current treatments for hcvfor...
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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
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Mitchell L. Shiffman, MD, FACG
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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Mitchell L. Shiffman, MD, FACG
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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Mitchell L. Shiffman, MD, FACG
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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Mitchell L. Shiffman, MD, FACG
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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Mitchell L. Shiffman, MD, FACG
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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Mitchell L. Shiffman, MD, FACG
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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Mitchell L. Shiffman, MD, FACG
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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Mitchell L. Shiffman, MD, FACG
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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Mitchell L. Shiffman, MD, FACG
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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Mitchell L. Shiffman, MD, FACG
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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Mitchell L. Shiffman, MD, FACG
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
Faldaprevir 120 mg QD
PEGINFRBV
PEGINFRBV
IVer
Faldaprevir 240 mg QD
PEGINFRBV
4824120
Sulkowski MS, et al. Hepatology 2013;57:2143-54.
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Mitchell L. Shiffman, MD, FACG
NEW PROTEASE INHIBITORSTREATMENT NAIVE
IVerManns M, et al. EASL 2013Ferenci P, et al. EASL 2013
With RVR RVR
NEW PROTEASE INHIBITORSTREATMENT NAIVE
IVerManns M, et al. EASL 2013Ferenci P, et al. EASL 2013
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Mitchell L. Shiffman, MD, FACG
NEW PROTEASE INHIBITORSTREATMENT NAIVE
IVerManns M, et al. EASL 2013Ferenci P, et al. EASL 2013
SIMEPREVIR-PEGINF-RIBAVIRINTREATMENT NAIVE
IVerManns M, et al. EASL 2013.
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Mitchell L. Shiffman, MD, FACG
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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Mitchell L. Shiffman, MD, FACG
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%
Jacobson IM, et al. N Engl J Med 2013;368:1867-77
SOFOSBUVIR-PEGINF-RIBAVIRINGENOTYPE 1
IVerLawitz E, et al. N Engl J Med 2013;368:1878-1887.
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Mitchell L. Shiffman, MD, FACG
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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Mitchell L. Shiffman, MD, FACG
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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Mitchell L. Shiffman, MD, FACG
GT 2 and 3: PRIOR PEGINF NON-SVRSOFOSBUVIR AND RIBAVIRIN
Weeks ofTreatment:
IVer
Genotype 3Genotype 2
Jacobson IM, et al. N Engl J Med 2013;368:1867-77
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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Mitchell L. Shiffman, MD, FACG
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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