Predictors of response with boceprevir and telaprevir combined with pegylated interferon and...
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Predictors of response with boceprevir and telaprevir combined with pegylated
interferon and ribavirin
Paul Y Kwo, MDProfessor of Medicine
Medical Director, Liver TransplantationGastroenterology/Hepatology DivisionIndiana University School of Medicine
975 W. Walnut, IB 327Indianapolis, IN 46202-5121
phone 317-274-3090fax 317-274-3106
Factors Predictive of Response to IFN/RBV based therapy
1995-2000• Genotype 2/3
• No advanced fibrosis
• Low viral load
• Younger age
• <40 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. 2009;361(6):580-593. Manns MP, et al. Lancet. 2001;358(9286):958-965.Patton HM, et al. J Hepatol. 2004;40(3):484-490. Poynard T, et al. Lancet. 1998;352(9138):1426-1432.
2011-present• Race/ethnicity
• low viral load
• absence of cirrhosis
• statin use
• IIL-28B
• Genotype 1a/1b
• On treatment viral response
Lead-in
eRVR
Pre-treatment predictors of responseTelaprevir based therapy
3
Significantly Higher SVR rates in Telaprevir-Treated Patients Compared to Peg
IFN/Ribavirin Alone
SVRSVR
7575
4444
P<0.0001
271/363271/363 158/361158/361n/N =n/N =
Per
cen
t o
f p
atie
nts
w
ith
SV
RP
erce
nt
of
pat
ien
ts
wit
h S
VR
0
10
20
30
40
50
60
70
80
90
100
T12PRT12PR PRPR
Jacobson IM, et al. NEJM 2011
100%
0 %
50%
Race
75
62(16/26)
46
25(7/28)
Pat
ien
ts A
chie
vin
g S
VR
(%
)
75%
25%
White Black
Jacobson NEJM 2011
ADVANCE Study: Influence of race on SVR with PegIFN/RBV
±Telaprevir
RaceWhite Black
PR+TVR PR
Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011;
100%
0 %
50%
83
70
Age
52
Pat
ien
ts A
chie
vin
g S
VR
(%
)
75%
25%
< 45 ≥ 45<65
ADVANCE Study: Role of Age on SVR with PegIFN/RBV
±Telaprevir
Age
38
PR+TVR PR
< 45 ≥ 45<65
Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011;
100%
0 %
50%
78
74
HCV RNA
70
Pat
ien
ts A
chie
vin
g S
VR
(%
)
75%
25%
< 800,000 ≥ 800,000
ADVANCE Study: Role of viral level on SVR with PegIFN/RBV
±Telaprevir
HCV RNA < 800,000 ≥ 800,000
36
PR+TVR PR
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
8
Journal of Medical Virology 81:2029–2035 (2009)Journal of Medical Virology 83:437–444 (2011)Science, 2000
Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011;
100%
0 %
50%
Genotype
79
71
48
41
Pat
ien
ts A
chie
vin
g S
VR
(%
)
75%
25%
1b 1a
ADVANCE Study: Influence HCV Genotype on SVR with
PegIFN/RBV ±Telaprevir
Genotype1b 1a
PR+TVR
PR
Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011;
100%
0 %
50%
8175
FibrosisF0-F1 F2 F3 F4
62
46
33(7/21)
48
Pat
ien
ts A
chie
vin
g S
VR
(%
)
75%
25%
ADVANCE Study: Influence of hepatic fibrosis on SVR with
PegIFN/RBV ±Telaprevir
62(13/21)
33
PR+TVR PR
FibrosisF0-F1 F2 F3 F4
Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011;
100%
0 %
50%
90
71
IL-28BCC CT TT
73
Pat
ien
ts A
chie
vin
g S
VR
(%
)
75%
25%
ADVANCE Study: Role of IL28B on SVR with PegIFN/RBV ±Telaprevir
PR+TVRPR
64
2523
42% (454 of 1088) of patients available for IL28B analysis; all patients were whiteTVR increased SVR rates across IL28B genotypes, but CC still did better
IL-28BCC CT TT
On treatment response predicts SVR with Telaprevir based therapy
12
ADVANCE/ILLUMINATE: Anemia and Ribavirin dose reduction did not predict SVR in Telaprevir arms
Anemia No AnemiaRBV Dose Reduction
No RBV Dose Reduction
145/196
116/165
247/344
44/92
206/265
173/255
164/534
135/262
135/172
106/148
241/300
37/48
226/293
163/272
434/545
117/245n/N = n/N =
Anemia :Hgb < 10 g /dl
SVR Rates According to Maximum Hemoglobin Decrease from Baseline
0
10
20
30
40
50
60
70
80
90
100
0/60/6 244/321244/321
4242
7676
6262
4747
Pat
ien
ts
wit
h S
VR
(%
)P
atie
nts
w
ith
SV
R (
%)
T12PRT12PR
n/N =n/N =
7676
4242 4343 4646
8/198/19 211/275211/275
7777
25252929
00
PRPR
53/8653/86 135/178135/178
1/41/4 35/7435/74
4/144/14 42/9242/92
27/6527/65 45/10545/105
≤ 1≤ 1 > 1-2> 1-2 > 2-3> 2-3 > 3-4> 3-4 > 4-5> 4-5 > 5 g/dL> 5 g/dL
Achieving extended RVR Associated with SVR
189/212189/212 28/2928/29 130/332130/33282/15182/151
89899797
5454
3939
eRVR+eRVR+ eRVR- eRVR-
n/N =n/N =
Per
cen
t of
pat
ien
ts w
ith
SV
RP
erce
nt
of p
atie
nts
wit
h S
VR
0
10
20
30
40
50
60
70
80
90
100
(All patients received48 weeks regimen)
(TVR patients received a 24 weeks regimen)
T12PRT12PR PRPR
23
4253
14 12 17
0
20
40
60
80
100
48 P/R BOC RGT BOC/PR48
Per
cen
t
SPRINT 2: SVR* and Relapse Rates
40
67 68
239 8
0
20
40
60
80
100
48 P/R BOC RGT BOC/PR48
Per
cen
t
p < 0.0001
p <0.0001
Non-Black Patients
p = 0.044
p =0.004
Black Patients
SVR
Relapse Rate
*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.
125311
211316
213311
1252
2252
2955
37162 21
23218
2302
143
25
635
Pre-treatment predictors of responseBoceprevir based therapy
17
Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011;
100%
0 %
50%
68
53(29/55)
67
42(22/52)
Pat
ien
ts A
chie
vin
g S
VR
(%
)
75%
25%
SPRINT 2 : Influence of Race on SVR with PegIFN/RBV
±Boceprevir
PR+BOC PR+ BOC RGT PR
40
23(12/52)
Race
White Black White Black White Black
Race Race
Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011;
100%
0 %
50%
69 65 73 64
Pat
ien
ts A
chie
vin
g S
VR
(%
)
75%
25%
SPRINT 2 : Influence of Age on SVR with PegIFN/RBV
±Boceprevir
PR+BOC PR+ BOC RGT PR
52
34
Age
< 40 >40 < 40 >40 < 40 >40
AgeAge
Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011;
100%
0 %
50%
85
63
76
61
Pat
ien
ts A
chie
vin
g S
VR
(%
)
75%
25%
SPRINT 2 : Influence of Viral Level on SVR with
PegIFN/RBV ±Boceprevir
PR+BOC PR+ BOC RGT PR
64
33
HCV RNA < 800,000 ≥ 800,000
HCV RNA < 800,000 ≥ 800,000
HCV RNA < 800,000 ≥ 800,000
Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011;
100%
0 %
50%
Genotype
70
6366
59
Pat
ien
ts A
chie
vin
g S
VR
(%
)
75%
25%
1b 1a
SPRINT 2 : Influence of HCV Genotype on SVR with
PegIFN/RBV ±Boceprevir
Genotype1b 1a
PR+BOC PR+ BOC RGT
Genotype
1b 1a
PR
40 35
Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011;
100%
0 %
50%
67
52(22/42)
67
4114/34)
Pat
ien
ts A
chie
vin
g S
VR
(%
)
75%
25%
SPRINT 2 : Influence of Fibrosis on SVR with
PegIFN/RBV ±Boceprevir
PR+BOC PR+ BOC RGT PR
38
38(9/34)
Fibrosis F0-F2 F3-F4
Fibrosis F0-F2 F3-F4
Fibrosis F0-F2 F3-F4
Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters presented at: EASL: The International Liver Congress 2011;
100%
0 %
50%
67
42(10/24)
66
31(5/16)
Pat
ien
ts A
chie
vin
g S
VR
(%
)
75%
25%
SPRINT 2 : Influence of Cirrhosis SVR with PegIFN/RBV
±Boceprevir
PR+BOC PR+ BOC RGT PR
37
46(6/13)
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;
100%
0 %
50%
86(6/7)
6667
(6/9) 63
Pat
ien
ts A
chie
vin
g S
VR
(%
)
75%
25%
SPRINT 2 : Influence of Statin use on SVR with PegIFN/RBV ±Boceprevir
PR+BOC PR+ BOC RGT PR100(3/3)
37
Statin user non-statin user Statin user non-statin user Statin user non-statin user
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
25Pandya Gastro 2011Hepatology. 2009 Jul;50(1):6-16.
SPRINT-2: SVR by IL28B Polymorphism%
SV
R
5064
6377
4455
33116
67103
82115
1037
2342
2644
*~90% eligible for short duration therapy
*
62% of individuals (653/1048) had consented to IL28 pharmacogenomic studies
On treatment response predicts SVR with Boceprevir based therapy
27
SVR by Week 4 PR Lead-In Response
52
82 82
5
2939
0
20
40
60
80
100
48 P/R BOC RGT BOC/PR48
Non-Black Patients Black Patients
≥1 log 10 HCV RNA decline from baseline
<1 log 10 HCV RNA decline from baseline
46
6761
0
2531
0
20
40
60
80
100
48 P/R BOC RGT BOC/PR48
SV
R (
%)
SV
R (
%)
121234
187228
178218
1226
1624 22
36
362
2173
3179
624
516
021
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) < 0.0001
BOC/RGT vs PR48 6.0 (3.5, 10.2) < 0.0001
Baseline HCV-RNA: ≤400,000 vs. >400,000 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) < 0.0001
Genotype: 1b/others vs 1a 2.3 (1.5, 3.6) < 0.001
BMI: 25-30 kg/m2 vs. >30 kg/m2 2.3 (1.4, 3.9) 0.002
BMI: ≤25 kg/m2 vs. >30 kg/m2 1.9 (1.1, 3.3) 0.02
Only covariates remaining significant at α=0.05 after adjustment for the other variables were retained in the model as shown in the table. Only covariates remaining significant at α=0.05 after adjustment for the other variables were retained in the model as shown in the table.
Anemia on treatment was identified as a significant factor for attaining SVR (P<0.001)
SVR by Absence/Presence of Anemia
Sulkowski M, et al. EASL 2011, Abst. 476.
SV
R (
%)
Hb≥10g/dL
Hb<10g/dL
Hb≥10g/dL
Hb<10g/dL
PR48 BOC/PR
SPRINT-2
77246
80109
212363
263362
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
31