Host and Viral Predictors of Response to Antiviral Therapy in Chronic Hepatitis B

235 Pages·2013·1.83 MB·English

by  Milan J. Sonneveld

Host and Viral Predictors of Response
to Antiviral Therapy in Chronic Hepatitis B
Milan J. Sonneveld
Colofon
© M.J. Sonneveld, the Netherlands, 2013.
All rights reserved. No parts of this thesis may be reproduced or transmitted in any form or
by any means, without prior written permission of the author.
Cover designed by Angelo Betti
Layout and printing: Optima Grafische Communicatie, Rotterdam, the Netherlands.
The work presented in this thesis was conducted at the Department of Gastroenterology
and Hepatology, Erasmus MC University Medical Center Rotterdam, the Netherlands.
ISBN: 978-94-6169-361-7
Printing of this thesis was supported by F. Hoffmann-La Roche, Erasmus Universiteit
Rotterdam, the department of Gastroenterology and Hepatology of the Erasmus MC
Rotterdam, Nederlandse Vereniging voor Hepatologie, J.E. Jurriaanse Stichting, Merck,
Sharp & Dohme B.V., Gilead Sciences, Innogenetics, Abbott, Boehringer Ingelheim BV and
Virology Education B.V.
Host and Viral Predictors of Response
to Antiviral Therapy in Chronic Hepatitis B
Voorspellers van respons op behandeling in chronische hepatitis B
Proefschrift
ter verkrijging van de graad van doctor aan de
Erasmus Universiteit Rotterdam
op gezag van de
rector magnificus
Prof.dr. H.G. Schmidt
en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op
vrijdag 19 april 2013 om 13:30 uur
door
Milan Johan Sonneveld
geboren te Rotterdam
PRoMoTieCoMMiSSie
Promotor: Prof.dr. H.L.A. Janssen
overige leden: Prof.dr. U.H.W. Beuers
Prof.dr. C.A.B. Boucher
Dr. R.A. de Man
Paranimfen: Drs. J. Lagendijk
Drs. W.P. Brouwer
Voor Sonia
Contents
General Introduction 9
Chapter 1 Polymorphisms near IL28B and serologic response to 17
peginterferon in HBeAg-positive patients with chronic hepatitis
B. Gastroenterology 2012.
Chapter 2 Presence of precore and core promoter mutants limits the 35
probability of response to peginterferon in hepatitis B e
antigen-positive chronic hepatitis B. Hepatology 2012.
Chapter 3 Precore and core promoter mutants are associated with higher 53
HBeAg seroconversion but low disease remission rates in HBV
patients treated with nucleo(s)tide analogues. Journal of Viral
Hepatitis 2012.
Chapter 4 Serum levels of interferon gamma-inducible protein-10 and 67
response to peginterferon therapy in HBeAg-positive chronic
hepatitis B. Journal of Hepatology 2013.
Chapter 5 Peginterferon results in higher serological, but not virological, 81
response rates when compared to continuous entecavir.
Antiviral Therapy 2012.
Chapter 6 Prediction of sustained response to peginterferon alfa-2b 89
for hepatitis B e antigen-positive chronic hepatitis B using
on-treatment hepatitis B surface antigen decline. Hepatology
2010.
Chapter 7 Durable hepatitis B surface antigen decline in hepatitis B 105
e antigen-positive chronic hepatitis B patients treated with
pegylated interferon alfa-2b: relation to response and HBV
genotype. Antiviral Therapy 2012.
Chapter 8 Response-guided peginterferon therapy in HBeAg-positive 119
chronic hepatitis B using serum hepatitis B surface antigen
levels. Submitted.
Chapter 9 Close monitoring of HBsAg levels helps classify flares during 135
peginterferon therapy and predicts treatment response. Clinical
Infectious Diseases 2012.
6
Chapter 10 A comparison of two assays for quantification of hepatitis B 147
surface antigen in patients with chronic hepatitis B. Journal of
Clinical Virology 2011.
Chapter 11 Hepatitis B e antigen levels and response to peginterferon: 157
influence of precore and basal core promoter mutants. Antiviral
Research 2013.
Chapter 12 Quantification of hepatitis B surface antigen: is it useful for the 173
management of chronic hepatitis B? Gut 2012.
Chapter 13 Correspondence 189
Summary and discussion 197
Samenvatting 209
Dankwoord 219
Bibliografie 225 Co
n
te
n
Curriculum vitae 227 ts
PhD Portfolio 229
Abbreviations 235
7

Introduction
Based on:
Sonneveld MJ, Janssen HL. Chronic hepatitis B: peginterferon or nucleos(t)ide
analogues? Liver Int 2011;31 Suppl 1:78-84
Rijckborst V, Sonneveld MJ, Janssen HL. Review article: chronic hepatitis B - anti-viral
or immunomodulatory therapy? Aliment Pharmacol Ther 2011;33:501-13.
Sonneveld MJ, Zoutendijk R, Janssen HL. Hepatitis B surface antigen monitoring and
management of chronic hepatitis B. J Viral Hepat 2011; 18:449-57
inTRoduCTion
Chronic hepatitis B (CHB) is a major cause of liver disease worldwide despite the
availability of effective vaccination. There are still more than 350 million people
chronically infected with the hepatitis B virus (HBV)1 and progression of HBV-related
liver inflammation to cirrhosis, hepatic decompensation and hepatocellular carcinoma
(HCC) is estimated to result in up to 1.2 million deaths annually.1
PHASeS of infeCTion
Patients with CHB may present in any one of four, not necessarily sequential, phases
of infection.2 During the immunotolerant phase, hepatitis B e antigen (HBeAg) is
detectable and serum HBV DNA level is high (generally >20,000 IU/mL), while serum
alanine aminotransferase (ALT) is within the normal range and liver histology shows
minimal inflammation. In the immune clearance phase, the host immune response
results in a decline in HBV DNA levels, elevated ALT levels and hepatic necroinflam-
mation. During this phase HBeAg loss and seroconversion to anti-HBe can occur.
HBeAg seroconversion is often followed by an inactive carrier state characterized by
a low serum HBV DNA level (<2,000 IU/mL) and normalization of ALT. However, in a
significant proportion of HBeAg-negative patients viral replication recurs or persists
at higher levels, resulting in active HBeAg-negative CHB. This phase of the infection
develops through presence of viral strains harbouring mutations in the precore or
basal core promoter region that reduce or abolish the expression of HBeAg.3 Serum
levels of hepatitis B surface antigen (HBsAg) also vary across the 4 phases of infection,
with the highest levels observed in immunotolerant patients, a significant decrease in
patients progressing to immune clearance, and the lowest levels in patients achieving
sustained immune control.4
TReATMenT of CHRoniC HePATiTiS B: PARAdigMS And
RATionAle
Complete eradication of HBV from host hepatocytes cannot be achieved with cur-
rently available agents, due to the persistence of HBV covalently closed circular DNA
(cccDNA) in host hepatocytes. The main goal of treatment of CHB is therefore to halt
the progression of liver inflammation to fibrosis, cirrhosis or hepatocellular carcinoma
(HCC).5 Because these outcomes typically do not occur until after decades of active
infection, surrogate outcomes are used as measures of therapy efficacy and success.