CURRENT TREATMENTS FOR HCVFOR...

Mitchell L. Shiffman, MD, FACG

CURRENT TREATMENTS FOR HCVFOR HCV

Mitchell L Shiffman, MDDirector

Liver Institute of Virginia

Liver Institute of VirginiaEducation, Research and Treatment for Patients with Liver Disease

IVerBon SecoursHealth System

Liver Institute of VirginiaBon Secours Health System

Richmond and Newport News, VA, USA

TREATMENT OF HCVCURRENT AND FUTURE TREATMENT

INF freeMulti DAA

PeginterferonRibavirin

GT 2-3SofosbuvirRibavirin

TelaprevirBoceprevir

SimeprevirGT 1

SofosbuvirGT 1,4-6

FaldaprevirDaclatasvir

Multi-DAAINF free

GT 1GileadAbbottBMS

BI –GT 1BGT1

IVer

2000 2011 10/2013 2014 2015+INF freeVertexMerck

Achillion

ACG's Hepatitis School - Nashville, TN Copyright 2013 American College of Gastroenterology

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TELAPREVIR AND BOCEPREVIRTREATMENT NAIVE

IVerIM Jacobson et al. N Eng J Med 2011;364:2405-2416F Poordad et al. N Engl J Med 2011;364:1195-1206

TELAPREVIR AND BOCEPREVIRRETREATMENT OF PEGINF FAILURES

IVerZeuzem S, et al. N Engl J Med 2011;364:2417-2428.Bacon B, et al. N Engl J Med 2011;364:1207-12017.

UnresponsiveF


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TELAPREVIR AND BOCEPREVIRCIRRHOSIS

Cirrhosis

IVerJacobson IM, et al. N Engl J Med 2011;364:2405-2416.Poordad F, et al. N Engl J Med 2011;364:1195-1206.

FDA RECOMMENDED ALGORITHMTELAPREVIR

If eRVR:

TPV+PEGINF+RBV

PEGINF+RBV

If NO eRVR:PEGINF+RBV

Treatment naïve and Prior Relapse

Measure HCV RNA

0 4 24 4812<1000HCV RNA

Hard Stop Rules<1000 UD


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FDA RECOMMENDED ALGORITHMBOCEPREVIR

If RVR

PEGINF+RBV

If eRVR:BOC+PEGINF+RBV

If NO eRVR:BOC+PEGINF+RBV

Treatment Naïve

PEG + RBV

Measure HCV RNA

<100 UDHCV RNAHard Stop Rules

0 4 24 36 4812 288

Measure HCV RNA

EXTENDED RVRRESPONSE GUIDED THERAPY

Developed from observations

Telaprevir

Boceprevir

Developed from observations made from peginterferon/ribavirin

Applied to the triple therapy paradigms

Patients who achieve RVR • Treated for a shorter duration• Achieve maximum SVR Patients with delayed virologic

IVer

Boceprevirresponse

• Become HCV RNA negative after week 4

• Require 48 weeks of treatment to reduce relapse

• Have lower SVR rates


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TREATMENT NAÏVE - TELAPREVIRRAPID VIROLOGIC RESPONSE

PEG-RBV

TPV

IVerJacobson IM, et al. N Engl J Med 2011;364:2405-2416.

TREATMENT NAÏVE - BOCEPREVIRRAPID VIROLOGIC RESPONSE

BOC

PEG-RBV

IVerPoordad F, et al. N Engl J Med 2011;364:1195-1206.


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MEASURING HCV RNARVR AND STOP RULES

1000 IU/ml• Must use a PCR assay which can: Quantify the level of HCV RNA Differentiate UNQUANTIFIABLE

from UNDETECTABLE• An assay which reports that HCV

RNA is UNQUANTIFIABLE without qualifying if HCV RNA is

1000 IU/ml-- STOP for --

Telaprevir

100 IU/ml-- STOP for --

Boceprevir

IVer

qualifying if HCV RNA is UNDETECTBALE is insufficient

• A value of <25 IU/ml detectable is NOT undetectable and not eligible for a shorter duration of treatment

NotQuantifiable

NotDetectable

MEASURING HCV RNAVR AND STOP RULES: BOCEPREVIR

ALL MEET ALL MEETALL MEET STOP RULES

ALL MEET CRITERIA TO CONTINUE TREATMENT

IVer


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MEASURING HCV RNARVR AND STOP RULES: TELAPREVIR

ALL MEET ALL MEETALL MEET STOP RULES

ALL MEET CRITERIA TO CONTINUE TREATMENT

IVer

HEPATITIS C VIRUSTHE POOL OF VIRUS

Wild type

Sensitive mutant

Sensitive mutant

Sensitive mutant

Resistant mutants


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CHRONIC HCVIMPACT OF VIRAL MUTATIONS

Wild type viral proteinWild type viral proteinAnti-viral agent enters the binding siteViral protein inhibited

Sensitive mutant viral proteinAnti-viral agent still able to enter binding site Viral protein inhibited

Resistant mutant viral proteinAnti-viral agent unable to enter binding site Viral protein not inhibited

TREATMENT OF CHRONIC HCVEMERGENCE OF RESISTANCE

• The use of multiple agents acting at different sites

• Either a: A single DAA+PEGINF+

RBV in patients who are genetically sensitive to INF

Multiple DAAs (2-3) with or ith t RBVwithout RBV

• Will suppress the emergence of resistance and yield high rates of SVR


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TREATMENT OF CHRONIC HCVMISTAKES WE MADE

• The majority of patients treated with boceprevir and telaprevir had: Cirrhosis Previously failed peginterferon and ribavirin

• Results were: Substantially less than observed in phase 3

IVer

y pclinical trials Adverse events were more frequent

INTERFERON RESPONSIVENESS

CIRRHOSIS

IVerBruno S, et al. J Hepatol 2013;58:479-487.

INFNon-Responsive

INF Responsive


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HCV TREATMENT WITH CIRRHOSISCUPIC COHORT

TPV BOCTRV BOC

N 295 190

RelapsePartial ResponseNull Response

39%46%10%

45%42%5%

Esophageal Varices 35% 38%

TPV BOC

SAE 49% 38%

Premature DC 26% 24%

Infections 26% 24%

Death 2% 1.3%

Decompensation 4.4% 4.4%

A i 8 0 /dl 10% 10%

IVer

SVRRelapsePartial responseNull Response

40%53%32%29%

41%51%40%11%

Fontaine H, et al. EASL 2013

Anemia <8.0 gm/dl 10% 10%

EPO use 57% 66%

Platelets <25,000 1.3% 0.6%

TPO use 1.7% 1.9%

HCV TREATMENT WITH CIRRHOSISINCREASED INFECTION

N/%

N/%

N 191

Stage 0-2Stage 3Stage 4

31%19%50%

Naïve 21%

Stop for: FutilityAEInfection

17%20%8%

Risk of InfectionAlbumin >3.5

< 3.512%60%

IVer

RelapseNon-response

30%49%

TelaprevirBoceprevir

50%50%

Rutter K, et al. EASL 2012

Platelets >90,000<90,000

14%24%

SVRStage 0-2Stage 3Stage 4

65%47%28%


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LIMITATIONS OF CURRENT TREATMENTSIDE EFFECTS

Telaprevir Boceprevir

Anemia 38% 49%Anemia 38% 49%

Nausea 41% 45%

Vomiting 13% 17%

Diarrhea 30% 25%

Dysgusea 10% 39%

Pruritus 47% NR

IVer

Pruritus 47% NR

Rash 36% 18%

Anorectal Symptoms 11% <5%

Pill Burdon (per day) 9 12Poordad F, et al. N Engl J Med 2011;364:1195-1206.Jacobson IM, et al. N Engl J Med 2011;364:2405-2416.

NEW PROTEASE INHIBITORSSIMEPREVIR AND FALDAPREVIR

Simeprevir Faldaprevir

Binding location Same as TPV and BOC

Used for 12 weeks with PEGINF + Ribavirin RGT

Genotype 1

Dosing Once daily

More anemia than PEG/RBV No No

IVer

Drug-Drug interactions No No

Rash No Mild

Additional AE No Increase Bili

Manns M, et al. EASL 2013Ferenci P, et al. EASL 2013


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SIMEPREVIRSTUDY DESIGN

Simeprevir 150 mg QD

Simeprevir 150 QD

PEGINF + RBV

PEGINFRBV

PEGINFRBV

IVer

150 mg QD RBV

4824120

Manns M, et al. J Hepatol 2013;58(suppl; abstr 1413).

FALDAPREVIRSTUDY DESIGN

PEGINF + RBV

Faldaprevir 120 mg QD


PEGINFRBV

PEGINFRBV

IVer


PEGINFRBV

4824120

Sulkowski MS, et al. Hepatology 2013;57:2143-54.


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NEW PROTEASE INHIBITORSTREATMENT NAIVE

IVerManns M, et al. EASL 2013Ferenci P, et al. EASL 2013

With RVR RVR




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SIMEPREVIR-PEGINF-RIBAVIRINTREATMENT NAIVE

IVerManns M, et al. EASL 2013.


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TREATMENT OF HCVSOFOSBUVIR

SOFOSBUVIR 400 mg QD PEGINF + RBV

GT1PEGINF + RBV

PEGINF + RBV

GT

Placebo

GT2 and 3 Naive

SOF + RBV

IVer

SOF + RBV

SOF + RBV

24120 16

Lawitz E, et al. N Engl J Med 2013;368:1878-1887Jacobson IM, et al. N Engl J Med 2013;368:1867-77

GT2 and 3 Failures

INTERFERON INELIGIBILITYREASONS

Psychiatric DiseaseI t l t t INFIntolerant to INFAutoimmune DiseaseOther:DiabetesSeizure disorderRetinal DiseaseThyroid Disease

IVer

Thyroid DiseaseRecent drug useOlder ageThrombocytopenia

Jacobson IM, et al. N Engl J Med 2013;368:1867-77


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SOFOSBUVIR AND RIBAVIRINSIDE EFFECTS

Placebo SOF+RBV

Stop due to AE 4% 2%Stop due to AE 4% 2%

SAE 3% 5%

Fatigue 24% 44%

Nausea 18% 22%

Headache 20% 21%

Rash 8% 9%

Arthralgia 1% 8%

IVer

Arthralgia 1% 8%

Cough 3% 5%

Anemia<10 gm/dl< 8.5 gm/dl

0% 13%7%1%


SOFOSBUVIR-PEGINF-RIBAVIRINGENOTYPE 1

IVerLawitz E, et al. N Engl J Med 2013;368:1878-1887.


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SVR (%)

SOFOSBUVIR-PEGINF-RIBAVIRINGENOTYPE 1, 4, 5, 6

• Treatment naïveSVR (%)

N 327

All Patients 90%

GT1 89%

GT4, 5 and 6 96%, 100%

N Ci h i 92%

• All patients treated for only 12 weeks with all 3 drugs

• 1 pill per day• All patients respond• No RGT needed• No resistance

IVer

No Cirrhosis 92%

Cirrhosis 80%

• No resistance• All failures are due to

relapse

Lawitz E, et al. N Engl J Med 2013;368:1878-1887.

SOFOSBUVIR vs PEGINF/RIBAVIRINGENOTYPE 2 and 3

IVerGane E, et al. EASL 2013


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SOFOSBUVIR vs PEGINFGENOTYPE 2 and 3: TX NAIVE

100

20

40

60

80

SV

R (

%)

SOF+RBV

PEGINF+RBV

12 weeks

24 weeks

IVer

0

No Cx Cx No Cx CxGenotype 3Genotype 2

Lawitz E, et al. N Engl J Med 2013;368:1878-1887.

GT 2 and 3: PRIOR PEGINF NON-SVRSOFOSBUVIR AND RIBAVIRIN

Weeks ofTreatment:

IVerJacobson IM, et al. N Engl J Med 2013;368:1867-77


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GT 2 and 3: PRIOR PEGINF NON-SVRSOFOSBUVIR AND RIBAVIRIN

Weeks ofTreatment:

IVer

Genotype 3Genotype 2


GENOTYPE 3 PEGINF/RBV NON-SVRSOFOSBUVIR

Cirrhosis:

IVer

SOFOSBUVIR+RBVLawitz E, et al. AASLD 2013Zeuzem S, et al. AASLD 2013Jacobson IM, et al. N Engl J Med 2013;368:1867-77

SOF+RBV+ PEGINF


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TREATMENT OF HCVSUMMARY

Protease inhibitors T l i • G t 1 ifi Telaprevir Boceprevir Simeprevir Faldaprevir

• Genotype 1 specific• Not generally effective against other

HCV genotypes• All act at the same site• Virologic failure cannot be overcome

with a different protease Polymerase inhibitor

IVer

Polymerase inhibitor Sofosbuvir Effective against all genotypes Used with peginterferon and ribavirin in GT 1,4,5 and 6 Used with ribavirin in GT 2 and 3


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