Tp Traitement Hcv Du 2009

16 janv. 2009

LiverCenter

VHC

Traitement des cas simples

Traitement des cas compliqués

Thierry Poynard

Vlad Ratziu, Yves Benhamou

16 janv. 2009

LiverCenter

Treatment of Acute Hepatitis C:

A la carte from 0 to 1 year

16 janv. 2009

The Definition of Acute Hepatitis C

• Exposure to HCV

• Within 4 months

• Anti-HCV seroconversion

• Raised ALTs

• HCVRNA positivity

3

16 janv. 2009

Rationale for Treating Acute HCV

• High risk of chronicity

• Risk of spreading the virus

• Chances for better cure (no fibrosis, recovery of immune response)

4

16 janv. 2009

Anti-Viral Treatment of Acute HCV

• Randomized controlled trials

• Meta-analysis

• Uncontrolled trials

5

16 janv. 2009

RCTs of IFN! in Acute HCV

• VILLADOMIU n=28 ! ! Hepatology ! 1992 ! !

• LI n=32 ! ! ! China J Int Med 1993! !

• LAMPERTICO n=48 ! Hepatology ! 1994 !!

• HWANG n=23 ! ! J Hepatol ! 1994 !!

4 trials; n=141

All patients transfused

Age 51yrs, 62% males

All IFN !-2b alone

12 weeks of treatment

9-15 months fw-up

6

16 janv. 2009

Meta-Analysis of IFN !-2b RCTs in Acute HCV

Sustained Response (12mo)

0

15

30

45

60

P < 0.0001

Myers R, Cochrane Database Syst Rev 2003

Normal ALT Negative HCVRNA

% Response ControlInterferon

7

16 janv. 2009

Meta-Analysis of IFN !-2b RCTs in Acute HCV

Sustained Viral Response

Myers R, Cochrane Database Syst Rev 2003

*P<0.0001

Hwang 1994 (n=33)

Lampertico 1994 (n=48)

Li 1993 (n=32)

TOTAL (n=113)

1.0 100100.1

4.8 (1.1-22)

7.7 (1.6-38)

9.9 (1.5-65)

6.8 (2.6-17.5) *

Favours IFNFavours Control

OR (95% CI)

8

16 janv. 2009

IFN-!2b Treatment of Acute Hepatitis C

Uncontrolled Trial (N=44)

• Characteristics:

• Young 36 yrs

• Females (57%)

• Symptomatic (jaundice 68%)

• Genotype 1 (68%)

Interferon a-2b for 6 months:

Induction dose: 5MU daily for 4 wks

Regular dose: 3MU tiw for 20 wks

Follow-up 24 wks post Rx for viral end-point

CONTAMINATION SYMPTOMS TREATMENT

54 days (15-105)

89 days

(30-112)

Jackel, N Engl J Med 2001

9

16 janv. 2009

0

25

50

75

100

Inclusion 12w 24w 48w

Acute Hepatitis C :

43 patients followed 42 sustained responders normal ALT 1 lost follow up

Tolerance: 1 stop 12 weeks adverse events

IFN 5 M TIWIFN 5 M/day

Jaeckel E et al. N Engl J Med 2001

% HCV RNA+

16 janv. 2009

Anti-Viral Treatment of Acute HCV

STRATEGIES

11

16 janv. 2009

Hypothesis:

Early control of viral replication prevents chronicity

• Treat all patients ?

• Treat early ?

• Doses of IFN ?

• Ribavirin ?

• Duration of treatment ?

12

16 janv. 2009

Spontaneous Viral Clearance After

Acute HCV Infection

38*

44

14

67

1985-1991 Alter (n=106)

1993-2000 Gerlach (n=54)

1988-1996 Villano (n=43)

2000-2001 Hofer (n=12)

AUTHOR (N)TIME PERIOD% VIRAL

CLEARANCE

* No PCR, ALT data only

13

16 janv. 2009

Prevalence of Symptoms According to Outcome

0

25

50

75

100

JAUNDICE

OR 4.9 (1.3-19)

FLU-LIKE SYMPTOMS

OR 7.8 (2.2-29)

87 %

59 %

87 %

47 %

P=0.02 P=0.002

Gerlach, Gastroenterology 2003

14

Self limited Chronic

16 janv. 2009

Predictors of Spontaneous Viral Clearance ...

• Younger age (?)

• Females (?)

• White vs. Blacks (?)

• Rare Quasispecies

• Genotype non-1

• ALT useless

• Can normalize despite viral persistence (50%)

15

16 janv. 2009

Early Prediction of HCV Clearance

After Acute Infection ?

Days after onset of symptoms

Self Limited Chronic

Hofer, Hepatology 2003

16

16 janv. 2009

Proposal: Treatment Restricted to Patients

that Fail to Clear the Virus

• Asymptomatic or

• HCVRNA still detectable 3-4 months after onset of

symptoms

• PEG IFN (± ribavirin) treatment, at least 24 weeks ??

17

16 janv. 2009

LiverCenter

Treatment of Chronic Hepatitis C:

A la carte from 0 to 5 years

16 janv. 2009

Prise en charge de l’Hépatite C en 2008

• Améliorer le dépistage

• Simplifier le bilan

• Améliorer le traitement

• A la carte

• Ne pas baisser les bras

19

16 janv. 2009

Chronic Hepatitis B or C

FibroTest ActiTest

Advanced Fibrosis

Severe Activity

Hepatologist

Fibroscan if FibroTest

not applicable

No Advanced Fibrosis

No Severe Activity

FibroTest

every 2-4 years

HAS for HCV Dec 2007

16 janv. 2009

Date Endpoint Treatment Approval Reference

1991 ALT Interferon Davis NEJM

1998 SVR Interferon RibavirinPoynard Lancet

McHutchison NEJM

2001 SVR PEG Interferon RibavirinManns NEJM,

Fried NEJM

2011 ? SVRPEG Interferon Ribavirin,

Boceprevir, Telaprevir ????

2015 ? SVR Xprevir+Yprevir ??

Approval of HCV treatments

16 janv. 2009

Sustained Virological Response

HCV RNA negative

0

25

50

75

100

Control IFN 24w IFN 48w IFN-R PEG 1.5-R opt

G 1-4-5-6 G 2-3

22

SVR %

16 janv. 2009

Factors associated with SVR in HCV

Sure

• Genotype

• Viral load

• Fibrosis stage

• Age (Duration)

• HIV

• Male

• BMI,Steatosis,Diabetes

Poynard et al Lancet 2003

23

16 janv. 2009

24

Traitement à la carte avec PEG-Riba?

• Attention aux faux amis

• G2 et G3

! mais

• F2F3F4

• Attention au gras et au sucre

Poynard et al Hepatology 2000, Lancet 2003, Hepatology 2003

16 janv. 2009

25

Results: SVR Genotype 2 and 3

PEG-IFN !-2b 1.5 "g/kg QW !-2b + ribavirin 800-1,400 mg/day

0

25

50

75

100

HCV 2 (n=42) HCV 3 (n=182)

Zeuzem et al, J Hepatol, 2004

16 janv. 2009

26

Results: SVR Genotype 2 and 3

! or > 600,000 IU

PEG-IFN !-2b 1.5 "g/kg QW !-2b + ribavirin 800-1,400 mg/day

0

25

50

75

100

G2 " 6 (n=20) G2 > 6 (n=22) G3 " 6 (n=99) G3 > 6 (n=83)


16 janv. 2009

27

A la carte regimen with PEG-Riba?

• Longer duration for Genotype 2 and 3 if

• Advanced fibrosis F2F3F4

• Steatosis in genotype 2

• HIV


16 janv. 2009

Genotype 2 and 3 patients F2F3F4

treated PEG IFN alfa 2b and ribavirin flat dose

0

20

40

60

80

PEG IFN-R 48w n=54


SVR %

16 janv. 2009

Genotype 2 and 3 patients with bridging fibrosis

treated PEG IFN alfa 2a and ribavirin weight based dose

0

25

50

75

100

PEG IFN-R 24w n=20 PEG IFN-R 48w n=33

EOT SVR

Hadziyannis et al Ann Inter Med, 2004

29

16 janv. 2009

Genotype 2 and 3 patients with bridging fibrosis

treated PEG IFN alfa 2b and ribavirin weight based dose

14 weeks for VEVR*, 24 weeks for NVEVR

0

25

50

75

100

EVR PEG IFN-R 14w n=14 NEVR PEG IFN-R 24w n=14

EOT SVR

Dalgart et al Hepatology, 2004

*Undetectable 4,8 W

30

16 janv. 2009

31

A la carte regimen with PEG-Riba?

• Shorter duration (2-4 months)

• For Genotype 2 and 3, if no relapse factors


16 janv. 2009

32

Genotype 2 and 3 patients

treated PEG IFN alfa 2b 1.0 ug/Kg and ribavirin weight based dose

12 weeks for VEVR*, 24 weeks for NVEVR

0

20

40

60

80

VEVR SVR

Standard Variable

Mangia et al NEJM, 2005*Undetectable 4 W

16 janv. 2009

33


N=96 patients naïfs consécutifs: facteurs de risque de rechute

• Plus d’un facteur de risque# # 84%

• Génotype 1,4,5,6 ## # 58%

• Charge virale >= 800,000 IU/ml ! 38%

• Age >40 ans ! ! ! ! 66%

• Sexe masculin !! ! ! 60%

• Fibrose avancée: F2, F3, F4 # # 34%

Poynard et al Hepatology 2000, D’Arondel JVH 2006

16 janv. 2009

34

Traitement à la carte PEG-Riba

D’Arondel JVH 2006

35

Background

16 janv. 2009

Impact of Steatosis on SVR (uni and multivariate)

No Steatosis Steatosis

Poynard Hepatology 2003

16 janv. 2009

A la carte suisse, ou à l’américaine ?

37

16 janv. 2009

38

IDEAL Study Design

HCV 1 Naive to Previous Therapy

PEG-IFN !-2b + ribavirin 800-1400mg/daily

1.0 µg/kg QW (48 wks) N=960

PEG-IFN !-2a + ribavirin 1000-1200mg/daily

N=960180 µg QW (48 weeks)

Screening

PEG-IFN !-2b + ribavirin 800-1400mg/daily

N=9601.5 µg/kg QW (48 wks)

Endpoint

Follow-up48 weeks 24 weeks

Primary Endpoint: Loss of serum HCV RNA 24 weeks posttreatment

S* Stratification: Baseline HCV < vs ! 600,000 IU & African American vs non AA

S*

16 janv. 2009

IDEAL results n=3,070

0

10

20

30

40

50

SVR Relapse Discontinuation AE

PEG 2b 1.5 PEG 2b 1.0 PEG 2a

82% >= 600.000 IU/mL, 11% F3F4, 19% African American

16 janv. 2009

Prediction of Sustained Response

based on Week 12 HCV-RNA

0

30

60

90

PCR+ <2log drop n=31 PCR+ >=2 log n=23 PCR- n=120

90

26

16 janv. 2009

Count favorable factors:genotype 2/3, viral load <1 MIU mL

F0–F1 (FibroTest), BMI <27

Treatment à la Carte 2009

Stop at 48 weeks

Positive

PCR at 12/24 weeks

Negative or >2-log decrease <2-log decrease

RBV >10.6 mg/kg/dPEG IFN 1.5 µg/kg QW

<3 favorable factors

Stop at 12/24 weeks

3 or 4 favorable factors

Stop at 12 weeks ? Discuss slow responder

PEG IFN for fibrosis prevention if progression is rapid

Quantitative viral load at 4/12 weeks

Negative

16 janv. 2009

LiverCenter

VHC

Traitement des cas simples

Traitement des cas compliqués

Thierry Poynard

Vlad Ratziu, Yves Benhamou

16 janv. 2009

Prise en charge de l’Hépatite C en 2008

• Améliorer le dépistage

• Simplifier le bilan

• Améliorer le traitement

• A la carte


43

16 janv. 2009

44



• Traitement anti-fibrosant

• Sujet de plus de 65 ans

Poynard et al, Lancet 2003, Thabut et al AJG 2006

16 janv. 2009

Progression de la fibrose chez les patients VHC avec doubles

biopsies traités ou non par IFN 24-48 semaines

0

1

2

3

4

0 10 20 30 40

Titre de catégorieSobesky et al, Gastroenterology 1999

Années

102 contrôles

91 “non répondeurs” ALT 3 mo

94 “répondeurs” ALT 3mo

F METAVIR

16 janv. 2009

Incidence (per year) of Cirrhosis in patients with Chronic hepatitis C:

2 Randomized trials

"

0

5

10

15

Poynard Degos

Reinforced 3MU TIW 6 mo

p=0.004p=0.14

Poynard T, N Engl J Med 1995 Degos F, J Hepatol 1998

16 janv. 2009

Histologic Improvement of Fibrosis in Patients with Hepatitis C

Who Have Sustained Response to Interferon Therapy

• 593 patients 2 biopsies

• 106 Untreated patients 4.8 years

• 304 IFN virologic non-responders 3.2 years

• 183 IFN virologic responders 3.2 years

47

Y Shiratori, Ann Int Med 2000

16 janv. 2009

Fibrosis progression rate per year in Patients with Hepatitis C

-30

-20

-10

0

10

IFN-SR IFN-NR Untreated

Four pivotal International RCTs SPRI

Poynard et al, McHutchison et al, Lindsay et al, Manns et al

3,010 Patients with paired biopsies

One pathologistOne virologist

4,493 Patients4 Trials

Naive HCV patients

Poynard et al Gastroenterology, 2002

Fibrosis progression rate per year in patients F2-F3-F4

with paired biopsies and known duration of infection

Before After

P<0.001

Poynard et al Gastroenterology, 2002

51

FibroTest: Estimates Anti-Fibrotic Impact

0

0,2

0,4

0,6

0,8

1,0

F234 NR n=110 F234 SVR n=65

0,47

0,64 0,680,71

Baseline EOF

-10%-31%

Poynard et al Hepatology, 2003

FibroTest

52

Reversal of cirrhosis in 75 (49%) of patients

F4F3F2F1F0

Poynard et al Gastroenterology 2002, Pol et al Hum Pathol 2004, Camma et al Hepatology 2004

0.00

0.25

0.50

0.75

1.00

Impact of treatment on FibroTest n=817

Baseline

Fibr

otes

tF METAVIR difference

-3-2-10123

Follow-upPoynard et al Hepatology, 2003

Disappearance of cirrhosis? Significant factors

No more cirrhosis n=75

Persistent cirrhosis n=78

Multivariate analysis P=0.02Poynard et al Gastroenterology, 2002

Reversibility of Cirrhosis

Wanless, Arch Pathol Lab Med 2000

F4

F3

Regression Pararameters

(Repair Complex)

Delicate perforated septa

Isolated thick collagen fibers

Delicate periportal fibrosis spikes

Portal tracts, Hepatic Vein remnants

Prolapsed Hepatocytes, Inside Portal tracts or

splitting septa, minute regenerative nodules,

aberrant parenchymal veins.

10 Years Later Right Lobe

Impact in SVR

Less cirrhosis

Less complications

Less deaths

Beware of HepatoCellular Carcinoma in Sustained Virological responders

previously F3 or F4

60

Maintenance Therapy Trials

HALT-C COPILOT EPIC3

Patients Ishak 4-6 Ishak 3 – 6 Metavir 2 –4

N 1000 800 2200 (3 studies)

End-point Fibrosis/Clinical Fibrosis /Clinical Fibrosis/Clinical

Initial Tx.PEG-IFN !"2a

+riba 800 mgNone

PegIntron®+ Rebetol® WBD

Maintenance Tx. PEG-IFN !"2a

90 #g

PegIntron®0.5 µg/kg


Maintenance Control Placebo Colchicine Observation

TreatmentDuration (years) 3.5 4 3-5

RecruitmentStatus Complete Mid-point Analysis Complete

HALT-C Peg 2a 90 mcg/w3.5 years

Significant ALT, HCV Viral load and Activity (P<0.0001)

Non significant main endpoint:

Compliance: 53% still on treatment, 10% lower dose,

37% stopped therapy

64

Maintenance Therapy TrialsHALT-C COPILOT EPIC3

Patients Ishak 4-6 Ishak 3 – 6 Metavir 2 –4

N 1000 800 2200 (3 studies)

End-point Fibrosis/Clinical Fibrosis /Clinical Fibrosis/Clinical

Initial Tx.PEG-IFN !"2a

+riba 800 mgNone

PegIntron®+ Rebetol® WBD

Maintenance Tx. PEG-IFN !"2a

90 µg



Maintenance Control Placebo Colchicine Observation

TreatmentDuration (years)

3.5 4 3-5

RecruitmentStatus

Complete Mid-point Analysis Enrolling

65

Colchicine 0.6 mg bid

LB, US,

endoscopy

PEG-IFN-!2b 0.5 !g/kg/wk

Clinical

Evaluation

q 12 Weeks

US

q 24

Weeks

Endoscopy,

LB

Endoscopy,

LB

Interferon /Rebetron / PEG + RIB

Non-respondersF2-F4

5 JahreBaseline 12 weeks 24 weeks 2 years 4 years

COPILOT – Study Design

! 600 patients – 557 currently enrolled

! Ishak Fibrosis Stage > 3

66

PEG-IFN alfa-2b Highly Effective Maintenance For

Patients With Portal Hypertension (PHTN)

No. PHTN PHTN

Colchicine 134 126

Events 8 (6%) 34 (27%)*

PEG-IFN alfa-2b 155 111

Events 12 (7%) 14 (11%)*

*Fishers test, P<0.004: PEG-IFN alfa-2b vs. Colchicine

67

Development of PHTN at Year 2Among patients without PHTN at baseline

COLCHICINE

92 patients at risk

20 varices

4 gastropathy

2 patients developed new varices with bleeding within initial 2 years

Overall 28%*

! PEG-IFN alfa 2b

! 95 patients at risk

! 8 varices

! 4 gastropathy

! Overall 12%*

* Chi Square 5.44; p = 0.025

68

Portal Pressure Studies on Peg-IFN alfa 2b 0.5mcg/kg

0

5

10

15

20

25

30mm Hg

Baseline 24 weeks

Mean 15mmHg

Mean 8mmHg

Chronic Suppression for Non-Cirrhotics, n=700

HCV RNA positive at week 12METAVIR F2 or F3 subjects

PEG-Intron 0.5µg/kg/wk vs. control

Duration: 3 years385 Randomized*

69

EPIC 3 Program DesignNon-Responder Trial: N=2200

CHC with fibrosis (F2, F3 or F4 METAVIR) who failed to respond any IFN alfa/alpha + Ribavirin

PEG-Intron 1.5 µg/kg/wk + Rebetol 800-1400mg/d

N=3136 screened*, 1843 treated* 1369 analyzed for EVR *

HCV RNA negative at week 12Subject continue 36 weeks trt

+ 24 weeks follow-up978 analyzed for SVR*

570 EVR: 341 neg 229 pos346 non EVR 2 na

Chronic Suppression for Cirrhotics, n=1000HCV RNA positive at week 12

METAVIR F4 subjects PEG-Intron 0.5µg/kg/wk vs. control

Max duration: 5 years404 Randomized*

METAVIR F4 CHC subjects Non-responder to any

IFN alfa/alpha + Ribavirin DIRECT ENROLLERS

*As of March 4 2005

16 janv. 2009

70

Multivariate Regression Analysis

Predictors of Response

• HCV genotype

• G2/3 vs. G1, OR = 4.9; P < 0.0001

• Previous treatment response

• Relapser vs. non-responder, OR = 3.8, P <0.0001

• Baseline METAVIR fibrosis score

• F2 vs. F4, OR = 2.2; P = <.0001 / F3 vs F4, OR = 1.4; P = 0.0183

• Previous treatment

• IFN ! + RBV vs. PEG-IFN ! + RBV, OR = 2.0, P <0 .0001

• Baseline viral load

• "600,000 IU/mL vs. > 600,000 IU/mL, OR = 1.9, P < 0.0001

16 janv. 2009

71

SVR in Prior Non-Responders

Peg-IFN !-2 a + b/R,n = 476

All Patients 0,04

G1 F4 0,04

G1 F3 0,04

G1 F2 0,06

G2/3 F4 0,18

G2/3 F3 0,38

G2/3 F2 0,56

16 janv. 2009

72

SVR in Prior Relapsers

Peg-IFN !-2 a + b/R,n = 344

All Patients 0,32

G1 F4 0,18

G1 F3 0,21

G1 F2 0,32

G2/3 F4 0,51

G2/3 F3 0,62

G2/3 F2 0,61

16 janv. 2009

0

20

40

60

80

All FibroTest n=1459 EVR FibroTest n=506 All Biopsy n=1459 EVR Biopsy n=506

48

16

52

15

65

24

57

20

63

27

60

27

61

29

75

40

F0 F1 F2 F3 F4

Prognostic value of FibroTest

in 1,459 HCV virological non responders

EPIC-3 Trial 2009

74

Maintenance therapy with Ribavirin alone

0

20

40

60

80

100

120

Baseline EOT 12 months 18 months

Sustained R

Ribavirin

Placebo

Hoofnagle et al Hepatology, 2003

Interferon

Ribavirin Tx

Follow-up

P=0.06 n=32ALT (IU/L)

Improvement of Activity Grade (HAI) with Ribavirin

16 Ribavirin 1.0-1.2 vs 16 patients placebo non viral responders

0

2

4

6

8

10

M0 M18

Ribavirin

Placebo

Hoofnagle et al, Hepatology 2003

P=0.02

16 janv. 2009

4

Molécules en Développement

Phase 1 Phase 3 Phase 2

Protease

Inhibitors

Polymerase

Inhibitors

• Telaprevir (Vertex)

• Boceprevir

(Schering Plough)

Novel

Mechanisms of Action

• ITMN-191 (Intermune/Roche)

•!MK-7009 (Merck)

• GS-9190 (Gilead)

• BMS-790052 (BMS)

•! PF-00868554 (Pfizer) •! ANA598 (Anadys)

•! BILB 1941 (Boehringer

Ingelheim)

• Bavituximab (Peregrine)

• TMC435350 (Medivir/

Tibotec)

•!BI 201335 (Boehringer Ingelheim)

• R7128 (Pharmasset/Roche)

• DEBIO-025 (Debiopharm)

• NIM811 (Novartis)

• Nitazoxanide (Romark) • Celgosivir (Migenix)

16 janv. 2009

A venir

16 janv. 2009

Candidat bi-thérapie ??

16 janv. 2009

Candidat bi-thérapie ??

80

Traitement hépatite C 2009

Intensifier dépistage

Simplifier bilan initial et suivi

Traiter «!à la carte!»:

• Fibrose, Poids, Stéatose, Age

Tolérance

Efficacité non virologique:

• Freiner la progression de la Fibrose

81

Difficult to treat patientsAdverse events

Coinfected HIV

Cirrhotic

Aged patients

Uremic

Hemophiliac

Thalassemic

Anemic

Neutopenic

Thrombopenic

IV drug user

82

0 4 5 11 12

IFN Treatment (Weeks)

Severi

tyTime Course of Side Effects

6 7 8 9 101 2 3

FatigueFlu-likesymptoms

Depressive/anxietysymptoms

Hematologic side effects

83

Adherent "80% of both drugs (n=35/146)

Not Adherent <80% of one or both drugs (n=7/21)

Effect of Adherence on SVRPEG-IFN !-2b 1.5 #g/kg QW !-2b + ribavirin 800-1,400 mg/day


Dose Modifications / Discontinuations

Rebetol > 10.6 mg/kg

Peg2b 1.5 ug/Kg IntronA 3MU

Discontinuations

Dose Modification

14% 12%

49% 33%

Anemia

Neutropenia

12% 14%

21% 8%

Due to AE’s

Neutrophils

0

1

2

3

4

5

0 2 4 6 8 12 18 24 30 36 42 48 4 12 24

Peg1.5/R<10.6 Peg1.5/R>10.6 I/R<10.6 I/R>10.6

Treatment Week Follow-up Week

Mea

n Neu

trop

hil Cou

nts

x 10

9/l

Hemoglobin

10,0

11,4

12,8

14,2

15,6

17,0

0 2 4 6 8 12 18 24 30 36 42 48 4 12 24

Peg1.5/R<10.6 Peg1.5/R>10.6 I/R<10.6 I/R>10.6


Mea

n Hem

oglobi

n Con

cent

ration

g/d

l

Platelets

0

50

100

150

200

250

0 2 4 6 8 12 18 24 30 36 42 48 4 12 24

Peg1.5/R<10.6 Peg1.5/R>10.6 I/R<10.6

I/R>10.6


Mea

n Pl

atelet

Cou

nts

x 10

6/l

88

Hepatitis C Virus-Infected Patients ReportCommunication Problems With Physicians

Susan Zickmund, Stephen L. Hillis, Mitchell J.

Barnett, Laura Ippolito, and Douglas R. LaBrecque

Hepatology 2004;39:999 –1007

89

322 Outpatients

131 (41%) of patients

report poor communication

with physicians

28%

Physician incompetence

Dx and Tx

(n=91)

23%

Feelings of Misdiagnosis

Abandoned

(n=74)

9%

Stigmatized by Physician

(n=29)

Zickmund S, Hepatology 2004;39:999 –1007

90


Coinfected HIV

Cirrhotic

Aged patients

Uremic

Hemophiliac

Thalassemic

Anemic

Neutopenic

Thrombopenic

IV drug user

91

Large Scale Studies (Boston 2004)

32,527 patients: Fibrotest-Actitest-HCV-FibroSURE and ALT

ALT 50 IU/L: 65 years+ n=3,084

for F2F3F4 Se=60% NPV 42% (prevalence 73%)

for Cirrhosis Se=69% NPV 75% (prevalence 40%)

92

HCV treatment in aged patients n=166

65-80 yrs >80 yrs

Number of treated patients 162 4

Number of treatments 275 4

Type of treatment

-IFN alone

-IFN-Ribavirin

-PEGinterferon alone

-PEG Ribavirin

-Ribavirin alone

-Other

143

42

11

16

30

33

0

1

0

2

0

1

Interruption of treatment 55 (20 %) 0Thabut et al AJG 2006

93

Genotype 1 Genotype 2 Genotype 3 Other Total

Classic IFN 4/79 0/10 1/2 5/52 10/143 (7 %)

Ribavirin 1/16 0/1 0/0 1/13 2/30 (7 %)

PEG alone 0/6 0/0 0/0 0/4 0 /10

IFN-Ribavirin 3/28 3/5 0/0 1/9 7 /42 (16 %)

PEGIFN-

Ribavirin5/12 1/1 1/2 2/5 9/19 (45%)

Sustained Virological Response in aged patients n=166

Thabut et al AJG 2006

94


Coinfected HIV

Cirrhotic

Aged patients

Uremic

Hemophiliac

Thalassemic

Anemic

Neutopenic

Thrombopenic

IV drug user

95


Coinfected HIV

Cirrhotic

Aged patients

Uremic

Hemophiliac

Thalassemic

Anemic

Neutopenic

Thrombopenic

IV drug user

96

Renal Diseases

Renal insufficiency

Hemodialysis

Renal transplantation

97

Renal insufficiency

IFN, PEG-IFN:

Same dose or slightly reduced

Ribavirin:

Adjusted plasma concentration ?,

• 10-15 micromol/L ?

Start 200mg per week

• Range 170-300 mg/day

EPO: 20,000-30,000 UI/week

98

0.0

1.0

2.0

3.0

4.0

5.0

6.0

0 48 96 144 192 240 288336384432480528

Time [h]

PEGASYS

® C

onc. [ng

/mL]

Group 1: Cl >100 (n=5)

Group 2: 100 < Cl >80 (n=4)

Group 3: 80 < Cl >60 (n=5)

Group 4: 60 < Cl >40 (n=6)

Group 5: 40 < Cl >20 (n=3)

Martin et al. AASLD 2000. NP15579

Kinetics of PEG-IFN 2a in renal failure

99

Renal insufficiencyIFN, PEG-IFN:

Same dose or slightly reduced

Ribavirin:

Adjusted plasma concentration ?,

• 10-15 micromol/L ?

Start 200mg per week

• Range 170-300 mg/day

EPO: 20,000-30,000 UI/week

100

Renal Diseases

Renal insufficiency

Hemodialysis


101

Interferon alfa for HCV infection in hemodialyzed

INF alfa is feasable in dialysis patients

Poorly tolerated

• discontinuation: 20-40%;

• reduction: 60%

Efficient: at least as efficient than in the general population (pharmacokinetic of INF)

Frequent histological improvement

102

Ribavirin in Hemodialyzed

Warning Hemolysis +++

increased risk despite the absence of variation of the level of serum ribavirin

long duration of the risk; accumulation of metabolites in erythrocytes

Particularly with aziathioprine

Low doses of ribavirin

200 mg after each dialysis

200 daily

Increased doses of EPOThervet et al. Transplantation 1994

Thevenot et al. JVH 1997

103

Interferon and Ribavirin in Hemodialyzed

Associated (synergistic effect?) with IFN or PEG-IFN

Low doses of ribavirin

200 mg after each dialysis

200 daily

Increased doses of EPO

# Tang et al. J Hepatol 2003

Park J et al. DDW 2005

Personal experience 25 cases 40% SVR

104

Renal Diseases

Renal insufficiency

Hemodialysis


105

Summary

Treatment options in HCV patients with Renal disorders

No Transplantation Scheduled:

As in non uremic:

• F0F1: Follow-up FibroTest /12mo or biopsy /3y

• F1-F2: FibroTest /6mo or biopsy /y

• F2F3F4: Treatment A la Carte

Transplantion Scheduled:

• Treatment A la Carte as soon as possible

• Double transplantation in F4 non-responders

Transplanted:

• F0F1: Follow-up FibroTest /12mo or biopsy /3y

• F1-F2: FibroTest /6mo or biopsy /y

• F2F3F4:

– Ribavirin

– Liver Transplantation in F4 non-responders

106

Conclusions

Prevention of hepatitis in renal diseases

Treatment “A la Carte” feasible and effective before transplantation

Treatment limited after transplantation

107


Coinfected HIV

Cirrhotic

Aged patients

Uremic

Hemophiliac

Thalassemic

Anemic

Neutropenic

Thrombopenic

IV drug user

Hemophiliac Patients

Massively contaminated,

Coinfection HIV,

Same natural history,

Biopsy worse cost-benefit rate

Same treatments, including transplantation

Same results than in non-hemophiliacs

Thalassemic PatientsMassively contaminated,

Progression of fibrosis

• Iron overload

• Insulin-resistance

Same treatments, including bone marrow transplantation

Blood transfusion sometimes needed

Anemic PatientsRibavirin dose dependent reversible hemolytic anemia

Erythropoietin (epoetin alfa)

• 40,000 U/week vs standard

• Hemoglobin drop: 0.3 g vs 2.9 g/dL

• 900 vs 700 mg/day ribavirin

• When to start ?

–Anemic at baseline <11g Hb?

–During treatment if <11g Hb ?

Neutropenic PatientsGranulocyte colony-stimulating factor (G-CSF)

• Potentiates effect of EPO

• 300 microG SC 1-3 / week

• Maintain Neutrophils >750/mm3

• Adverse events

– Skin rash

– Vasculatis

– Bone pain, myalgia

– Thrombocytopenia, splenomegaly

– Leukemoid reaction

– Exacerbation of psoriasis

Thrombopenic Patients

Problematic in cirrhotic patients

Severe thrombopenia exceptional in non cirrhotic

Thrombopoietin

0%

25%

50%

75%

100%

Placebo 30mg 50mg 75mg

95%

79%75%

>100,000 /mm3 week 4

McHutchison NEJM 2007

Elthrombopag: 4 weeks impact + 12 weeks PEG-Riba74 HCV Cirrhosis 20,000-70,000 platelets

0%

0%

25%

50%

75%

100%

Placebo 30mg 50mg 75mg

65%53%

36%

6%

Completed HCV treatment week 12

McHutchison NEJM 2007

Elthrombopag: 4 weeks impact + 12 weeks PEG-Riba74 HCV Cirrhosis 20,000-70,000 platelets

Elthrombopag: Adverse events

Headache

Thrombosis

116

Traitement hépatite C 2008

Intensifier dépistage

Simplifier bilan initial et suivi

Traiter « à la carte »:

• Fibrose, Poids, Stéatose, Age

Tolérance

Efficacité non virologique:

• Freiner la progression de la Fibrose

Health & Medicine

Tp Traitement Hcv Du 2009