Chronic Viral Hepatitis (eBook)

Preface 6
Contents 7
Contributors 9
Molecular Virology of Hepatitis B and C: Clinical Implications 11
1 Introduction 11
2 Hepatitis B Virus 12
2.1 Structure of HBV 13
2.2 Replication Cycle 13
2.3 Cellular Entry 14
2.4 cccDNA 15
2.5 Transcription 16
2.6 Translation 17
2.7 Encapsidation and Reverse Transcription 17
2.8 Integration 18
2.9 X Protein and Hepatocarcinogenesis 19
2.10 Virion Production 21
2.11 Immune System Evasion 22
2.12 Viral Mutation 22
2.13 Immune-Escape Mutants 23
2.14 Polymerase Mutants 25
3 Hepatitis C Virus 26
3.1 Replication Cycle and Experimental Systems 27
3.2 Viral Entry 29
3.3 Translation 30
3.4 Protein Processing 31
3.5 Immune System Evasion 33
3.6 Inhibition of the Intracellular Antiviral Response 34
3.7 HCV Proteins and Hepatocarcinogenesis 35
3.8 RNA Replication 36
3.9 Assembly and Secretion 38
4 Conclusion: Future Treatment Strategies 39
5 Acknowledgments 39
References 39
Epidemiology, Risk Factors, and Natural History of ChronicHepatitis C 42
1 Epidemiology 43
1.1 Global Prevalence and Incidence 43
1.2 United States Prevalence and Incidence 44
1.3 Genotype 46
2 Risk Factors 47
2.1 Intravenous Drug Use 49
2.2 Blood Products 50
2.3 High-Risk Sexual Activity 50
2.4 Intrafamilial and Monogamous Sexual Transmission 51
2.5 Mother to Infant Transmission 53
2.6 Breastfeeding 54
2.7 Hemodialysis 54
2.8 Intranasal Drug Use 55
2.9 Tattoos 56
2.10 Health Care Setting 56
3 Natural History Of HCV 57
3.1 Chronic Hepatitis C 57
3.2 Cirrhosis, Hepatocellular Cancer, and Liver-Related Death 58
3.2.1 Study Design 59
3.2.2 Host-Related Factors 63
3.2.3 Virus-Related Factors 66
4 Conclusions 68
References 69
Current and Future Therapy of Chronic Hepatitis C 80
1 Introduction 43
2 Current Standard of Care 81
2.1 Current Agents 82
2.2 Optimizing Treatment Regimens 44
2.3 Patient Selection, Drug Administration, and Monitoring Therapy 46
2.4 Assessing Treatment Response 92
3 Treatment of Specific Patient Groups 92
3.1 Fibrosis or Cirrhosis 50
3.2 African-Americans 50
3.3 HIV--HCV Coinfection 51
3.4 Obesity and Fatty Liver Disease 53
3.5 Extrahepatic Manifestations 54
3.6 Post-transplantation 54
3.7 Viral Non-Responders 55
4 Therapeutics Agent in Development 98
References 69
Hepatitis C in Special Populations 106
1 Introduction 43
2 Co-Infection with Human Immunodeficiency Virus (HIV) 81
2.1 Prevalence and Epidemiology 82
2.2 Natural History 44
2.3 Treatment of Co-infection 46
3 Co-Infection with Hepatitis B (HBV) 47
4 Ethnic Variations in HCV 92
4.1 Latinos and African Americans 3 50
5 HCV and Insulin Resistance/Diabetes 124
6 HCV in Chronic Kidney Diseases (CKD) 127
7 Conclusions 129
References 69
Extrahepatic Manifestations of Chronic Hepatitis C Infection 144
1 Introduction 145
2 Spectrum of Extrahepatic Manifestations 147
2.1 Vascular 147
2.2 Lymphoproliferative Disorders 148
2.3 Renal 149
2.4 Dermatological 150
2.5 Endocrine 152
2.6 Rheumatologic 153
2.7 Neurological 155
2.8 Pulmonary 156
2.9 Cardiac 157
3 Conclusions 157
References 157
Anti-HCV Agents in Development 167
1 Introduction 145
2 Life Cycle and Structure of HCV 147
3 Current Therapy of Chronic HCV Infection 171
4 Refinement of Current Therapy 172
4.1 Novel Interferons 149
4.2 Alternatives to Ribavirin 150
5 Specifically Targeted Antiviral Therapy (STAT-C) 174
5.1 Protease Inhibitors 153
5.2 Polymerase Inhibitors 155
5.3 Anti-HCV Nucleic Acids 156
6 Drugs Targeting the Host Cell 181
7 Nonspecific Immunomodulators 157
8 Hepatitis C Virus Vaccination 182
9 Conclusion 183
References 157
Epidemiology, Screening, and Natural History of Chronic Hepatitis B Infection 192
1 Introduction 193
2 Epidemiology 193
2.1 Global Patterns of HBV Infection 193
2.2 Patterns of HBV Infection in Specific Areas 194
2.2.1 Africa 194
2.2.2 United States of America 196
2.2.3 Latin America 198
2.2.4 Western Pacific and Southeast Asia 199
2.2.5 China (Mainland) 200
2.2.6 Taiwan 201
2.2.7 India 201
2.2.8 Middle East 203
2.2.9 Europe 203
2.3 Patterns of HBV Transmission 204
2.3.1 Specific Modes of Transmission 204
2.4 Effect of Vaccination on the Epidemiology of Chronic Hepatitis B 209
2.5 Epidemiology of Special Situations 212
2.5.1 HBV HCV Coinfection 212
2.5.2 HBV-HIV Coinfection 213
2.5.3 Epidemiology of Occult HBV 213
2.6 Molecular Epidemiology 214
2.6.1 Double Infections and Recombinants 217
3 Screening High-Risk Populations to Identify HBV-Infected Persons 217
4 Natural History of Chronic HBV Infection 219
4.1 Phases of Chronic HBV Infection Following Vertical Transmission 219
4.1.1 Immune-Tolerant Phase 219
4.1.2 Immune-Reactive Phase 220
4.1.3 Low-Replicative Phase 221
4.1.4 Reactivation Phase 222
4.2 Phases of Chronic HBV Infection Following Horizontal Transmission 223
4.3 Predictors of Disease Progression in Chronic HBV Infection 223
4.3.1 Chronic HBV Infection and Cirrhosis 223
4.3.2 Chronic HBV Infection and HCC 224
4.3.3 HBV DNA Levels and Disease Progression 225
4.3.4 ALT Levels and Disease Progression 226
4.3.5 HBV DNA Levels in Patients with Normal ALT 227
4.3.6 Histology in Patients with Normal ALT 227
4.3.7 Interventions to Modify the Natural History of Chronic HBV Infection 229
4.4 Natural History of HBV- and HCV-Coinfected Patients 229
4.5 Natural History of Chronic Hepatitis B in HIV-Coinfected Patients 231
4.6 Natural History of Occult HBV Infection 233
5 Summary and Future Directives 235
References 235
Current Treatment of Chronic Hepatitis B 249
1 Introduction 193
2 Natural History 193
3 Indications for Treatment 253
4 Approved Drugs for Treatment of Chronic Hepatitis B 254
4.1 Peginterferon Alfa-2a 255
4.2 Lamivudine 256
4.3 Adefovir Dipivoxil 256
4.4 Entecavir 257
4.5 Telbivudine 257
4.6 Tenofovir 258
5 Drugs in Development for Treatment of Chronic Hepatitis B 258
6 New Treatment Strategies 258
6.1 Combination Therapy 258
7 Roadmap Concept for on-Treatment Management 259
8 Conclusion 260
References 235
Management of Patients Co-Infected with ChronicHepatitis B (CHB) and the Human Immunodeficiency Virus (HIV) 264
1 Introduction 265
2 Epidemiology 265
3 Natural History 266
3.1 Influence of HBV on Outcome of HIV Disease 266
3.2 Influence of HIV on Outcome of HBV Disease 266
3.3 Elevated Serum ALT Levels During HAART Therapy in HBV/HIV Co-infection 267
4 Management 268
4.1 Prevention 268
4.2 Therapy 268
4.2.1 Goals 268
4.2.2 Who and When to Treat HBV 268
4.2.3 Treatment Medications 269
4.3 Interferon 269
4.4 Lamivudine 270
4.5 Adefovir 270
4.6 Entecavir 270
4.7 Tenofovir 271
4.8 Which Regimen to Use? 271
4.9 Patients Who Do Not Require Treatment for HIV 272
4.10 Patients Who Require Therapy for HIV and HBV 273
4.11 Patients Who Require Treatment for HIV but not HBV 273
4.12 When to Stop Therapy? 273
4.13 Management of End-Stage Liver Disease in Co-Infection 274
4.13.1 Liver Transplantation 274
References 274
Management of Antiviral Resistance in Chronic Hepatitis B 278
1 Introduction 279
2 Why Does Antiviral Resistance Develop? 279
3 Nomenclature of Antiviral Drug Resistance 280
3.1 Primary Antiviral Treatment Failure (or Primary Non-Response) 280
3.2 Secondary Antiviral Treatment Failure (or Virological Breakthrough) 281
3.3 Biochemical Breakthrough 281
3.4 Genotypic Resistance 281
3.5 Phenotypic Resistance 281
3.6 Recognition of Antiviral Resistance 281
4 Rates of Resistance to Approved Agents 282
4.1 l -Nucleosides 282
4.2 Acyclic Phosphonates 283
4.3 Cyclopentane Group 284
5 Clinical Consequences of Antiviral Resistance 284
6 Management of Antiviral Resistance 285
6.1 Options for Management of Antiviral Resistance 286
7 Prevention of Antiviral Resistance 288
References 289
Herbal and Non-Traditional Therapies for Viral Hepatitis 293
1 Economics of Complimentary Alternative Medicine 294
2 Burden of Viral Hepatitis 295
3 Selected Herbal Therapies 296
3.1 Silymarin 296
3.1.1 Silymarin Use in Hepatitis C 297
3.1.2 Silymarin Use in Hepatitis B 297
3.2 Glycyrrhizin 298
3.3 Phyllanthus amarus 298
3.4 TJ-9 (Xiao-Chai-Hutang/Sho-Saiko-To) 299
3.5 St. John's Wort 300
3.6 Plantago Asiatic 300
3.7 Herbal Medicine 861 300
3.8 CH-100 301
3.9 Liv 52 301
4 Antioxidants and Dietary Supplements 301
4.1 N-Acetyl Cysteine (NAC) 302
4.2 S-Adenosylmethionine (SAM) 302
4.2.1 Acupuncture 302
5 Discussion 302
References 305
Hepatitis B Reactivation in the Setting of Chemotherapy and Immunosuppression 310
1 Introduction 311
2 History of Hepatitis B Reactivation 312
3 Incidence/Prevalence of Hepatitis B Reactivation 313
4 Risk Factors for Reactivation 314
4.1 A. Host Risk Factors for HBV Reactivation 315
4.2 Role of Chemotherapeutic Agents/Steroids/Immunosuppressants 317
4.3 Occult HBV 318
5 Pathophysiology of Reactivation 318
6 Clinical Manifestations of Hepatitis B Reactivation 319
7 Screening of Patients Prior to Chemotherapy or Immunosuppression 321
8 Immunization Against Hepatitis B 322
9 Management of Established HBV Reactivation 322
10 Preemptive Antiviral Therapy Against HBV Reactivation 324
11 Cost-Effectiveness of Preemptive Therapy 327
12 Awareness of HBV Reactivation Among Oncologists 328
13 Addendum 328
References 329
Support of Patients During Antiviral Therapyfor Hepatitis B and C 340
1 Introduction 341
2 Chronic Hepatitis C 341
2.1 Hematologic Side Effects 342
2.1.1 Anemia 342
2.1.2 Thrombocytopenia 343
2.1.3 Neutropenia 344
2.2 Psychiatric Side Effects 345
2.3 Ophthalmologic Side Effects 346
2.4 Pulmonary Side Effects 346
2.5 Endocrine Side Effects 347
2.6 Dermatologic Side Effects 348
2.7 General Side Effects 348
3 Hepatitis B 349
3.1 Standard Interferon Alfa-2b or Pegylated Interferon Alfa-2a 349
3.2 Lamivudine 350
3.3 Adefovir Dipivoxil 350
3.4 Entecavir 351
3.5 Telbivudine 351
3.6 Tenofovir 351
4 Conclusion 352
References 352
Viral Hepatitis, A Through E, In Pregnancy 355
1 Introduction 356
2 Effect of Pregnancy on Liver Function 357
3 Viral Hepatitis in Pregnancy 357
3.1 Hepatitis A 358
3.2 Hepatitis E 360
3.3 Hepatitis B 362
3.3.1 Perinatal Transmission 362
3.3.2 Prophylaxis to Prevent Perinatal Transmission 362
3.3.3 Screening of Pregnant Women 363
3.3.4 Postexposure Prophylaxis During Pregnancy 363
3.3.5 Maternal Outcome in Pregnancy 364
3.3.6 Treatment of HBV in Pregnancy 364
3.4 Hepatitis D (Delta) 366
3.5 Hepatitis C 367
3.5.1 Screening of Pregnant Women 367
3.5.2 Vertical Transmission of HCV 367
4 Conclusions 369
References 370
Chronic Viral Hepatitis and Liver Transplantation 376
1 Introduction 377
2 Liver Transplantation for Viral Hepatitis B 378
3 Post-LT HBV Recurrence 378
3.1 Mechanisms of Recurrent Hepatitis B 378
3.2 Patterns of Recurrent Hepatitis B 379
3.3 Factors Affecting HBV Recurrence 379
4 Antiviral Therapy 380
4.1 Treatment Prior to LT 380
4.2 Management of Hepatitis B in Liver Transplant Recipients 383
4.2.1 Prevention of Hepatitis B Following Liver Transplantation 383
4.2.2 Treatment of Recurrent Hepatitis B Post-LT 387
5 Liver Transplantation for Viral Hepatitis C 387
6 Post-LT Recurrence of HCV 388
6.1 Natural History of Recurrent Hepatitis C 388
6.2 Kinetics of Post-Transplant HCV Infection 388
6.3 Patterns of Recurrent hepatitis C 388
6.4 Factors Affecting HCV Recurrence 389
7 Antiviral Therapy 391
7.1 Prior to LT (Pre-Transplant Antiviral Therapy) 391
7.2 Treatment of LT Recipients 392
7.3 IFN and the Risk of Rejection in Liver Transplant Recipients 394
8 The Use of Virologically Compromised Organs in Liver Transplantation 395
8.1 Use of HCV-Infected Grafts 395
8.2 Use of Anti-Hepatitis B Core (Anti-HBc-Positive) Grafts 395
9 Liver Transplantation in HIV Coinfected Individuals 396
10 Conclusions 396
References 397
Treatment of Viral Hepatitis in Children 2008 405
1 Hepatitis B: Introduction 406
2 Natural History 407
3 Screening and Prevention 408
4 Treatment 409
5 Immunomodulatory Therapy 410
5.1 Interferons 410
5.2 Limitations 413
5.3 Oral Antiviral Agents 413
5.4 Lamivudine 413
5.5 Combination Therapy 414
5.6 Limitations 415
5.7 Adefovir 415
5.8 Newer Therapy 416
6 Summary and Recommendations 416
7 Hepatitis C: Introduction 416
8 Natural History 417
9 Screening and Prevention 418
10 Treatment 419
10.1 Interferon Alpha 420
10.2 Interferon-Alpha and Ribavirin 421
10.3 Pegylated Interferon (PEG-IFN) Monotherapy 422
10.4 Peginterferon and Ribavirin Combination Therapy 423
10.5 Newer Therapies 424
10.6 Considerations and Recommendations 424
References 425
Viral Hepatitis and Hepatocellular Carcinoma 430
1 Introduction 406
2 Epidemiology 407
2.1 General 431
2.2 Viral Factors 431
2.3 Non-Viral Factors 434
3 Diagnostic Evaluation 434
3.1 Surveillance 413
3.2 Diagnosis 413
4 Treatment 437
4.1 Staging 414
4.2 Treatment 415
4.2.1 Very Early Stage 438
4.2.2 Early Stage HCC 439
4.3 Intermediate Stage 440
4.4 Advanced Stage 440
4.5 Terminal Stage 441
5 Prevention 418
5.1 Hepatitis B 441
5.2 Hepatitis C 420
References 425
Hepatitis B Vaccines 447
1 Introduction 406
2 Structure and Genomic Organization of The Hepatitis B Virus Envelope Proteins Relevant to Vaccine Development 407
3 Role of The Immune Response Against HBV Envelope Proteins in Long-Term Protection Against HBV 408
4 Transmission of HBV Infection 409
5 History of HBV Vaccination 410
6 Immunogenicity and Efficacy of Hepatitis B Vaccines 434
7 Hepatitis B Virus Mutants Following Immunization Against HBV 454
8 Mode of Administration 455
9 Interchangeability of Vaccines 437
10 Strategies of Immunization andWorldwide Impact 456
11 Safety and Tolerability of HBV Vaccines 458
12 Rationale for Immunization of Special Populations at Risk 458
13 Non-Responders to Conventional Vaccination 459
14 Recipients of Bone Marrow and Peripheral Stem-Cell Transplantation 416
15 Contraindications 416
16 The Future of HBV Vaccines 417
17 Summary 418
References 425
T-Cell-Mediated Immunity and Immunotherapy of Chronic Hepatitis C 469
1 Introduction 470
2 T-Cell-Mediated Immune Responses To HCV Infection 471
3 General Overview of T-Cell-Mediated Immunity 472
3.1 Cells of the Immune System 473
3.2 Humoral Immunity in Response to Exogenous (Extracellular) Antigens 476
3.3 Cellular Immunity in Response to Endogenous (Intracellular) Antigens 476
3.4 Th1 vs. Th2 Cells: Cell-Mediated vs. Antibody-Mediated Immunity 477
3.5 Regulatory T Cells 478
4 Immunotherapeutic Vaccines and Concepts 479
4.1 Conventional Vaccine Approaches 479
4.2 Recombinant DNA and Virus-based Vaccine Approaches 481
4.3 Vaccine Approaches that Target Pattern Recognition Receptors 481
5 Goals and Evaluation of Immunotherapy in Chronic HCV Infection 483
6 Summary 484
References 485
Index 489