Maria Buti

Hospital General Universitario Vall Hebron

Barcelona-. Spain

Relapser or Non Responder?Chronic Hepatitis C

•36 years old male

•Blood transfusion in the infancy

•No diseases, no alcohol, no iv drugs

•Diagnosed with Hepatitis C 22 years ago by ALT

elevation in a routine check up

Relapser or Non Responder?Chronic Hepatitis C

In 1997, he was treated with Interferon 3 MU/ for 48 week

without response

In 2002 was referred to our hospital

Asymptomatic

Physical Examination Normal, Weight 89 kg, Height 1,75

ALT 44 UI/ml, Hb 17% gr>/dl, no hypergammaglobulinemia

Genotype 1

• Abdominal US : Normal

•Liver biopsy: Chronic Active Hepatitis, Metavir F3

• May 2002 PegInterferon alfa 2b 1.5 1.5 g/kg/ week g/kg/ week and

ribavirin 1,200 mg for 48 weeks

• HCV-RNA undetectable at the end of treatment and

relapse in the follow-up

• Follow-up Elevated ALT, HCV RNA positive

• Evaluation and Inclusion in the EPIC 3 study

HCV RNA negative at week 12HCV RNA negative at week 12Subject continueSubject continue

for additional 36 weeks for additional 36 weeks + 24 weeks follow-up+ 24 weeks follow-up

EPIC3 Program DesignNon-Responder TrialNon-Responder Trial: N=2200: N=2200

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

PEG-INTRON® 1.5 PEG-INTRON® 1.5 g/kg/wk + REBETOLg/kg/wk + REBETOL®® 800-1400mg/d 800-1400mg/d

Evaluation of virological response at week 12Evaluation of virological response at week 12N=3136 screened*, 1843 treated*N=3136 screened*, 1843 treated*

Chronic Suppression for Chronic Suppression for Non-Cirrhotics, n=700Non-Cirrhotics, n=700

HCV RNA positive at week 12HCV RNA positive at week 12METAVIR F2 or F3 subjects METAVIR F2 or F3 subjects

PEG-INTRON® 0.5PEG-INTRON® 0.5g/kg/wk vs. controlg/kg/wk vs. controlDuration: 3 yearsDuration: 3 years

Chronic Suppression Chronic Suppression for Cirrhotics, for Cirrhotics, n=1000n=1000

HCV RNA positive at week 12METAVIR F4 subjects

PEG-INTRON® 0.5g/kg/wk vs. controlMax duration: 5 years

*

METAVIR F4 CHC subjects Non-responder to any

IFN alfa/alpha + Ribavirin DIRECT ENROLLERS

March 2005 started PegIntron 1.5 mg/kg /week and

Ribavirin 1,200 mg/day

ALT 43 UI/ml, Hb 17.4 mg/dl, 6.400 mm leukocytes 262.000

platelets, HCV RNA 218.032 UI/ml

Week 12: ALT 24 UI/ml, Hb 14.5 mg/dl, 4.400 leukocytes,

204.000 platelets, HCV-RNA 1.520 UI/ml

HCV RNA negative at week 12HCV RNA negative at week 12Subject continueSubject continue

for additional 36 weeks for additional 36 weeks + 24 weeks follow-up+ 24 weeks follow-up

EPIC3 Program DesignNon-Responder TrialNon-Responder Trial: N=2200: N=2200

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

PEG-INTRON® 1.5 PEG-INTRON® 1.5 g/kg/wk + REBETOLg/kg/wk + REBETOL®® 800-1400mg/d 800-1400mg/d

Evaluation of virological response at week 12Evaluation of virological response at week 12N=3136 screened*, 1843 treated*N=3136 screened*, 1843 treated*

Chronic Suppression for Chronic Suppression for Non-Cirrhotics, n=700Non-Cirrhotics, n=700

HCV RNA positive at week 12HCV RNA positive at week 12METAVIR F2 or F3 subjects METAVIR F2 or F3 subjects

PEG-INTRON® 0.5PEG-INTRON® 0.5g/kg/wk vs. controlg/kg/wk vs. controlDuration: 3 yearsDuration: 3 years

Chronic Suppression Chronic Suppression for Cirrhotics, for Cirrhotics, n=1000n=1000

HCV RNA positive at week 12METAVIR F4 subjects

PEG-INTRON® 0.5g/kg/wk vs. controlMax duration: 5 years

*

METAVIR F4 CHC subjects Non-responder to any

IFN alfa/alpha + Ribavirin DIRECT ENROLLERS

July 2005 He started maintenance therapy with

PegIntron 0.5 0.5 g/kg/week for 3 yearsg/kg/week for 3 years

ALT 43-51 UI/ml, Hb 16.5-17.4 mg/dl, HCV RNA 18.032-

66.000 UI/ml. Excellent tolerance

June 2008 stop maintenance therapy

ALT 33 UI/ml, HCV-RNA 66.000UI/ml

US: Normal

Liver biopsy: improvement of the inflammatory activity

and F2

Non Responder to Interferon

Relapser to PegInterferon and Ribavirin

Non Responder to Maintenance therapyNon Responder to Maintenance therapy

Lost of follow-upLost of follow-up

Nov 2011 he return to our out patients clinicNov 2011 he return to our out patients clinic

He would like to be treated with a Protease inhibitorHe would like to be treated with a Protease inhibitor

AsymptomaticAsymptomatic

Hb 17.3, ALT 41 UI/ml, HCV-RNA 7x10Hb 17.3, ALT 41 UI/ml, HCV-RNA 7x1055 UI/mL UI/mLGenotype 1Genotype 1

1. Relapser

2. Partial Responder

3. True Non-responder

He is a previously treated patient Type of Response and SVR with PI?

What SVR rates were seen with telaprevir in REALIZE according to prior response type?

SV

R (

%)

Prior relapsers Prior partialresponders

Prior null responders

**

**

**

Telaprevir EU SmPC

*p<0.001 vs PR48SVR, considered virologic cure, was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used

PR48

4/27

T12/PR48

30/49

LI T12/PR48

27/48n/N=

PR48

2/37

T12/PR48

22/72

LI T12/PR48

25/75

PR48

15/68

T12/PR48

122/145

LI T12/PR48

124/141

29

6975

7

40

52

0

20

40

60

80

100

PR48

2/29

BOC44/PR48

SV

R (

%)

Prior relapsers Prior partialresponders

BOCRGT

PR48

15/51

BOC RGT

72/105

Boceprevir EU SmPC

What SVR rates were seen with boceprevir in RESPOND-2 and Provide studies?

SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow-up Week 24. If there was no such value, the follow-up Week 12 value was carried forward

BOC44/PR48

Prior Nullresponders

36

1. Liver biopsy or Fibroscan

2. IL28b

3. HCV Subtype

Management of Patient?

Prior relapsers

Prior partial responders

Prior null responders

53/62n/N= 2/1512/38 145/167 10/180/53/17 36/47 16/380/91/5 11/32

No, minimal or portal fibrosis

CirrhosisStage

Pbo/PR48

Pooled T12/PR48

SV

R (

%)

48/571/15 1/18 24/59 1/10 7/50

Bridgingfibrosis

No, minimal or portal fibrosis

CirrhosisBridgingfibrosis

No, minimal or portal fibrosis

CirrhosisBridgingfibrosis

How effective was telaprevir in patients with bridging fibrosis or cirrhosis?

http://www.fda.gov/downloads/AdvisoryCommittees/Committees/MeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf

SVR was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used

SVR by IL-28B Polymorphism

50

17

46

5561

79727377

0

10

20

30

40

50

60

70

80

90

100

CC CT TT

PR48 BOC RGT BOC/PR48

% S

VR

613

2228

1722

529

3862

4866

510

611

1318

*~80% eligible for short duration therapy

*

1. Lead-in phase and then Triple therapy with BOC

2. Lead-in-phase and then Triple therapy with TVR

3. Triple therapy with TVR

He likes to be treatedWhat is the best strategy?

25

7379

0

20

40

60

80

100

SVR by Week 4 PR Lead-In Response

Poorly Responsive to IFN<1 log10 viral load decline at

treatment week 4

Responsive to IFN≥1 log10 viral load decline at

treatment week 4

0

33 34

0

20

40

60

80

100

012

1546

1544

1767

80110

90114

SV

R (

%)

PR 48 BOC RGT BOC/PR48 PR 48 BOC RGT BOC/PR48

REALIZE (telaprevir): SVR by Week 4 response according to prior response category (LI T12PR48 arm)

137/168n/N=

Foster GR, et al. J Hepatol 2011;54(Suppl. 1):S3

100

80

60

40

20

0

82

SV

R

(%)

<1 log10 HCV RNA reduction after 4-week Peg-IFN/RBV lead-in phase

≥1 log10 HCV RNA reduction after 4-week Peg-IFN/RBV lead-in phase

OverallPrior

relapsers

62

8/13

Prior partial responders

56

10/18

Prior null responders

15

6/41

10%10% 40%40% 59%59%

Proportion of patients in each category with <1 log10 HCV RNA reduction

SVR was defined as undetectable HCV RNA 24 weeks after last planned dose

1. Assess drug-drug interactions

2. Abdominal US

Anything else before treatment?

1. Assess drug-drug interaction

2. Abdominal US

- Tumor 3 cm diameter in lobule right of the liver

suggestive of HCC

Anything else before treatment?

1. Importance of define the type of previous

response

2. Appropriate pre-treatment evaluation

3. Discuss the usefulness of the predictive factors

4. Role of lead-in phase

5. Always exclude HCC

Summary