Cacoub hcv ehm & inflam du16

1. HCV and its Extra Hepatic Manifestations:
From Immune- to Inflammatory-Related
Manifestations
Pr Patrice CACOUB, MD
Dept of Internal Medicine and Clinical Immunology
CNRS UMR 7087, INSERM UMR S-959, DHU I2B
Université Pierre et Marie Curie
Hôpital La Pitié-Salpêtrière, Paris, FRANCE

2. Disclosures
• Dr P. Cacoub has received consulting and lecturing fees from : Abbvie, Astra
Zeneca, Bristol-Myers Squibb, Gilead, Glaxo Smith Kline, Janssen, Merck
Sharp Dohme, Roche, Servier, Vifor.
• Dr P. Cacoub is an inventor of a patent application owned by his academic
institution and licensed to ILTOO pharma, a biotechnology company
developing low dose IL-2 in autoimmune diseases, in which in holds shares.
• Dr P. Cacoub has received grants from : CNRS , INSERM , Université Pierre et
Marie Curie, ANRS

3. 35
30
25
20
15
10
5
0
Chronic HCV Infection Increases Mortality
*P<0.001 for comparison among all 3 groups and P<0.001 for HCV RNA
detectable vs. undetectable. †P<0.001 for comparison among all 3 groups and
P=0.002 for HCV RNA detectable vs. undetectable
Lee MH, et al. J Infect Dis 2012;206:469–77
Follow-up
(Years)
20
18
16
14
12
10
2
0
8
6
4
Follow-up
(Years)
12
10
8
6
4
2
0
All causes
(n=2,394)
Liver cancer
(n=115)
Extrahepatic diseases
(n=2,199)
Cumulativemortality(%)
Follow-up
(Years)
30.1%*
12.8%
12.4%
10.4%*
1.6%
0.3%
19.8%†
12.2%
11.0%
Anti-HCV+, HCV RNA detectable Anti-HCV+, HCV RNA undetectable Anti-HCV-
0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20
• 23 820 adults, Taiwan
• 1095 anti-HCV positive
• 760 (69%) HCV-RNA detectable
HCV+, RNA+
HCV+, RNA-
HCV-

4. 35
30
25
20
15
10
5
0
Chronic HCV Infection Increases Mortality from
both Hepatic and Extra Hepatic Diseases
*P<0.001 for comparison among all 3 groups and P<0.001 for HCV RNA detectable vs.
undetectable. †P<0.001 for comparison among all 3 groups and P=0.002 for HCV RNA
detectable vs. undetectable
Follow-up
(Years)
20
18
16
14
12
10
2
0
8
6
4
Follow-up
(Years)
12
10
8
6
4
2
0
All causes
(n=2,394)
Liver cancer
(n=115)
Extrahepatic diseases
(n=2,199)
Follow-up
(Years)
30.1%*
12.8%
12.4%
10.4%*
1.6%
0.3%
19.8%†
12.2%
11.0%
0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20
Lee MH, et al. J Infect Dis 2012;206:469–77
HCV+, RNA+
HCV+, RNA-
HCV-
Cumulativemortality(%)

5. Chronic HCV Infection Increases Mortality from
both Hepatic and Extra Hepatic Diseases
*P<0.001 for comparison among all 3 groups and P<0.001 for HCV RNA detectable
vs. undetectable. †P<0.001 for comparison among all 3 groups and P=0.002 for
HCV RNA detectable vs. undetectable
Follow-up
(Years)
20
18
16
14
12
10
2
0
8
6
4
Extrahepatic
diseases
(n=2,199)
Cumulativemortality(%)
19.8%†
12.2%
11.0%
0 2 4 6 8 10 12 14 16 18 20
Lee MH, et al. J Infect Dis 2012;206:469–77
HCV+, RNA+
HCV+, RNA-
HCV-

6. Chronic HCV Infection Increases Mortality from
both Hepatic and Extra Hepatic Diseases
 Compared with anti-HCV negative individuals, anti-HCV positive
individuals had higher mortality
 Higher mortality in individuals with detectable HCV RNA vs. those with
undetectable HCV RNA
CI: confidence interval Lee MH, et al. J Infect Dis 2012;206:469–77
Hazard ratio [95% CI]
All causes 1.89 [1.66–2.15]
Hepatic diseases
Extra hepatic diseases
Cardiovascular diseases
Nephritis
Esophageal cancer
Prostate cancer
Thyroid cancer
12.48 [9.34–16.66]
1.35 [1.15–1.57]
1.50 [1.10–2.03]
2.77 [1.49–5.15]
4.08 [1.38–12.08]
4.19 [1.18–14.94]
8.22 [1.36–49.66]

7. 1. Cryoglobulinemia vasculitis and lymphoproliferation
2. Chronic HCV infection : a new cardio-vascular risk
factor ?
3. Insulin-Resistance and Type 2 Diabetes Mellitus
4. Fatigue, depression and cognitive impairment
5. Impact of HCV cure on extrahepatic manifestations
HCV and its Extra Hepatic Manifestations:
Agenda

8. Auto-immune Manifestations and
Lymphoproliferative Diseases

9. Manifestation certainly associated with HCV
%
 Vasculitis (PAN, cryoglobulinemia) 5-40
 Arthralgia-myalgia 25-35
 Sicca syndrome 10-25
 Auto-antibodies 10-40
 Thrombocytopenia 20-40
 Lymphoma RR=35

10. HCV Chronic Infection: More than One Target Cell
1. Choo GL, et al. Science 1989;21;244:359–62.; 2. Zignego AL, et al.
J Hepatol 1992;15:382–6.; 3. Ferri C, et al. Blood. 1993;82:3701–4
• Hepatitis
• Cirrhosis
• Hepatocarcinoma
• Cryoglobulinaemia
• Auto-Ab
• B-NHL
Hepatocyte1 Lymphocyte2,3

11. VASCULARITES: CLASSIFICATION
Chapel Hill, révisé en 2012

12. HCV Chronic Infection Is the Main Cause of
Mixed Cryoglobulinemia
Saadoun, Arch Intern Med, 2006
N = 1,434 patients with mixed cryoglobulin

13. Ferri C et al. Orphanet J Rare Dis 2008
Brouet J et al. Am J Med 1974
Les cryoglobulines sont des Immunoglobulines
qui précipitent à une température < 37°C et se
dissolvent lors du réchauffement

14. 14
Endothelial cells
Cryoprecipitation

15. 15
Skin Purpura
Glomerulonephritis CNS Vasculitis
Neuropathy
Cryoglobulinemia Vasculitis

16. Distal Polyneuropathy 80%
Cacoub P et al, AIDS 2005
Mixed Cryoglobulin and Neuropathy
• Chronic progressive course,
• Distal, symetric, axonal PN, mainly sensory
• Few extra neurological signs : purpura
• Severe liver involvement
• Moderate inflammatory syndrome
Mononeuropathy
Multiplex 20%

17. Cryoglobulinemic Membrano-Proliferative
Glomerulonephritis
Doubles Contours
Pseudo-thrombi
GNMP de type 1
IgG/IgM
Kappa/
lambda
C3 ±C1q

18. 18
HCV Mixed Cryoglobulinemia and Digestive Tract
Mesenteric artery stenosis Intestinal wall thickening
Terrier B et al, GUT 2011

19. 19
Cardiac Involvement in Hepatitis
C Virus-Related Vasculitis
Terrier B et al, Am J Cardiol 2013

20. Central Nervous System Involvement
in HCV-Cryoglobulinemia Vasculitis
HCV-vasculitis HCV Controls
(n=40) (n=11) (n=36)
--------------------------------------------------------------------------------------
Gender (F/M) 23/17 6/5 20/16
Age (yrs) 59 ± 13 56 ± 10 58 ± 12
WMHS 7.0 ± 9.9 0.9 ± 1.8 * 2.0 ± 3.1
PVHS 2.5 ± 3.1 0.4 ± 0.5 * 0.8 ± 1.4
NCFD 2.2 ± 1.8 0.9 ± 0.8 * -
--------------------------------------------------------------------------------------
* P<0.01
WMHS: White Matter Hypersignals
PVHS: Periventricular Hypersignals
NCFD: Number of Cognitive Function Deficiency
Casato M et al, J Hepatol 2004

21. 21
Age at disease onset 54 ± 13 (29-72)
Female/Male ratio 3
Purpura 98%
Weakness 98%
Arthralgias 91%
Arthritis (non-erosive) 8%
Raynaud's phenomenon 32%
Sicca syndrome 51%
Peripheral neuropathy 81%
Renal involvement 31%
B-cell non-Hodgkin's lymphoma 11%
Hepatocellular carcinoma 3%
Features of Mixed Cryoglobulinemia
n=250 Ferri C, Mascia MT, Saadoun D, Cacoub P. 2009

22. HCV-Cryoglobulinemia Vasculitis Mechanisms: Major
Role for B and T Lymphocytes
Rocatello D, Nephrol Dial Transplant, 2004
• Th1 lympho/cytokines
• Treg deficit

23. - important peri-vascular infiltrate of lymphocyte
- around small vessels i.e. venules, capillaries
- no PMN, no destruction of the vascular wall
Mixed Cryoglobulin and Distal Polyneuropathy
Peripheral Nerve Biopsy

24. 24
HCV Core Protein in Skin Vascular Structures
Who’s the culprit ?
Cellular Infiltrate in HCV-Vasculitis

25. 25
Detection of Genomic Viral RNA in Nerve
and Muscle of Patients with HCV Neuropathy
 Inflammatory vascular lesions in 26/30 (87%) patients
 Positive-strand genomic HCV RNA detected in 10/30
patients (muscle 9, nerve 3)
 Negative-strand replicative HCV RNA never
detected
--> HCV neuropathy probably results from virus-triggered
immune-mediated mechanisms rather than direct nerve
infection and in situ replication
Authier JF et al, Neurology, 2003

26. 26
Antigen-Insensitive
B Cell Proliferation
Oligo/Monoclonal
proliferation
Uncontrolled
proliferation
Antigen-Sensitive
B Cell Proliferation
Polyclonal
proliferation
B-cell lymphoma
Cytokines
BAFF
Hyperglobulinemia
 Cryoglobulinemia
Vasculitis
 B-cell lymphoma
IgH-bcl2? Other
oncogenic
events ?
CD81
HCV (E2)
B cell
Anti-E2 IgM/Rheumatoid factorIgG
HCV Induced Lymphoproliferative Disorders:
from Cryoglobulinemia to B-Cell Lymphoma
Treg deficit

27. Chronic HCV infection
Poly- oligoclonal
B-cell expansion
Autoantibodies
RF - IC
Mixed cryoglobulins
Cryoglobulinaemic vasculitis
Monoclonal B-cell
proliferation
Overt lymphoma
HCV eradication
Immunosuppressors
Chemotherapy
Plasma exchange
Steroids
Strategies to Treat Auto-Immune Manifestations
IC: immune complexes; RF: rheumatoid factor Cacoub P et al, Dig Liv Dis. 2014

28. 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, D et al , Ann Rheum Dis 2014
Non virological
response
Sustained virological
response
Clinical Remission in HCV-Cryoglobulinemia
Vasculitis Correlates with Virological Response

29. Sofosbuvir plus Ribavirin for HCV
Cryoglobulinemia Vasculitis
Clinical response Virological
response
complete partial HCV RNA<12UI/mL
During treatment (n=24)
at week 4 6 1 1
at week 8 4 19
at week 12 7 2 2
at week 16 3
at week 20 1
at week 24 21/24 (87.5%) 2/24 (8.3%)* 22/24 (91.7%)
After the end of
treatment
at week 12 20/23 (86.9%)* 17/23 (74%) †
virological failure 2
relapse 2 4
*one out the 24 patients was not evaluable for clinical response at week 24 and week 36 because he died at week 16 during therapy.
† one out the 24 patients was not evaluable for SVR12 because he died at week 16 during therapy.
Saadoun D et al, Ann Rheum Dis, 2015

30. 30De Vita S, Arthritis Rheum 2012
Rituximab (RTX) is Superior to Immunosuppressants
for Severe HCV-Cryoglobulinemic Vasculitis
RTX
non-RTX
Probabilityofresponse
Non RTX group included conventional treatment i.e., glucocorticosteroids,
azathioprine or cyclophosphamide, or plasmapheresis.

31. 31
Better Course of Kidney Parameters in HCV-Cryoglobulinemia
who Received Rituximab plus PegIFN/Ribavirin
PegIFN-ribavirin RTX-PegIFN-
ribavirin
n=10 p n=21 p
Kidney inv. CR 4 (40) 17 (80.9) 0.04
Creatininemia (µmol/l)
Baseline 150 ± 30 217 ± 47
EOF 169 ± 44 0.28 136 ± 27 0.03
GFR (ml/min)
Baseline 58 ± 7 42 ± 5
EOF 59 ± 9 0.41 57 ± 4 0.01
Daily Proteinuria (gr/d)
Baseline 3.1 ± 0.9 3 ± 1
EOF 1.2 ± 0.5 0.046 0.4 ± 0.1 <0.001
Hematuria (n,%)
Baseline 10 (100) 19 (90.5)
EOF 2 (20) 2 (10.5) <0.001

32. 32
IFN/RBV PegIFN/RBV PegIFN/RBV/
PI
SOF/RBV
N=30 N=42 N=30 N=24
Complete clinical response
- week 12
- end of Rx
18.7%
37.5%
37.5%
70%
46.6%
66.7%
71%
87.5%
Virological response (SVR)
- week 12
- 12/24 weeks post Rx
50%
53%
62.5%
62.5%
73.9%
66.6%
92%
74%
Cryoglobulin clearance (W24) 15% _ 22.2% 41.6%
Serious adverse events ND ND 46.6% 8%
Steroids / Rituximab 53% 45% 43% 16%
Treatments for HCV Related Vasculitis: Better Antiviral
Efficacy, Less Immunosuppressant Use
Cacoub P, Saadoun D, personal communication, 2015

33. HCV Cryoglobulinemia Vasculitis
Therapeutic Strategies
Severe
Renal disease,
mononeuropathy multiplex,
skin necrosis
Catastrophic
Rapidly progressive GN,
CNS, digestive, pulmonary
involvement
Mild - moderate
Arthralgia, purpura,
polyneuropathy
Cacoub P et al, Ann Rheum Dis 2013
Optimized IFN
free antivirals
Rituximab plus
Optimized IFN free
antivirals
Rituximab, PE,
Steroids,
Optimized IFN free
antivirals
 If failure or contra-indication to HCV treatment, Rituximab may be used
alone. HCV: hepatitis C virus; GN: glomerulonephritis; CNS: central nervous system

34. • N=125,
• DLBCL, 39 % ; MZL, 38 %; FL, 13 % ; autre,
10 %.
• HCV Rx in 79 pts
• SVR 48/79 (61 %)
• SVR correlated with
hematological response in
marginal zone lymphoma
(p<0.001)
HCV related B cell Lymphoma: Favorable Impact
of Antivirals
Michot JM et al, Am J Hematol 2014
GlobalSurvivalProgressionFreeSurvival

35. Chronic HCV infection :
a new cardio-vascular risk
factor ?

36. HCV Control Odds ratio Odds ratio
Study or subgroup Events Total Events Total Weight IV, random, 95% CI Year IV, random, 95% CI
Guiltinan 2008 73 10259 34 10259 31.8% 2.16 [1.43, 3.24] 2008
Lee 2012 38 760 477 18541 34.8% 1.99 [1.42, 2.80] 2012
Vajdic 2015 59 14498 54 14048 33.4% 1.06 [0.73, 1.53] 2015
Total (95% CI) 25517 42848 100.0%
1.65
[1.07, 2.56]
Total events 170 565
Meta-analysis, random effect model
Increased Risk of Cardiovascular Death
in HCV Patients
5210.50.2
Controls HCV positives
Heterogeneity: Tau2=0.11; Chi2=8.37, df=2 (p=0.02); I2=76%
Test for overall effect: Z=2.25 (p=0.02)
Petta S et al, Gastroenrology 2015

37. Stroke
Heart
Kidney

38. Cumulative Incidence of Stroke in three Diabetic
Study Cohorts
HCV+ non treated
HCV+ treated
Non HCV
Hsu YC et al, Hepatology, 2014 Apr;59(4):1293-302.Death adjusted as a competing risk event

39. Association Between HCV infection and Ischemic
Cerebrovascular Accident
Domont F & Cacoub P, Liver Int in press
References, year Type of study Country HCV+ (n) HCV- (n)
Studies showing an association
Lee et al. , 2010 Prospective cohort Taiwan 1307 22,358
Liao et al. , 2012 Population Taiwan 4094 16,376
Hsu et al. 2013 Retrospective cohort Taiwan 2875 12,450
Adinolfi et al. , 2013 Retrospective cohort Italy 79 741
Studies NOT showing an association
Younossi et al. , 2013 Retrospective pop; USA 173 19,568

40. HCV Control Odds ratio Odds ratio
Study or subgroup Events Total Events Total Weight IV, random, 95% CI Year IV, random, 95% CI
Arcari 2006 23 52 269 530 5.9% 0.77 [0.43, 1.36] 2006
Butt 2009 6169 82083 5594 89582 17.8% 1.22 [1.18, 1.27] 2009
Forde 2012 16 4809 248 71668 6.9% 0.96 [0.58, 1.60] 2012
Liao 2012 482 4094 1499 16376 16.7% 1.32 [1.19, 1.48] 2012
Adinolfi 2013 33 79 90 741 7.0% 5.19 [3.15, 8.54] 2013
Hsu CS 2013 220 2875 1141 12452 15.7% 0.82 [0.71, 0.95] 2013
Enger 2014 584 21919 1456 67109 16.9% 1.23 [1.12, 1.36] 2014
Pothineni 2014 84 1434 480 14799 13.2% 1.86 [1.46, 2.36] 2014
Total (95% CI) 117345 273257 100.0%
1.30
[1.10, 1.55]
Total events 7611 10777
Heterogeneity: Tau2=0.04; Chi2=76.44, df=7 (p<0.00001); I2=91%
Test for overall effect: Z=3.08 (p=0.002)
HCV infection and Ischemic Cerebrovascular Accident
Meta-analysis, random effect model
5210.50.2
Controls HCV positives
Petta S et al, Gastroenrology 2015

41. p=0.008
N=21 CHC
≤ 55 yrs
F3-4
N=67 CHC
≤ 55 yrs
F0-2
N=43 CHC
> 55 yrs
F3-4
N=43 CHC
> 55 yrs
F0-2
p=0.51
CarotidPlaques(%)
0
20
80
60
40
100
High Incidence and Risk Factors Associated with the
Presence of Carotid Plaques in HCV patients
Petta S, et al. Hepatology 2012;55:1317–23

42. HCV Control Odds ratio Odds ratio
Study or subgroup Events Total Events Total Weight IV, random, 95% CI Year IV, random, 95% CI
Ishizaka 2002 40 104 1030 4680 20.2% 2.21 [1.48, 3.31] 2002
Ishizaka 2002 16 25 480 1967 7.8% 5.51 [2.42, 12.54] 2003
Targher 2007 22 60 9 60 7.0% 3.28 [1.36, 7.92] 2007
Bilora 2008 11 40 4 40 3.9% 3.41 [0.98, 11.85] 2008
Tien 2009 7 53 27 452 7.0% 2.40 [0.99, 5.81] 2009
Caliskan 2009 16 36 17 36 6.4% 0.89 [0.35, 2.96] 2009
Mostafa 2010 12 187 10 192 7.2% 1.25 [0.53, 2.96] 2010
Adinolfi 2012 91 326 74 477 23.1% 2.11 [1.49, 2.98] 2012
Petta 2012 73 174 40 174 17.3% 2.42 [1.52, 3.85] 2012
Total (95% CI) 1005 8078 100.0%
2.27
[1.76, 2.94]
Total events 288 1691
Heterogeneity: Tau2=0.04; Chi2=11.52, df=8 (p=0.17); I2=31%
Test for overall effect: Z=6.25 (p<0.00001)
Petta S et al, Gastroenrology 2015
Carotid Plaques and HCV Infection
50101
Controls HCV positives
0.10.02
Meta-analysis, random effect model

43. IBT, interferon based therapy
Interferon-Based Therapy and Stroke-Free Survival
in HCV patients
Hsu CS, et al. APT 2013;38:415–23
Log-rank test,
p = 0.003
Stroke-freesurvivalrate
0.80
0.85
0.95
0.90
100
0 1 2 3 4 5
Time (years)
Non-IBT
IBT
 IFN-based therapy was associated with a 61% decreased risk
of stroke in HCV patients, after adjusting for known
prognostic factors.

44. HCV infection and Ischemic Heart Disease
References, year Type of study Country HCV+ (n) HCV- (n)
Studies showing an association
Vassalle et al. (9), 2004 Cross-over Italy 491 195
Völzke et al. (41), 2004 Transversal Germany 21 4033
Butt et al. (28), 2009 Cross-over USA 60 60
Tsui et al. (27), 2009 Cohort USA 84 -
Ramdeen et al. (41), 2010 Cohort USA 78 -
Studies NOT showing an association
Butt et al. (32), 2007 Cohort USA 126,926 126,926
Domont F & Cacoub P, Liver Int in press

45. Myocardial Injury in HCV patients
BNP, brain natriuretic peptide; CPK: creatinine phosphokinase; HAI, histology activity index; HANP, human
atrial natriuretic peptide; LDH: lactate dehydrogenase; LVDd, left ventricular end diastolic dimension Maruyama S, et al. J Hepatol 2012;58:11–5
Characteristics Chronic hepatitis C (n = 217) Normal range
Age (yr) 57 + 9
Sex 104/113
Liver function
Bilirubin (mg/dl) 0.7 + 0.3 0.2 - 1.0
ALT (IU/L) 77 + 61 5 - 45
Y-globulin (g/dl) 1.6 + 0.3 0.7- 1.2
Prothrombin percent activity (%) 90 + 16 80 - 100
IGC disappearance rate 0.172 + 0.041 0.158 - 0.232
HAI score (point) 8.9 + 3.3
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 (%) 87
Cardiac function HCV patients normal range
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 (%) 87

46. 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
SPECT: single-photon emission computed tomography Maruyama S, et al. J Hepatol 2012;58:11–5
Before therapy
End of therapy
6 months after therapy

47. SVR Relapse
Myocardial SPECT Images in HCV Patients
According to Virological Response
SPECT: single-photon emission computed tomography Maruyama S, et al. J Hepatol 2012;58:11–5
Before therapy
End of therapy
6 months after therapy
Before therapy
End of therapy
6 months after therapy
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.

48. SVR Relapse Non Response
Myocardial SPECT Images in HCV Patients
According to Virological Response
Maruyama S, et al. J Hepatol 2012;58:11–5
Before therapy
End of therapy
6 months after therapy
Before therapy
End of therapy
6 months after therapy
Before therapy
End of therapy
6 months after therapy
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.

49. 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 PEG-IFN/RBV
RBV: ribavirin; NVR: non-virological response Maruyama S, et al. J Hepatol 2012;58:11–5

50. 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 PEG-IFN/RBV
RBV: ribavirin; NVR: non-virological response Maruyama S, et al. J Hepatol 2012;58:11–5

51. 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 PEG-IFN/RBV
RBV: ribavirin; NVR: non-virological response Maruyama S, et al. J Hepatol 2012;58:11–5

52. Favorable Impact of HCV Eradication on
Cardiovascular Events in Cirrhotics
Prospective Cohort, ANRS CO12 CirVir
3 yrs 5 yrs
2.3 %
9.1 %
12.3 %
3.5 %
2012-2015; 1,323 patients; F-up 51 months Nahon P et al, AASLD 2015

53. 1. Negro F. J Hepatol 2014; 61:S69–S78;
2. Negro F, et al. Gastroenterology 2015; 149:1345–1360;
HCV and Cardiovascular Events: Possible
Mechanisms
IR=insulin-resistance; HCC=hepatocellular carcinoma

54. HCV, Insulin-Resistance
and Type 2 Diabetes Mellitus (T2DM)

55. Jacobson I et al, Clin Gastroienterol Hepatol 2010

56. Increased Risk of T2DM in HCV Patients
Controls =
healthy subjects
White DL, et al. J Hepatol 2008
Controls =
HBV

57. Age >50 yrs
Cumulative Development Rate of T2DM in HCV
Patients with or without SVR after IFN
Arase Y, et al. Hepatology 2009
Cirrhotics

58. Eslam M et al, Aliment Pharmacol Ther. 2011
Insulin Resistance (HOMA-IR) is Associated with
Lower Sustained Virological Response, Meta-analysis

59. Changes in Insulin Sensitivity According to Virological
Response After PegIFN/Ribavirin for HCV Infection

60. Abnormalities of Glucose Metabolism and Severe Liver Fibrosis in
HCV Patients
Author Year Country
Number of
HCV patients
Patient
profile
Glucose
abnormality
Statistical method
Association with
severe fibrosis
Genotypes Statistics
Konrad[41] 2000 Germany 10 non DM FPG
Multivariate
Yes All p=0.01
Sud [54] 2004 Australia 170 - HOMA-IR
Multivariate
Yes All OR 1.47 [1.14, 1.89]; p=0.003
Muzzi [55] 2005 Switzerland 221 non DM HOMA-IR
Multivariate
Yes All (except G3) OR 1.57 [1.04; 2.39]
D'souza [56] 2005 UK 59 - HOMA-IR
Multivariate
Yes All
p=0.001
Taura [57] 2006 Japan 83 - HOMA-IR
Multivariate
Yes All
OR 7.32 [1.59; 33.73]; p=0.01
Bugianesi [58] 2006 Italy 132 G3 with steatosis HOMA-IR
Multivariate
Yes
G3
OR 2.98 [1.13-7.89]p=0.028
Kita [59] 2007 Japan 68 Post tranfusion DM Multivariate Yes All OR 8.4 [2.23; 31.54] p=0.002
Petta [60] 2008 Italy 201 G1 DM
Multivariate
Yes G1 OR 2.69 [1.46; 4.95]; p<0.001
Moucari [33] 2008 France 500 - HOMA-IR
Multivariate
Yes All OR 1.8 [1.16; 2.81]; p=0.009
Cua[61] 2008 Australia 346 G1, G3, untreated IR
Multivariate
Yes G3 OR 3.15 [1.56; 6.35]; p=0.001
Hsu [62] 2009 Taiwan 528 G1, G2 FPG
Multivariate
Yes G1 OR 13.72 [2.15; 87.7] ; p<0.05
Moucari [63] 2009 France 226 G4 HOMA-IR
Multivariate
Yes G4 OR 3.86 [1.859 ; 8.034] ; p<0.001
Persico [53] 2009 Italy 726 - DM
Multivariate
Yes All p<0.05
Hung[14] 2011 Taiwan 1,470 - DM Univariate Yes All p<0.001
Patel[64] 2011 Asia 263 G2, G3 HOMA-IR
Multivariate
Yes G2 and G3 OR 8.42 [2.1 ; 34.3] ; p=0.003
Mohamed [65] 2011 Egypt 50 G4 HOMA-IR
Multivariate
Yes G4 OR 3.73 ; p=0.001
Miyaaki [66] 2011 Japan 171 - DM
Multivariate
Yes All OR 8.739 [2.85 ; 26.85] p=0.0002
Conjeevaram[67] 2011 US 341 G1 HOMA-IR
Multivariate
Yes G1 OR 1.28 [1.07; 1.51] ; p=0.005
Petta [49] 2011 Italy 170 G1 HOMA-IR
Multivariate
Yes G1 OR 2.64 [1.11; 6.28] p=0.02
Khattab [68] 2012 Egypt 107 G4 HOMA-IR
Multivariate
Yes G4 OR 1.87 [1.09; 8.29] ; p=0.04
Ziada[69] 2012 Egypt 140
non DM
HOMA-IR
Multivariate
Yes All
OR 1.92 [0.97; 3.4] ; p=0.049
Thompson[13] 2012 US 1,038
non DM
HOMA-IR
Multivariate
Yes All
OR 1.6 [1.1; 2.33] ; p=0.02
Alfaleh[70] 2013 Saudi Arabia 157 - DM Multivariate Yes All (except G4) OR: 0.37 [0.148; 0.927] ; p=0.034
Dokmeci [71] 2014 Turkey 104 - HOMA-IR Multivariate Yes All OR 3.36 |1.32; 31.25] =0.021
Huang[72] 2015 Taiwan 1,077 - DM Multivariate Yes All OR:1.81 [1.14; 2.65]; p=0.002
Fartoux[73] 2005 France 141 non DM HOMA-IR Univariate No No NS
Leandro [74] 2006 Italy 3068 DM Multivariate No No NS
Elgouhari[75] 2008 US 183 - DM
Multivariate
No No NS
Petta[76] 2009 Italy 156 non DM HOMA-IR
Multivariate
No No NS
Rueger[77] 2014 Switzerland 1,461 - IR
Multivariate
No No NS
Desbois AC & Cacoub P, 2015

61. Abnormalities of Glucose Metabolism and Hepatocarcinoma
in HCV Patients
Author Year Country Patient
number
Patient profile Association
Statistical
method
Association
DM and HCC
Statistics
Diabetes mellitus/insulin resistance in HCV-related HCC
Kutala[15] 2014 France 162 HCC, not treated for HCV DM and HCC Multivariate Yes HR 3.13 [1.17; 8.38]; p=0.022***
Hung[104] 2010 Taiwan 188 59 HCC; 129 non-HCC DM and HCC Multivariate Yes OR 11.6 [2.500-53.800]; p=0.002
Hung[104] 2010 Taiwan 188 59 HCC; 129 non-HCC HOMA-IR and HCC
Multivariate
Yes OR 2.0 [1.35 ; 3]; p=0.001
Khattab [105] 2012 Egypt 294 147 HCC ; 147 non-HCC HOMA-IR and HCC
Multivariate
Yes OR 2.5 [1.7; 3.69] p=0.001
Mohamed[65] 2011 Egypt 100
50 HCC ; 50 non-HCC; 20 non
HCV
HOMA-IR and HCC Univariate No NS
Diabetes mellitus/insulin resistance and development of HCC in HCV-infected patients
Chen[106] 2008 Taiwan 1,095 - DM and HCC Multivariate Yes OR 3.52 [1.29 ; 9.24]
Veldt[16] 2008 Europe 541 DM and HCC Multivariate Yes OR 3.28 [1.35 ; 7.97] p=0.009***
Konishi [107] 2009 Japan 197 non DM, treated for HCV DM* and HCC Multivariate Yes HR 4.63 [1.677–12.766] ; p=0.003
Hung [14] 2010 Taiwan 1,470 treated for HCV DM and HCC Multivariate Yes HR 4.32 [1.23; 15.25]; p=0.023**
Nkountchou [108] 2010 France 248 cirrhotics HOMA-IR and HCC
Multivariate
Yes HR 1.10 [1.01; 1.21] ; p=0.026
Takahashi[109] 2011 Japan 203 non DM, treated for HCV DM* and HCC Multivariate Yes HR 6.9 [1.7; 28.4]; p<0.05
Arase[110] 2013 Japan 4,302 non treated for HCV DM and HCC Multivariate Yes HR 1.73 [1.3; 2.3]; p<0.001
Elkrief [42] 2014 France 348† cirrhotics DM Multivariate Yes HR 1.938 [1.129 ; 3.328] ; p=0.016
Toyoda[111] 2015 Japan 522 patients with SVR DM and HCC Multivariate Yes HR 2.08 [1.0170-4.0133] ; p= 0.045
Lai [112] 2006 Taiwan 2,141 - DM and HCC Multivariate No NS
Chen[113] 2013 Taiwan 5,186 - DM and HCC Multivariate No NS
Desbois AC & Cacoub P, 2015

62. HCV & Health Related Quality of Life
Fatigue, depression
and cognitive
impairment

63. 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 pegIFN/ribavirin.
 HCV may directly affect the CNS:
 through alterations in serotonergic and dopaminergic
neurotransmission with resultant depressive symptoms.
Cacoub P et al, Dig Liver Dis. 2014

64. Baseline 18 months
18 months vs
baseline
Non treated (n=72)
 No fatigue
 Moderate
 Severe
39%
35%
26%
42%
39%
19%
P=0.74
Sustained responders (n=82)
 No fatigue
 Moderate
 Severe
41%
37%
22%
69%
24%
7%
P<0.001
Non responders (n=224)
 No fatigue
 Moderate
 Severe
40%
42%
18%
46%
40%
14%
P=0.18
Decreased Fatigue Rate in HCV
Patients with Sustained Response to IFN-RBV
IFN: interferon; RBV: ribavirin Cacoub P, et al. J Hepatol. 2002 Jun;36(6):812-8
Rates of moderate/severe fatigue
decreased from 59% to 31% after SVR

65. PRO: Patient Reported Outcomes. Scores transformed to be on a scale from 0 to 100 %
* p < 0,05 vs baseline
50
60
70
80
90
100
SF-36 :
physical
SF-36 :
mental
FACIT-F :
fatigue
FACIT-F :
total
CLDQ-HCV Professional
productivity
Activity SF-6D
PROnormalised(%)
Inclusion End of treatment SVR12 SVR24
*
*
*
*
*
*
*
*
*
*
*
*
*
* *
Improved Patient Reported Outcomes in the SIRIUS
Study (SOFOSBUVIR + LEDIPASVIR +/- RBV)
Younossi Z et al. EASL 2015, Abs. P0713

66. Cerebral MR Signal in HCV patients
and Spectral Analysis
MR: magnetic resonance Byrnes V, et al. J Hepatol 2012;56:549–56
A
C
B
PC22

67. T1 vs. T3 in SVR; p<0.05
MR Signal in Basal Ganglia Myo-inositol/Creatinine in
HCV Patients According to Virological Response
Byrnes V, et al. J Hepatol 2012;56:549–56
Baseline (T1), week 12 t2), and for treatment candidates, 12 weeks post treatment with PEG-IFN and ribavirin (T3)

68. T1 vs. T3 in SVR; p<0.05
MR Signal in Basal Ganglia Myo-inositol/Creatinine in
HCV Patients According to Virological Response
Byrnes V, et al. J Hepatol 2012;56:549–56
Baseline (T1), week 12 t2), and for treatment candidates, 12 weeks post treatment with PEG-IFN and ribavirin (T3)
 SVRs demonstrated improvements in verbal learning and
visuo-spatial memory.
 Reduced cerebral infection and/or immune activation
in those who cleared the virus.

69. What is the impact of HCV eradication
on extrahepatic manifestations ?

70. Proven Extra-hepatic Benefits of HCV Eradication
(SVR following peginterferon and ribavirin) -1-
• reduced all-cause mortality,
• improvement in myocardial perfusion defects,
• reduced incidence of stroke,
• reduced renal and cardiovascular outcomes in diabetics.
• complete resolution of mixed cryoglobulin complications,
• regression/remission of HCV-associated lymphoma.
Negro Fet al, Gastroenterology 2015

71. Proven Extra-hepatic Benefits of HCV Eradication
(SVR following peginterferon and ribavirin) -2-
• reduced steatosis,
• reduced risk of insulin resistance,
• reduced risk of type 2 diabetes.
• improved cognitive performance,
• reduction in fatigue,
• improved patient-reported outcomes ,
• gains in quality of life.
Negro Fet al, Gastroenterology 2015

72. HCV and Extrahepatic Manifestations
Summary of Unsolved Issues, January 2016
• What is the impact of DAAs on main extrahepatic manifestations ?
• Are the proven extra-hepatic benefits of HCV eradication following
peginterferon and ribavirin similar or higher with DAAs ?
• Does the DAA profile (i.e. nuc vs. non nuc, PI vs. non-PI …)
impacts on extra-hepatic benefits of HCV eradication ?
• Healthcare costs imposed by these conditions must be
considered in addition to those normally associated with chronic
HCV infection.
• Urgent need for clinical trials using DAAs, with mid-/long-
term follow-up, including pre-specified well defined
extrahepatic endpoints.