Mitchell L. Shiffman, MD

1
Hepatitis CEpidemiology, Diagnosis and
Treatment

• Mitchell L. Shiffman, MD
• Professor of MedicineChief, Hepatology
  SectionMedical Director, Liver Transplant
  ProgramVirginia Commonwealth University Health
  SystemRichmond, Virginia

2
Hepatitis CEpidemiology
3
Hepatitis C Virus InfectionMagnitude of the
Problem

• Nearly 4 million persons in United States
  infected
• Approximately 35,000 new cases yearly
• 85 of new cases become chronic
• Leading cause of
• Chronic liver disease
• Cirrhosis
• Liver cancer
• Liver transplantation

Centers for Disease Control and Prevention.
Hepatitis C fact sheet. Available at
http//www.cdc.gov/ncidod/diseases/hepatitis/c/fac
t.htm. Accessed February 1, 2006.
4
Hepatitis C VirusFate of Acute Infection
Spontaneous resolution
15
Chronic
85
Alter MJ, et al. N Eng J Med. 1999341556-562.
5
Hepatitis C VirusResponse to Acute Infection
200
/-

-
HCV RNA
150
Resolution
ALT (IU/l)
100
Chronic
50
0
0
6
12
18
24
Month
Illustration by Mitchell L. Shiffman, MD.
6
Hepatitis C Virus InfectionNatural History
Acute HCV
Resolved 15 (15)
Chronic HCV 85 (85)
Stable 80 (68)
Cirrhosis 20 (17)
HCC Liver failure 25 (4)
Slowly progressive 75 (13)
HCC, hepatocellular carcinoma
7
Hepatitis C Virus InfectionPopulation at Risk

• Transfusion of blood products before 1992
• Intravenous drug use
• Nasal inhalation of cocaine
• Chronic renal failure on dialysis
• Incarceration
• Occupational exposure to blood products
• Transplantation of an organ/tissue graft from an
  HCV-positive donor
• Body piercing and potentially tattoo

Centers for Disease Control and Prevention.
Hepatitis C fact sheet. Available at
http//www.cdc.gov/ncidod/diseases/hepatitis/c/fac
t.htm. Accessed February 1, 2006.
8
Hepatitis C Virus InfectionPrevalence
4.0
3.0
Anti-HCV Positive ()
1.8
2.0
1.0
0
All
W
B
H
M
F
Sex
Race
B, Blacks F, female H, Hispanic M, male W,
Whites.
Alter MJ, et al. N Eng J Med. 1999341556-562.
9
Hepatitis C Virus Infection Prevalence by Age
5.0
4.0
3.0
Anti-HCV Positive ()
2.0
1.0
0
lt 11
11-19
20-29
30-39
40-49
50-59
60-69
70
Age Group
Alter MJ, et al. N Eng J Med. 1999341556-562.
10
Hepatitis CDiagnosis and Management
11
Management of Chronic HCVTests Utilized
Disease Severity Response to Therapy
AST/ALT Bilirubin Albumin Pro-time (INR) Platelet count Liver histology ALT HCV RNA HCV genotype Liver histology
LFTs
12
Viral HepatitisRole of Diagnostic Testing

• Identify patients with viral hepatitis infection
• Previous exposure to hepatitis virus
• Active infection
• Inactive infection
• Resolved infection
• Assess response to therapy
• Prior to onset of treatment
• During and following treatment

13
Hepatitis C VirusDiagnostic Testing
Diagnostic Test Type Diagnostic Test Type
Specifications Serologic Virologic
Mode of detection Antibodies Virus
Sensitivity gt 95 gt 98
Specificity Variable gt 98
Detection postexposure 2-6 months 2-6 weeks
Use Screening Confirmation
14
Hepatitis C VirusHost Production of HCV
Antibodies

• HCV infects cell
• HCV proteins expressed on surface of hepatocytes
• Antibodies to HCV proteins produced by host
• HCV antibodies DO NOT convey immunity

Y
Y
Y
Y
Y
Y
Y
Y
Illustration by Mitchell L. Shiffman, MD.
15
Testing for Hepatitis C VirusAnti-HCV Antibodies

• ELISA screening test
• Sensitivity 97
• Detects circulating HCV antibodies
• False positive reactions may occur
• Cross-reacting circulating antibodies
• Nonspecific binding of anti-HCV antibodies
• Positive predictive value
• 95 with risk factors and elevated ALT
• 50 without risk factors and normal ALT

Illustration by Mitchell L. Shiffman, MD.
16
HCV Antibody TestingLimitations

• False positives
• Autoimmune disorders
• Spontaneous resolution of viral infection
• False negatives
• Chronically immune suppressed
• Transplant recipients
• Chronic renal failure on dialysis
• HIV positive

17
Testing for Hepatitis C VirusRecombinant
Immunoblot Assay

• Supplemental assay
• Detects circulating antibodies to 4 HCV proteins
• Antigen-antibody reaction
• More specific than anti-HCV enzyme immunoassay
• False positive reaction can still occur
• Largely replaced by HCV RNA testing

Control
Positive 2 bands
Indeterminate 1 band
Illustration by Mitchell L. Shiffman, MD.
18
Testing for Hepatitis C VirusIndications for HCV
RNA

• Confirm HCV infection
• Persistently normal serum ALT
• No risk factors
• HCV antibody positive
• Antinuclear antibodies
• Prior to initiating therapy
• Assess effectiveness of treatment
• Predict likelihood of response before and during
  therapy
• Confirm response after therapy completed

19
Testing for Hepatitis C VirusVirologic Assays
PCR TMA b-DNA
Polymerase chain reaction Transcription mediated amplification Branched chain DNA
Amplifies target Amplifies target Amplifies probe
Qualitative Quantitative Qualitative Quantitative
20
Quantitative HCV RNA AssaysInherent Variability

• Normal variation of 1 log unit in HCV RNA assays
• Differences of lt 1 log between samples of
  probably NOT significant
• HCV RNA titer best reported in log units

100,000,000
10,000,000
1,000,000
100,000
HCV RNA (IU/mL)
10,000
1000
100
10
1
I
II
III
IV
V
Sample
Nolte FS, et al. J Clin Microbiol.
2001394005-4012.
21
Serum HCV RNA LevelStability Over Time
8
Patient
1
6
2
(IU/mL)
Log HCV RNA
3
4
4
5
2
Limit of detection
0
Baseline
1
2
3
4
Time (Years)
Ferreira-Gonzalez A, et al. Semin Liver Dis.
2004249-18.
22
HCV RNA and Liver HistologyFibrosis

• Serum HCV RNA does not correlate with level of
  fibrosis

8
Genotype
6
1
Log HCV RNA
(copies/mL)
2
4
3
4
2
0
No Fibrosis
Portal Fibrosis
Bridging Fibrosis
Cirrhosis
Ferreira-Gonzalez A, et al. Semin Liver Dis.
2004249-18.
23
HCV RNA and Liver HistologyInflammation

• Serum HCV RNA does not correlate with level of
  inflammation

8
Genotype
6
1
2
(copies/mL)
Log HCV RNA
4
3
4
2
0
0
2
4
6
8
10
12
Inflammation Score
Ferreira-Gonzalez A, et al. Semin Liver Dis.
2004249-18.
24
Hepatitis C VirusGenotypes in the USA
Type 2
17
Type 3
10
Type 1
72
All others
1
McHutchinson JG, et al. N Engl J Med.
19983391485-1492.
25
Determination of HCV GenotypeINNOLiPA Assay

• HCV genotype
• Best pretreatment predictor of response
• Determines duration of therapy
• All patients should have genotype determined
  prior to initiating therapy

Illustration by Mitchell L. Shiffman, MD.
26
Hepatitis C Virus InfectionLiver Biopsy

• Only test that can accurately assess
• Severity of inflammation
• Degree of fibrosis
• Determines the following
• Risk for developing cirrhosis in future
• Need for therapy
• Need for ongoing therapy when initial treatment
  has failed

27
Management of Chronic HCVIs Liver Biopsy
Necessary?
NO
Patient wants treatment even if no fibrosis Patient does not want treatment or treatment contraindicated even if advanced fibrosis Labs and radiographic studies do not suggest cirrhosis Patient achieves SVR
YES
Patient would only accept treatment if advanced fibrosis Labs or radiographic studies suggest cirrhosis may be present Patient fails to achieve SVR and no recent biopsy available
28
Assessment of Liver HistologyNoninvasive Serum
Tests
1.0
1.0
0.8
0.8
0.6
0.6
ACTITEST
FIBROTEST
0.4
0.4
0.2
0.2
0
0
0
1
2
3
4
0
1
2
3
Fibrosis Stage
Activity Grade
Poynard T, et al. Hepatology. 200338481-492.
29
Chronic HCV With Normal Serum ALTALT Patterns
and Flares
120
Single elevations
100
Periodic elevations
Always normal
80
60
ULN
ALT (IU/l)
40
20
0
0
3
6
9
12
15
18
21
24
Month
Illustration by Mitchell L. Shiffman, MD.
30
Chronic HCV InfectionNormal Serum ALT
Normal ALT Elevated ALT
n 37 n 58
Race White, Black, 48 29 52 71
Serum ALT, IU/L 46.6 5.2 76.7 6.0
Log HCV RNA, copies/mL 5.42 0.13 5.50 0.07
Histology score Inflammation Fibrosis 4.2 0.1 0.7 0.2 5.3 0.1 1.6 0.2
Shiffman ML, et al. J Infect Dis.
20001821595-1601.
31
Chronic HCV InfectionNormal vs Elevated Serum ALT
Portal
Bridging
26
13
Cirrhosis
Bridging
Portal
18
6
20
No
Cirrhosis
fibrosis
6
23
No
fibrosis
Mild
16
Mild
33
39
Normal ALT
Elevated ALT
Shiffman ML, et al. J Infect Dis.
20001821595-1601.
32
Chronic HCV InfectionSymptoms
Symptomatic
100
37
Cirrhosis
80
7
60
Percentage of Patients
40
20
56
Asymptomatic
0
Fatigue
Unpublished data from MCV Hepatitis Program, 1995.
33
Chronic HCV InfectionProgression to Cirrhosis
Proportion of Patients Developing Cirrhosis
According to Initial Level of Fibrosis
Approximate Percentage of Patients With Cirrhosis
100
80
Bridging
60
Portal
40
None
20
0
0
5
10
15
20
Time (Years)
Yano M, et al. Hepatology. 1996231334-1340.
34
Fibrosis Progression of HCVEffect of Inflammation
Change in Fibrosis Score According to Necrosis Score at Baseline Change in Fibrosis Score According to Necrosis Score at Baseline Change in Fibrosis Score According to Necrosis Score at Baseline Change in Fibrosis Score According to Necrosis Score at Baseline
Piecemeal Necrosis Score at Baseline Piecemeal Necrosis Score at Baseline Piecemeal Necrosis Score at Baseline
0-1 3-2 gt 4
Number of patients 30 66 27
Mean change in fibrosis score per year .05 .19 .37
Ghany MG, et al. Gastroenterol. 200312497-104.
35
HCV Fibrosis Progression Effect of Alcohol
4.0
3.0
Alcohol intake
2.0
Fibrosis Score
gt 50 g/day
lt 50 g/day
1.0
0
11-20
21-30
31-40
gt 40
lt 10
Duration of Infection (Years)
50 g is equal to approximately 3.5 drinks
Poynard T, et al. Lancet. 1997349825-832.
36
HCV Fibrosis ProgressionEffect of Age
4.0
3.0
Age at time of infection
gt 40 years
2.0
Fibrosis Score
lt 40 years
1.0
0
11-20
21-30
31-40
gt 40
lt 10
Duration of Infection (Years)
Poynard T, et al. Lancet. 1997349825-832.
37
HCV Fibrosis ProgressionEffect of Histology
4.0
3.0
Fibrosis
Grade or Stage
2.0
Inflammation
1.0
0
11-20
21-30
31-40
gt 40
lt 10
Duration of Infection (Years)
Poynard T, et al. Lancet. 1997349825-832.
38
HCV and AlcoholRisk of Cirrhosis
100
80
60
HCV
Cirrhosis ()
HCV alcohol
40
20
0
10
20
30
40
Years Following Exposure
Excessive alcohol intake characterized as gt 40
g/day for women and gt 60 g/day for men.
Wiley TE, et al. Hepatology. 199828805-809.
39
Fibrosis Progression in HCVEffect of Steatosis
Cumulative Probability of Fibrosis According to
Level of Steatosis
100
80
60
Year 4
Cumulative Probability of
Fibrosis Progression ()
Year 6
40
33
30
18
18
20
7
6
4
2
0
lt 5
5-10
11-30
gt 30
Percentage of Steatosis at Initial Biopsy
Fartoux L, et al. Hepatology. 20054182-87.
40
HCV in Patients With CirrhosisSurvival and Rate
of Decompensation
10-Year Cumulative Survival
Cumulative Probability
50
100
Decompensation
Decompensation
Stable
40
80
HCC
30
60
Percentage of Patients
Survival ()
20
40
10
20
0
0
0
2
4
6
8
10
Years
Fattovich G, et al. Gastroenterology.
1997112463-472.
41
Hepatocellular CarcinomaIncidence in the United
States
12
10
Black male
8
White male
6
Cases/100,000
Black female
White female
4
2
0
1976-1980
1991-1995
El-Serag HB, et al. N Engl J Med.
1999340745-750.
42
Chronic Hepatitis C InfectionProgression to
Cirrhosis
Mild
Moderate
Severe
Cirrhosis A
Cirrhosis C
HCC
0
10
20
30
40
50
Years
Shiffman ML. Viral Hepatitis Rev. 1999527-43.
43
Hepatitis C Virus InfectionThe Burden of Disease
3.0
All patients
2.0
Infection for
Anti-HCV Positive ()
gt 20 years
1.0
0
1960
1980
2000
2020
Year
Armstrong GL, et al. Hepatology. 200031777-782.
44
Hepatitis C Virus InfectionIdentification of
Patients

• Found to have elevated serum ALT during
• Routine physical examination
• Routine blood testing after starting certain
  medications
• Test positive for anti-HCV during
• Volunteer blood donation
• Health or life insurance applications
• Physician
• Inquires about previous risk behaviors

45
Hepatitis CExtrahepatic Manifestations
46
Chronic Hepatitis C VirusExtrahepatic
Manifestations

• Nonspecific antibodies
• Essential mixed cryoglobulinemia
• Glomerulonephritis
• Porphyria cutanea tarda
• Leukocytoclastic vasculitis
• Moorens corneal ulcer
• Non-Hodgkins lymphoma
• Autoimmune thyroiditis
• Diabetes mellitus
• Sjögrens syndrome

47
Chronic Hepatitis C VirusAutoantibodies
HCV, Control,
Rheumatoid factor 70 8
Cryoglobulins 36 lt 1
ANA gt 140 gt 1180 21 13 10 2
Antismooth muscle gt 140 gt 1180 21 7 2 lt 1
Antiliver-kidney microsome 5 lt 1
Antithyroid 7 2
Pawlotsky JM, et al. Hepatology. 199419841-848.
48
Chronic Hepatitis C Virus Autoantibodies (contd)

• No relationship between presence of
  autoantibodies and
• Severity of chronic HCV
• HCV genotype
• Correlation between rheumatoid factor titer and
• Cryoglobulinemia
• But not symptomatic cryoglobulinemia
• Circulating autoantibodies from autoimmune
  disorders may result in
• False positive anti-HCV

49
CryoglobulinemiaClassification
Immunoglobulin Classification
I Monoclonal No rheumatoid factor Primary
II Polyclonal IgG Monoclonal IgM Rheumatoid factor Secondary mixed HCV infection
III Polyclonal IgG Polyclonal IgM Secondary mixed Infections Autoimmune disorders Lymphoproliferative diseases
Cacoub P, et al. Curr Opin Rheumatol.
20021429-35.
50
Immune Manifestations of HCVPathogenesis
Illustration by Mitchell L. Shiffman, MD
51
HCV and CryoglobulinemiaDermatitis

• Occurs in dependent areas
• Deposition of cryoglobulins in small capillaries
• Ulcerations may develop
• Pruritic

52
Extrahepatic Effects of HCVCryoglobulinemia
100
80
Elevated ALT
60
Anti-HCV
Percentage of Patients
40
HCV RNA
20
0
Cryoglobulinemia
Controls
Misiani R, et al. Ann Int Med. 1992117573-577.
53
HCV and CryoglobulinemiaManifestations

• Dermatitis (dependent areas)
• Vasculitis
• Myalgias (fibromyalgia?)
• Arthralgias (RA and/or ANA positive)
• Membranoproliferative glomerulonephritis
• Neuropathy
• Chronic fatigue syndrome (?)

54
Extrahepatic Effects of HCVLymphocytic
Sialadenitis
Characteristic HCV Sialadenitis Primary Sjögrens Syndrome
SS-A, SS-B Negative Positive
Lymphocytic capillaritis Mild Pericapillary Mostly CD8 cells Severe Periductal Mostly CD4 cells
Sicca syndrome Xerophthalmia Xerostomia Absent 8-36 Present Present
55
Extrahepatic Effects of HCVB-Cell Lymphoma
Ferri (1994)
8 case series 1754 pts evaluated
Mazzaro (1996)
Silvestri (1996)
Izumi (1996)
McColl (1996)
Zignego (1997)
DeRosa (1997)
Zuckerman (1997)
0
10
20
30
0
10
20
30
B Cell Lymphoma
Controls
56
Chronic HCV and Diabetes MellitusCase Prevalence

• N 179 with chronic HCV
• Prevalence of diabetes mellitus and insulin
  resistance noted
• Compared with expected rate based on NHANES III
  study after adjusting for
• Age
• Sex
• Race
• Prevalence of DM or insulin resistance higher in
  those with chronic HCV

20
Observed
Expected
16
12
Number of Cases
8
4
0
Females
Males
Zein CO, et al. Am J Gastroenterol.
200510048-55.
57
Chronic HCV and Diabetes MellitusRelationship to
Fibrosis Stage
40
30
20
Percentage of Patients
10
0
0
1
2
3
4
Histologic Stage
Zein CO, et al. Am J Gastroenterol.
200510048-55.
58
Extrahepatic Effects of HCVPorphyria Cutanea
Tarda
Fargion (1992)
De Castro (1993)
Criber (1995)
2 case series 3 uncontrolled series 280
patients Alcohol 36-77
Stolzel (1995)
Kondo (1997)
0
20
40
60
80
100
0
5
10
15
20
PCT
Control
59
Extrahepatic Effects of HCVLichen Planus

• Occurs in lt 1 of the general population
• 10-30 of patients with chronic HCV
• Appearance
• Flat topped, violaceous, pruritic papules
• Throughout body
• Oral mucosa
• Histology
• Dense infiltration of dermis with T lymphocytes

Nagao Y, et al. J Gastroenterol Hepatol.
2004191101-1113.
60
Hepatitis CTreatment
61
Treatment of Chronic HCVPeginterferon and
Ribavirin
100
80
60
Sustained Virologic
Response ()
PegIFN-2a/RBV
40
PegIFN-2b/RBV
20
0
1
2-3
Genotype
Fried MW, et al. N Eng J Med. 2002347975-982.
Manns MP, et al. Lancet 2001358958-965.
62
Treatment of Chronic HCVEffect on Survival

• Interferon treatment reduces risk of death,
  transplantation, and complications of cirrhosis

Risk Factors for Survival (Multivariate Cox Regression Analysis) Risk Factors for Survival (Multivariate Cox Regression Analysis) Risk Factors for Survival (Multivariate Cox Regression Analysis)
Survival Outcome Risk Ratio 95 Confidence Interval
Interferon therapy vs no therapy
Death and liver transplantation 0.5 0.3-0.9
Death, liver transplantation, and complications 0.5 0.3-0.7
Development of HCC 0.7 0.2-2.7
P lt .05.
Niederau C, et al. Hepatology. 1998281687-1695.
63
Treatment of Chronic HCVEffect on Development of
HCC

• Interferon treatment reduces the risk of
  developing hepatocellular carcinoma among
  patients with chronic HCV (P .002)
• Hepatocellular carcinoma incidence
• Untreated controls 38 (24-58)
• Interferon-treated patients 4 (1-15)
• HCC risk ratio 0.067 (0.009-0.530 P .01)

Nishiguchi S, et al. Lancet. 19953461051-1055.
64
The Many Faces of HCV InfectionSummary

• Chronic HCV infection leads to cirrhosis and
  liver failure in a large number of persons
• Primary care physicians must recognize that
  chronic HCV is common in specific nonliver
  disorders
• Effective treatment of chronic HCV can prevent
  fibrosis progression and reduce complications of
  HCV

65
Go Online to View More CCO Programs!

• Conference Coverage of all the key data
  presented at major hepatitis meetings
• News and Capsule Summaries covering the latest
  findings in the field of hepatitis
• Downloadable Slides, and much more!
• clinicaloptions.com/hep