cacoub hcv ehm & inflam du16

HCV and its Extra Hepatic Manifestations: From Immune- to Inflammatory-Related

Manifestations

Pr Patrice CACOUB, MDDept 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

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

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)

Cum

ulat

ive

mor

talit

y (%

)

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-

35

30

25

20

15

10

5

0

Chronic HCV Infection Increases Mortality from both Hepatic and Extra Hepatic Diseases


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


HCV+, RNA+

HCV+, RNA-

HCV-

Cum

ulat

ive

mor

talit

y (%

)

Chronic HCV Infection Increases Mortality from both Hepatic and Extra Hepatic Diseases


Follow-up (Years)

20

18

16

14

12

10

2

0

8

6

4

Extrahepatic diseases

(n=2,199)

Cum

ulat

ive

mor

talit

y (%

)19.8%†

12.2%11.0%

0 2 4 6 8 10 12 14 16 18 20


HCV+, RNA+

HCV+, RNA-

HCV-

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 diseasesExtra hepatic diseasesCardiovascular diseasesNephritisEsophageal cancerProstate cancerThyroid 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]

1. Cryoglobulinemia vasculitis and lymphoproliferation2. Chronic HCV infection : a new cardio-vascular risk

factor ?3. Insulin-Resistance and Type 2 Diabetes Mellitus 4. Fatigue, depression and cognitive impairment5. Impact of HCV cure on extrahepatic manifestations

HCV and its Extra Hepatic Manifestations: Agenda

Auto-immune Manifestations and Lymphoproliferative Diseases

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

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

VASCULARITES: CLASSIFICATION

Chapel Hill, révisé en 2012

HCV Chronic Infection Is the Main Cause of Mixed Cryoglobulinemia

Saadoun, Arch Intern Med, 2006

N = 1,434 patients with mixed cryoglobulin

Ferri C et al. Orphanet J Rare Dis 2008Brouet 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

Endothelial cells

Cryoprecipitation

15

Skin Purpura

Glomerulonephritis CNS Vasculitis

Neuropathy

Cryoglobulinemia Vasculitis

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

MononeuropathyMultiplex 20%

Cryoglobulinemic Membrano-Proliferative Glomerulonephritis

Doubles Contours

Pseudo-thrombi

GNMP de type 1

IgG/IgM

Kappa/lambda

C3 ±C1q

18

HCV Mixed Cryoglobulinemia and Digestive Tract

Mesenteric artery stenosis

Intestinal wall thickening

Terrier B et al, GUT 2011

19

Cardiac Involvement in HepatitisC Virus-Related Vasculitis

Terrier B et al, Am J Cardiol 2013

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 20/16Age (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 ± 1.4NCFD 2.2 ± 1.8 0.9 ± 0.8 * - --------------------------------------------------------------------------------------* P<0.01WMHS: White Matter Hypersignals PVHS: Periventricular HypersignalsNCFD: Number of Cognitive Function Deficiency

Casato M et al, J Hepatol 2004

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

HCV-Cryoglobulinemia Vasculitis Mechanisms: Major Role for B and T Lymphocytes

Rocatello D, Nephrol Dial Transplant, 2004

• Th1 lympho/cytokines• Treg deficit

- 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 PolyneuropathyPeripheral Nerve Biopsy

24

HCV Core Protein in Skin Vascular Structures

Who’s the culprit ?

Cellular Infiltrate in HCV-Vasculitis

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

Antigen-InsensitiveB Cell Proliferation

Oligo/Monoclonal proliferation

Uncontrolled proliferation

Antigen-SensitiveB Cell Proliferation

Polyclonal proliferation

B-cell lymphoma

DC

CytokinesBAFF

DC

Hyperglobulinemia 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

Chronic HCV infection

Poly- oligoclonal B-cell expansion

AutoantibodiesRF - ICMixed

cryoglobulins

Cryoglobulinaemic vasculitis

Monoclonal B-cell

proliferationOvert 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

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 responseSustained virological response

Clinical Remission in HCV-Cryoglobulinemia Vasculitis Correlates with Virological Response

Sofosbuvir plus Ribavirin for HCV Cryoglobulinemia Vasculitis

Clinical response

Virological

response complete partial HCV RNA<12UI/mLDuring treatment (n=24) at week 4 6 1 1at week 8 4 19at week 12 7 2 2at 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 2relapse 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

30De Vita S, Arthritis Rheum 2012

Rituximab (RTX) is Superior to Immunosuppressants for Severe HCV-Cryoglobulinemic Vasculitis

RTX

non-RTX

Prob

abili

ty o

f res

pons

e

Non RTX group included conventional treatment i.e., glucocorticosteroids, azathioprine or cyclophosphamide, or plasmapheresis.

31

Better Course of Kidney Parameters in HCV-Cryoglobulinemia who Received Rituximab plus PegIFN/Ribavirin

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

Saadoun D et al, Blood 2010

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

HCV Cryoglobulinemia Vasculitis Therapeutic Strategies

SevereRenal disease,

mononeuropathy multiplex, skin necrosis

CatastrophicRapidly progressive GN,

CNS, digestive, pulmonary involvement

Mild - moderateArthralgia, 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

• 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

Glob

al S

urvi

val

Prog

ress

ion

Free

Sur

viva

l

Chronic HCV infection : a new cardio-vascular risk

factor ?

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

5210.50.2Controls 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

Stroke

Heart

Kidney

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

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

HCV Control Odds ratio Odds ratioStudy 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]


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


5210.50.2Controls HCV positives


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

Caro

tid P

laqu

es

(%)

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

HCV Control Odds ratio Odds ratioStudy 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]


Heterogeneity: Tau2=0.04; Chi2=11.52, df=8 (p=0.17); I2=31%Test for overall effect: Z=6.25 (p<0.00001)


Carotid Plaques and HCV Infection

50101Controls HCV positives

0.10.02


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

Stro

ke-fr

ee su

rviv

al ra

te

0.80

0.85

0.95

0.90

100

0 1 2 3 4 5Time (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.

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

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 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 HCV patients normal range

Abnormal 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

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

SVR Relapse


SPECT: single-photon emission computed tomography Maruyama S, et al. J Hepatol 2012;58:11–5

Before therapy

End of therapy


Before therapy

End of therapy



SVR Relapse Non Response


Maruyama S, et al. J Hepatol 2012;58:11–5

Before therapy

End of therapy


Before therapy

End of therapy


Before therapy

End of therapy



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

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

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

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

Jacobson I et al, Clin Gastroienterol Hepatol 2010

Increased Risk of T2DM in HCV Patients

Controls = healthy subjects

White DL, et al. J Hepatol 2008

Controls = HBV

Age >50 yrs

Cumulative Development Rate of T2DM in HCV Patients with or without SVR after IFN

Arase Y, et al. Hepatology 2009

Cirrhotics

Eslam M et al, Aliment Pharmacol Ther. 2011

Insulin Resistance (HOMA-IR) is Associated with Lower Sustained Virological Response, Meta-analysis

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

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 StatisticsKonrad[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-IRMultivariate

YesG3

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 IRMultivariate

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

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 HCCMultivariate

Yes OR 2.0 [1.35 ; 3]; p=0.001

Khattab [105] 2012 Egypt 294 147 HCC ; 147 non-HCC HOMA-IR and HCCMultivariate

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 HCCMultivariate

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

HCV & Health Related Quality of Life

Fatigue, depression and cognitive impairment

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

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

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 Professionalproductivity

Activity SF-6D

PRO

nor

mal

ised

(%

)

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

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

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)

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.

What is the impact of HCV eradication on extrahepatic manifestations ?

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

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

HCV and Extrahepatic ManifestationsSummary 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.

cacoub hcv ehm & inflam du16

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