HEPATITIS WEB STUDY
HEPATITIS C ONLINE
Ribavirin (Copegus, Rebetol, Ribasphere)
Prepared by: David Spach, MD and H. Nina Kim, MD
Last Updated: February 14, 2014
Hepatitis
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RIBAVIRIN (COPEGUS, REBETOL, RIBASPHERE)
Background
Hepatitis
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Ribavirin: Mechanism of Action
Th2
Defective HCV
Particle
Th1
X X
CTL
RBV
IFN-γ
TNF-α
1: Immune Clearance
Hepatocyte
RBV
IMP
RBV
–
P
IMPDH
GMP
2: Inhibition of IMPDH
GTP
HCV RNA
RdRp
RBV
P
3: Inhibition of HCV RdRp
P
–
RNA Mutagen
RBV
P
P
4: RNA Mutagenesis
P
X
Modified from: Feld JJ, Hoofnagle JH. Nature. 2005;436:967-72.
X
X X
Hepatitis
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Ribavirin (Copegus, Rebetol, Ribasphere)
• Mechanism: purine nucleoside analog
• Approval Status:
- First approved by FDA in 1998
- Multiple preparations subsequently FDA approved
• Indications
- In combination with other agents for all HCV genotypes
• Dosing (brand dependent):
- Fixed dose (800 mg PO per day in two divided doses)
- Weight based (1000-1200 mg per day in two divided doses)
- Weight based (800-1400 mg per day in two divided doses)
• Drug Interactions
- Use of ribavirin and didanosine can cause life-threatening toxicity
- Use of ribavirin and azathioprine can cause azathioprine-related toxicity
• Adverse Effects (AE)
- Hemolytic anemia
- Birth defects (pregnancy category X)
Hepatitis
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Ribavirin: Key Studies
• Interferon alfa-2b +/- Ribavirin for 24 or 48 weeks
• Peginterferon alfa-2a +/- Ribavirin for Chronic HCV
• Duration and Dose Finding Peginterferon alfa-2a + Ribavirin
• Flat versus Weight-Based Ribavirin Dosing: WINR Study
Hepatitis
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Phase 3
Treatment Naïve, Chronic HCV
Interferon alfa-2b +/- Ribavirin for 24 or 48 weeks
McHutchison JG, et al. N Engl J Med. 1998;339:1485-92.
Hepatitis
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Interferon alfa-2b +/- Ribavirin for Chronic HCV
Study Outline
• Study
- Randomized, double-blinded, placebo controlled, phase 3 trial
- Conducted in 44 centers in United States
• Subjects
- N = 912 with chronic hepatitis C
- Treatment naïve; 72% genotype 1
• Regimens
- Interferon alfa-2b + Placebo x 24 or 48 weeks
- Interferon alfa-2b + Ribavirin (weight based) x 24 or 48 weeks
• Primary Endpoint
- Undetectable serum HCV RNA 24 weeks after stopping treatment
*Ribavirin weight based dosing: <75 kg = 1000 mg/day; >75 kg = 1200 mg/day
Source: McHutchison JG, et al. N Engl J Med. 1998;339:1485-92.
Hepatitis
web study
Interferon alfa-2b +/- Ribavirin for Chronic HCV
Study Design
Week 0
24
Interferon
48
72
SVR24
(n = 231)
Interferon
SVR24
(n = 225)
Interferon + Ribavirin
(n = 228)
SVR24
Interferon + Ribavirin
(n = 228)
SVR24
Drug Dosing
Interferon alfa-2b 3 million U 3x/week
Weight-based Ribavirin (divided bid): 1000 mg/day if < 75kg or 1200 mg/day if ≥ 75kg
Source: McHutchison JG, et al. N Engl J Med. 1998;339:1485-92.
Hepatitis
web study
Interferon alfa-2b +/- Ribavirin for Chronic HCV
Study Results
SVR 24, by Treatment Regimen
Patients with SVR 24 (%)
50
38
40
31
30
20
13
10
0
6
13/231
29/225
70/228
87/228
Interferon
(24 weeks)
Interferon
(48 weeks)
Interferon + Ribavirin
(24 weeks)
Interferon + Ribavirin
(48 weeks)
Source: McHutchison JG, et al. N Engl J Med. 1998;339:1485-92.
Hepatitis
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Interferon alfa-2b +/- Ribavirin for Chronic HCV
Study Conclusions
Conclusions: “In patients with chronic hepatitis C, initial therapy with
interferon and ribavirin was more effective than treatment with
interferon alone.”
Source: McHutchison JG, et al. N Engl J Med. 1998;339:1485-92.
Hepatitis
web study
Phase 3
Treatment Naïve, Chronic HCV
Peginterferon alfa-2a +/- Ribavirin for Chronic HCV
Fried MW, et. al. N Engl J Med. 2002;347:975-82.
Hepatitis
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Peginterferon alfa-2a +/- Ribavirin for Chronic HCV
Study Design
• Study
- Open-label randomized controlled trial
• Subjects
- N = 1149 with chronic hepatitis C randomized
- Treatment naïve; 62% genotype 1
- Serum ALT above upper limit of normal x prior 6 months
• Regimens (48 Week Treatment)
- Peginterferon alfa-2a 180 µg 1x/week + Ribavirin 1000-1200 mg/day
- Peginterferon alfa-2a 180 µg 1x/week + Placebo
- Interferon alfa-2b 3 million U 3x/week + Ribavirin 1000-1200 mg/day
• Primary Endpoint
- Undetectable serum HCV RNA 24 weeks after stopping treatment
*Ribavirin dosing: <75 kg = 1000 mg/day; >75 kg = 1200 mg/day
Source: Fried MW, et. al. N Engl J Med. 2002;347:975-82.
Hepatitis
web study
Peginterferon alfa-2a +/- Ribavirin for Chronic HCV
Study Design
Week
0
48
72
N = 453
Peginterferon alfa-2a + Ribavirin
SVR24
N = 224
Peginterferon alfa-2a + Placebo
SVR24
N = 444
Standard interferon + Ribavirin
SVR24
Drug Dosing
Peginterferon alfa-2a 180 µg 1x/week
Weight-based Ribavirin (divided bid): 1000 mg/day if < 75kg or 1200 mg/day if ≥ 75kg
Interferon alfa-2b 3 million U 3x/week
Source: Fried MW, et. al. N Engl J Med. 2002;347:975-82.
Hepatitis
web study
Peginterferon alfa-2a + Ribavirin for Chronic HCV
Results
Response after 48 Weeks of Treatment
100
Peginterferon alfa-2a 180 µg + Ribavirin
Peginterferon alfa-2a 180 µg + Placebo
Interferon alfa-2b + Ribavirin
80
Patients (%)
69
60
59
52
56
44
40
29
20
0
313/453 132/224 231/444
End of Treatment Response
Source: Fried MW, et. al. N Engl J Med. 2002;347:975-82.
255/453
66/224
197/444
Sustained Virologic Response
Hepatitis
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Peginterferon alfa-2a + Ribavirin for Chronic HCV
Predictive Value of Early Virologic Response
Yes
Week 12
HCV RNA
(N = 453)
N = 390
(86%)
SVR
N = 253
(65%)
No SVR
N = 137
(35%)
SVR
N=2
(3%)
No SVR
N = 61
(97%)
2-log drop or
undetectable
HCV RNA
No
N = 63
(14%)
Source: Fried MW, et. al. N Engl J Med. 2002;347:975-82.
Hepatitis
web study
Peginterferon (with and without Ribavirin) versus
Interferon and Ribavirin
Conclusions: “In patients with chronic hepatitis C, once-weekly
peginterferon alfa-2a plus ribavirin was tolerated as well as interferon
alfa-2b plus ribavirin and produced significant improvements in the rate
of sustained virologic response, as compared with interferon alfa-2b plus
ribavirin or peginterferon alfa-2a alone.”
Source: Fried MW, et. al. N Engl J Med. 2002;347:975-82.
Hepatitis
web study
Phase 3
Treatment Naïve, Chronic HCV
Duration and Dose Finding Peginterferon alfa-2a + Ribavirin
Randomized study of low-dose versus weight based ribavirin and 24 versus 48 weeks of therapy
Hadziyannis SJ, et. al. Ann Intern Med. 2004;140:346-55.
Hepatitis
web study
Peginterferon alfa-2a + Ribavirin for Chronic HCV
Treatment Duration and Ribavirin Dose
• Study
- Randomized, double-blind trial
• Subjects
- N = 1311 with chronic hepatitis C (1284 treated)
- Treatment naïve adult patients; 58% genotype 1
- Serum ALT above upper limit of normal x prior 6 months
• Regimens
- Peginterferon alfa-2a: 180 µg/wk + Ribavirin: 800 mg/day x 24 wks
- Peginterferon alfa-2a: 180 µg/wk + *Ribavirin: 1000-1200 mg/day x 24 wks
- Peginterferon alfa-2a: 180 µg/wk + Ribavirin: 800 mg/d x 48 weeks
- Peginterferon alfa-2a: 180 µg/wk + *Ribavirin: 1000-1200 mg/day x 48 wks
• Primary Endpoint
- Undetectable serum HCV RNA at end of treatment (ETR)
- Undetectable serum HCV RNA 24 wks after cessation of treatment (SV
*Ribavirin dose: 1000 mg/day for Wt <75 kg, 1200 mg/day for Wt ≥75 kg
Source: Hadziyannis SJ, et. al. Ann Intern Med. 2004;140:346-55.
Hepatitis
web study
Peginterferon alfa-2a + Ribavirin for Chronic HCV
Treatment Duration and Ribavirin Dose
Week 0
12
24
48
72
Randomize
Peginterferon alfa-2a +
Ribavirin (low dose)
(n = 214)
SVR24
Peginterferon alfa-2a +
Ribavirin (weight-based dose)
(n = 288)
SVR24
Peginterferon alfa-2a + Ribavirin (low dose)
(n = 365)
SVR24
Peginterferon alfa-2a + Ribavirin (weight-based dose)
(n = 158)
SVR24
Source: Hadziyannis SJ, et. al. Ann Intern Med. 2004;140:346-55.
Hepatitis
web study
Peginterferon alfa-2a + Ribavirin for Chronic HCV
Treatment Duration and Ribavirin Dose
SVR24 Rates, by Regimen
PEG + RBV (low dose) x 24 weeks
PEG + RBV (weight-based dose) x 24 weeks
PEG + RBV (low dose) x 48 weeks
PEG + RBV (weight-based dose) x 48 weeks
100
Patients with SVR (%)
84
81
79
80
n = 144
n = 99
n = 153
80
60
40
52
42
41
n = 118
n = 250
29
20
n = 101
0
n = 271
n = 96
Genotype 1
Genotypes 2 or 3
Genotype
Source: Hadziyannis SJ, et. al. Ann Intern Med. 2004;140:346-55.
Hepatitis
web study
Peginterferon alfa-2a + Ribavirin for Chronic HCV
Treatment Duration and Ribavirin Dose
Rates of SVR with Different Peginterferon + Ribavirin Regimens
Peginterferon + Ribavirin (low dose) x 24 weeks
Peginterferon + Ribavirin (weight-based dose) x 24 weeks
Patients with SVR (%)
Peginterferon + Ribavirin (low dose) x 48 weeks
Peginterferon + Ribavirin (weight-based dose) x 48 weeks
100
80
84 81
79 80
85 83 88
84
77
80
82
74
60
40
20
0
All Patients
Low Viral Load
Source: Hadziyannis SJ, et. al. Ann Intern Med. 2004;140:346-55.
High Viral Load
Hepatitis
web study
Peginterferon alfa-2a + Ribavirin for Chronic HCV
Treatment Duration and Ribavirin Dose
Conclusion: “Treatment with peginterferon-alpha2a and ribavirin may be
individualized by genotype. Patients with HCV genotype 1 require
treatment for 48 weeks and a standard dose of ribavirin; those with HCV
genotypes 2 or 3 seem to be adequately treated with a low dose of
ribavirin for 24 weeks.”
Source: Hadziyannis SJ, et. al. Ann Intern Med. 2004;140:346-55.
Hepatitis
web study
Phase 3
Treatment Naïve, Chronic HCV
WINR Study
Flat versus Weight-Based Ribavirin Dosing
Jacobson IM, et. al. Hepatology. 2007;46:971-81.
Hepatitis
web study
Peginterferon alfa-2b + Ribavirin (weight-based or flat-dose)
WIN-R Study: Design
• Study
- Prospective, randomized, open-label trial
• Subjects
- N = 5027 with chronic hepatitis C (4913 analyzed)
- Treatment naïve adult patients (Age 18-70)
• Treatment Regimens
- Peginterferon alfa-2b: 1.5 µg/kg/wk + Wt-based* Ribavirin: 800-1400 mg/d
- Peginterferon alfa-2b: 1.5 µg/kg/wk + Flat-dose Ribavirin: 800 mg/d
• Treatment Duration
- Genotypes 1,4,5,6: duration of 48 weeks
- Genotypes 2,3: duration of 24 or 48 weeks
• Primary Endpoint
- Undetectable serum HCV RNA at end of treatment (ETR)
- Undetectable serum HCV RNA 24 weeks after cessation of treatment (SVR)
*Weight-based ribavirin dosing: < 65 kg: 800 mg/d; 65-85 kg: 1000 mg/d; >85-105 kg: 1200 mg/d; >105 kg: 1400 mg/d
Source: Jacobson IM, et. al. Hepatology. 2007;46:971-81.
Hepatitis
web study
Peginterferon alfa-2b + Ribavirin (weight-based or flat-dose)
WIN-R Study: Design
Week
0
24
PEG + Ribavirin
GT
1-6
48
(weight-based)
GT
2, 3
SVR24
(n = 2111)
PEG + Ribavirin (flat dose)
(n = 2144)
PEG + RBV (weight-based)
(n = 333)
PEG + Ribavirin
(flat dose)
(n = 335)
72
SVR24
SVR24
SVR24
Drug Dosing
Peginterferon alfa-2b: 180 µg once weekly
Weight-based Ribavirin (in 2 divided doses):
- 800 mg/d if < 65 kg; 1000 mg/d if 65-85 kg; 1200 mg/d if >85-105 kg; 1400 mg/d if >105 kg
Flat-dose Ribavirin (in 2 divided doses): 800 mg/day
Source: Jacobson IM, et. al. Hepatology. 2007;46:971-81.
Hepatitis
web study
Peginterferon alfa-2b + Ribavirin (weight-based or flat-dose)
WIN-R Study: Results
SVR 24, by Genotype and Treatment Regimen
Weight-Based Ribavirin
Patients with SVR 24 (%)
80
Flat Dose Ribavirin
P = .252
62
60
60
P = .008
P = .005
44
41
40
34
29
20
938/2121
0
852/2121
All
447/1313
377/1305
GT-1
Source: Jacobson IM, et. al. Hepatology. 2007;46:971-81.
479/775
462/777
GT-2,3
Hepatitis
web study
Peginterferon alfa-2b + Ribavirin (weight-based or flat-dose)
WIN-R Study: Results
All Treated: SVR24 by Weight Distribution
100
65-85 kg
>85-105 kg
Patients with SVR (%)
80
>105 kg
60
P = .973
45.2
P = .001
47.3
42.0
40
43.8
38.8
33.5
20
0
Weight-Based Ribavirin
Source: Jacobson IM, et. al. Hepatology. 2007;46:971-81.
Flat-Dose Ribavirin
Hepatitis
web study
Peginterferon alfa-2b + Ribavirin (weight-based or flat-dose)
WIN-R Study: Results
Genotype 1: SVR24 by Weight Distribution
80
65-85 kg
>85-105 kg
>105 kg
Patients with SVR (%)
60
P = .569
40
33.8
P = .019
37.3
33.3
31.1
28.8
21.3
20
0
Weight-Based Ribavirin
Source: Jacobson IM, et. al. Hepatology. 2007;46:971-81.
Flat-Dose Ribavirin
Hepatitis
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Peginterferon alfa-2b & Weight-based or Flat-dose Ribavirin
WIN-R Study: Results
Genotypes 2,3: SVR24 by Weight Distribution
100
65-85 kg
>85-105 kg
Patients with SVR (%)
80
>105 kg
P = .356
64
60
59
61
64
P = .034
55
55
40
20
0
Weight-Based Ribavirin
Source: Jacobson IM, et. al. Hepatology. 2007;46:971-81.
Flat-Dose Ribavirin
Hepatitis
web study
Peginterferon alfa-2b + Ribavirin (weight-based or flat-dose)
WIN-R Study: Results
Sustained Virologic Response (SVR) by Weight Distribution
African American Genotype 1
100
Patients with SVR (%)
65-85 kg
>85-105 kg
80
>105 kg
60
P = .036
40
P = .446
31.3
22.2
20
13.1
11.7
9.9
6.7
0
Weight-Based Ribavirin
Source: Jacobson IM, et. al. Hepatology. 2007;46:971-81.
Flat-Dose Ribavirin
Hepatitis
web study
Peginterferon alfa-2b & Weight-based or Flat-dose Ribavirin
WIN-R Study: Results
Relapse Rates among Patients who Achieved End-of-Treatment Responses
Weight-Based Ribavirin
Flat-Dose Ribavirin
35
29.6
Relapse Rates (%)
30
25
23.0
19.0
20
15.3
15
10
7.0
8.3
5
0
All Treated
Genotype 1
Source: Jacobson IM, et. al. Hepatology. 2007;46:971-81.
Genotypes 2 & 3
Hepatitis
web study
Peginterferon alfa-2b & Weight-based or Flat-dose Ribavirin
WIN-R Study: Conclusions
Conclusion: “Peginterferon alfa-2b plus weight-based ribavirin is more
effective than flat-dose ribavirin, particularly in genotype 1 patients,
providing equivalent efficacy across all weight groups. Ribavirin 1400
mg/day is appropriate for patients 105 to 125 kg. For genotype 2/3
patients, 24 weeks of treatment with flat-dose ribavirin is adequate; no
evidence of additional benefit of extending treatment to 48 weeks was
demonstrated.”
Source: Jacobson IM, et. al. Hepatology. 2007;46:971-81.
Hepatitis
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This slide deck is from the University of Washington’s
Hepatitis C Online and Hepatitis Web Study projects.
Hepatitis C Online
www.hepatitisc.uw.edu
Hepatitis Web Study
http://depts.washington.edu/hepstudy/
Funded by a grant from the Centers for Disease Control and Prevention.
Hepatitis
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