Hepatitis C Epidemiology, Diagnosis and Treatment

1
Hepatitis CEpidemiology, Diagnosis and Treatment

• Dr.Peter Buggisch
• Universitätsklinikum Eppendorf
• Zentrum für Innere Medizin
• I. Medizinische Klinik und Poliklinik

2
Chronic Hep. C Clinical
3
HCV

• Single strain RNA Virus
• Family of Flaviviruses
• 9200 kb
• No Animal model

4
HCV - Genotypes
Simmonds Typ 1a 1b 2a 2b 3 4 5 6
5
HCV Seroprevalence

• Wide Range
• lt 1 in Hongkong and Germany
• 2 - 2.5 in mainland China
• gt 14 in Egypt and Cameron
• Estimated 500.- 800.000 people in Germany
• Only 30 - 40 are identified
• 10 - 15 get therapy

6
Hepatitis C Virus InfectionMagnitude of the
Problem in the US

• 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.
7
Hepatitis B and C

• HBV
• World 350 Mill. infected
• BRD 700000 Hbs Ag
• 60 Mill Cirrhosis
• 250000 HCC /year
• 6 th- leading cause for Tx

• HCV
• World 300 Mill. infected
• BRD 500-800000
• 40 Mill Cirrhosis
• 250000 HCC/year
• 2 th- leading cause for Tx

8
Risk of Transmission
Blood, needle injuries, (Sexual)
HIV
HDV
HBV
HCV
10 3-5
10 1-3
10 9-11
10 7-9
No of virus/ ml
Transmissionrisk 30 3
0,3
9
HCV Risk of Transmission

• Transmission risk with household contacts very
  low
• Sexual transmission rare
• Partner of HCV-Infected only 4
• Gordon, Am.J.Gastroenterol 1992
• Zeuzem, J. of Hepatology 1996
• Mother Child rare 5
• Influence of viral load unclear
• High risk in coinfected mothers
• Koff, Annals of Int. Med. 1992
• Ohto, NEJM 1994

10
Hepatitis C Virus InfectionPopulation at Risk

• Transfusion of blood products before 1992
• Intravenous drug use
• Nasal inhalation of cocaine
• Chronic renal failure on dialysis
• Low hygienic standards in medicine (single use
  syringes)
• 27 prevalence in chinese commercial blood donors
  in rural Shanzi Province
• 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.
11
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.
12
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.
13
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.
14
HCV-Infection and disease progression
Infections per 100.000
140
120
Incidence
100
80
60
40
20
0
1960
1970
1980
2000
1990
2010
2020
2030
Prevalence
2,0
Prevalence
1,5
1,0
Liver diseases(Cirrhosis, HCC ...)
0,5
0,0
1960
1970
1980
2000
1990
2010
2020
2030
15
Hepatitis C Virus InfectionNatural History
Only 30 are symptomatic
Acute HCV
Resolved 30 (30)
Chronic HCV 70 (70)
Stable 75- 80
Cirrhosis 20- 25
HCC Liver failure 25 (3-4)
Slowly progressive 75
HCC, hepatocellular carcinoma
16
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.
17
The Cellullar (adaptive) Immune Response most
important for chronicity / healing
Activation,
Clonal expansion
differentiation
B cell
Neutralizing
HCV antibodies
Th2 cytokines
HCV
(IL-4, IL-5, IL-6,
Viral entry
Lysis
IL-9, IL-10, IL-13)
MHC II
CD4
MHC I
TCR
Th
cell
Hepatocyte
TCR
CD8
CTL
CD4
Th1 cytokines
Clonal
expansion
cell
Th
(IFN-?TNF-a)
(Th1 or Th2)
IFN-a
Adapted from Liang TJ, et al. Ann Intern Med.
2000132296-305.
18
Hep. C Virus escape mechanism
19
Viral Replication in Infected Host Cell
Y
Y
NUCLEUS
20
Hepatitis C Virus InfectionNatural History
Acute HCV
Resolved 30 (30)
Chronic HCV 70 (70)
Stable 75- 80
Cirrhosis 20- 25
HCC Liver failure 25 (3-4)
Slowly progressive 75
HCC, hepatocellular carcinoma
21
Natural course of Hepatitis C ?
Anti-D Immunoglobulin-Study (20 years FU)
Staging
Grading
HCV-RNA posHCV-RNA neg
HCV-RNA posHCV-RNA neg
()
()
98
98
100
100
87
80
75
58
60
50
38
40
25
20
14
4
2
0.40
0
2
0
0
0
0
0
0 bis 1
0 bis 3
4 bis 6
7 bis 9
gt 9
2 bis 4
5 bis 6
Wiese et al. Hepatology 2000
22
Natural course of Hepatitis C ?
Anti-D Immunoglobulin-Study (25 years FU)
Staging
Grading
HCV-RNA posHCV-RNA neg
HCV-RNA posHCV-RNA neg
()
()
98
96
100
100
80
70
75
58
60
50
38
40
26
25
20
4
4
4
3
2
0
0
0
0
0
0 bis 1
0 bis 3
4 bis 6
7 bis 9
gt 9
2 bis 4
5 bis 6
Wiese et al. Hepatology 2005
23
HCV- Disease-burden in 2008 ?
Cirrhosis
528
HCC
279
Liver-related death
223
Decompensation
68
Need for Transplantation
61
0
100
200
300
400
500
600
Estimated increase in 2008
Davis GL. Hepatology. 199828(4 pt 2)390a.
24
Progression of liver fibrosis
F Metavir
4 3 2 1 0
Rapid
Intermediate
Slow fibroser
0
10
20
30
40
50
Duration in years
Lancet 1997 349 825
25
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.
26
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.
27
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.
28
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.
29
Fibrosis Progression of HCVEffect of Inflammation
Ghany MG, et al. Gastroenterol. 200312497-104.
30
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.
31
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.
32
Hepatitis CDiagnosis
33
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.
34
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

35
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.
36
Management of Chronic HCVTests Utilized
LFTs
37
Hepatitis C VirusDiagnostic Testing
38
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.
39
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.
40
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

41
Testing for Hepatitis C VirusIndications for HCV
RNA

• Confirm HCV infection
• Persistently normal serum ALT
• HCV antibody positive
• Prior to initiating therapy
• Assess effectiveness of treatment
• Predict likelihood of response before and during
  therapy
• Guiding therapy during therapy (viral kinetics)
• Confirm response after therapy completed

42
Testing for Hepatitis C VirusVirologic Assays
43
HCV RNA Assays

• HCV RNA titer best reported in log units
• Sensitivity has increased
• Quantitative testing should at least detect gt 500
  IU/ml
• Automated testing by Taqman within the range of
  50 IU/ml

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.
44
Viral kinetics under therapy
nach Pawlotsky Antiviral Research 2003
45
Ansprechen auf eine antivirale Therapie
HCV-RNA
Time without virus
Time without virus
Slow responder
Limit of detection
Fast responder
72
48
24
12
0
Wochen
46
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.
47
Hepatitis C Virus InfectionNatural History
Acute HCV
Resolved 30 (30)
Chronic HCV 70 (70)
Stable 75- 80
Cirrhosis 20- 25
HCC Liver failure 25 (3-4)
Slowly progressive 75
HCC, hepatocellular carcinoma
48
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.
49
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.
50
Decompensation with HBV / HCV
Benvegnu et al. Gut 200453744-749
51
Cancer Mortality Development
Stomach
men
women
CRC
Prostate
Bronchial
Pancreas
Ösoph.
HCC
NHL
change
change
SEER-ProgrammeNational Center for Health
Statistics Clin. Oncology 200018 2258-2268
52
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.
53
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

54
Immune Manifestations of HCVPathogenesis

• Why do individuals with hepatitis C develop so
  many autoantibodies?

Illustration by Mitchell L. Shiffman, MD
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
Hepatitis CTreatment
58
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.
59
Treatment results from 1993 - 2005
60
50
40
Sustained Virologic Response
30
20
10
0
60
Viral Kinetics After IFN Therapy
Viral kinetics
IFN (efficacy e)
0
1st phase antiviral efficacy (r) (innate)
-1
2nd phase clearance ofinfected hepatocytes (d)
(adaptive)
HCV RNA (log IU mL-1)
-2
Two phases ofviral decline
-3
-4
-7
0
7
14
21
28
Days After Start of Therapy
Adapted from Feld JJ, et al. Nature.
2005436967-972.
61
The Adaptive (Cellular) Immune Response Finishes
the Job
Activation,
Clonal expansion
differentiation
B cell
Neutralizing
HCV antibodies
Th2 cytokines
HCV
(IL-4, IL-5, IL-6,
Viral entry
Lysis
IL-9, IL-10, IL-13)
MHC II
CD4
MHC I
TCR
Th
cell
Hepatocyte
TCR
CD8
CTL
CD4
Th1 cytokines
Clonal
expansion
cell
Th
(IFN-?TNF-a)
(Th1 or Th2)
IFN-a
Adapted from Liang TJ, et al. Ann Intern Med.
2000132296-305.
62
Ribavirin

• Initially developed as an antiviralguanosine
  analogue
• No antiviral activity but improved ALT when given
  as monotherapy
• Combination with IFN improved ETR but greatly
  enhanced SVR rates by decreasing relapse
• Does not alter 1st phase kinetics appreciably
• Modest ? of PEG-IFN antiviral effect (0.5-1.0
  log)
• Mechanistic models must explain clinical
  observations

63
Ribavirin Proposed Mechanisms of Action
TH2
Defective HCV particles (decreased fitness)
Ribavirin
Immunomodulation (2nd phase)
TH1
CTL
IFN-?, TNF-?
Hepatocyte
RDP
RTP
RMP
Ribavirin
(-)
IMP
GMP
RdRp
HCV RNA
HCV RNA
IMPDH
RNA Mutagen
Replication
GTP
Inhibition of HCV (1st phase)
Inhibition of IMPDH (1st phase)
RNA mutagenesis (2nd phase)
Adapted from Feld JJ, et al. Nature.
2005436967-972.
64
Side effects of PEGIFN a-2a/RBV and Peg IFN
a-2b/RBVvs Standard IFN/RBV
more side effects
less side effects
22
Inject.Reactions
2
10
Asthenia
-1
13
Alopezia
-6
-2
Depression
-9
10
Nausea
-4
0
Myalgia
-8
13
Fever
-13
Peginterferon alfa-2b 1.5 µg/kg QW 800mg /d RBV
PEGASYS 180 µg / QW 1000-1200mg/d RBV
Fried et al. DDW 2001 Manns et al. Lancet
2001
65
Rates of patients stopping treatment

12.4
Hadziyannis, EASL 2002
66
Treatment of Chronic HCVEffect on Survival

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

P lt .05.
Niederau C, et al. Hepatology. 1998281687-1695.
67
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.
68
HCV Treatment 1

• HCV is curable
• Rates of SVR have increased over 15 years
• Genotype 1 / 6 ----- 50 with 48 weeks
  treatment
• Genotype 4 ----- 72 with 36 weeks treatment
• Genotype 2 / 3 ----- 80 with 24 weeks
  treatment
• SVR is stable and long lasting
• Influence of HCC-rate

69
HCV Treatment 2

• Treatment has severe side effects
• Treatment is very expansive
• There are still 30 40 without cure
• New treatment options are necessary

70
Target Infection of the Hepatocyte
71
Therapeutics Infection of the Hepatocyte

• Polyclonal preparations1
• Neutralize infectious inoculae ex vivo
• Inhibit or prevent infection in chimps
• Studies in man disappointing to date
• Monoclonal antibodies2
• Anti-E2 human monoclonal XTL
• Mild HCV RNA suppression with daily dosing

• Vaccine-derived anti-E1E23
• Neutralizing antibody
• In vitro inhibition of CD81

1. Davis, et al. Liver Transpl 2005. Willems, et
al. J Hepatol. 2002. 2. Schiano, et al. Hepatol.
2005. 3. DiBisceglie, et al. Hepatol. 2005.
72
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73
Therapeutics Viral RNA TranscriptionHCV
polymerase inhibitors in development

• NM-283 (valopicitabine, Idenix)
• R1626 (Roche)
• HCV-796 (Viropharma)

74
Therapeutics Translation and Protein Processing
Proteaseinhibitors
Serine protease (trans)
HCV polyprotein
NS2
NS3
NS4A
NS4B
NS5A
NS5B
E1
E2
p7
C
Serine protease (cis)
75
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76
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77
VX- 950 /- IFN-?2a
Median viral load decline, log10 IU/mL
5.5
4
1
HCV RNA lt 30 IU/mL, n
6
1
0
HCV RNA lt 10 IU/mL, n
4
1
0

• VX-950 peginterferon well tolerated
• Most common adverse events included headache,
  myalgia, dry skin, and diarrhea
• No serious adverse events observed
• No patient discontinued study treatment

78
Role of New Agents in Treating HCV

• Primary aim should remain eradication
• Chronic suppression may be achievable
• Interferon likely to remain foundation of therapy
• Combination therapy will be key
• Other agents may allow lower doses or shorter
  duration of poorly tolerated drugs
• New agents will be able to target different
  processes of the HCV replication cycle

79
Problems of New Agents in Treating HCV

• Side effects still unknown
• Effective only as combination
• Probably Genotype specific
• Development of resistant mutants shown in vitro

80
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81
HCV - Conclusion

• Wide spread disease
• Important health problem in Asia
• Major risk factor for cirrhosis and HCC
• Associated diseases
• Coinfections with negative implications
• Animal models are urgently needed
• Primary care physicians should think of it
• Cure is possible, but
• Expansive, with side effects and limitations
• New treatments are on the horizon