Hepatitis C: A Global Time Bomb
Patrizia Farci, M.D.
Hepatic Pathogenesis Unit
Hepatitis Viruses Section
LID/NIAID/NIH
Michael Houghton & Harvey J. Alter
Albert 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!
….
….
Long-Term Sequelae of Chronic Hepatitis
HBV
HCV
HDV
Hepatocellular
carcinoma
Normal Chronic Cirrhosis
liver hepatitis
Overlapping HCV & HIV Epidemics
HIV HCV
50 million
170 million
10
million
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
Diagnosis of HCV Infection
Acute Chronic
Immunocompetent
Immunodeficient
Diagnosis of HCV Infection
Commercial HCV Assays
Indirect Direct
Serological assays Virological assays
Antibody assays HCV RNA detection
EIA-III - Qualitative
RIBA-III - Quantitative
Molecular HCV
genotyping
Acute HCV Infection
Symptoms +/–
HCV RNA
Anti-HCV (EIA-III)
Exposure
ALT
0 2 4 6 8 10 12 14 16 18 20 22 1 2 3 4 5 6
Weeks Years
Time after exposure
Acute HCV Infection
Symptoms +/–
HCV RNA
Anti-HCV (EIA-III)
Exposure
ALT
0 2 4 6 8 10 12 14 16 18 20 22 1 2 3 4 5 6
Weeks Years
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
Chronic HCV Infection
Persistence of HCV RNA for at least 6 mos
Diagnosis of Assessment
infection of disease
Treatment
evaluation
Testing Strategy in Clinical Practice:
Diagnosis of Chronic HCV Infection
Immunocompetents
HCV antibody screening
If positive +
HCV RNA qualitative or HCV RNA quantitative
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
Anti-HCV+ by EIA-III
HCV RNA+ by PCR
300 7
6
HCV RNA Log10
250
ALT (IU/L)
(IU/ml)
200 5
150
4
3
100 2
50 1
0 0
0 4 8 12 16 20 24 28
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
Treatment of Chronic Hepatitis C
Predictive Value of Early Viral Kinetics
Baseline
Week 4
HCV RNA - HCV RNA +
Shorter treatment Longer treatment
HCV
Genetic 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
Prevention
Therapy
Available Tools for the
Control of HCV infection
Prevention
Therapy
Global Control of HCV
infection
Prevention
Therapy
Vaccine
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
National Institutes of Health, Bethesda, MD
Laboratory of Infectious Department of Transfusion
Diseases, NIAID Medicine, Clinical Center
Robert H. Purcell Harvey J. Alter
Ashley Tice
Marta Melis
University of Cagliari, Italy
Liver Unit Liver Transplantation Center
Eliana Lai Fausto Zamboni
Luchino Chessa
Stefania Farci Department of Cytomorphology
Rita Strazzera Giacomo Diaz
Cinzia Balestrieri
Giancarlo Serra
