predictors of treatment response, baseline and on-treatment a case study of telaprevir therapy alex...
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Predictors of treatment response, baseline and on-treatment
A case study of telaprevir therapy
Alex Thompson
Key learning objectives
• Identify the key predictors of treatment response for HCV genotype 1:– peg-IFN + RBV
• IL28B genotype, fibrosis stage, baseline viral load• On-treatment response (RGT)
– DAA – telaprevir• IL28B genotype, fibrosis stage, HCV 1a vs 1b• Past treatment response• Importance of on-treatment response
– eRVR (RGT)– Stopping rules
Mrs CW
• 55-year-old professional woman• Experimental IDU in early 20s• Moderate-heavy alcohol intake 25-50 years
– 40-60 g alcohol/day– Abstinent since diagnosis of HCV 3 years prior
• No symptoms of HCV or CLD
Mrs CW
• Obese (BMI 37)• Hyperlipidaemia• Glucose intolerance• Medication
– Atorvastatin– Fish oil tablets
Mrs CW
What results do you want to know?
Mrs CW• Investigation results:
– FBE – platelets 130– LFTs – albumin 36, ALT 150, BR 6– HCV – 1a – HCV viral load 900,000 IU/mL– IL28B genotype TT– Fasting glucose 6.2, fasting lipids TC 5.6, LDL 3.0– US – echogenic liver c/w fatty infiltration, spleen
at upper limit normal
Mrs CW
• Fibroscan – not possible (body habitus)
• Liver biopsy – cirrhotic
Mrs CW
• What is the likelihood that she will be cured:
– peg-IFN + RBV?
– DAA therapy?
Peg-IFN + RBV
peg-IFN + RBV: SVR rates
0
20
40
60
80
100
8-12%
SVR
(%)
15-20%
38-43%
25-30%
50-60%
Standard IFN
(6 mths)[1]
StandardIFN
(12-18 mths)[2,3]
IFN /RBV
(6-12 mths)[3,4] peg-IFNmonotherapy(6-12 mths)[5,6]
peg-IFN /RBV
(6-12 mths)[6,7]
1. Carithers RL Jr., et al. Hepatology. 1997;26:83S-88S. 2. Zeuzem S, et al. N Engl J Med. 2000;343:1666-1672. 3. Poynard T, et al. Lancet. 1998;352:1426-1432. 4. McHutchison JG, et al. N Engl J Med. 1998;339:1485-1492. 5. Lindsay KL, et al. Hepatology. 2001;34:395-403. 6. Fried MW, et al. N Engl J Med. 2002;347:975-982. 7. Manns MP, et al. Lancet. 2001;358:958-965.
1991 20011995 1998
peg-IFN alfa-2b 1.0 µg/kg/wk +
RBV 800-1400 mg/day
peg-IFN alfa-2a 180 µg/wk +
RBV 1000-1200 mg/day
ITT analysis(n=3070)
IDEAL Study: peg-IFN alfa-2a vs alfa-2b in treatment-naive HCV genotype 1 patients
40% 38% 41%
0
20
40
peg-IFN alfa-2b 1.5 µg/kg/wk +
RBV 800-1400 mg/day
SVR
(%) 60
80
100
McHutchison JG, et al. N Engl J Med. 2009;361:580-593.
0
20
40
60
80
100
Resp
onse
rate
(%)
33
SVR
n=1171
27
69
TT CT CC
peg-IFN and RBV: IL28B-type and fibrosis stage predict for SVR in HCV genotype 1
Thompson, Gastro, 2010
0
20
40
60
80
100
3430
72
TT CT CC0
20
40
60
80
100
22
11
41
TT CT CC
SVR
n=133
SVR
n=988
F0-2 F3-4HCV-1
Marcellin, AASLD, 2007Fried, EASL, 2008
SVR <5%
SVR 29%
SVR 88%
SVR 68%
106
105
104
103
102
10
4 8 12 20 24 48 wks
Likelihood of SVR
HC
V R
NA
(IU
/mL
)
//
0
RVR cEVR
pEVR
2 log10 IU/mLdecline
Undetectable < 50 IU/mL
16 %
42 %22 %
20 %
NR
peg-IFN + RBV: On-treatment virological response predicts SVR in HCV genotype 1
Telaprevir therapy
ADVANCE: Telaprevir + peg-IFN/RBV in HCV-1 treatment-naive patients
Treatment-naive patients with
genotype 1 HCV
(n=1088)
Wk 12
TVR + PR*(n=364)
TVR + PR*(n=363)
PR*(n=361)
eRVR†: PR*
Wk 72Wk 48Wk 8
Follow-up
Follow-up
Follow-up
*TVR 750 mg q8h, peg-IFN alfa-2a 180 µg/wk, weight-based RBV 1000-1200 mg/day. †eRVR: extended rapid virologic response = undetectable HCV RNA at Wks 4 and 12.
Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
Wk 24
PR*
eRVR†: PR*
PR*
Follow-up
Follow-up
p<0.001
SV
R (
%)
0
20
40
60
80
100
PR T12 PR
75
271/363
44
158/361
n/N =
1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Dusheiko GM, et al. EASL 2011. Abstract 1788.
Pooled analysis from ADVANCE and ILLUMINATE[2]
ADVANCE[1]
SV
R (
%)
0
20
40
60
80
100
PR T12 PR
n/N =
NonblackBlack
75
599/804
61
60/99
45
151/333
25
7/28
Telaprevir triple therapy: SVR rates in treatment-naïve genotype 1 patients
Delta = 33%
T12/PR683/903
PR 48166/361n/N =
74–79*
Telaprevir EU SmPC
*p<0.0001 T12/PR vs PR48 (79% versus 46%) in ADVANCE. SVR, 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
Telaprevir triple therapy: SVR rates in treatment-naïve genotype 1 patients*
Predicting response in treatment-naïve patients:1. Baseline:
– Fibrosis stage– IL28B genotype– Other - Genotype 1a vs 1b, HCV viral load, etc.
2. On-treatment:– Extended RVR (eRVR) and response-guided therapy (RGT)– Stopping rules
Telaprevir
*
SVR
(%)
PR 48
140/288n/N=
Telaprevir EU SmPC
T12 PR
237/290
PR 48
18/52
T12 PR
33/52
F0 – F2 F3
SVR, 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
PR 48
8/21
T12 PR
15/21
Cirrhosis
SVR by advanced fibrosis or cirrhosis in patients receiving TVR + peg-IFN/RBV
Direct antiviral therapy & IL28B
23
59
73
25
58
7164
87 90
0102030405060708090
100
PR T8PR T12PR
SVR (%)TT
CT
CC
ADVANCE (telaprevir, treatment-naïve)
n=454/1088 (42%)
Jacobson, EASL, 2011
22 68 5032 76 4526 80 55
Extended RVR (eRVR) = undetectable HCV RNA at Weeks 4 and 12
Patie
nts
with
und
etec
tabl
e H
CV R
NA
(%)
Week 4 (RVR) Weeks 4 and 12 (eRVR)Patients eligible to receive 24 weeks of
treatment in total
PR 48
34/361
T12 PR
635/903
T12 PR
565/903
PR 48
29/361n/N=
Adapted from Sherman KE, et al. CROI 2011. Abstract 957
58 -65%66-72%
Telaprevir: SVR rates by eRVR status
SVR
(%)
PR 48
27/29n/N=
eRVR+ eRVR–
T12 PR
195/212
PR 48
139/332
T12 PR
90/151
24-week regimen48-week regimen
Telaprevir EU SmPCSVR 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
IL28B CC genotype predicts for short duration therapy
ADVANCE – Telaprevir arms, n=293
Jacobson, EASL, 2011
5448
6154
7872
0
10
20
30
40
50
60
70
80
90
RVR eRVR
TT
CT
CC
HCV RNA
undetectable
(%)
Telaprevir: Duration of therapy for treatment-naive patients
• After 12 wks, telaprevir should be discontinued and peg-IFN/RBV continued– Cirrhotic patients with undetectable HCV RNA at Wks 4 and 12 may nevertheless benefit
from additional 36 wks of peg-IFN/RBV (48 wks total) rather than response-guided therapy
Response-Guided Therapy
HCV RNA Triple Therapy:TVR + peg-IFN/RBV
Dual Therapy: peg-IFN/RBV
Total Treatment Duration
Undetectable at Wks 4 and 12 First 12 wks Additional 12 wks 24 wks
Detectable (but ≤1000 IU/mL) at Wks 4 and/or 12
First 12 wks Additional 36 wks 48 wks
Stopping Rules
Time Point Criteria Action
Wk 4 or 12 HCV RNA >1000 IU/mL Discontinue all therapy
Wk 24 HCV RNA detectable Discontinue peg-IFN/RBV
Any Discontinuation of peg-IFN/RBV for any reason Discontinue TVR
Telaprevir [package insert]. 2011.
Mrs CW
• Key issues:– Treatment naïve– Cirrhotic– Poor response IL28B genotype– HCV-1a– High VL– Obese/metabolic syndrome
Mrs CW• OPTIMIZE study: Telaprevir BD
• Well tolerated
• Week 4 HCV RNA = detected <1000
Retrospective analysis of TVR Ph III trials underscores validity of TVR futility rules
• No pt with HCV RNA >1000 IU/mL at Wk 4 (n=25) or Wk 12 (n=12) had SVR
• Viral kinetics analysis of pts with HCV RNA >1000 IU/mL at Wk 4
– 23 of 25 reached HCV RNA nadir before Wk 4
– In most pts, HCV RNA already increasing from nadir by Wk 4
• Emergence of highly TVR-resistant variants in majority of pts with HCV RNA >1000 IU/mL at Wk 4
Jacobson I, et al. EASL 2012. Abstract 55.
HCV NS3/4A variant
Level of TVRresistance
Tx-naive pts with HCV RNA >1000 IU/mL at Wk 4, n (n=14)
Tx-exp’d pts with HCV RNA >1000 IU/mL at Wk 4, n (n=11)
V36M + R155K High 12* 8
A156S/T/V High 1 0
R155K Low 0 2
Wild type None 1 1
*1 patient had R155K present at baseline.
Tx Experienced (n = 11)Tx Naive (n = 14)
Wks on treatment0 2 4 6 8 10 12
10
102
103
104
105
106
107
108
0 2 4 6 8 10 1210
102
103
104
105
106
107
108
HC
V R
NA
, IU
/mL
Wks on treatment
Mrs CW• OPTIMIZE study: Telaprevir BD
• Week 12 HCV RNA = 33– Stopping rule for the study
• Continued on peg-IFN / RBV off-study
• Week 16 HCV RNA = 62,000
• Treatment stopped
Key issues:
Telaprevir – Predicting response in treatment-naïve HCV-1 patients:
1. Baseline predictors of SVR:– Fibrosis stage– IL28B genotype– HCV-1a vs 1b
2. On-treatment response:– eRVR– Week 4, week 12 stopping rules
PR*
REALIZE: Telaprevir + peg-IFN/RBV in HCV-1 treatment-experienced patients
Treatment-experienced patients with
genotype 1 HCV
(n=663)
Wk 12
TVR + PR*(n=264)
TVR + PR*(n=266)
PR*(n=132)
Wk 72Wk 48Wk 4
Follow-up
Follow-up
Follow-up
*TVR 750 mg q8h, peg-IFN alfa-2a 180 µg/wk, weight-based RBV 1000-1200 mg/day. †eRVR: extended rapid virologic response = undetectable HCV RNA at Wks 4 and 12.
Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428
PR*
Follow-up
Follow-up
Wk 16
Telaprevir triple therapy: SVR in prior relapsers,partial responders, null responders
PR 48
4/27
T12/PR 48
30/49
SVR
(%)
Prior relapsers Prior partialresponders
LI T12/PR 48
27/48n/N=
PR 48
2/37
T12/PR 48
22/72
LI T12/PR 48
25/75
PR 48
15/68
T12/PR 48
122/145
LI T12/PR 48
124/141
Prior null responders*
*
**
* *
Telaprevir EU SmPC*p<0.001 vs PR 48. SVR, 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
IL28B genotyping is less useful if IFN-experienced
Relapsers Partial responders Null responders
