Patrick MARCELLIN

THE CHALLENGE OF TREATING

NON RESPONDERS

Patrick Marcellin

Service d’Hépatologie and INSERM CRB3Hôpital Beaujon, Clichy

University of Paris

WHO TO RETREAT?

SIDE EFFECTSTOLERANCECOST

FIBROSIS 0-1

PROS CONS

SYMPTOMSGENOTYPEMOTIVATION

FIBROSIS 2-4

HOW TO TREAT A NON RESPONDER?

Two strategies

- Viral eradication

- Maintenance therapy

HOW TO TREAT A NON RESPONDER?

Two strategies

- Viral eradication

- Maintenance therapy

The probability of viral eradicationdepends on:

- Type of non response

- Previous therapy

- Cause(s) of non response

The probability of viral eradicationdepends on:

- Type of non response

- Previous therapy

- Cause(s) of non response

0 1 2 311

2

3

4

5

6

7

7 14 21 28

Limit of detection

Days

Ser

um

HC

V R

NA

1st phase

2nd phase

Partial non responder

Slow responder

Rapid responder

Null non responder

Neumann et al. 2000

Type of non response

0 1 2 311

2

3

4

5

6

7

7 14 21 28

Limit of detection

Days

Ser

um

HC

V R

NA

1st phase

2nd phase

Partial non responder

Slow responder

Rapid responder

Null non responder

Neumann et al. 2000

Type of non response

The probability of viral eradicationdepends on:

- Type of non response

- Previous therapy

- Cause(s) of non response

Previous therapy

- Conventional interferon

- Standard combination

- Pegylated combination

HALT-CSVR according to previous therapy

28%

12%

0

10

20

30

40

50

%

IFN (n=219)

IFN + RBV (n=385)

p<0.0001

Schiffman. Gastroenterology 2005

BEAUJON SVR according to previous therapy

35%

10%

0

10

20

30

40

50

%

IFN (n=49)

IFN + RBV (n=50)

Ripault et al. DDW 2003

SVR to PEG IFN+RBV in NRs to IFN+RBVAccording to Genotype

0%

37%

0

10

20

30

40

50

SVR

%

Genotype 2-3 Genotype 1

Moucari et al. J Hepatol in press

SVR to PEG IFN+RBV in NRs to IFN+RBVAccording to Cirrhosis

0%

32%

0

10

20

30

40

50

SVR

%

No cirrhosis Cirrhosis

Moucari et al. J Hepatol in press

0

1

2

3

4

5

6

7

8

W0 W4* W8* W12

SVR (+)SVR (-)

HC

V R

NA

(lo

g10

co

pie

s/m

l)

Treatment Week

RETREATMENT BY PEGYLATED COMBINATION OF 154 NON RESPONDERS TO STANDARD COMBINATION

Moucari et al. J Hepatol, in press

RETREATMENT FOR ERADICATION

Partial response Non response

Genotype 2-3 Genotype 1

No cirrhosis Cirrhosis

PROS CONS

PROBABILITY OF SVR TO RETREATMENT

P = P2 - P1

P is the probability of response to retreatment according to the probability of response to the new treatment (P2) minus the probability of response to the prior treatment (P1)

The probability of viral eradicationdepends on:

- Type of non response

- Previous therapy

- Cause(s) of non response

Cause(s) of non responserelated to the patient:

To manage before retreatment

- Alcool: stop - Overweight: weight loss- Insulin resistance treatment?- Iron overload: phlebotomy- Psychologic: prepare

Cause(s) of non responserelated to reduced dosing:

To manage during retreatment

- Anemia: EPO- Neutropenia: GCSF- Depression: anti-depressive- Others …

PERSPECTIVES

- Optimise current therapy

- New drugs

PERSPECTIVES

- Optimize current therapy

- New drugs

OPTIMIZE CURRENT THERAPY

- Increase dose of PEG IFN

- Increase duration of therapy

- Better adjust dose of RBV according to body weight

- Improve PEG IFN pharmacokinetic (2 injections/week for PEG IFN a2b?)

REPEATBackground

• Initial retreatment studies have suggested a benefit of induction doses and/or prolonged duration of treatment in previous non-responders

Jacobson. Hepatology 2005Strader. Hepatology 2004Diago. Hepatology 2003

REPEATPatients

• Non-responders to ≥12 weeks’ treatment with standard-dose PEG IFN alfa-2b plus ribavirin

Follow-up

Study Week0 4824 9612 36 60 72 84

Follow-up360 g Peg-IFN alpha2a + RBV

Follow-up360 g Peg-IFN alpha2a + RBV

180 g Peg-IFN alpha2a + RBV Follow-up

REPEAT study design950 patients randomized 2:1:1:2

A

B

C

D

180 g Peg-IFN alpha2a + RBV

Marcellin et al. AASLD 2005

Virological Response at Week 12P

atie

nts

(%

)

<600 IU/mL <50 IU/mL≥2-log10 drop

25

42*

1320*

45

62*

p<0.0001 180 g (n=469)360 g (n=473)

HCV RNA

0

10

20

30

40

50

60

70

p<0.0001

p=0.0031

Marcellin et al. AASLD 2005

PERSPECTIVES

- Optimise current therapy

- New drugs

NEW DRUGS

• New “IFN”: Albuferon

Gene shuffled interferon

• New “ribavirins”: Levovirine

Merimepodib

Viramidine

• Enzyme inhibitors: Anti-polymerase

Anti-protease

Merimepodib (VX 497) in non responders (IFN+RBV)

Weeks

2

3

4

5

6

7

8

0 4 8 12 16 20 24

Med

ian

HC

V R

NA

(lo

g 1

0)

PEG IFN + Riba PEG IFN + Riba + 25 mg VX 497

PEG IFN + Riba + 50 mg VX 497

Marcellin et al. EASL 2004

ViramidineAnemia

Viramidine

Hemoglobine <10 g/dL

%

%

30%

25%

20%

15%

10%

5%

0%

400 mg 600 mg 800 mg

Ribavirin1000/1200 mg

0%2%

11%

27%

Viramidine Phase 3 VISER 1 SVR

Viramidine 800mg Ribavirin 1000/1200 mg

52% 38%

.

100%

75%

50%

25%

0%

%

%

ENZYME INHIBITORS

• Anti-polymerase• NM 283 (Idenix/Novartis)

• R1626 (Roche)

• HCV 796 (Wyeth)…

•Anti-protease• VX 950 (Vertex)

• Schering 503034

• Others...

Valopicitabine (NM283)

HCV RNA

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

1 3 5 8 11 1615 17 22

JDays

Placebo

50 mg x 1/j

100 mg x 1/j

200 mg x 1/j

400 mg x 1/j

200 mg x 2/j

Doses croissantes100-800 mg

Doses croissantes400-800 mg + anti-émetiqueTraitement

2 4

(Godofsky et al., DDW 2004)

R1626 (Roche)

(Roberts et al, AASLD 2006)(Roberts et al, AASLD 2006)

PlaceboPlacebo

500 mg x 2/j500 mg x 2/j

1500 mg x 2/j1500 mg x 2/j

3000 mg x 2/j3000 mg x 2/j

4500 mg x 2/j4500 mg x 2/j

TreatmentTreatment F-UF-U

DaysDays

00 55 1010 1515 2020 2525 3030

HC

V R

NA

HC

V R

NA

-5-5

-4-4

-3-3

-2-2

-1-1

00

11

-2,6 log-2,6 log1010

-3,7 log-3,7 log1010

-1,2 log-1,2 log1010

HCV 796 (Wyeth)

(Chandra et al, DDW 2006)(Chandra et al, DDW 2006)

--11 22 55 88 1111 1144 1177 2200 2233 2266 2299--33

--22

--11

00

11

PPllaacceebboo5500 mmgg110000 mmgg225500 mmgg550000 mmgg11000000 mmgg11550000 mmgg

DaysDays

HC

V R

NA

HC

V R

NA

TreatmentTreatment F-UF-U

PegIFN-Ribavirine-VX 950

0

1

2

3

4

5

6

7

8

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

HC

V R

NA

(L

og

10 I

U/m

L)

Study Time (in Days)

median

Limit of Quantitation

Limit of Detection

Lawitz et al., DDW 2006Lawitz et al., DDW 2006

SCH 503034 ± IFN PEG a2b 1.5g/kg HCV 1, IFN Non-Responders

-3

-2,5

-2

-1,5

-1

-0,5

0

0 1 2 3 5 7 8 9 10 12 13 Days

HC

V R

NA

Le

vel

s C

han

ge

PEG IFN PEG IFN +200 mg SCH PEG IFN + 400 mg SCH )

MAINTENANCE THERAPY

MAINTENANCE THERAPY

Reduce necro-inflam. Tolerability

Reduce HCC? Cost

Improve survival? Not proven

F3-F4 F1-F2

ALT decrease No ALT decrease

PROS CONS

- The probability of SVR to ReTX depends ontype of non response, previous therapy and characteristics of patients (genotype, cirrhosis)

-Viral eradication is rarely obtained (10%) with pegylated combination in NRs to optimal standard combination

- Viral eradication may be obtained in NRs to sub-optimal combination (correct causes of NR)

TREATMENT OF NON RESPONDERS

- The efficacy of new drugs(anti-protease, anti-polymerase…) remains to be demonstrated. Triple or double TX?- Maintenance therapy is justifiedIn patients with severe liver disease, if it induces a biochemical response (ALT<2N)- Its modalities and the patients who benefit need to be precised

TREATMENT OF NON RESPONDERS

IN PRACTICAL

Non Responder

Non Responder

False non Responder

Non Responder

False non Responder

Cause of non response?

Treat the cause

Non Responder

False non Responder

Cause of non response?

Treat the cause

ReTX

Response

Eradication

Non Responder

False non Responder

Cause of non response?

Treat the cause

ReTX

Response

Maintenance therapy- if F3 or F4- if biochemical response- if tolerance OK

Eradication

Non response

Non Responder

False non Responder True non Responder

Cause of non response?

Treat the cause

ReTX

Response

Maintenance therapy- if F3 or F4- if biochemical response- if tolerance OK

Eradication

Non response

Non Responder

False non Responder True non Responder

Cause of non response?

Treat the cause

ReTX

Response

Maintenance therapy- if F3 or F4- if biochemical response- if tolerance OK

Eradication

Non response

Trial