How to manage G1 relapsers and non-responders

George V. Papatheodoridis, MD

Associate Professor in Medicine & Gastroenterology

2nd Department of Internal Medicine,

Athens University Medical School,

Hippokration General Hospital,

Athens, Greece

Case 1 - AM

01/2008

• Male, 42 y.o., H: 1.75 m, W 77 Kg, BMI 25.1 Kg/m2, no other disease

G1a, HCV RNA 1,200,000 IU/mL, Fibroscan 6.3 (0.9) kPa

• Peg-IFNa-2a (180 μg/wk) + RBV (1.2 g/d) x48 wks

• HCV RNA (-) at 12 & 48 wks, (+) at 72 wks

2009-2011

• No therapy - Transient, mild ALT elevations

12/2011

• HCV RNA 2,200,000 IU/mL, Fibroscan 6.0 (1.0) kPa

Case 1 – AM – Question 1

Would you retreat this patient today?

(BOC/TPV available)

1. No

2. Yes

a. Peg-IFN + RBV

b. Peg-IFN + RBV + BOC/TPV

SV

R (

%)

4-wk PR + 44-wk BOC+PR

All relapsers

48-wk PR 4-wk PR + 32-wk BOC+PR ± 12-wk PR

RESPOND-2: SVR after ΒΟC based therapyin G1 relapsers

Bacon BR et al. ΝΕJM 2011; 364: 1207-17

29

6975

0

20

40

60

80

100

Ν= 51 105 103

33

0

74

43

76

86

FO/F1/F2/F3 Relapsers F4

N= 42 87 81 6 14 14

PROVE 3 / REALIZE: SVR under TPV based therapy in G1 relapsers

0

20

40

60

80

100

SV

R (

%)

McHutchison JG et al. NEJM 2010;362:1292-303. Zeuzem S et al. NEJM 2011;364:2417-28.

12-wk TPV+PR 24-wk TPV+PR 48-wk PR + 12-wk PR + 24-wk PR

6976

20

PROVE 3 trial

8388

24

P < .0001

12-wk TPV+PR 4-wk PR + 48-wk PR + 36-wk PR 12-wk TPV+PR + 32-wk PR

REALIZE trial

P < .0001

REALIZE: SVR in G1 prior relapsers by baseline fibrosis stage

Stage No, minimal or portal Bridging fibrosis Cirrhosis fibrosis

Pa

tie

nts

wit

h S

VR

, %

87 85 84

32

137

0

20

40

60

80

100Pooled T12/PR48 Pbo/PR48

n/N 145/167 12/38 53/62 2/15 48/57 1/15

Pol S et al. Hepatology 2011;54(Suppl. S1): 374A-375A.

Case 1 – AM – Question 2

If you retreat this patient with a triple

combination, do you think that the virological

response during a 4-week lead-in period with

only Peg-IFN+RBV might offer useful information

even in case of TPV based triple therapy?

1. No

2. Yes

REALIZE (telaprevir): SVR by Week 4 on-treatment response according to prior response category

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

n/N =

Foster GR et al. J Hepatol 2011; 54 (Suppl.): S3.

Prior relapsers

8/13

Prior partial responders

10/18

Prior null responders

6/41

Prior relapsers

106/113

Prior partial responders

16/27

Prior null responders

15/28

6256

15

0

20

40

60

80

100 94

5954

P=0.001P=0.001

SVR by Week 4 on-treatment response in the LI T12/PR48 arm in prior relapsers

6760

9289

95

0

20

40

60

80

100

SV

R (

%)

Zeuzem S et al. Hepatology 2011; 54 (Suppl. S1): 986A-987A.

Reduction in HCV RNA at Week 4, log10 IU/mL

0-0.5 0.5-1.0 1.0-1.5 1.5-2.0 >2.00-0.5 0.5-1.0 1.0-1.5 1.5-2.0 >2.0

n/N= 2/3 6/10 11/12 16/18 79/83

Proportions of patients in each group 2% 8% 10% 14% 66%

Proportions of patients in each group 2% 8% 10% 14% 66%

Case 1 – AM – Question 4

Would you retreat this patient with?

1. BOC based triple therapy

2. TPV based triple therapy

3. Any of the above combinations

BOC or TPV in G1 prior relapsers without cirrhosis

Boceprevir, Telaprevir EU SmPC

240 4812 364Weeks

TPV + PR PR

PRif RNA detectable at Week 4 or 12

HCV RNA

Stop treatment at Week 24 if RNA undetectable at Week 4 and 12

If >1000 IU/mL at Week 4 or 12:discontinue all drugs

If detectable at Week 24 or 36:discontinue PR

PRlead-in

BOC + PR PR

0 484 24 3612

If ≥100 IU/mL: If detectable:

Discontinue all drugs

HCV RNA

Weeks

Case 2 - GS 02/2009

• Female, 58 years, H 1.60 m, W 70 Kg, BMI 27.3 Kg/m2, Diabetes

G1b, HCV RNA 2,000,000 IU/mL, Fibroscan 14.3 (1.9)

kPa

• Peg-IFNa-2b (100 μg/wk) +RBV (1.0 g/d)

• HCV RNA 1,200,000 IU/mL at 12 wks – stop treatment

05/2009-12/2011

• Moderate ALT elevations, increased γ-globulin

12/2011

• HCV RNA 1,000,000 IU/mL, Fibroscan 17.5 (2.5) kPa

Would you retreat this patient today?

(BOC/TPV available)

1. No

2. Yes

a. Peg-IFN + RBV

b. Peg-IFN + RBV + BOC/TPV

Case 2 – GS – Question 1

REALIZE: SVR under TPV based therapy in G1 null responders

Zeuzem S et al. NEJM 2011;364:2417-28.

2933

5

0

20

40

60

80

100P

ati

en

ts w

ith

SV

R, %

12-wk TPV+PR 4-wk PR + 48-wk PR + 36-wk PR 12-wk TPV+PR + 32-wk PR

12-wk TPV+PR 4-wk PR + 48-wk PR + 36-wk PR 12-wk TPV+PR + 32-wk PR

P<0.001P<0.001

n/N 21/72 25/37 2/37n/N 21/72 25/37 2/37

REALIZE: SVR in G1 prior null responders by baseline fibrosis stage

Stage No, minimal or portal Bridging fibrosis Cirrhosis fibrosis

Pa

tie

nts

wit

h S

VR

, %

41 42

14

60

10

0

20

40

60

80

100Pooled T12/PR48 Pbo/PR48

n/N 24/59 1/18 16/38 0/9 7/50 1/10

Pol S et al. Hepatology 2011;54(Suppl. S1): 374A-375A.

BOC in G1 null responders to PR

PROVIDE study: prospective, one arm PROVIDE study: prospective, one arm

Patients

Ν= 37 from SPRINT-2 (naive)

N= 11 from RESPOND-2

N= 42 HCV RNA >800.000 IU/ml

N=31 G1a

Duration of PR

discontinuation: 5-112 wks

Patients

Ν= 37 from SPRINT-2 (naive)

N= 11 from RESPOND-2

N= 42 HCV RNA >800.000 IU/ml

N=31 G1a

Duration of PR

discontinuation: 5-112 wks

Vierling J et al. Hepatology 2011; 54 (Suppl. S1): 796A-797A.

4738

16

0

20

40

60

80

100

EOT SVR Relapse

n/N= 20/43 16/42 3/19 n/N= 20/43 16/42 3/19

Pat

ien

ts,

%P

atie

nts

, %

PROVIDE: SVR rates by baseline patient characteristics*

n/m (%) SVR, % (n/N)

MaleFemale

27 (4/15)44 (12/27)

BlackNon-black

27 (3/11)42 (13/31)

Age <50 yearsAge ≥50 years

50 (9/18)29 (7/24)

Weight <75 kgWeight ≥75 kg

25 (4/16)46 (12/26)

Baseline viral load ≤800,000 IU/mLBaseline viral load >800,000 IU/mL

67 (4/6)33 (12/36)

F0/1/2/3†

F4†38 (15/39)

50 (1/2)

Platelets† <200,000Platelets† ≥200,000

0 (0/8)48 (16/33)

ALT normalALT elevated

50 (5/10)34 (11/32)

HCV genotype 1a‡

HCV genotype 1b‡41 (11/27)33 (5/15)

Vierling J et al. Hepatology 2011; 54 (Suppl. S1): 796A-797A.

Case 2 – GS – Question 2

If you retreat this patient with a triple

combination, do you think that the virological

response during a 4-week lead-in period with

only Peg-IFN+RBV might offer useful information

even in case of TPV based triple therapy?

1. No

2. Yes

SVR rates of null responders to PR under BOC+PR in relation to virological response during the lead-in period

Vierling J et al. Hepatology 2011; 54 (Suppl. S1): 796A-797A.

34

50

3831

56

00

20

40

60

80

100Proportions of patients in each group

76% 24% 38% 38% 21% 3%Proportions of patients in each group

76% 24% 38% 38% 21% 3%

<1.0 ≥1.0 <0.5 0.5-<1.0 1.0-<1.5 1.5-2.0 <1.0 ≥1.0 <0.5 0.5-<1.0 1.0-<1.5 1.5-2.0

Reduction in HCV RNA at Week 4, log10 IU/mL

n/N= 11/32 5/10 6/16 5/16 5/9 0/1

SV

R (

%)

REALIZE (telaprevir): SVR by Week 4 on-treatment response according to prior response category

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

n/N =

Foster GR et al. J Hepatol 2011; 54 (Suppl.): S3.

Prior relapsers

8/13

Prior partial responders

10/18

Prior null responders

6/41

Prior relapsers

106/113

Prior partial responders

16/27

Prior null responders

15/28

6256

15

0

20

40

60

80

100 94

5954

P=0.001P=0.001

SVR by Week 4 on-treatment response in the LI T12/PR48 arm in prior null responders

6

20

44

60

80

0

20

40

60

80

100

SV

R (

%)

Zeuzem S et al. Hepatology 2011; 54 (Suppl. S1): 986A-987A.

Reduction in HCV RNA at Week 4, log10 IU/mL

<0.5 0.5-1.0 1.0-1.5 1.5-2.0 >2.0<0.5 0.5-1.0 1.0-1.5 1.5-2.0 >2.0

n/N= 1/16 5/25 8/18 3/5 4/5

Proportions of patients in each group 23% 36% 26% 7% 7%

Proportions of patients in each group 23% 36% 26% 7% 7%

Case 2 – GS – Question 3

Would you retreat this patient with?

1. BOC based triple therapy

2. TPV based triple therapy

3. Any of the above combinations

BOC or TPV in G1 prior null responders

240 4812 364Weeks

TPV + PR PR

HCV RNA If >1000 IU/mL at Wk 4 or 12:discontinue all drugs

If detectable at Wk 24 or 36:discontinue PR

0 484 2412

PRlead-in

BOC + PR

If ≥100 IU/mL If detectable

Discontinue all drugs

HCV RNA

Weeks

Boceprevir, Telaprevir EU SmPC