The Future: Is Ribavirin Still Useful? David Nelson, MD Professor of Medicine, Microbiology, and...

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)