Cover Page

Contents

Cover

Title Page

Copyright

Contributors

Preface

Section I: Foundations for Understanding Antiviral Therapies in HCV

Chapter 1: HCV Replication

Introduction

The HCV Genome

Models to Study HCV Replication

The HCV Virion and Entry

HCV Replication

Chapter 2: Hepatitis C Virus Genotypes

Introduction

HCV Genotypes and Subtypes

Intergenotypic Recombinants

Quasispecies

Genotype-Specific Effects of HCV Proteins on Response to Antiviral Therapy

Insulin Resistance

Steatosis

Conclusion

Chapter 3: Immune Responses to HCV: Implications for Therapy

Introduction

Humoral Immune Responses to HCV

Adaptive Cellular Immune Responses to HCV

HCV and Immune Evasion: Mechanisms of Viral Persistence

Immune Responses to HCV: Implications for HCV Therapy

Concluding Remarks

Chapter 4: Mechanisms of Action of Antiviral Drugs: The Interferons

Introduction

Hepatocyte Response to HCV Infection

Recognition of HCV by RIG-I and TLR-3

Activation and Antagonism of HCV Recognition Pathways

Interferon-stimulated Genes and HCV Control

ISGs and Prediction of Treatment Outcome in CHC Infection

IL28B and its Prediction to CHC Treatment Response and Spontaneous Clearance

Concluding Remarks

Chapter 5: Pharmacology and Mechanisms of Action of Antiviral Drugs: Ribavirin Analogs

Introduction

Ribavirin

Ribavirin Analogs

Levovirin

Taribavirin

Inosine 5′-Monophosphate Dehydrogenase (IMPDH) Inhibitors

Summary

Chapter 6: Pharmacology and Mechanisms of Action of Antiviral Drugs: Polymerase Inhibitors

Introduction

Nucleoside Inhibitors

Non-Nucleoside Inhibitors

Perspectives

Acknowledgments

Chapter 7: Pharmacology and Mechanisms of Action of Antiviral Drugs: Protease Inhibitors

Introduction

Need for Improved Anti-HCV Therapies

Design of NS3 Protease Inhibitor Ciluprevir/BILN 2061: First Anti-HCV Proof-of-Concept in Humans

NS3 Protease Inhibitors in Clinical Development

Challenges and Future Directions

Acknowledgments

Chapter 8: Measuring Antiviral Responses

HCV RNA Level Measurement

Response-Guided Therapy with Current Standard-of-Care

Response-Guided Therapy with Future Standard-of-Care

Section II: Efficacy and Clinical Use of Antiviral Therapies

Chapter 9: Genotype 1: Standard Treatment

Goals of Therapy

Duration of Treatment

Deriving the Regimen

Monitoring Treatment Response

Medication Dosing

Side Effects and Dose Adjustments

Identifying Candidates for Therapy

The Future

Chapter 10: Individually Tailored Treatment Strategies in Treatment-naïve Chronic Hepatitis C Genotype 1 Patients

Introduction

Assessment of Baseline Viral Load

Viral Kinetics during Therapy: When to Measure HCV-RNA in Serum

Is it Possible to Further Individualize Treatment Beyond the Time Points of Weeks 4, 12, and 24?

Impact of Ribavirin in Individualized Treatment Strategies for Chronic Hepatitis C Genotype 1 Infection

Patients in Whom Shorter Treatment Durations May Not Be Considered

Impact of IL28B Genotype on Treatment Individualization

Summary

Chapter 11: Genotype 1 Relapsers and Non-responders

The Burden of Failures of Anti-HCV Therapy

Management of Patients Who Failed to Respond to Antiviral Therapy

Emerging Treatments

Conclusion

Chapter 12: Standard Therapy for Genotypes 2/3

Introduction

Peginterferon Alfa and Ribavirin for Genotype 2 or 3

Differences in Response to Treatment between HCV Genotype 2 and 3 Infections

Relevance of a Rapid Virological Response in HCV Genotype 2 or 3

Peg-IFN Formulations, Ribavirin Dose, and Response to Treatment

Albinterferon in the Treatment of Hepatitis C Genotype 2 or 3

Duration of Treatment in Hepatitis C Genotype 2 or 3

Treatment of Patients with Advanced Liver Disease

Predictors of Treatment Response: Other Factors to Consider

Long-Term Outcome of Peg-IFN Alfa and RBV Treatment

Summary and Conclusions

Chapter 13: Altered Dosage or Durations of Current Antiviral Therapy for HCV Genotypes 2 and 3

Background

Variable Length of Antiviral Therapy

Studies Randomizing Patients at Baseline to Short or Standard Treatment Duration

Conquering HCV Clearance in All Patients

Optimal Treatment Duration for Non-RVR Patients

Dosages of Peginterferon Alfa

Dosages of Ribavirin

Conclusions

Chapter 14: Genotypes 2 and 3 Relapse and Non-response

Background

Why Do Patients Infected with Genotypes 2 and 3 Not Have SVR?

Preventing Treatment Failure in G2/G3 Patients

Management of Relapse or Non-response to Antiviral Therapy

Management of Relapse in Patients Who Underwent Short Treatment Regimens

Future Therapies for Patients Who Experienced a Treatment Failure

Acknowledgments

Chapter 15: Hepatitis C Genotype 4 Therapy: Progress and Challenges

HCV Genotype 4: Shifting Epidemiology

Treatment of Chronic HCV-4 Naïve Patients

Duration of Chronic HCV-4 Therapy

The Efficacy of Different Pegylated Interferon Formulations in HCV-4 Infections

HCV-4 Therapy in Special Populations

Emerging New Regimen for Treatment of Chronic HCV-4

Personalizing Chronic HCV-4 Therapy

Conclusions and Future Prospects

Chapter 16: Antivirals in Acute Hepatitis C

Diagnosis of Acute Hepatitis C

Prevention of HCV Transmission

Treatment of Acute Hepatitis C

Timing of Therapy

Duration of Therapy

Is Ribavirin Needed to Treat Acute Hepatitis C?

Conclusions

Chapter 17: Antivirals in Cirrhosis and Portal Hypertension

Introduction

Compensated Cirrhosis

Decompensated Cirrhosis

Maintenance Interferon

Side Effects

Conclusions

Chapter 18: Treatment of Recurrent Hepatitis C Following Liver Transplantation

Introduction

Timing of Antiviral Therapy

Tolerability of Current Antiviral Therapy

Efficacy of Current Antiviral Therapy for Established Chronic Hepatitis

Future Antiviral Strategies

Summary

Chapter 19: Antiviral Treatment in Chronic Hepatitis C Virus Infection with Extrahepatic Manifestations

Introduction

HCV-Associated Mixed Cryoglobulinemia Vasculitis

HCV-Associated B-Cell Non-Hodgkin Lymphoma

Other HCV-Associated Extrahepatic Manifestations

Conclusion

Chapter 20: Cytopenias: How they Limit Therapy and Potential Correction

Mechanisms by which Interferon Contributes to Cytopenia

Mechanisms by Which Ribavirin Contributes to Anemia

Management of Neutropenia

Management of Thrombocytopenia

Management of Anemia

The Importance of Assessing Response During Therapy

Disclosures of Conflicts of Interest

Chapter 21: The Problem of Insulin Resistance and its Effect on Therapy

Introduction

Defining Insulin Resistance

Insulin Signaling

Molecular Mechanisms of Insulin Resistance in CHC

Host Factors Influencing IR

Effect of IR on Treatment Response

Management Strategies for CHC in the Setting of IR

Summary

Chapter 22: HIV and Hepatitis C Co-infection

Global Prevalence of HIV/HCV Co-Infection

Natural History of HCV in HIV Co-infection

Diagnosis and Monitoring of HCV in HIV Infection

Treatment of HIV-HCV Co-infection

Management of Treatment Non-Response and End-Stage Liver Disease

New Directions in Therapy

Chapter 23: HCV and Racial Differences

Introduction

Epidemiology

Treatment

Summary

Chapter 24: HCV and the Pediatric Population

Epidemiology and Natural History

Clinical Trials: Past, Present, and Future

Special Treatment Considerations for Pediatric Populations

Chapter 25: New Horizons: IL28, Direct-acting Antiviral Therapy for HCV

Introduction

NS3/4A Protease Inhibitors

NS5B Polymerase Inhibitors

NS5B Nucleos(t)ide Inhibitors

NS5B Non-Nucleos(t)ide Inhibitors

NS5A Inhibitors

Cyclophilin Inhibitors

Other DAA Targets

Other Novel Therapeutic Approaches

Drug Resistance

Combination Strategies

IL28B Polymorphism

Unresolved Issues

Summary and Conclusions

Authors’ Declaration of Personal Interests

Index

Title Page

Contributors

Nezam H. Afdhal MD
Beth Israel Deaconess Medical Center
Boston, MA, USA

Angelo Andriulli MD
Gastroenterology Department
IRRCS Casa Sollievo della Sofferenza
San Giovanni Rotondo, Italy

Martin Baril PhD
Research Associate
Institut de Recherche en Immunologie et Cancérologie (IRIC)
Montréal, Québec, Canada

Michael R. Beard PhD
Head, Hepatitis C Virus Research Laboratory
School of Molecular and Biomedical Science
The University of Adelaide & Center for Cancer Biology, SA Pathology
Adelaide, SA, Australia

Thomas Berg MD
Professor
Department of Gastroenterology and Rheumatology
Division of Hepatology
University of Leipzig
Leipzig, Germany

David G. Bowen MBBS, PhD
Sydney Medical School, University of Sydney
Royal Prince Alfred Hospital
Sydney, NSW, Australia

Patrice Cacoub MD, PhD
Professor
Department of Internal Medicine
Groupe Hospitalier Pitié-Salpêtrière
Université Pierre et Marie Curie
Paris, France

Laurent Chatel-Chaix PhD
Post-doctoral Fellow
Institut de Recherche en Immunologie et Cancérologie (IRIC)
Montréal, Québec, Canada

Grace M. Chee PharmD
Hepatology Department
Cedars-Sinai Medical Center
Los Angeles, CA, USA

Stéphane Chevaliez PharmD, PhD
National Reference Center for Viral Hepatitis B, C and delta
Department of Virology & INSERM U955
Hôpital Henri Mondor
Université Paris-Est
Créteil, France

Lotte Coelmont PhD
Laboratory of Virology and Chemotherapy
Rega Institute for Medical Research
University of Leuven
Leuven, Belgium

Antonio Craxì, MD
Full Professor of Gastroenterology
Sezione di Gastroenterologia, Di.Bi.M.I.S. Policlinico Paolo Giaccone
University of Palermo
Palermo, Italy

Leen Delang PhD
Laboratory of Virology and Chemotherapy
Rega Institute for Medical Research
University of Leuven
Leuven, Belgium

Gregory J. Dore BSc, MBBS, MPH, PhD, FRACP
Professor and Head, Viral Hepatitis Clinical Research Program
National Centre in HIV Epidemiology and Clinical Research
The University of New South Wales;
Infectious Diseases Physician
St Vincent's Hospital
Sydney, NSW, Australia

Mark W. Douglas BSc (Med)(Hons), MBBS (Hons), PhD, FRACP
Senior Lecturer, Hepatology and Virology
Storr Liver Unit, Westmead Millennium Institute
Sydney Emerging Infections and Biosecurity Institute
University of Sydney
Sydney, NSW, Australia

Xavier Forns MD, PhD
Liver Senior Specialist
Liver Unit, Hospital Clinic
IDIBAPS and Ciberehd (Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas)
Barcelona, Spain

Mathy Froeyen PhD
Assistant Professor of Pharmacy
Laboratory of Medicinal Chemistry
Rega Institute for Medical Research
University of Leuven
Leuven, Belgium

Ed Gane MB ChB, MD, FRACP
Associate Professor and Hepatologist
New Zealand Liver Transplant Unit
Auckland City Hospital
Auckland, New Zealand

Jacob George MBBS (Hons), FRACP, PhD
Director of Gastroenterology and Hepatic Services
Storr Liver Unit, Westmead Millenium Institute
University of Sydney
Sydney, NSW, Australia

Rebekah G. Gross MD
Assistant Professor of Medicine
Division of Gastroenterology and Hepatology
Weill Cornell Medical College
New York, NY, USA

Piet Herdewijn PhD
Professor of Pharmacy
Laboratory of Medicinal Chemistry
Rega Institute for Medical Research
University of Leuven
Leuven, Belgium

Ira M. Jacobson MD
Vincent Astor Professor of Medicine
Chief, Division of Gastroenterology and Hepatology
Division of Gastroenterology and Hepatology
Weill Cornell Medical College
New York, NY, USA

Sanaa M. Kamal MD, PhD
Department of Gastroenterology and Liver Disease
Ain Shams Faculty of Medicine
Cairo, Egypt;
Department of Gastroenterology
Tufts School of Medicine
Boston, MA, USA

Daniel Lamarre PhD
Full Professor, Department of Medicine
Faculty of Medicine
Institute for Research in Immunology and Cancer (IRIC)
Université de Montréal
Montréal, Québec, Canada

Alessandra Mangia MD
Liver Unit
IRRCS Casa Sollievo della Sofferenza
San Giovanni Rotondo, Italy

Diarmuid S. Manning MB, BCh
Beth Israel Deaconess Medical Center
Harvard Medical School
Boston, MA, USA

Stella Martínez MD
Liver Unit, Hospital Clinic
IDIBAPS and Ciberehd (Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas)
Barcelona, Spain

Gail V. Matthews MBChB, MRCP (UK), FRACP, PhD
Clinical Academic
National Centre in HIV Epidemiology and Clinical Research
University of New South Wales
Sydney, NSW, Australia

Geoffrey W. McCaughan MBBS, PhD, FRACP
Head of Liver Immunobiology Program
Centenary Research Institute
A.W. Morrow Professor of Medicine
Director A.W. Morrow GE/Liver Center
Director Australian Liver Transplant Unit
Royal Prince Alfred Hospital
University of Sydney
Sydney, NSW, Australia

John G. McHutchison, MD
Senior Vice President, Liver Disease Therapeutics
Gilead Sciences, Inc.
Foster City, CA, USA

Leonardo Mottola PhD
Liver Unit
IRRCS Casa Sollievo della Sofferenza
San Giovanni Rotondo, Italy

Andrew J. Muir MD MHS
Director, Gastroenterology/Hepatology Research
Duke Clinical Research Institute
Duke University Medical Center
Durham, NC, USA

Johan Neyts PhD
Professor of Virology
Laboratory of Virology and Chemotherapy
Rega Institute for Medical Research
University of Leuven
Leuven, Belgium

Venessa Pattullo MBBS, FRACP
Storr Liver Unit, Westmead Millennium Institute
University of Sydney, Sydney, NSW, Australia;
Division of Gastroenterology
Toronto Western Hospital
University Health Network, University of Toronto
Toronto, Ontario, Canada

Jean-Michel Pawlotsky MD, PhD
Director, French National Reference Center for Viral Hepatitis B, C and delta
Head, Department of Virology, Bacteriology, and Hygiene
INSERM U955
Hôpital Henri Mondor
Université Paris Est
Créteil, France

Salvatore Petta MD, PhD
Sezione di Gastroenterologia, Di.Bi.M.I.S. Policlinico Paolo Giaccone
University of Palermo
Palermo, Italy

Fred Poordad MD
Associate Professor of Medicine
David Geffen School of Medicine at UCLA;
Chief, Hepatology and Liver Transplantation
Cedars-Sinai Medical Center
Los Angeles, CA, USA

Scott A. Read MSc
Storr Liver Unit, Westmead Millennium Institute
University of Sydney
Sydney, NSW, Australia

Jose María Sánchez-Tapias MD, PhD
Senior Consultant
Liver Unit, Hospital Clinic
IDIBAPS and Ciberehd (Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas)
Barcelona, Spain

Kathleen B. Schwarz MD
Director, Pediatric Liver Center
Division of Pediatric Gastroenterology and Nutrition
Professor of Pediatrics
Johns Hopkins University School of Medicine
Baltimore, MD, USA

Mitchell L. Shiffman MD
Director
Liver Institute of Virginia
Bon Secours Virginia Health System
Richmond and Newport News, VA, USA

Benjamin Terrier MD
Department of Internal Medicine
Groupe Hospitalier Pitié-Salpêtrière
Université Paris 6 Pierre et Marie Curie
Paris, France

Alexander J. Thompson MD, PhD
St. Vincent's Hospital Melbourne, University of Melbourne, Melbourne, VIC, Australia;
Victorian Infectious Diseases Reference Laboratory (VIDRL), North Melbourne, VIC, Australia;
Department of Gastroenterology and Duke Clinical Research Institute
Duke University
Durham, NC, USA

Edmund Tse MBBS, FRACP
School of Molecular and Biomedical Science
The University of Adelaide and the Center for Cancer Biology
SA Pathology
Adelaide, SA, Australia

Heiner Wedemeyer MD
Professor
Department of Gastroenterology, Hepatology and Endocrinology
Medizinische Hochschule Hannover
Hannover, Germany

Johannes Wiegand MD
Private Lecturer
Department of Gastroenterology and Rheumatology
Division of Hepatology
University of Leipzig
Leipzig, Germany

Kenneth Yan MBBS, Mmed (Clin Epi), FRACP
Conjoint Associate Lecturer
St George Clinical School
Faculty of Medicine
University of New South Wales
Sydney, NSW, Australia

Amany Zekry MBBS, PhD, FRACP
Department of Gastroenterology and Hepatology
Clinical School of Medicine
St George Hospital
Sydney, NSW, Australia

Preface

Hepatitis C virus results in chronic liver disease in over 170 million people worldwide. This book arrives at a watershed in the history of antiviral treatment of the hepatitis C virus. It is the beginning of the end of non-specific antiviral approaches via interferon-based therapies. From now on the field will be dominated by the arrival of HCV-specific direct antiviral agents. Initially these agents will still require interferon and ribavirin but already clinical trials are under way that do not include either of these agents.

This publication outlines the current standard of care up until this time and includes therapeutic approaches to wide patient groups. We believe that the structure of the book will remain relevant for future editions as the new therapies are gradually rolled out across these patient groups, as well as across an increasing number of countries.

G.W.M.
J.G.M.
J-M.P.

I

Foundations for Understanding Antiviral Therapies in HCV