This document discusses hepatitis C virus (HCV)-related vasculitis. It begins by noting an abnormal T lymphocyte distribution and Th1 cytokine profile in vasculitis lesions, as well as a deficit in regulatory T lymphocytes. A genome-wide association study found an association between HLA-DRB1/DQA1 and HCV-related vasculitis. Treatment of HCV-vasculitis includes antiviral therapy to achieve sustained virological response, as well as immunosuppressants. Complete clinical response is associated with increased levels of regulatory T cells. Rituximab and low-dose interleukin-2 may also be effective treatments.

1. Prolifération
polyclonale
Prolifération de LyB
clonaux et autoréactifs
Maintien de la tolérance
périphérique
TLR
Anergie
EGR2
Cbl-b
Vascularite
Stimulation par la voie
des TLR des
LyB anergiques
2

2. A Major Role for T Cell Immunity
in HCV-Vasculitis
 Abnormal T lymphocytes distribution
 Predominant T lymphocytes infiltration in vasculitis lesions
 Th1 cytokines profile in vasculitis lesions
 MHC-II polymorphism (DR11)
 Deficit in Treg lymphocytes
3

3. GWAS Study of HCV- and Cryoglobulin Related Vasculitis
An association with rs9461776 (OR= 2.14, p=1.40E-07) between
HLA-DRB1 and DQA1 was detected and further replicated (p=0.01)
in additional samples.
Zignego AL et al Washington AASLD 20013
5

4. Quantitative Deficit in Treg Lymphocytes
(CD4+CD25+) in HCV-Vasculitis
Boyer O, Saadoun D et al, Blood 2004
6

5. 7

6. Complete clinical response of HCV-vasculitis to anti-viral
treatment is associated with
an increase in CD4+CD25high Treg cells
6
6
**
-CR
†
**
†
-NR/PR
5
5
4
4
4
3
Before treatment
On treatment arly F/u
E
On
Before
treat.
Treat.
Early
F/U
Late F/U
Late F/U.
After Treat.
C
†
*
40
CD
25high(cells
/μl)
CD25high (% of CD4+)
A
30
20
10
0
N
R
C
R
CR
NR/PR
After Treat.
B
ef
or
e
T
x
Before
Treat.
Landau DA et al, Arthritis Rheum 2008
8

7. Correlation between Immunological Response
and Treg Lymphocytes in HCV MC Vasculitis
0.4
3
R²-0.16 , p<0.005
2
C 4 (g/l )
Cryoglobulins ( g/l )
R²-0.1, p< 0.005
1
0.2
0.0
0
0
20
40
60
CD 25high (cells /μl)
Landau DA et al, Arthritis Rheum 2008
80
100
0
20
40
60
80
100
CD25 high (cells /μl)
9

8. HCV-related B-Cell Lymphoproliferative Disorders
Antigen-sensitive
B cell proliferation
HCV (E2)
DC
Antigen-insensitive
B cell proliferation
DC
CD81
Cytokines
BAFF
B cell
Hyperγglobulinemia
Polyclonal
proliferation
IgG
IgH-bcl2?
Cryoglobulinemia
Vasculitis
B-cell lymphoma
Oligo/Monoclonal
proliferation
Anti-E2 IgM/Rheumatoid factor
Other
oncogenic
events ?
B-cell lymphoma
Uncontrolled
proliferation
10

9. HCV Cr yoglobulinemic
Vasculitis
Tr eatments

10. Chronic HCV infection
HCV eradication
Poly- oligoclonal
B-cell expansion
Immunosuppressors
Autoantibodies
RF - IC
Mixed cryoglobulins
Monoclonal B-cell
proliferation
Overt lymphoma
Chemotherapy
Plasma exchange
Cryoglobulinemic vasculitis
Steroids
12

11. Chronic HCV infection
HCV eradication
Poly- oligoclonal
B-cell expansion
Immunosuppressors
Autoantibodies
RF - IC
Mixed cryoglobulins
Monoclonal B-cell
proliferation
Overt lymphoma
Chemotherapy
Plasma exchange
Cryoglobulinemic vasculitis
13

12. Clinical Remission of HCV-Related Vasculitis is
Correlated to Sustained Virological Response (SVR)
 Progress in
Anti-viral
Therapy of HCV
(1990-2011)
Zuckerman, J Rheumatol 2000. Naarendorp, J Rheumatol 2001. Cacoub, Arthritis Rheum 2002, Zaja F, Blood 2003.
Sansonno D, Blood 2003 , Cacoub, Arthritis Rheum 2005, Saadoun, Arthritis Rheum 2007, Saadoun, Ann Rheum Dis 2013
14

13. Predictive Factor s of Response to HCV
T herapy in Cr yoglobulinemic Vasculitis
Multivariate Analysis
Odds ratio
[95%CI]
p
• Renal involvement
0.27
[0.08-0.87]
0.02
• Renal insufficiency (GFR<70)
0.18
[0.05-0.67]
0.01
• Daily proteinuria > 1g
0.32
[0.09-1.11]
0.05
• Early virological response
3.53
[1.18-10.59]
0.02
Cacoub, Arthritis Rheum 2005, Saadoun, Arthritis Rheum 2007
15

14. Clinical Remission of HCV-Related Vasculitis is
Correlated to Sustained Virological Response (SVR)
 Progress in
Anti-viral
Therapy of HCV
(1990-2011)
Zuckerman, J Rheumatol 2000. Naarendorp, J Rheumatol 2001. Cacoub, Arthritis Rheum 2002, Zaja F, Blood 2003.
Sansonno D, Blood 2003 , Cacoub, Arthritis Rheum 2005, Saadoun, Arthritis Rheum 2007, Saadoun, Ann Rheum Dis 2013
16

15. Chronic HCV infection
Poly- oligoclonal
B-cell expansion
Autoantibodies
RF - IC
Mixed cryoglobulins
Immunosuppressors
Monoclonal B-cell
proliferation
Overt lymphoma
Chemotherapy
Cryoglobulinemic vasculitis
17

16. Overall Survival of 151 HCV-Vasculitis Patients
Overall survivall
32 deaths after a median
follow-up of 54 months (IQR
26-89)
Causes of death:
- Infection (n=10)
- Cirrhosis (n=10; 4 HCC)
- Non-HCC neoplasia (n=4)
- Cardiovascular (n=4)
- Renal failure (n=2)
- Vasculitis (n=2)
- Unknown (n=2)
Years
Terrier B et al. Arthritis Rheum 2010
18

17. Prognostic Factors
During follow-up
Use of Peg-IFN/riba had a positive prognostic impact
HR = 0.34 (0.16-0.67)
After adjustment on vasculitis severity,
immunosuppressants showed a negative impact
HR = 4.05 (1.75-9.36)
19
Terrier B et al. Arthritis Rheum 2010

18. Chronic HCV infection
Poly- oligoclonal
B-cell expansion
Autoantibodies
RF - IC
Mixed cryoglobulins
Immuno-modulators
Rituximab
Monoclonal B-cell
proliferation
Overt lymphoma
Cryoglobulinemic vasculitis
20

19. Rationale for
Rituximab treatment
in cryoglobulinemic
vasculitis
Roccatello, D. et al. Nephrol. Dial. Transplant. 2004
Rocatello D, Nephrol Dial Transplant, 2004
21

20. Treatment of Mixed Cryoglobulinemia Resistant
to Interferonα with Rituximab
Sansonno D et al, Zaja F et al, Blood 2003
22

21. Cryoglobulinemia Vasculitis: Poor Response
Maintenance after Discontinuation of Rituximab
15 (93.7)
100
90
13 (81.2)
12 (75)
80
70
60
10 (62.5)
50
40
6 (37.5)
30
20
10
1 2 3
4 5
24
6 7 8 9 10 11 12
36
48
MONTHS
Sansonno D et al, 2007
23

22. Rituximab for the Treatment of Severe
Cryoglobulinemic Vasculitis
RTX
non-RTX
De Vita S, Arthritis Rheum 2012
24

23. PegIFN plus Ribavirin
Rituximab
HCV Vasculitis: a TwoFaces Disease
…
Needs a Two Faces
Treatment Strategy
27

24. 28

25. Outcome of HCV-MC according to treatment
All
PegIFNα-ribavirin
n=93
Parameters
n=55
RTX-PegIFNαribavirin
n=38
P
8.4 ± 4.7
5.4 ± 4.0
0.004
68 (73.1)
40 (72.7)
28 (73.7)
0.98
22 (23.6)
3 (3.2)
17 (18.3)
13 (23.6)
2 (3.6)
10 (18.1)
9 (23.7)
1 (2.6)
7 (18.4)
49 (52.7)
24 (43.6)
26 (68.4)
35 (37.6)
8 (8.6)
17 (18.3)
25 (45.4)
6 (10.9)
10 (18.1)
10 (26.3)
2 (5.2)
7 (18.4)
55 (59.1)
33 (60)
22 (57.9)
5 (5.4)
2 (3.6)
3 (7.9)
Time clinical response, months 6.8 ± 4.7
Clinical response
CR
PR
NR
Relapse
Immunological response
CR
PR
NR
Relapse
0.001
Virological response
SVR
Death
0.94
0.70
29

26. Course of kidney parameters in HCV-MC
according to the type of treatment
PegIFNα-ribavirin
n=10
Kidney inv. CR
Creatininemia (µmol/l)
Baseline
EOF
GFR (ml/min)
Baseline
EOF
p
4 (40)
150 ± 30
169 ± 44
58 ± 7
59 ± 9
RTX-PegIFNαribavirin
n=21
p
17 (80.9) 0.04
0.28
217 ± 47
136 ± 27
0.03
0.41
42 ± 5
57 ± 4
0.01
Daily Proteinuria (gr/d)
Baseline
3.1 ± 0.9
EOF
1.2 ± 0.5
3±1
0.046
0.4 ± 0.1
<0.001
Hematuria (n,%)
Baseline
EOF
10 (100)
19 (90.5)
2 (20)
2 (10.5)
<0.001
30

27. RTX/Peg-IFNα-Ribavirin vs. Peg-IFNα-Ribavirin in
HCV Systemic Vasculitis
Maintenance of Complete Response
Dammacco F et al, Blood 2010
31

28. 32

29. Time Course of HCV Viral Load
Terrier B et al. Arthritis Rheum 2009
33

30. 34

31. 35

32. 36

33. • If failure or contra-indication to PegINF/ribavirin, Rituximab may be used alone
• If Geno1 HCV infection, combination of PegIFN/Ribavirin/Protease inhibitor.
HCV: hepatitis C virus; PegIFN: pegylated interferon alpha; CNS: central nervous system;
37

34. Chronic HCV infection
Poly- oligoclonal
B-cell expansion
Autoantibodies
RF - IC
Mixed cryoglobulins
Immuno-modulators
Low dose IL2
Monoclonal B-cell
proliferation
Overt lymphoma
Cryoglobulinemic vasculitis
38

35. Reversible Quantitative Deficit in Treg Lymphocytes
(CD4+CD25+) in HCV-Systemic Vasculitis
A
CD25high (% of CD4+)
Boyer, Blood 2004. Landau Arthritis Rheum 2008
**
†
-CR
6 6
5 5
4
4 4
3
Before treatmentOn
On treatment arly F/u
E
Before
treat.
3
Treat.
Early
F/U
Late F/U
Late F/U.
After Treat.
R²-0.1, p< 0.005
2
0.4
R²-0.16, p<0.005
C4 (g/l)
Cryoglobulins ( g/l )
**
†
-NR/PR
1
0
0
20
40
60
CD 25high (cells /μl)
80
100
0.2
0.0
0
20
40
60
80
CD25 high (cells /μl)
100
39

36. 40

37. Effects of Low-Dose Interleukin-2 on Levels of CD4Treg in Patients with HCV-Vasculitis, According to
Treatment Course (C).
41

38. No Impact of Low-Dose Interleukin-2 on Levels Effector T
Cells CD4+CD8+ in Patients with HCV-Vasculitis
42

39. Temporal Effects of Low-Dose Interleukin-2 on
Clinical Features & Levels of Regulatory T Cells
for Each Study Patient
CD4+Treg (%)
30
30
30
30
20
20
20
20
10
10
10
10
Baseline C1
C2
C3
C4 Post IL-2
0
Baseline C1
C2
C3
C4 Post IL-2
0
Baseline C1
C2
C3
C4 Post IL-2
0
Baseline C1
C2
C3
C4 Post IL-2
Arthralgia
Fatigue
Kidney Involvement
Neuropathy
Purpura
CLINICAL
RESPONSE
0
Baseline C1
C2
C3
C4 Post IL-2
Baseline C1
C2
C3
C4 Post IL-2
Baseline C1
C2
C3
C4 Post IL-2
Baseline C1
C2
C3
C4 Post IL-2
Saadoun D et al, NEJM 2012

40. Anti-inflammatory Effects of Low-Dose Interleukin-2
Revealed through Unsupervised Transcriptome
Analyses of PBMCs.
BEFORE IL2
AFTER IL-2
CCL3
CCL3L1
CCL3L3
Up
Down
Khi2 test
Inflammation
0
251
1,30E-40
Immune Response
16
684
3,40E-94
Lymphocyte
77
555
7,00E-49
Cell Cycle
1701
208
1,50E-138
Control
226
343
2,50E-01
Autoimmune &
transplantation
pathologies
0
46
7,60E-09
Inflammatory infectious
diseases
6
242
7,60E-36
190
211
4,15E-02
IER3
CXCR7
OLR1
PDE48
PTGS2
IL1B
IL1A
CCL20
IL6
CLECL1
CD79A
BLK
CCL4L2
EBF1
CCL4L1
CXCR5
BAFFR
4-1BBL
PLAUR
NLRP3
RIPK2
ATF3
NAMPT-PBEF1
TNFRSF21DR6
ETS2
MAPK3K8-COT
Other diseases
GOS2
CD83
Saadoun D et al. NEJM 2011
45

41. Other Extra Hepatic Manifestations Associated
with HCV Infection
Fatigue
Poor Health Related Quality of Life (HRQoL)
Depression, cognitive impairment
Major Cardiovascular Events (MACE)
Insulin-resistance, T2DM
Chronic kidney diseases

42. Fatigue, Depression and Extra Hepatic
Manifestations (EM) in HCV Patients
% of patients
n=1614
% of controls
n=412

Fatigue without depression
48
0.7

Fatigue with depression

Depression without fatigue

No fatigue and no depression
5
2
45
100
19
35
21
25
100
0
0
99.3
100
0.5
0.2
3.4
96
100
TOTAL

Fatigue without EM

Fatigue with EM

EM without fatigue

No fatigue and no EM
TOTAL
Poynard T et al. J Viral Hep, 2002

43. Fatigue, Depression and Extra Hepatic
Manifestations (EM) in HCV Patients
% of patients
n=1614
% of controls
n=412

Fatigue without depression
48
0.7

Fatigue with depression

Depression without fatigue

No fatigue and no depression
5
2
45
100
19
35
21
25
100
0
0
99.3
100
0.5
0.2
3.4
96
100
TOTAL

Fatigue without EM

Fatigue with EM

EM without fatigue

No fatigue and no EM
TOTAL
Poynard T et al. J Viral Hep, 2002

44. Association Fatigue, Depression and Extrahepatic
manifestations (EM) in HCV Patients
Multivariate analysis
Fatigue (moderate or severe) in comparison to absence
of fatigue was associated with:
female gender,
 age > 50 years,
 Cirrhosis or many septa,
 purpura.

Independently, fatigue was associated with:

arthralgia, myalgia, paresthesia, sicca sd & pruritus.
Poynard T et al. J Viral Hep, 2002

45. Fatigue Rate in Untreated HCV Patients
18 months vs
baseline
Baseline
18 months
39%
35%
26%
42%
39%
19%
P=0.74
41%
37%
22%
69%
24%
7%
P<0.001
40%
42%
18%
46%
40%
14%
P=0.18
Non treated (n=72)
No
fatigue
Moderate
Severe
Sustained responders (n=82)
No
fatigue
Moderate
Severe
Non responders (n=224)
No
fatigue
Moderate
Severe
Poynard T et al. J Viral Hep, 2002

46. Fatigue Rate in HCV Patients Non-Responders
to IFN-RBV
18 months vs
baseline
Baseline
18 months
39%
35%
26%
42%
39%
19%
P=0.74
41%
37%
22%
69%
24%
7%
P<0.001
40%
42%
18%
46%
40%
14%
P=0.18
Non treated (n=72)
No
fatigue
Moderate
Severe
Sustained responders (n=82)
No
fatigue
Moderate
Severe
Non responders (n=224)
No
fatigue
Moderate
Severe
Poynard T et al. J Viral Hep, 2002

47. Decreased Fatigue Rate in HCV
Patients Sustained Responders to IFN-RBV
18 months vs
baseline
Baseline
18 months
39%
35%
26%
42%
39%
19%
P=0.74
41%
37%
22%
69%
24%
7%
P<0.001
40%
42%
18%
46%
40%
14%
P=0.18
Non treated (n=72)
No
fatigue
Moderate
Severe
Sustained responders (n=82)
No
fatigue
Moderate
Severe
Non responders (n=224)
No
fatigue
Moderate
Severe
Poynard T et al. J Viral Hep, 2002

48. HCV Infection, Fatigue and Depression
Fatigue
prevalence ranges from 50 to 67%
 independently predicts poor HRQOL

Depression
documented in 28% of HCV patients prior to HCV therapy (DSM-IV).
 predictive of HRQOL during HCV therapy with peginterferon
plus ribavirin.

HCV may directly affect the CNS:

through alterations in serotonergic and dopaminergic
neurotransmission with resultant depressive symptoms.

49. Functional Assessment of Chronic Illness Fatigue
(FACIT-F) in Patients Treated with SOF + PR
FACIT-F Scores During and
Post-Treatment in FUSION
FACIT-F Scores During and
Post-Treatment in NEUTRINO
†
†
†
0.75
*
*
Normalized FACIT-F
Normalized FACIT-F
†
†
*
0.65
FACIT-F: All
FACIT-F: No SVR
FACIT-F: SVR
0.55
0.75
0.65
*
FACIT-F: All
FACIT-F: No SVR
FACIT-F: SVR
0.55
0
4
8
12
16
Week
20
24
28
0
4
8
12
16
20
24
28
Week
 SVR12 associated with an improvement in fatigue scores
 Fatigue is worsened by PEG-IFN and/or RBV-related side effects and is less severely
impacted by IFN-free regimens regardless of the length of active treatment
FUSION & NEUTRINO Trials
*P<0.05 decrement from patients’ own baseline
†
P<0.05 improvement from patients’ own baseline
Younossi ZM, et al. AASLD 2013. Washington, DC. #2211

50. 2013

51. Actigraphy Parameters in HCV Patients
Monday
18.04.2011
Tuesday
19.04.2011
Wednesday
20.04.2011
Thursday
21.04.2011
Friday
22.04.2011

52. 24 hours physical activity levels in HCV patients
and controls
Patients
(n = 20)
Controls
(n = 19)
P-value
Daily sedentary time
654.7 (134.5)
642.3 (100.5)
0.747
Daily light time
227.3 (36.5)
227.3 (36.5)
260.0 (54.5)
260.0 (54.5)
0.038
0.038
Daily lifestyle time
255.6 (57.7)
245.7 (64.9)
0.616
Daily moderate time
219.8 (69.0)
211.6 (102.2)
0.773
Daily vigourous time
2.7 (9.8)
7.3 (19.7)
0.363
222.5 (72.9)
214.9 (104.4)
0.793
MVPA
Total counts in bouts/24h 516043.2 (193788.9) 517989.0 (411773.6)
0.985
Total bouts
0.576
39.8 (13.6)
36.2 (24.7)

53. 2012

54. Cerebral MR Signal in HCV Patients
and Spectral Analysis
A
C
B

55. MR Signal in Basal Ganglia Myo-Inositol/Creatinine
Ratio in HCV Patients According to Virological Response
Significant reductionsT3 inbasal ganglia Cho/Cr and
T1 vs. in SVR; p<0.05
MI/Cr in SVRs but not in NRs/relapsers.
SVRs demonstrated improvements in verbal learning
and visuo-spatial memory.
Baseline (T1), week 12 t2), and for treatment candidates, 12 weeks post treatment with PEG-IFN and ribavirin (T3)
T1 vs. T3 in SVR; p<0.05

56.  Using PET, microglial activation positively correlated
with HCV viraemia and altered cerebral metabolism
in the brains of patients with mild hepatitis C.
 In vivo evidence for a neurotropic role for HCV.

57. HCV Infection and Poor HRQoL
SF-36 questionnaire:

patients with chronic HCV infection consistently show deficits
in several domains.
HRQOL worsens:
with more advanced liver disease.
 with interferon- and ribavirin-based therapy, potentially leading
to a reduction in adherence.

Eradication of HCV:

correlates positively with improvements in HRQoL.

58. 2013
2013

59. Health Related Quality of Life and HCV Therapy
using Sofosbuvir
physical functioning (PF),
bodily pain (BP),
general health (GH),
vitality (VT),
and mental health (MH).

60. HRQoL in FISSION
GT 2 and GT 3 Treatment-Naïve: SOF+RBV vs Peg-IFN+RBV
P<0.05
Significant difference between treatment arms at weeks 12 and 24
HRQoL Change in Summary Score
2
SOF+RBV EOT
0
SOF+RBV Physical
Component Summary
SOF+RBV Mental
Component Summary
SOF+RBV EOT
-2
Peg-IFN+RBV Physical
Component Summary
-4
Peg-IFN+RBV EOT
-6
Peg-IFN+RBV Mental
Component Summary
Peg-IFN+RBV EOT
-8
Baseline
12 Weeks
24 Weeks
Follow Up
Week 12
 Patients treated with SOF+RBV had better HRQoL scores
at the end of treatment as compared to patients receiving PegIFN+RBV
Younossi ZM, et al. EASL 2013. Amsterdam, The Netherlands. #1431

61. Other Extra Hepatic Manifestations Associated
with HCV Infection
Fatigue
Poor Health Related Quality of Life (HRQoL)
Depression, cognitive impairment
Major Cardiovascular Events (MACE)
Insulin-resistance, T2DM
Chronic kidney diseases

62. Antiviral treatment for hepatitis C virus infection
is associated with improved renal
and cardiovascular outcomes in diabetic patients
Short running title: Antiviral treatment for HCV and outcomes of DM
Yao-chun Hsu1,2, Jaw-Town Lin 2,3,4, Hsiu J. Ho3, Yu-Hsi Kao5, Yen-Tsung Huang6,
Nai-Wan Hsiao7, Ming-Shiang Wu8, Yi-Ya Liu9, Chun-Ying Wu1,9,12
Hepatology, 2013, in press

63. 2,267,270 patients with a diagnosis of diabetes mellitus (DM) between January 1, 1997 and December 31, 2011
1,630,156 DM patients without hepatitis B virus infection
746,280 patients with diabetes mellitus
3,957 HCV-infected
patients ever treated
with Peg-IFN+RBV
20,239 HCV-infected
patients never treated
with Peg-IFN+RBV
720,302 patients
without HCV infection
1,411 patients in the
treated cohort
1,411 patients in the
untreated cohort
5,644 patients in the
uninfected cohort

64. Baseline characteristics and follow-up status
of the tree study cohorts
Age (mean + SD)
Gender, n (%)
Female
Male
Comorbidity, n (%)
Hyperlipidemia
Hypertension
Thyroid disorder
Compensated cirrhosis
COPD
Peripheral arterial disease
Diabetes medication, n(%)
Metformin monotherapy
Other oral monotherapy
Two oral agents
Three or more oral drugs
Insulin dependence
Uncategorized
Treated cohort
(n = 1411)
54.92 + 8.06
Untreated cohort
(n = 1411)
55.01 + 7.99
Uninfected
(n = 5644)
54.93 + 8.07
491 (34.8)
920 (65.2)
493 (34.9)
918 (65.1)
1964 (34.8)
3680 (65.2)
177 (12.5)
606 (42.9)
139 (9.9)
324 (23)
482 (34.2)
95 (6.7)
175 (12.4)
606 (42.9)
137 (9.7)
322 (22.8)
481 (34.1)
91 (6.4)
718 (12.7)
2444 (43.3)
544 (9.6)
1289 (22.8)
1924 (34.1)
373 (6.6)
96 (6.8)
533 (37.8)
302 (21.4)
174 (12.3)
138 (9.8)
168 (11.9)
80 (5.7)
569 (40.3)
311 (22)
157 (11.1)
117 (8.3)
177 (12.5)
346 (6.1)
2366 (41.9)
1093 (19.4)
682 (12.1)
474 (8.4)
683 (12.1)
P*
0.932
0.995
0.952
0.953
0.96
0.994
0.999
0.954
0.107

65. Cumulative Incidence of End Stage Renal Disease
(death adjusted as a competing risk event)

66. Cumulative Incidence of Stroke
(death adjusted as a competing risk event)

67. Cumulative Incidence of Acute Coronary Events
(death adjusted as a competing risk event)

68. Hepatology, 2012

69. Baseline Features in Gen1 HCV Patients
and Gender, Age & BMI-Matched Controls
Carotid intima-media
1.04 + 0.21
0.90 + 0.16
< 0.001
73 (41.9)
40 (23)
< 0.001
Thickness, mm
Carotid plaques

70. Risk Factors Associated with the Presence of Carotid
Plaques in Gen1 HCV Patients
Histology at biopsy
Steatosis (%)
13 + 18.5
14.5 + 19
0.60
28/73
8/65
0.007
0.756 (0.327, 1.748) 0.51
73/28
37/36
0.003
2.177 (1.043, 4.542) 0.03
Grade of inflammation
1-2/3
Stage of fibrosis
1-2/3-4

71. Risk Factors Associated with the Presence of Carotid
Plaques in Gen1 HCV Patients
Carotideal Plaques (%)
100
80
P=0.008
P=0.51
60
40
20
0
N=67 CHC
Age ≤55 yrs
F0-2
N=21 CHC
Age ≤55 yrs
F3-4
N=43 CHC
Age >55 yrs
F0-2
N=43 CHC
Age >55 yrs
F3-4

72. 2013

73. LHID 2000
1,000,000 individuals
9220 Patients with a new diagnosis of
HCV between January 1, 2004
and December 31, 2007
2453 Exclused
Patients who were diagnosed as having HCV
on only 1 occassion
6767 Patients with a new diagnosis of HCV
3654 Exclused
43
Age <20
2986 History of HCV before January 1, 2004
84
History of IBT before the first HCV diagnosis
1167 History of Stroke before the first
HCV diagnosis
12452
Non-HCV cohort
Matched by age and sex at a ratio of 1:4
3113 HCV cohort with a diagnosis of
HCV on at least two occassions
30
208
IBT cohort received treatment for
a period of >3 months
2875 Non-IBT cohort received no IBT between
2004 and 2008
Exclused
Received IBT for a period of <3 months

74. Hepatitis C virus infection and stroke risk
Cohorts
Hazard ratio
Non HCV
P-value*
1.21
HCV
95% CI
1.05 - 1.40
0.011
1.06 - 1.43
0.006
1.06 - 1.42
0.008
1
1.23
HCV ‡
Non HCV
1
1.23
HCV †
Non HCV
1
HCV invection was associated with a 23% increased risk of stroke,
after adjusting for known prognostic factors.
† Adjusted for age, sex, hyperlipidaemia, DM, IHD, hypertension, alcohol-related illness, COPD, aspirin use, clopidogrel use,
warfarin use, dipyridamole use, ticlopidine use, statin use, ACE inhibitors use and influenza vaccination.
‡ Adjusted for age, DM, aspirin use and ACE inhibitors use.

75. Interferon-Based Therapy and Stroke-Free Survival
in HCV Patients
100
Stroke-free survival rate
IBT
0.95
Non-IBT
Log-rank test,
p = 0.003
0.90
0.85
IBT, interferon based therapy
0.80
0
1
2
3
Time (years)
4
5

76. Interferon-based therapy and stroke risk in patients
with hepatitis C
Hazard ratio
Non IBT
IBT ‡
Non IBT
IBT †
Non IBT
P-value*
0.28
IBT
95% confidence interval
0.12 - 0.69
0.005
0.16 - 0.93
0.033
0.16 - 0.95
0.039
1
0.38
1
0.39
1
Interferon based therapy was associated with a 61% decreased risk
of stroke in HCV patients after adjusting for known prognostic factors.
† Adjusted for age, sex, hyperlipidaemia, DM, IHD, hypertension, alcohol-related illness, COPD, aspirin use, clopidogrel use,
warfarin use, dipyridamole use, ticlopidine use, statin use, ACE inhibitors use and influenza vaccination.
‡ Adjusted for age, DM, aspirin use and ACE inhibitors use.

77. 2012

78. Myocardial injury in HCV patients
Characteristics
Age (yr)
Sex
Liver function
Bilirubin (mg/dl)
ALT (IU/L)
Cardiac function
Y-globulin (g/dl)
Abnormal ECG (%) activity (%)
Prothrombin percent
IGC disappearance rate
CPK (IU/L)
HAI score (point)
LDH (IU/L)
Cardiac function
Abnormal ECG (%)
BNP (pg/ml)
CPK (IU/L)
LDH (IU/L)
HANP (pg/ml)
BNP (pg/ml)
LVDd (mm)
HANP (pg/ml)
LVDd (mm)
Ejection fraction (%)
Ejection fraction (%)
Severity score (point)
Severity score (point)
Severity score > 3 (%)
Severity score > 3 (%)
Chronic hepatitis C (n = 217)
57 + 9
104/113
0.7 + 0.3
77 + 61
1.6 + 0.3
90 + 16
0.172 + 0.041
8.9 + 3.3
9
94 + 46
172 + 38
22 + 18.8 94 9 46
+
19.6 + 12.5 172 + 38
22 + 18.8
48 + 5 19.6 + 12.5
48 + 5
66 + 7
66 + 7
4.3 + 1.6 4.3 + 1.6
87
87
Normal range
0.2 - 1.0
5 - 45
0.7- 1.2
80 - 100
300.158 - 0.232
- 190
107 - 230
Less than -18.4
30 190
107 230
Less than-43
Less than 18.4
39 - 55 43
Less than
55 - 39 - 55
80
55 - 80
Less Less than 3
than 3
HAI, histology activity index; BNP, brain natriuretic peptide;
HANP, human atrial natriuretic peptide; LVDd, left ventricular end diastolic dimension

79. Myocardial SPECT Images in HCV Patients According
to Virological Response
SVR
Before IFN therapy (M0; A), at the completion of IFN therapy (M6; B) and 6 months after
the completion of IFN therapy (M12; C). The arrows show the regions of myocardial perfusion defects.

80. Myocardial SPECT Images in HCV Patients According
to Virological Response
SVR
Relapse
Before IFN therapy (M0; A), at the completion of IFN therapy (M6; B) and 6 months after
the completion of IFN therapy (M12; C). The arrows show the regions of myocardial perfusion defects.

81. Myocardial SPECT Images in HCV Patients According
to Virological Response
SVR
Relapse
Non Response
Before IFN therapy (M0; A), at the completion of IFN therapy (M6; B) and 6 months after
the completion of IFN therapy (M12; C). The arrows show the regions of myocardial perfusion defects.

82. Severity Score of Myocardial Perfusion Defects
in HCV Patients after 24 Weeks IFN
IFN
SVR group
(n= 62)
Relapse group
(n= 48)
NVR group
(n= 45)

83. Severity Score of Myocardial Perfusion Defects
in HCV Patients after 48 weeks PegIFN/Ribavirin
IFN
SVR group
(n= 30)
Relapse group
(n= 9)
NVR group
(n= 6)

84. Other Extra Hepatic Manifestations Associated
with HCV Infection
Fatigue
Poor Health Related Quality of Life (HRQoL)
Depression, cognitive impairment
Major Cardiovascular Events (MACE)
Insulin-resistance, T2DM
Chronic kidney diseases

85. Manifestation
Prevalence
certainly associated with HCV
%
-----------------------------------------------------5-40
• Vasculitis (PAN, cryoglobulinemia)
35-54
• Fatigue
• Arthralgia-myalgia
25-35
10-25
• Sicca syndrome
10-40
• Autoantibodies
• Thrombocytopenia
20-40
?
• Lymphoma

86. Auto-antibody production in chronic HCV infection.
70
60
A-nuclear
A-phospholipid
A-thyroglobulin
A-smooth muscle
≥ one auto-Ab
≥ three auto-Ab
50
40
30
20
10
0
%
Pawlotsky JM, Hepatology 1994. Pawlotsky JM, Ann Intern Med 1994.
Prieto J, Hepatology 1996. Cacoub P, J Rheumatol 1997. Cacoub P, Medicine 2000.

87. Extrahepatic manifestations associated with HCV infection.
(Prospective study in 321 HCV patients)
Autoantibody
Number
%
----------------------------------------------------Antinuclear
124
41
• A-nucleosome
6
2
• A-DNA
8
3
• A-histone
9
3
• A-ENA
10
3
Cacoub P et al. Medicine 2000; 79: 47-56

89. Hepatitis C virus : extrahepatic manifestations, an update 2007
B-cell-Non Hodgin’s Lymphoma
2462 tested
13.5 % positive
• vs 0-5 % in controls
• vs 5 % in other malignant
hemopathy
Hepatitis C virus
469 tested
0 - 39 %

90. Hepatitis C virus : extrahepatic manifestations, an
Effects of alpha-interferon on HCV+/SLVL course update 2007
HCV antibodies : B-NHL (< 3%) vs SLVL (15%)
----> Splenic lymphoma with villous lymphocytes may be
associated with HCV infection
After 6 months of IFN alpha treatment in SLVL/HCV+:
Complete clinical hematologic response (spleen size < 12 cm,
lymphocytosis <4500/mm3, No cytopenia ):
---> 7/9 HCV RNA negative
Partial clinical hematologic response
(spleen size or lymphocytosis decrease >50%) :
---> 2/9 HCV RNA +
Hermine O. et al, N Engl J Med 2002; 347: 89-94

91. Extrahepatic Manifestations of HCV Infection
Summary
 Extra-hepatic manifestations of chronic HCV infection include
vasculitis, lymphomas, glucose related disorders, and rheumatologic
conditions.
 Chronic HCV is associated with reduced health-related quality of life,
in which depression, cognitive impairment and fatigue may be factors.
 Increased risk of major cardiovascular events and chronic kidney
disease require attention.
 Clinicians should appreciate the extra-hepatic as well as the hepatic
consequences of HCV infection and the potential of treatment
strategies to reduce this overall impact.
 Healthcare costs imposed by these conditions must be considered
in addition to those normally associated with chronic HCV infection.

92. 
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











Merci
D. Saadoun, Paris
D. Sene, Paris
B. Terrier, Paris
G. Géri, Paris
P. Hausfater, Paris
O. Lidove, Paris
A. Gatel, St Brieuc
J-M. Léger, Paris
N. Limal, Paris
T. Maisonobe, Paris
JC Piette, Paris
S. Caillat-Zucman, Paris
P. Ghillani, Paris
D. Klatzmann, Paris
L. Musset, Paris
M. Rosenzwajg, Paris
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
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



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L. Calabrese, Cleveland
M. Casato, Roma
C. Ferri, Modena
G. Kerr, Washington
E. Sasso, Seattle
JA. Schifferli, Basel
V. Soriano, Madrid
L. Alric, Toulouse
M. Bourlière, Marseille
P. Halfon, Marseille
S. Pol, Paris
T. Poynard, Paris
V. Thibault, Paris
Les membres du GERMIVIC
107