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The Future: Is Ribavirin Still Useful?
David Nelson, MDProfessor of Medicine, Microbiology, and Molecular GeneticsAssociate Dean, Clinical Research and TrainingDirector, Clinical and Translational Science InstituteUniversity of Florida
5th Paris Hepatitis Conference
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
Series10
20
40
60
80
100
6%
16%
34%42% 39%
55%
70+%
Adapted from US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring MD.
SVR (%)
IFN6m
Peg-IFN/ RBV 12m
IFN12m
IFN/RBV12m
Peg-IFN12m
2001
1998
2011
StandardInterferon
Ribavirin
Peginterferon
1991
Direct ActingAntivirals
Peg-IFN/RBV/DAA
IFN/RBV6m
Interferon-Based TherapyCritical Role for Ribavirin in HCV Therapy
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
7
PROVE-21 PROVE-32
SVR
(%)
0
20
40
60
80
100
PR 48 wk(no lead-in)
(n = 16)
B + P + low-dose R (48 wk)(n = 59)
SPRINT-13
36% 50% 36%24%53%60%
Ribavirin Is Critical for Protease Inhibitor Combination Therapy: Phase 2 Trials
Dosages not consistent between above studies.Abbreviations: B, boceprevir; P, peg-IFN -2a and -2b; R, ribavirin; T, telaprevir.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
T 12 wk + PR 12 wk(n = 82)
T 12 wk + P 12 wk(n = 78)
T 24 wk + PR 48 wk(n = 113)
T 24 wk + P 24 wk(n = 111)
PROVE II PROVE III SPRINT-1
Impact of RBV on Virologic Breakthrough Role of Viral Subtype
Patie
nts
with
con
firm
ed v
irolo
gic
brea
kthr
ough
(%)
T12/PR240
10
20
30
40
50
T24/P24 (no RBV)
T24/PR48
Genotype 1a
Genotype 1b
2
PR48 (control)
1
10
2
10
3
23
6
McHutchison JG, et al. Hepatology. 2009;50:334A-335A. (PROVE III)
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
Day
Med
ian
HCV
RN
A (IU
/ml)
Log
10
0
1
3
2
4
7 14 21 28
6
5
7
GS-9256: protease inhibitorGS-9190: polymerase inhibitor
GS-9256 + GS-9190 (n = 15)
GS-9256 + GS-9190 + RBV (n = 13)
GS-9256 + GS-9190 + PEG IFN/RBV (n = 3)
Breakthrough
Ribavirin Reduces Viral BreakthroughIn Protease + Polymerase Combination
Zeuzem S, et al. Hepatology. 2010;52:Abstract LB-1.
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.
*†PegIFN 180 µg/wk + weight-based RBV 1000-1200 mg/day.
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)
VX-222 400 mg BID + Telaprevir 1125 mg BID + PR†
(n = 30)
Wk 12
VX-222 100 mg BID + Telaprevir 1125 mg BID(n = 18)
Wk 36‡Wk 24
Nelson DR, et al. AASLD 2011. Abstract LB-14.
PR for 12 wks if HCV RNA detectable at
Wks 2 or 8†
Stop tx ifHCV RNA
undetectable at Wks 2 and 8†
HCV Gen 1b Can Be Cured Without IFN or RBVBMS-790052 (NS5A) + BMS-650032 (NS3)
1. Lok A, et al. EASL 2011. Abstract 1356.2. Chayama K, et al. AASLD 2011. Abstract LB-4.
100
80
60
40
20
0
36SVR2
4 (%
)
90 90†
N/A
US Study[1]
AASLD 2011:Japan Study
(N = 10)[2]
9/10n/N = 4/11 9/10
BMS-790052 60 mg QD + BMS-650032 600 mg BID
+ PEG-IFN/RBV
An=11
Bn=10
BMS-790052 60 mg QD + BMS-650032 200 mg BID
BMS-790052 60 mg QD + BMS-650032 600 mg BID
Expansion A1n=10 (GT-1b)
weeks0 24
8
PSI-7977 400 mg + PegIFN/RBV
PSI-7977 400 mg + PegIFN/RBV
Week
PSI-7977 400 mg + RBV
12
PSI + R12 weeks
n=10
PSI + PR12 weeks
n=10
4
PSI-7977 400 mg + RBV
PSI-7977 400 mg +PegIFN/RBV
PSI + PR8 weeks
n=10
PSI + PR4 weeks
n=10PSI-7977 400 mg + RBV
15
ELECTRONPSI-7977 + RBV (GT-2/3)
Gane EJ, et al. AASLD 2011. Abstract 34
PSI-7977 400 mgPSI
12 weeks n=10
PSI-7977 ELECTRONWhat is the role of Ribavirin?
Assay LLOD 15 IU/mL
PSI-7977/RBV
Combined IFN Arms
Time (Days)
0 2 7 14 21 28
Mea
n H
CV R
NA
(Log
10 IU
/mL)
0
1
2
3
4
5
6
7
PSI-7977 Monotherapy
PSI-7977 + RBV (GT-2/3)Ribivirin Prevents relapse
Gane EJ, et al. AASLD 2011. Abstract 34
SVR40
20
40
60
80
100
PSI + R PSI + PR 4 wks PSI + PR 8 wksPSI + PR 12 wks PSI
Patie
nts
wit
h un
dete
ctab
le H
CV R
NA
(%)
100 100 100 100
60
ELECTRON: Anemia RBV Impact on Hemoglobin with IFN-free PSI-7977/RBV
PSI-7977 + RBVPSI-7977 + RBV
Alisporivir 600 mg BID +RBV
Alisporivir 600 mg BID +PegIFN
Week
Alisporivir 800 mg QD +RBV*
24
ALV1000n=83
ALV-Pn=39
1
Alisporivir 600 mg BID
Alisporivir 600 mg BID +RBV
ALV800Rn=94
ALV600Rn=84
Alisporivir 600 mg QD +RBV*
19
Alisporivir (GT-2/3)
Pawlotsky JM, et al. AASLD 2011. Abstract LB-11
PegIFN/RBVPR
n=40
VITAL-1: phase IIb trial of alisporivir in treatment-naïve HCV GT-2 or GT-3 patients
Alisporivir 1000 mg QD*
Alisporivir 600 mg QD +PegIFN*
*Patients with HCV RNA ≥25 IU/mL at Week 4 received alisporivir 600 mg QD + PegIFN/RBV from Week 6 until Week 24
20
Alisporivir in Genotyope 2/3
Pawlotsky JM, et al. AASLD 2011. Abstract LB-11
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 IFN-containing 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)