Key Facts

Hepatitis C is a major cause of chronic liver disease worldwide. The development of DAAs has revolutionised treatment, with cure rates >95% and short treatment durations. The UK aims for elimination by 2030.

Epidemiology

Global: ~58 million chronic carriers. UK: ~120,000 chronic infections (~50% undiagnosed). IVDU is the primary route in the UK (90%). Genotype 1 is commonest worldwide; genotype 3 commonest in UK IVDU population. Prior to screening (introduced 1991), blood transfusion was a major route.

Aetiology

• Hepatitis C virus (HCV): single-stranded RNA virus (Flaviviridae); 8 genotypes (1-8)
• Transmission: percutaneous (IVDU — sharing needles/equipment; needlestick; tattooing/piercing), blood products (pre-1991 UK), vertical (~5%), sexual (primarily MSM with HIV co-infection)

Pathophysiology

HCV replicates in hepatocytes using RNA-dependent RNA polymerase. Unlike HBV, HCV does not integrate into host genome. Chronic infection persists due to high mutation rate (quasispecies) evading immune clearance. Persistent hepatocyte damage → progressive fibrosis → cirrhosis (20-30% over 20-30 years). HCV-related cirrhosis carries 1-5% annual HCC risk. Extrahepatic manifestations include cryoglobulinaemia (immune complex deposition) and lymphoproliferative disorders.

Acute HCV (often subclinical)

• 80% asymptomatic; 20% mild jaundice, malaise
• Incubation 2-12 weeks
• ~25% spontaneously clear virus; ~75% become chronic

Chronic HCV

• Often asymptomatic for 20-30 years
• Fatigue (commonest symptom)
• RUQ discomfort
• Features of chronic liver disease/cirrhosis (late)

Extrahepatic Manifestations

• Mixed cryoglobulinaemia (type II/III): purpura, arthralgia, glomerulonephritis, peripheral neuropathy
• Membranoproliferative glomerulonephritis
• Porphyria cutanea tarda
• Lichen planus
• B-cell non-Hodgkin lymphoma
• Type 2 diabetes (insulin resistance)

Red Flags

• Decompensated cirrhosis (ascites, variceal bleed, encephalopathy)
• HCC (new hepatic mass, rising AFP)
• Acute-on-chronic liver failure
• Fulminant hepatitis (very rare with HCV)

Bedside

• Risk factor assessment: IVDU (current/past), blood transfusion pre-1991, country of origin, tattoos, MSM

Bloods

• Anti-HCV antibody: screening test; indicates exposure (current or past)
• HCV RNA (quantitative PCR): confirms active infection (positive = viraemia); if anti-HCV positive but RNA negative = cleared/treated
• HCV genotype: guides treatment duration (less important with pangenotypic regimens but still useful)
• LFTs: ALT often mildly raised (may be normal despite significant disease)
• FBC: thrombocytopaenia (cirrhosis)
• INR, albumin: synthetic function
• Co-infection testing: HBV (HBsAg, anti-HBc), HIV
• Fibrosis assessment: FIB-4, ELF test, FibroScan

Imaging

• Transient elastography (FibroScan): fibrosis staging
• USS abdomen: cirrhosis features, HCC screening

Special Tests

• Liver biopsy: rarely needed now — mainly for diagnostic uncertainty or concurrent pathology
• Cryoglobulins, complement (C3/C4), RF: if extrahepatic manifestations suspected
• HCV resistance-associated substitutions (RAS) testing: if prior DAA failure

Non-pharmacological

• Harm reduction: needle exchange, opiate substitution therapy; treatment does not require abstinence from IVDU
• Avoid alcohol: accelerates fibrosis progression
• HCC surveillance: USS ± AFP every 6 months in all cirrhotics (continue AFTER cure — risk persists, although reduced)

Pharmacological

• ALL chronic HCV patients should be offered treatment (NICE)
• Pangenotypic DAA regimens (first-line):
  • Sofosbuvir/velpatasvir (Epclusa) 1 tablet OD × 12 weeks — SVR >95% across all genotypes (ASTRAL trials)
  • Glecaprevir/pibrentasvir (Maviret) 3 tablets OD × 8 weeks (treatment-naïve, non-cirrhotic) or 12 weeks (cirrhotic) — SVR >97% (ENDURANCE/EXPEDITION trials)
• SVR (sustained virological response) = undetectable HCV RNA 12 weeks post-treatment = cure
• Decompensated cirrhosis: sofosbuvir/velpatasvir ± ribavirin; avoid protease inhibitor-containing regimens (hepatotoxic risk)
• HBV co-infection: risk of HBV reactivation during DAA therapy — monitor HBV DNA, consider prophylactic antivirals
• Treatment of cryoglobulinaemia: HCV cure is first-line; rituximab if severe/refractory

Surgical/Interventional

• Liver transplantation: for decompensated HCV cirrhosis or HCC; DAAs can be given pre- or post-transplant with excellent results

Referral Criteria

• All HCV RNA-positive patients to hepatology/specialist for DAA treatment
• Community-based treatment models (ODN networks, pharmacies, drug services) increasingly used — "test and treat" pathways
• Transplant assessment: decompensated cirrhosis, HCC

DAA therapy achieves SVR (cure) in >95% of all patients regardless of genotype. SVR halts fibrosis progression and may allow fibrosis regression. HCC risk is reduced but NOT eliminated after cure — continued surveillance required in cirrhotics. Untreated chronic HCV: 20-30% develop cirrhosis over 20-30 years; once cirrhotic, 1-5% annual HCC risk. Re-infection is possible after cure (no lasting immunity) — harm reduction essential. Post-SVR, extrahepatic manifestations (cryoglobulinaemia) often improve or resolve.

HCV Serology and Virology Interpretation

DAA Drug Classes

Key Trials