness in blocking viral production was 96% and the median half-life of viral turn-over was 16 h. The median half-life of infected hepatocytes was 257 h. Data on levels of cccDNA in the liver in these patients could be helpful in supporting the parameters as calculated with the model. Tenofovir, an antihuman immunodefi ciency virus (HIV) drug, has activity against lamivudine-resistant HBV mutants. In Chapter 4.2 the effi cacy of tenofovir is described in patients with lamivudine-resistant hepatitis B. Two investigative approaches based on mathematical models of viral dynamics were applied: the individual nonlinear fi tting and the mixed-effect group fi tting approaches. Eleven chronic HBV patients on lamivudine for a median of 176 weeks (range: 72–382) with YMDD mutation-related HBV-DNA breakthrough received ‘add-on’ tenofovir 300 mg once-daily, while maintaining their existing therapy. Sequential sera assessing HBV DNA levels were frequently taken during the fi rst 4 weeks of treatment and every 4 weeks thereafter. Median baseline log HBV-DNA was 8.62. Tenofovir treatment resulted in a mean log HBV-DNA decline of 1.37 in the fi rst phase, 2.54 after 4 weeks, and 4.95 log HBV-DNA after 24 weeks. The median effectiveness of blocking viral replication in the individual
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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
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Statistical analysis Dynamic predic
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Dynamic prediction of response to P
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References Dynamic prediction of re
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Cha pter 2.4 Dynamic prediction of
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INTRODUCTION Dynamic prediction of
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For the indirect approach we rewrit
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logit pi,j = logit Pr(Ri =1|visit =
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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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Page 190 and 191: Chapter 4.1 188 13. Seifer M, Hamat
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Page 195 and 196: INTRODUCTION Viral dynamics during
Page 197 and 198: Viral dynamics during tenofovir the
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Page 211 and 212: Chap ter 4.3 Modelling of early vir
Page 213 and 214: INTRODUCTION HBV viral kinetics dur
Page 215 and 216: HBV viral kinetics during PEG-IFN 2
Page 229: HBV viral kinetics during PEG-IFN 2
Page 233 and 234: SUMMARY AND CONCLUSION Summary and
Page 235: Summary and conclusion 233 The mode
Page 239: Summary and conclusion 237 Early st
Page 243 and 244: SAMENVATTING EN CONCLUSIE Samenvatt
Page 245 and 246: Samenvatting en conclusie 243 Er we
Page 247 and 248: Samenvatting en conclusie 245 Data
Page 249 and 250: Samenvatting en conclusie 247 Behan
Page 253: Dan kwoord
Page 256 and 257: Dankwoord 254 Lieve Marion en Margr
Page 259 and 260: BIBLI OGRAPHY Bibliography 257 1. K
Page 261 and 262: Bibliography 259 Interferon-ribavir
Page 263 and 264: Bibliography 261 Long term clinical
Page 265 and 266: Bibliography 263 Flares in chronic
Page 267 and 268: Bibliography 265 Genetic characteri
Page 269: Bibliography 267 106. Reijnders JG,
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