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Chapter 4.3 216 Figure 1. Median HBV DNA (log 10 copies/ml) in patients with HBeAg-positive chronic hepatitis B in the fi rst month of treatment with PEG-IFN alone (A) or in combination with lamivudine (B). week 1 and 4. All patients treated with combination therapy showed a biphasic HBV DNA decline pattern. The median decline in viral load was 1.59 log10 copies/ml (range, -0.26 – 2.36) in the fi rst week of treatment. The median slope of viral decline at the end of the fi rst week (day 4 to day 7) was 0.083 log10 copies/ml (range, -0.297 – 0.250) per day in the combination therapy group. Pharmacokinetics of pegylated interferon-alpha-2b In a fi rst attempt to understand why HBV DNA levels showed a minimal decline during the fi rst month, we analyzed PEG-IFN α-2b levels in all 96 patients. Maximum levels of PEG-IFN α-2b concentration were reached one day after administration. Thereafter, a decline in the PEG-IFN α-2b levels was seen in all patients (Figure 2A). No signifi cant
HBV viral kinetics during PEG-IFN 217 Figure 2. Pharmacokinetics of PEG-IFN in patients treated with PEG-IFN with or without lamivudine in the fi rst week (A) and the modelled pharmacokinetics in the fi rst month (B) of treatment. differences in PEG-IFN α-2b levels between patients treated in the PEG-IFN α-2b monotherapy and the PEG-IFN α-2b plus lamivudine combination therapy group were observed. In 52 out of 96 patients (54%), the PEG-IFN α-2b concentration had returned to undetectable levels 7 days after drug administration; this was still the case in 24/96 (25%) patients at day 28, 7 days after the fourth injection. In those with detectable PEG- IFN α-2b levels at day 7 and 28, these concentrations were in general low with a mean of 1175 pg/mL and 1645 pg/mL, respectively. The pharmacokinetics were modelled using a non-linear mixed model. The fi tted nonlinear mixed model resulted in a population mean of the pharmacokinetic parameters ka , ke and F/Vd of all 96 patients as well as an individual fi t of these parameters (Figure 2B). The estimated population mean of ka was 2.363 d-1 (SE 0.461), of ke 0.420 d-1 (SE 0.029) and of F/Vd 1.023 pg/mL (SE 0.084) (Table 2 gives per patient data). The modelled interval between PEG-IFN α-2b administration and the maximum modelled drug concentration (tmax ) was 0.89 day (0.71-1.24). There was a signifi cant negative correlation between the
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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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Page 167 and 168: Discriminant analysis using a MLMM
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Page 171 and 172: Appendix Discriminant analysis usin
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Page 178 and 179: Chapter 4.1 176 ABSTRACT Nucleoside
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Page 182 and 183: Chapter 4.1 180 Table 1. Baseline c
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Page 186 and 187: Chapter 4.1 184 Figure 1. Viral dec
Page 188 and 189: Chapter 4.1 186 suppression in seru
Page 190 and 191: Chapter 4.1 188 13. Seifer M, Hamat
Page 193 and 194: Cha pter 4.2 Viral dynamics during
Page 195 and 196: INTRODUCTION Viral dynamics during
Page 197 and 198: Viral dynamics during tenofovir the
Page 201 and 202: log HBV DNA (copies/mL) 10.0 9.0 8.
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 217: 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 and 236: Summary and conclusion 233 The mode
Page 237 and 238: Summary and conclusion 235 The infe
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
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Bibliography 267 106. Reijnders JG,
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