Table Of ContentMilestones in Drug Therapy
MDT
Series Editors
Prof. Dr. Michael J. Parnham Prof. Dr. J. Bruinvels
Senior ScientificAdvisor Sweelincklaan 75
PLIVA dd NL-3723 JC Bilthoven
Prilaz barona Filipovica 25 The Netherlands
HR-10000 Zagreb
Croatia
Hepatitis Prevention
and Treatment
Edited by J.M. Colacino and B.A. Heinz
Springer Basel AG
Editors
Joseph M. Colacino Beverly A. Heinz
PTC Therapeutics Eli Lilly and Company
Drug Discovery Discovery Research
100 Corporate Court Lilly Corporate Center
South Plainfield, NJ 07080 Indianapolis, IN 46285-0438
USA USA
Advisory Board
J.c. Buckingham (Imperial College School of Medicine, London, UK)
RJ. Flower (The William Harvey Research Institute, London, UK)
G. Lambrecht (J.w. Goethe Universităt, Frankfurt, Gennany)
Library of Congress CataIoging-in-Publication Data
Hepatitis prevention and treatment / Joseph M. Colacino, Beverly A. Heinz, editors.
p. cm. --(Milestones in drug therapy)
IncIudes biblographical references and index.
ISBN 978-3-0348-9617-7 (alk. paper)
1. Hepatitis, VITal. 1. Colacino, Joseph M., 1953-II. Heinz, Beverly A. III. Series.
RC848.H43H47 2004
616.3'623--dc22 2004048866
Bibliograpbic information published by Die Deutsche Bibliothek
Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailed biblio
graphic data is available in the internet at http://dnb.ddb.de
ISBN 978-3-0348-9617-7 ISBN 978-3-0348-7903-3 (eBook)
DOI 10.1007/978-3-0348-7903-3
The publisher and editor can give no guarantee for the information on drug dosage and administration
contained in this publication. The respective user must check its accuracy by consulting other sources
of reference in each individual case.
The use of registered names, trademarks etc. in this publication, even if not identified as such, does
not imply that they are exempt from the relevant protective laws and regulations or free for general
use.
This work is subject to copyright. AII rights are reserved, whether the whole or part of the material is
concerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation, broad
casting, reproduction on microfilms or in other ways, and storage in data banks. For any kind of use,
permission of the copyright owner must be obtained.
© 2004 Springer Basel AG
Originally published by Birkhăuser Verlag, Basel -Boston -Berlin in 2004
Printed on acid-free paper produced from chlorine-free pulp. TFC
00
Cover illustration: HBV (top) and HCV (bottom) genomes. With the friendly permission of J.M.
Colacino and L. Condreay.
ISBN 3-7643-5956-0
987654321 www.birkhauser.ch
v
Contents
Listofcontributors VII
Preface IX
GururajKalkeri andAnnD. Kwong
History ofviral hepatitis 1
Lawrence M. BlattandMyron Tong
Epidemiology ofchronic hepatitis viruses:
hepatitis B virus andhepatitis C virus 29
LynnD. CondreayandSarahA. Harris
Molecularvirology ofhepatitisB virus 39
Guangxiang (George) Luo
Molecularvirology ofhepatitis C virus 67
TomaszI. Michalak
Immunology ofhepatitis B virus 87
EleanorJ. Barnes, NasserSemmoandPaul Klenerman
Immunology ofhepatitis C virus 107
NathanielA. BrownandRichardE. Boehme
Currenttreatmentofpatients with chronic hepatitis B virus infection 125
AnoukDev, KeyurPatelandJohn G. McHutchison
Current standardofcare in hepatitis C virus infection 141
Craig S. Gibbs
Viral response to therapy: viral dynamics 157
RaymundR. Razonable andJames M. McGill
Investigational drugs inclinical developmentfor the treatment
ofchronic viral hepatitis 175
Tim Shaw andStephen Locarnini
Problems inherentto antiviral therapy 203
Index 239
VII
List of contributors
Eleanor J. Barnes, Nuffield Department of Medicine, University of Oxford,
Peter Medawar Building for Pathogen Research, South Parks Rd, Oxford
OXI3SY, UK
Lawrence M. Blatt, InterMune Inc, 3280 Bayshore Boulevard, Brisbane, CA
94005, USA; e-mail: [email protected]
Richard E. Boehme, Idenix Pharmaceuticals, 60 Hampshire St., Cambridge,
MA02139, USA; e-mail: [email protected]
Nathaniel A. Brown, Idenix Pharmaceuticals, 60 Hampshire St., Cambridge,
MA02139, USA; e-mail: [email protected]
Lynn D. Condreay, GlaxoSrnithKline, Department of Virology, P.O.Box
13398, Research Triangle Park, NC 27709-3398, USA; e-mail:
[email protected]
Anouk Dev, Duke Clinical Reserach Institute and Division of
Gastroenterology, Duke University Medical Centre, P.O. Box 17969,
Durham, NC 27715, USA
Craig S. Gibbs, GileadSciences, 333 Lakeside Drive, FosterCity, CA 94404,
USA; e-mail: [email protected]
Sarah A. Harris, GlaxoSrnithKline, Department ofVirology, P.O.Box 13398,
Research Triangle Park, NC 27709-3398, USA; e-mail:
[email protected]
Gururaj Kalkeri, Vertex Pharmaceuticals, Inc., Infectious Diseases Biology,
130 Waverly Street, Cambridge, MA 02139, USA; e-mail:
[email protected]
Paul Klenerman, Nuffield Department of Medicine, University of Oxford,
Peter Medawar Building for Pathogen Research, South Parks Rd, Oxford
OXI 3SY, UK; e-mail: [email protected]
Ann D. Kwong, Vertex Pharmaceuticals, Inc., Infectious Diseases Biology,
130 Waverly Street, Cambridge, MA 02139, USA; e-mail:
[email protected]
Stephen Locarnini, Victorian Infectious Diseases Reference Laboratory,
Locked Bag 815, Carlton South, Victoria 3053, Australia; e-mail:
[email protected]
Guangxiang (George) Luo, Department of Microbiology, Immunology and
MolecularGenetics,UniversityofKentuckyCollegeofMedicine,800Rose
Street, MN475, UKMC, Lexington, Kentucky, 40536, USA; e-mail:
[email protected]
James M. McGill, Bone & Inflammation Research, Lilly Research Labora
tories, Indianapolis, IN46285, USA, and DivisionofGastroenterology and
VIII Listofcontributors
Hepatology,IndianaUniversitySchoolofMedicine,Indianapolis,IN,USA;
e-mail:[email protected]
John G. McHutchison, Duke Clinical Reserach Institute and Division of
Gastroenterology, Duke University Medical Centre, P.O. Box 17969,
Durham, NC 27715, USA; e-mail: [email protected]
TomaszI. Michalak,MolecularVirologyandHepatologyResearch, Facultyof
Medicine, Health Sciences Centre, Memorial University, St. John's,
Newfoundland, CanadaAlB 3V6;e-mail: [email protected]
Keyur Patel, Duke Clinical Reserach Institute and Division of
Gastroenterology, Duke University Medical Centre, P.O. Box 17969,
Durham, NC 27715, USA
Raymund R. Razonable, Bone & Inflammation Research, Lilly Research
Laboratories, Indianapolis, USA; and Division of Infectious Diseases and
InternalMedicine,MayoClinicCollegeofMedicine,Rochester,MN,USA;
e-mail: [email protected]
NasserSemmo,NuffieldDepartmentofMedicine,UniversityofOxford,Peter
Medawar Building for Pathogen Research, South Parks Rd, Oxford OXI
3SY, UK
Tim Shaw, Victorian Infectious Diseases Reference Laboratory, Locked Bag
815,CarltonSouth,Victoria3053,Australia;e-mail:[email protected]
Myron Tong, The Liver Center, Huntington Medical Research Institutes,
Pasadena, CA94005, USA
IX
Preface
Despite remarkable advances in our understanding oftheir replicative strate
gies, the human hepatotrophic viruses hepatitis Band C remain majorcauses
ofviralhepatitisworldwideandrepresentimportantmedicalneedsthatarenot
fully met. Hepatitis B virus (HBV) andhepatitisCvirus (HCV) are genetical
ly unrelated and belong to different virus families; thus they must betargeted
by separate approaches.
HBVistheprototypevirusofthe Hepadnaviridaefamily. ItisasmallDNA
virus that is most prevalent in Asia and in developing countries, chronically
infecting nearly 400 million people worldwide. Approximately 10-15% of
individuals who becomeinfectedwith HBVgoontobecomechroniccarriers
ofthis virus. ChronicHBVinfectioncanresultinmorbidityandmortalitythat
includes severe liver disease, cirrhosis and hepatocellular carcinoma.
Importantly, chronically infected individuals serve as sources of this blood
borne and sexually transmitted virus. Although there is a safe and effective
vaccine for the prevention ofHBV infection, the large pool ofchronic carri
ersmustbetreatedwitheffectiveantiviralagentsinordertoameliorateorcure
diseaseandreducehorizontaland vertical(in utero) transmissionofthe virus.
Currently there are three approved therapies for chronic HBV infection
including interferon a, the nucleoside analog lamivudine (3TC), and the pro
drug ofthe nucleotide analog PMEA known as Hepsera (adefovirdipivoxil).
Because of the limitations of these therapies, the search for more effective
antiviral agents continuesandanumberofagents are in preclinical orclinical
development.
HCV is a small, positive-strand RNA virus that is a member of the
Flaviviridae family and that infects an estimated 170-350 million people
worldwide. In contrast to HBV, the vast majority (85%) of people who
become infected with HCV go on to develop a chronic infection and, of
these, approximately 20% develop severe sequelae including liver dysfunc
tion, cirrhosis and, in many cases, hepatocellular carcinoma. Chronic infec
tion with HCV is currently the leading reason for livertransplantation in the
United States. There is no vaccine available for the prophylaxis of HCV
infectionandtheonlyapprovedtherapy,acombinationofinterferonplusrib
avirin, is not effective in over half of the patients and is associated with
severe adverse effects.
This monographbringstogetherinonevolume themostrecentinformation
on all aspects of these two fascinating and medically important viruses. In
planning and developing this book, we sought contributors who are active in
their fields and well known for their significant contributions to our under-
x Preface
standing ofHBV and HCV and the diseases they establish. We have selected
authors who can survey their areas authoritatively and from a personal per
spective. Ourcontributorsincludescientistsandclinicianswhohavemadesin
gularly important advances in our understanding ofthe molecular biology of
HBVandHCV,haveincreasedourunderstandingofthehostimmuneresponse
to viral infection, have been integral to the discovery and development of
agentsthatholdpromiseforthetreatmentofchronicHBVandHCVinfection,
and who have been instrumental in the design and implementation ofclinical
trials for the evaluation ofagents that are now approved for use against HBV
and HCV orare in development.
The first two chapters offer an interesting look at the history and epidemi
ologyofthe differentcausesofviral hepatitis with, ofcourse, an emphasis on
HBV andHCY.Atimeis certainly within the memory ofmanyofourreaders
whentherewas noHBV,butrather"Australiaantigen,"andwhentherewasno
HCV, but rather "non-A, non-B hepatitis." Since those earlier times, rapid
advances in the characterization of the etiologic agents that cause these dis
eases have been made and our understanding of the molecular virology of
HBVandHCVhas increaseddramatically.Accordingly, thenexttwochapters
are concerned with the molecular virology ofHBV and HCV and offer state
of-the-artdiscussions ofthe latestfindings concerning the virus genomes, the
structure and function of viral proteins, and virus-replication strategies. Our
understandingoftheimmunologyofHBVandHCVhasincreasedremarkably
over the last decade, and the next two chapters are concerned with the
immunologic basis ofthe host immune response to infection. The topics cov
eredincludetheantibody,cellular,andinnateresponsestoviralinfection,viral
resistancetointerferon,andpersistenceofviralinfection.Thenextthreechap
tersareconcernedwiththecurrentstandard-of-careforHBY-andHCY-infect
edpatients.Theefficacy,adverseevents,limitationsofapprovedtherapies,and
the viral response to therapy are topics that are covered in these chapters.
Finally, the lasttwo chapters contain discussions ofHBV and HCV therapies
under development. Here are presented surveys ofthe more classical as well
as novelapproachestoviral andcellulartargetsthatarebeingexploredrecent
ly.Importantly,thelimitationsinherenttothesetherapiesandtheprospectsfor
future approaches are summarized.
We have intended that this bookwill be relevantfor working virologists in
industryandacademia,clinicalinvestigatorsandphysicians,graduatestudents
and post-doctoral fellows. Itis hoped that this up-to-date and comprehensive
single source ofinformation regarding HBV and HCV will be a useful intro
duction to researchers not yet well acquainted with these viruses and a con
venient source of review and state-of-the-art information for those scientists
already established in the field. The book directs the reader to useful primary
sourcesas wellascurrentreview articlesforamorein-depthtreatmentofspe
cific areas ofinterest. It is certain that the fields ofHBV and HCV will con
tinue to advance as we learn even more about the molecular virology and
immunology of these viruses and as new experimental therapies become
Preface XI
approved. Therefore, in theyears to come, itis hopedthatthis bookwill serve
as a convenient source ofknowledge that will provide a solid foundation for
an understanding and appreciation ofthe basic discoveries and key therapeu
tic advances ofthe future.
J.M. Colacino
B.A. Heinz May 2004
