HEPATITIS C: UPDATE AND MANAGEMENT · Professor of Medicine Associate Dean for Educational...
Transcript of HEPATITIS C: UPDATE AND MANAGEMENT · Professor of Medicine Associate Dean for Educational...
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HEPATITISC:UPDATEANDMANAGEMENT
JoséFranco,MDProfessorofMedicine
AssociateDeanforEducationalImprovementAssociateDirector,KernInstitute
STARCenterDirector
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JoséFranco,MDDisclosures
• Ihavenodisclosuresrelevanttothispresentation
• IwillonlybespeakingregardingFDA-approvedtherapies
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HEPATITISCUPDATEANDMANAGEMENT:OBJECTIVES
• ExplaintheprevalenceandnaturalhistoryofhepatitisC
• IdentifywhichcohortsshouldbetestedforhepatitisC
• RecognizethecurrentlyavailabletherapiesforthetreatmentofhepatitisC
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HEPATITISCTREATMENT:PREDICTION
Themajorityofnon-cirrhoticpatientsandcompensatedcirrhoticswillbetreatedbyprimarycarephysicians.
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References in slidenotes.
IFN6 Mos
PegIFN/ RBV
12 Mos
IFN12 Mos
IFN/RBV12 Mos
PegIFN12 Mos
20011998
2011StandardInterferon
RibavirinPeginterferon
1991
PegIFN/RBV +DAA
IFN/RBV6 Mos
616
3442 39
5570+
0
20
40
60
80
100
DAA + RBV ±PegIFN
90+2013
All–OralDAA±
RBV
Current95+
All-Oral Therapy
Direct-Acting
Antivirals
Slide credit: clinicaloptions.com
Nearly Everyone With HCV Can Now Be Treated Successfully§ Very high SVR rates; therapies highly tolerable
§ All-oral therapy for almost every patient
§ Treatment generally just 12 weeks
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CHRONICVIRALHEPATITISINUSA:2013
3.2MILLLION
HepatitisC
1.2MILLIONHepatitisB
CDC
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CDC
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WISCONSINHCVREPORTING- 2013
• Reportedcases:2638– 22%inMilwaukeecounty– 10%Correctionalinstitutions
• 43%female(upfrom30%in2003)• 27%nowinthoseunder30(upfrom5%in2003)
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HEPATITISCRISKFACTORS• Riskbehaviors
– Currentorpastinjectiondruguse– Intranasalillicitdruguse
• Riskexposures– Long-termhemodialysis– Unregulatedpercutaneous/parenteralexposure– Healthcareproviderswithneedlesticks ormucosalexposurestoHCV-infectedblood
– ChildrenborntoHCV-infectedwomen– Transfusionspriorto1992,clottingfactorspriorto1987– Incarceratedindividuals
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HEPATITISCTESTING
Onetimetestingalsorecommendedforindividualsbornbetween1945-1965,withoutpriorascertainmentofrisk
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HCVINFECTION:WORLDWIDEGENOTYPEDISTRIBUTION
Simmonds P. Curr Stud Hematol Blood Transfus. 1998;62:38-63.
1a,1b2a, 2b,
3a
1b2a, 2b, 2c,
3a
4
5a
4
1b,3a
1b
2a
1b,6
3b
1b,3a
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HEPATITISCGENOTYPESINU.S.
• Genotype1A37%• Genotype1B30%• Genotype210%• Genotype36%• Otherormixed9%• Indeterminate5%
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NATURALHISTORYOFHCVINFECTION
ExposureAcute Phase
Resolved15%
Chronic85%
Cirrhosis20%
ESLD 6%/yr
HCC4%/yr
Transplantation3-4%/yr
0 yrs 10 yrs 20 yrs 30 yrsDi Bisceglie
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HostFactors ViralFactorsNon-Modifiable Co-infectionwithHBVorHIV
FibrosisstageInflammationgradeOlderage attimeofinfectionMalesexOrganTransplant
ModifiableAlcoholconsumptionNonalcoholicfattyliverdiseaseObesityInsulinresistance
FACTORSASSOCIATEDWITHMOREADVANCEDDISEASE
AASLDGuidelines2014
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Stage0Stage2 Stage3Stage4
CIRRHOSIS
STAGESOFFIBROSIS
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FIBROSCAN
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FIBROSCANSCORING
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HCV in the US: Gaps in Current PracticePt
s (%
)
n = 3,500,000 1,743,000 1,514,667 952,726 581,632 555,883 326,859
0
20
40
60
80
100
ChronicHCV
Infected
Diagnosedand
Aware
Access to
Care
HCV RNAConfirmed
Liver Biopsy
Prescribed HCV
Treatment
AchievedSVR
100%
50%43%
27%
17% 16%9%
Yehia BR, et al. PLoS One. 2014;9:e101554.
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WHOSHOULDPRIMARYCAREPHYSICIANSNOTTREAT?
• Decompensatedcirrhosis• HIV/HCVco-infection• Patientswithrenalimpairment• AcuteHCV• RecurrentHCVafterlivertransplant
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HEPATITISCERADICATION:DEFINITION
AbsenceofhepatitisCviralRNAatleast12weeksfollowingcompletionofantiviraltherapy(SVR-sustainedvirological response)
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StructuralNon-structural
C E1 E2 NS2 NS3 NS4b NS5a NS5b
HEPATITIS C VIRUS5’UT
Neumann, Science, 1998Rosenberg, J Mol Biology, 2001Lauer, NEJM, 2001
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3’UTR5’UTR Core E1 E2 NS2 NS3 NS5A NS5BP7
Ribavirin (RBV)
Polymerase
Daclatasvir (DCV)Elbasvir (EBR)
Ledipasvir (LDV)Ombitasvir (OBV)Velpatasvir (VEL)
Pibrentasvir (PIB)*
Sofosbuvir(SOF)
Dasabuvir (DSV)
NS5BNUC
Inhibitors
NS5AReplication
Complex Inhibitors
NS5BNon-NUC Inhibitors
Grazoprevir (GZR)Paritaprevir/Ritonavir
(PTV/RTV) Simeprevir (SMV)
Voxilaprevir (VOX)*Glecaprevir (GLE)*
NS3Protease Inhibitors
Protease
Approved DAAs From Multiple Classes: Basis of 2016 Combination HCV Regimens
Structural Domain
4A NS4B
Nonstructural Domain
*Possible approval in 2017. Slide credit: clinicaloptions.com
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HCVGuidelines.org,2017
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LEDISPAVIR/SOFOSBUVIR
• Firstapproved11/2014• Canbeusedin
- compensatedcirrhosis- decompensatedcirrhosis- post-livertransplant
• Welltolerated• Fewdrug-drug
interactions
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3’UTR5’UTR Core E1 E2 NS2 NS3 NS5A NS5BP7
Ribavirin (RBV)
Polymerase
Daclatasvir (DCV)Elbasvir (EBR)
Ledipasvir (LDV)Ombitasvir (OBV)Velpatasvir (VEL)
Pibrentasvir (PIB)*
Sofosbuvir(SOF)
Dasabuvir (DSV)
NS5BNUC
Inhibitors
NS5AReplication
Complex Inhibitors
NS5BNon-NUC Inhibitors
Grazoprevir (GZR)Paritaprevir/Ritonavir
(PTV/RTV) Simeprevir (SMV)
Voxilaprevir (VOX)*Glecaprevir (GLE)*
NS3Protease Inhibitors
Protease
Approved DAAs From Multiple Classes: Basis of 2016 Combination HCV Regimens
Structural Domain
4A NS4B
Nonstructural Domain
*Possible approval in 2017. Slide credit: clinicaloptions.com
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Ledipasvir-Sofosbuvirfor8or12WeeksinTreatment-NaïveHCVGT1ION-3Study:Results
ION-3: SVR 12* by Treatment Duration and Regimen
Source: Kowdley, K, et al. N Engl J Med. 2014;370:1879-88.
94 93 95
0
20
40
60
80
100
LDV-SOF LDV-SOF +RBV LDV-SOF
Patie
nts
with
SVR
12
(%)
202/215
8-Week Regimen
201/216 206/216
12-Week Regimen
Abbreviations: LDV-SOF= ledipasvir-sofosbuvir; RBV = ribavirin*Primary end-point by intention-to-treat analysis
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Elbasvir/Grazoprevir (Zepatier)
All-oral, once-daily regimen¨ Approved 1/2016 for GT 1 and 4
1. Summa V, et al. Antimicrobial Agents Chemother. 2012;56(8):4161-67.2. Coburn CA, et al. ChemMedChem. 2013;8(12):1930-40.3. Harper S, et al. ACS Med Chem Lett. 2012;3(4):332-6.4. Yeh WW, et al. Hepatology. 2014;60(suppl 4):1940.
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3’UTR5’UTR Core E1 E2 NS2 NS3 NS5A NS5BP7
Ribavirin (RBV)
Polymerase
Daclatasvir (DCV)Elbasvir (EBR)
Ledipasvir (LDV)Ombitasvir (OBV)Velpatasvir (VEL)
Pibrentasvir (PIB)*
Sofosbuvir(SOF)
Dasabuvir (DSV)
NS5BNUC
Inhibitors
NS5AReplication
Complex Inhibitors
NS5BNon-NUC Inhibitors
Grazoprevir (GZR)Paritaprevir/Ritonavir
(PTV/RTV) Simeprevir (SMV)
Voxilaprevir (VOX)*Glecaprevir (GLE)*
NS3Protease Inhibitors
Protease
Approved DAAs From Multiple Classes: Basis of 2016 Combination HCV Regimens
Structural Domain
4A NS4B
Nonstructural Domain
*Possible approval in 2017.Slide credit: clinicaloptions.com
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SVR12: Immediate and Deferred Treatment Groups
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PTV/r/OBV+DSV (Viekira Pak)
• Approved 12/2014 for GT 1• GT 1a and cirrhotics require Ribavirin which increases pillBurden and side effects• Contraindicated in advanced cirrhosis
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3’UTR5’UTR Core E1 E2 NS2 NS3 NS5A NS5BP7
Ribavirin (RBV)
Polymerase
Daclatasvir (DCV)Elbasvir (EBR)
Ledipasvir (LDV)Ombitasvir (OBV)Velpatasvir (VEL)
Pibrentasvir (PIB)*
Sofosbuvir(SOF)
Dasabuvir (DSV)
NS5BNUC
Inhibitors
NS5AReplication
Complex Inhibitors
NS5BNon-NUC Inhibitors
Grazoprevir (GZR)Paritaprevir/Ritonavir
(PTV/RTV) Simeprevir (SMV)
Voxilaprevir (VOX)*Glecaprevir (GLE)*
NS3Protease Inhibitors
Protease
Approved DAAs From Multiple Classes: Basis of 2016 Combination HCV Regimens
Structural Domain
4A NS4B
Nonstructural Domain
*Possible approval in 2017.Slide credit: clinicaloptions.com
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Source: Ferenci P, et al. N Engl J Med. 2014;370:1983-92.
Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir +/- RBV in GT1PEARL-III and PEARL-IV: Results
97.090.2
99.5 99.0
0
20
40
60
80
100
3D + RBV 3D 3D + RBV 3D
Patie
nts
with
SVR
12 (%
)
Genotype 1a Genotype 1b
3D = Ombitasvir-Paritaprevir-Ritonavir and DasabuvirRBV = Ribavirin
97/100 185/205 209/210 207/209
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Sofosbuvir/Velpatasvir (Epclusa)
¨ Velpatasvir, an NS5A inhibitor and Sofosbuvir, an NSEB inhibitor, once daily single tablet regimen¤ FDA approval 2016¤ Pangenotypic
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3’UTR5’UTR Core E1 E2 NS2 NS3 NS5A NS5BP7
Ribavirin (RBV)
Polymerase
Daclatasvir (DCV)Elbasvir (EBR)
Ledipasvir (LDV)Ombitasvir (OBV)Velpatasvir (VEL)
Pibrentasvir (PIB)*
Sofosbuvir(SOF)
Dasabuvir (DSV)
NS5BNUC
Inhibitors
NS5AReplication
Complex Inhibitors
NS5BNon-NUC Inhibitors
Grazoprevir (GZR)Paritaprevir/Ritonavir
(PTV/RTV) Simeprevir (SMV)
Voxilaprevir (VOX)*Glecaprevir (GLE)*
NS3Protease Inhibitors
Protease
Approved DAAs From Multiple Classes: Basis of 2016 Combination HCV Regimens
Structural Domain
4A NS4B
Nonstructural Domain
*Possible approval in 2017. Slide credit: clinicaloptions.com
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37
Feld, AASLD, 2015, LB-2. Feld JJ, et al. N Engl J Med. 2015. DOI: 10.1056/NEJMoa1512610
99 98 99 100 100 97 100
0
20
40
60
80
100
SVR1
2 (%
)
618/624
Total
206/210 117/118 104/104 116/116 34/35 41/41
1a 1b 2 4 5 6
Genotype
1 relapse2 LTFU1 WC
1 relapse 1 death
LTFU=lost to follow up; WC=withdrew consent
‡
ASTRAL-1: SOF/VEL STR for 12 Weeks in GT 1, 2, 4, 5, 6 HCV-Infected Patients
Sofosbuvir/Velpatasvir:SVR12 by Genotype
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HCVGuidelines.org,2017
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HCVGuidelines.org,2017
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HCVGuidelines.org,2017
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HCVGuidelines.org,2017
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HCVGuidelines.org,2017
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HCVGuidelines.org,2017
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HCVGuidelines.org,2017
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HCVGuidelines.org,2017
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Healthline,2016
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WHATDRUGSARECHOSENFORHCVTHERAPY?
Medicaidcoverageguidelines:– Genotype1:Zepatier orViekira XR– Genotype2&3:Epclusa– Genotype4:Zepatier orTechnivie
MedicarePartDandCommercialInsurancetrends(eachplanhasadifferentformulary):
– Genotype1:Harvoni– Genotype2:Epclusa– Genotype3:Epclusa orDaklinza+Sovaldi– Genotype4:Harvoni
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HCVTHERAPY:RECENTMEDICAIDCHANGES
Summaryofmajorupdates:-Treatmentcoveragewillbeavailabletostage0&1fibrosispatients-Fibroscan/fibrosisstagingisnotrequiredunlessadvancedfibrosis/cirrhosisissuspected-Patientswith“recent”(notdefinedinguideline)drugusemustbeparticipatinginarecoveryprogramandmustnolongerbeactivelyusingIVdrugsforatleast3monthspriortoandduringHCVtherapy-MedicaidwillnowprovideapprovalforthefullcourseofHCVtherapy,andnotrequirerenewals/labsthroughouttreatmentasbefore
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HEPATITISCTREATMENT:SUMMARY
• HepatitisCtreatmentishighlyeffectivewithgreaterthan95%sustainedvirological response
• HepatitisCtreatmentiswelltolerated• Currenttreatmentoptionsarecostly• Multiplebarrierstotherapypersistincludingidentifyinginfectedindividualsandperformingappropriatetesting
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