Transcript Document

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 13 - 14, 2002
Therapy of chronic hepatitis C
Future therapies ?
80%
60%
IFN & Ribavirin
48 weeks
40%
PEG-IFN &
Ribavirin
48 weeks
PEG-IFN 48 weeks
20%
IFN 48 weeks
IFN 24 weeks
0%
1988 1990 1992 1994 1996 1998
2002
The PEG Molecule
IFN- conjugated to a
40kD (PEG-2a)
or
12kD (PEG-2b)
polyethylenglycol polymer
Comparison of Pharmacokinetic Profiles:
PEG-IFN alfa vs. IFN alfa
IFN 
Mo.
HCV
RNA
Di.
Mi.
Do.
Fr.
Sa.
So.
PEG-IFN 
Mo.
Di.
HCV
RNA
Mi.
Do.
Fr.
Sa.
So.
Sustained Response
PEG-IFN alfa-2b/RBV
Manns et al., Lancet 2001
60%
40%
54%
47%
47%
n = 505
n = 514
n = 511
1/1.2 g RBV
0.8 g RBV
0,5 PEG-IFN + RBV
1,5 PEG-IFN + RBV
20%
0%
IFN + RBV
Sustained Response
PEG-IFN alfa-2a/RBV
Fried et al., DDW 2001
56%
60%
45%
40%
30%
20%
n = 444
n = 224
IFN + RBV
PEG-IFN + P
n = 453
0%
PEG-IFN + RBV
Sustained Response
PEG-IFN alfa-2b/RBV
60%
Manns et al., Lancet 2001
40%
Genotype 1
+ 9%
42%
33%
20%
0%
IFN + RBV
Sustained Response
PEG-IFN alfa-2a/RBV
Fried et al., DDW 2001
1,5 µg PEG-IFN + RBV
60%
Genotype 1
40%
+ 9%
46%
37%
20%
0%
IFN + RBV
180 µg PEG-IFN + RBV
Optimizing Response Rates
•
Body weight adjusted dosing
•
Treatment duration
•
80/80/80
•
New adjuncts (amantadine)
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%
Genotype 2/3
80%
88%
Manns et al., Lancet 2001
Conclusion
Optimum ribavirin Dosing with PEG-IFN alfa2b 1.5 µg/kg
Patient Weight
ribavirin Dose
<65 kg
800 mg/day
65-85 kg
1000 mg/day
>85 kg
1200 mg/day
Prospective analyses are needed
Optimizing Response Rates
•
Body weight adjusted dosing
•
Treatment duration
•
80/80/80
•
New adjuncts (amantadine)
EASL Consensus
1999
HCV- Genotype 1/4
HCV- Genotype 2/3
HCV-RNA
< 0.8 x 106 IE/ml
HCV-RNA
> 0.8 x 106 IE/ml
HCV-RNA
< 0.8 x 106 IE/ml
HCV-RNA
> 0.8 x 106 IE/ml
24 weeks
48 weeks
24 weeks
24 weeks
PEG-IFN alfa-2a and Ribavirin (n=1284)
Hadziyannis et al., EASL 2002
180 µg PEG-IFN alfa-2a
N=207
+ 800 mg RBV
24 weeks
180 µg PEG-IFN alfa-2a
N=280
+ 1000/1200 mg RBV
24 weeks
180 µg PEG-IFN alfa-2a
N=361
+ 800 mg RBV
48 weeks
180 µg PEG-IFN alfa-2a
N=436
+ 1000/1200 mg RBV
48 weeks
PEG-IFN alfa-2a and Ribavirin
SVR Results HCV-Genotype 1
Hadziyannis et al., EASL 2002
60%
51%
41%
40%
40%
29%
20%
24 weeks
48 weeks
0%
PEG
+0,8RBV
PEG
+1/1,2RBV
PEG
+0,8RBV
PEG
+1/1,2RBV
PEG-IFN alfa-2a and Ribavirin
SVR Results HCV-Genotype 1 and low viral load
80%
Hadziyannis et al., EASL 2002
61%
60%
51%
53%
41%
40%
20%
24 weeks
48 weeks
0%
PEG
+0,8RBV
PEG
+1/1,2RBV
PEG
+0,8RBV
PEG
+1/1,2RBV
PEG-IFN alfa-2a and Ribavirin
SVR Results HCV-Genotype NON-1
Hadziyannis et al., EASL 2002
100%
80%
78%
78%
73%
77%
60%
40%
24 weeks
48 weeks
20%
0%
PEG
+0,8RBV
PEG
+1/1,2RBV
PEG
+0,8RBV
PEG
+1/1,2RBV
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
What is the impact of
adherence to therapy
on SVR?
Patient Categories
 80/80/80 Group
• > 80% interferon
• > 80% ribavirin
• > 80% expected duration therapy
 < 80 ± < 80 + > 80 Group
• < 80% interferon and/or
• < 80% ribavirin and/or
• > 80% expected duration therapy
• Early discontinuations excluded
Sustained virologic response (%)
All Patients - PEG IFN 1.5 µg/kg + ribavirin
100
Manns et al., Lancet 2001
McHutchison et al, EASL 2001
80
63%
54%
p = 0.04
52%
60
40
20
N=511
N=305
N=118
ITT
80/80/80
(305)
<80±80+>80
(118)
0
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
Optimizing Response Rates
•
Body weight adjusted dosing
•
Treatment duration
•
80/80/80
•
New adjuncts (amantadine)
Other Combination Adjuncts





Ribavirin
Amantadine
Rimantadine
NSAIDs
N-acetyl-cysteine

Vitamin E

Antibiotics

Corticosteroid priming

Ursodeoxycholic acid

Pentoxifylline

Thymosin alpha

Phlebotomy

Extra-corporeal
photophoresis

Mycophenolate

Maxamine
Italian nonresponder pilot study:
IFN & Ribavirin & amantadine:
60
57%
ALT normal
patients (%)
48%
HCV-RNA negative
40
n=20
n=40
20
10%
5%
0
5 MU IFN tiw
800-1000mg Riba
200mg Amantadine
5 MU IFN tiw
800-1000mg Riba
Brillanti et al., Hepatology 2000
German multicenter study (400 naive patients)
9 MU IFN
alfa-2a qd 6 MU IFN alfa-2a qd
6 MU IFN alfa-2a tiw
3 MU IFN alfa-2a tiw
16 weeks
24 weeks
6 weeks
2 weeks
1000/1200 mg Ribavirin
200 mg Amantadine / Placebo
60%
Sustained Response
52%
P=0,055
43%
40%
20%
N=200
N=200
0%
IFN, RBV, Amantadine
IFN, RBV, Placebo
Berg et al., AASLD 2001,
GASL 2002, EASL 2002
Optimize treatment algorithm
•
Optimum duration to determine
treatment response
PEG-IFN -2a in Combination Therapy:
Predictability / Compliance Analysis
Week 12 (N = 453)
Yes
n = 390
(86%)
SVR
n = 253
(65%)
No SVR
n = 137
(35%)
SVR
n=2
(3%)
No SVR
n = 61
(97%)
2 log10 drop
or neg HCV RNA
No
Fried MW et al. DDW 2001
n = 63
(14%)
Proposed treatment algorithm
24wks
PEG-IFN alfa-2b study
RNA (+) < 2 log drop
discontinue Assess fibrosis F2/F3/F4:
consider maintenance
n=31
12 wks
n=188*
RNA (-)
Continue for 48 wks
SVR = 90%
108/120
n=120
PCR (+)
RNA (+)  2 log drop
n=23
Loss of SVR =26%
Week *12 HCVRNA not available in 14 patients
McHutchison et al, EASL, 2002
SVR = 0%
0/17
PCR (-)
SVR =100%
6/6
Continue
to 48 wks
Other patient groups
•
Patients with acute HCV Infection
•
Nonresponder patients
•
Patients after liver transplantation
Acute HCV-Infection
10-50%
Recovery
50-90%
Chronic infection
(PEG)-Interferon alfa
Ribavirin
Is a prevention of the chronic
course possible ?
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: 1452-1457
Schedule
Jaeckel, et al., NEJM 2001
Therapy within 4 months after infection
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
Patients
44 Patienten in
24 Behandlungszentren
Virological Response during therapy
100%
98%
HCV-RNA negative
80%
therapy n=44
natural course n=40
60%
40%
30%
20%
Santantonio et al. (Bari, Italy)
0%
0
4
8
12
weeks
Jaeckel, Cornberg, Wedemeyer et al., NEJM 2001
16
20
24
48
=F24
Sustained Response (%)
Re-therapy in IFN - nonresponder patients
with IFN/Ribavirin
50
40
Summary of 23 publications
34,5%
30
20
7,4%
10
0
ETR
SR
Wedemeyer et al., 1998
HCV therapies - new strategies
•
Daily dosing
•
Induction dosing
•
New adjuncts (amantadine)
•
New interferons (CIFN, PEG-IFN)
Hannover-Study: SCHEDULE
0 weeks
8 weeks
24 weeks
A
9 µg Consensus Interferon (Inferax) daily
1. – 48. weeks
1.000/1.200 mg Ribavirin Meduna daily
B
18 µg
Inferax
daily
1. – 8. wk
9 µg Inferax daily
9. – 48. weeks
1.000/1.200 mg Ribavirin weeks
Follow-up 24 weeks
48 weeks
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
Chronic Hepatitis C - Nonreponder Patients:
Therapeutic goals
• Viral clearance
• Histological response
• Prevention of HCC
Incidence of HCC in patients with chronic
hepatitis C: Relevance of IFN
Cumulative Incidence
of HCC [%]
50
Control
40
30
Interferon alpha
20
10
1
2
3
4
5
6
7
Follow up [years]
Nishiguchi, Lancet 1995, 2001
% Cumulative Incidence of HCC
882 patients with F3 / F4
NR (6 mo IFN)
NR = Non Responders
15
PR = Partial Responders (ALT < x 2.5 n.v.)
Untreated
SR = Sustained Response
12
9
PR (12 mo IFN)
6
PR (24 mo IFN)
3
SR
0
1
2
3
Years after inclusion
4
5
Alberti, 2000
PEG-IFN 2a therapy: naive patients
histological response (HAI-Score reduction >2)
83%
80%
Peg-IFN 180µg 1x/week 48 week (n=228)
79%
IFN 3MU 3x/week 48 week (n=202)
p=0.001
Patients
60%
57%
44% 43%
41%
47%
p=0.06
40%
30%
20%
0%
all Patients
Patients
with SR
Partially
Responder
Nonresponder
Heathcote et al., 2000
PEG-IFN & Ribavirin in Nonresponder
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 (HALTC)
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
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
Therapy of HCV-Reinfection with
Interferon with or without Ribavirin
IFN
Patients
n=43
Biochemical Response
ca. 20%
Viral elimination (PCR-neg. ETR) 0%
Histological Response
ca. 5%
Rejection episodes
ca. 15%
IFN+Riba
n=21
100%
48%
100%
0%
Wright et al 1992, 1994, Feray et al 1995, Bizollon et al 1997
Liver transplantation
More important
• Deciding the best
immunosuppression regimen
rejection
Disease
progression
Summary
Naive patients
with elevated ALT and fibrosis
HCV-Genotype-1
HCV-Genotype-2/3
Acute Hepatitis C
Nonresponder
No fibrosis
fibrosis
advanced fibrosis/cirrhosis
Liver transplantation
PEG-IFN 48 weeks
and high ribavirin (>10,6mg ribavirin/kg)
PEG-IFN 24 weeks
and (800mg) ribavirin
5MU IFN qd 4 wk, 5MU IFN tiw 20 wk
or PEG-IFN oiw 24 wk (ongoing study)
no treatment
Studies (PEG-IFN, CIFN, etc.)
Studies (long-term IFN)
Multicenter trials