Transcript Viral kinetics in HCV-infected patients treated with

Optimal therapy in
genotype 1 patients
3rd Paris Hepatitis Conference
19-20 January 2009
Stefan Zeuzem, MD
J.W. Goethe University Hospital
Frankfurt, Germany
Standard Treatment
Peginterferon alfa-2a/2b + Ribavirin
for treatment of chronic hepatitis C
100
Sustained virologic
response (%)
100
80
76
61
60
HCV-1
HCV-2,3
60
46
40
37
40
20
20
0
0
IFN + RBV
82
79
80
PEG-IFN
alfa-2a +
RBV
Fried et al., N Engl J Med 2002;
347:975-982
42
33
IFN + RBV
PEG-IFN
alfa-2b +
RBV
Manns et al., Lancet 2001;
358:958-965
Sustained virologic
response (%)
Individualized Dosing Efficacy vs. Flat Dosing
to Assess Optimal Pegylated Interferon
Therapy (IDEAL study)
50
40
38
41
40
30
20
10
0
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)
Virologic response in HCV
genotype 1 or 4 infected patients
100
ETR
90
SVR
REL
Percentage
80
P<0.0003
70
75,3
75.3
P=0.04
60
62,3
62.3
50
40
P=0.04
54,8
54.8
49,5
49.5
47,3
47.3
39,8
39.8
30
20
10
20,4
20.4
15.1
9.7
0
Overall
PEG IFN alfa-2a
PEG IFN alfa-2b
Ascione et al., EASL 2008
Milan Safety Tolerability (MIST) Study
p = 0.02
p = 0.02
p = 0.8
96%
100%
Sustained virologic
response rates
p = 0.01
82%
80%
66%
60%
40%
65%
54%
48%
32%
69%
PEG alfa-2a
PEG alfa-2b
20%
0%
Rumi, Colombo et al, AASLD 2008, A212
Sustained virologic
relapse rate (%)
Retrospective analysis of patients treated
with either peginterferon alfa-2a or alfa-2b
(PRACTICE study)
100
90
80
70
60
50
40
30
20
10
0
alfa-2a
alfa-2b
78.3%
76.8%
59.1%
54.4%
49.6%
43.7%
P=0.05
all GT (N=1672)
HCV-1 (N=1108)
HCV-2,3 (N=544)
Witthöft et al., EASL 2008
Optimization of Standard
Treatment
Effect of pre-tx HCV RNA on SVR
5.6 log10 IU/mL
Probability of SVR*
0.998
0.98
0.88
0.5
3
*Logit scale
5.6 log10 IU/mL ~400 x103 IU/mL
4
5
6
Baseline HCV RNA (log10 IU/ml)
7
Relation between the dynamics of virologic
response and relapse prediction in patients
receiving PEG-IFN / RBV x 48 weeks (n=225)
50
40
Relapse rate (%)
40
Baseline viremia > 800.000 IU/mL
30
23
17
20
All patients
10
10
0
0
4
8
Baseline viremia ≤ 800.000 IU/mL
0
0
Time to HCV RNA < 5.3 IU/mL by TMA in weeks
Berg et al., AASLD 2007 (179A)
12
Individualisation according
to HCV genotype:
Shorter treatment in HCV-1?
Virologic response in patients with HCV-1
and HCV RNA < 600,000 IU/mL
90
Patients (%)
80
70
SVR
Relapse
89%
80%
75%
60
50
40
30
50%
37%
20
25%
10
0
17%
8%
All patients
Zeuzem et al., J Hepatol 2006
Week 4
(47%)
Week 12
(26%)
Week 24/EOT
(10%)
Time to first negative HCV RNA
PEG-IFN a-2b + RBV
Early identification of HCV 1 patients
responding to 24 wks PEG-IFN alfa-2a/RBV
Sustained virologic
response (%)
100
91
89 88
80
73
60
44
40
35
16
20
0
24-LD
24-SD
48-LD
48-SD
18
33
40
55
HCV RNA < 50
IU/mL at week 4
81
23
84
208
210
HCV RNA > 50
IU/mL at week 4
Jensen et al., Hepatology 2006;43:954-60
Response (%)
Rates of relapse and SVR according
to RVR and baseline viral load
100
90
80
70
60
50
40
30
20
10
0
24 wk tx
48 wk tx
96,4
100
71,4
50,8
44,4
16,7
3,6
0
Relapse
SVR
LVL and RVR
Relapse
SVR
HVL or non-RVR
Yu et al., Hepatology 2008; 47:1884-1893
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
Sustained virologic
response rate (%)
80
80
76
48 wks
72 wks
70
60
50
P=0.040
40
29
30
17
20
10
104/130
90/119
0
HCV RNA < 50 IU/mL
at week 12
17/100
31/106
HCV RNA ≥ 50 IU/mL
at week 12
Berg, et al. Gastroenterology 2006;130:1086-1097
Virologic relapse rate (%)
Virologic relapse rates in patients with
slow virologic response
70
64
48 wks
72 wks
60
50
40
40
37
30
20
23
P=0.016
P=0.021
10
46/124
28/122
30/47
21/52
0
> 50 IU/mL
> 50 IU/mL
Week 4
Week 12
Berg, et al. Gastroenterology 2006;130:1086-1097
Peginterferon alfa-2a plus ribavirin for 48
vs. 72 weeks in patients with detectable
HCV RNA at week 4 of treatment
Sustained virologic
response rate (%)
60
50
48 wks
72 wks
51%
40
44%
37%
30
20
28%
27%
28%
10
P=0.003
P=0.002
P=0.35
HCV-1
HCV-1 /
<800,000 IU/mL
HCV-1 /
>800,000 IU/mL
0
Sanchez-Tapias et al., Gastroenterology 2006;131:451-460
Peginterferon alfa-2a plus ribavirin for 48
vs. 72 weeks in patients with detectable
HCV RNA at week 4 of treatment
Virologic
relapse rate (%)
60
50
48 wks
72 wks
55%
53%
50%
40
30
27%
20
10
23%
17%
P=0.002
P=0.007
P=0.15
HCV-1
HCV-1 /
<800,000 IU/mL
HCV-1 /
>800,000 IU/mL
0
Sanchez-Tapias et al., Gastroenterology 2006;131:451-460
Viral kinetics: tailoring of therapy
in HCV genotype 1 infected patients
HCV-1 (LVL, RVR)
24 weeks
Zeuzem et al. 2004; Zeuzem et al. 2005; Jensen et al. 2006
HCV-1 (cEVR)
48 weeks
Manns et al. 2002; Hadziyannis et al. 2004; Kamal et al. 2005
HCV-1 (SPR)
Buti et al. 2003; Berg et al. 2006; Sanchez-Tapias et al. 2006
72 weeks
Treatment of
„Difficult-to-cure“ Patients
Virologic Response in
G1, HVL, > 85 kg patients
PEG-IFN alfa-2a 180 ug + RBV 1200 mg
PEG-IFN alfa-2a 270 ug + RBV 1200 mg
PEG-IFN alfa-2a 180 ug + RBV 1600 mg
PEG-IFN alfa-2a 270 ug + RBV 1600 mg
80%
Arm A (n=46)
% Patients with VR
70%
Arm B, C,& D (n=47)
60%
50%
40%
(n=66)
33%
47%
(n=53)
36%
28%
30%
32%
36%
20%
10%
0%
NV15801 (Fried)
VR = HCV RNA < 50 copies/mL
NV15492
(Hadziyannis)
NV17318
Fried et al., AASLD 2006
SVR and anemia as functions of
exposure AUC – HCV genotype 1
n = 242, Snoeck et al, Br J Clin Pharm 2006
Treatment response (%)
Weight-based exposure of
ribavirin and treatment response
90
80
70
60
50
40
30
20
10
86,7
<13.3 mg/kg/day
13.3-15.2 mg/kg/day
>15.2 mg/kg/day
72,1
82,1
67,7
48,4 50
46,4 48
22,5
25
7,1 5,9
0
24 wk tx
48 wk tx
Relapse
24 wk tx
48 wk tx
SVR
Yu et al., Hepatology 2008; 47:1884-1893
Case: HCV1, HVL, cirrhosis
5/06
8/06
9/06
12/06
3/07
9/08
1/09
Standard therapy
< 2 log decline (Hb 12.8)
High dose (270 µg PEG-IFN
alfa-2a + 1600 mg RBV)
> 2 log decline (RBV 2000 mg)
HCV RNA negative
18 months therapy with HD + EPO
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