cacoub manif extra hépatiques

Extrahepatic Manifestations of

Hepatitis C Virus Infection

Service de Médecine Interne, et CNRS UMR 7087 Université Pierre et Marie Curie

Hôpital La Pitié-Salpêtrière, Paris, FRANCE

Pr. Patrice CACOUB, MD, PhD

Manifestation Prevalences

certainly associated with HCV %

--------------------------------------------------

• Vasculitis (PAN, cryoglobulinemia) 4-40

• Fatigue 35-54

• Arthralgia-myalgia 25-35

• Sicca syndrome 10-25

• Autoantibodies 10-40

• Thrombocytopenia 20-40

• Lymphoma (SLVL) ?

Cryoprecipitation

Endothelial cells

Pathogenesis of cryoglobulinaemic

nephritis

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

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

Distal Polyneuropathy 80%

Skin Purpura

Membrano-proliferative Glomerulonephritis CNS Vasculitis

Cryoglobulinemia-Systemic Vasculitis

Neuropathy

Prevalence of HCV infection in patients with essential cryoglobulinemia

0

10

20

30

40

50

60

70

80

90

100

Ferri Disdier Casato Pechere Misiani Agnello Cacoub Dupin Monti

Hepatitis C Virus Chronic Infection :two main target cells

• Hepatitis • Cirrhosis• Hepatocarcinoma

• Cryoglobulinemia• B-NHL

HepatocyteChoo. Science 1989

LymphocyteZignego. J Hepatol 1992Ferri. Blood 1993

53%

41%48%

28%

12%

0%

10%

20%

30%

40%

50%

60%

1972-79 1980-84 1985-89 1990-94 1995-99

FREQUENCY OF HBV-RELATED PAN: 1972-1999

Guillevin L

Clinical features of 231 MC Patients

end beginning

follow-up follow-up p°

Purpura 89% 81% .05Weakness 91% 80% .001Arthralgias 90% 72% .001Arthritis 6% 8% nsRaynaud's phen. 44% 36% nsSicca syndrome 48% 29% .001Skin ulcers 20% 11% .02Periph. neuropathy 73% 58% .001Liver involvement 70% 58% .02Renal involvement 27% 20% nsB-cell lymphoma 9% 0.4% .001Hepat. carcinoma 3% 0% .05

Ferri C, Sem Arthr Rheum 2004

MC and Skin

Cutaneous Manifestations of HCV

HCV Core Protein in Skin Vascular Structures

Systemic Vasculitis and Hepatitis C virus

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Wei

ght l

oss

Pur

pura

Live

do-u

lcer

s-

Ery

nod

.

SM

mul

tifoc

.

Neu

rop.

Sen

sory

poly

neur

op.

Ren

al

insu

ffici

ency

Sev

ere

HTA

Cacoub P et al. Arthritis Rheum 2002

Distal Polyneuropathy 80%

Cacoub P et al, AIDS 2005

MC and Neuropathy

• First symptoms : 61 years

• Chronic course, progressive

• Distal, symetric, axonal

polyneuropathy, mainly sensory and

painful

• Few extra neurological signs :

purpura, Raynaud, kidney ...

• Severe liver involvement

• Moderate inflammatory syndrome

MononeuropathyMultiplex 20%

Cacoub P et al, AIDS 2005

MC and Neuropathy

Mononeuropathy multiplex (20%)Mononeuropathy multiplex (20%)

• Younger age at first symptoms (< 60 years)

• Acute or subacute involvement

• Severe, sensory-motor, mononeuritis multiplex

• Weight loss, inflammatory syndrome

• Extra-neurological manifestations

• Moderate liver involvement

N %

Membranoproliferative GN 5 -

Leucocytoclastic vasculitis 6 -

PAN-type vasculitis 7/23 30 %

Mixed cryo-type vasculitis 14/23 61 %

Both 2/23 9 %

Knodell score 6.5 (1-12) -

Cirrhosis 3/26 12 %

Pathological data in HCV related vasculitisCacoub P et al. Arthritis Rheum 2002

Central Nervous System Involvement in HCV-Infected Patients

Stroke (ischemic or haemorraghic)- usually associated with numerous extra-

neurologic manifestations, i.e. renal, PNS, skin, digestive tract

- 4 cases with isolated CNS involvement

Encephalopathy with coma or convulsions- multiple ischemic strokes,- in two cases, brain biopsy showed small vessel

vasculitis -> Possible improvement under steroids,

immunosuppressive and anti-viral treatment.

Central Nervous System Involvement in HCV-Cryoglobulinemia Vasculitis

HCVHCVHCVHCV----vasculitisvasculitisvasculitisvasculitis HCVHCVHCVHCV ControlsControlsControlsControls(n=40) (n=11) (n=36)

--------------------------------------------------------------------------------------Sex ratio F/M 23/17 6/5 20/16Age (yrs) 59 ± 13 56 ± 10 58 ± 12WMHS 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 * -

--------------------------------------------------------------------------------------

WMHS: White Matter Hypersignals PVHS: Periventricular HypersignalsCasato M et al, J Hepatol 2004

* P<0.01

• Proteinuria (g/d)

• Albumin (g/L)

• Creatinine (µmol/L)

• Cryoglobulin (II/III)

• Cryoglobulin level (g/L)

• ALT (IU x N/ml)

• Genotype 1/ 2/ 3/ 4

• Treatment of nephrotic sdplasmapheresissteroidsfurosemideACE

3.1 ± 2.2

29 ± 5

118 ± 41

16 / 2

1.4 ± 1.8

1.5 ± 1

11/ 3/ 2/ 2

132 (66%)8 (44%)

18 (100%)12 (66%)

HCV and membranoproliferative glomerulonephritis

Alric L. Am J K Dis, 2004

Therapeutic strategy in HCV+ Mixed Cryoglob.

Chronic HCV infection

Poly- oligoclonal B-cell expansion

AutoantibodiesRF - IC

Mixed cryoglobulins

Cryoglobulinemic vasculitis

Monoclonal B-cellproliferation

Overt lymphoma

HCV eradication

Immunosuppressors

Chemotherapy

Plasma exchange

Steroids

Treatment Efficacy in HCV-Related Systemic Vasculitis

0000

10101010

20202020

30303030

40404040

50505050

60606060

70707070

80808080

90909090

100100100100

SkinSkinSkinSkin RenalRenalRenalRenal NerveNerveNerveNerve

IFN + RBVIFN + RBVIFN + RBVIFN + RBV

Zuckerman, J Rheumatol 2000. Naarendorp, J Rheumatol 2001. Cacoub, Arthritis Rheum 2002,

% improvement

Treatment Efficacy in HCV-Related Systemic Vasculitis

0

10

20

30

40

50

60

70

80

90

100

Skin Renal Nerve

IFN + RBV

PegIFN + RBV

Zuckerman, J Rheumatol 2000. Naarendorp, J Rheumatol 2001. Cacoub, Arthritis Rheum 2002, Zaja F, Blood 2003. Sansonno D, Blood 2003 , Cacoub, Arthritis Rheum 2005

% improvement

All MC patients IFNα2α2α2α2b-Riba PegIFNα2α2α2α2b-RibaParameter (n=72) (n=32) (n=40)

Treatment

Duration of anti-HCV therapy (months) 16.63 ± 7.8 18.35 ± 10.0 13.25 ± 4.4

Ribavirin dosage (mg/day) 915.9 ± 182.8 875.9 ± 195.7 945 ± 169.3

Previous antiviral therapy (n,%) 20 (27.8) 7 (21.9) 13 (32.5)

Corticosteroids use (n,%) 29 (40.3) 15 (46.9) 14 (35)

Plasmapheresis (n,%) 9 (12.5) 8 (25) 1 (2.5)

Immunosuppressors (n,%) 4 (5.6) 4 (12.5) 0 (0)

All adverse events (n,%) 39 (54.2) 17 (53.1) 22 (55)Outcome

Deaths (n,%) 8 (11.1) 6 (18.8) 2 (5)Clinical CR † (n,%) 40 (55.5) 12 (37.5) 28 (70)*Virological CR † (n,%) 49 (68.0) 19 (59.3) 30 (75)Immunological CR † (n,%) 33 (45.8) 9 (28.1) 24 (60)*

Lower use of associated treatments in patients who received a combination of PegIFN + Ribavirin

Predictive Factors of Clinical Response to HCV Therapy in Mixed Cryoglobulinemia Vasculitis

Multivariate Analysis

Odds ratioOdds ratioOdds ratioOdds ratio [95%CI][95%CI][95%CI][95%CI] pppp

------------------------------------------------------------------

-------------------------------

• Renal involvement 0.270.270.270.27 [0.08-0.87] 0.02

• Renal insufficiency (GFR<70) 0.190.190.190.19 [0.04-0.69] 0.01

• Daily proteinuria > 1g 0.320.320.320.32 [0.09-1.11] 0.05

• Early virological response (M3) 2.862.862.862.86 [0.97-8.78] 0.05

Renal insufficiency (GFR<70) 0.18 0.18 0.18 0.18 [0.05-0.67] 0.01

Early virological resp. (M3)3.533.533.533.53 [1.18-10.59] 0.02

Is there a place for other treatments in HCV-systemic vasculitis ?

• Steroids

– at the initial phase, multivisceral lifethreatening disease, i.e. kidney, CNS, digestive tract involvement.

– in combination with anti-HCV treatments.

– prednisone 0.5-1 mg/kg/d, rapidly tapered to 10 mg/d

• Immunosuppressive

– cyclophosphamide: if no response with CT + IFN + ribavirin

– azathioprine, methotrexate: cautious with liver disease

• Plasmapheresis

– if multivisceral involvement, particularly kidney.

– if no response with CT + IFN + ribavirin

Pathogenesis of cryoglobulinaemic

nephritis and

rationale for Rituximab treatment

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

Treatment of Mixed Cryoglobulinemia Resistant to Interferon-alfa with an Anti-CD 20 Monoclonal

Antibody (Rituximab*)

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

0

10

20

30

40

50

60

70

80

90

Purpura

Ar thralgia

Nerve

KidneyCryo

Relapses

PegIFN-RBV (n=40) Rituximab (n=43)

% improvement

HCV-Vasculitis Treatment : PegIFN-Ribavirin vs. Rituximab

Cryoglobulinemia Vasculitis : Response Maintenance after Discontinuation of Rituximab

RESPONSE MAINTENANCE (%)

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 10 11 24 36 48

10 (62.5)

6 (37.5)

Sansonno D et al, 2007

RITUXIMAB (375 mg/m²)

Time (months)0 1

RIBAVIRIN (600-1200 mg/d)

PEGYLATED INTERFERON αααα2b (1.5 μμμμg/Kg/wk)

12

RRRRituximab plus Pegituximab plus Pegituximab plus Pegituximab plus Peg----IFNIFNIFNIFNαααα2b2b2b2b----RibavirinRibavirinRibavirinRibavirin in in in in RefractoryRefractoryRefractoryRefractory

HCVHCVHCVHCV----Related Systemic VasculitisRelated Systemic VasculitisRelated Systemic VasculitisRelated Systemic Vasculitis

2

Cacoub P, 2007

Response rate of HCV-cryoglobulinemia vasculitis during Rituximab & Peg-IFNα2b + Ribavirin.

10

30

50

70

2 3 4 5 6 7 8 9 10 11 12 Months

18.7

20

37.5

1

50

62.5

Rituximab Peg-Interferon-ribavirin

% o

fco

mpl

ete

resp

onde

rs

Figure 1

10

30

50

70

2 3 4 5 6 7 8 9 10 11 12 Months

18.7

20

37.5

1

50

62.5

Rituximab Peg-Interferon-ribavirin

% o

fco

mpl

ete

resp

onde

rs

Figure 1

Immunologic parameters in HCV-MC patients during treatment with Rituximab & Peg-IFNα2b-ribavirin.

Cryoglobulin

0

0,4

0,8

1,2

1,6

2

0 3 6 9 12 EOF

g/l

Months

C4

0

0,03

0,06

0,09

0,12

0,15

0,18

0 3 6 9 12 EOFMonths

g/l

RF

0

40

80

120

160

200

240

0 3 6 9 12 EOF

IU/lIgM

0

0,4

0,8

1,2

1,6

2

2,4

2,8

0 3 6 9 12 EOF

g/l

A B

C D

Months Months

Figure 4

Cryoglobulin

0

0,4

0,8

1,2

1,6

2

0 3 6 9 12 EOF

g/l

Months

C4

0

0,03

0,06

0,09

0,12

0,15

0,18

0 3 6 9 12 EOFMonths

g/l

RF

0

40

80

120

160

200

240

0 3 6 9 12 EOF

IU/lIgM

0

0,4

0,8

1,2

1,6

2

2,4

2,8

0 3 6 9 12 EOF

g/l

A B

C D

Months Months

Figure 4

HCV RNA viral load during treatment with Rituximab & Peg-IFNα2b + Ribavirin in HCV-cryoglobulinemia vasculitis.

0

1

2

3

4

5

6

7

Peg-Interferon-ribavirin

0 3 6 9 12 EOF

Rituximab

Log

copi

es/m

l

Months0

1

2

3

4

5

6

7

Peg-Interferon-ribavirin

0 3 6 9 12 EOF

Rituximab

Log

copi

es/m

l

Months

Outcome of 93 HCVOutcome of 93 HCVOutcome of 93 HCVOutcome of 93 HCV----MC patients according to the MC patients according to the MC patients according to the MC patients according to the type of treatmenttype of treatmenttype of treatmenttype of treatment

Parameters All PegIFNαααα-ribavirin RTX-PegIFNαααα-ribavirin

n=93 n=55 n=38 pTime of clinical response (months) 6.8 ± 4.7 8.4 ± 4.7 5.4 ± 4.0 0.004Clinical response

CR 68 (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 responseCR 49 (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 responseSVR 55 (59.1) 33 (60) 22 (57.9) 0.94NR 38 (40.8) 22 (40) 16 (42.1)

Death 5 (5.4) 2 (3.6) 3 (7.9) 0.70Cirrhosis 1 (1.1) _ 1 (2.6)Liver carcinoma 3 (3.2) 2 (3.6) 1 (2.6)Unknown 1 (1.1) _ 1 (2.6)

Course of kidney parameters in HCVCourse of kidney parameters in HCVCourse of kidney parameters in HCVCourse of kidney parameters in HCV----MC patients MC patients MC patients MC patients according to the type of treatment according to the type of treatment according to the type of treatment according to the type of treatment

PegIFNαααα-ribavirin RTX-PegIFN αααα-ribavirin

n=10 p n=21 p- CR of kidney involv. 4 (40) 17 (80.9) 0.04- Creatininemia (µmol/l)Baseline 150.0 ± 30.6 217.5 ± 47.4EOF 169.2 ± 44.2 0.28 136.9 ± 27.1 0.03- GFR (ml/min)Baseline 58.0 ± 7.4 42.8 ± 5.8EOF 59.5 ± 9.9 0.41 57.6 ± 4.5 0.01- Daily Proteinuria (g)Baseline 3.1 ± 0.9 3.5 ± 0.9EOF 1.2 ± 0.5 0.046 0.35 ± 0.1 <0.001- Hematuria (n,%)Baseline 10 (100) 19 (90.5)EOF 2 (20) 2 (10.5) <0.001

Course of B lymphocytes in HCVCourse of B lymphocytes in HCVCourse of B lymphocytes in HCVCourse of B lymphocytes in HCV----MC patients according MC patients according MC patients according MC patients according to the type of treatmentto the type of treatmentto the type of treatmentto the type of treatment

n=38 n=55n=38 n=55n=38 n=55n=38 n=55

Antiviral therapy alone decreases the memory B cells Antiviral therapy alone decreases the memory B cells Antiviral therapy alone decreases the memory B cells Antiviral therapy alone decreases the memory B cells in HCVin HCVin HCVin HCV----MC patientsMC patientsMC patientsMC patients

n=38 n=38 n=38 n=38 n=55n=55n=55n=55

Antiviral therapy in association with Rituximab Antiviral therapy in association with Rituximab Antiviral therapy in association with Rituximab Antiviral therapy in association with Rituximab decreases naive Bdecreases naive Bdecreases naive Bdecreases naive B----cells in HCVcells in HCVcells in HCVcells in HCV----MC patients : MC patients : MC patients : MC patients :

n=38 n=55n=38 n=55n=38 n=55n=38 n=55

Time Course of HCV Viral Load

Therapeutic Strategies in HCV-related Cryoglobulinemic Vasculitis

Mild to Moderatedisease

(Purpura, arthralgia, polyneuropathy)

Severe disease(Progressive renal disease,

mononeuritis multiplex, skin ulcer)

Life threatening(Rapidly progressive nephritis,

CNS, digestive and/or pulmonaryinvolvement)

Peg IFN-α + Ribavirin Rituximab

Peg IFN-α + Ribavirin

Steroids, plasma exchange, cyclophosphamide and/or

rituximab.

Peg IFN-α + Ribavirin(differed)

Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007

ManifestationManifestation Prevalences Prevalences

certainly associated with HCV certainly associated with HCV %%

------------------------------------------------------------------------------------------------------------------------------

�� Vasculitis (PAN, cryoglobulinemia) Vasculitis (PAN, cryoglobulinemia) 44--40 40

� Fatigue 35-54

�� ArthralgiaArthralgia--myalgiamyalgia--arthritisarthritis 2525--3535

�� Sicca syndromeSicca syndrome 1010--2525

�� AutoantibodiesAutoantibodies 1010--4040

�� ThrombocytopeniaThrombocytopenia 2020--4040

�� Lymphoma (SLVL)Lymphoma (SLVL) --


% of patients

n = 1614

% of controls

n = 412

Fatigue without depression

Fatigue with depression

Depression without fatigue

No fatigue and no depression

Total

485

2

45

100

0.70

0

99.3

100

Fatigue without EM

Fatigue with EM

EM without fatigue

No fatigue and no EM

Total

19

35

21

25

100

0.5

0.2

3.4

96

100

Association between fatigue, depression and clinical extrahepatic manifestations (EM)

Poynard T et al. J Viral Hep, 2002

Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007Multivariate analysisMultivariate 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 of these associations, fatigue (moderate-severe) was associated with: arthralgia, myalgia, paresthesia, sicca sd & pruritus.

Poynard T et al. J Viral Hep, 2002Poynard T et al. J Viral Hep, 2002

Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007Prevalence of fatigue at baseline and at 18 months follow-up in treated

and untreated patients

Baseline 18 months 18 months vsbaseline

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

Relapsers (n= 47) No fatigue Moderate Severe

45 %43 %13 %

40 %45 %15 %

P = 0.68

Non responders (n= 224) No fatigue Moderate Severe

40 %42 %18 %

46 %40 %14 %

P = 0.18

Poynard T et al. J Viral Hep, 2002




------------------------------------------------------------------------------------------------------------------------------


�� FatigueFatigue 3535--5454

� Arthralgia-myalgia-arthritis 25-35






0%5%

10%15%20%25%30%35%40%

Arthra

lgia

M0

M18

Pares

thes

ia M

0

M18

Mya

lgia

M0

M18

Sicca

sd M

0

M18

Sustained responders (n = 83)

Impact of Treatment on Extra hepatic Manifestations in HCVpatients.

At Baseline and 18 months Follow-up in Responders.

Cacoub P et al. J Hepatol 2002


0%5%

10%15%20%25%30%35%40%

Arthralgia M

0 M18Paresth

esia M

0 M18Mya

lgia M0

M18Sicc

a sd M

0 M18

Sustained responders (n = 83) Non responders - RNA + (n = 348)

Cacoub P et al. J Hepatol 2002

Impact of Treatment on Extra hepatic Manifestations in HCVpatients.

At Baseline and 18 months Follow-up in Responders.




------------------------------------------------------------------------------------------------------------------------------





� Autoantibodies 10-40



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.

Auto-antibody production in chronic HCV infection.

Most patients were negative for all other autoAbs :

• neutrophil cytoplasmic, β2 GP1

• Langherans islet, insulin, GAD

• liver-kidney microsome, mitochondria

There was no correlation between :

• Clinical or immunological abnormalities

• α-IFN & clinical/immunological abnormalities

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




------------------------------------------------------------------------------------------------------------------------------







� Lymphoma (SLVL) -

Hepatitis C Virus Chronic Infection :two main target cells

• Hepatitis • Cirrhosis• Hepatocarcinoma

• Cryoglobulinemia• B-NHL

HepatocyteChoo. Science 1989

LymphocyteZignego. J Hepatol 1992Ferri. Blood 1993


BB--cellcell--Non HodginNon Hodgin’’ s Lymphomas Lymphoma

Hepatitis C virusHepatitis C virus

2462 tested2462 tested

13.5 % positive•• vs 0vs 0--5 % in controls5 % in controls

•• vs 5 % in other malignant vs 5 % in other malignant hemopathyhemopathy

469 tested469 tested

0 - 39 %

Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007Effects of alpha-interferon on HCV+/SLVL course

After 6 months of IFN alpha treatment in SLVL/HCV+:

� Complete clinical hematologic response (spleen size < 12 cm, lymphocytosis <4500/mm3, No cytopenia ):

---> 7/9 HCV RNA negative

� Partial clinical hematologic response

(spleen size or lymphocytosis decrease >50%) :

---> 2/9 HCV RNA +

Hermine O. et al, N Engl J Med 2002; 347: 89-94

�� HCV antibodies : BHCV antibodies : B--NHL (< 3%) vs SLVL (15%)NHL (< 3%) vs SLVL (15%)

----> Splenic lymphoma with villous lymphocytes may be associated with HCV infection


Median Follow-up of 3 years (2-5)

�� 6 Complete Responses 6 Complete Responses ------> HCV RNA still negative> HCV RNA still negative

�� 1 relapse off therapy at 1 year,1 relapse off therapy at 1 year,

•• associated with positivity of HCV RNA. associated with positivity of HCV RNA.

•• second CR following IFN & negativity HCV RNAsecond CR following IFN & negativity HCV RNA

�� 2 Partial Responses 2 Partial Responses

•• CR after Combination of Interferon and Ribavirin CR after Combination of Interferon and Ribavirin

•• PR after Interferon and Ribavirin PR after Interferon and Ribavirin


Effects of alpha-interferon on HCV+/SLVL course

Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007HCV negative / SLVL Patients Treated with Alpha-Interferon

�� Median age 65 (54Median age 65 (54--72)72)

�� Prior therapy (2/6), chemotherapy (1), splenectomy(1)Prior therapy (2/6), chemotherapy (1), splenectomy(1)

�� Splenomegaly (4/6)Splenomegaly (4/6)

�� Hyperlymphocytosis Median 25,000 (500Hyperlymphocytosis Median 25,000 (500--100.000)100.000)

�� Cytopenia (2/6)Cytopenia (2/6)

�� Cryoglobulinemia or rheumatoid factor (0/6)Cryoglobulinemia or rheumatoid factor (0/6)

Alpha-Interferon 3 M IU x 3/W during 6 monthsNo response


Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007Conclusion

Extra hepatic manifestations of HCV infection are

frequent, & may be curred by HCV treatment :

• Systemic vasculitis (cryoglobulinemia, PAN)

• Fatigue

• Arthralgia - myalgia - arthritis (±)

• Auto-antibodies (?)

• Splenic lymphoma with villous lymphocytes

• Thrombocytopenia

cacoub manif extra hépatiques

Health & Medicine

hcv treatment

vasculitis hcv controls

prevalence of hcv infection

positivity of hcv rna

hcvinfected patients

hcv core protein

hcv negative slvl patients

ifn negativity hcv rna