Janin speaks on the dawn of a revolution for treating Hepatitis C. This was recorded at Bedside Critical Care Conference 4. Full postings can be found at www.intensivecarenetwork.com
5. 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
6.
7. Study of Infection, Replication and Release
Difficult:
Lack of reliable culture system
Does not integrate into host genome
Low number of circulating virions
10. Complex, dynamic
distributions of non-identical
but related mutant RNA
genomes
Encompasses a master
genome (dominant) and a
multitude of minor genomes
12. Exposure
(Acute Phase)
Resolved Chronic
CirrhosisStable
Liver Decompensation
Hepatocellular Carcinoma
5%-25% over 20-30 years
15-45%
55-85%
5%/yr decompensation
2-8%/yr HCC
75-95%
Primary Point
of Intervention
Acute Hepatitis C
Generally benign:
No jaundice (80%). Usually asymptomatic.
Can be severe, but liver failure rare
15-40% will usually resolve.
13. Only real threat of acute Hepatitis C is its ability to
reach chronic stages undetected and untreated.
16. 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)
17. 221.000 people with chronic hepatitis C
Leading reason for liver transplant
Deaths have surpassed HIV
HIV HCV
18.
19.
20. Indirect
Serological assays
Direct
Virological assays
Commercial HCV Assays
Antibody assays
EIA-III
RIBA-III
HCV RNA detection
- Qualitative
- Quantitative
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
21. Genetic heterogeneity
High rate of viral persistence
Lack of solid immunity
Poor definition of protection correlates
Technical limitations in the study of HCV
23. SVR is defined as absence of HCV RNA in the serum
at the end of treatment and 6 months later
Patients who achieve an SVR may be deemed
clinically cured of chronic HCV
27. RVR
RapidVirologic Response
HCV RNA negative at 4 weeks (< 50 IU/mL)
EVR
EarlyVirologic Response
HCV RNA negative or > 2 log10 drop at week 12.
cEVR (complete) or pEVR (partial)
SVR
Sustained Virologic
Response
HCV RNA negative 24 weeks after end of treatment
Relapse
HCV RNA negative at end of treatment but HCV RNA
positive after treatment stopped
28.
29. 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
response
Quantification of HCV viremia is essential for
tailoring the treatment schedule: Response Guided
Therapy
30. Favorable
Genotype 2 and 3
HCV RNA < 400,000 IU/ml
Mild fibrosis (F0-F2)
Age < 40
IL28B CC
Adherence
RVR and cEVR
Unfavorable
Genotype 1
HCV RNA > 400,000 IU/ml
Advanced fibrosis (F3-F4)
Age > 40
Steatosis, Insulin Resistance,
high BMI
IL28B CT or TT
Dose reduction > 60%
Non-adherence
31. Side effects
Flu-like symptoms
Weight loss
Depression
Neutropenia
Concentration/memory
disturbance
Insomnia
Thrombocytopenia
38. Are added to (do not replace) original therapy.
Indications:
treatment of chronic Hep C (genotype 1).
with compensated liver disease, including cirrhosis.
previously untreated or who have failed previous interferon
and ribavirin therapy.
56. DCV (PI) + SOF (Nuc-PoI) in Boceprevir/PR failures.
57.
58.
59. Genotype 1:
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
60. Emerging DAA therapy against 3 major viral proteins will
provide solutions for most patients with HCV.
Strong potency
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
resistance.