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Hepatitis C: A Global Time Bomb
Patrizia Farci, M.D.
Hepatic Pathogenesis UnitHepatitis Viruses Section
LID/NIAID/NIH
Michael Houghton & Harvey J. AlterAlbert Lasker Award for Clinical Medical
Research 2000
History of Hepatitis C
Blumberg and Alter, 1965
Feinstone, Kapikian & Purcell, 1973
The hepatitis puzzle was still incomplete!
….
….
Normal liver
Chronic hepatitis
Cirrhosis
Hepatocellular
carcinoma
Long-Term Sequelae of Chronic Hepatitis
HBVHCVHDV
Overlapping HCV & HIV Epidemics
50 million 170
million10
million
HIV HCV
Exposures Associated with the Majority of HCV Infections
Injecting drug use Transfusion, transplant from infectious donor Contaminated therapeutic injections Occupational blood exposure (needle sticks) Birth to an infected mother Sex with infected partners (multiple partners)
Diagnosis of HCV Infection
Acute Chronic
Diagnosis of HCV Infection
ImmunocompetentImmunodeficient
IndirectSerological
assays
DirectVirological assays
Diagnosis of HCV Infection
Commercial HCV Assays
Antibody assaysEIA-IIIRIBA-III
HCV RNA detection - Qualitative - Quantitative
Molecular HCV genotyping
Acute HCV Infection
0 2 4 6 8 10 12 14 16 18 20 22Weeks
Time after exposureYears
2 3 4 5
Exposure
HCV RNA
Anti-HCV (EIA-III)
Symptoms +/–
ALT
1 6
Acute HCV Infection
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
0 2 4 6 8 10 12 14 16 18 20 22Weeks Years
2 3 4 5
Exposure
HCV RNA
Anti-HCV (EIA-III)
Symptoms +/–
ALT
1 6
Diagnosis of
infection
Assessment of disease
Chronic HCV InfectionPersistence of HCV RNA for at least 6
mos
Treatment evaluation
Testing Strategy in Clinical Practice: Diagnosis of Chronic HCV Infection
Immunocompetents
HCV antibody screening
If positive
+
HCV RNA quantitative
HCV RNA qualitative
or
HCV Genotype
A Negative Anti-HCV Test Does Not Exclude HCV Infection in Patients with Suspected Liver Disease in:
Acute HCV infection
HIV infection
Chronic hemodialysis
In immunosuppressed individuals, HCV RNA testing should be performed regardless of a negative anti-HCV test
Stable Levels of Viremia over Time in
Chronic HCV infection
0
50
100
150
200
250
300
0 4 8 12 16 20 24 28
ALT (IU/L)01234567
Anti-HCV+ by EIA-III
HCV RNA+ by PCR
HCV RNA Log10
(IU/ml)
Months of follow-up
Repeated testing for HCV RNA levels is not indicated in the routine management
and monitoring of untreated patients with hepatitis C
HCV RNA Testing Has No Prognostic Value:
The level of viremia does not correlate with the severity of liver disease (activity grade or fibrosis stage)
Does not predict the outcome of HCV infection (resolution vs. persistence)
Does not predict the natural course of the disease
Quantification of HCV viremia is essential for tailoring the treatment schedule to the individual patient
with chronic hepatitis C
Previously, treatment recommendation was based on the HCV genotype
Presently, the early kinetics of HCV viremia (week 4) are emerging as the most reliable predictive marker of
response
Baseline
Week 4
HCV RNA - HCV RNA +
Shorter treatment Longer treatment
Treatment of Chronic Hepatitis CPredictive Value of Early Viral Kinetics
HCVGenetic Variability
Pathogenesis
Prevention
Structural genes Non-structural genes
Perinatal HCV Infection: European Pediatric HCV Network
n = 12 children
Farci et al., PNAS 2006
Farci et al., PNAS 2006
Protection Neutralization escape
These data provide the first evidence for the in vivo emergence of an immune escape and identify the HVR1 as a major target of HCV-neutralizing antibodies
Immune escape may represent an important mechanism whereby HCV establishes persistent infection in the majority of infected individuals
Pathogenesis
Prevention
Available Tools for the Control of HCV
infection
PreventionTherapy
Available Tools for the Control of HCV
infection
PreventionTherapy
Global Control of HCV infection
PreventionTherapyVaccine
Major Obstacles in Developing an HCV Vaccine
Genetic heterogeneity
High rate of viral persistence
Lack of solid immunity
Poor definition of protection correlates
Technical limitations in the study of HCV
Major Obstacles in Developing an HCV Vaccine
Genetic heterogeneity
High rate of viral persistence
Lack of solid immunity
Poor definition of protection correlates
Technical limitations in the study of HCV
J. Bukh et al., 2008
Major Obstacles in Developing an HCV Vaccine
Genetic heterogeneity
High rate of viral persistence
Lack of solid immunity
Poor definition of protection correlates
Technical limitations in the study of HCV
HCV Pathogenesis: Major Unsolved Questions
Why do some patients clear HCV infection whereas the majority progress to chronicity?
Why do some patients respond to antiviral therapy while others don’t?
Why do some patients develop non-progressive chronic hepatitis C, whereas others rapidly progress to cirrhosis and, eventually, HCC?
Why is cirrhosis the strongest predisposing factor for the development of HCC?
Acknowledgements
University of Cagliari, Italy
Department of Cytomorphology Giacomo Diaz
Liver Unit Eliana Lai
Luchino ChessaStefania FarciRita Strazzera
Cinzia BalestrieriGiancarlo Serra
National Institutes of Health, Bethesda, MD
Laboratory of Infectious Diseases, NIAIDRobert H. Purcell Ashley Tice Marta Melis
Department of Transfusion Medicine, Clinical Center
Harvey J. Alter
Liver Transplantation Center Fausto Zamboni