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HEPATITIS B & C: COMPLETE CLINICAL NOTES FOR WARD & OPD

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PART 1 - HEPATITIS B VIRUS (HBV)

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1.1 VIROLOGY AT A GLANCE

• Family: Hepadnaviridae - partial double-stranded DNA virus
• Replication: Uses reverse transcriptase (RNA-dependent DNA polymerase) - hence susceptible to NRTIs/NtRTIs
• Reservoir for persistence: Covalently Closed Circular DNA (cccDNA) - stays in hepatocyte nucleus indefinitely; this is why cure is rare
• 8 genotypes (A-H), 4 serotypes (adw, adr, ayw, ayr)
• Genotype C carries ~2x higher HCC risk vs genotype B
• Key genes: C (core), S (surface/HBsAg - 3 forms: small, medium, large), P (polymerase/reverse transcriptase), X (unknown, possibly oncogenic)

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1.2 EPIDEMIOLOGY & TRANSMISSION

• Perinatal (vertical) - most important in endemic Asia/Africa (horizontal child-to-child in <4 years also common)
• Sexual contact
• Percutaneous: needlestick, IVDU, tattooing, acupuncture
• Blood products/medical equipment

Infectivity: Up to 10^10 particles/mL at peak - more infectious than HIV

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1.3 SEROLOGY MADE EASY

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• Vaccination: Vaccine = only anti-Bs = Vaccine
• Natural immunity post-recovery: anti-HBs + anti-HBc total (IgG)
• Occult HBV infection (OBI): HBsAg negative, but anti-HBc positive + HBV DNA detectable

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1.4 PHASES OF CHRONIC HBV

• Pre-core mutant (HBeAg-negative chronic hepatitis): Stop codon mutation at nucleotide 1896 → no HBeAg produced, but virus still replicates actively. Common in Mediterranean, Middle East, Asia. More difficult to treat.

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1.5 EXTRAHEPATIC MANIFESTATIONS

• Polyarteritis nodosa
• Lupus-like / serum sickness-like illness (urticaria, arthralgias in prodrome)
• Acral papular dermatitis (Gianotti-Crosti - in children)
• Cryoglobulinemia
• Essential mixed cryoglobulinemia, glomerulonephritis (membranous/MPGN)

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1.6 SCREENING

CDC 2023: Universal screening of ALL adults ≥18 years (replaced risk-based screening because most acute HBV cases occurred in persons NOT in traditional high-risk groups)

• Born in countries with HBV prevalence ≥2% (intermediate/high endemic)
• Household/sexual contacts of HBsAg+ persons
• Neonates of HBsAg+ mothers
• IVDU
• Multiple sexual partners / STI history
• MSM
• Incarcerated persons
• Elevated ALT/AST of unknown cause
• HCV or HIV co-infection
• Hemodialysis patients
• Healthcare workers with blood exposure
• Persons requiring immunosuppressive/cytotoxic therapy (AASLD/AGA 2025: mandatory screening before starting B-cell depleting agents, anti-TNF, anthracyclines, high-dose steroids)

• HBsAg+: Confirm with HBV DNA, HBeAg, Anti-HBe, LFTs → assess for treatment
• Anti-HBs+ only: Vaccinated or resolved - no further action
• Anti-HBc+ only (isolated): Possible OBI or false positive - check HBV DNA
• All negative: Vaccinate

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1.7 TREATMENT: WHO TO TREAT

• Treat if: ALT >2× ULN AND HBV DNA >20,000 IU/mL
• Monitor if: ALT normal (immune tolerant phase) - check every 3 months × 1 year, then every 6 months

• Treat if: ALT >2× ULN AND HBV DNA >2000 IU/mL
• Consider treatment if: ALT 1-2× ULN + HBV DNA >2000 IU/mL + fibrosis ≥F2, or inflammation ≥A3, or age >40 years
• Always treat if: cirrhosis (any level of HBV DNA)

• Cirrhosis (compensated or decompensated)
• HCC
• Prior to immunosuppression/chemotherapy (preemptive)
• HBV-HIV co-infection
• Pregnancy with viral load >200,000 IU/mL (start antiviral in 3rd trimester)

1. Suppress HBV DNA to undetectable
2. HBeAg seroconversion (HBeAg → Anti-HBe)
3. ALT normalization
4. Improve liver histology
5. Prevent cirrhosis and HCC
6. (Ideal): HBsAg loss ("functional cure") - occurs in <1% annually spontaneously

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1.8 TREATMENT DRUGS

E - Entecavir (ETV)         ← PREFERRED (first-line)
N - (Not lamivudine/adefovir first line)
T - Tenofovir TDF            ← PREFERRED (first-line)
E - tEnofovir TAF            ← PREFERRED (renal/bone disease)
L - Lamivudine               ← No longer recommended (high resistance)
A - Adefovir                 ← No longer recommended (nephrotoxic, low efficacy)
PEG - PEG-IFN α2a            ← Finite duration option

• Bone disease (osteoporosis/fragility fractures)
• Renal impairment (GFR <60)
• Old age on steroids (chronic steroid use)
• Fanconi syndrome risk
• Switching from lamivudine-resistant (prefer TAF over ETV)

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1.9 SPECIAL SCENARIOS

• Treat BOTH regardless of HIV stage
• Use tenofovir (TDF or TAF) + emtricitabine as the backbone of ART (dual activity against HBV and HIV)

• Compensated: ETV or TDF/TAF preferred; PEG-IFN CONTRAINDICATED
• Decompensated: ETV or TDF/TAF; consider liver transplant evaluation

• Highest risk: B-cell depleting agents (rituximab), anthracyclines, high-dose corticosteroids ≥4 weeks
• Moderate risk: Anti-TNF agents, cytokine/integrin inhibitors, tyrosine kinase inhibitors
• Low risk: Methotrexate, azathioprine
• AASLD/AGA 2025: Screen ALL patients (HBsAg + Anti-HBc) before immunosuppression; prophylax with ETV or TDF/TAF if HBsAg+; also consider prophylaxis if anti-HBc+ (resolved HBV) receiving high-risk agents

• Screen all pregnant women for HBsAg
• If HBV DNA >200,000 IU/mL: Start TDF in 3rd trimester (Pregnancy Category B) to reduce vertical transmission
• Neonate of HBsAg+ mother: HBV vaccine + HBIG 0.5 mL within 12 hours of birth → test at 12 months (HBsAg, anti-HBs, anti-HBc)

• HBIG (IV × 5-7 days) + lifelong ETV or TDF/TAF to prevent graft reinfection
• Anti-HBc+ donor liver recipients: lifelong oral antiviral (no HBIG needed)

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1.10 PREVENTION

• Schedule: 0, 1, 6 months IM (deltoid) - 3 doses
• Accelerated schedule: 0, 1, 2 months + booster at 12 months
• Response: >90% achieve protective anti-HBs (≥10 mIU/mL) after 3rd dose
• Non-responders: Repeat 3-dose series; if still non-responsive, check for OBI
• Universal infant vaccination recommended worldwide

• HBIG 0.04-0.07 mL/kg + HBV vaccine dose 1 at different sites
• Do within 48 hours (max 7 days for needlestick; max 14 days for sexual exposure)
• HBIG second dose at 30 days post-exposure
• Complete 3-dose vaccine series

• No treatment needed

• Give HBIG + vaccine booster; test anti-HBs; if inadequate, second HBIG dose at 1 month

• Recombinant HBsAg vaccines (Engerix-B, Recombivax-HB)
• Heplisav-B: 2-dose schedule (0 and 1 month) with novel CpG adjuvant - approved for adults
• PreHevbrio: 3-dose, CpG adjuvanted, higher efficacy in immunocompromised
• Twinrix: Combined HAV/HBV vaccine

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1.11 HCC SURVEILLANCE

HBV carriers without cirrhosis: ~0.5% annual HCC incidence (rises to 1% in elderly). Risk ↑ with: genotype C, HBeAg positivity, HBV DNA >10^5 copies/mL, co-infection (HCV/HIV), family history of HCC.

• African: any age
• Family history of HCC: any age
• Risk cirrhosis: any age
• Inactive BUT Asian male: ≥40
• Carrier Asian female: ≥50
• Any cirrhosis: always

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PART 2 - HEPATITIS C VIRUS (HCV)

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2.1 VIROLOGY AT A GLANCE

• Family: Flaviviridae - single-stranded positive-sense RNA virus
• No reverse transcriptase, no DNA intermediate → cure possible (unlike HBV)
• High mutation rate (no proofreading by NS5B RNA polymerase) → quasispecies, 6 major genotypes
• Key proteins:
  • NS3/NS4A - serine protease (processes polyprotein)
  • NS5A - replication complex scaffold, interferon resistance
  • NS5B - RNA-dependent RNA polymerase (sole RNA polymerase)

• 3 = NS3/NS4A protease (protease inhibitors: "-previr" suffix)
• 5A = NS5A protein (NS5A inhibitors: "-asvir" suffix)
• 5B = NS5B polymerase (polymerase inhibitors: sofosbuvir "-buvir" suffix)

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2.2 GENOTYPES & GEOGRAPHIC DISTRIBUTION

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2.3 NATURAL HISTORY

• Acute HCV: 20-30% jaundiced; 10-20% nonspecific symptoms; most asymptomatic
• Spontaneous clearance: only 20-35% clear without treatment
• Chronic HCV: 70-80% of exposed → chronic infection
• Chronic → Cirrhosis: ~20% over 20 years
• Cirrhosis → HCC: 1-4% per year
• Unlike HBV: DAAs achieve ~97-99% cure (SVR = sustained virologic response)

• 20% clear spontaneously
• 80% go chronic
• 20% of chronic → cirrhosis (over 20 years)
• 4%/year of cirrhotics → HCC

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2.4 SEROLOGY & DIAGNOSIS

• Positive = current or past exposure (cannot distinguish)

• If RNA positive: Active infection → genotype, assess for treatment
• If RNA negative: Resolved/false-positive serology

• Anti-HCV appears 1-3 months after exposure (window period possible)
• Anti-HCV persists lifelong (even after SVR = "cure") - cannot use it to confirm current active infection in previously treated patients; use HCV RNA
• Acute vs chronic: RNA detectable 1-2 weeks post-exposure; ALT elevation occurs later; no IgM test to distinguish acute vs chronic (unlike HBV)

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2.5 SCREENING

• All adults aged 18-79 years - once in lifetime (universal one-time screen)
• All pregnant women during each pregnancy
• Persons born 1945-1965 (baby boomer cohort) - 3.2% prevalence; HCV mortality exceeds all other reportable infectious diseases combined in this age group

• IVDU (each year or more frequently)
• HIV-positive persons
• Hemodialysis patients (annually)
• Incarcerated persons
• Healthcare workers with HCV needlestick exposure
• Sexual partners of HCV+ persons (especially MSM with multiple partners)
• Persons with unexplained elevated ALT
• Neonates of HCV-RNA+ mothers (test at 18 months or HCV RNA at 2-6 months)

• Persons who inject drugs
• Repeated high-risk sexual activity (MSM)
• Incarcerated individuals
• Steal (sharing of needles/equipment)
• Ongoing HIV infection
• Neonates of HCV+ mothers
• Hemodialysis patients
• Infected source of needlestick
• Viral load elevated ALT unexplained
• Dialysis
• Antiretroviral therapy patients (HIV)
• Liver disease of unclear etiology

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2.6 TREATMENT: GOALS & PRINCIPLES

• SVR12 = Undetectable HCV RNA 12 weeks post-treatment completion
• Represents 97-100% chance of remaining HCV RNA negative long-term
• Associated with: histologic improvement, ↓ cirrhosis risk, ↓ HCC risk (though HCC surveillance continues in established cirrhosis), ↓ all-cause mortality

• ALL patients with chronic HCV and detectable HCV RNA regardless of ALT level or fibrosis stage - with rare exception of very short life expectancy
• Acute HCV: Treat (do not delay for spontaneous clearance - no longer recommended per Harrison's 22E/2025)

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2.7 DAA DRUG CLASSES & MECHANISM

• Mechanism: Inhibit viral serine protease that cleaves HCV polyprotein into individual active proteins
• Lower barrier to resistance than sofosbuvir
• Contraindicated in decompensated cirrhosis (Child-Pugh B/C) - drug accumulates, risk of liver decompensation
• Drug interactions: CYP3A substrates - check carefully
• Agents: Grazoprevir, Voxilaprevir, Glecaprevir

• Mechanism: Inhibit NS5A protein involved in replication complex assembly and virion secretion
• Pangenotypic (velpatasvir, pibrentasvir) or genotype-specific (ledipasvir, elbasvir)
• Agents: Ledipasvir, Velpatasvir, Pibrentasvir, Elbasvir

• Nucleotide (NI) inhibitors: Sofosbuvir - HIGH barrier to resistance; backbone of most regimens
• Mechanism: Sofosbuvir is a uridine nucleotide prodrug; incorporated into viral RNA → chain termination
• Agents: Sofosbuvir ("-buvir")

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2.8 CURRENT DAA REGIMENS

Exclusions: prior DAA failure, cirrhosis, HBsAg positive, pregnancy, HCC, liver transplant

1. Sofosbuvir/Velpatasvir (SOF/VEL) × 12 weeks - OR -
2. Glecaprevir/Pibrentasvir (GLE/PIB) × 8 weeks

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• SOF/VEL = pangenotypic, use for all
• GLE/PIB = pangenotypic, especially for renal disease
• VOSEVI = salvage for prior DAA failure

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2.9 SPECIAL POPULATIONS

• Compensated (Child-Pugh A): Most regimens acceptable; extend duration if needed
• Decompensated (Child-Pugh B/C): SOF/VEL ± ribavirin (protease inhibitors CONTRAINDICATED); priority for liver transplant

• GFR <30 or hemodialysis: Prefer GLE/PIB (no dose adjustment needed); EBR/GZR (GT1,4)
• Sofosbuvir-containing regimens: Now approved for severe renal failure (safety established)

• Same regimens as mono-infection; check for drug-drug interactions with ART
• Screen for HBV (risk of HBV reactivation when treating HCV with DAAs - especially if HBsAg+ or anti-HBc+; AGA 2025 CPG, PMID 39863345)

• HBV reactivation can occur during/after DAA therapy for HCV
• AASLD/EASL: Screen HBsAg + anti-HBc before starting DAAs; prophylax if HBsAg+

• SOF-based or GLE/PIB regimens highly effective
• Check calcineurin inhibitor (tacrolimus, cyclosporine) interactions - especially with NS3/4A inhibitors

• DAAs: Limited safety data; not currently recommended
• Defer treatment until after delivery

• SOF/VEL/VOX (Vosevi) × 12 weeks OR GLE/PIB × 16 weeks
• Consider resistance-associated substitution (RAS) testing
• Refer to expert center

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2.10 IMPORTANT DRUG INTERACTIONS

• Amiodarone + Sofosbuvir (+ beta blockers) → Severe bradycardia/cardiac arrest - CONTRAINDICATED
• CYP3A inducers (rifampin, carbamazepine, phenytoin, St John's Wort) → reduce protease inhibitor levels
• Antiretrovirals (ritonavir-boosted): major interactions with PIs and NS5A inhibitors
• Ribavirin: Hemolytic anemia; teratogenic - use contraception × 6 months after
• Immunosuppressants (tacrolimus, cyclosporine): levels altered by NS3/4A inhibitors

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2.11 PREVENTION OF HCV

• Safe injection practices (needle exchange programs, harm reduction)
• Single-use, sterile medical equipment
• Blood product screening
• Safe sex practices (condoms); post-exposure prophylaxis NOT recommended for HCV
• Healthcare worker precautions (standard/universal precautions)

• Universal screening of adults 18-79
• "Treat all" policy - SVR = microbiological cure = breaks transmission chain
• WHO target: Eliminate HCV as a public health threat by 2030 (90% reduction in incidence, 65% reduction in mortality)

• No vaccine, no HCVIG, no PEP medication available
• Baseline anti-HCV + HCV RNA → recheck at 6 weeks (HCV RNA) and 4-6 months (anti-HCV)
• If acute HCV detected: Treat promptly (same DAA regimen as chronic)

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PART 3 - QUICK COMPARISON TABLE: HBV vs HCV

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PART 4 - WARD MNEMONICS SUMMARY CARD

"VITAL Signs of HBV" (Initial Workup)

• Viral load (HBV DNA)
• Immune markers (HBeAg, Anti-HBe, Anti-HBs)
• Transaminases (ALT, AST)
• Antigen (HBsAg, Anti-HBc)
• Liver staging (ultrasound, fibroscan, biopsy if needed)

"CURE Is Possible with HCV" (Why Treat HCV)

• Cirrhosis prevented
• Undetectable RNA = SVR = cure
• Reduced HCC risk
• Extrahepatic manifestations improve (cryoglobulinemia, GN)

"3-5A-5B = DAA targets"

• 3 = "-previr" (protease)
• 5A = "-asvir" (NS5A)
• 5B = "-buvir" (NS5B / sofosbuvir)

"BITES" - Contraindications to Protease Inhibitors in HCV

• Both decompensated cirrhosis (Child-Pugh B and C)
• Inducers of CYP3A (rifampin, etc.) - reduce levels
• Transplant post-liver (interactions with CNI)
• Elevated drug levels (hepatic metabolism - accumulates in liver failure)
• Severe drug interactions (anticonvulsants, amiodarone)

"PELTS" - Side effects of PEG-IFN (HBV/HCV)

• Psychiatric (depression, suicide risk)
• Elevated autoantibodies (thyroiditis, autoimmune disease)
• Leucopenia + thrombocytopenia (bone marrow suppression)
• Thermo-dysregulation (flu-like: fever, chills, myalgia)
• Seizures/neurotoxicity (somnolence, confusion)

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PART 5 - OPD/WARD FLOWCHART SUMMARIES

HBV OPD Decision Tree

Patient with ↑LFT or jaundice or risk factors
          ↓
SCREEN: HBsAg + Anti-HBs + Anti-HBc total
          ↓
HBsAg POSITIVE
          ↓
Check: HBeAg, Anti-HBe, HBV DNA, ALT, CBC, LFTs, Creatinine, Coagulation
     + Abdominal US for cirrhosis/HCC + Fibroscan
          ↓
HBeAg+ + DNA >20,000 + ALT >2×ULN → TREAT (ETV or TDF/TAF)
HBeAg- + DNA >2000 + ALT >2×ULN → TREAT (ETV or TDF/TAF)
Any cirrhosis → TREAT (ETV or TDF/TAF preferred)
Immune tolerant / Inactive carrier → MONITOR
          ↓
On treatment: Check HBV DNA at 3 months, 6 months, then every 6 months
           Check ALT, creatinine, phosphorus (TDF) every 3-6 months

HCV OPD Decision Tree

Patient with risk factors or Universal Screen (18-79 yrs)
          ↓
Anti-HCV antibody
          ↓
Positive → HCV RNA (quantitative PCR)
          ↓
RNA POSITIVE (active infection)
          ↓
HCV Genotype (if needed) + ALT, CBC, Cr, Bilirubin
Assess for cirrhosis (Fibroscan, FIB-4 score)
Check: HBsAg + HIV (co-infection screen)
          ↓
TREAT ALL with detectable HCV RNA
     ↓
Simplified algorithm (no cirrhosis, no prior DAA failure, no HBsAg+):
  → SOF/VEL (Epclusa) × 12 weeks  OR
  → GLE/PIB (Mavyret) × 8 weeks
     ↓
Check HCV RNA at 12 weeks post-treatment (SVR12)
SVR12 = CURE
If cirrhosis: Continue HCC surveillance 6-monthly ultrasound ± AFP

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PART 6 - KEY NUMBERS TO MEMORIZE

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PART 7 - SURVEILLANCE CALENDAR FOR YOUR WARD

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REFERENCES (Textbooks and Guidelines)

• Harrison's Principles of Internal Medicine, 22nd Ed. (2025) - Chapters 350, 351, 352 - Primary source for screening, DAA algorithms, epidemiology
• Washington Manual of Medical Therapeutics - AASLD treatment criteria, HBV phases
• Katzung's Basic & Clinical Pharmacology, 16th Ed. - Drug mechanisms and tables
• Lippincott Illustrated Reviews: Pharmacology - Drug class summaries
• Yamada's Textbook of Gastroenterology, 7th Ed. - HCC surveillance criteria
• Goldman-Cecil Medicine - TAF/TDF, pangenotypic regimens
• Henry's Clinical Diagnosis & Management by Lab Methods - Serology interpretation
• EASL Clinical Practice Guidelines on HBV Management, 2025 (PMID: 40348683, J Hepatol 2025) - latest comprehensive guidelines
• AGA Clinical Practice Guideline: Prevention and Treatment of HBV Reactivation, 2025 (PMID: 39863345, Gastroenterology 2025)
• ACOG Clinical Practice Guideline No. 6: Viral Hepatitis in Pregnancy, 2023 (PMID: 37590986)
• www.hcvguidelines.org (AASLD-IDSA, continuously updated)

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• EASL HBV Guidelines 2025 (PMID 40348683)
• AGA HBV Reactivation CPG 2025 (PMID 39863345)
• Harrison's 22E (2025) - simplified DAA algorithm
• USPSTF/AASLD-IDSA universal HCV screening (all adults 18-79)
• CDC 2023 universal HBV screening recommendation