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Hepatitis C: A Global Time Bomb

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.

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Hepatitis C: A Global Time Bomb

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  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

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

  4. …. ….

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

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

  7. 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)

  8. Diagnosis of HCV Infection

  9. Diagnosis of HCV Infection Acute Chronic Immunocompetent Immunodeficient

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

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

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

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

  14. + Testing Strategy in Clinical Practice: Diagnosis of Chronic HCV Infection Immunocompetents HCV antibody screening If positive or HCV RNA quantitative HCV RNA qualitative HCV Genotype

  15. 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

  16. 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

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

  18. 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

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

  20. 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

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

  22. HCV Genetic Variability

  23. Pathogenesis Prevention

  24. Structural genes Non-structural genes

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

  26. Farci et al., PNAS 2006

  27. Farci et al., PNAS 2006

  28. Protection Neutralization escape

  29. 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 antibodiesImmune escape may represent an important mechanism whereby HCV establishes persistent infection in the majority of infected individuals

  30. Pathogenesis Prevention

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

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