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Chapter 2.1 38 DNA was observed in patients who lost HBeAg during PEG-IFN therapy compared with placebo. A signifi cant difference in HBV DNA decline between the two groups was already present at week 4, which progressed to an estimated 2 log at week 48. These fi ndings suggest that HBeAg loss induced by PEG-IFN may be accompanied by a more profound suppression of viral replication compared with spontaneous HBeAg loss. Treatment induced and spontaneous fl ares of liver infl ammation are often observed in patients with CHB. These fl ares appear to refl ect the activity of the host immune system against the virus. Our study is the fi rst to report that fl ares induced by PEG-IFN are accompanied with a higher consecutive decline in HBV DNA compared with that observed after a spontaneously occurring fl are during placebo therapy. As previously reported, a trend towards a higher chance of HBeAg loss in PEG-IFN treated patients with an on-treatment fl are was observed. 24 In contrast, the rate of HBeAg loss was similar in placebo-treated patients with or without fl are. The observation that the decline of HBV DNA was stronger in patients with fl ares, and also in patients with HBeAg loss, during PEG-IFN therapy compared with placebo further underlines the importance of the immunomodulatory effects of PEG-IFN which results in an improved activity of the immune response against HBV. Although this study is the fi rst to investigate the antiviral effi cacy of PEG-IFN compared with placebo, it has limitations. Since the treatment groups were derived from two different randomized controlled trials, their baseline characteristics were not completely comparable at baseline. Baseline ALT and HBV DNA levels were higher in the PEG-IFN group. Therefore, we corrected the linear mixed regression analysis of HBV DNA decline for baseline ALT. Baseline HBV DNA was not associated with the estimated HBV DNA decline. Furthermore, the distribution of HBV genotypes differed between the two treatment arms. However, genotypes A-D were present in substantial numbers across both groups, which allowed us to perform separate analyses of the overall decline of HBV DNA according to genotype. In conclusion, PEG-IFN therapy resulted in a larger HBV DNA decline compared with placebo. The degree of viral suppression was stronger in HBeAg-positive patients who lost HBeAg or who had an ALT fl are during PEG-IFN therapy compared with spontaneous HBeAg loss or fl ares during placebo therapy.
References 1. Liaw YF, Chu CM. Hepatitis B virus infection. Lancet 2009;373:582-92. PEG-IFN versus placebo for HBeAg-positive CHB 39 2. Wong SN, Lok AS. Treatment of hepatitis B: who, when, and how? Arch Intern Med 2006;166:9- 12. 3. European Association For The Study Of The L. EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009;50:227-42. 4. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009;50:661-2. 5. Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, Lok AS, Han KH, Goodman Z, Zhu J, Cross A, DeHertogh D, Wilber R, Colonno R, Apelian D. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 2006;354:1001-10. 6. Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OO, Shiffman ML, Trinh H, Washington MK, Sorbel J, Anderson J, Snow-Lampart A, Mondou E, Quinn J, Rousseau F. Tenofovir Disoproxil Fumarate versus Adefovir Dipivoxil for Chronic Hepatitis B. N Engl J Med 2008;359:2442-2455. 7. Peters M. Actions of cytokines on the immune response and viral interactions: an overview. Hepatology 1996;23:909-16. 8. Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, Gane E, Fried MW, Chow WC, Paik SW, Chang WY, Berg T, Flisiak R, McCloud P, Pluck N. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005;352:2682-95. 9. ter Borg MJ, van Zonneveld M, Zeuzem S, Senturk H, Akarca US, Simon C, Hansen BE, Haagmans BL, de Man RA, Schalm SW, Janssen HL. Patterns of viral decline during PEGinterferon alpha-2b therapy in HBeAg-positive chronic hepatitis B: relation to treatment response. Hepatology 2006;44:721-7. 10. Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, Jeffers L, Goodman Z, Wulfsohn MS, Xiong S, Fry J, Brosgart CL. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003;348:808-16. 11. Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol 2008;48:335-52. 12. Sanchez-Tapias JM, Costa J, Mas A, Bruguera M, Rodes J. Infl uence of hepatitis B virus genotype on the long-term outcome of chronic hepatitis B in western patients. Gastroenterology 2002;123:1848-56. 13. Buster EH, Hansen BE, Lau GK, Piratvisuth T, Zeuzem S, Steyerberg EW, Janssen HL. Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa. Gastroenterology 2009;137:2002-9. 14. Livingston SE, Simonetti JP, Bulkow LR, Homan CE, Snowball MM, Cagle HH, Negus SE, McMahon BJ. Clearance of hepatitis B e antigen in patients with chronic hepatitis B and genotypes A, B, C, D, and F. Gastroenterology 2007;133:1452-7.
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 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 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
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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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