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Chapter 4.3 210 ABSTRACT Treatment with pegylated interferon (PEG-IFN) α-2b is effective for HBeAg-positive chronic hepatitis B although its mechanism of action remains unclear. HBeAg loss is achieved in 36% of patients after one year of PEG-IFN α-2b treatment and combination therapy with lamivudine is not superior to PEG-IFN α-2b monotherapy. In this study, we analyzed early pharmaco- and viral kinetics in patients treated for 52 weeks with PEG- IFN α-2b with or without lamivudine. After 4 weeks of treatment, there was a median viral decline of 2.94 log10 copies/ml in those treated with PEG-IFN α-2b and lamivudine and only 0.45 log10 copies/ml in the PEG-IFN α-2b monotherapy group. Peak IFN levels were reached approximately one day after administration and subsequently declined exponentially consistent with a viral load rebound near to baseline levels at the end of the dosing period in most patients receiving PEG-IFN α-2b monotherapy. Modelling of pharmaco- and viral kinetics data in this group revealed that viral load was minimal 3.6 days after PEG-IFN α-2b administration, the mean maximal and mean antiviral effectiveness was 70% and 48% with a mean infected cell loss rate of 0.07 per day, while no signifi cant biphasic decline was observed. We conclude that PEG-IFN α-2b induces a sustained response in a considerable number of patients despite limited direct antiviral activity during the fi rst weeks of antiviral therapy.
INTRODUCTION HBV viral kinetics during PEG-IFN 211 Patients with HBeAg-positive chronic hepatitis B often have high levels of circulating virus and immune responses directed against the virus cause infl ammation which in turn may lead to cirrhosis and hepatocellular carcinoma. 1 Although treatment with nucleos(t) ide analogues, like lamivudine, adefovir and entecavir, is effective for viral load reduction, long-term treatment is often necessary and carries the risk of viral resistance. 2-4 Using interferon therapy, a durable treatment response can be achieved in 35-45% of HBeAg-positive and HBeAg-negative chronic hepatitis B patients. Pegylated interferons induce HBeAg seroconversion in approximately one third of HBeAg-positive patients. 5-9 In a recent trial, a durable loss of HBeAg was achieved in 36% of patients after a 52 week course of PEG-IFN α-2b treatment with a 26 week followup period. 6 The decline in viral load during PEG-IFN α-2b therapy was not uniform and different patterns of viral decline could be recognized both during treatment and followup. 10 Remarkably, a marked viral decline between weeks 4 and 32 of treatment resulted in the highest rate of HBeAg-loss. 10 In general, there was only minimal decline in viral load in the fi rst month of treatment. Until now, no viral kinetics data are available during PEG-IFN treatment in HBeAg-positive chronic hepatitis B. 11 Therefore, we analyzed the relation between viral kinetics and pharmacokinetics of PEG-IFN α-2b in HBeAg-positive chronic hepatitis B. To our knowledge, this is the fi rst analysis fi tting data from both pharmacokinetics and viral kinetics during treatment in patients with chronic hepatitis B. MATERIAL AND METHODS Patients A total of 96 patients who participated in an international multicenter randomized double-blinded study reported previously6 , underwent frequent blood sampling in the fi rst month of therapy. Eligible patients were men and women over 16 years of age with chronic hepatitis B, documented by liver biopsy and HBsAg positivity for over six months, and positive serum HBV DNA levels. All patients were HBeAg-positive and had ALT levels of at least 2 times the upper limit of normal on two occasions within eight weeks before randomization. Patients received PEG-IFN α-2b 100 μg once weekly and were randomized to receive either lamivudine 100 mg once daily or placebo. The dose of PEG-IFN α-2b was reduced to 50 μg once weekly after 32 weeks of therapy. Patients were treated for 52 weeks and followed for 6 months post-treatment.
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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 161 and 162: Discriminant analysis using a MLMM
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 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: Chap ter 4.3 Modelling of early vir
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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
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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
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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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