What is hepatitis C virus (HCV)?

What is Hepatitis C Virus (HCV)?

HCV is a single-stranded RNA virus of the Flaviviridae family that causes both acute and chronic liver disease, affecting approximately 71 million people worldwide and representing a major cause of cirrhosis, hepatocellular carcinoma, and liver-related mortality. 1

Viral Characteristics

HCV is an enveloped, positive-sense, single-stranded RNA virus with a genome length of approximately 9.6 kilobases that belongs to the Flaviviridae family. 2 The virus displays both hepatotropic and lymphotropic properties, meaning it infects both liver cells and lymphocytes, which explains its diverse clinical manifestations. 2

Key Viral Features:

• High genetic diversity: HCV exists in 6 major genotypes and over 90 subtypes, with genotypes 1a and 1b being most common in the United States (approximately 75%). 3
• Rapid replication and mutation: The virus produces approximately 10^12 virions per day with a low-fidelity RNA-dependent RNA polymerase, creating a "quasispecies" of genetically related variants within each infected individual. 2
• Genome organization: The viral RNA encodes a single polyprotein that is cleaved into 10 polypeptides, including 3 structural proteins (core, E1, E2) and multiple nonstructural proteins (NS2-NS5) necessary for viral replication. 3

Disease Progression and Clinical Impact

Acute to Chronic Infection:

• HCV RNA appears in serum within 1-2 weeks of exposure, followed by elevated liver enzymes (ALT), then symptoms and jaundice. 3
• 55-85% of infected individuals fail to clear the virus and develop chronic hepatitis C, making it highly prone to chronicity. 4, 3
• Only 15-45% achieve spontaneous viral clearance during acute infection. 3

Long-term Consequences:

• Chronic HCV infection leads to progressive liver fibrosis, cirrhosis, and hepatocellular carcinoma in a significant proportion of untreated patients. 1, 4, 3
• The natural history is highly variable, ranging from minimal liver changes to extensive fibrosis and cirrhosis. 1
• Viral eradication significantly reduces non-liver related deaths, as HCV is associated with numerous extrahepatic complications. 2

Extrahepatic Manifestations

HCV causes numerous diseases beyond the liver due to its lymphotropic properties and immune-mediated mechanisms. 2 These include:

• Cryoglobulinemic vasculitis (the most frequent and studied extrahepatic manifestation) 2
• B-cell lymphoproliferative disorders and lymphoma 2
• Cardiovascular diseases 2
• Neurologic disorders 2
• Endocrine-metabolic diseases (including insulin resistance and diabetes) 2
• Renal diseases (including glomerulonephritis) 2, 3
• Sicca syndrome and porphyria cutanea tarda 3

Multiple extrahepatic manifestations often coexist in the same patient, requiring multidisciplinary management. 2

Transmission

HCV is primarily transmitted through blood exposure, including:

• Blood transfusions (particularly before screening implementation in the early 1990s) 1
• Injection drug use and needle sharing 2
• Other percutaneous exposures 1

Important distinction: Unlike hepatitis A virus, HCV is not effectively transmitted via the fecal-oral route. 5

Treatment and Cure

Modern Treatment Approach:

• The primary goal of HCV therapy is achieving sustained virological response (SVR), defined as undetectable HCV RNA 12-24 weeks after completing treatment. 2, 1
• Direct-acting antivirals (DAAs) can cure over 90% of patients (typically >95% SVR rates), representing a dramatic improvement over older interferon-based regimens. 2, 1
• SVR is considered curative, as 99% of patients who achieve SVR remain HCV RNA negative during long-term follow-up. 2

Benefits of Viral Eradication:

• Normalization of liver enzymes 1
• Improvement in liver inflammation and fibrosis 1
• Reduced risk of hepatic decompensation and hepatocellular carcinoma 1
• Resolution of liver disease in patients without cirrhosis 2
• Regression of hepatic fibrosis even in patients with established cirrhosis 2

Critical caveat: Patients with cirrhosis who achieve SVR remain at risk for complications and require ongoing surveillance for hepatocellular carcinoma. 1

Global Health Impact

Approximately 71 million people are chronically infected with HCV worldwide (about 2.35% of the global population), with many unaware of their infection status. 1 HCV remains one of the main causes of chronic liver disease globally and a leading indication for liver transplantation. 1