Hepatitis C Virus-Host Interactions and Therapeutics: Current Insights and Future Perspectives

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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
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