5th Paris Hepatitis Conference
The Future: Is Ribavirin Still Useful?
David Nelson, MD
Professor of Medicine, Microbiology, and Molecular Genetics
Associate Dean, Clinical Research and Training
Director, Clinical and Translational Science Institute
University of Florida
History of Ribavirin
• 1970: first synthesized at ICN Pharmaceuticals
• 1972: ribavirin active against a variety of RNA viruses
(including flavivirus)
– Failed FDA approval for influenza
• 1980: approved indication in inhalant form for RSV
• 1998: oral ribavirin approved as part of a combination
treatment (with interferon) for hepatitis C
– Improved SVR rates by 20-30%
• Prevention of relapse
Interferon-Based Therapy
Critical Role for Ribavirin in HCV Therapy
Direct Acting
Antivirals
100
2011
Peginterferon
80
60
2001
Ribavirin
Standard
Interferon
70+%
1998
55%
1991
42%
40
34%
39%
16%
20
6%
0
IFN
6m
IFN
12m
IFN/RBV
6m
IFN/RBV
12m
Adapted from US Food and Drug Administration,
Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring MD.
Peg-IFN
12m
Peg-IFN/
RBV 12m
Peg-IFN/
RBV/
DAA
Proposed mechanisms of action for
ribavirin against HCV include
• Direct effect against the HCV RNA dependent RNA polymerase
• Induction of mis-incorporation of nucleotides leading to
lethal mutagenesis
• Depletion of intracellular pools via inhibition of inosine
monophosphate dehydrogenase
• Alteration in the cytokine balance between a Th2 profile
(anti-inflammatory) to a Th1 profile (pro-inflammatory)
• Potentiating the effect of interferon via up-regulation of genes
involved in interferon signalling
Clark V, Nelson DR. Liver Int 2012; 32:103-7
Perspectives on Ribavirin
Role in DAA Combinations
• Pros
– It works: leads to higher SVR across all trials to date
• Cons
– Very “weak” antiviral
– Lack of understanding MOA: difficult to predict best
combination with DAA
– Adverse events
• Hemolytic anemia (monotherapy trials)
– Mean hgb reduction > 2gms by week 4
– 20% pts have > 4 gm drop
• Teratogen
• Pill burden and bid dosing
In-Vitro Prediction of RBV + DAAs
• Protease inhibitors1
– PI + RBV = additive antiviral activity
– PI + PEG/RBV = synergistic effect
• Reduce emergence of drug resistant variants
1. Hofmann WP, et al. Antivir Ther 2011; 16:695-704
Ribavirin Is Critical for Protease Inhibitor
Combination Therapy: Phase 2 Trials
100
PROVE II
PROVE-21
SVR (%)
80
PROVE III
SPRINT-1
PROVE-32
SPRINT-13
60
40
20
0
60%
36%
53%
T 12 wk +
PR 12 wk
(n = 82)
T 12 wk +
P 12 wk
(n = 78)
T 24 wk +
PR 48 wk
(n = 113)
24%
T 24 wk +
P 24 wk
(n = 111)
50%
36%
PR 48 wk
(no lead-in)
(n = 16)
B + P + low-dose
R (48 wk)
(n = 59)
Dosages not consistent between above studies.
Abbreviations: B, boceprevir; P, peg-IFN -2a and -2b; R, ribavirin; T, telaprevir.
7
Hezode C et al N Engl J Med 2009;360:1839.; McHutchinson JG, et al. N Engl J Med 2010;362:1292; Kwo PY et al. Lancet 2010;376:705
Patients with confirmed
virologic breakthrough (%)
Impact of RBV on Virologic Breakthrough
Role of Viral Subtype
50
Genotype 1a
Genotype 1b
40
30
23
20
10
10
10
6
2
1
2
3
0
PR48
(control)
T12/PR24
McHutchison JG, et al. Hepatology. 2009;50:334A-335A. (PROVE III)
T24/P24
(no RBV)
T24/PR48
Summary
• Patients that did not receive RBV in the PROVE
trials and those with low dose RBV in the
SPRINT-1 trial had
– Increased viral breakthrough
– Higher relapse rates
– Lower SVR
• Standard dose RBV is required to optimize
response to first generation PIs
Balapiravir (RG1626): RBV provides significant
antiviral activity with IFN + Nuc
Treatment Arm Mean Reduction in HCV RNA Level from Baseline log10 IU/mL
Week 1
Week 2
Week 3
Week 4
PEG-IFN +
RG1626
2.4
3.1
3.9
3.6
PEG-IFN +
RG1626 + RBV
3.3
4.6
5.1
5.2
PEG-IFN + RBV
1.1
1.6
2.1
2.4
Nelson DR et al. Ann Hepatol 2012; 11(1):15-31
Role of Ribavirin
Interferon-free Regimens
Ribavirin Reduces Viral Breakthrough
In Protease + Polymerase Combination
GS-9256 + GS-9190 (n = 15)
Median HCV RNA (IU/ml) Log 10
7
GS-9256 + GS-9190 + RBV (n = 13)
6
GS-9256 + GS-9190 + PEG IFN/RBV (n = 3)
5
4
Breakthrough
3
2
GS-9256: protease inhibitor
GS-9190: polymerase inhibitor
1
0
7
14
Day
Zeuzem S, et al. Hepatology. 2010;52:Abstract LB-1.
21
28
ZENITH: VX-222 + Telaprevir ± PegIFN/ RBV in
Genotype 1 Treatment-Naive Pts
•
VX-222, NS5B nonnucleoside, polymerase inhibitor
•
2-drug arms terminated due high rates (>25%) of on-treatment breakthrough
– 12 vBT (11 G1a and 1G1b)
– new arm added: VX-222 400 mg QD + telaprevir 1125 mg BID + RBV.
Wk 12
Wk 24
VX-222 100 mg BID + Telaprevir 1125 mg BID
(n = 18)
Treatment-naive
patients with
chronic genotype 1
HCV infection*
(N = 106)
VX-222 400 mg BID + Telaprevir 1125 mg BID
(n = 29)
VX-222 100 mg BID + Telaprevir 1125 mg BID
+ PR†
(n = 29)
Stop tx if
HCV RNA
undetectable at Wks
2 and 8†
VX-222 400 mg BID + Telaprevir 1125 mg BID
+ PR†
(n = 30)
PR for 12 wks if HCV
RNA detectable at
Wks 2 or 8†
*†PegIFN 180 µg/wk + weight-based RBV 1000-1200 mg/day.
Nelson DR, et al. AASLD 2011. Abstract LB-14.
Wk 36‡
HCV Gen 1b Can Be Cured Without IFN or RBV
BMS-790052 (NS5A) + BMS-650032 (NS3)
US Study[1]
BMS-790052 60 mg QD +
BMS-650032 600 mg BID
A
n=11
100
AASLD 2011:
Japan Study
(N = 10)[2]
90
90†
9/10
9/10
80
SVR24 (%)
BMS-790052 60 mg QD +
BMS-650032 600 mg BID
+ PEG-IFN/RBV
B
n=10
BMS-790052 60 mg QD +
BMS-650032 200 mg BID
Expansion A1
n=10 (GT-1b)
60
40
20
0
0
weeks
36
24
1. Lok A, et al. EASL 2011. Abstract 1356.
2. Chayama K, et al. AASLD 2011. Abstract LB-4.
n/N = 4/11
N/A
ELECTRON
PSI-7977 + RBV (GT-2/3)
PSI + R
12 weeks
n=10
PSI + PR
4 weeks
n=10
PSI + PR
8 weeks
n=10
PSI-7977 400 mg + RBV
PSI-7977 400 mg +
PegIFN/RBV
PSI-7977 400 mg + RBV
PSI-7977 400 mg + RBV
PSI-7977 400 mg + PegIFN/RBV
PSI + PR
12 weeks
n=10
PSI-7977 400 mg + PegIFN/RBV
PSI
12 weeks
n=10
PSI-7977 400 mg
Week
4
8
12
Gane EJ, et al. AASLD 2011. Abstract 34
15
PSI-7977 ELECTRON
What is the role of Ribavirin?
7
Combined IFN Arms
Mean HCV RNA (Log10 IU/mL)
6
PSI-7977/RBV
PSI-7977 Monotherapy
5
4
3
2
1
Assay LLOD 15 IU/mL
0
0
2
7
14
Time (Days)
21
28
PSI-7977 + RBV (GT-2/3)
Ribivirin Prevents relapse
100
Patients with undetectable HCV RNA (%)
100
100
100
100
80
60
60
40
20
0
SVR4
PSI + R
PSI + PR 4 wks
PSI + PR 8 wks
PSI + PR 12 wks
PSI
Gane EJ, et al. AASLD 2011. Abstract 34
ELECTRON: Anemia
RBV Impact on Hemoglobin with IFN-free PSI-7977/RBV
PSI-7977 + RBV
Alisporivir (GT-2/3)
VITAL-1: phase IIb trial of alisporivir in treatment-naïve HCV GT-2 or GT-3 patients
ALV1000
n=83
Alisporivir 600 mg BID
Alisporivir 1000 mg QD*
ALV600R
n=84
Alisporivir 600 mg BID +
RBV
Alisporivir 600 mg QD +
RBV*
ALV800R
n=94
Alisporivir 600 mg BID +
RBV
Alisporivir 800 mg QD +
RBV*
ALV-P
n=39
Alisporivir 600 mg BID +
PegIFN
Alisporivir 600 mg QD +
PegIFN*
PR
n=40
Week
PegIFN/RBV
1
*Patients with HCV RNA ≥25 IU/mL at Week 4 received alisporivir 600
mg QD + PegIFN/RBV from Week 6 until Week 24
24
Pawlotsky JM, et al. AASLD 2011. Abstract LB-11
19
Alisporivir in Genotyope 2/3
Pawlotsky JM, et al. AASLD 2011. Abstract LB-11
20
Conclusions
• The question of the role of RBV remains as real today as it was
two decades ago!
• Critical role for RBV in combination with DAAs for both IFNcontaining and IFN-sparing regimens
– Leads to higher SVR
• Additive antiviral activity
– Accelerates second slope of viral decline
• Prevents relapse and viral breakthrough
• RBV-free regimens more likely with potent and high-genetic
barrier regimens and subtype (1b >1a)