Overcome the challenges maximize success

Response-guided therapy: achieving new heights

Ming-Lung Yu Kaohsiung Medical University Kaohsiung Taiwan

Overcome the challenges, maximize success

TREATMENT OPTIMIZATION
Identify and manage factors of poor response
(Prior non response, G1 HVL, metabolic syndrome, insulin resistance, alcohol abuse, psychosocial issues)

Prior to therapy
Educate: medical staff and patients New perspectives on overcoming the challenges Patrick Marcellin Hpital Beaujon, France

Response-guided therapy: achieving new heights Ming-Lung Yu Kaohsiung Medical University, Taiwan

During therapy
PEGASYS and ribavirin: a successful partnership K Rajender Reddy University of Pennsylvania, USA

A fixed treatment duration is not always appropriate

The probability of SVR increases with the speed of viral load decline 7 6 log HCV RNA 5 4 3 2 Treatment duration

1
0 Time

A fixed treatment duration is not always appropriate

The probability of SVR increases with the speed of viral load decline 7 6 log HCV RNA 5 4 3 2
detection limit <50 IU/mL detection limit <10 IU/mL

Treatment duration

undetectable

1
SVR 0 Time

A fixed treatment duration is not always appropriate

The probability of SVR increases with the speed of viral load decline 7 6 Relapse log HCV RNA 5 4 3 2
detection limit <50 IU/mL detection limit <10 IU/mL

Treatment duration

undetectable

undetectable

1
SVR 0 Time

RVR is a more important predictor of SVR than genotype

PEGASYS 180 g/wk plus COPEGUS (n=1383)

Variable RVR vs. no RVR Genotype 2 vs. 1 Genotype 3 vs. 1 Genotype 4 vs. 1

p-value <0.0001 0.1630 0.8420 0.0524

Odds ratio for SVR 7.549 1.276 1.032 2.844

95% CI 5.58910.195 0.9061.798 0.7581.405 0.9898.181

RVR = HCV RNA <50 IU/mL at week 4

Fried M, et al. 18th APASL 2008; Abstract FP024

New definitions of early virological response

Response
RVR* EVR** Complete EVR (cEVR) Partial EVR (pEVR) No RVR, but HCV RNA negative (<50 IU/mL) at week 12 No RVR and HCV RNA positive at week 12, but 2 log10 drop from baseline <2 log10 drop from baseline at week 12

Definition
HCV RNA negative (<50 IU/mL) at week 4

Non-EVR**

* RVR = rapid virological response ** EVR = early virological response

Achieving new heights in genotype 1 patients

High SVR rates in genotype 1 patients with RVR or cEVR

PEGASYS 180 g/wk plus COPEGUS 1000/1200 mg/day for 48 weeks; n=569

SVR: 5%
(5/111)

No EVR 20%
(111/569)

RVR 16%
(90/569)

SVR: 87%
(78/90)

SVR: 27%
(34/128)

pEVR 22%
(128/569)

cEVR 42%
(240/569)

SVR: 68%
(162/240)

Marcellin P, et al. 18th APASL 2008; Abstract FP022

Overall, 24 weeks treatment is as effective as 48 weeks in G1 patients with an RVR

PEGASYS 180 g/wk plus COPEGUS 1000/1200 mg/day 100 90 80 70 60 50 40 30 20 10 0
88%
91%

SVR (%)

n=

33 24 weeks

56 48 weeks

RVR = HCV RNA <50 IU/mL at week 4

Jensen D, et al. Hepatology 2006; 43: 954

Very high SVR rates with 24 weeks therapy in genotype 1 patients with an RVR and LVL
PEGASYS 180 g/wk plus COPEGUS 1000/1200 mg/day 100 90 80 70 60 50 40 30 20 10 0
93% 96% 88% 75%

SVR (%)

n=

27

27 48 weeks

4 24 weeks

24 48 weeks

24 weeks
RVR = HCV RNA <50 IU/mL at week 4 LVL (low viral load) = 800 000 IU/mL HVL (high viral load) = >800 000 IU/mL

LVL

HVL
PEGASYS EU SPC, revised 2007 (based on: Jensen D, et al. Hepatology 2006; 43: 954)

Very high SVR rates with 24 weeks therapy in Taiwanese G1 patients with an RVR and LVL
PEGASYS 180 g/wk plus COPEGUS 1000/1200 mg/day

100 90 80 70 60 50 40
30 20 10 0

96%

100%

SVR (%)

p=1.00

n=

28 24 weeks

24 48 weeks

RVR = HCV RNA <50 IU/mL at week 4 LVL (low viral load) = 400 000 IU/mL

Yu M, et al. 58th AASLD 2007; Abstract 1316

High SVR rates in genotype 1 patients with a cEVR treated for 48 weeks
100 80
65 PEGASYS 180 g/wk plus ribavirin for 48 weeks 77 67 58 73 76 Mean=67%

SVR (%)

60
40 20
n= 77/118
79/118

52
*cEVR = detectable HCV RNA at week 4, but HCV RNA <50 IU/mL at week 12

60/103

61/79

30/58

65/88

38/50

Study 1 2 Ribavirin 1000/1200 dose mg/day

800 mg/day

6 6001000 mg/day

Marcellin P, et al. 42nd EASL 2007; Abstract 613

1. Fried M, et al. N Engl J Med 2002; 347: 975 and Ferenci P, et al. J Hepatol 2005; 43: 425 2. Hadziyannis S, et al. Ann Intern Med 2004; 140: 346 3. Berg T, et al. Gastroenterology 2006; 130: 1086 4. Snchez-Tapias JM, et al. Gastroenterology 2006; 131: 451 5. Bronowicki JP, et al. Gastroenterology 2006; 131: 1040 6. Sakai T, et al. 41st EASL 2006; Abstract 605

Investigating extended treatment duration: study designs

Week
Berg et al.
G1 only RBV 800 mg

12

48
48 weeks 72 weeks

72

RVR SnchezTapias et al.

All genotypes RBV 800 mg 48 weeks 72 weeks

RVR
48 weeks 72 weeks

Ferenci et al.
G1/4 RBV 1000/1200 mg
Randomization

Snchez-Tapias JM, et al. 42nd EASL 2007; Abstract 641

NR

1. Berg T, et al. Gastroenterology 2006; 130: 1086 2. Snchez-Tapias J, et al. Gastroenterology 2006; 131: 451 3. Ferenci P, et al. 57th AASLD 2006; Abstract 390

SVR rates in patients with a cEVR: no consistent improvement with 72 weeks therapy
100 90 80 70 60 50 40 30 20 10 0

87%
75% 70% 61% 52% 78%

48 weeks 72 weeks

SVR (%)

n=

79

87

58

74 RBV

60

46

Berg et al.
RBV 800 mg/day

TeraVic-4
800 mg/day

Ferenci et al.*
RBV 1000/1200 mg/day

Complete EVR = no RVR but HCV RNA <50 IU/mL at week 12 * Includes small number (<10%) of G4 patients Snchez-Tapias JM, et al. APASL 2007; Abstract 0-196

SVR rates in patients with a pEVR: consistent improvement with 72 weeks therapy
100 90 80 70 60 50 40 30 20 10 0 48 weeks 72 weeks 69% 52% 46% 33% 16%
n= 46 46 31 25 25 16

SVR (%)

44%

Berg et al.
RBV 800 mg/day

TeraVic-4
RBV 800 mg/day

Ferenci et al.*
RBV 1000/1200 mg/day

Slow (partial) EVR = no RVR and >2 log10 drop but HCV RNA >50 IU/mL at week 12 * Includes small number (<10%) of G4 patients

Snchez-Tapias JM, et al. APASL 2007; Abstract 0-196

Response-guided therapy: achieving new heights in G1 patients

Those patients with an RVR and LVL can halve their
treatment duration (to 24 weeks) and still preserve efficacy (up to 96% SVR rates)

Patients with a cEVR achieve high SVR rates with 48

weeks therapy

Those with a pEVR have a greater chance of success

with extended treatment duration of 72 weeks (up to 69% SVR rates)

Achieving new heights in genotype 2/3 patients

RVR is a strong predictor of SVR in genotype 2/3 patients

PEGASYS 180 g/wk plus COPEGUS 800 mg/day for 24 weeks: ACCELERATE

SVR: 49%
(108/220)

SVR: 94% RVR, LVL*: 24% No RVR: 34% SVR: 88%

(229/260) (141/150)

SVR: 90%
(370/410)

RVR, HVL**: 42%

*LVL: 800 000 IU/mL **HVL: >800 000 IU/mL

Shiffman M et al. 18th APASL 2008; Abstract FP023

High SVR rates with a shorter treatment duration in G2/3 patients with RVR: ACCELERATE
PEGASYS + COPEGUS 800 mg/day RVR: YES
100% 80% 60% 40% 20%

SVR

67%
(871/1291)

82%

90%

16 weeks 24 weeks

All patients (n=1291) RVR: NO

0% 100% 80% 60% 40% 20% 0%

378/461
SVR

370/410

33%
(420/1291)

16 weeks 24 weeks
49% 27%
55/205 108/220

RVR = HCV RNA <50 IU/mL at week 4

Shiffman M, et al. 57th AASLD 2006; Abstract 340

High SVR rates with a shorter treatment duration in Taiwanese G2 patients achieving an RVR
PEGASYS 180 g/wk plus COPEGUS 1000/1200 mg/day
RVR: YES
100% 80% 60%

SVR

87%
(130/150)

100%
40% 20%

98%

16 weeks 24 weeks

All patients (n=150) RVR: NO

0% 100% 80% 60% 40% 20% 0%

43/43
SVR

85/87

13%
(20/150)

77% 57%

16 weeks 24 weeks

RVR = HCV RNA <50 IU/mL at week 4 G2 = genotype-2

4/7

10/13
Yu M-L, et al. Gut 2007: 56: 553

Very high SVR rates with a shorter treatment duration in G2/3 patients with an RVR and LVL
16 weeks PEGASYS plus COPEGUS 800 mg/day 24 weeks PEGASYS plus COPEGUS 800 mg/day 100 80 90%

95%
84%

92% 78%

88%

SVR (%)

60 40

20
n=123 n=101 0 400 000 IU/mL
Standard analysis

n=43

n=49

n=295 n=260
>800 000 IU/mL

400800 000 IU/mL

Shiffman M, et al. 57th AASLD 2006; Abstract 340

Predictors of non-RVR in G2/3 patients

0.5 1.0 2.0 4.0

Bodyweight >85 kg vs. <65 kg

2.2 (1.53.3, p<0.001)

HCV genotype 3 vs. 2

2.1 (1.62.8, p<0.001)

Histological diagnosis: (bridging fibrosis/cirrhosis vs. minimal fibrosis) Baseline HCV RNA level: >800,000 vs. 400,000 IU/mL) 400,000 to 800,000 vs. <400 000 IU/mL
1.6 (1.02.7, p<0.05) 2.0 (1.52.6, p<0.001) 2.6 (1.93.7, p<0.001)

ALT quotient 2.3 vs. >2.3 x ULN

1.7 (1.32.0, p<0.001) 0.5 1.0 2.0 4.0

Odds ratio (95% CI)

RVR = HCV RNA <50 IU/mL at week 4
Shiffman M, et al. 42nd EASL 2007; Abstract 648

Benefit from intensification of treatment in G2/3 patients without an RVR

NV15942 (Hadziyannis): ITT 100 80 Patients (%)
67 65 67 76

PEGASYS + COPEGUS
24 wk, 800 mg 24 wk, 1000/1200 mg 48 wk, 800 mg 48 wk, 1000/1200 mg

60 40
26 24 13

20 0
n= 21 34 30 37 19 29

4
23 27

SVR
RVR = HCV RNA <50 IU/mL at week 4

Relapse
Willems B, et al. 42nd EASL 2007; Abstract 8

Response-guided therapy: achieving new heights in G2/3 patients

Those patients with an RVR and LVL can have shorter
treatment duration (16 weeks) and still maintain efficacy (up to 90% SVR rates)

Patients with an RVR and HVL achieve high SVR rates

with 24 weeks therapy

Patients without an RVR may benefit from extended

treatment duration of 48 weeks The possibility of improving SVR in non-RVR patients by
intensifying treatment (longer duration/higher RBV dosage) will be explored in two prospective trials (NCORE 2/3 study; NCT00532701 in Taiwan)

PEGASYS response-guided therapy: achieving new heights

On-treatment predictors of response are simple and
reliable tools allowing us to tailor treatment to the individual

With PEGASYS response-guided therapy we can be

confident that we are offering the best treatment solutions for our patients:

High SVR rates for patients who are early responders Shorter duration of therapy as an option for some
rapid responders

Improved SVR rates with extended treatment duration

for partial responders