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Chapter 4.1 184 Figure 1. Viral decline and rebound during and after withdrawal of entecavir therapy. (A) Viral decline in ten patients. X-axis: 0–30 days; Y-axis: level of HBV DNA on a log scale. (B) Viral rebound in nine patients. X-axis: 0–200 days; Y-axis: level of HBV DNA on a log scale. DISCUSSION The main action of nucleoside analogues is inhibition of viral replication through termination of the proviral chain. Lamivudine, which has been evaluated most extensively, has not been shown to have any effect on cccDNA in vitro systems. 9-10 As a result, lamivudine therapy should be continued for a long time in order to be able to eliminate the virus through cell division and death of infected cells. It has been calculated that therapy should be continued for many years to achieve complete eradication of the virus from the liver. 22 Unfortunately, indefi nite prolongation of nucleoside analogue therapy will not result in complete eradication of the virus due to a cumulative incidence of viral resistance (40–60% after 2–3 years of lamivudine monotherapy). 23–25 As a result, one should aim for a compound which does exhibit two features: interference with viral replication as well as a reduction of infected hepatocytes. Entecavir has proved to cause minimal side-effects during short-term application26 and in vitro data imply the possible effect on cccDNA. 14 Therefore, therapy with this drug may reduce the amount of infected cells to a greater extent and in a shorter amount of time.
Viral dynamics during and after entecavir therapy 185 Although the results of this study are based on a small number of patients, the antiviral activity during short-term therapy with entecavir seems somewhat greater than during lamivudine therapy27 and lower than during adefovir dipivoxil therapy, 17 although it should be realized that this is a head-to-head comparison and randomized studies are needed to identify the actual differences in parameters between these nucleoside analogues. Our analysis is based on four low doses of entecavir during the fi rst study in chronic hepatitis B patients; some of these doses might have been insuffi cient for the optimal treatment of HBV. Moreover, the majority of our patients had previously failed lamivudine therapy which could also result in a less favour-able response to reintroduction of another antiviral agent. Entecavir did show continuing activity in patients with detectable lamivudine-induced mutant virus. Theoretically, the second phase of more gradual decline in viral concen tration may be infl uenced by death of infected hepatocytes and turn-over of cccDNA harbouring cells. After the fi rst 28 days of therapy, the decline of viral concentration can be either slower than, equal to, or faster than observed during the second phase. We do not observe a difference in the slope of the second phase between lamivudine-and entecavir-treated patients in a head-to-head comparison. We could therefore speculate that in both lamivudine and entecavir treated patients, this second phase is primarily infl uenced by death of infected hepatocytes. If entecavir exhibits a direct effect on cccDNA, this effect may surface only during a longer treatment period. All nine patients who were evaluated after withdrawal of therapy showed a bi-phasic pattern with an initial fast increase of viral replication followed by a more or less steady state. This initial fast return of viral replication, which was calculated to last 30 days, could refl ect the production capacity of the reservoir of hepatocytes that is still infected with HBV, as well as infection of non-infected hepatocytes leading to a larger productivity. The part of the cccDNA pool which is not affected by entecavir can be used as a template from which the virus can re-initiate replication once the inhibitor has been removed. This implies that a larger pool of still infected hepatocytes could result in a faster return of viral replication to baseline level. The second phase of this model represents a steady state of viral production, counteracted by turn-over of free virus and infected hepatocytes. Patients who were treated with the two higher doses of entecavir (0.5 and 1.0 mg) showed a more gradual increase in HBV DNA to baseline levels than those patients who were treated with lower doses, even though viral load was suppressed to the same extent in all dose groups. Slower return of viral replication in the high dosed groups may therefore be due to a smaller remnant pool of infected hepa tocytes and not to the extent of viral
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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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Page 137 and 138: Glycyrrhizin for IFN-non responders
Page 139 and 140: Glycyrrhizin for IFN-non responders
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).
Page 171 and 172: Appendix Discriminant analysis usin
Page 175: Cha pter 4 Statistical models of ea
Page 178 and 179: Chapter 4.1 176 ABSTRACT Nucleoside
Page 180 and 181: Chapter 4.1 178 at day 1 at t =0 an
Page 182 and 183: Chapter 4.1 180 Table 1. Baseline c
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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 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
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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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