تعاملات ویروس هپاتیت C و میزبان و درمان‌ها: بینش‌های کنونی و چشم‌اندازهای آینده

The burden of hepatitis C virus (HCV) infection on the public health care system continues to remain significant despite the remarkable progress made in HCV therapeutics in the recent past. There are now almost a dozen oral interferon-free direct-acting antivirals available for the treatment of hepatitis C virus infection. Despite advances in the treatment of HCV, therapeutic gaps remain that are yet to be fully explored. Researchers and scientists still strive to understand virus-host interactions to map the disease’s progression along with extrahepatic manifestations and virus invasion strategies impacting the host’s immune system. This book briefly discusses the biology of HCV infection, virus-host interactions, molecular epidemiology of the infection, and the full spectrum of immune responses to hepatitis C. It also provides in-depth information about HCV, clinical diagnostics, and therapeutic knowledge to all stakeholders involved in HCV screening, diagnosis, treatment, and management. Topics covered in the chapters include 1) HCV-host interactions leading to asymptomatic acute infection, 2) the progression of acute HCV infection to chronic disease and subsequent extrahepatic comorbidities, 3) Innate and adaptive immune responses in HCV infections, 4) Consensus-based Approaches for Hepatitis C Screening and Diagnosis, 5) advances in hepatitis C therapy and global management of HCV, and 6) the outcomes of Oral Interferon-free Direct-acting Antivirals as Combination Therapies to Cure Hepatitis C. This book is a valuable addition to undergraduate and postgraduate hepatology students and physicians, clinicians, hepatologists, and health care officials involved in HCV clinical diagnosis and therapeutics. Cover Title Copyright End User License Agreement Contents Foreword Preface CONSENT FOR PUBLICATION CONFLICT OF INTEREST ACKNOWLEDGEMENT Dedication HCV-Host Interactions: A Plethora of Genes and their Intricate Interplay Part 1: Virus Specific Factors INTRODUCTION Hepatitis C Virus Taxonomy HCV: Route of Transmission HCV Genome Organization HCV MOLECULAR BIOLOGY HCV MOLECULAR VIROLOGY HEPATITIS C PROTEINS IN MOLECULAR PATHOGENESIS OF INFECTION 5’ Untranslated Region (5’ UTR) HCV Antigen (Core;C) Protein HCV Core Protein Morphology HCV Core Protein and Hepatic Steatosis HCV Core Protein and Hepatocarcinogenesis HCV Core Protein and Insulin Resistance (IR) HCV Envelope Glycoproteins (E1 and E2) HCV E1 and E2 Morphology HVR1 of E2 Glycoprotein Modulates the Immune System HCV NONSTRUCTURAL PROTEINS AND THEIR ROLE IN HEPATITIS C PATHOGENESIS NS2 Metalloprotease NS3/4A Serine Protease/Helicase NS4B NS5A: An Interferon Resistance Protein NS5B: RNA Dependent RNA Polymerase (RdRp) 3’ UTR CONCLUSIONS REFERENCES HCV-Host Interactions: Interplay Part 2: Host Related Determinants and Intracellular Signaling INTRODUCTION CERTAIN HOST SPECIFIC FACTORS ARE VITAL FOR HCV REPLICATION PPP2R5D (Protein Phosphatase 2 Regulatory Subunit B'Delta) Protein Micro RNAs (miRNA) miR-122: A Key Regulator of HCV Replication in Hepatocytes miR-135a Drives Chronic Hepatitis C Infection to HCC Cytokines Gene Polymorphisms in Chronic Hepatitis C Patients The Importance of Cytokines against Viral Infections Cytokine Gene Polymorphism for IL-10 Cytokine Gene Polymorphism for IL-13 Gene Polymorphisms of Tumor Necrosis Factor-alpha (TNF-α) Role of Cytokine Storm in HBV Reactivation in HBV/HCV Coinfections Genetic Polymorphism in Host Genetic Factors of HIV-1/HCV Coinfected Patients Progress Toward Advanced Hepatic Fibrosis Genetic Polymorphisms of Interferon Lambda (IFNL 3/4) Genes in HCV Patients and its Clinical Significance DIFFERENTIAL EXPRESSION OF HOST CELLS LIPID METABOLISM REGULATORS IMPACT HEPATITIS C INFECTION PROGRESSION ANGPTL-3 and -4: Potent Regulators of Lipid Metabolism in Hepatocytes ANGPTLs Linked to HCV Induced Hepatic Fibrosis and Tumorigenesis ANGPTL Expression in Various Stages of Hepatic Fibrosis ANGPTL-3/4 Interacts With TGF-β to Promote Hepatic Fibrosis and Cirrhosis VITAMIN D AND HCV INDUCED HEPATOCELLULAR CARCINOMA INTRACELLULAR SIGNALING MODULATION IN HEPATITIS C INFECTION TLR Activation and their Implications in HCV Molecular Pathogenesis TNF/TNF Receptor Activation in CHC Patients FAS/FASL Activation in CHC Patients NF-ƙB Cell Signaling and HCV Progression CONCLUSIONS REFERENCES Immune Responses and Immunopathology of Acute and Chronic Hepatitis C Virus Infection INTRODUCTION THE TYPICAL TIMELINE OF HEPATITIS C VIRUS INFECTION INNATE AND ADAPTIVE IMMUNE RESPONSES AGAINST HEPATITIS C Activation of Innate Immune Responses and their Implications Against HCV Replication In Vitro Innate Immune Responses Against Hepatitis C In Vivo Activation of Innate Immune Responses Against Hepatitis C Antibodies Against HCV Infection IFN Responses in CHC Infection How HCV Evades Innate Immune Responses Adaptive Immune Responses in Hepatitis C Infection Activation of T-helper and T-cytotoxic Immune Cells Immunopathology of HCV Infection and T-cell Immune Responses THE ROLE OF VIRAL PROTEINS IN HCV IMMUNOPATHOLOGY T-cell Exhaustion SOME PRETTY MIND-BOGGLING ASPECTS OF HCV IMMUNOLOGY PROPHYLACTIC HCV VACCINES CONCLUSIONS REFERENCES Consensus-based Approaches for Hepatitis C Screening and Diagnosis in General and Vulnerable Populations INTRODUCTION GRADING OF EVIDENCE AND RECOMMENDATION RECOMMENDATIONS BEFORE SCREENING AND DIAGNOSIS OF HEPATITIS C VIRUS Key Points Cohort-Based Screening Risk-Based Screening Pregnancy and Hepatitis C Screening Post-partum Patient and Hepatitis C Screening Annual HCV Screening Screening for Occupational or Other HCV Exposure Screening for at-risk Adolescents and Young Adults Screening for Acute HCV Infection Diagnosing HCV Infection Vulnerable Population Groups to be Considered for Targeted Hepatitis C Screening with Suggested Diagnostic Algorithms CURRENT PARADIGMS OF HEPATITIS C SCREENING AND DIAGNOSIS BASICS OF HEPATITIS C SCREENING AND DIAGNOSIS Step 1: Hepatitis C Screening Anti-HCV Antibody Screening Step 2: Hepatitis C Diagnosis Confirmation Tests HCV RNA or HCV Core Ag (cAg) Confirmation HCV GENOTYPING/SUBTYPING HCV LIVER DISEASE STAGING ASSESSMENT Liver Fibrosis Detection Recommendations Liver Fibrosis Evaluation Tests Liver Cirrhosis Evaluation Liver Cirrhosis Evaluation Tests WHY ARE WE IN NEED OF SCREENING MORE PATIENTS FOR HEPATITIS C? Current CDC Guidelines Miss 25% of Hepatitis C Infections Hepatitis C Prevalence in Women of Reproductive Age (WORA) Low HCV Screening Rates Among Children Exposed to Pregnancy HCV Infections Among Infants are Vastly Underreported Hepatitis C And Drug Abuse Often Go Hand in Hand, but HCV Screening Lags HCV Diagnostic and Treatment Costs Would Always be a Crosscutting Barrier for HCV Affected IDUs Occurrence of New Hepatitis C Incidences in Public Services Screening Liver Cancer on the Rise in Backdrop of Undiagnosed Hepatitis C Birth Cohort Screening for Hepatitis C To Increase Quality-adjusted Life Years (QALY) in Hepatitis C Infected Individuals Screen All New Cancer Patients for Hepatitis C Hepatitis C Screening Could Prevent Complications in Cancer patients To Minimize the Steps to Hepatitis C Cascade of Care CONCLUSIONS REFERENCES The Current Paradigms of Hepatitis C Diagnosis and Innovations in the Pipeline INTRODUCTION HCV Serology and RNA Detection Hepatitis C Virus Rapid Diagnostics Tests (HCV-RDTs) Hepatitis C Point-of-Care Testing (HCV-POCT) Hepatitis C Core (C) Antigen Detection Assay Nanocomposites as Hepatitis C Diagnostic Approach Hepatitis C Detection in Dried Blood Spot (DBS) Samples Multi-disease Analyzers REAL-WORLD CHALLENGES TO IMPLEMENT CURRENT HEPATITIS C DIAGNOSTICS AND PLAUSIBLE SOLUTIONS Millions of HCV Infected are Still Undiagnosed A Need for Short Turnaround Time Diagnostic Platforms for Mass HCV Screening Campaigns Costs of HCV Screening and Diagnostic Platforms in LMICs HCV RNA POC Test With Good Accuracy in Real-world Clinical Practice HCV-antigens EIA Detects Viremic Hepatitis C Virus Infection HCV Core Antigen Could be Cost-Saving Alternative for Diagnosing Hepatitis C Quick Portable Test Could Widen Reach of HCV Diagnosis CONCLUSIONS REFERENCES Current Landscape of HCV Therapeutics INTRODUCTION MECHANISM OF ACTION OF DAAS NS3/4A Protease Inhibitors (NS3/4A PIs) NS5A Inhibitors NS5B RNA-dependent RNA Polymerase Inhibitors PANGENOTYPIC DAA REGIMENS GOALS OF HCV TREATMENT HCV GT-1 TREATMENT HCV GT-2 TREATMENT HCV GT-3 TREATMENT HCV GT-4 TREATMENT HCV GT-5 TREATMENT HCV GT-6 TREATMENT RECENT ADVANCES IN THE DEVELOPMENT OF NEW DAAS CONCLUSIONS REFERENCES Consensus Treatment Guidelines and Recommendations to Treat Hepatitis-C Infected Populations INTRODUCTION MEDICAL HISTORY AND PHYSICAL EXAMINATION CIRRHOSIS EVALUATION BEFORE INITIATING HCV TREATMENT EVALUATION OF COMORBIDITIES STATUS IN HCV PATIENTS BEFORE INITIATING TREATMENT DAAS RECOMMENDATIONS IN HCV INFECTED PREGNANT WOMEN GENERALLY ACCEPTED INDICATORS FOR HEPATITIS C TREATMENT CONTRAINDICATIONS FOR HEPATITIS C TREATMENT Absolute Contraindications Relative Contraindications WHO TO ASSESS FOR TREATMENT Acute HCV Infection Keypoints for Acute HCV Treatment Chronic HCV Infection Referral to a Liver Specialist for Treatment Initiation KEY POINTS FOR PHYSICIANS, CLINICIANS, AND PATIENTS WHILE STARTING HCV TREATMENT Overall Considerations Contraindications MONITORING DURING DAA TREATMENT Monitoring for DAAs Treatment Efficacy Lower Limit of Quantification (LLOQ) Limit of Detection (LOD) Target Detected (TD) Target Not Detected (TND) RECOMMENDED SCHEDULE FOR HCV RNA MONITORING On-Treatment HCV RNA Monitoring On-Treatment Persistent Low-Level Viremia Determining Sustained Virologic Response MONITORING FOR SAFETY DURING TREATMENT Baseline Safety Laboratory Studies Monitoring of Patients Taking RBV Safety Laboratory Studies at Week 4 of Therapy Management of Abnormal ALT During Therapy A 10-fold or Greater Increase in ALT Levels Clinical Symptoms and Increase in ALT Levels of Less than 10-Fold Asymptomatic Infection and Increases in ALT Levels Less than 10-Fold HEPATITIS B REACTIVATION ASSOCIATED WITH HCV DAA THERAPY POST-TREATMENT CARE Approach to Monitoring After Receiving HCV Therapy Individuals with Minimal to Moderate Fibrosis (F0-F2) Individuals with Advanced Fibrosis (F3-F4) Individuals with Persistently Abnormal Liver Tests Persons with Ongoing Risk of HCV Reinfection Monitoring of Persons Who Do Not Achieve SVR All Individuals Persons with Advanced Fibrosis (F3-F4) CONCLUSIONS REFERENCES Treatment Recommendations for Harder-to-Cure and Vulnerable Populations INTRODUCTION HCV Treatment in Patients with Compensated or Decompensated Cirrhosis Compensated Cirrhosis Decompensated Cirrhosis HCV TREATMENT IN PATIENTS WITH COMPENSATED CIRRHOSIS HCV TREATMENT IN PATIENTS WITH DECOMPENSATED CIRRHOSIS HCV TREATMENT IN PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC) HCC TREATMENT FOR LIVER AND OTHER SOLID ORGAN TRANSPLANTATION TREATMENT FOR RECIPIENTS OF AN HCV VIREMIC ORGAN TREATMENT FOR HCV/HIV CO-INFECTED PATIENTS TREATMENT FOR HBV/HCV DUAL INFECTION TREATMENT OF HCV IN PATIENTS WITH RENAL IMPAIRMENT Chronic Kidney Disease (CKD) Glomerular Filtration Rate (GFR) Creatinine Clearance (CrCl) Staging of Kidney Disease DAAS DOSE ADJUSTMENTS IN HCV/CKD PATIENTS RIBAVIRIN DOSING IN PATIENTS WITH HCV/CKD CO-INFECTIONS HCV TREATMENT IN PATIENTS WITH RENAL TRANSPLANTATION TREATMENT OF HCV IN PATIENTS WITH SUBSTANCE USE DISORDERS TREATMENT OF HCV IN CORRECTIONAL SETTINGS TREATMENT OF ACUTE HEPATITIS C INFECTION HCV TREATMENT FOR HEALTH CARE PROFESSIONALS WITH OCCUPATIONAL EXPOSURE REGIMENS FOR RETREATMENT OF HCV IN TREATMENT-EXPERIENCED PATIENTS HAVING FAILURE WITH DAAS HCV TREATMENT FOR CHILDREN AND ADOLESCENTS HCV TREATMENT IN PREGNANCY CONCLUSIONS REFERENCES Real-World Therapeutic Outcomes of Direct-Acting Antiviral Regimens and Formidable Challenges INTRODUCTION FORMIDABLE CHALLENGES TO DAAS THERAPY IN REAL-LIFE CLINICAL SETTINGS DAAs Cost DAAs Were Quite Expensive a Few Years Ago DAAs are Now Cheap but Accessibility is Still an Issue in Many LMICs and Even in Resource Replete Nations DAAs are State-of-the-Art Regimens but Drug Innovation is Slow Availability, Accessibility, and Affordability of DAAs in LMICs and Resource-Rich Nations DAAs Associated Adverse Events and Potential Drug-Drug Interactions (DDIs) DAAs Associated Adverse Events DAAs Interactions with Other Primary Care Medications DDIs Between DAAs and Antiretroviral Therapy (ART) The Emergence of Resistance-Associated Substitutions (RAS) and Resistance-Associated Variants (RAV) with DAAs Treatment Potential Implications of RAS on DAAs Efficacy Virus fitness against DAAs RAS Interpretation also Contain Flaws and Cumbersome RAS Identification is Not an Authentic Tool to Know DAAs Sensitivity or Resistance Against HCV Baseline HCV Resistance Testing HCV Retreatment is a Rare Emergency for Prior Treatment Failures with the Presence of Pre-existing, Baseline, or Treatment Acquired RASs NS5A Associated RAS are More Prone to DAAs Resistance Hepatitis B virus (HBV) Reactivation Risk with DAAs HBV Screening For All HCV Affected or HBV/HCV Co-infected Patients HCV DAAs and Cancer Risk Liver Cancer Risk and HCC Recurrence with DAAs Studies Evidence of No Difference in HCC Risk with DAAs Studies Evidence of Higher HCC Risk with DAAs Studies Evidence of Lower HCC Risk with DAAs Impact of HCC Occurrence or Recurrence on DAAs Achieved SVR rates Consensus Guidelines For HCV Treatment in HCV-Induced HCC Patients Other Clinical Challenges CONCLUSIONS REFERENCES Appling Drug Discovery in HCV-therapeutics: A snapshot from the past and glimpse into the future INTRODUCTION HCV DIAGNOSIS AND DRUG DISCOVERY-A CONTINUED JOURNEY ANTI-MRNA BASED TREATMENT STRATEGIES RNA Interference (RNAi) is Still Infancy for HCV Treatment RNAi-A powerful Therapeutic Tool Against Single-Strand RNA Viruses HCV mRNA-A potential Candidate for siRNA Therapeutics Approval of First siRNA Therapy: A Ray of Hope to Refocus the Tool Against HCV Crosscutting Barriers to Reinvigorate siRNA Therapy Strategies to Overcome Challenges to Revive siRNA Therapeutic Potential Structural Configuration Bioconjugation Robust and Durable siRNA Delivery Vehicles Dendriplexes Cationic Lipophilic Modifications Dynamic Polyconjugates Use of Multiplexed siRNAs to Prevent the Emergence of Virus Escape Mutants Gaps Need to Fill and Some Tricky Questions Must be Answered Prior to Consider siRNA as an Anti-HCV Therapy Micro RNAs (miRNAs) and miRNA inhibitors miRNAs Modulation in Hepatitis C Infection miRNA Kinetics in Hepatitis C Infection Progression miR-122- A Key Regulator of HCV Replication in Host Cells miRNA Knockdown Models Host-Targeting Agents (HTA) for HCV Treatment HTAs Against Hepatitis C Entry into Host Cells HTAs to Inhibit HCV Replication HTAs Against HCV Assembly HTAs Against HCV Assembly and Release Nanomedicine-Based Anti-HCV Agents HCV Vaccine Models-a Now or Never Situation in This Decade CONCLUSIONS REFERENCES Global Health Sector Strategy (2016-2021) Toward Ending Hepatitis-C: Promises, Policies, and Progress INTRODUCTION THE MAIN GOALS OF GHSS (2016-2021) AND MAJOR GAPS GHSS (2016-2021) VISION, GOAL, TARGETS, STRATEGIC DIRECTIONS, AND PRIORITY ACTIONS FOR HCV ELIMINATION BY 2030 Strategic Direction 1 Priority Actions Strategic Direction 2 Priority Actions Strategic Direction 3 Priority Actions Strategic Direction 4 Priority Actions Strategic Direction 5 Priority Actions KEY COMPONENTS OF GHSS (2016-2021) STRATEGY IMPLEMENTATION COUNTRY TARGETS OF GHSS (2016-2021) FOR HCV ELIMINATION BY 2020 AND 2030 AND THEIR PROGRESS STATUS: GLOBAL PROGRESS REPORT 2021 FOR ACCOUNTABILITY OF GHSS (2016-2021) FOR HCV ELIMINATION PROGRESS TOWARD IMPACT The Progress View of the WHO Strategic and Technical Committee on HIV and Viral Hepatitis (STAC-HIVHEP) External Review of Progress by STAC-HIVHEP in Implementing the GHSS (2016-2021) for Viral Hepatitis Weaknesses in the GHSS Strategic Plan and Its Implementation PROGRESS ACHIEVED UNDER EACH GHSS TOWARD IMPACT, SERVICE COVERAGE TARGETS, AND STRATEGIC DIRECTIONS WHO global progress report on HIV, viral hepatitis, and STIs 2021 GHSS (2016-2021) Progress on Viral Hepatitis in 2020 Increasing WHO Member States Having National Hepatitis Strategic Plan PROGRESS BY STRATEGIC DIRECTION Progress Toward Information for Focused Actions Progress Toward Interventions for Impact Progress Toward Delivering Equity Progress Toward Financing for Sustainability Progress Toward Innovation for Acceleration CONCLUSIONS REFERENCES WHO Hepatitis C Elimination Goal by 2030: Feasible or not? INTRODUCTION IS HCV ELIMINATION POSSIBLE BY 2030?------PLAUSIBLE QUALMS AND JUSTIFICATIONS HCV Must be a Sufficient Priority for Healthcare Management Worldwide HCV can be Cured with Pan-genotypic DAAs Top-level Coordination is Required to Escalate HCV Screening and Treatment Expanding HCV Diagnosis and Cascade of Care are Must HCV Surveillance Data are Essentially Required But Lacking in the WHO Member States Social Determinants of Health must be Addressed to Enhance HCV Diagnosis and Care Diagnostic Burnout: A Potential Threat to Off-Track HCV Elimination CURRENT PROGRESS OF HCV ELIMINATION BY THE WHO MEMBER STATES Progress in the African Region Egyptian HCV Elimination Model WHO Progress Toward Eliminating HCV in the Region of America Progress in the South-East Asian Region Progress in European Region Progress Toward HCV Elimination in Eastern Mediterranean Region Egyptian Model of Scaling-up HCV Diagnosis and Treatment Pakistan Following Micro-elimination Approaches to Eliminate Hepatitis C Progress Toward HCV Elimination in the Western Pacific Region China ---- Unblocking the Barriers of High DAA Prices to Achieve Universal Coverage for HCV Medicines LOOKING AHEAD IN THIS DECADE TO ACHIEVE HCV ELIMINATION BY 2030 Expansion of HCV Service Delivery Task-Shifting to Utilize Existing Resources for HCV Elimination WHO GLOBAL HEALTH SECTOR STRATEGY 2022-2030 FOR HEPATITIS C ELIMINATION Key Features of GHSS 2022-2030 for Viral Hepatitis Elimination by 2030 Gaps to Need Fill and Steps to Address These Gaps in WHO Strategies by 2030 GLOBAL MESSAGES AND ACTIVIST LESSONS Community Engagement and Community-led Service Delivery to Vulnerable and Harder-to-Reach HCV Populations Exploring the Potential of Digital Health to Maintain Hepatitis C Surveillance Data and to Reach Young HCV-Infected Populations Expansion of Self-Testing for Key HCV-Infected Populations Acceleration of Progress Within Primary Healthcare and Frameworks of Universal Health Coverage for Hepatitis C Propagation of Universal Health Coverage Framework for HCV CONCLUSIONS REFERENCES Appendices APPENDIX A APPENDIX B Subject Index Back Cover The burden of hepatitis C virus infection on the public health care system continues to remain significant despite the remarkable progresses made in HCV therapeutics in the recent past. There are now almost a dozen oral interferon-free direct-acting antivirals available for the treatment of hepatitis C virus infection. Despite advances in the treatment of HCV, therapeutic gaps remain that are yet to be fully explored, researchers and scientists still strive to understand virus-host interactions to map the disease's progression; extrahepatic manifestations and virus invasion strategies impacting the host's immune system. This book briefly discusses the biology of HCV infection, virus-host interactions, molecular epidemiology of the infection, and the full spectrum of immune responses to hepatitis C. It also provides in-depth information about HCV, clinical diagnostics, and therapeutic knowledge to all stakeholders involved in HCV screening, diagnosis, treatment, and management.Topics covered in chapters include 1) HCV-host interactions leading to asymptomatic acute infection, 2) the progression of acute HCV infection to chronic disease and subsequent extrahepatic comorbidities, 3) Innate and adaptive immune responses in HCV infections, 4) Consensus-based Approaches for Hepatitis C Screening and Diagnosis, 5) advances in hepatitis C therapy and global management of HCV, and 6) the outcomes of Oral Interferon-free Direct-acting Antivirals as Combination Therapies to Cure Hepatitis C.This book would be a valuable addition to undergraduate and postgraduate hepatology students and physicians, clinicians, hepatologists, and health care officials involved in HCV clinical diagnosis and therapeutics.