Predictors of response with boceprevir and telaprevir combined with pegylated interferon and ribavirin

1
Predictors of response with boceprevir and
telaprevir combined with pegylated interferon and
ribavirin
Paul Y Kwo, MD Professor of Medicine Medical
Director, Liver Transplantation Gastroenterology/H
epatology Division Indiana University School of
Medicine 975 W. Walnut, IB 327 Indianapolis, IN
46202-5121 phone [phone] fax [phone] pkw
o_at_iupui.edu
2
Factors Predictive of Response to IFN/RBV based
therapy

• 2011-present
• Race/ethnicity
• low viral load
• absence of cirrhosis
• statin use
• IIL-28B
• Genotype 1a/1b
• On treatment viral response
• Lead-in
• eRVR

• 1995-2000
• Genotype 2/3
• No advanced fibrosis
• Low viral load
• Younger age
• lt40 years
• Female
• Weight

• 2007-2011
• Lack of steatosis/insulin resistance
• Adherence
• Rapid viral response (RVR)
• Ribavirin dosage
• Race/ethnicity
• IL-28B
• Anemia

McHutchison JG, et al. N Engl J Med.
2009361(6)580-593. Manns MP, et al. Lancet.
2001358(9286)958-965. Patton HM, et al. J
Hepatol. 200440(3)484-490. Poynard T, et al.
Lancet. 1998352(9138)1426-1432.
3
Pre-treatment predictors of responseTelaprevir
based therapy
4
Significantly Higher SVR rates in
Telaprevir-Treated Patients Compared to Peg
IFN/Ribavirin Alone
Plt0.0001
100
90
75
80
70
60
Percent of patients with SVR
44
50
40
30
20
10
0
271/363
158/361
n/N
SVR
Jacobson IM, et al. NEJM 2011
5
ADVANCE Study Influence of race on SVR with
PegIFN/RBV Telaprevir
PRTVR
PR
Race
White Black
Jacobson NEJM 2011
6
ADVANCE Study Role of Age on SVR with
PegIFN/RBV Telaprevir
PRTVR
PR
38
Age
lt 45 45lt65
Marcellin P, et al. 451 Dusheiko GM, et al.
415. Posters presented at EASL The
International Liver Congress 2011
7
ADVANCE Study Role of viral level on SVR with
PegIFN/RBV Telaprevir
PRTVR
PR
36
HCV RNA
lt 800,000
800,000
Marcellin P, et al. 451 Dusheiko GM, et al.
415. Posters presented at EASL The
International Liver Congress 2011
8
Role of HCV Genotype

• Evidence that 1a more difficult to treat than 1b
  with PR
• Genotype 1a associated with lower SVR than
  genotypes 1b, 4a, and 4d when treated with PR
  for 48 weeks in 537 patients
• Genotype 1a associated with lower SVR in 115
  patients receiving PR for 48 weeks than 1b
• Initial HCV subgenomic replicons derived from
  genotype 1b virus

Journal of Medical Virology 8120292035
(2009) Journal of Medical Virology 83437444
(2011) Science, 2000
9
ADVANCE Study Influence HCV Genotype on SVR
with PegIFN/RBV Telaprevir
PRTVR
PR
Genotype
1b 1a
Marcellin P, et al. 451 Dusheiko GM, et al.
415. Posters presented at EASL The
International Liver Congress 2011
10
ADVANCE Study Influence of hepatic fibrosis on
SVR with PegIFN/RBV Telaprevir
PRTVR
PR
62 (13/21)
33
Fibrosis F0-F1 F2 F3
F4
Marcellin P, et al. 451 Dusheiko GM, et al.
415. Posters presented at EASL The
International Liver Congress 2011
11
ADVANCE Study Role of IL28B on SVR with
PegIFN/RBV Telaprevir
42 (454 of 1088) of patients available for IL28B
analysis all patients were white TVR increased
SVR rates across IL28B genotypes, but CC still
did better
PRTVR
PR

64
25
23
IL-28B CC CT TT
Marcellin P, et al. 451 Dusheiko GM, et al.
415. Posters presented at EASL The
International Liver Congress 2011
12
On treatment response predicts SVR with
Telaprevir based therapy
13
ADVANCE/ILLUMINATE Anemia and Ribavirin dose
reduction did not predict SVR in Telaprevir arms
Anemia Hgb lt 10 g /dl
135/172 106/148 241/300 37/48 226/293 163/272 434/545 117/245
145/196 116/165 247/344 44/92 206/265 173/255 164/534 135/262
n/N
n/N
Anemia No Anemia RBV Dose Reduction No RBV Dose Reduction
14
SVR Rates According to Maximum Hemoglobin
Decrease from Baseline
1
gt 1-2
gt 2-3
gt 3-4
gt 4-5
gt 5 g/dL
77
76
76
62
47
46
42
43
42
Patients with SVR ()
29
25
0
0/6
244/ 321
8/19
211/ 275
53/86
1/4
35/ 74
4/14
42/ 92
27/65
45/ 105
135/ 178
n/N
T12PR
PR
15
Achieving extended RVR Associated with SVR
97
100
89
90
80
70
54
60
Percent of patients with SVR
50
39
40
30
20
10
0
189/212
28/29
130/332
82/151
n/N
eRVR
eRVR-
(TVR patients received a 24 weeks regimen)
(All patients received 48 weeks regimen)
16
SPRINT 2 SVR and Relapse Rates
SVR
Relapse Rate
p lt0.0001
p 0.004
p lt 0.0001
p 0.044
211 316
213 311
29 55
125 311
22 52
12 52
37 162
6 35
21 232
18 230
2 14
3 25
Non-Black Patients
Black Patients
SVR was defined as undetectable HCV RNA at the
end of the follow-up period. The 12-week
post-treatment HCV RNA level was used if the
24-week post-treatment level was missing (as
specified in the protocol). A sensitivity
analysis was performed counting only patients
with undetectable HCV RNA documented at 24 weeks
post-treatment and the SVR rates for Arms 1, 2
and 3 in Cohort 1 were 39, 66 and 68,
respectively and in Cohort 2 were 21, 42 and
51, respectively.
17
Pre-treatment predictors of responseBoceprevir
based therapy
18
SPRINT 2 Influence of Race on SVR with
PegIFN/RBV Boceprevir
PR BOC RGT
PRBOC
PR
40
23 (12/52)
Race
Race
Race
White Black
White Black
White Black
Marcellin P, et al. 451 Dusheiko GM, et al.
415. Posters presented at EASL The
International Liver Congress 2011
19
SPRINT 2 Influence of Age on SVR with
PegIFN/RBV Boceprevir
PR BOC RGT
PRBOC
PR
52
34
Age
Age
Age
lt 40 gt40 lt 40 gt40
lt 40 gt40
Marcellin P, et al. 451 Dusheiko GM, et al.
415. Posters presented at EASL The
International Liver Congress 2011
20
SPRINT 2 Influence of Viral Level on SVR with
PegIFN/RBV Boceprevir
PRBOC
PR BOC RGT
PR
64
33
HCV RNA
HCV RNA
HCV RNA
lt 800,000
lt 800,000
lt 800,000
800,000
800,000
800,000
Marcellin P, et al. 451 Dusheiko GM, et al.
415. Posters presented at EASL The
International Liver Congress 2011
21
SPRINT 2 Influence of HCV Genotype on SVR
with PegIFN/RBV Boceprevir
PR BOC RGT
PRBOC
PR
40
35
Genotype
Genotype
1b 1a
1b 1a
Marcellin P, et al. 451 Dusheiko GM, et al.
415. Posters presented at EASL The
International Liver Congress 2011
22
SPRINT 2 Influence of Fibrosis on SVR with
PegIFN/RBV Boceprevir
PR BOC RGT
PRBOC
PR
38 (9/34)
38
Fibrosis
Fibrosis
Fibrosis
F0-F2 F3-F4
F0-F2 F3-F4
F0-F2 F3-F4
Marcellin P, et al. 451 Dusheiko GM, et al.
415. Posters presented at EASL The
International Liver Congress 2011
23
SPRINT 2 Influence of Cirrhosis SVR with
PegIFN/RBV Boceprevir
PR BOC RGT
PRBOC
PR
46 (6/13)
37

No Cirrhosis Cirrhosis
No Cirrhosis Cirrhosis
No Cirrhosis Cirrhosis
Marcellin P, et al. 451 Dusheiko GM, et al.
415. Posters presented at EASL The
International Liver Congress 2011
24
SPRINT 2 Influence of Statin use on SVR with
PegIFN/RBV Boceprevir
PR
PRBOC
PR BOC RGT
100 (3/3)
37

Statin user non-statin user
Statin user non-statin user
Statin user non-statin user
Marcellin P, et al. 451 Dusheiko GM, et al.
415. Posters presented at EASL The
International Liver Congress 2011
25
Why would statin use be associated with SVR?

• HCV forms lipoviral particles which represent the
  primary form of HCV within the circulation
• LDL receptor is thought to play a role in the
  receptor binding and endocytosis of the virus
• Antiviral effects of statins have been shown with
  HIV-1 respiratory syncytial virus, and HCV
• Higher SVR rates with PR reported for those
  taking statins
• Statins reduce/delay resistance in combination
  with HCV protease inhibitors
• Significant Drug-Drug interactions occur with
  TVR/BOC w
• and certain statins

Pandya Gastro 2011 Hepatology. 2009
Jul50(1)6-16.
26
SPRINT-2 SVR by IL28B Polymorphism
62 of individuals (653/1048) had consented to
IL28 pharmacogenomic studies
SVR
50 64
63 77
44 55
33 116
67 103
82 115
10 37
23 42
26 44

90 eligible for short duration therapy
27
On treatment response predicts SVR with
Boceprevir based therapy
28
SVR by Week 4 PR Lead-In Response
1 log 10 HCV RNA decline from baseline
lt1 log 10 HCV RNA decline from baseline
178 218
187 228
16 24
22 36
SVR ()
SVR ()
121 234
12 26
31 79
5 16
21 73
6 24
3 62
0 21
Non-Black Patients
Black Patients
29
IL28B is no longer an important predictor of SVR
when Lead-in Response is considered
SPRINT-2 (effect) Odds Ratio (95 CI) p-value
BOC/PR48 vs PR48 7.0 (4.1, 12.0) lt 0.0001
BOC/RGT vs PR48 6.0 (3.5, 10.2) lt 0.0001
Baseline HCV-RNA 400,000 vs. gt400,000 IU/mL 5.8 (1.9, 17.5) 0.002
Log decline in HCV-RNA at TW 4 (continuous variable) 2.6 (2.1, 3.0) lt 0.0001
Genotype 1b/others vs 1a 2.3 (1.5, 3.6) lt 0.001
BMI 25-30 kg/m2 vs. gt30 kg/m2 2.3 (1.4, 3.9) 0.002
BMI 25 kg/m2 vs. gt30 kg/m2 1.9 (1.1, 3.3) 0.02

Only covariates remaining significant at a0.05
after adjustment for the other variables were
retained in the model as shown in the table.
30
Anemia on treatment was identified as a
significant factor for attaining SVR (Plt0.001)

• SVR by Absence/Presence of Anemia

SPRINT-2
PR48
BOC/PR
SVR ()
80 109
263 362
77 246
212 363
Hb 10g/dL
Hb lt10g/dL
Hb 10g/dL
Hb lt10g/dL
Sulkowski M, et al. EASL 2011, Abst. 476.
31
Summary Addition of TVR or BOC to Peg IFN/RBV
improves SVR rates across all treatment groups

• Black race, high baseline HCV RNA, genotype 1a,
  age, cirrhosis all with lower SVR rates
• Anemia, statin use predicts SVR with BOC
• IL-28B
• CC High likelihood of 24-28 weeks of therapy
• CT/TT marked improvement with TVR/BOC addition
• On treatment response remains strongest predictor
  of SVR
• Response to 4 week lead in
• Achieving eRVR