1. Stefan ZEUZEM

2. Stefan Zeuzem J.W. Goethe University Hospital Frankfurt, Germany
What is the optimal treatment of naive patients with chronic hepatitis C ? 2nd Paris Hepatitis Conference Palais des Congrès, Paris, January 2007
Stefan Zeuzem J.W. Goethe University Hospital Frankfurt, Germany

3. Sustained virologic response (%)
Peginterferon alfa-2a/2b + Ribavirin for treatment of chronic hepatitis C
Sustained virologic response (%)
Fried et al., N Engl J Med 2002; 347:
Manns et al., Lancet 2001; 358:

4. PEG-IFN alfa-2a + RBV (LD vs SD) for treatment of chronic hepatitis C
RBV 800 mg/d
RBV mg/d
Sustained virologic response (%)
HCV-1
HCV-2,3
Hadziyannis et al., Ann Intern Med 2004;40:

5. HCV genotyping stop treatment or continue with PEG-IFN alone
HCV RNA quant.
HCV-2,3
Combination treatment
mg Ribavirin
Combination treatment
800 mg Ribavirin for 24 weeks
HCV RNA quant. at week 12
< 2log decline
 2log decline HCV RNA +
 2log decline HCV RNA -
stop treatment or
continue with
PEG-IFN alone
for inhibition of fibrosis progression
continue tx until week 24
if HCV RNA -
continue tx until week 48
continue tx until week 48

6. Individualisation according to HCV genotype: Shorter treatment in HCV-1?

7. Time to first negative HCV RNA PEG-IFN a-2b + RBV
Virologic response in patients with HCV-1 and HCV RNA < 600,000 IU/mL
89%
80%
75%
Patients (%)
50%
37%
25%
17% 8%
(47%)
(26%)
(10%)
Time to first negative HCV RNA PEG-IFN a-2b + RBV
Zeuzem et al., J Hepatol 2006

8. Patients with HCV-1 and HCV RNA < 600,000 IU/mL
Investigator
HCV-1 patients
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%)
Ann Intern Med 2004
Total
5209
1799 (34.5%)
Zeuzem, J Hepatol 2006

9. Sustained virologic response (%)
Early identification of HCV 1 patients responding to 24 wks PEG-IFN alfa-2a/RBV
Sustained virologic response (%) 18 33 40 55 81 84
208
210
Jensen et al., Hepatology 2006;43:954-60

10. GAM analysis Effect of pre-treatment HCV RNA on SVR
5.6 log10 IU/mL
0.998
0.98
Probability of SVR*
0.88
0.5 3 4 5 6 7
*Logit scale 5.6 log10 IU/mL ~400 x103 IU/mL
Baseline HCV RNA (log10 IU/ml)

11. Individualisation according to HCV genotype: Longer treatment in HCV-1 ?

12. Sustained virologic response rate (%)
Extended treatment duration for HCV 1: 48 vs 72 weeks of PEG-IFN alfa-2a + RBV
P=0.040
Sustained virologic response rate (%)
104/130
90/119
17/100
31/106
Berg, et al. Gastroenterology 2006;130:

13. Virologic relapse rates in patients with rapid virologic response
3/46
5/32
19/123
12/101
Week 4
Week 12
Berg, et al. Gastroenterology 2006;130:

14. Virologic relapse rates in patients with slow virologic response
46/124
28/122
30/47
21/52
Week 4
Week 12
Berg, et al. Gastroenterology 2006;130:

15. Sustained virologic response rate (%)
Peginterferon alfa-2a plus ribavirin for 48 vs. 72 weeks in patients with detectable HCV RNA at week 4 of treatment
51%
44%
Sustained virologic response rate (%)
37%
28%
27%
28%
P=0.003
P=0.002
P=0.35
Sanchez-Tapias et al., Gastroenterology 2006;131:

16. Virologic relapse rate (%)
Peginterferon alfa-2a plus ribavirin for 48 vs. 72 weeks in patients with detectable HCV RNA at week 4 of treatment
55%
53%
50%
Virologic relapse rate (%)
27%
23%
17%
P=0.002
P=0.007
P=0.15
Sanchez-Tapias et al., Gastroenterology 2006;131:

17. Individualisation according to HCV genotype: Shorter treatment in HCV-2 and HCV-3 ?

18. PEG-IFN-a2b + RBV for treatment of chronic HCV-2 and -3 infection (ITT)
90%
82%
56%
Patients (%)
26%
19%
14%
10% 4% 0%
Dalgard et al., Hepatology 2004;40:

19. Virologic response (%)
End-of-treatment (ETR) and sustained virologic response (SVR) - HCV genotypes 2 and 3 combined -
SVR B vs C: P = 0.003
94%
86%
82%
81%
69%
Virologic response (%)
39%
67/71
58/71
59/69
56/69
9/13
5/13
(16 weeks)
(24 weeks)
(24 weeks)
v. Wagner et al, Gastroenterology 2005

20. Sustained virologic response (SVR) according to HCV genotype
Tx: PEG-IFN alfa-2b 1.0 µg/kg + RBV mg
87%
77%
76%
76%
72%
SVR (%)
41%
40/53
13/17
89/102
24/31
42/58
9/22
(24 weeks)
(12 weeks)
(24 weeks)
Mangia et al, N Engl J Med 2005

21. Virologic response (%)
Treatment of chronic HCV-2 infection with PEG-IFN alfa-2a + RBV for 16 vs. 24 weeks
94%
95%
86%
87%
Virologic response (%)
43/50
87/100
47/50
95/100
M-L Yu et al, GUT 2006

22. PEG-IFN alfa-2a + RBV for 16 or 24 weeks in HCV-2 and -3 (ACCELERATE Study)
Shiffman et al., Late-Breaker Abstract EASL 2006

23. PEG-IFN alfa-2a + RBV for 16 or 24 weeks in HCV-2 and -3 (ACCELERATE Study)
98%
94%
92%
90%
85%
72%
80%
77%
74%
67%
75%
70%
65%
60%
56%
SVR (%)
52%
tpcr05_p
N=61
N=46
N=285
N=257
N=92
N=84
N=241
N=243
Genotype 2
Genotype 3
Standard population; VR = HCV RNA < 50 IU/mL
Shiffman et al., Late-Breaker Abstract EASL 2006

24. ACCELERATE MANGIA VON WAGNER DALGARD
PEG-IFN alfa-2a 180 µg qw
Ribavirin 800 mg qd
PEG-IFN α-2b
1.0 µg/kg qw
Ribavirin
mg qd
PEG-IFN α-2a
180 µg qw
Ribavirin
mg qd
PEG-IFN α-2b
1.5 µg/kg qw
Ribavirin
mg qd
Regimen
1469
(993 US)
273
153
122
Number
Global
Italy
Germany
Norway
Region
50%
78%
25%
19%
% GT 2
Treatment
duration based
on RVR? No
Yes
Yes
Yes
5.6 x 106
~1 x 106
~0.6 x 106
50%
<0.6 x 106
Mean baseline
viral load IU/ml 46
38-42
37 (median)
Mean Age (yrs)
81.5
69.5
74-80
76 (median)
Mean body
weight (kg)

25. Individualisation according to HCV genotype: Longer treatment in HCV-3 (HVL) ?

26. Relapse rate by HCV genotype and baseline viral load in patients treated for 24 weeks (Peg-IFN alfa-2b + RBV)
23%
Relapse (%) 9% 8% 5%
HCV-2
HCV-3
Zeuzem et al., J Hepatol 2004

27. Individualisation according to HCV genotype: Treatment duration for HCV-4 ?

28. sustained virologic response (%)
PEG-IFN-a2a + ribavirin for treatment of patients with chronic HCV-4 infection
79%
67%
63%
sustained virologic response (%) 0%
M Diago et al., Ann Intern Med 2004;140:72-73

29. Sustained virologic response (SVR) in patients infected with HCV-4
Tx: PEG-IFN alfa-2b 1.5 µg/kg + RBV mg
SVR (%)
69%
66%
29%
Kamal et al, GUT 2005

30. Sustained virologic response (SVR) in patients infected with HCV-4 (HVL)
Tx: PEG-IFN alfa-2b 1.5 µg/kg + RBV mg
SVR (%)
65%
35% 0%
Kamal et al, GUT 2005

31. Future individualization of therapy
HCV-2, HCV-3 (LVL)
12-16 Wochen Delgaard et al. 2005; v. Wagner et al Mangia et al. 2005, Shiffman et al. 2006
HCV-2 (HVL)
24 Weeks Shiffman et al. 2006
HCV-3 (HVL), HCV-4 (LVL)
36-48 (?) Wochen
v. Wagner et al. 2005, Kamal et al. 2006
HCV-1 (LVL, RVR)
24 Wochen
Zeuzem et al. 2004, Zeuzem et al. 2005
HCV-1, HCV-4
48 Wochen Manns et al. 2002, Hadziyannis et al Kamal et al., 2005
HCV-1 (SPR)
72 Wochen
Buti et al. 2003, Berg et al. 2006 7
NR (c < 0,2) 6
FPR (0.0  d < 0,05) 5
Serum HCV RNA (log) 4
SPR
(0.05  d < 0.35) 3
RVR
(d  0.35) 2
Limit of detection 1 1 2 3 7 14 21 28
days 7 a 6 b 5
copies/mL) c
Serum HCV RNA 4 10 3
(log
detection limit 2 1 1 2 3 7 14 21 28
t (days)

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

33. 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)