1. Michael P. Manns Markus Cornberg
PUBLIC HEALTH CHALLENGES FOR CONTROLLING HCV INFECTION
Hepatitis C:
Therapeutic options
Michael P. Manns
Markus Cornberg
Medizinische Hochschule Hannover
Dept. of Gastroenterology, Hepatology and Endocrinology
Germany
VHPB Meeting, Ferney Voltaire, France
May , 2002

2. Therapy of chronic hepatitis C PEG-IFN & Ribavirin 48 weeks
Future therapies ?
80%
60%
PEG-IFN & Ribavirin 48 weeks
IFN & Ribavirin 48 weeks
40%
Sustained response (%)
PEG-IFN 48 weeks
20%
IFN 48 weeks
IFN 24 weeks 0%
1988
1990
1992
1994
1996
1998
2002

3. The PEG Molecule
IFN- conjugated to a 40kD (PEG-2a) or 12kD (PEG-2b) polyethylenglycol polymer

4. Comparison of Pharmacokinetic Profiles: PEG-IFN alfa vs. IFN alfa
HCV RNA
IFN 
Mo.
Di.
Mi.
Do.
Fr.
Sa.
So.
PEG-IFN 

5. Sustained Response PEG-IFN alfa-2b/RBV Sustained Response
Manns et al., Lancet 2001
n = 505
n = 514
n = 511
1/1.2 g RBV
0.8 g RBV
Sustained Response
PEG-IFN alfa-2a/RBV
Fried et al., DDW 2001
n = 444
n = 224
n = 453

6. Sustained Response PEG-IFN alfa-2b/RBV Sustained Response
Genotype 1
+ 9%
Manns et al., Lancet 2001
Sustained Response
PEG-IFN alfa-2a/RBV
Genotype 1
+ 9%
Fried et al., DDW 2001

7. Optimizing Response Rates
Body weight adjusted dosing
Treatment duration
80/80/80
New adjuncts (amantadine)

8. Sustained Virologic Response Optimal ribavirin Dosing (retrospective)
Optimal ribavirin >10.6 mg/kg
IFN alfa-2b 3MU
Peg IFN alfa-2b 1.5
Overall
47%
61%
Genotype 1
34%
48%
Highlight the genotype 2/3 for the 1.5
Genotype 2/3
80%
88%
Manns et al., Lancet 2001 19

9. Conclusion Optimum ribavirin Dosing with PEG-IFN alfa2b 1.5 µg/kg
Patient Weight
ribavirin Dose
<65 kg mg/day
65-85 kg mg/day
>85 kg mg/day
Note additions
Prospective analyses are needed 18

10. Optimizing Response Rates
Body weight adjusted dosing
Treatment duration
80/80/80
New adjuncts (amantadine)

11. EASL Consensus 1999 HCV- Genotype 1/4 HCV- Genotype 2/3 24 weeks
HCV-RNA < 0.8 x 106 IE/ml
HCV-RNA > 0.8 x 106 IE/ml
24 weeks
48 weeks

12. PEG-IFN alfa-2a and Ribavirin (n=1284)
Hadziyannis et al., EASL 2002
180 µg PEG-IFN alfa-2a mg RBV
N=207
24 weeks
180 µg PEG-IFN alfa-2a /1200 mg RBV
N=280
24 weeks
180 µg PEG-IFN alfa-2a mg RBV
N=361
48 weeks
180 µg PEG-IFN alfa-2a /1200 mg RBV
N=436
48 weeks

13. PEG-IFN alfa-2a and Ribavirin SVR Results HCV-Genotype 1
Hadziyannis et al., EASL 2002
48 weeks
24 weeks
PEG +0,8RBV
PEG +1/1,2RBV
PEG +0,8RBV
PEG +1/1,2RBV

14. PEG-IFN alfa-2a and Ribavirin
SVR Results HCV-Genotype 1 and low viral load
Hadziyannis et al., EASL 2002
48 weeks
24 weeks
PEG +0,8RBV
PEG +1/1,2RBV
PEG +0,8RBV
PEG +1/1,2RBV

15. PEG-IFN alfa-2a and Ribavirin SVR Results HCV-Genotype NON-1
Hadziyannis et al., EASL 2002
24 weeks
48 weeks
PEG +0,8RBV
PEG +1/1,2RBV
PEG +0,8RBV
PEG +1/1,2RBV

16. Conclusion (Ribavirin dosing / Treatment duration)
Patients with HCV-Genotype-1: 48 weeks therapy with optimal (high) ribavirin dosing independent of viral load
Patients with HCV-Genotype-2/3: 24 weeks therapy high ribavirin dosing seems not to be necessary

17. What is the impact of adherence to therapy on SVR?

18. Patient Categories 80/80/80 Group < 80 ± < 80 + > 80 Group
> 80% interferon
> 80% ribavirin
> 80% expected duration therapy
< 80 ± < 80 + > 80 Group
< 80% interferon and/or
< 80% ribavirin and/or
Early discontinuations excluded

19. All Patients - PEG IFN 1.5 µg/kg + ribavirin
54%
63%
52%
N=511
N=305
N=118
Manns et al., Lancet 2001
McHutchison et al, EASL 2001
Sustained virologic response (%)

20. Conclusions 80/80/80
Patients who can be maintained on > 80% of PEG interferon and ribavirin for the proposed duration of therapy may have an enhanced sustained response rate
Every effort should be made to continue the maximum tolerable doses of therapy for the duration of treatment

21. Optimizing Response Rates
Body weight adjusted dosing
Treatment duration
80/80/80
New adjuncts (amantadine)

22. Other Combination Adjuncts
Corticosteroid priming
Ursodeoxycholic acid
Pentoxifylline
Thymosin alpha
Phlebotomy
Extra-corporeal photophoresis
Mycophenolate
Maxamine
Ribavirin
Amantadine
Rimantadine
NSAIDs
N-acetyl-cysteine
Vitamin E
Antibiotics

23. Italian nonresponder pilot study: IFN & Ribavirin & amantadine:
57% 20 40 60
HCV-RNA negative
ALT normal
48%
n=20
patients (%)
n=40
10% 5%
5 MU IFN tiw mg Riba 200mg Amantadine
5 MU IFN tiw mg Riba
Brillanti et al., Hepatology 2000

24. German multicenter study (400 naive patients)
9 MU IFN alfa-2a qd
2 weeks
6 MU IFN alfa-2a qd
6 weeks
6 MU IFN alfa-2a tiw
16 weeks
3 MU IFN alfa-2a tiw
24 weeks
1000/1200 mg Ribavirin
200 mg Amantadine / Placebo
Sustained Response
P=0,055
52%
43% 0%
20%
40%
60%
IFN, RBV, Amantadine
IFN, RBV, Placebo
N=200
Berg et al., AASLD 2001, GASL 2002, EASL 2002

25. Optimize treatment algorithm
Optimum duration to determine treatment response

26. PEG-IFN -2a in Combination Therapy: Predictability / Compliance Analysis
Week 12 (N = 453)
SVR
n = 253 (65%)
n = 390 (86%)
Yes
No SVR
n = 137 (35%)
2 log10 drop or neg HCV RNA
SVR
n = 2 (3%)
n = 63 (14%)
No SVR No
n = 61 (97%)
Fried MW et al. DDW 2001

27. Proposed treatment algorithm
PEG-IFN alfa-2b study
RNA (+)  2 log drop
n=23
Loss of SVR =26%
24wks
discontinue
RNA (+) < 2 log drop
n=31
Assess fibrosis F2/F3/F4:
consider maintenance
RNA (-)
n=120
Continue for 48 wks
SVR = 90%
108/120
n=188*
12 wks
PCR (+)
SVR = 0%
0/17
PCR (-)
Continue to 48 wks
SVR =100%
6/6
Week *12 HCVRNA not available in 14 patients McHutchison et al, EASL, 2002

28. Patients with acute HCV Infection
Other patient groups
Patients with acute HCV Infection
Nonresponder patients
Patients after liver transplantation

29. Is a prevention of the chronic course possible ?
Acute HCV-Infection
10-50%
Is a prevention of the chronic course possible ?
50-90%
Recovery
Chronic infection
(PEG)-Interferon alfa
Ribavirin

30. Treatment of Acute Hepatitis C with Interferon Alfa-2b
Elmar Jaeckel, M.D., Markus Cornberg, M.D., Heiner Wedemeyer, M.D., Teresa Santantonio, M.D., Julika Mayer, M.D., Myrga Zankel, D.V.M., Giuseppe Pastore, M.D., Manfred Dietrich, M.D., Christian Trautwein, M.D., Michael P. Manns, M.D., and the German Acute Hepatitis C Therapy Group
NEJM November 15, 2001; 345:

31. 5 MU tiw Interferon alfa-2b Therapy within 4 months after infection
Schedule
Induction
Therapy
Follow-up
Week 1-4
Week 5-24
Week 25-48
5 MU daily
Interferon alfa-2b
5 MU tiw Interferon alfa-2b
Jaeckel, et al., NEJM 2001
Therapy within 4 months after infection

32. Patients
44 Patienten in
24 Behandlungszentren

33. Virological Response during therapy
100%
98%
80%
therapy n=44
60%
natural course n=40
HCV-RNA negative
40%
30%
20%
Santantonio et al. (Bari, Italy) 0% 4 8 12 16 20 24
48 =F24
weeks
Jaeckel, Cornberg, Wedemeyer et al., NEJM 2001

34. Re-therapy in IFN - nonresponder patients with IFN/Ribavirin
Summary of 23 publications
34,5%
7,4% 10 20 30 40 50
ETR SR
Sustained Response (%)
Wedemeyer et al., 1998

35. HCV therapies - new strategies
Daily dosing
Induction dosing
New adjuncts (amantadine)
New interferons (CIFN, PEG-IFN)

36. Hannover-Study: SCHEDULE
0 weeks
8 weeks
24 weeks
48 weeks
18 µg Inferax daily
1. – 8. wk B A
9 µg Consensus Interferon (Inferax) daily
1. – 48. weeks
1.000/1.200 mg Ribavirin Meduna daily
9 µg Inferax daily
9. – 48. weeks
1.000/1.200 mg Ribavirin weeks
Follow-up 24 weeks

37. VIROLOGICAL response (intent to treat)
40 Nonreponder patients (>90% HCV-G-1)
80%
Group A (n=21)
71,4%
Group B (n=19)
57,9%
60%
40%
65%
20% 0%
ETR SR

38. Chronic Hepatitis C - Nonreponder Patients:
Therapeutic goals
Viral clearance
Histological response
Prevention of HCC

39. Cumulative Incidence of HCC [%]
Incidence of HCC in patients with chronic hepatitis C: Relevance of IFN
Follow up [years]
Cumulative Incidence of HCC [%] 1 2 3 4 5 6 7 10 20 30 40 50
Interferon alpha
Control
Nishiguchi, Lancet 1995, 2001

40. % Cumulative Incidence of HCC
882 patients with F3 / F4
NR (6 mo IFN)
NR = Non Responders
PR = Partial Responders (ALT < x 2.5 n.v.)
SR = Sustained Response 15
Untreated 12 9
PR (12 mo IFN) 6
PR (24 mo IFN) 3 SR 1 2 3 4 5
Years after inclusion
Alberti, 2000

41. PEG-IFN 2a therapy: naive patients
histological response (HAI-Score reduction >2)
Peg-IFN 180µg 1x/week 48 week (n=228)
83%
79%
80%
IFN 3MU 3x/week 48 week (n=202)
p=0.001
57%
60%
p=0.06
47%
44%
43%
41%
Patients
40%
30%
20% 0%
Patients with SR
Partially Responder
all Patients
Nonresponder
Heathcote et al., 2000

42. PEG-IFN & Ribavirin in Nonresponder Peg-IFN alfa-2a + Ribavirin
HALT-C-Study (NIH)
AASLD 2001: Shiffman et al.
146 Nonresponder
20 weeks
Peg-IFN alfa-2a + Ribavirin
8 drop outs
59/138 Response
(ITT 40,1%)
79 Nonresponder
PEG-IFN + RBV
48 Wochen
PEG-IFN Mono (HALT-C)

43. Prevention of Progression of Fibrosis
Anti-fibrotic effect of IFN alfa
Inhibition of collagen synthesis in cell culture and in vivo
Clinical Experience
Histological improvement with IFN-based therapy in responders and non responders
Fibrosis regression in subjects on maintenance IFN compared with subjects who stop IFN
Decrease in development of HCC and/or decrease in mortality rate in all studies

44. Liver transplantation
Problems of the combination therapy
Ribavirin leads to anemia and accumulation of iron
Significant side effects of IFN/RBV
Reported sustained response rates differ between different centers
No data on long-term benefit are available
 multicenter trials

45. Therapy of HCV-Reinfection with Interferon with or without Ribavirin
IFN IFN+Riba
Patients n=43 n=21
Biochemical Response ca. 20% 100%
Viral elimination (PCR-neg. ETR) 0% 48%
Histological Response ca. 5% 100%
Rejection episodes ca. 15% 0%
Wright et al 1992, 1994, Feray et al 1995, Bizollon et al 1997 2

46. Liver transplantation
More important
Deciding the best immunosuppression regimen
rejection
Disease progression

47. Summary Naive patients with elevated ALT and fibrosis HCV-Genotype-1
PEG-IFN 48 weeks
and high ribavirin (>10,6mg ribavirin/kg)
PEG-IFN 24 weeks
and (800mg) ribavirin
Acute Hepatitis C
5MU IFN qd 4 wk, 5MU IFN tiw 20 wk or PEG-IFN oiw 24 wk (ongoing study)
Nonresponder
No fibrosis
fibrosis
advanced fibrosis/cirrhosis
no treatment
Studies (PEG-IFN, CIFN, etc.)
Studies (long-term IFN)
Liver transplantation
Multicenter trials