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Chapter 2.1 30 been hepatitis B surface antigen (HBsAg) positive for >6 months, were HBeAg positive on two occasions within 8 weeks prior to enrolment, had elevated serum ALT levels of 2 - 10 times the upper limit of normal (ULN), and had a serum HBV DNA level >1.0 x 105 copies/mL. Major exclusion criteria were: antiviral therapy within 6 months prior to enrolment, presence of viral co-infections, pre-existing cytopenia or decompensated liver disease. Treatment comprised of PEG-IFN alfa-2b 100 μg weekly (PegIntron, Merck, Whitehouse Station, NJ, USA) for 52 weeks. The dose of PEG-IFN was reduced to 50 μg after 32 weeks of treatment. 16 The 167 patients who received placebo for 48 weeks were eligible for the original study if they had been HBsAg positive for >6 months, had a serum HBV DNA level ≥1 x 106 copies/mL and an ALT level of 1.2 -10 x ULN. Key exclusion criteria were antiviral therapy within 6 months prior to enrolment, presence of viral co-infections or decompensated liver disease. 10 Laboratory tests Serum HBV DNA levels were measured with 4-week intervals. For the PEG-IFN study, an in-house developed TaqMan PCR assay based on the EuroHep standard was used (lower limit of detection 400 copies/mL). 17 For the placebo group, the Roche Amplicor Monitor PCR assay was used. 10 An excellent correlation between these assays has previously been shown. 18 Serum ALT levels were measured using automated techniques and are expressed as values representing a ratio to the upper limit of the normal range (ULN). Determination of HBsAg and HBeAg was performed with the use of commercially available enzyme immunoassays. HBV genotypes were assigned by INNO-LiPa assay (Innogenetics, Gent, Belgium) or by phylogenetic analyses of HBV DNA sequences in the PEG-IFN and placebo group, respectively. 19 Statistical analysis Continuous variables are expressed as means ± standard deviation (SD) or medians with interquartile range (IQR), where appropriate. Comparisons between groups were made using the Chi-square test or Fisher’s exact test for categorical variables and the t-test or Mann-Whitney test for continuous variables. Patterns of HBV DNA decline were modelled using linear mixed regression analysis with a heterogeneous autoregressive covariance structure depending on treatment regimen (PEG-IFN versus placebo). Declines of HBV DNA were compared for patients with and without response, defi ned as HBeAg negativity at the end of treatment (EOT), by extending the model with response and interaction terms with treatment and time. The estimated declines of HBV DNA are
PEG-IFN versus placebo for HBeAg-positive CHB 31 presented as means with 95% confi dence intervals (95% CI). ALT levels were categorized according to the WHO grades: 10 x ULN (grade 4). An ALT fl are was defi ned as a serum ALT concentration >5 times ULN (grade ≥3 according to WHO). The association between ALT fl ares and HBV DNA decline was analysed using linear mixed regression analysis with a heterogeneous compound symmetry covariance structure depending on treatment regimen. Statistical analyses were performed using SPSS version 15.0 (SPSS Inc., Chicago, IL, USA) and the SAS 9.2 program (SAS Institute Inc., Cary, NC, USA). All statistical tests were two-sided and were evaluated at the 0.05 level of signifi cance. RESULTS Baseline characteristics Baseline characteristics of the PEG-IFN (N=136) and the placebo (N=167) group are presented in table 1. The groups were comparable in terms of age and gender. The majority of patients in the PEG-IFN group were of Caucasian origin infected with HBV genotypes A and D, while Asian patients infected with genotypes B and C prevailed in the placebo group (table 1). Nevertheless, a substantial number of genotypes A-D were observed in both groups. Baseline HBV DNA and ALT levels were higher in the PEG-IFN compared with the placebo group (table 1). Table 1. Baseline characteristics Characteristics PEG-IFN Placebo p-value (N=136) (N=167) Mean (SD) age, years 36 (14) 37 (12) 0.53 Male (%) 107 (78.7) 119 (71.3) 0.15 Ethnicity (%)
Page 1: Statistical Models of Treatment Eff
Page 4 and 5: ISBN: 978-90-8559-069-9 © Bettina
Page 6 and 7: PROMOTIECOMMISSIE Promotor: Prof.dr
Page 9 and 10: CONTENTS Chapter 1. Introduction 11
Page 13: Cha pter 1 Introduction
Page 16 and 17: Chapter 1 14 Epidemiology Worldwide
Page 18 and 19: Chapter 1 16 Prediction models with
Page 20 and 21: Chapter 1 18 standard method fails
Page 22 and 23: Chapter 1 20 The extended non-linea
Page 24 and 25: Chapter 1 22 References 1. Blumberg
Page 27: Cha pter 2 Prediction of response t
Page 30 and 31: Chapter 2.1 28 ABSTRACT The aim of
Page 34 and 35: Chapter 2.1 32 HBV DNA decline The
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Page 38 and 39: Chapter 2.1 36 Figure 4. Estimated
Page 40 and 41: Chapter 2.1 38 DNA was observed in
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Page 46 and 47: Chapter 2.2 44 ABSTRACT Background:
Page 48 and 49: Chapter 2.2 46 low baseline HBV DNA
Page 50 and 51: Chapter 2.2 48 patient subgroups wa
Page 52 and 53: Chapter 2.2 50 p=0.002). Previous I
Page 54 and 55: Chapter 2.2 52 Application of the m
Page 56 and 57: Chapter 2.2 54 PEG-IFN, the proport
Page 58 and 59: Chapter 2.2 56 References 1. Lavanc
Page 60 and 61: Chapter 2.2 58 26. Bonino F, Lau GK
Page 63 and 64: Chap ter 2.3 Prediction of the resp
Page 65 and 66: INTRODUCTION Dynamic prediction of
Page 67 and 68: Statistical analysis Dynamic predic
Page 69 and 70: Dynamic prediction of response to P
Page 77 and 78: References Dynamic prediction of re
Page 81 and 82: 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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Appendix Discriminant analysis usin
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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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