Download - Cacoub p hcv meh 2014 - partie ii
2
Proliférationpolyclonale
Prolifération de LyB clonaux et autoréactifs
Maintien de la tolérance périphérique
AnergieEGR2Cbl-b
TLR
Stimulation par la voiedes TLR des
LyB anergiques
Vascularite
3
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
5
GWAS Study of HCV- and Cryoglobulin Related Vasculitis
Zignego AL et al Washington AASLD 20013
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.
6
Quantitative Deficit in Treg Lymphocytes (CD4+CD25+) in HCV-Vasculitis
Boyer O, Saadoun D et al, Blood 2004
7
8
Before treatmentOn treatmentEarly F/u Late F/U3
4
5
6
CD
25
hig
h (
% o
f C
D4
+)
44
5
6
Before treat.
On Treat.
Early F/U
Late F/U.
**†
**†
-CR
-NR/PR
0
10
20
30
40
CD25h
igh
(ce
lls/μl)
†*
BeforeTreat.
CR NR/PRAfter Treat.
C
After Treat.
A
Complete clinical response of HCV-vasculitis to anti-viral treatment is associated with an increase in CD4+CD25high Treg cells
Landau DA et al, Arthritis Rheum 2008
9
0 20 40 60 80 1000.0
0.2
0.4
CD25high (cells /μl)C
4 (
g/l
)
R²-0.16, p<0.005
0 20 40 60 80 1000
1
2
3
CD25high (cells /μl)
Cry
og
lob
uli
ns
(g
/l)
R²-0.1, p<0.005
Correlation between Immunological Response and Treg Lymphocytes in HCV MC Vasculitis
Landau DA et al, Arthritis Rheum 2008
10
Antigen-insensitiveB cell proliferation
Oligo/Monoclonal proliferation
Uncontrolled proliferation
Antigen-sensitiveB cell proliferation
Polyclonal proliferation
B-cell lymphoma
DC
CytokinesBAFF
DC
HyperglobulinemiaCryoglobulinemia
VasculitisB-cell lymphoma
IgH-bcl2? Other oncogenic events ?
CD81
HCV (E2)
B cell
Anti-E2 IgM/Rheumatoid factorIgG
HCV-related B-Cell Lymphoproliferative Disorders
HCV Cryoglobulinemic Vasculitis Treatments
12
Chronic HCV infection
Poly- oligoclonal B-cell expansion
AutoantibodiesRF - ICMixed cryoglobulins
Cryoglobulinemic vasculitis
Monoclonal B-cellproliferationOvert lymphoma
HCV eradication
Immunosuppressors
Chemotherapy
Plasma exchange
Steroids
13
Chronic HCV infection
Poly- oligoclonal B-cell expansion
AutoantibodiesRF - ICMixed cryoglobulins
Cryoglobulinemic vasculitis
Monoclonal B-cellproliferationOvert lymphoma
HCV eradication
Immunosuppressors
Chemotherapy
Plasma exchange
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
15
Predictive Factors of Response to HCV Therapy in Cryoglobulinemic 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
16
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
17
Chronic HCV infection
Poly- oligoclonal B-cell expansion
AutoantibodiesRF - ICMixed cryoglobulins
Cryoglobulinemic vasculitis
Monoclonal B-cellproliferationOvert lymphoma
Immunosuppressors
Chemotherapy
18
Years
Overa
ll su
rviv
all
Overall Survival of 151 HCV-Vasculitis Patients
Terrier B et al. Arthritis Rheum 2010
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)
19
Use of Peg-IFN/riba had a positive prognostic impact
HR = 0.34 (0.16-0.67)
Prognostic Factors
During follow-up
After adjustment on vasculitis severity, immunosuppressants showed a negative
impact
HR = 4.05 (1.75-9.36)
Terrier B et al. Arthritis Rheum 2010
20
Chronic HCV infection
Poly- oligoclonal B-cell expansion
AutoantibodiesRF - ICMixed cryoglobulins
Cryoglobulinemic vasculitis
Monoclonal B-cellproliferationOvert lymphoma
Immuno-modulatorsRituximab
21
Rationale for Rituximab treatment in cryoglobulinemic vasculitis
Rocatello D, Nephrol Dial Transplant, 2004Roccatello, D. et al. Nephrol. Dial. Transplant. 2004
22
Treatment of Mixed Cryoglobulinemia Resistant
to Interferon with Rituximab
Sansonno D et al, Zaja F et al, Blood 2003
23
10
20
30
40
50
60
70
80
90
MONTHS
100
6 12
15 (93.7)
13 (81.2)
12 (75)
1 2 3 4 5 7 8 9 1011 24 36 48
10 (62.5)
6 (37.5)
Cryoglobulinemia Vasculitis: Poor Response Maintenance after Discontinuation of
Rituximab
Sansonno D et al, 2007
24De Vita S, Arthritis Rheum 2012
RTX
non-RTX
Rituximab for the Treatment of Severe Cryoglobulinemic Vasculitis
27
HCV Vasculitis: a Two-Faces Disease…Needs a Two Faces Treatment Strategy
Rituximab
PegIFN plus Ribavirin
28
29
Outcome of HCV-MC according to treatment
Parameters All PegIFN-ribavirin RTX-PegIFN-
ribavirinn=93 n=55 n=38 P
Time clinical response, months
6.8 ± 4.7
8.4 ± 4.75.4 ± 4.0
0.004
Clinical response
CR68
(73.1) 40 (72.7) 28 (73.7) 0.98PR 22 (23.6) 13 (23.6) 9 (23.7)NR 3 (3.2) 2 (3.6) 1 (2.6)Relapse 17 (18.3) 10 (18.1) 7 (18.4)
Immunological response
CR49
(52.7) 24 (43.6) 26 (68.4) 0.001PR 35 (37.6) 25 (45.4) 10 (26.3)NR 8 (8.6) 6 (10.9) 2 (5.2)Relapse 17 (18.3) 10 (18.1) 7 (18.4)
Virological response
SVR55
(59.1) 33 (60) 22 (57.9) 0.94Death 5 (5.4) 2 (3.6) 3 (7.9) 0.70
30
Course of kidney parameters in HCV-MC according to the type of treatment
PegIFN-ribavirin RTX-PegIFN-
ribavirinn=10 p n=21 p
Kidney inv. CR 4 (40) 17 (80.9) 0.04Creatininemia (µmol/l)Baseline 150 ± 30 217 ± 47EOF 169 ± 44 0.28 136 ± 27 0.03GFR (ml/min)Baseline 58 ± 7 42 ± 5EOF 59 ± 9 0.41 57 ± 4 0.01Daily Proteinuria (gr/d)Baseline 3.1 ± 0.9 3 ± 1EOF 1.2 ± 0.5 0.046 0.4 ± 0.1 <0.001Hematuria (n,%)Baseline 10 (100) 19 (90.5)EOF 2 (20) 2 (10.5) <0.001
31Dammacco F et al, Blood 2010
RTX/Peg-IFNα-Ribavirin vs. Peg-IFNα-Ribavirin in HCV Systemic VasculitisMaintenance of Complete Response
32
33
Time Course of HCV Viral Load
Terrier B et al. Arthritis Rheum 2009
34
35
36
37
• 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;
38
Chronic HCV infection
Poly- oligoclonal B-cell expansion
AutoantibodiesRF - ICMixed cryoglobulins
Cryoglobulinemic vasculitis
Monoclonal B-cellproliferationOvert lymphoma
Immuno-modulatorsLow dose IL2
39
Reversible Quantitative Deficit in Treg Lymphocytes (CD4+CD25+) in HCV-Systemic
Vasculitis
Before treatmentOn treatmentEarly F/u Late F/U3
4
5
6
CD
25
hig
h (
% o
f C
D4
+)
4 4
5
6
Before
treat.
On Treat.
Early F/U
Late F/U.
**†
**†
-CR
-NR/PR
After Treat.
A
0 20 40 60 80 1000
1
2
3
CD25high (cells /μl)
Cry
og
lob
uli
ns
(g
/l)
R²-0.1, p<0.005
0 20 40 60 80 1000.0
0.2
0.4
CD25high (cells /μl)
C4
(g/l )
R²-0.16, p<0.005
Boyer, Blood 2004. Landau Arthritis Rheum 2008
40
41
Effects of Low-Dose Interleukin-2 on Levels of CD4-Treg in Patients with HCV-Vasculitis, According to
Treatment Course (C).
42
No Impact of Low-Dose Interleukin-2 on Levels Effector T Cells CD4+CD8+ in Patients with HCV-Vasculitis
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
Baseline C1 C2 C3 C4 Post IL-20
10
20
30
Baseline C1 C2 C3 C4 Post IL-20
10
20
30
Baseline C1 C2 C3 C4 Post IL-20
10
20
30
Baseline C1 C2 C3 C4 Post IL-20
10
20
30
PurpuraNeuropathy
ArthralgiaFatigueKidney Involvement
CD
4+Tr
eg
(%
)C
LIN
ICA
LR
ES
PO
NS
ETemporal Effects of Low-Dose Interleukin-2 on
Clinical Features & Levels of Regulatory T Cells for Each Study Patient
Saadoun D et al, NEJM 2012
45
BEFORE IL-2
AFTER IL-2CCL3CCL3L1CCL3L3
IL1ACCL20
IL6CLECL1CD79A
BLKCCL4L2
EBF1CCL4L1CXCR5
IER3
CXCR7OLR1PDE48PTGS2IL1B
BAFFR
4-1BBL
PLAURNLRP3RIPK2ATF3
NAMPT-PBEF1
TNFRSF21-DR6ETS2
MAPK3K8-COT
GOS2
CD83
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
Other diseases 190 211 4,15E-02
Saadoun D et al. NEJM 2011
Anti-inflammatory Effects of Low-Dose Interleukin-2 Revealed through Unsupervised Transcriptome
Analyses of PBMCs.
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
Fatigue, Depression and Extra Hepatic Manifestations (EM) in HCV Patients
% of patientsn=1614
% of controls n=412
Fatigue without depression 48 0.7 Fatigue with depression 5 0 Depression without fatigue 2 0 No fatigue and no depression 45 99.3TOTAL 100 100 Fatigue without EMEM 19 0.5 Fatigue with EM 35 0.2 EM without fatigue 21 3.4 No fatigue and no EM 25 96TOTAL 100 100
Poynard T et al. J Viral Hep, 2002
Fatigue without depression 48 0.7
Fatigue, Depression and Extra Hepatic Manifestations (EM) in HCV Patients
% of patientsn=1614
% of controls n=412
Fatigue without depression 48 0.7 Fatigue with depression 5 0 Depression without fatigue 2 0 No fatigue and no depression 45 99.3TOTAL 100 100 Fatigue without EM 19 0.5 Fatigue with EM 35 0.2 EM without fatigue 21 3.4 No fatigue and no EM 25 96TOTAL 100 100
Poynard T et al. J Viral Hep, 2002
Association Fatigue, Depression and Extrahepatic manifestations (EM) in HCV PatientsMultivariate 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
Poynard T et al. J Viral Hep, 2002
Baseline 18 months 18 months vs baseline
Non treated (n=72)No fatigueModerateSevere
39%35%26%
42%39%19%
P=0.74
Sustained responders (n=82)No fatigueModerateSevere
41%37%22%
69%24%7%
P<0.001
Non responders (n=224)No fatigueModerateSevere
40%42%18%
46%40%14%
P=0.18
Fatigue Rate in Untreated HCV Patients
Fatigue Rate in HCV Patients Non-Responders to IFN-RBV
Poynard T et al. J Viral Hep, 2002
Baseline 18 months 18 months vs baseline
Non treated (n=72)No fatigueModerateSevere
39%35%26%
42%39%19%
P=0.74
Sustained responders (n=82)No fatigueModerateSevere
41%37%22%
69%24%7%
P<0.001
Non responders (n=224)No fatigueModerateSevere
40%42%18%
46%40%14%
P=0.18
Decreased Fatigue Rate in HCV Patients Sustained Responders to IFN-RBV
Baseline 18 months 18 months vs baseline
Non treated (n=72)No fatigueModerateSevere
39%35%26%
42%39%19%
P=0.74
Sustained responders (n=82)No fatigueModerateSevere
41%37%22%
69%24%7%
P<0.001
Non responders (n=224)No fatigueModerateSevere
40%42%18%
46%40%14%
P=0.18
Poynard T et al. J Viral Hep, 2002
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.
*P<0.05 decrement from patients’ own baseline†P<0.05 improvement from patients’ own baseline
FACIT-F: No SVR
0.55
0.65
0.75
0 4 8 12 16 20
Week24 28
FACIT-F: SVR
FACIT-F: AllNor
mal
ized
FAC
IT-F
FACIT-F Scores During and Post-Treatment in FUSION
FACIT-F: No SVR
0.65
0.75
0 4 8 12 16 20
Week24 28
FACIT-F: SVR
FACIT-F: AllNor
mal
ized
FAC
IT-F
FACIT-F Scores During and Post-Treatment in NEUTRINO
0.55
**
*
†
†
†
*
†
†
FUSION & NEUTRINO Trials
Functional Assessment of Chronic Illness Fatigue (FACIT-F) in Patients Treated with SOF + PR
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
Younossi ZM, et al. AASLD 2013. Washington, DC. #2211
2013
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
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) 260.0 (54.5) 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
MVPA 222.5 (72.9) 214.9 (104.4) 0.793
Total counts in bouts/24h 516043.2 (193788.9) 517989.0 (411773.6) 0.985
Total bouts 39.8 (13.6) 36.2 (24.7) 0.576
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) 260.0 (54.5) 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
MVPA 222.5 (72.9) 214.9 (104.4) 0.793
Total counts in bouts/24h 516043.2 (193788.9) 517989.0 (411773.6) 0.985
Total bouts 39.8 (13.6) 36.2 (24.7) 0.576
24 hours physical activity levels in HCV patients and controls
2012
Cerebral MR Signal in HCV Patients and Spectral Analysis
A
C
B
T1 vs. T3 in SVR; p<0.05
MR Signal in Basal Ganglia Myo-Inositol/Creatinine Ratio in HCV Patients According to Virological Response
Significant reductions in basal ganglia Cho/Cr and 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
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.
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.
HCV Infection and Poor HRQoL
2013
2013
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).
Baseline 12 Weeks 24 Weeks
2
-2
-6
-8
HRQ
oL C
hang
e in
Sum
mar
y Sc
ore
0
-4
P<0.05Significant difference between treatment arms at weeks 12 and 24
Follow UpWeek 12
SOF+RBV EOT
SOF+RBV EOT
Peg-IFN+RBV EOT
Peg-IFN+RBV EOT
HRQoL in FISSION GT 2 and GT 3 Treatment-Naïve: SOF+RBV vs Peg-IFN+RBV
Patients treated with SOF+RBV had better HRQoL scores at the end of treatment as compared to patients receiving Peg-IFN+RBV
Younossi ZM, et al. EASL 2013. Amsterdam, The Netherlands. #1431
SOF+RBV Physical Component Summary
SOF+RBV Mental Component Summary
Peg-IFN+RBV Physical Component Summary
Peg-IFN+RBV Mental Component Summary
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
Hepatology, 2013, in press
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
2,267,270 patients with a diagnosis of diabetes mellitus (DM) between January 1, 1997 and December 31, 2011
3,957 HCV-infected patients ever treated
with Peg-IFN+RBV
1,411 patients in the treated cohort
20,239 HCV-infected patients never treated
with Peg-IFN+RBV
720,302 patients without HCV infection
1,411 patients in the untreated cohort
5,644 patients in the uninfected cohort
1,630,156 DM patients without hepatitis B virus infection
746,280 patients with diabetes mellitus
Baseline characteristics and follow-up status of the tree study cohorts
Treated cohort(n = 1411)
Untreated cohort(n = 1411)
Uninfected(n = 5644) P*
Age (mean + SD) 54.92 + 8.06 55.01 + 7.99 54.93 + 8.07 0.932Gender, n (%) 0.995
Female 491 (34.8) 493 (34.9) 1964 (34.8)Male 920 (65.2) 918 (65.1) 3680 (65.2)
Comorbidity, n (%)
Hyperlipidemia 177 (12.5) 175 (12.4) 718 (12.7) 0.952Hypertension 606 (42.9) 606 (42.9) 2444 (43.3) 0.953Thyroid disorder 139 (9.9) 137 (9.7) 544 (9.6) 0.96Compensated cirrhosis 324 (23) 322 (22.8) 1289 (22.8) 0.994COPD 482 (34.2) 481 (34.1) 1924 (34.1) 0.999Peripheral arterial disease 95 (6.7) 91 (6.4) 373 (6.6) 0.954
Diabetes medication, n(%) 0.107Metformin monotherapy 96 (6.8) 80 (5.7) 346 (6.1)Other oral monotherapy 533 (37.8) 569 (40.3) 2366 (41.9)Two oral agents 302 (21.4) 311 (22) 1093 (19.4)Three or more oral drugs 174 (12.3) 157 (11.1) 682 (12.1)Insulin dependence 138 (9.8) 117 (8.3) 474 (8.4)Uncategorized 168 (11.9) 177 (12.5) 683 (12.1)
Cumulative Incidence of End Stage Renal Disease(death adjusted as a competing risk event)
Cumulative Incidence of Stroke(death adjusted as a competing risk event)
Cumulative Incidence of Acute Coronary Events(death adjusted as a competing risk event)
Hepatology, 2012
Baseline Features in Gen1 HCV Patients and Gender, Age & BMI-Matched Controls
Carotid intima-media 1.04 + 0.21 0.90 + 0.16 < 0.001Thickness, mm
Carotid plaques 73 (41.9) 40 (23) < 0.001
Risk Factors Associated with the Presence of Carotid Plaques in Gen1 HCV Patients
Histology at biopsy
Steatosis (%) 13 + 18.5 14.5 + 19 0.60Grade of inflammation
1-2/3 28/73 8/65 0.007 0.756 (0.327, 1.748) 0.51Stage of fibrosis
1-2/3-4 73/28 37/36 0.003 2.177 (1.043, 4.542) 0.03
Risk Factors Associated with the Presence of Carotid Plaques in Gen1 HCV Patients
P=0.008
N=21 CHCAge ≤55 yrs
F3-4
N=67 CHCAge ≤55 yrs
F0-2
N=43 CHCAge >55 yrs
F3-4
N=43 CHCAge >55 yrs
F0-2
P=0.51
Caro
tidea
l Pla
ques
(%)
00
20
80
60
40
100
2013
LHID 20001,000,000 individuals
9220 Patients with a new diagnosis of HCV between January 1, 2004 and December 31, 2007
2453 ExclusedPatients who were diagnosed as having HCV on only 1 occassion
6767 Patients with a new diagnosis of HCV
3654 Exclused43 Age <202986 History of HCV before January 1, 200484 History of IBT before the first HCV diagnosis1167 History of Stroke before the first
HCV diagnosis
3113 HCV cohort with a diagnosis of HCV on at least two occassions
30 ExclusedReceived IBT for a period of <3 months
208 IBT cohort received treatment for a period of >3 months
2875 Non-IBT cohort received no IBT between 2004 and 2008
12452 Non-HCV cohortMatched by age and sex at a ratio of 1:4
Hepatitis C virus infection and stroke risk
Cohorts Hazard ratio 95% CI P-value*
HCV 1.21 1.05 - 1.40 0.011
Non HCV 1
HCV ‡ 1.23 1.06 - 1.43 0.006
Non HCV 1
HCV † 1.23 1.06 - 1.42 0.008
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.
IBT, interferon based therapy
Interferon-Based Therapy and Stroke-Free Survival in HCV Patients
Log-rank test,p = 0.003
Stro
ke-f
ree
surv
ival
rate
0.80
0.85
0.95
0.90
100
0 1 2 3 4 5Time (years)
Non-IBT
IBT
Interferon-based therapy and stroke risk in patients with hepatitis C
Hazard ratio 95% confidence interval P-value*
IBT 0.28 0.12 - 0.69 0.005
Non IBT 1
IBT ‡ 0.38 0.16 - 0.93 0.033
Non IBT 1
IBT † 0.39 0.16 - 0.95 0.039
Non IBT 1
Interferon based therapy was associated with a 61% decreased riskof 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.
2012
Myocardial injury in HCV patients
Characteristics Chronic hepatitis C (n = 217) Normal rangeAge (yr) 57 + 9Sex 104/113
Liver functionBilirubin (mg/dl) 0.7 + 0.3 0.2 - 1.0ALT (IU/L) 77 + 61 5 - 45Y-globulin (g/dl) 1.6 + 0.3 0.7- 1.2Prothrombin percent activity (%) 90 + 16 80 - 100IGC disappearance rate 0.172 + 0.041 0.158 - 0.232HAI score (point) 8.9 + 3.3
Cardiac functionAbnormal ECG (%) 9CPK (IU/L) 94 + 46 30 - 190LDH (IU/L) 172 + 38 107 - 230BNP (pg/ml) 22 + 18.8 Less than 18.4HANP (pg/ml) 19.6 + 12.5 Less than 43LVDd (mm) 48 + 5 39 - 55Ejection fraction (%) 66 + 7 55 - 80Severity score (point) 4.3 + 1.6 Less than 3Severity score > 3 (%) 87
Cardiac function
Abnormal ECG (%) 9
CPK (IU/L) 94 + 46 30 - 190
LDH (IU/L) 172 + 38 107 - 230
BNP (pg/ml) 22 + 18.8 Less than 18.4
HANP (pg/ml) 19.6 + 12.5 Less than 43
LVDd (mm) 48 + 5 39 - 55
Ejection fraction (%) 66 + 7 55 - 80
Severity score (point) 4.3 + 1.6 Less than 3
Severity score > 3 (%) 87HAI, histology activity index; BNP, brain natriuretic peptide;
HANP, human atrial natriuretic peptide; LVDd, left ventricular end diastolic dimension
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.
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.
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.
Myocardial SPECT Images in HCV Patients According to Virological Response
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)
IFN
SVR group(n= 30)
Relapse group(n= 9)
NVR group(n= 6)
Severity Score of Myocardial Perfusion Defects in HCV Patients after 48 weeks PegIFN/Ribavirin
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
Manifestation Prevalence
certainly associated with HCV %-------------------------------------------------------• Vasculitis (PAN, cryoglobulinemia) 5-40 • Fatigue 35-54• Arthralgia-myalgia 25-35• Sicca syndrome 10-25• Autoantibodies 10-40• Thrombocytopenia 20-40• Lymphoma ?
Auto-antibody production in chronic HCV infection.
0
10
20
30
40
50
60
70
%
A-nuclearA-phospholipidA-thyroglobulinA-smooth muscle≥ one auto-Ab≥ three auto-Ab
Pawlotsky JM, Hepatology 1994. Pawlotsky JM, Ann Intern Med 1994.Prieto J, Hepatology 1996. Cacoub P, J Rheumatol 1997. Cacoub P, Medicine 2000.
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
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007
B-cell-Non Hodgin’s LymphomaB-cell-Non Hodgin’s Lymphoma
Hepatitis C virusHepatitis C virus
2462 tested2462 tested
13.5 % positive • vs 0-5 % in controlsvs 0-5 % in controls
• vs 5 % in other malignant vs 5 % in other malignant hemopathyhemopathy
469 tested469 tested
0 - 39 %
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007Effects of alpha-interferon on HCV+/SLVL course
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
HCV antibodies : B-NHL (< 3%) vs SLVL (15%)HCV antibodies : B-NHL (< 3%) vs SLVL (15%)
----> Splenic lymphoma with villous lymphocytes may be associated with HCV infection
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.
Extrahepatic Manifestations of HCV InfectionSummary
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S. Caillat-Zucman, Paris
P. Ghillani, Paris D. Klatzmann, Paris L. Musset, Paris M. Rosenzwajg, Paris
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
Merci
L. Alric, Toulouse M. Bourlière, Marseille P. Halfon, Marseille S. Pol, Paris T. Poynard, Paris V. Thibault, Paris Les membres du GERMIVIC
L. Calabrese, Cleveland M. Casato, Roma C. Ferri, Modena G. Kerr, Washington E. Sasso, Seattle JA. Schifferli, Basel V. Soriano, Madrid