HEPATITIS B VIRUS AND LIVER DISEASE

Foreword
Preface of the Second Edition
Contents
1: Molecular Virology and Life Cycle of Hepatitis B Virus
	1	 Viral Structure
		1.1	 Classification
		1.2	 Viral Particle
			1.2.1	 Genome
				Relaxed Circular DNA
				Double-Stranded Linear DNA
			1.2.2	 Proteins
				Surface Proteins: L-, M-, and S-HBsAg
				Capsid Protein: HBc
				Pre-Core Protein: HBeAg
				Polymerase
				X Protein: HBx
		1.3	 Other Viral Particles
			1.3.1	 Subviral Particles
			1.3.2	 Noncanonical Particles
	2	 Viral Life Cycle
		2.1	 Entry
		2.2	 Nuclear Import
		2.3	 cccDNA Biogenesis and Regulation
			2.3.1	 Formation
			2.3.2	 Chromatin Structure
			2.3.3	 Regulatory Sequences
				Core Promoter
				S Promoters
				X Promoter
				Enhancer I and Enhancer II
				Splicing and Export Signals
				Polyadenylation Signals
			2.3.4	 Epigenetic Regulation
				DNA Methylation
				Histone PTMs
			2.3.5	 Transregulatory Factors
				Viral Proteins
				Host Proteins
			2.3.6	 Mechanisms of cccDNA Persistence
		2.4	 Integration
		2.5	 Transcripts
			2.5.1	 Pregenomic RNA
			2.5.2	 Subgenomic RNAs
			2.5.3	 Truncated RNAs
			2.5.4	 Spliced RNAs
		2.6	 Nucleocapsid Assembly and RT
		2.7	 Assembly and Secretion
	3	 HBV Genomic Variability
		3.1	 Genotypes
		3.2	 Mutants
	4	 Perspectives
	References
2: Unmet Needs in Basic Research of Hepatitis B Virus Infection: In Vitro and In Vivo Models
	1	 Introduction
		1.1	 Hepatitis B Virus
		1.2	 Woodchuck Hepatitis Virus
		1.3	 Duck Hepatitis B Virus
	2	 HBV In Vivo Experimental Models
		2.1	 Chimpanzee Model
		2.2	 Macaque Model
		2.3	 Tupaia Model
		2.4	 Transgenic Mice
		2.5	 Human Hepatocyte Chimeric Mice
		2.6	 Immune-Competent Mouse Models
		2.7	 Hydrodynamic Injection HBV Mouse Model
		2.8	 Adenovirus-Mediated Delivery
	3	 HBV In Vitro Experimental Systems
		3.1	 Primary Human Hepatocytes
		3.2	 Hepatoma Cell Lines
		3.3	 HepG2 Cells
		3.4	 HepaRG Cells
		3.5	 HepCHLine-4 Cell
		3.6	 Recombinant cccDNA
		3.7	 NTCP Expression as a Limiting Factor for HBV Infection
		3.8	 NTCP-Expressing Cell Lines.
		3.9	 Human Hepatocytes Isolated from Humanized Mice
		3.10	 Non-Cancer-Derived Immortalized Human Hepatocytes
		3.11	 Improvements to Primary Hepatocyte Culturing
		3.12	 Hepatic Cell Lines Derived from Human Induced Pluripotent Stem Cells
	4	 Conclusions
	References
3: Unmet Needs in Clinical Research Hepatitis B
	1	 Introduction
	2	 Hepatitis B Lifecycle
	3	 Improved Screening, Diagnostic Testing and Linkage to Care
	4	 Improved Strategies to Control Hepatitis B
	5	 Antiviral Treatment
		5.1	 Indications for Treatment
	6	 Therapy with Current Drugs
		6.1	 Nucleoside Analogues and PEG IFN
	7	 Cessation of Nucleoside Analogues After Long-Term Suppression
	8	 Reactivation of Hepatitis B
	9	 Scaling Up Treatment
	10	 Monitoring and Low-Intensity Monitoring
	11	 Risk Factor Analysis and Assessment of the Stage of Disease
	12	 Functional Cure of Hepatitis B
	13	 Cure of Hepatitis B
	14	 HBsAg Seroclearance Strategies
	15	 Inhibitors of HBV Replication
	16	 Augmentation and Restoration of both T and B Cell Host Immunity
	17	 Newer Biomarkers
	18	 Prevention
		18.1	 Prevention of Mother-to-Child Transmission
		18.2	 Vaccination
	19	 Awareness and communication
	20	 Conclusions
	References
4: Immunopathogenesis of Hepatitis B Virus Infection
	1	 Introduction
	2	 Acute HBV Infection
		2.1	 Innate Immunity in Acute HBV Infection
		2.2	 HBV-Specific T Cells in Acute HBV Infection
		2.3	 B Cells in Acute HBV Infection
		2.4	 Immunopathology During Acute HBV Infection
	3	 Chronic Hepatitis B
		3.1	 Innate Immune Response in Chronic HBV Infection
		3.2	 HBV-Specific T Cells in Chronic HBV Infection
		3.3	 B Cells in Chronic HBV Infection
		3.4	 Immunopathology in Chronic HBV Infection
	References
5: Pathology of Hepatitis B Virus (HBV) Infection and HBV-Related Hepatocellular Carcinoma
	1	 Pathology of Hepatitis from HBV Infection
		1.1	 Acute Hepatitis B
		1.2	 Chronic Hepatitis B
		1.3	 Post-viral Eradication
		1.4	 Immunohistochemical Stains
		1.5	 Grading and Staging in Chronic Hepatitis B
	2	 Pathologic Differential Diagnosis with Other Liver Diseases
	3	 Hepatitis B and Hepatocellular Carcinoma
	References
6: Molecular Carcinogenesis of Hepatitis B Virus-Related Hepatocellular Carcinoma
	1	 Introduction
	2	 HBV-Derived Liver Injury and Inflammation
	3	 Genome Integration of HBV DNA
	4	 Oncogenesis of the HBx Protein
		4.1	 Cancer-Related Signaling Pathways
		4.2	 Cell Cycle and Division
		4.3	 Non-coding RNAs
		4.4	 Epigenetic Regulation
		4.5	 Stemness
	5	 HBV Genotypes and Mutations
	6	 HBV-Related Molecular Subtypes of HCC
	7	 HBV-Related Cholangiocarcinoma
	8	 Prevention and Treatment
	9	 Concluding Remarks
	References
7: Epidemiology and Natural History of Hepatitis B Virus Infection: Time-Dependent Driving Factors of Chronic Hepatitis B Progression
	1	 Epidemiology of Hepatitis B Virus Infection
	2	 A Brief View of the Natural History of HBV Infection
	3	 Milestones of Progression in Chronic HBV Infection
	4	 The Serological Milestone of HBeAg Seroclearance
	5	 The Serological Milestone of HBV DNA Seroclearance
	6	 The Serological Milestone of HBsAg Seroclearance
	7	 HBeAg-Negative Chronic Hepatitis B
	8	 The Development of Cirrhosis
	9	 The Development of Hepatocellular Carcinoma
	10	 Occult Hepatitis B Infection
	References
8: Hepatitis B Vaccines
	1	 Development of Hepatitis B Vaccines for Active Immunization
		1.1	 Recombinant DNA Vaccines
		1.2	 Combination Vaccines
	2	 Development of HBIG for Passive Immunization
	3	 Vaccine Dosage, Schedule, and Duration of Protection
		3.1	 Vaccine Dosage
		3.2	 Vaccine Schedule
		3.3	 Duration of Protection
	4	 Vaccine-Associated Adverse Events
	5	 Development of New Hepatitis B Vaccines
	6	 Recommendations for Hepatitis B Vaccination
		6.1	 Infants Born to HBsAg-Positive Mothers
		6.2	 HBeAg-Positive Pregnant Women
		6.3	 Persons with Percutaneous or Sexual Exposures
	7	 Recommendations for Pre- and Post-vaccination Serologic Testing
	8	 Strategies for Increasing Hepatitis B Vaccination of Newborns
	9	 Strategies for Increasing Hepatitis B Vaccination of Children, Adolescents, and Adults
	10	 Rates of Vaccine Coverage
	11	 Impact of Vaccination
	12	 Targets and Goals for Eliminating New Cases of HBV
		12.1	 WHO Western Pacific Region
		12.2	 WHO Southeast Asia Region
		12.3	 Eastern Mediterranean Region
		12.4	 WHO European Region (EUR)
		12.5	 WHO Americas Region (AMR)
		12.6	 African Region (AFR)
	References
9: Viral and Host Factors Affecting Disease Progression of Hepatitis B Virus Infection
	1	 The Natural History and Disease Progression of Chronic Hepatitis B
	2	 Viral Factors That Affect the Disease Progression of CHB
	3	 HBV DNA Level
	4	 HBeAg Serostatus and Level
	5	 HBsAg State and Level
	6	 HBV Genotype
	7	 HBV Mutants
	8	 Quantitative HBcrAg
	9	 Serum HBV RNA
	10	 Host Factors
	11	 HLA
	12	 Total Anti-HBc Level
	13	 Fibrosis, A Key Step of Disease Progression
	14	 HCC Surveillance
	15	 Development of Risk Scores for Cirrhosis and HCC by Integration of Viral and Host Factors in CHB Patients
	16	 Conclusions
	References
10: Novel Biomarkers for the Management of Chronic Hepatitis B Virus Infection
	1	 Introduction
	2	 Viral Biomarkers for the Diagnosis and Screening of CHB
	3	 Viral Biomarkers Predictive of Disease Progression and Response to Therapy
		3.1	 HBV DNA and Quantitative HBsAg
		3.2	 Hepatitis B Core-Related Antigen
		3.3	 HBV RNA
		3.4	 Quantification of HBV Core Antibodies (Total Anti-HBc)
	4	 Novel Biomarkers for Predicting HBV-Related HCC
		4.1	 Hepatitis B Core-Related Antigen
		4.2	 Mac-2 Binding Protein Glycosylation Isomer (M2BPGi)
		4.3	 Circulating Cell-Free or Virus–Host Chimera DNA and microRNA
	5	 Conclusion
	References
11: Chronic Hepatitis B Virus Infection: Noninvasive Assessment of Liver Disease
	1	 Introduction
	2	 Noninvasive Tests of Liver Fibrosis
		2.1	 Serum Tests
			2.1.1	 Class I Biomarkers
			2.1.2	 Class II Biomarkers
		2.2	 Physical Measurements
	3	 Combination of Serum Tests and Physical Measurements of Liver Stiffness
	4	 Portal Hypertension
	5	 Hepatocellular Carcinoma and Mortality
	6	 Unresolved Questions
	7	 Conclusion
	References
12: Chronic Hepatitis B Virus Infection: Interferon Therapy and Long-Term Outcomes
	1	 Introduction
	2	 Mechanisms of Action of IFNa
	3	 Indications and Contraindications for PegIFNa
	4	 Safety OF PegIFNa
	5	 Regimens and Monitoring of PegIFNa Treatment
	6	 Goals of PegIFNa Treatment and Definitions of Response
	7	 Efficacy OF PegIFNa
		7.1	 HBeAg-Positive CHB
		7.2	 HBeAg-Negative CHB
	8	 Predictors of Response and Stopping Rules for PegIFNa
		8.1	 HBeAg-Positive CHB
		8.2	 HBeAg-Negative CHB
	9	 Combinations OF PegIFNa with Current NAs
	10	 Long-Term Outcomes after IFNa
	11	 Conclusions
	References
13: Nucleos(t)ide Therapy and Long-Term Outcomes
	1	 Nucleos(T)Ide Analogues
		1.1	 Lamivudine
		1.2	 Adefovir
		1.3	 Telbivudine
		1.4	 Entecavir
		1.5	 Tenofovir Disoproxil Fumarate (TDF)
		1.6	 Tenofovir Alafenamide
	2	 Treatment Strategies
		2.1	 Definition of Treatment Response
		2.2	 On-Treatment Monitoring
		2.3	 Treatment Failure
		2.4	 Endpoint of Treatment with NUCs
	3	 Treatment for Antiviral Resistant Cases
		3.1	 Lamivudine Resistance
		3.2	 Adefovir Resistance
		3.3	 Telbivudine Resistance
		3.4	 Entecavir Resistance
		3.5	 Tenofovir Resistance
	4	 Risk of HCC Development with Oral Antiviral Treatment
	5	 Oral Antiviral Treatments May Not Have the Same Effect of HCC Prevention
	6	 Expanding Treatment Indication Based on HBV Viral Load May Reduce HCC Incidence and Mortality
	7	 Summary and Conclusions
	References
14: Combination Therapy
	1	 Goals of Therapy and Definition of “Functional Cure” for HBV Infection
	2	 Advantages and Disadvantages of Current Anti-HBV Therapies
	3	 Combining Different NUCs as Rescue Therapy
	4	 Interferon-Based Combination Therapy
	5	 De Novo Combination Strategy
	6	 “Switch-to” Strategy
	7	 “Add-on” Strategy
	8	 Optimal Approach to Combination Therapy
	9	 Roadmap for NA and Peg-IFN Combination Treatment in NA-Treated Patients
	10	 The Mechanisms Involved in Immune Restoration Induced by Peg-IFN and NUC Combination Therapy
	11	 Novel Antiviral Strategies and Possible Combination Therapies toward a Cure of HBV Infection
	12	 Conclusions
	References
15: Treatment of HCV, HDV, or HIV Coinfections
	1	 Introduction
	2	 HBV and HIV Coinfection
		2.1	 Epidemiology of HBV and HIV Coinfection
	3	 Natural History of HBV and HIV Coinfection
		3.1	 Diagnosis and Screening
	4	 Approach to Treatment for Hepatitis B and HIV Coinfection
		4.1	 Treatment Considerations in HIV-HBV Coinfection
	5	 Hepatitis C and B Virus Coinfection
		5.1	 Epidemiology
	6	 Natural History HBV and HCV Coinfection
	7	 Indications for Antiviral Therapy
	8	 Approach to Antiviral Therapy for HBV-HCV Coinfection
		8.1	 Risk of HBV Reactivation with DAAs for HCV
	9	 Hepatitis D Virus Infection
		9.1	 Epidemiology
	10	 Natural History of HBV and HDV Infection
	11	 Diagnosis and Screening
	12	 Indications for Antiviral Therapy
	13	 Interferon Therapy
	14	 New Therapies for HDV Infection
		14.1	 Prenylation Inhibitors
		14.2	 Entry Inhibitors
		14.3	 Subviral Particle Release Inhibitors
		14.4	 Interferon Lambda
	15	 Triple Infections with Chronic HBV
		15.1	 Epidemiology and Natural History
		15.2	 Approach to Treatment
	16	 Liver Transplantation for Patient with Chronic HBV and Coinfections
	17	 Summary
	References
16: Management of Chronic Hepatitis B Virus Infection in Children and Pregnant Women
	1	 Introduction
	2	 Management of Children with Chronic Hepatitis B
		2.1	 Identifying Infected Children
			2.1.1	 Postvaccination Serologic testing in High-Risk Infants
			2.1.2	 Screening Immune-Compromised Patients
			2.1.3	 Other Risk Groups
		2.2	 Antiviral Therapy in Children with Chronic Hepatitis B Virus Infection
			2.2.1	 Natural History of CHB Infection and its Clinical Implication in Children
			2.2.2	 Current Treatment for Children with Chronic Hepatitis B (Table 16.1)
			2.2.3	 Who, When, and How to Treat Children with Chronic HBV Infection?
			2.2.4	 HCC surveillance in Children with Chronic HBV Infection
	3	 Management of Pregnant Women with HBV Infection
		3.1	 Acute Hepatitis B in Pregnancy
		3.2	 Chronic Hepatitis B Virus infection in Pregnancy
			3.2.1	 Effect of Pregnancy on Maternal Chronic HBV Infection
			3.2.2	 Effect of Chronic HBV Infection on Pregnancy Outcomes
		3.3	 Management of Pregnant Women with Chronic HBV Infection
			3.3.1	 Managing Women Who Become Pregnant when under Antiviral Therapy for CHB
			3.3.2	 Indications for Initiating Antiviral Therapy during Pregnancy
		3.4	 Antiviral Therapy to Reduce Mother-to-Infant-Transmission of HBV
			3.4.1	 Risk of Transmission
			3.4.2	 Risk Factors of Mother-to-Infant Transmission
			3.4.3	 Algorithm to Prevent Mother-to-Infant Transmission (Fig. 16.2)
			3.4.4	 Choice of Antiviral Agents
			3.4.5	 Efficacy and Safety of Antiviral therapy in Preventing MTIT of HBV
			3.4.6	 Postpartum Cessation of AVT
			3.4.7	 Breastfeeding during Maternal Antiviral Therapy
	4	 Conclusions and Future Scope
	References
17: Occult Hepatitis B Infection
	1	 Introduction
	2	 Classifications of OBI Patients
	3	 Diagnosis
	4	 Epidemiology of OBI
	5	 Prevalence of OBI in the East
	6	 Prevalence of OBI in the West
	7	 Prevalence of OBI in Different Clinical Situations
	8	 Clinical Implications
		8.1	 Transmission of HBV through OBI
	9	 HCC Development
	10	 HBV Reactivation after Immunosuppressant
	11	 Reactivation of HBV in Chronic Hepatitis C Patients Receiving DAA Therapy
	12	 Conclusion
	References
18: Hepatitis B Virus Reactivation and Management of Patients Undergoing Immunosuppression
	1	 Introduction
	2	 Definition of HBR
	3	 Clinical Manifestations of HBR
	4	 Mechanisms of HBR
		4.1	 Corticosteroids
		4.2	 B Cell Depleting Agents
		4.3	 Cytotoxic Chemotherapeutic and Immunosuppressant Agents
		4.4	 Biological Immunomodulants
		4.5	 Kinase Inhibitors and Proteasome Inhibitors
		4.6	 Immune Checkpoint Inhibitors
		4.7	 Chimeric Antigen Receptor T Cell Therapy
	5	 Incidence of HBR
		5.1	 Patients Undergoing Cancer Chemotherapy
		5.2	 Patients Undergoing Treatment with Other Biologics
		5.3	 Patients Undergoing Organ/Cell Transplantation
			5.3.1	 Hematopoietic Stem Cell Transplantation
		5.4	 Solid Organ Transplantation
	6	 Risk Assessment for HBR
	7	 Management Strategies for HBR
		7.1	 Screening and Risk Stratification
		7.2	 Antiviral Prophylaxis Algorithm
		7.3	 Treatment of Established HBR
		7.4	 Management of Transplant Recipients
	8	 HBR after Successful Treatment of Hepatitis C
	9	 Current Challenges and Future Directions
	References
19: Novel Therapy for Functional Cure of Chronic Hepatitis B Virus Infection
	1	 Introduction
	2	 Functional Cure: Definition and Implications
	3	 Novel Therapeutic Approaches
		3.1	 Induction of “Good Flare” by Cessation of Long-Term NRTI
		3.2	 Inhibition of Alternative Steps of Viral Replication
			3.2.1	 Inhibition of Viral Entry
			3.2.2	 Interference of RNA
			3.2.3	 Inhibition of Capsid Assembly or Encapsidation
			3.2.4	 Inhibition of Viral Protein Export
		3.3	 Enhancement of Host Immunity
			3.3.1	 Toll-Like Receptor Agonist
			3.3.2	 Enhancing T Cell Function
			3.3.3	 Therapeutic Vaccine
	4	 Other Mechanisms
	5	 Conclusion
	References
20: Is Cure of Hepatitis B Infection a Mission Possible?
	1	 Introduction
	2	 Definition of HBV Cure
	3	 HBV Life Cycle and Barriers to Cure
	4	 Efficacy of Current Therapy in Achieving Functional Cure
	5	 HBV New Drug Development
	6	 Path to HBV Functional Cure
	7	 Challenges in Developing New HBV Treatments
	8	 Future Perspective
	References
Index