View PDF Version - RePub - Erasmus Universiteit Rotterdam

More documents

Recommendations

Info

Chapter 2.1 28 ABSTRACT The aim of this study was to compare the decline of HBV DNA during peginterferon (PEG-IFN) therapy with spontaneous fl uctuations in viral load in placebo-treated patients with HBeAg-positive chronic hepatitis B. A total of 136 HBeAg-positive patients who participated in a randomized trial were treated with PEG-IFN alfa-2b for 52 weeks. This group was compared with 167 HBeAgpositive patients who received placebo for 48 weeks using linear mixed regression analysis. Response was defi ned as negative HBeAg at end of treatment (EOT). Overall, decline of HBV DNA at EOT was larger in the PEG-IFN group compared with placebo (mean decline 2.3 versus 1.0 log, p
INTRODUCTION PEG-IFN versus placebo for HBeAg-positive CHB 29 More than 350 million people worldwide are chronically infected with the hepatitis B virus (HBV) and are at risk for cirrhosis, liver failure and hepatocellular carcinoma. 1 Hepatitis B e antigen (HBeAg-)positive chronic hepatitis B (CHB) is regarded as the earliest phase of infection. 2 Treatment is generally recommended for patients with HBeAg-positive CHB who do not clear HBeAg spontaneously, have high serum HBV DNA levels and persistently elevated alanine aminotransferase (ALT) levels. 3-4 First-line treatment options consist of third generation nucleos(t)ide analogues (NA), including entecavir (ETV) and tenofovir (TDF), and peginterferon alfa (PEG-IFN). 3-4 ETV and TDF are potent inhibitors of the HBV polymerase activity and are highly effective in maintaining suppression of HBV replication. 5-6 In contrast, PEG-IFN therapy aims at the induction of a sustained off-treatment response through its immunomodulatory effects, but only has a modest direct antiviral effect. 7 Consequently, one year of PEG-IFN therapy in patients with HBeAg-positive CHB resulted in 2.3-4.5 log copies/mL decline of HBV DNA, 8-9 while there was a 6.2-6.9 log drop of HBV DNA after 1 year of therapy with third generation NA. 5-6 In contrast to suppression of HBV DNA, HBeAg loss as a marker of immunological control was observed more often in patients treated with PEG-IFN compared with NA (29-30% versus 21-22%). 5-6, 8-9 Fluctuations in HBV DNA and alanine aminotransferase (ALT) levels occur spontaneously during the natural course of CHB, 10 and spontaneous HBeAg clearance occurs at an annual rate of 10–15% in adults with elevated ALT levels. 11 Furthermore, the clinical signifi cance of different HBV genotypes for the natural course and treatment response of CHB has become increasingly recognized in recent years. 12-15 Nevertheless, extensive viral kinetics data during PEG-IFN therapy have not been compared to natural occurring fl uctuations in viral load during placebo therapy in patients with HBeAg-positive CHB. Therefore, the aim of our study was (1) to compare the pattern of HBV DNA decline between HBeAg-positive patients treated with PEG-IFN alfa-2b and placebo, particularly in patients achieving HBeAg loss and (2) to study the association between HBV genotype and on-treatment ALT levels with HBV DNA kinetics. PATIENTS AND METHODS Patients A total of 136 patients treated with PEG-IFN alfa-2b monotherapy and 167 patients who received placebo within two randomized controlled trials were included in this study. 10, 16 The inclusion and exclusion criteria of both trials have been reported in detail previously. 10, 16 In summary, patients were eligible for the original PEG-IFN trial if they had
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 32 and 33: Chapter 2.1 30 been hepatitis B sur
Page 34 and 35: Chapter 2.1 32 HBV DNA decline The
Page 36 and 37: Chapter 2.1 34 Figure 2 continued.
Page 38 and 39: Chapter 2.1 36 Figure 4. Estimated
Page 40 and 41: Chapter 2.1 38 DNA was observed in
Page 42: Chapter 2.1 40 15. Kao JH. Role of
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
Page 83 and 84:
INTRODUCTION Dynamic prediction of
Page 85 and 86:
For the indirect approach we rewrit
Page 87 and 88:
logit pi,j = logit Pr(Ri =1|visit =
Page 89 and 90:
Dynamic prediction of response usin
Page 91 and 92:
Page 93 and 94:
Page 95 and 96:
Page 97 and 98:
Page 99 and 100:
Page 101 and 102:
Table 1. Results of different stopp
Page 103 and 104:
Page 105:
Page 108 and 109:
Chapter 2.5 106 ABSTRACT Peginterfe
Page 110 and 111:
Chapter 2.5 108 and placebo daily.
Page 112 and 113:
Chapter 2.5 110 for patients with a
Page 114 and 115:
Chapter 2.5 112 Mean HBV DNA declin
Page 116 and 117:
Chapter 2.5 114 peginterferon and n
Page 118 and 119:
Chapter 2.5 116 hepatocellular carc
Page 120 and 121:
Chapter 2.5 118 13. Werle-Lapostoll
Page 122:
Chapter 2.5 120 Greece - G Germanid
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 137 and 138:
Page 139 and 140:
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 151 and 152:
Page 153 and 154:
where wi,k(y i, θ) = (k =1,...,K).
Page 155 and 156:
Page 157 and 158:
Page 159 and 160:
Page 161 and 162:
Page 163 and 164:
Page 165 and 166:
Page 167 and 168:
Page 169 and 170:
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
Page 184 and 185:
Chapter 4.1 182 Figure 1.
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 199 and 200:
Page 201 and 202:
log HBV DNA (copies/mL) 10.0 9.0 8.
Page 203 and 204:
Page 205 and 206:
Page 207 and 208:
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 217 and 218:
Page 219 and 220:
Page 221 and 222:
Page 223 and 224:
Page 225 and 226:
Page 227 and 228:
Page 229:
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
Page 253:
Dan kwoord
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
Page 263 and 264:
Bibliography 261 Long term clinical
Page 265 and 266:
Bibliography 263 Flares in chronic
Page 267 and 268:
Bibliography 265 Genetic characteri
Page 269:
Bibliography 267 106. Reijnders JG,
show all

View PDF Version - RePub - Erasmus Universiteit Rotterdam

Create successful ePaper yourself

Delete template?

Save as template?