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