Hepatitis C

Epidemiology, 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
Causes of Death in the United States,
2003
Rank All Ages 35 – 54 Years
1 Heart diseases Malignant neoplasms
2 Malignant neoplasms Heart diseases
3 Cerebrovascular Unintentional injury
4 Lower respiratory disease Suicide
5 Unintentional injury Chronic liver disease
6 Diabetes mellitus HIV/AIDS
7 Influenza & pneumonia Cerebrovascular disease
8 Alzheimer’s Diabetes mellitus
9 Nephritis Homicide
10 Septicemia Lower respiratory disease
11 Suicide Influenza & pneumonia
12 Chronic liver disease Septicemia

National Center for Health Statistics

 Etiology of Chronic Liver
Disease in the U.S.
HBV 4%
Insufficient
Data 6%
Other 8%

HCV 42%
NAFLD 10%

Alcohol 8%

HCV & Alcohol

22%

Bell BP et al. Hepatology 2001;34:468A

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
 HEPATITIS C VIRUS
Genome
5’ 3’
C E1 E2/NS1 NS2 NS3 NS4A NS4B NS5A NS5B

Internal RNA Envelope Signal Serine protease/ RNA dependent

peptide
Ribosomal Binding Glyco- helicase RNA polymerase
proteins
Entry Site Site

STRUCTURAL NONSTRUCTURAL
PROTEINS PROTEINS
 HCV DIVERSITY
• HCV replicates at high levels (>10 trillion
virions/day
• Lack of error correction leads to drift
• Drift is observed in two forms
– Quasispecies
– Genotypes
 6B 7B 11A
6A

8B

4A
9A

2C

5A

2A

1A

2B 1C

1B

Patient
10% 10A 3A
 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
 Prevalence of HCV Infection in General
Population
NH White NH Black Mex Amer
10
Percent Anti-HCV Positive

9
8
7
6
5
4
3
2
1
0
6-19 20-29 30-39 40-49 50-59 60-69 70+
Age group

Armstrong GL, Ann Intern Med 2006;144:705-714

 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 2000;31:377-382
2 CDC. Hepatitis C Fact Sheet. Available at: www.cdc.gov. Accessed March 29, 2005
3 Armstrong et al. Ann Intern Med 2006;144:705-714.
4 Wasley AM et al. ISVHLD 2006, Paris
 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

 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

Based on need for exposure management

• Healthcare and emergency personnel after exposure
• Children born to HCV-positive women
 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 1998;47(RR-19)
² Strader et al. Hepatology 2004;39:1147-1171
³ Hwang et al. Hepatology 2006;44:341-351
 Tests for Hepatitis C

 Enzyme Immunoassay (EIA)

 Recombinant Immunoblot Assay (RIBA)

 Qualitative HCV RNA

 Quantitative HCV RNA

 HCV Genotype
HCV RNA levels in Sequential Serum Samples
 Viral Dynamics of Hepatitis C Virus Infection
Rate of production of target cells , pt

Uninfected
hepatocytes
Cell death 
T

Viral load
V Clearance
Productively of virions c
Cell death infected
 hepatocytes
I
 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
 STEADY STATE

• Yields steady state

(equilibrium)
differential equation
before therapy:

dV
 P  cV  0
dt
 INTERVENTION

• INTERFERON
• RIBAVIRIN
• OTHER IMMUNE MODULATORS (e.g.
Thymosin, Therapeutic Vaccines)
• ANTIVIRALS
– Serine Protease
– Helicase
– RNA Dependent RNA Polymerase
– Fusion Inhibitors
 THE “PERFECT DRUG”

If Production (P) is Stopped (P=0)

Then……

dV
 cV
dt
1 dV
or  c
V dt
 MOST DRUGS CANNOT
BLOCK 100% of
PRODUCTION
• IFN partially blocks
viral production
(drug efficacy = ):

dV
 (1   ) pI  cV
dt
Biphasic viral dynamic model
Antiviral therapy
Phase 1: Inhibition of Production/Release
Phase 2:Inhibition +
/clearance of infected cells
Therapeutic Implications
When E < 1, biphasic: at the same e,
therapeutic outcome relies on the 2nd
decline phase (i.e., Infected cell death
rate by individual’s 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
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
 Coinfected patient treated with PEG-IFN
+ ribavirin

Cleared at day 56, model predicted 64 days to clearance

Case: Baseline log10 HCV VL = 6.85

ε = 0.961
λ2 = 0.014
Days to clear = 56
 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 Control: Baseline log10 HCV VL = 4.90
ε = 0.723 ε = 0.997
λ2 = 0.028 λ2 = 0.158
Days to clear = never cleared (predicted = 492) Days to clear = 3
Model Failure
 NON-LINEAR MODEL
Mean Fitted Curve

Sherman et al., 10th CROI, 2002

NON-LINEAR MODEL
Mean Fitted Curve
HCV vs COINFECTED
Pooled Model:14 days
 HCV vs COINFECTED
Pooled Model: To Clearance

Differential time to clearance= 62 days

 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
 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
 PEG IFN Alfa-2a + RBV
Predictability Analysis
Week 12 (N = 453)
SVR n = 253
65%
Yes n = 390
86% n = 137
No SVR 35%
2-log10 drop
or neg HCV RNA
SVR n=2
3%
n = 63
No 14% n = 61
97%
Fried et al. N Engl J Med. 2002;347:975-982. No SVR
 Predictability of SVR Following
PEG-IFN -2b + RBV
Week 12 (N = 512)
n = 273
SVR
(70%)
Yes n = 388
(76%) No SVR
n = 115
(30%)
2 log10 drop
or neg HCV RNA

SVR n=1
(1%)
n = 124 No SVR
No (24%) n = 123
(99%)

Davis GL. HEPATOLOGY 2002;36:S145-S151

 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
 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
 FIBROTIC PROGRESSION

Mild

Moderate 15-33%

Severe fibrosis

Cirrhosis- mild

Cirrhosis - severe
20-33%
HCC
0 10 20 30 40 50
Years

adapted from Afdhal, Sem Liver Disease, 2004

 Histologic Progression of HCV

Normal Mild Chronic Hepatitis

Moderate Chronic Hepatitis Cirrhosis

 Rates of Progression
Degree of Fibrosis on Initial Liver Biopsy
Percent of Progression to Cirrhosis

100

75

50

25

0 5 10 15 20

Years
 HCV in Cirrhotic Patients
Risk of Decompensation and HCC

Fattovich et al., Gastroenterology 1997; 112:463

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. 2000;90:1562–1569.
…and miles to go before we sleep.
paraphrased from Robert Frost- 1923