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Chapter 2.5 108 and placebo daily. Duration of therapy was 48 weeks, followed by a 24-week observation period. Patients attended the outpatient clinic every 4 weeks. Results at the end of treatment (week 48) and at the end of follow-up (week 72) have been reported previously. 9 Patients who were treated according to the protocol and completed the follow-up phase were selected for the present study. Eligible patients for the original study had been positive for HBsAg for more than 6 months; were HBeAg negative and anti-HBe positive on 2 occasions within 2 months before randomization; had had 2 episodes of elevated serum alanine aminotransferase (ALT) levels (>1.5 but ≤10 times the upper limit of normal (ULN) of the normal range) within 2 months prior to randomization and had a serum HBV DNA level >100,000 copies/mL (17,143 IU/mL). Exclusion criteria were: antiviral or immunosuppressive therapy within the previous 6 months; co-infection with hepatitis C, hepatitis D or human immunodefi ciency virus (HIV); other acquired or inherited causes of liver disease; pre-existing cytopenia or decompensated liver disease. The study was conducted in accordance with the guidelines of the Declaration of Helsinki and the principles of Good Clinical Practice. All patients gave written, informed consent. Laboratory measurements Serum HBsAg was quantifi ed in samples taken at baseline, during the treatment period (weeks 4, 8, 12, 24, 36, 48) and during follow-up (weeks 60 and 72) using the ARCHI- TECT HBsAg assay (Abbott laboratories; range 0.05-250 IU/mL). 18 Serum HBV DNA was measured at the same time points using the Taqman polymerase chain reaction assay (Taqman HBV assay, Roche Diagnostics, lower limit of quantifi cation: 35 copies/mL (6 IU/mL)). Transaminases were measured locally at the time of sampling in accordance with standard procedures. HBV genotype was assessed using the INNO-LiPA assay (Innogenetics). Liver histology A liver biopsy was performed in all patients within one year before randomization. Necroinfl ammation grade (range 0-18) and fi brosis stage (range 0-6) were assessed using the Ishak scoring system. 19
Statistical analysis Early on-treatment prediction of response to PEG 109 Sustained response (SR), the predefi ned primary endpoint in the original study, was defi ned according to the EASL guidelines as the combined presence of serum HBV DNA level below 10,000 copies/mL (1,714 IU/mL) and normalization of ALT at the end of follow-up (week 72). 20 The association between baseline factors and SR was assessed by univariate logistic regression analyses. Predictive values of early on-treatment serum HBsAg, as well as HBV DNA and ALT levels (weeks 4, 8, and 12) were explored applying logistic regression analysis techniques. Discrimination, which is the ability to distinguish patients who will develop SR from those who will not, was quantifi ed by the area under the receiver-operating characteristic curve (AUC). The best model-fi t was assessed comparing the AUC and the Akaike’s Information Criteria (AIC). Hereafter the optimal cut-off values for serum HBsAg and HBV DNA levels during treatment were established with the use of explanatory plots and the maximum chi-square approach to fi nd a clinically useful rule for (dis)continuation of therapy. 21 SPSS version 15.0 (SPSS Inc., Chicago, IL, USA) and the SAS 9.2 program (SAS Institute Inc., Cary, NC, USA) were used to perform statistical analyses. All statistical tests were two-sided and were evaluated at the 0.05 level of signifi cance. RESULTS Sustained response rate Twenty-four (22%) of 107 patients developed SR. The number of sustained responders was comparable between the peginterferon alfa-2a monotherapy and the peginterferon alfa-2a and ribavirin combination therapy group (14 (26%) of 53 versus 10 (19%) of 54 patients, respectively, p=0.33). The two treatment groups were therefore pooled for further analysis. Among the 24 sustained responders, one patient cleared HBsAg from serum and developed anti-HBs. Baseline characteristics Baseline characteristics of the 107 patients are shown in table 1. The mean pretreatment serum HBsAg level was 3.8 log IU/mL (range 1.1-5.0 log IU/mL) and the mean serum HBV DNA level was 6.8 log copies/mL (range 4.3-9.5 log copies/mL), both were stable during the screening period. There was no signifi cant correlation between serum HBsAg and other factors at baseline including serum HBV DNA and ALT, HBV genotype, age, gender, body mass index (BMI) or liver histology. Baseline characteristics were comparable
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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
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
Page 83 and 84: INTRODUCTION Dynamic prediction of
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Page 89 and 90: Dynamic prediction of response usin
Page 101 and 102: Table 1. Results of different stopp
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Page 108 and 109: Chapter 2.5 106 ABSTRACT Peginterfe
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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 and 128: Chap ter 3.1 Long-term clinical out
Page 129 and 130: INTRODUCTION Glycyrrhizin for IFN-n
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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Discriminant analysis using a MLMM
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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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