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

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

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

Overlapping HCV & HIV Epidemics 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 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

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

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

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

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 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

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 34

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

Farci et al., PNAS 2006

Farci et al., PNAS 2006

Neutralization escape 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

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Available Tools for the Control of HCV infection Prevention Therapy 51

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Global Control of HCV infection Prevention Therapy Vaccine 53

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

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?

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