Epidemiology

Etiology

Parenteral
- Needle sharing among individuals who use injection drugs
- Needlestick injury (e.g., health care workers)
- Blood transfusion
- Dialysis
Organ transplantation
Sexual: rare (in contrast to HBV and HIV)

The risk of chronic infection is multifactorial and depends on the host’s ability to clear the pathogen through activation of multiple innate immunity pathways against the viral envelope.
- Flawed proofreading capability of RNA-dependent RNA polymerase (no 3′– 5′ exonuclease activity) introduces mutations into genes encoding viral glycoprotein envelope and enabling novel antigen production.
- Rapid replication rate produces many antigenically unique viral envelopes.
- Infection persists because the production rate of new mutant virions exceeds the production rate of host antibodies.

Mnemonic

HAV only has acute phase, HCV mostly has chronic phase (and is curable)

Acute Infection: Often asymptomatic or presents with mild, non-specific symptoms like malaise, nausea, and RUQ pain. Jaundice is uncommon.
Chronic Infection: Typically asymptomatic for decades. When symptoms develop, they are often nonspecific, such as fatigue, malaise, and poor concentration.
Complications of Chronic HCV:
- Leads to cirrhosis in 20-30% of patients over 20-30 years.
- Once cirrhosis develops, there is an increased risk of hepatocellular carcinoma (HCC) and decompensated liver disease (ascites, variceal hemorrhage, encephalopathy).
Extrahepatic Manifestations
- Occur in up to 74% of patients and are immune-complex mediated.
- Mixed Cryoglobulinemia: The most classic association, leading to palpable purpura, arthralgias, and glomerulonephritis.
- Renal: Membranoproliferative glomerulonephritis (MPGN) is a common finding.
- Dermatologic: Porphyria cutanea tarda (fragile skin, blisters on sun-exposed areas) and lichen planus are strongly associated.
- Hematologic: Increased risk of B-cell non-Hodgkin lymphoma and ITP.
- Metabolic: Association with insulin resistance and an increased risk of type 2 diabetes.

Biopsy: Not routinely required for diagnosis but can be used to stage fibrosis. Histology may show lymphoid aggregates in portal tracts and macrovesicular steatosis.

Direct-acting antivirals (DAAs): target specific enzymes in the HCV life cycle to inhibit viral replication and assembly
- Classes:
  - NS3/4A Protease inhibitors (-previr)
  - NS5A inhibitors (-asvir)
  - NS5B RNA Polymerase inhibitors (-buvir)
- Regimens typically combine 2-3 DAAs (e.g., Sofosbuvir-Velpatasvir).
Screening before Tx: Test for HBV coinfection, as DAA therapy can cause HBV reactivation.
Interferon PLUS ribavirin
- Was the preferred treatment before the development of DAAs
- Associated with severe adverse effects (e.g., arthralgias, thrombocytopenia, leukopenia, depression, anemia) and teratogenicity
- Contraindicated in patients with decompensated cirrhosis (high risk of worsening cirrhosis decompensation)
- Ribavirin
  - Mechanism of action
    - Guanosine analogue (nucleoside inhibitor)
    - Competitive inhibition of IMP dehydrogenase → prevention of guanine nucleosides synthesis
  - Adverse effects
    - Hemolytic anemia
    - Highly teratogenic

Tip

DAAs have superior efficacy and safety profiles compared with interferon or ribavirin-based regimens and are thus preferred.