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

Manifestations

Pr Patrice CACOUBDept of Internal Medicine and Clinical Immunology

CNRS UMR 7087

Université Pierre et Marie Curie

Centre Référence Maladies Auto-immunes

Hôpital La Pitié-Salpêtrière, Paris, FRANCE

PC01

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

PC02

Let’s vote

Do you think that extrahepatic manifestations are a major problem in chronic HCV infection?

1. Yes

2. No

PC03

Let’s vote

Which category of extra-hepatic manifestations of HCV represents the major problem?

1. Auto-immune manifestations

2. Fatigue, depression and cognitive impairment

3. Cardiovascular events

4. Insulin resistance and type 2 diabetes

5. I don’t consider any of the above to be a major problem

PC04

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. undetectableLee 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)

Cu

mu

lati

ve

mo

rtali

ty (

%)

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

PC05

• 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

*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

PC05

Lee MH, et al. J Infect Dis 2012;206:469–77

HCV+, RNA+

HCV+, RNA-

HCV-

Cu

mu

lati

ve

mo

rta

lity

(%

)

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)

Cu

mu

lati

ve

mo

rta

lity

(%

)

19.8%†

12.2%

11.0%

0 2 4 6 8 10 12 14 16 18 20

PC05

Lee MH, et al. J Infect Dis 2012;206:469–77

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 diseases

Extrahepatic diseases

Circulatory diseases

Nephritis, nephrotic syndrome

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]

PC05a

HEPATITIS C VIRUS:A WORLD-WIDE

INFECTION…

…and A BODY-WIDE DISEASE

2.35% (160 million) chronically infected

PC06

Lavanchy D. Clin Microbiol Infect 2011;17:107–115

Hepatitis C global prevalence 2010 (%)1

Auto-immune manifestations

PC07

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

PC08

Prevalence of Main Auto-Immune Manifestations Associated with HCV

Cacoub P et al, Dig Liv Dis. 2014

%

Vasculitis 5–40

Arthralgia-myalgia 25–35

Sicca syndrome 10–25

Auto-antibodies 10–40

Lymphoma RR=35

PC09

Skin Purpura

MembranoproliferativeGlomerulonephritis

Neuropathy

Cryoglobulinaemia vasculitis

CNS Vasculitis

PC10

Jacobson IM et al, Clin Gastroenterol Hepatol. 2010 Dec;8(12):1017-29.

14

Rationale for

Rituximab treatment

in cryoglobulinemic

vasculitis

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

HCV-Related Mixed

Cryoglobulinemia

Vasculitis Mechanisms

15

Age at disease onset (yrs) 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%

Features of Mixed Cryoglobulinemia Vasculitis

n=250 patients Ferri C, Mascia MT, Saadoun D, Cacoub P. 2009

16

Age at disease onset (yrs) 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 Vasculitis

n=250 patients Ferri C, Mascia MT, Saadoun D, Cacoub P. 2009

RR=34

17

Antigen-Insensitive

B Cell Proliferation

Oligo/Monoclonal

proliferation

Uncontrolled

proliferation

Antigen-Sensitive

B Cell Proliferation

Polyclonal

proliferation

B-cell lymphoma

Cytokines

BAFF

HyperglobulinemiaCryoglobulinemia

Vasculitis

B-cell lymphoma

IgH-bcl2? Other

oncogenic

events ?

CD81

HCV (E2)

B cell

Anti-E2 IgM/Rheumatoid factorIgG

HCV-Related Lymphoproliferative Disorders:

from Cryoglobulinemia to B-NHL

Treg deficit

Chronic HCV infection

Poly- oligoclonal B-cell expansion

AutoantibodiesRF - IC

Mixed cryoglobulins

Cryoglobulinaemic vasculitis

Monoclonal B-cellproliferation

Overt lymphoma

HCV eradication

Immunosuppressors

Chemotherapy

Plasma exchange

Steroids

PC14Strategies 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

response

Sustained virological

response

Clinical Remission in HCV-Cryoglobulinemia

Vasculitis Correlates with Virological Response

Prevalence of Main Auto-Immune Manifestations Associated with HCV

Cacoub P et al, Dig Liv Dis. 2014

%

Vasculitis 5–40

Arthralgia-myalgia 25–35

Sicca syndrome 10–25

Auto-antibodies 10–40

Lymphoma RR=35

PC09

Auto-antibody production in chronic HCV infection.

0

10

20

30

40

50

60

70

%

A-nuclear

A-phospholipid

A-thyroglobulin

A-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

HCV & Health Related Quality of Life

Fatigue, depressionand cognitive impairment

PC16

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 dopaminergicneurotransmission with resultant depressive symptoms.

Fatigue, Depression and ExtrahepaticManifestations (EM) in HCV patients

Poynard T, et al. J Viral Hepatitis 2002;9:295–303

% of patientsn=1614

% of controlsn=412

Fatigue without depression 48 0.7 Fatigue with depression 5 0

Depression without fatigue 2 0

No fatigue and no depression 45 99.3

TOTAL 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 96

TOTAL 100 100

Fatigue without depression 48 0.7

PC17

Fatigue, Depression and ExtrahepaticManifestations (EM) in HCV patients

Poynard T, et al. J Viral Hepatitis 2002;9:295–303

% of patientsn=1614

% of controlsn=412

Fatigue without depression 48 0.7 Fatigue with depression 5 0

Depression without fatigue 2 0

No fatigue and no depression 45 99.3

TOTAL 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 96

TOTAL 100 100

PC18

Baseline 18 months18 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

PC19Decreased 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

FACIT-F: No SVR

0.55

0.65

0.75

0 4 8 12 16 20

Week

24 28

FACIT-F: SVR

FACIT-F: AllNo

rmal

ized

FA

CIT

-F

FACIT-F Scores During and Post-Treatment in FUSION

FACIT-F: No SVR

0.65

0.75

0 4 8 12 16 20

Week

24 28

FACIT-F: SVR

FACIT-F: AllNo

rmal

ized

FA

CIT

-F

FACIT-F Scores During and Post-Treatment in NEUTRINO

0.55

**

*

†

†

†

*

†

†

FUSION (SOF + RBV) & NEUTRINO (SOF + IFN) Trials

Chronic Fatigue (FACIT-F) in Patients Treated with SOF + PEG-IFN/RBV

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

*P<0.05 decrement from patients’ own baseline; †P<0.05 improvement from patients’ own baseline;

PEG-IFN: pegylated interferon; SOF: sofosbuvir; SVR: sustained virological response Younossi ZM, et al. AASLD 2013. #2211

PC20

Actigraphy Parameters in HCV patientsActive at Night, Sleepy All Day !

Heeren M, et al. J Hepatol 2014;60:732–40

Monday 18.04.20

11

Tuesday 19.04.20

11Wednesd

ay 20.04.20

11Thursday 21.04.20

11

Friday 22.04.20

11

PC21

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/Creatininein 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)

PC23

T1 vs. T3 in SVR; p<0.05

MR Signal in Basal Ganglia Myo-inositol/Creatininein 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.

PC24

Chronic HCV infection : a new cardio-vascular risk

factor ?

PC25

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

Hsu YC et al, Hepatology, 2014 Apr;59(4):1293-302.

HCV+ non treated

HCV+ treated

Non HCV

Cumulative Incidence of Stroke in three Diabetic Study Cohorts (death adjusted as a competing risk event)

HCV+ non treated

HCV+ treated

Non HCV

Hsu YC et al, Hepatology, 2014 Apr;59(4):1293-302.

Risk Factors Associated with the Presence of Carotid Plaques in Geno1 HCV patients

Petta S, et al. Hepatology 2012;55:1317–23

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

Car

oti

dea

lPla

qu

es (

%)

00

20

80

60

40

100

PC29

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-f

ree

surv

ival

rat

e

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 riskof stroke in HCV patients, after adjusting for knownprognostic factors.

PC30

Studies assessing the association between HCV infection and ischemic cerebrovascular accident.

Domont F & Cacoub P, 2014

References, year Type of study Country HCV+ (n) HCV- (n)

Studies showing an association

Lee et al. (22), 2010 Prospective cohort Taiwan 1307 22,358

Liao et al. (24), 2012 Population Taiwan 4094 16,376

Hsu et al. (26), 2013 Retrospective cohort Taiwan 2875 12,450

Adinolfi et al. (23), 2013 Retrospective cohort Italy 79 741

Studies NOT showing an association

Younossi et al. (25), 2013 Retrospective

population

USA 173 19,568

References, year Type of study Country HCV + (n) HCV- (n)

Studies showing an association between HCV infection and carotid atherosclerosis

Ishizaka et al. (10), 2002 Population Japan 104 4784

Ishizaka et al. (11), 2003 Population Japan 25 1967

Tomiyawa et al. (12), 2003 Cohort Japan 87 7427

Fukui et al. (37), 2003 Cohort Japan 31 179

Boddi et al. (14), 2007 Cohort Italy 31 120

Targher et al. (15), 2007 Cohort Italy 60 60

Butt et al. (28), 2009 Observational USA 82,083 89,562

Mostafa et al. (16), 2010 Cohort Egypt 329 795

Petta et al. (38), 2012 Cross-over Italy 174 174

Adinolfi et al. (23) , 2013 Cohort Italy 326 477

Studies NOT showing an association between HCV infection and carotid atherosclerosis

Bilora et al. (19), 2008 Cohort Italy 40 40

Caliskan et al. (18), 2009 Cohort Turkey 36 36

Tien et al. (39), 2009 Cohort USA 273 1502

Masia et al. (40) , 2011 Cohort Spain 63 138

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 + 9Sex 104/113

Liver function

Bilirubin (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 function

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

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

PC31

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

PC32

Before therapy

End of therapy

6 months after therapy

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

PC33

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.

SVR Relapse Non Response

Myocardial SPECT Images in HCV Patients According to Virological Response

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

PC34

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.

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

PC35

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

PC35

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

PC35

Main studies assessing the association between 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, 2014

HCV, Insulin-Resistanceand Type 2 Diabetes

Mellitus (T2DM)

PC36

PC37

PC38

PC39

ALT: alanine aminotransferase; AST: aspartate

aminotransferase; Arase Y, et al. Hepatology 2009;49:739–44

N 2.842

Body mass index 23.3 + 3.2

Staging (non LC/LC) 2.649/193

Efficacy of treatment (SVR/non-SVR) 1.175/1.667

PC41Type 2 Diabetes in HCV Patients Treated with IFN

Type 2 Diabetes in HCV Patients Treated with IFN

Cumulative development rate of T2DM in HCV patients treated with IFN

Arase Y, et al. Hepatology 2009;49:739–44

PC42

Predictive factors for Type 2 Diabetes Development in HCV Patients Treated with IFN

Arase Y, et al. Hepatology 2009;49:739–44

Histological diagnosis (LC/non-LC) 4.03 (2.55 - 6.36) <0.0001 3.30 (2.06 - 5.28) <0.001

Efficacy (non-SVR/SVR) 2.73 (1.77 - 4.20) <0.0001 2.78 (1.75 - 4.41) <0.001

PC44

Age >50 yrs

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

Arase Y, et al. Hepatology 2009;49:739–44

Cirrhotics

PC43

Extrahepatic Manifestations of HCV infectionSummary (1)

Chronic HCV infection increases mortality from both hepatic and extra hepatic diseases.

Extra-hepatic immunologic manifestations include vasculitis, lymphomas, and rheumatologic conditions.

Chronic HCV is associated with reduced health-related quality of life, in which depression, cognitive impairment and fatigue may be factors.

PC45

Increased risk of major cardiovascular events, chronic kidney disease and glucose related disorders require attention.

Healthcare costs imposed by these conditions must be considered in addition to those normally associated with chronic HCV infection.

Extrahepatic Manifestations of HCV infectionSummary (2)

PC46