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Chapter 4.1 180 Table 1. Baseline characteristics Entecavir 0.05 mg Entecavir 0.1 mg Entecavir 0.5 mg Entecavir 1.0 mg (n = 3) (n = 3) (n = 2) (n = 2) Sex (M:F) 1:2 2:1 1:1 2:0 Age (years, range) Race 23 (20–63) 39 (29–51) 38 (18–58) 27 (19–35) Asian 0 2 0 1 Caucasian 1 1 1 1 Other 2 0 1 0 Previous lamivudine therapy 3 3 0 1 HBeAg positivity 3 3 2 2 HBV DNA (geq/ml) (median, range) 3.11x108 –5.35x109 4.83x108 –1.52x109 1.68x109 –1.5x1010 5.52x107 –3.34x109 ALTxULN (median, range) 1 (1–1.5) 1.2 (1–3.4) 1.6 (1–2.2) 1.3 (1–1.5) YVDD, respectively). All patients were positive for HBeAg at the start of therapy. Median baseline HBV DNA was 1.68 x 109 geq/ml (range 5.52 x 107 –1.50 x 10 10 geq/ml), and median elevation of ALT at baseline was 1.1 x the upper limit of normal (ULN) (range 1–3.5). Viral decay was determined during 28 days of entecavir therapy (Figure 1). The median effectiveness of blocking viral replication in all ten patients on entecavir therapy was 96% (range 87–98%). Turn-over of free virus was 16 h (median; range 12–29 h, n = 10), and turn-over of infected hepatocytes was estimated to be 10.7 days (range 5.2–31.8 days, n = 9). For calculation of the viral decline during the second phase, patient 10 was excluded. This patient discontinued medication after 1 week due to a serious adverse event (Table 2). Entecavir was still capable of blocking viral replication in both patients with detectable lamivudine-induced mutant virus (effectiveness in blocking viral production of 87 and 98%, respectively). Rebound of viral replication was followed until 6 months after withdrawal of therapy (n = 9, excluding patient 10) (Table 2, Figure 1). For mathematical description of return of viral concentration, the inverse of the bi-phasic model for viral decay describes the observed patient data accurately. The doubling time was 129 h (median; range 62–247 h) and the slope of the second phase of the rebound in viral concentration approaches zero in all patients (median 0.0016, range 20.051 to 10.03). The change from the fi rst to the second phase of viral return was calculated to be at a median of 30 days (range 12–109 days). No relation between viral load at the moment of withdrawal of entecavir and the fi rst and second phase of viral rebound with the dose of entecavir could be found. However, the three patients in the higher dose groups showed a more gradual return of viral replication to baseline levels than did the six patients in the lower dose groups (p = 0.024).
Table 2. Dynamic parameters during and after 1 month of entecavir therapy Patient (mg) During entecavir therapy After withdrawal of entecavir therapy Effi ctiveness in Initial viral Duration of fast increase of viral Viral load at the Half-life fi rst Half-life second Doubling time blocking viral load concentration (fi rst phase of viral return) end of follow-up phase (h) phase (days) of virus (h) production (%) (qeq/ml) (days) (qeq/ml) 1 (0.05) 96 24 18.6 3.40x108 95 23 2.58x109 2 (0.05) 97 18 10.7 2.25 x109 129 40 1.83x109 3 (0.05) 96 22 15.2 6.63 x109 120 30 4.21x109 4 (0.1) 87 16 31.8 1.92 x109 140 16 1.05x109 5 (0.1) 96 13 5.2 5.18 x108 62 14 2.32x107 6 (0.1) 89 29 25.0 7.03 x108 102 12 3.06x108 Viral dynamics during and after entecavir therapy 181 7 (0.5) 97 12 4.7 1.44 x109 247 101 2.24x109 8 (0.5) 95 13 5.6 8.16 x109 244 89 5.35x109 9 (1.0) 92 16 10.7 3.61 x107 230 109 8.33x108 10 (1.0) 98 17 NA* 3.04 x109 NA* NA* NA* Median 96 16 10.7 1.92 x109 129 (~5 days) 30 1.05x109 * Not applicable; this patient was withdrawn from therapy after 1 week
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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
Page 131 and 132: Statistics Glycyrrhizin for IFN-non
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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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Page 178 and 179: Chapter 4.1 176 ABSTRACT Nucleoside
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Page 186 and 187: Chapter 4.1 184 Figure 1. Viral dec
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Page 190 and 191: Chapter 4.1 188 13. Seifer M, Hamat
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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
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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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