Hepatitis C virus

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Hepatitis C virus

• Dr. Amanj Saeed
• MB.CH.B MSc PhD
• Clinical virologist

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Hepatitis C Virus (HCV)
Envelope

• HCV is small enveloped positive sense RNA virus
• Belongs to Genus Hepacivirus of Flaviviridae
  family
• Genome is 9.6 kb.
• 6 major genotypes.

Core
Envelope Glycoproteins
Viral RNA (9400 nucleotides)
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HCV

• Hepatitis C virus (HCV) is a small, enveloped
  positive strand RNA virus belong to a genus
  Hepacivirus of the Flaviviridae family
• An estimated 200?? million people worldwide are
  infected with HCV .
• 80 of infected individuals will develop chronic
  persistent infection, and of these 30 will
  develop progressive liver diseases including
  chronic hepatitis, cirrhosis and hepatocellular
  carcinoma (HCC).

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HCV

• HCV infection has a major impact on public
  health, yet no vaccine is available to prevent
  the infection and the antiviral therapies are
  characterised by
• limited efficacy
• high cost
• substantial side effects.

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STRUCTURAL GENES
NON-STRUCTURAL GENES
ve ss RNA Genomic
organisation
FLAVIVIRUS
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HCV receptor interaction

• E1 and E2 are essential for host cell entry by
  binding to receptors and inducing fusion of the
  host cell membrane
• Several cell surface molecules have been proposed
  to play a role in mediating HCV attachment and
  entry
• the tetraspanin CD81
• scavenger receptor class B type 1 (SRB1)
• heparin sulphate (HS)
• and the low density lipoprotein (LDL) receptor,
  claudin-1 and occludin.
• Epidermal growth factor Receptor
• Ephrin receotor

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Translation of HCV genome

• Translation of HCV genome yields a polyprotein
  precursor that is subsequently processed by
  cellular and viral proteases.
• Structural proteins include (core, E1, E2, P7)
• Nonstructural proteins include NS2, NS3, NS4A,
  NS4B, NS5A, NS5B.

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HCV replication

• HCV Replication proceeds via formation of
  complementary minus strand RNA using a viral
  genome as a template and subsequent synthesis of
  plus strand
• Both these steps are dependent on NS5B (viral RNA
  Dependent RNA polymerase).

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HCV

• HCV genome replication is associated with a high
  mutation rate and sequence diversity which
  eventually results in a circulating population of
  diverse but closely related HCV variants, known
  as a quasispecies which underlies the following
• capacity to escape against immune responses
• presence of multiple variants which facilitate
  the selection of adaptive mutations.

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HCV genetic diversity consequences

• Diagnosis
• may result in false negativity
• Pathogenicity
• are all genotypes equally dangerous?
• Treatment
• do all genotypes respond equally to therapy?
• Vaccine development
• creates problems

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Models for studying HCV pathogenesis

• Analyzing the effect of HCV on transformed cell
  lines.
• transgenic technology.
• Infection with related viruses (like GBV-B)
• The best model for HCV study is using chimpanzees
  (economic and moral reasons limit the use of
  chimpanzee in research).

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Models for studying HCV pathogenesis

• Sub-genomic replicon systems .
• generation of an infectious clone of a genotype 2
  isolate of HCV known as JFH-1 which has the
  capacity to go through a full viral life cycle
  and produce infectious virus in hepatocyte
  derived cell lines.

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Models for studying HCV pathogenesis

• HCV pseudoparticles (HCVpp).
• Recent studies developed an experimental system
  to use primary human hepatocytes as a model for
  studying HCV pathogenesis

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Anti-HCV POSITIVE

• Evidence of infection at some time
• Gives no indication as to when infection occurred
• Gives no indication as to whether infection was
  cleared or is still present

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Anti-HCV Negative

• No evidence of infection with HCV
• BUT - be aware of possible false negatives
• if infection very recent (window period)
• if patient immunosuppressed at time of infection

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Genome Detection

• Requires amplification eg Reverse Transcriptase
  Polymerase Chain Reaction
• Technically more exacting
• Expensive

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Interpretation RT/PCR results

• POSITIVE
• infectious
• at risk of chronic liver disease
• requires liver biopsy

• NEGATIVE
• not infectious
• not at risk of chonic liver disease
• may not require biopsy

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Hepatitis C virus routes of transmission

• Parenteral
• Injecting drug use
• Blood/blood products
• Other needles
• Failure of infection control eg outbreaks (see
  refs)
• Mother-to-baby (5)
• Sexual (?real)

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CLINICAL OUTCOMES OF HCV INFECTION
ACUTE INFECTION Usually asymptomatic
Infection Resolved 15-25
CHRONIC INFECTION 75-85
ASYMPTOMATIC, mild liver disease
20 yrs
CHRONIC INFLAMMATORY HEPATITUS
CIRRHOSIS eg 20
5 yrs
HEPATOCELLULAR CARCINOMA
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Mechanism of hepatic fibrogenesis in HCV infected
patient
Chronic inflammation and the wound healing
response are likely to be the framework within
which HCV induces hepatic fibrosis
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Hepatitis C
Natural history of Hepatitis C Infection
Infection by Hepatitis C Virus
Acute Hepatitis (gt90 Asymptomatic)
6 Months
Chronic hepatitis (75-85)
Spontaneous recovery (15-25)
Chronic active (20)
Asymptomatic (80)
10-30 Years
Treatment
Cirrhosis (20)
Transplantation
HCC
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HCV Natural History
Infection
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Prevention of patient-to-patient HCV transmission
- screening
Blood donors anti-HCV Organ and tissue donors
anti-HCV Renal units regular anti-HCV
testing Antenatal screening NOT currently
recommended
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Needlestick transmission of blood-borne hepatitis
viruses
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Surgeon-to-patient HCV transmission phylogenetic
evidence
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HCW-to-patient transmission of HCV UK data
Known transmissions from 5 surgeons (1 cardiac, 2
general, 2 OG) thus far
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Protection of patientsGuidelines??

• Known HCV RNA ve HCWs OUT
• Current HCWs doing EPPs encouraged to be tested
  if risk factors .
• Needlestick injuries early Rx benefit to HCW
• For HCWs entering EPP-specialties test for HCV
  infection

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Diagnosis

• Test for viral antigen and Antibody (ELISA)
• Test for genome (Quantitative RNA PCR)

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Treatment

• Pegylated INF-a Ribavirin