Part of Flaviviridae family of viruses
Associated with both human and animal disease
3 genera: pestiviruses (cattle, pigs), flaviviruses (dengue,
yellow fever), hepaciviruses (HCV)
In hepacivirus family
6 major clades
>100 different subtypes
Countless quasispecies: mult. seen in each infected individual
Study of Infection, Replication and Release
Lack of reliable culture system
Does not integrate into host genome
Low number of circulating virions
5%-25% over 20-30 years
Acute Hepatitis C
No jaundice (80%). Usually asymptomatic.
Can be severe, but liver failure rare
15-40% will usually resolve.
Only real threat of acute Hepatitis C is its ability to
reach chronic stages undetected and untreated.
3.2 million persons chronically infected (average age 55 years,
perhaps 40% have cirrhosis)
8000-10.000 deaths each year (US)
Majority unaware of infection: not clinically ill (only 25-30% have been
diagnosed, only 11% have been treated)
221.000 people with chronic hepatitis C
Leading reason for liver transplant
Deaths have surpassed HIV
Commercial HCV Assays
HCV RNA detection
Molecular HCV genotyping
There is a seronegative window in which HCV RNA is the only
marker that permits the diagnosis of primary HCV infection and the
identification of potentially infectious patients that would be missed
by conventional antibody testing
High rate of viral persistence
Lack of solid immunity
Poor definition of protection correlates
Technical limitations in the study of HCV
HCV RNA negative at 4 weeks (< 50 IU/mL)
HCV RNA negative or > 2 log10 drop at week 12.
cEVR (complete) or pEVR (partial)
HCV RNA negative 24 weeks after end of treatment
HCV RNA negative at end of treatment but HCV RNA
positive after treatment stopped
Previously, treatment recommendation was based on
the HCV genotype
The early kinetics of HCV viremia (week 4) are
emerging as the most reliable predictive marker of
Quantification of HCV viremia is essential for
tailoring the treatment schedule: Response Guided
Genotype 2 and 3
HCV RNA < 400,000 IU/ml
Mild fibrosis (F0-F2)
Age < 40
RVR and cEVR
HCV RNA > 400,000 IU/ml
Advanced fibrosis (F3-F4)
Age > 40
Steatosis, Insulin Resistance,
IL28B CT or TT
Dose reduction > 60%
Are added to (do not replace) original therapy.
treatment of chronic Hep C (genotype 1).
with compensated liver disease, including cirrhosis.
previously untreated or who have failed previous interferon
and ribavirin therapy.
DCV (PI) + SOF (Nuc-PoI) in Boceprevir/PR failures.
PEG / RBV + Simeprevir (2nd gen PI)
PEG / RBV + Sofosbuvir (PoI)
Genotype 2, 3:
RBV + Sofosbuvir
Off label combination of available DAA classes
Simeprevir + Sofosbuvir + RBV for GT1
Emerging DAA therapy against 3 major viral proteins will
provide solutions for most patients with HCV.
Nonoverlapping resistance profile
Enough genotypic / subgenotypic range
High barriers compounds desirable for simplified regimens.
Can be matched by combinations of DAA classes.
Novel host targets increasingly identified, including many
involved in Lipid metabolism. Inherently high barrier to
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