Hepatitis web study H EPATITIS W EB S TUDY H EPATITIS C O NLINE Ribavirin (Copegus, Rebetol, Ribasphere) Prepared by: David Spach, MD and H. Nina Kim,

Hepatitisweb study

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

X

4: 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


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


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

Pat

ien

ts w

ith

SV

R 2

4 (%

)

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


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


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

52

44

Peginterferon alfa-2a 180 µg + Ribavirin Peginterferon alfa-2a 180 µg + Placebo Interferon alfa-2b + Ribavirin

Pa

tie

nts

(%

)Peginterferon alfa-2a + Ribavirin for Chronic HCV

Results

Response after 48 Weeks of Treatment


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


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



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

Pa

tie

nts

wit

h S

VR

(%

)Peginterferon alfa-2a + Ribavirin for Chronic HCV

Treatment Duration and Ribavirin Dose

SVR24 Rates, by Regimen


n = 101 n = 118 n = 250 n = 271 n = 96 n = 144 n = 99 n = 153

Hepatitisweb study

All Patients Low Viral Load High Viral Load0

20

40

60

80

100

84 85 8481 83 807988

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

Pa

tie

nts

wit

h S

VR

(%

)


Rates of SVR with Different Peginterferon + Ribavirin Regimens


Hepatitisweb studySource: Hadziyannis SJ, et. al. Ann Intern Med. 2004;140:346-55.


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 Study

Flat versus Weight-Based Ribavirin Dosing

Phase 3


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


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


All GT-1 GT-2,3 0

20

40

60

80

44

34

62

41

29

60

Weight-Based Ribavirin Flat Dose Ribavirin

Pat

ien

ts w

ith

SV

R 2

4 (%

)

938/2121 852/2121 447/1313 377/1305 479/775 462/777

P = .008

P = .005

P = .252

Hepatitisweb study

Weight-Based Ribavirin Flat-Dose Ribavirin 0

20

40

60

80

100

45.2 43.842.038.8

47.3

33.5

65-85 kg

>85-105 kg

>105 kg

Pa

tie

nts

wit

h S

VR

(%

)

P = .973 P = .001


All Treated: SVR24 by Weight Distribution


Hepatitisweb study


Genotype 1: SVR24 by Weight Distribution



20

40

60

80

33.831.133.3

28.8

37.3

21.3

65-85 kg

>85-105 kg

>105 kg

Pa

tie

nts

wit

h S

VR

(%

)

P = .569P = .019

Hepatitisweb study

Peginterferon alfa-2b & Weight-based or Flat-dose RibavirinWIN-R Study: Results

Genotypes 2,3: SVR24 by Weight Distribution



20

40

60

80

100

64 6459

5561

55

65-85 kg

>85-105 kg

>105 kg

Pa

tie

nts

wit

h S

VR

(%

) P = .356P = .034

Hepatitisweb study


Sustained Virologic Response (SVR) by Weight Distribution



20

40

60

80

100

13.1 11.7

22.2

9.9

31.3

6.7

African American Genotype 1

65-85 kg

>85-105 kg

>105 kg

Pa

tie

nts

wit

h S

VR

(%

)

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


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

Re

lap

se

Ra

tes

(%

)

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

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.

http://www.hepatitisc.uw.edu/




Documents

Hepatitis web study H EPATITIS W EB S TUDY H EPATITIS C O NLINE Ribavirin (Copegus, Rebetol, Ribasphere) Prepared by: David Spach, MD and H. Nina Kim,