Predictors of response with boceprevir and telaprevir combined with pegylated interferon and ribavirin Paul Y Kwo, MD Professor of Medicine Medical Director,

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

[email protected]

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


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


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


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


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


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


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


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


52

34

Age

< 40 >40 < 40 >40 < 40 >40

AgeAge


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


64

33

HCV RNA < 800,000 ≥ 800,000

HCV RNA < 800,000 ≥ 800,000

HCV RNA < 800,000 ≥ 800,000


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


Genotype1b 1a

PR+BOC PR+ BOC RGT

Genotype

1b 1a

PR

40 35


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



38

38(9/34)

Fibrosis F0-F2 F3-F4




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


37

46(6/13)

No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis


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


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


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

Predictors of response with boceprevir and telaprevir combined with pegylated interferon and ribavirin Paul Y Kwo, MD Professor of Medicine Medical Director,

Documents

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advance study

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pegifnrbv telaprevir

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