1. Hepatitis C: A Global Time Bomb
Patrizia Farci, M.D.
Hepatic Pathogenesis Unit
Hepatitis Viruses Section
LID/NIAID/NIH

2. Michael Houghton & Harvey J. Alter
Albert Lasker Award for Clinical Medical Research 2000

4. The hepatitis puzzle was still incomplete!
History of Hepatitis C
Blumberg and Alter, 1965
Feinstone, Kapikian & Purcell, 1973
The hepatitis puzzle was still incomplete!

7. …. 7

12. Long-Term Sequelae of Chronic Hepatitis Hepatocellular carcinoma
HBV
HCV
HDV
Hepatocellular carcinoma
Normal liver
Chronic hepatitis
Cirrhosis 12

15. Overlapping HCV & HIV Epidemics
50 million
170 million
10 million

16. 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)

17. Diagnosis of HCV Infection

18. Diagnosis of HCV Infection
Acute
Chronic
Immunocompetent
Immunodeficient

19. Diagnosis of HCV Infection Molecular HCV genotyping
Commercial HCV Assays
Indirect
Serological assays
Direct
Virological assays
Antibody assays
EIA-III
RIBA-III
HCV RNA detection
- Qualitative
- Quantitative
Molecular HCV genotyping

20. Acute HCV Infection Exposure ALT 1 2 3 4 5 6 Years Time after exposure
Symptoms +/–
HCV RNA
Anti-HCV (EIA-III)
Exposure
ALT 1 2 3 4 5 6
Years
Time after exposure

21. Acute HCV Infection
Symptoms +/–
HCV RNA
Anti-HCV (EIA-III)
Exposure
ALT 1 2 3 4 5 6
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

22. Persistence of HCV RNA for at least 6 mos Diagnosis of infection
Chronic HCV Infection
Persistence of HCV RNA for at least 6 mos
Diagnosis of infection
Assessment of disease
Treatment evaluation

23. 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

24. 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

25. Stable Levels of Viremia over Time in
Chronic HCV infection
Anti-HCV+ by EIA-III
HCV RNA+ by PCR
HCV RNA Log10
(IU/ml)
Months of follow-up

26. Repeated testing for HCV RNA levels is not indicated in the routine management and monitoring of untreated patients with hepatitis C

27. 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

28. Quantification of HCV viremia is essential for tailoring the treatment schedule to the individual patient with chronic hepatitis C

29. 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

30. Treatment of Chronic Hepatitis C
Predictive Value of Early Viral Kinetics
Baseline
Week 4
HCV RNA -
HCV RNA +
Shorter treatment
Longer treatment

31. HCV
Genetic Variability

32. Pathogenesis
Prevention

34. Structural genes Non-structural genes34

42. Perinatal HCV Infection: European Pediatric HCV Network
n = 12 children

43. Farci et al., PNAS 2006

44. Farci et al., PNAS 2006

46. Neutralization escape
Protection
Neutralization escape

47. 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

48. Pathogenesis
Prevention

49. Available Tools for the Control of HCV infection
Prevention
Therapy

50. 50

51. Available Tools for the Control of HCV infection
Prevention
Therapy 51

52. 52

53. Global Control of HCV infection
Prevention
Therapy
Vaccine 53

54. 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

55. 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

58. J. Bukh et al., 2008

59. 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

64. Major Unsolved Questions
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?

65. Acknowledgements National Institutes of Health, Bethesda, MD
Laboratory of Infectious
Diseases, NIAID
Robert H. Purcell
Ashley Tice
Marta Melis
Department of Transfusion
Medicine, Clinical Center
Harvey J. Alter
University of Cagliari, Italy
Liver Transplantation Center
Fausto Zamboni
Liver Unit
Eliana Lai
Luchino Chessa
Stefania Farci
Rita Strazzera
Cinzia Balestrieri
Giancarlo Serra
Department of Cytomorphology
Giacomo Diaz 65