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