Optimal therapy in genotype 1 patients

3rd Paris Hepatitis Conference19-20 January 2009

Stefan Zeuzem, MDJ.W. Goethe University Hospital

Frankfurt, Germany

Standard Treatment

Peginterferon alfa-2a/2b + Ribavirin for treatment of chronic hepatitis C

37

61

46

76

0

20

40

60

80

100

IFN + RBV PEG-IFNalfa-2a +

RBV

33

79

42

82

0

20

40

60

80

100

IFN + RBV PEG-IFNalfa-2b +

RBV

HCV-1

HCV-2,3

Su

sta

ine

d vi

rolo

gic

S

ust

ain

ed

viro

log

ic

resp

ons

e (

%)

resp

ons

e (

%)

Manns et al., Lancet 2001;358:958-965

Fried et al., N Engl J Med 2002; 347:975-982

Individualized Dosing Efficacy vs. Flat Dosing to Assess Optimal Pegylated Interferon

Therapy (IDEAL study)

38 40 41

0

10

20

30

40

50

PEG-IFN alfa-2b(1.0 µg/kg)

PEG-IFN alfa-2b(1.5 µg/kg)

PEG-IFN alfa-2a(180 µg)

EASL 2008 (Late-Breaker Abstract)EASL 2008 (Late-Breaker Abstract)

Sus

tain

ed v

irolo

gic

Sus

tain

ed v

irolo

gic

resp

onse

(%

)re

spon

se (

%)

Virologic response in HCV genotype 1 or 4 infected patients

62,3

75,3

49,547,3

54,8

39,8

20,4

0

10

20

30

40

50

60

70

80

90

100

P<0.0003

P=0.04

Overall PEG IFN alfa-2a PEG IFN alfa-2b

ETR SVR REL

P=0.04

Per

cent

age

15.19.7

Ascione et al., EASL 2008Ascione et al., EASL 2008

62.362.3

47.347.3

75.375.3

54.854.8

20.420.4

49.549.5

39.839.8

Milan Safety Tolerability (MIST) Study

Rumi, Colombo et al, AASLD 2008, A212

p = 0.02 p = 0.02 p = 0.01 p = 0.8

48%

96%

65%

54%

32%

82%

69%66%

0%

20%

40%

60%

80%

100%

Overa

ll SVR

SVR G1/

4

SVR G2

SVR G3

Sus

tain

ed v

irolo

gic

resp

onse

rat

es

PEG alfa-2a

PEG alfa-2b

Retrospective analysis of patients treated with either peginterferon alfa-2a or alfa-2b

(PRACTICE study)

0102030405060708090

100

all GT (N=1672) HCV-1 (N=1108) HCV-2,3 (N=544)

alfa-2a

alfa-2b

Witthöft et al., EASL 2008

Sus

tain

ed v

irolo

gic

rela

pse

rate

(%

)

54.4%

59.1%

43.7%

76.8%

49.6%

78.3%

P=0.05

Optimization of Standard Treatment

*Logit scale5.6 log10 IU/mL ~400 x103 IU/mL

Effect of pre-tx HCV RNA on SVR

Pro

bab

ility

of

SV

R*

Baseline HCV RNA (log10 IU/ml)

3 4 6 75

0.5

0.88

0.98

0.9985.6 log10 IU/mL

0

10

23

0 0 00

17

40

0

10

20

30

40

50

4 8 12

Re

lap

se r

ate

(%

)

Baseline viremia > 800.000 IU/mL

All patients

Baseline viremia ≤ 800.000 IU/mL

Time to HCV RNA < 5.3 IU/mL by TMA in weeks

Relation between the dynamics of virologic response and relapse prediction in patients

receiving PEG-IFN / RBV x 48 weeks (n=225)

Berg et al., AASLD 2007 (179A)Berg et al., AASLD 2007 (179A)

Individualisation according to HCV genotype:

Shorter treatment in HCV-1?

Virologic response in patients with HCV-1 and HCV RNA < 600,000 IU/mL

0

10

20

30

40

50

60

70

80

90

All patients Week 4 Week 12 Week 24/EOT

SVR

Relapse

Time to first negative HCV RNAPEG-IFN -2b + RBVZeuzem et al., J Hepatol 2006

Pat

ient

s (%

)

(47%) (26%) (10%)

50%

37%

89%

25%17%

8%

75%80%

Early identification of HCV 1 patients responding to 24 wks PEG-IFN alfa-2a/RBV

89 88

73

91

1623

3544

0

20

40

60

80

100

HCV RNA < 50IU/mL at week 4

HCV RNA > 50IU/mL at week 4

24-LD

24-SD

48-LD

48-SD

Jensen et al., Jensen et al., HepatologyHepatology 2006;43:954-60

Sus

tain

ed v

irolo

gic

Sus

tain

ed v

irolo

gic

resp

onse

(%

)re

spon

se (

%)

18 33 40 55 81 84 208 210

Rates of relapse and SVR according to RVR and baseline viral load

3,60

96,4100

50,8

16,7

44,4

71,4

0102030405060708090

100

Relapse SVR Relapse SVR

24 wk tx

48 wk tx

Yu et al., Hepatology 2008; 47:1884-1893

LVL and RVRLVL and RVR HVL or non-RVRHVL or non-RVR

Res

pons

e (%

)R

espo

nse

(%)

Individualisation according to HCV genotype:

Longer treatment in HCV-1 ?

Extended treatment duration for HCV 1: 48 vs 72 weeks of PEG-IFN alfa-2a + RBV

80 76

17

29

0

10

20

30

40

50

60

70

80

HCV RNA < 50 IU/mL at week 12

HCV RNA ≥ 50 IU/mL at week 12

48 wks

72 wks

Sus

tain

ed v

irolo

gic

resp

onse

rat

e (%

)

Berg, et al. Gastroenterology 2006;130:1086-1097

104/130 90/119 17/100 31/106

P=0.040

Virologic relapse rates in patients with slow virologic response

37

23

64

40

0

10

20

30

40

50

60

70

> 50 IU/mL > 50 IU/mL

48 wks

72 wks

Berg, et al. Gastroenterology 2006;130:1086-1097

Viro

logi

c re

laps

e ra

te (

%)

Week 4 Week 12

30/47 21/5246/124 28/122

P=0.016 P=0.021

Peginterferon alfa-2a plus ribavirin for 48 vs. 72 weeks in patients with detectable

HCV RNA at week 4 of treatment

0

10

20

30

40

50

60

HCV-1 HCV-1 / <800,000 IU/mL

HCV-1 / >800,000 IU/mL

48 wks

72 wks

Sanchez-Tapias et al., Gastroenterology 2006;131:451-460

Sus

tain

ed v

irolo

gic

resp

onse

rat

e (%

)

28%

44%

27% 28%

51%

37%

P=0.003 P=0.002 P=0.35

Peginterferon alfa-2a plus ribavirin for 48 vs. 72 weeks in patients with detectable

HCV RNA at week 4 of treatment

0

10

20

30

40

50

60

HCV-1 HCV-1 / <800,000 IU/mL

HCV-1 / >800,000 IU/mL

48 wks

72 wks

Sanchez-Tapias et al., Gastroenterology 2006;131:451-460

Viro

logi

c re

laps

e ra

te (

%)

17%

53%

27%23%

55%50%

P=0.002 P=0.007 P=0.15

Viral kinetics: tailoring of therapyin HCV genotype 1 infected patients

HCV-1 (LVL, RVR) 24 weeksZeuzem et al. 2004; Zeuzem et al. 2005; Jensen et al. 2006

HCV-1 (cEVR) 48 weeksManns et al. 2002; Hadziyannis et al. 2004; Kamal et al. 2005

HCV-1 (SPR) 72 weeksButi et al. 2003; Berg et al. 2006; Sanchez-Tapias et al. 2006

Treatment of „Difficult-to-cure“ Patients

28%33%

36%32%

36%

47%

0%

10%

20%

30%

40%

50%

60%

70%

80%

NV15801 (Fried) NV15492(Hadziyannis)

NV17318

PEG-IFN alfa-2a 180 ug + RBV 1200 mg PEG-IFN alfa-2a 180 ug + RBV 1600 mgPEG-IFN alfa-2a 270 ug + RBV 1200 mg PEG-IFN alfa-2a 270 ug + RBV 1600 mg

Virologic Response in G1, HVL, > 85 kg patients

% P

ati

en

ts w

ith

VR

VR = HCV RNA < 50 copies/mL

Arm A (n=46)

Arm B, C,& D (n=47)

Fried et al., AASLD 2006

(n=66) (n=53)

SVR and anemia as functions of exposure AUC – HCV genotype 1

n = 242, Snoeck et al, Br J Clin Pharm 2006

Weight-based exposure of ribavirin and treatment response

46,4 48

22,5 25

7,1 5,9

48,4 50

72,167,7

86,782,1

0

10

20

30

40

50

60

70

80

90

24 wk tx 48 wk tx 24 wk tx 48 wk tx

<13.3 mg/kg/day

13.3-15.2 mg/kg/day

>15.2 mg/kg/day

Yu et al., Hepatology 2008; 47:1884-1893

Tre

atm

ent r

espo

nse

(%)

Tre

atm

ent r

espo

nse

(%)

RelapseRelapse SVRSVR

Case: HCV1, HVL, cirrhosis

5/06 Standard therapy

8/06 < 2 log decline (Hb 12.8)

9/06 High dose (270 µg PEG-IFN alfa-2a + 1600 mg RBV)

12/06 > 2 log decline (RBV 2000 mg)

3/07 HCV RNA negative

9/08 18 months therapy with HD + EPO

1/09 HCV RNA still negative (4 mo post-tx)

Conclusions

• Individualisation of treatment duration (24 – 72 weeks)

• Maintaining drug doses, subtle dose reductions when necessary

• Compliance and adherence very important• Successful treatment also possible in „difficult-to-

treat“ populations • Future options: small molecules (2011/12)

which influence treatment indications today