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Hepatitis C Epidemiology, Natural History, Impact, and Viral Kinetics

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Title: Hepatitis C Epidemiology, Natural History, Impact, and Viral Kinetics


1
Hepatitis CEpidemiology, Natural History,
Impact, and Viral Kinetics
  • Kenneth E. Sherman, MD, PhD
  • Gould Professor of Medicine
  • Director, Division of Digestive Diseases
  • University of Cincinnati Medical Center

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Causes of Death in the United States, 2003
National Center for Health Statistics
4
Etiology of Chronic Liver Disease in the U.S.
Bell BP et al. Hepatology 200134468A
5
  • Hepatitis C Virus

Morphology
Characteristics
  • Nucleic acid ssRNA
  • Classification related to pestiviruses and
    flaviviruses
  • Serotypes one with mulitple genotypes
  • In vivo replication liver and lymphocytes

6
HEPATITIS C VIRUSGenome
3
5
Internal Ribosomal Entry Site
RNA Binding Site
Envelope Glyco-proteins
Signal peptide
Serine protease/ helicase
RNA dependent RNA polymerase
NONSTRUCTURAL PROTEINS
7
HCV DIVERSITY
  • HCV replicates at high levels (gt10 trillion
    virions/day
  • Lack of error correction leads to drift
  • Drift is observed in two forms
  • Quasispecies
  • Genotypes

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HCV Infection
  • 200,000,000 Chronic Infections Worldwide
  • At least 4 Million in US
  • Highly Associated With Development of
  • Cirrhosis
  • Hepatocellular Carcinoma
  • Leading Etiology for Liver Transplant in the
    United States

11
Prevalence of HCV Infection in General Population
Armstrong GL, Ann Intern Med 2006144705-714
12
Current Hepatitis C Disease Burden, US
  • New infections per year
  • - 1985-1989 242,0001
  • - 2003 30,0002
  • Deaths from acute liver failure rare2
  • Persons ever infected (1.6) 4.1 million3
  • - Persons undiagnosed 2.1 million4
  • Persons with chronic infection 3.2 million3

Estimated deaths from chronic disease/year
8,000-10,0002
1Armstrong et al. Hepatology 200031377-382 2
CDC. Hepatitis C Fact Sheet. Available at
www.cdc.gov. Accessed March 29, 2005 3 Armstrong
et al. Ann Intern Med 2006144705-714. 4 Wasley
AM et al. ISVHLD 2006, Paris
13
Higher Estimates of HCV in US
  • NHANES (1988-1994)
  • 3.9 million infected
  • 2.7 active HCV infection
  • Excluded several high risk populations
  • Prevalence estimated in
  • Homeless
  • Prisoners
  • Military
  • Nursing Home
  • Hospitalized Patients
  • New Estimate 4.7-5.1 million infected and 3.4
    million with Active Disease

Edlin et. al. ,Hepatology Supp. Abs. 44, 2005
14
Who Should be Screened?
Based on increased risk for infection
  • Ever injected illegal drugs
  • Received clotting factors made before 1987
  • Received blood/organs before July 1992
  • Ever on chronic hemodialysis
  • Evidence of liver disease
  • HIV-positive
  • Healthcare and emergency personnel after exposure
  • Children born to HCV-positive women

Based on need for exposure management
15
Who Does Not Need Routine Screening?
  • Confirmed risk factor but prevalence low¹
  • Health-care, emergency medical, public safety
    workers
  • History of STDs or multiple sex partners
  • Long-term steady sex partners of HCV-positive²
  • Individualize counseling, testing partner may be
    beneficial
  • Unconfirmed and prevalence low³
  • Intranasal cocaine or other non-injecting illegal
    drug users
  • History of tattooing, body piercing

¹ CDC. MMWR 199847(RR-19) ² Strader et al.
Hepatology 2004391147-1171 ³ Hwang et al.
Hepatology 200644341-351
16
Tests for Hepatitis C
  • Enzyme Immunoassay (EIA)
  • Recombinant Immunoblot Assay (RIBA)
  • Qualitative HCV RNA
  • Quantitative HCV RNA
  • HCV Genotype

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HCV RNA levels in Sequential Serum Samples
Gordon et. al., HEPATOLOGY, 1998
19
Viral Dynamics of Hepatitis C Virus Infection
Rate of production of target cells , pt
Cell death ?
Viral load V
Clearance of virions c
Cell death ?
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Steady State
  • Terminology
  • Viral load, V, free virus particles in serum
  • p Production
  • c Clearance
  • pV cV ergo EQUILIBRIUM

Virus is being produced and cleared at the same
rate
What does the viral load at steady state tell
us? Predicts progression in HIV Predicts response
to interferon based therapy for HCV
21
STEADY STATE
  • Yields steady state (equilibrium) differential
    equation before therapy

22
INTERVENTION
  • INTERFERON
  • RIBAVIRIN
  • OTHER IMMUNE MODULATORS (e.g. Thymosin,
    Therapeutic Vaccines)
  • ANTIVIRALS
  • Serine Protease
  • Helicase
  • RNA Dependent RNA Polymerase
  • Fusion Inhibitors

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THE PERFECT DRUG
If Production (P) is Stopped (P0) Then
or
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MOST DRUGS CANNOTBLOCK 100 of PRODUCTION
  • IFN partially blocks viral production (drug
    efficacy ?)

25
Biphasic viral dynamic model
Antiviral therapy
Therapeutic Implications
  • When E lt 1, biphasic at the same e, therapeutic
    outcome relies on the 2nd decline phase (i.e.,
    Infected cell death rate by individuals immune
    activity).
  • Drug or dosing efficacy is a key parameter in
    the initial viral decline phase.
  • Estimated Time to Clearance is based upon the
    combination of E and the 2nd Phase Decline slope

Phase 1 Inhibition of Production/Release
Phase 2Inhibition /clearance of infected cells
26
Model predictions on the effect of efficacy of
inhibition of viral production
  • (A) Effect of efficacy on the kinetics of HCV
    clearance.
  • (B) Effect of efficacy on the time required to
    reduce viral load to clearance level.

Tsiang et. al., HEPATOLOGY, 1999
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Coinfected patient treated with PEG-IFN
ribavirin
Cleared at day 56, model predicted 64 days to
clearance
Case Baseline log10 HCV VL 6.85 e 0.961 ?2
0.014 Days to clear 56
28
Matched pair treated with PEG-IFN r
demonstrating a steep phase 1 slope for control,
indicating lack of fit of a 2-phase model
Case Baseline log10 HCV VL 6.75 e 0.723 ?2
0.028 Days to clear never cleared (predicted
492)
Control Baseline log10 HCV VL 4.90 e
0.997 ?2 0.158 Days to clear 3
29
Model Failure
30
NON-LINEAR MODELMean Fitted Curve
Sherman et al., 10th CROI, 2002
31
NON-LINEAR MODELMean Fitted Curve
Sherman et al., 10th CROI, 2002
32
HCV vs COINFECTEDPooled Model14 days
33
HCV vs COINFECTEDPooled Model To Clearance
Differential time to clearance 62 days
34
HOW DOES THIS HELP?
  • CHACTERIZES EFFECT OF INTERVENTION
  • PERMITS COMPARISONS
  • Different Agents
  • Different Population Groups
  • INTRODUCES PREDICTION CAPABILITY
  • CREATES HYPOTHETICAL FRAMEWORK THAT CAN BE TESTED

35
PREDICTION OF RESPONSE STOPPING RULES
  • Pretreatment
  • During Treatment Negative Prediction of SVR
  • 24 Weeks
  • 12 Weeks (EVR or Early Viral Response)
  • 4 Weeks (RVR or Rapid Viral Response)
  • ? 1-3 days

36
PEG IFN Alfa-2a RBV Predictability Analysis
Week 12 (N 453)
n 25365
SVR
Yes
n 390 86
n 137 35
No SVR
2-log10 dropor neg HCV RNA
SVR
n 23
n 6314
No
n 61 97
No SVR
Fried et al. N Engl J Med. 2002347975-982.
37
Predictability of SVR Following PEG-IFN ?-2b
RBV
Week 12 (N 512)
n 273(70)
SVR
Yes
n 388 (76)
No SVR
n 115 (30)
?2 log10 dropor neg HCV RNA
n 1(1)
SVR
n 124(24)
No SVR
No
n 123 (99)
Davis GL. HEPATOLOGY 200236S145-S151
38
SOURCES OF VARIABILITY IN MODELING
  • Assay Variability
  • Different Agents (IFN alfa 2a vs IFN alfa 2b)
  • Sampling Times/Frequency
  • Patient Populations including Controls
  • Inclusion of Outliers in Analysis
  • Nonresponders
  • Rapid Responders
  • Missing data points

39
WHY DOES A MODEL FAIL?
  • Fails to account for all parameters
  • Assumes clearance is constant
  • Assumes fixed rate of new hepatocyte formation
  • Assumes steady state of viral load prior to
    treatment
  • Assumes infected cell death rate is constant
  • Assumes one viral compartment
  • Does not permit selection for virus with
    different level of fitness

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FIBROTIC PROGRESSION
Mild
15-33
Moderate
Severe fibrosis
Cirrhosis- mild
Cirrhosis - severe
20-33
HCC
10
20
30
0
40
50
Years
adapted from Afdhal, Sem Liver Disease, 2004
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Histologic Progression of HCV
Normal
Mild Chronic Hepatitis
Cirrhosis
Moderate Chronic Hepatitis
44
Rates of Progression
Degree of Fibrosis on Initial Liver Biopsy
100
75
Percent of Progression to Cirrhosis
50
25
0
5
10
15
20
Years
45
HCV in Cirrhotic PatientsRisk of Decompensation
and HCC
Fattovich et al., Gastroenterology 1997 112463
46
Cumulative SurvivalChronic HCV
Niederau, et al. Hepatology, Dec 1998
47
Predicted HCV-Related Mortality in the USA
Hepatocellular carcinoma (HCC)
30,000
Non-HCC liver-related
20,000
10,000
5,000
0
1992
1995
1998
2001
2004
2007
2010
2013
2016
2019
Year
Wong JB, et al. Am J Public Health.
20009015621569.
48
HCV and Quality of Life
  • GR Foster, et al. Hepatology 1998

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53
and miles to go before we sleep.

paraphrased from Robert Frost- 1923
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