WHAT FUTURE FOR RIBAVIRIN? Mitchell L Shiffman, MD Chief, Hepatology Section Medical Director, Liver...
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WHAT FUTURE FOR RIBAVIRIN? Mitchell L Shiffman, MD Chief, Hepatology Section Medical Director, Liver Transplant Program Virginia Commonwealth University Medical Center Richmond, VA
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Transcript of WHAT FUTURE FOR RIBAVIRIN? Mitchell L Shiffman, MD Chief, Hepatology Section Medical Director, Liver...
WHAT FUTURE FOR RIBAVIRIN?
Mitchell L Shiffman, MDChief, Hepatology SectionMedical Director, Liver Transplant ProgramVirginia Commonwealth University Medical CenterRichmond, VA
ROLE OF RIBAVIRIN IN HCV TREATMENTMECHANISM OF ACTION
• Guanosine analog• Inhibits inosine 5’ monophosphate dehydrogenase• Reduces intracellular guanosine stores
• Reduces RNA replication• Modulates immune response by altering cytokine synthesis
and cytotoxic T cell response• Incorporated into viral RNA leading to extensive mutagenesis
TREATMENT OF CHRONIC HCVOPTIMIZING SVR
The ability to achieve SVR is the result of threeindependent steps:1. Achieving a virologic response2. Maintaining the virologic response3. Not relapsing
Ribavirin plays a role in all 3 of these steps. Side effects lead to dose reduction and/or discontinuation
of treatment in 10-40% of patients.
ROLE OF RIBAVIRIN IN HCV TREATMENTENHANCES VIROLOGIC RESPONSE
JG McHutchison et al. N Eng J Med 1998; 339:1485-1492.MW Fried et al. N Eng J Med 2002; 347:975-982.
24
5950
69
0
20
40
60
80
100
Standard IFN PEGIFN
EO
T V
iro
log
icR
esp
on
se (
%)
No
Yes
Ribavirin:
ROLE OF RIBAVIRIN IN HCV TREATMENTSPECTRUM OF RESPONSES
0
1
2
3
4
5
6
7
8
-6 0 6 12 18 24 30 36 42 48 54 60 66 72 78
WEEKS
Lo
g H
CV
RN
A (
IU/m
l)
SVR
2-log decline
Peginterferon/Ribavirin
Limit of detection
ROLE OF RIBAVIRIN IN HCV TREATMENT ENHANCES COMPLETE EVR
10
18 18
11
38
17
0
10
20
30
40
50
4 12 24
Week First Became HCV RNA (-)
% H
CV
RN
A (
-)
No
Yes
Ribavirin:
P Ferrenci et al.J Hepatology 2005; 43:453-471.
ROLE OF RIBAVIRIN IN HCV TREATMENTREDUCES RELAPSE
JG McHutchison et al. N Eng J Med 1998; 339:1485-1492.MW Fried et al. N Eng J Med 2002; 347:975-982.
4551
22 19
0
20
40
60
80
Standard IFN PEGIFN
Re
lap
se (
%)
No
Yes
Ribavirin:
TREATMENT OF CHRONIC HCVEXTENDING RIBAVIRIN TREATMENT
Interferon alfa x 6 monthsResponse then Relapse
Interferon alfa-2b 3 mU TIWRibavirin 1000-1200 mg/day
X 6 months
Ribavirin1000-1200 mg/day
X 6 months
Stop Treatment
ML Shiffman et al.J Infect Dis 2001; 184:405-409.
0
20
40
60
80
100
Continue Stop
Ribavirin
SV
R (
%)
13/26
15/20
ROLE OF RIBAVIRIN IN HCV TREATMENTIMPACT OF RIBAVIRIN DOSE
0 4824Weeks
PEGIFN-2a 180 mcg/wk +Ribavirin 800 mg/day
Peginterferon alfa-2a 180 mcg/wk +Ribavirin 800 mg/day
PEGIFN-2a 180 mcg/wk +Ribavirin 1000 –1200 mg/day
PEGIFN-2a 180 mcg/wk +Ribavirin 1000-1200 mg/day
SJ Hadziyannis et al.Ann Int Med 2004; 140:346-355.
72
Ribavirin Dose:
ROLE OF RIBAVIRIN IN HCV TREATMENT HIGHER DOSES REDUCE RELAPSE
60
4132
69
52
25
0
20
40
60
80
100
EOT SVR Relapse
% o
f P
atie
nts
800
1000/1200
SJ Hadziyannis et al.Ann Int Med 2004; 140:346-355.
HIGH DOSE RIBAVIRIN AND EPOETIN
STUDY DESIGN
24 48
Weeks0
PEGIFN + Ribavirin ~13.3 mg/kg/d + EPO
PEGIFN + Ribavirin ~15.2 mg/kg/d + EPO
PEGIFN + Ribavirin ~13.3 mg/kg/d
7212
ML Shiffman et al.Hepatology 2007; 46:371-379.
Prospective randomized trial Treatment naïve HCV genotype 1 N=50 per group
HIGH DOSE RIBAVIRIN AND EPOETIN VIROLOGIC RESPONSE
34
22
49
3640
8
0
20
40
60
80
PEGIFN PEGIFN PEGIFN
Re
spo
nse
(%
)
SVR
Relapse
WB-RBVEPO
HD-RBVEPO
WB-RBV
ML Shiffman et al.Hepatology 2007; 46:371-379.
TREATMENT OF CHRONIC HCVIMPACT OF STOPPING RIBAVIRIN
Continue peginterferonStop ribavirin
0 4824Weeks
HCV RNA (-)
Continue peginterferonand ribavirin
Peginterferon alfa-2aand ribavirin
JP Bronowicki et al.Gastroenterology 2006; 131:1040-1048.
ROLE OF RIBAVIRIN IN HCV TREATMENTIMPACT OF STOPPING RIBAVIRIN
0 2 2 3
14
2629
0
612
32
42 42
5
0
10
20
30
40
50
24 30 36 48 52 60 72
WEEKS
% H
CV
RN
A (
+) Continue RBV
Stop RBV
JP Bronowicki et al.Gastroenterology 2006; 131:1040-1048.
ROLE OF RIBAVIRIN ON HCV TREATMENTIMPACT OF DOSE REDUCTION
9
21
6
11
7
-20
5
10
15
20
25
4 12 24
Week First Became HCV RNA (-)
Diff
ere
nce
in S
VR
Before
After
Time of dosereduction in relation to when first became HCV RNA negative
ML Shiffman et al.AASLD 2008; abstract 1423.
PEGIFN+R+Telaprevir
TELAPREVIR – PROVE 2STUDY DESIGN
12 4824
Weeks0
PEGIFN+R+Telaprevir
PEGIFN + Ribavirin
PEGIFN+R
GM Dusheiko et al.EASL 2008
PEGIFN+Telaprevir
TELAPREVIR - PROVE 2PHASE 2 FINAL RESULTS
69
5162
7973
36
52
68
80
0
20
40
60
80
100
PEG+TPV 12 Wks 24 Wks
PEGINF+TPV+RVN
% H
CV
RN
A (
-)
Week 4
Week 12
SVR
GM Dusheiko et al.EASL 2008
12 Wks
TELAPREVIR - PROVE 3NON-RESPONDER RETREATMENT
45
24
5261
0
20
40
60
80
100
PEG+TPV PEG+TPV+RVN
% H
CV
RN
A (
-)
Week 4
SVR
JM McHutchison et al.AASLD 2008
ROLE OF RIBAVIRIN ON HCV TREATMENTWHAT WILL THE FUTURE BE?
PEGIFN + Ribavirin + Protease + Polymerase
PEGIFN + Protease + Polymeraseor
Ribavirin + Protease + Polymerase
PEGIFN + Ribavirin (45%)
PEGIFN + Ribavirin + Protease (~70%)
ROLE OF RIBAVIRIN IN HCV TREATMENTSUMMARY
Ribavirin is an essential component of HCV treatment: Enhances response Prevents breakthrough Reduces relapse
Higher starting doses of ribavirin are associated with lower relapse and higher SVR rates
Stopping ribavirin prematurely is associated with breakthrough and a higher relapse rate.
Reducing the dose of ribavirin has particularly after the patient has become HCV RNA undetectable has minimal impact on SVR.
RIBAVIRIN AND HCV TREATMENTWHAT IS THE FUTURE
Replacing ribavirin even with a potent protease inhibitor appear to: Reduce virologic response Increases relapse
Additional studies to remove ribavirin from the HCV treatment paradigm will be explored when several protease and/or polymerase inhibitors are available.
It may be more realistic to remove peginterferon as opposed to ribavirin in the future.
