Transcript
Page 1: Cacoub p  hcv meh 2014 - partie ii

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Proliférationpolyclonale

Prolifération de LyB clonaux et autoréactifs

Maintien de la tolérance périphérique

AnergieEGR2Cbl-b

TLR

Stimulation par la voiedes TLR des

LyB anergiques

Vascularite

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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

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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.

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Quantitative Deficit in Treg Lymphocytes (CD4+CD25+) in HCV-Vasculitis

Boyer O, Saadoun D et al, Blood 2004

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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

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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

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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

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HCV Cryoglobulinemic Vasculitis Treatments

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Chronic HCV infection

Poly- oligoclonal B-cell expansion

AutoantibodiesRF - ICMixed cryoglobulins

Cryoglobulinemic vasculitis

Monoclonal B-cellproliferationOvert lymphoma

HCV eradication

Immunosuppressors

Chemotherapy

Plasma exchange

Steroids

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Chronic HCV infection

Poly- oligoclonal B-cell expansion

AutoantibodiesRF - ICMixed cryoglobulins

Cryoglobulinemic vasculitis

Monoclonal B-cellproliferationOvert lymphoma

HCV eradication

Immunosuppressors

Chemotherapy

Plasma exchange

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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

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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

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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

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Chronic HCV infection

Poly- oligoclonal B-cell expansion

AutoantibodiesRF - ICMixed cryoglobulins

Cryoglobulinemic vasculitis

Monoclonal B-cellproliferationOvert lymphoma

Immunosuppressors

Chemotherapy

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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)

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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

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Chronic HCV infection

Poly- oligoclonal B-cell expansion

AutoantibodiesRF - ICMixed cryoglobulins

Cryoglobulinemic vasculitis

Monoclonal B-cellproliferationOvert lymphoma

Immuno-modulatorsRituximab

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Rationale for Rituximab treatment in cryoglobulinemic vasculitis

Rocatello D, Nephrol Dial Transplant, 2004Roccatello, D. et al. Nephrol. Dial. Transplant. 2004

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Treatment of Mixed Cryoglobulinemia Resistant

to Interferon with Rituximab

Sansonno D et al, Zaja F et al, Blood 2003

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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

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24De Vita S, Arthritis Rheum 2012

RTX

non-RTX

Rituximab for the Treatment of Severe Cryoglobulinemic Vasculitis

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HCV Vasculitis: a Two-Faces Disease…Needs a Two Faces Treatment Strategy

Rituximab

PegIFN plus Ribavirin

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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

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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

Page 27: Cacoub p  hcv meh 2014 - partie ii

31Dammacco F et al, Blood 2010

RTX/Peg-IFNα-Ribavirin vs. Peg-IFNα-Ribavirin in HCV Systemic VasculitisMaintenance of Complete Response

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Time Course of HCV Viral Load

Terrier B et al. Arthritis Rheum 2009

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• 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;

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Chronic HCV infection

Poly- oligoclonal B-cell expansion

AutoantibodiesRF - ICMixed cryoglobulins

Cryoglobulinemic vasculitis

Monoclonal B-cellproliferationOvert lymphoma

Immuno-modulatorsLow dose IL2

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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

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Effects of Low-Dose Interleukin-2 on Levels of CD4-Treg in Patients with HCV-Vasculitis, According to

Treatment Course (C).

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

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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

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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.

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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

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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

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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

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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

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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

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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

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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

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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.

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*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

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2013

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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

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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

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2012

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Cerebral MR Signal in HCV Patients and Spectral Analysis

A

C

B

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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

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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.

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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

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2013

2013

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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).

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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

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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

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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

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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

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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)

Page 65: Cacoub p  hcv meh 2014 - partie ii

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

Page 66: Cacoub p  hcv meh 2014 - partie ii

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

Page 67: Cacoub p  hcv meh 2014 - partie ii

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

Page 68: Cacoub p  hcv meh 2014 - partie ii

Hepatology, 2012

Page 69: Cacoub p  hcv meh 2014 - partie ii

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

Page 70: Cacoub p  hcv meh 2014 - partie ii

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

Page 71: Cacoub p  hcv meh 2014 - partie ii

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

Page 72: Cacoub p  hcv meh 2014 - partie ii

2013

Page 73: Cacoub p  hcv meh 2014 - partie ii

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

Page 74: Cacoub p  hcv meh 2014 - partie ii

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.

Page 75: Cacoub p  hcv meh 2014 - partie ii

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

Page 76: Cacoub p  hcv meh 2014 - partie ii

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.

Page 77: Cacoub p  hcv meh 2014 - partie ii

2012

Page 78: Cacoub p  hcv meh 2014 - partie ii

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

Page 79: Cacoub p  hcv meh 2014 - partie ii

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

Page 80: Cacoub p  hcv meh 2014 - partie ii

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

Page 81: Cacoub p  hcv meh 2014 - partie ii

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

Page 82: Cacoub p  hcv meh 2014 - partie ii

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)

Page 83: Cacoub p  hcv meh 2014 - partie ii

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

Page 84: Cacoub p  hcv meh 2014 - partie ii

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

Page 85: Cacoub p  hcv meh 2014 - partie ii

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 ?

Page 86: Cacoub p  hcv meh 2014 - partie ii

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.

Page 87: Cacoub p  hcv meh 2014 - partie ii

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

Page 88: Cacoub p  hcv meh 2014 - partie ii
Page 89: Cacoub p  hcv meh 2014 - partie ii

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 %

Page 90: Cacoub p  hcv meh 2014 - partie ii

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

Page 91: Cacoub p  hcv meh 2014 - partie ii

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

Page 92: Cacoub p  hcv meh 2014 - partie ii

107

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


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