Hepatitis C Virus (HCV)
Biological Characteristics:
ss RNA enveloped, helical RNA virus related to the dengue viruses.
One serotype with at least 11 genotypes and many subtypes.
Genotypes
1a: USA
1b: Western Europe, S-E Asia
2: World wide
3: India, Pakistan, Australia, & Scotland
4: Middle east, Saudi Arabia, Egypt & N- Africa
5: South Africa
6: Hong Kong, Macau
Saudi Arabia: 3 genotypes are found
Type 4a: Egypt, southern Saudi Arabia (50%)
Type 2b: USA, North Europe, Southern Saudi Arabia (41%)
Type 1a: N & S America, Australia, Southern Saudi Arabia (9%)
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Modes of Transmission:
Similar to HBV: Parentral, IV drug users sharing needles (40-60%), Dialysis: 10-30%, Sexual 10%, blood
transfusions, organ transplantation, perinatal transmission
Unlike HBV it can cross the placenta and infect the baby in utero
No oral transmission as it is an enveloped virus
Pathogenesis:
Similar to that of HBV. MHC Class I proteins present HCV proteins (antigens) on the infected cell surface leading
to cytotoxic T cell killing of the infected hepatocytes.
Cell injury to hepatocytes is mainly due to cell lysis.
Raised hepatic enzymes such as ALT indicate chronicity of HCV infection
In later stages the viruses infected cells try to prevent cell apoptosis resulting in continuous production of viruses
from infected cells.
An estimated1 trillion HCV virions are produced per day in untreated patients
Incubation Period: 2 kinds of patterns are observed
In Clinically apparent transfusion-transmitted HCV the IP is about 50 days (shorter)
In sexually transmitted HCV: IP can be longer (as long as 8 years)
HCV Replication:
Replication occurs in the cytoplasm.
RNA translates proteins at the ribosomes: 3 structural and 7 non-structural proteins are formed
RNA is replicated by the RNA polymerase enzyme. Positive strand first forms a complementary
negative strand which acts as a template to form a positive strand (Positive→Negative →Positive)
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Serology of HCV
Anti-HCV Antibodies start appearing in blood about 2-3 months after the infection and can be detected
in the blood throughout the patient's life. HCV RNA may be detected since the early phase of the
disease. Liver enzymes such as Alanine Aminotransferase (ALT or SGPT) are raised depicting
continuous damage to hepatic cells.
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A lengthy poly-protein chain is formed after translation of viral RNA in the cytoplasm of a hepatocyte.
This polyprotein chain is cleaved into smaller active proteins which serve as structural proteins or as
non-structural enzymes.
1. Structural Proteins are C (core) Envelope (E1 and E2): These are cleaved by the hepatic cell
enzymes.
2. Non-Structural Proteins are NS2, NS3, NS4 and NS5: These are cleaved by the viral enzymes
NS2 is a Cysteine protease
NS3 is a Serine protease
NS4A is a RNA helicase.
NS4B and NS5A form active sites for RNA replication
NS5B acts as the RNA polymerase enzyme necessary for replication of HCV
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Clinical picture / Prognosis:
Sub-clinical in majority of cases
Clinically apparent HCV (30%): similar to HBV. Jaundice is rare. Fatigue common
Rare extra-hepatic manifestations (74%):
Arthralgia (nearly 100%)
Myalgia
Pruritis
Nephropathy: Membrano-proliferative glomerulonephritis
Cryoglobulinemia:
(abnormal proteins in blood that clump together when blood is chilled at
low temperature)
Vasculitis and Essential Cryoglobulinemic vasculitis
Corneal ulcerations
Thyroiditis (Hypothyroidism as well as Hyperthyroidism)
Prognosis:
80% progress to chronic liver disease (The most important indication of liver transplantation)
20% progress to Cirrhosis of liver in 10 years
1-3% Hepato-cellular Carcinoma (HCC) per year after 15-20 years
Lab Diagnosis:
Samples: Blood for sera, liver biopsy
ELISA for the detection of IgG against HCV
I, II, III generation ELISAs:
I generation ELISA: c100-3 (NS4 region)
II generation ELISA: c100-3 + c33c = c200 (NS3 & NS4 regions)
III generation ELISA: c22-3 + c220 + NS5 (Core+ NS3/4 +NS5 regions)
Antibodies Positive %age in serum
Anti c-33c & c22-3 90%
Anti c100 -3 60%
Anti 5-1-1 50%
Western Blot analysis:
RIBA (Recombiant Immunoblot assay) detects for antibodies against
4 HCV antigens namely: c100-3, 5-1-1, c33c, c22-3, NS5 and
One enzyme: Superoxide dismutase
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Western Blot Assay (RIBA): ELISA performed on nitrocellulose paper
HCV proteins are embedded on nitrocellulose-paper strips and cross reacted with patient's serum
Band formation on paper strips is observed and interpreted as positive, negative or indeterminate.
Indeterminate results are usually repeated following a diagnostic algorithm given below
NS4
NS3
Core
NS5
Antigen detection: c33c, c22-3, c100-3, 5-1-1
HCV RNA viral load determination by PCR for prognosis and staging:
Nested or Real Time (RT-PCR)
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Diagnostic Algorithm for HCV
ELISA for detecting antibodies against HCV is performed on serum of patients.
If found positive, the sample is further tested with Western Blot Assay (RIBA)
Levels of HCV RNA are measured for determining the viral load, drug efficacy post initiation of therapy and
prognosis.
Prevention / Management:
1. General measures: similar to HBV.
2. Chronically infected individuals with elevated liver enzymes (increased ALT) require PEGylated-
Interferon ά (sustained level in serum for a longer duration)
Ribavirin may be required as a combination therapy for those who do not respond to interferon therapy.
Mechanism of action:
synthetic nucleoside analogue that blocks capping of viral m-RNA (transcription)
