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Chapter 3.1 126 ABSTRACT Background: In chronic hepatitis C patients not responding to interferon, glycyrrhizin may be used for reducing disease activity. Aim: To evaluate the effect of glycyrrhizin on the incidence of hepatocellular carcinoma (HCC) during long-term follow-up after interferon non-response. Methods: We analyzed individual patient data of all consecutive patients treated with interferon in 12 major Japanese hospitals between 1990 and 1995 who showed no sustained response. Results: We included 1093 patients. During a mean follow-up of 6.1±1.8 years, 107 patients developed HCC. Cox regression with time dependent variables showed that older age, male sex, higher alanine aminotransferase (ALT) and higher fi brosis stage were signifi cantly associated with a higher risk for developing HCC. Response to glycyrrhizin, defi ned as ALT
INTRODUCTION Glycyrrhizin for IFN-non responders 127 Chronic hepatitis C is a major cause of liver disease worldwide. Infection with the hepatitis C virus may lead to a chronic infl ammation of the liver, which is manifested in elevated liver enzymes such as alanine aminotransferase (ALT). This chronic infl ammation may lead to fi brosis and subsequent cirrhosis. It has been estimated that the delay for developing cirrhosis is about thirty years, but the individual prognosis may vary substantially depending on factors such as age at infection, gender, alcohol abuse and co-infection with hepatitis B or the human immunodefi ciency virus (HIV). 1 Over the past fi fteen years treatment regimens based on the administration of interferon have proven to be increasingly effective against hepatitis C. Combination treatment with pegylated interferon and ribavirin will lead to disappearance of the virus from the blood in 50% to 80% of the patients. 2,3 If the virus remains undetectable in the blood at 6 months after the end of treatment, we speak of a sustained virological response. Sustained virological response is almost always associated with normalization of serum ALT and a survival similar to the overall population. 4 There still remains a considerable proportion of patients who do not achieve a sustained virological response. These patients are in need of other therapeutic approaches. Various long-term interferon-based regimens are under investigation. 5,6 In Japan, glycyrrhizin has been propagated as an anti-infl ammatory drug, capable of minimizing disease activity in the chronically infected liver. Placebo controlled trials have proven that the administration of glycyrrhizin leads to a signifi cant reduction of ALT levels in chronic hepatitis C patients. 7 The question remains whether this reduction of ALT levels leads to a reduced risk of liver-related morbidity and mortality. Ideally, one should design a randomised controlled trial with a prolonged follow-up of at least several years in order to investigate the effect of glycyrrhizin on these clinical endpoints. However, even when such a study would be restricted to cirrhotics, based on the incidence of HCC, decompensation and mortality, 8 it would take at least 5 years before we had an answer whether glycyrrhizin is a benefi cial drug or not. Therefore we performed a large retrospective multicenter study, analyzing independently data collected in Japan, the only country so far where hepatologists have extensively used this compound. We were especially careful to minimize the various biases associated with retrospective studies and to apply the most sophisticated statistics designed for such studies.
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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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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
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Page 89 and 90: Dynamic prediction of response usin
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Page 108 and 109: Chapter 2.5 106 ABSTRACT Peginterfe
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Page 112 and 113: Chapter 2.5 110 for patients with a
Page 114 and 115: Chapter 2.5 112 Mean HBV DNA declin
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Page 118 and 119: Chapter 2.5 116 hepatocellular carc
Page 120 and 121: Chapter 2.5 118 13. Werle-Lapostoll
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Page 127: Chap ter 3.1 Long-term clinical out
Page 131 and 132: Statistics Glycyrrhizin for IFN-non
Page 133 and 134: Glycyrrhizin for IFN-non responders
Page 135 and 136: Table 2. Time dependent Cox regress
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 171 and 172: Appendix Discriminant analysis usin
Page 175: 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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