ribavirin ( copegus , rebetol , ribasphere )
DESCRIPTION
Ribavirin ( Copegus , Rebetol , Ribasphere ). Prepared by: David Spach, MD and H. Nina Kim, MD Last Updated: February 14, 2014. Ribavirin ( Copegus , Rebetol , Ribasphere ). Background. Ribavirin: Mechanism of Action. Defective HCV Particle. Th2. Th1. CTL. RBV. IFN- γ. - PowerPoint PPT PresentationTRANSCRIPT
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HEPATITIS WEB STUDY HEPATITIS C ONLINE
Ribavirin (Copegus, Rebetol, Ribasphere)
Prepared by: David Spach, MD and H. Nina Kim, MDLast Updated: February 14, 2014
Hepatitisweb study
Hepatitisweb study
BackgroundRIBAVIRIN (COPEGUS, REBETOL, RIBASPHERE)
Hepatitisweb study
P PRBV
RBV
P P PRBV
GMP GTP
IMP
PRBV
HCV RNA
XX
X4: RNA Mutagenesis
3: Inhibition of HCV RdRp
2: Inhibition of IMPDH
1: Immune Clearance
RNA Mutagen
IMPDH
RdRp
RBV
Th2 Th1
CTL
–
–
Hepatocyte
X
XXDefective HCV
Particle
IFN-γTNF-α
Ribavirin: Mechanism of Action
Modified from: Feld JJ, Hoofnagle JH. Nature. 2005;436:967-72.
Hepatitisweb study
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)
Hepatitisweb study
Hepatitisweb study
• 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
Ribavirin: Key Studies
Hepatitisweb study
Hepatitisweb study
Interferon alfa-2b +/- Ribavirin for 24 or 48 weeks
Phase 3
Treatment Naïve, Chronic HCV
McHutchison JG, et al. N Engl J Med. 1998;339:1485-92.
Hepatitisweb study
Interferon alfa-2b +/- Ribavirin for Chronic HCVStudy 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
Source: McHutchison JG, et al. N Engl J Med. 1998;339:1485-92.
*Ribavirin weight based dosing: <75 kg = 1000 mg/day; >75 kg = 1200 mg/day
Hepatitisweb study
Interferon + Ribavirin(n = 228)
Interferon(n = 225)
Interferon (n = 231)
48 720Week
Source: McHutchison JG, et al. N Engl J Med. 1998;339:1485-92.
Interferon alfa-2b +/- Ribavirin for Chronic HCVStudy Design
Drug DosingInterferon alfa-2b 3 million U 3x/weekWeight-based Ribavirin (divided bid): 1000 mg/day if < 75kg or 1200 mg/day if ≥ 75kg
SVR24
Interferon + Ribavirin(n = 228)
SVR24
24
SVR24
SVR24
Hepatitisweb study
Interferon alfa-2b +/- Ribavirin for Chronic HCVStudy Results
SVR 24, by Treatment Regimen
Source: McHutchison JG, et al. N Engl J Med. 1998;339:1485-92.
Interferon _x000d_(24 weeks)
Interferon _x000d_(48 weeks)
Interferon + Ribavirin _x000d_(24 weeks)
Interferon + Ribavirin _x000d_(48 weeks)
0
10
20
30
40
50
6
13
31
38
Patie
nts
with
SVR
24
(%)
13/231 29/225 70/228 87/228
Hepatitisweb studySource: McHutchison JG, et al. N Engl J Med. 1998;339:1485-92.
Interferon alfa-2b +/- Ribavirin for Chronic HCVStudy Conclusions
Conclusions: “In patients with chronic hepatitis C, initial therapy with interferon and ribavirin was more effective than treatment with interferon alone.”
Hepatitisweb study
Hepatitisweb study
Peginterferon alfa-2a +/- Ribavirin for Chronic HCV
Phase 3
Treatment Naïve, Chronic HCV
Fried MW, et. al. N Engl J Med. 2002;347:975-82.
Hepatitisweb study
Peginterferon alfa-2a +/- Ribavirin for Chronic HCVStudy 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
Source: Fried MW, et. al. N Engl J Med. 2002;347:975-82.
*Ribavirin dosing: <75 kg = 1000 mg/day; >75 kg = 1200 mg/day
Hepatitisweb study
Peginterferon alfa-2a + Ribavirin
Standard interferon + Ribavirin
Peginterferon alfa-2a + Placebo
48 720Week
Source: Fried MW, et. al. N Engl J Med. 2002;347:975-82.
Peginterferon alfa-2a +/- Ribavirin for Chronic HCVStudy Design
Drug DosingPeginterferon alfa-2a 180 µg 1x/weekWeight-based Ribavirin (divided bid): 1000 mg/day if < 75kg or 1200 mg/day if ≥ 75kgInterferon alfa-2b 3 million U 3x/week
SVR24
SVR24
SVR24
N = 224
N = 453
N = 444
Hepatitisweb study
End of Treatment Response Sustained Virologic Response0
20
40
60
80
100
69
5659
29
5244
Peginterferon alfa-2a 180 µg + Ribavirin Peginterferon alfa-2a 180 µg + Placebo Interferon alfa-2b + Ribavirin
Patie
nts
(%)
Peginterferon alfa-2a + Ribavirin for Chronic HCVResults
Response after 48 Weeks of Treatment
Source: Fried MW, et. al. N Engl J Med. 2002;347:975-82.
132/224313/453 231/444 66/224255/453 197/444
Hepatitisweb studySource: Fried MW, et. al. N Engl J Med. 2002;347:975-82.
Peginterferon alfa-2a + Ribavirin for Chronic HCVPredictive Value of Early Virologic Response
SVR
N = 137(35%)
N = 253(65%)
N = 63(14%)
N = 390(86%)
2-log drop or undetectable
HCV RNA
Yes
No
Week 12
HCV RNA(N = 453)
N = 61(97%)
N = 2(3%)
No SVR
SVR
No SVR
Hepatitisweb studySource: Fried MW, et. al. N Engl J Med. 2002;347:975-82.
Peginterferon (with and without Ribavirin) versusInterferon 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.”
Hepatitisweb study
Hepatitisweb study
Duration and Dose Finding Peginterferon alfa-2a + Ribavirin
Phase 3
Treatment Naïve, Chronic HCV
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.
Hepatitisweb study
*Ribavirin dose: 1000 mg/day for Wt <75 kg, 1200 mg/day for Wt ≥75 kg
Peginterferon alfa-2a + Ribavirin for Chronic HCVTreatment 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
Source: Hadziyannis SJ, et. al. Ann Intern Med. 2004;140:346-55.
Hepatitisweb study
Peginterferon alfa-2a + Ribavirin (low dose)(n = 214)
Peginterferon alfa-2a + Ribavirin (low dose)(n = 365)
Peginterferon alfa-2a + Ribavirin (weight-based dose)(n = 288)
Peginterferon alfa-2a + Ribavirin (weight-based dose)(n = 158)
48 720 12
Randomize
Week 24
Source: Hadziyannis SJ, et. al. Ann Intern Med. 2004;140:346-55.
Peginterferon alfa-2a + Ribavirin for Chronic HCVTreatment Duration and Ribavirin Dose
SVR24
SVR24
SVR24
SVR24
Hepatitisweb study
Genotype 1 Genotypes 2 or 30
20
40
60
80
100
29
84
42
81
41
79
52
80
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
Genotype
Patie
nts
with
SVR
(%)
Peginterferon alfa-2a + Ribavirin for Chronic HCVTreatment Duration and Ribavirin Dose
SVR24 Rates, by Regimen
Source: Hadziyannis SJ, et. al. Ann Intern Med. 2004;140:346-55.
n = 101 n = 118 n = 250 n = 271 n = 96 n = 144 n = 99 n = 153
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All Patients Low Viral Load High Viral Load0
20
40
60
80
10084 85 8481 83 8079
88
7480 77
82
Peginterferon + Ribavirin (low dose) x 24 weeks Peginterferon + Ribavirin (weight-based dose) x 24 weeks Peginterferon + Ribavirin (low dose) x 48 weeks Peginterferon + Ribavirin (weight-based dose) x 48 weeks
Patie
nts
with
SVR
(%)
Peginterferon alfa-2a + Ribavirin for Chronic HCVTreatment Duration and Ribavirin Dose
Rates of SVR with Different Peginterferon + Ribavirin Regimens
Source: Hadziyannis SJ, et. al. Ann Intern Med. 2004;140:346-55.
Hepatitisweb studySource: Hadziyannis SJ, et. al. Ann Intern Med. 2004;140:346-55.
Peginterferon alfa-2a + Ribavirin for Chronic HCVTreatment 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.”
Hepatitisweb study
Hepatitisweb study
WINR StudyFlat versus Weight-Based Ribavirin Dosing
Phase 3
Treatment Naïve, Chronic HCV
Jacobson IM, et. al. Hepatology. 2007;46:971-81.
Hepatitisweb study
*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
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)
Source: Jacobson IM, et. al. Hepatology. 2007;46:971-81.
Hepatitisweb study
PEG + Ribavirin (weight-based)(n = 2111)
PEG + RBV (weight-based)(n = 333)
48 720Week 24
Source: Jacobson IM, et. al. Hepatology. 2007;46:971-81.
Peginterferon alfa-2b + Ribavirin (weight-based or flat-dose) WIN-R Study: Design
SVR24
GT1-6
Drug DosingPeginterferon alfa-2b: 180 µg once weeklyWeight-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
GT2, 3 PEG + Ribavirin (flat dose)
(n = 335)
PEG + Ribavirin (flat dose)(n = 2144)
SVR24
SVR24
SVR24
Hepatitisweb study
Peginterferon alfa-2b + Ribavirin (weight-based or flat-dose) WIN-R Study: Results
SVR 24, by Genotype and Treatment Regimen
Source: Jacobson IM, et. al. Hepatology. 2007;46:971-81.
All GT-1 GT-2,3 0
20
40
60
80
44
34
62
41
29
60
Weight-Based Ribavirin Flat Dose Ribavirin
Patie
nts
with
SVR
24
(%)
938/2121 852/2121 447/1313 377/1305 479/775 462/777
P = .008P = .005
P = .252
Hepatitisweb study
Weight-Based Ribavirin Flat-Dose Ribavirin 0
20
40
60
80
100
45.2 43.842.0 38.847.3
33.5
65-85 kg>85-105 kg>105 kg
Patie
nts
with
SVR
(%)
P = .973 P = .001
Peginterferon alfa-2b + Ribavirin (weight-based or flat-dose) WIN-R Study: Results
All Treated: SVR24 by Weight Distribution
Source: Jacobson IM, et. al. Hepatology. 2007;46:971-81.
Hepatitisweb study
Peginterferon alfa-2b + Ribavirin (weight-based or flat-dose) WIN-R Study: Results
Genotype 1: SVR24 by Weight Distribution
Source: Jacobson IM, et. al. Hepatology. 2007;46:971-81.
Weight-Based Ribavirin Flat-Dose Ribavirin 0
20
40
60
80
33.8 31.133.328.8
37.3
21.3
65-85 kg>85-105 kg>105 kg
Patie
nts
with
SVR
(%)
P = .569P = .019
Hepatitisweb study
Peginterferon alfa-2b & Weight-based or Flat-dose RibavirinWIN-R Study: Results
Genotypes 2,3: SVR24 by Weight Distribution
Source: Jacobson IM, et. al. Hepatology. 2007;46:971-81.
Weight-Based Ribavirin Flat-Dose Ribavirin 0
20
40
60
80
100
64 6459
5561
55
65-85 kg>85-105 kg>105 kg
Patie
nts
with
SVR
(%) P = .356
P = .034
Hepatitisweb study
Peginterferon alfa-2b + Ribavirin (weight-based or flat-dose) WIN-R Study: Results
Sustained Virologic Response (SVR) by Weight Distribution
Source: Jacobson IM, et. al. Hepatology. 2007;46:971-81.
Weight-Based Ribavirin Flat-Dose Ribavirin 0
20
40
60
80
100
13.1 11.7
22.2
9.9
31.3
6.7
African American Genotype 165-85 kg>85-105 kg>105 kg
Patie
nts
with
SVR
(%)
P = .036 P = .446
Hepatitisweb study
Peginterferon alfa-2b & Weight-based or Flat-dose RibavirinWIN-R Study: Results
Relapse Rates among Patients who Achieved End-of-Treatment Responses
Source: Jacobson IM, et. al. Hepatology. 2007;46:971-81.
All Treated Genotype 1 Genotypes 2 & 30
5
10
15
20
25
30
35
15.3
23.0
7.0
19
29.6
8.3
Weight-Based Ribavirin Flat-Dose Ribavirin
Rela
pse
Rate
s (%
)
Hepatitisweb studySource: Jacobson IM, et. al. Hepatology. 2007;46:971-81.
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.”
Hepatitisweb study
Hepatitisweb study
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Hepatitis C Onlinewww.hepatitisc.uw.edu
Hepatitis Web Studyhttp://depts.washington.edu/hepstudy/
Funded by a grant from the Centers for Disease Control and Prevention.