stefan zeuzem. what is the optimal treatment of naive patients with chronic hepatitis c ? 2 nd paris...

Stefan ZEUZEM

What is the optimal treatment of naive patients

with chronic hepatitis C ?

2nd Paris Hepatitis Conference Palais des Congrès, Paris, 22-23 January 2007

Stefan ZeuzemJ.W. Goethe University Hospital

Frankfurt, Germany

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

PEG-IFN alfa-2a + RBV (LD vs SD) for treatment of chronic hepatitis C

29

42 41

52

0

20

40

60

80

100

24 wks 48 wks

84 81 79 80

0

20

40

60

80

100

24 wks 48 wks

Su

sta

ine

d vi

rolo

gic

S

ust

ain

ed

viro

log

ic

resp

ons

e (

%)

resp

ons

e (

%)

Hadziyannis et al., Ann Intern Med 2004;40:346-355

HCV-1 HCV-2,3

RBV 800 mg/d RBV 1000-1200 mg/d

HCV genotyping

HCV-1 (4,5,6)HCV RNA quant.

HCV-2,3

Combination treatment800 mg Ribavirin

for 24 weeks

Combination treatment1000-1200 mg Ribavirin

HCV RNA quant. at week 12

< 2log decline 2log declineHCV RNA +

stop treatmentor

continue withPEG-IFN alone

for inhibition of fibrosis

progression

continue txuntil week 24

if HCV RNA -continue tx

until week 48

2log declineHCV RNA -

continue txuntil week 48

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%

Patients with HCV-1 and HCV RNA < 600,000 IU/mL

Investigator HCV-1patients

HCV-1 & LVL

Quantification assay

Data source

Manns et al. 1034 290 (28.1%)

qPCR (NGI) Lancet 2001

Jacobson et al.

2710 989(36.5%)

SP TaqMan SPRI data base

Fried et al. 725 253(34.9%)

Cobas Amplicor HCV Monitor 2.0

NEJM 2002

Hadziyannis et al.

740 267(36.1%)

Cobas Amplicor HCV Monitor 2.0

Ann Intern Med 2004

Total 5209 1799(34.5%)

Zeuzem, Zeuzem, J HepatolJ Hepatol 2006 2006

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

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

GAM analysisEffect of pre-treatment 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


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 rapid virologic response

7

16 1512

0

5

10

15

20

25

30

< 50 IU/mL < 50 IU/mL

48 wks

72 wks


Viro

logi

c re

laps

e ra

te (

%)

Week 4 Week 12

19/123 12/1013/46 5/32

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


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


Shorter treatment in HCV-2 and HCV-3 ?

PEG-IFN-2b + RBV for treatment of chronic HCV-2 and -3 infection (ITT)

0%

20%

40%

60%

80%

100%

all patients 14 wks tx 24 wks tx

SVR

Relapse

NR

Pat

ient

s (%

)

82%

10%14%

90%

56%

26%

Dalgard et al., Hepatology 2004;40:1260-65

4% 0%

19%

End-of-treatment (ETR) and sustained virologic response (SVR)

- HCV genotypes 2 and 3 combined -

0%

20%

40%

60%

80%

100%

Group A Group B Group C

ETR

SVR

Viro

logi

c re

spon

se (

%) 94%

81%

67/71

SVR B vs C: SVR B vs C: PP = 0.003 = 0.003

(16 weeks)(16 weeks) (24 weeks)(24 weeks)

82% 86%

69%

39%

(24 weeks)(24 weeks)

58/71 59/69 56/69 9/13 5/13

v. Wagner et al, Gastroenterology 2005

Sustained virologic response (SVR) according to HCV genotype

0%

20%

40%

60%

80%

100%

Group A Group B Group C

HCV-2

HCV-3

SV

R (

%)

76% 77%

40/53

(24 weeks)(24 weeks) (12 weeks)(12 weeks)

76%87%

72%

41%

(24 weeks)(24 weeks)

13/17 89/102 24/31 42/58 9/22

Mangia et al, N Engl J Med 2005

Tx: PEG-IFN alfa-2b 1.0 µg/kg + RBV 1000-1200 mg

Treatment of chronic HCV-2 infection with PEG-IFN alfa-2a + RBV for 16 vs. 24 weeks

0%

20%

40%

60%

80%

100%

RVR SVR

16 weeks 24 weeks

Viro

logi

c re

spon

se (

%)

86%94%

43/50

87%95%

87/100 47/50 95/100

M-L Yu et al, GUT 2006

PEG-IFN alfa-2a + RBV for 16 or 24 weeks in HCV-2 and -3 (ACCELERATE Study)

65% 62%

76%70%

0%

20%

40%

60%

80%

100%

Standard Analysis Intent-to-treat

16 weeks PEG-IFN alfa-2a 180 ug + RBV 800 mg24 weeks PEG-IFN alfa-2a 180 ug + RBV 800 mg

P <.0001P <.0001 P =.0004P =.0004

N=679 N=732 N=731N=630

Shiffman et al., Late-Breaker Abstract EASL 2006Shiffman et al., Late-Breaker Abstract EASL 2006

84%

61%

83%

59%

89%80% 85%

66%

0%

20%

40%

60%

80%

100%

≤400,000 IU/mL >400,000 IU/mL ≤400,000 IU/mL >400,000 IU/mL

16 weeks PEG-IFN alfa-2a 180 ug + Ribavirin 800 mg24 weeks PEG-IFN alfa-2a 180 ug + Ribavirin 800 mg

SV

R (

%)

SV

R (

%)

Standard population; VR = HCV RNA < 50 IU/mLStandard population; VR = HCV RNA < 50 IU/mL

Genotype 2Genotype 2 Genotype 3Genotype 3

N=61 N=46 N=285 N=92 N=84 N=241 N=243N=257

74%74%

94%94%

80%80%

98%98%

56%56%

67%67%75%75%

85%85%90%90%

70%70%

92%92%

77%77%

52%52%

65%65%

72%72%

60%60%

Shiffman et al., Late-Breaker Abstract EASL 2006Shiffman et al., Late-Breaker Abstract EASL 2006

PEG-IFN alfa-2a + RBV for 16 or 24 weeks in HCV-2 and -3 (ACCELERATE Study)

PEG-IFN alfa-2a 180 µg qw Ribavirin 800 mg qd

PEG-IFN α-2a 180 µg qwRibavirin

800-1200 mg qd

PEG-IFN α-2b 1.0 µg/kg qw

Ribavirin 1000-1200 mg qd

PEG-IFN α-2b 1.5 µg/kg qw

Ribavirin 800-1400 mg qd

No Yes Yes Yes

1221531469

(993 US)273

Global Italy Germany Norway

~0.6 x 106 50%<0.6 x 106~1 x 1065.6 x 106

46 46.6-49.7 38-42 37 (median)

81.5 69.5 74-80 76 (median)

50% 78% 25% 19%

RegimenRegimen

% GT 2% GT 2

NumberNumber

RegionRegion

Mean baseline Mean baseline viral load viral load IU/mlIU/ml

Mean Age (yrs)Mean Age (yrs)

Treatment Treatment duration based duration based on RVR?on RVR?

Mean body Mean body weight (kg)weight (kg)

ACCELERATEACCELERATE VON WAGNERVON WAGNERMANGIAMANGIA DALGARDDALGARD


Longer treatment in HCV-3 (HVL) ?

Relapse rate by HCV genotype and baseline viral load in patients treated for

24 weeks (Peg-IFN alfa-2b + RBV)

0

5

10

15

20

25

< 600,000IU/mL

> 600,000IU/mL

< 600,000IU/mL

> 600,000IU/mL

Rel

apse

(%

)

HCV-2 HCV-3

5%9% 8%

23%

Zeuzem et al., J Hepatol 2004


Treatment duration for HCV-4 ?

PEG-IFN-2a + ribavirin for treatment of patients with chronic HCV-4 infection

0

10

20

30

40

50

60

70

80

24 weeks 48 weeks

800 mg RBV

1000/1200 mg RBV

sust

aine

d vi

rolo

gic

resp

onse

(%

)

0%

67%63%

79%

M Diago et al., Ann Intern Med 2004;140:72-73

Sustained virologic response (SVR) in patients infected with HCV-4

0%

20%

40%

60%

80%

100%

24 weeks 36 weeks 48 weeks

SV

R (

%)

66%

29%

69%

Kamal et al, GUT 2005


Sustained virologic response (SVR) in patients infected with HCV-4 (HVL)

0%

20%

40%

60%

80%

100%

24 weeks 36 weeks 48 weeks

SV

R (

%)

35%

0%

65%

Kamal et al, GUT 2005


Future individualization of therapy

0 1 2 31

2

3

4

5

6

7

7 14 21 28

Limit of detection

days

Se

rum

HC

V R

NA

(lo

g)

FPR (0.0 < 0,05)

RVR( 0.35)

NR (c < 0,2)

HCV-2, HCV-3 (LVL) 12-16 WochenDelgaard et al. 2005; v. Wagner et al. 2005Mangia et al. 2005, Shiffman et al. 2006

HCV-2 (HVL) 24 WeeksShiffman et al. 2006

HCV-3 (HVL), HCV-4 (LVL)36-48 (?) Wochenv. Wagner et al. 2005, Kamal et al. 2006

HCV-1 (LVL, RVR) 24 WochenZeuzem et al. 2004, Zeuzem et al. 2005

HCV-1, HCV-4 48 WochenManns et al. 2002, Hadziyannis et al. 2004Kamal et al., 2005

HCV-1 (SPR) 72 WochenButi et al. 2003, Berg et al. 2006

(0.05 < 0.35)SPR

Conclusions (1)

• Virologic response rates are better in HCV-2 than HCV-3 infected patients

• Certain patients with HCV-2 or HCV-3 infection may be successfully treated with 12-16 weeks of combination therapy

• Patients infected with HCV-3 and high viral load may require longer than 24 weeks of combination therapy

Conclusions (2)

• Patients infected with HCV-1 and low baseline viral load who respond early (at week 4) may only require 24 weeks of combination therapy

• Slow viral responders infected with HCV-1 benefit from longer than 48 weeks of combination therapy

• Compliance and adherence important

• Future options: small molecules (HCV protease and polymerase inhibitors)

stefan zeuzem. what is the optimal treatment of naive patients with chronic hepatitis c ? 2 nd paris...

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