HEPATITISC:UPDATEANDMANAGEMENT
JoséFranco,MDProfessorofMedicine
AssociateDeanforEducationalImprovementAssociateDirector,KernInstitute
STARCenterDirector
JoséFranco,MDDisclosures
• Ihavenodisclosuresrelevanttothispresentation
• IwillonlybespeakingregardingFDA-approvedtherapies
HEPATITISCUPDATEANDMANAGEMENT:OBJECTIVES
• ExplaintheprevalenceandnaturalhistoryofhepatitisC
• IdentifywhichcohortsshouldbetestedforhepatitisC
• RecognizethecurrentlyavailabletherapiesforthetreatmentofhepatitisC
HEPATITISCTREATMENT:PREDICTION
Themajorityofnon-cirrhoticpatientsandcompensatedcirrhoticswillbetreatedbyprimarycarephysicians.
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
CHRONICVIRALHEPATITISINUSA:2013
3.2MILLLION
HepatitisC
1.2MILLIONHepatitisB
CDC
CDC
WISCONSINHCVREPORTING- 2013
• Reportedcases:2638– 22%inMilwaukeecounty– 10%Correctionalinstitutions
• 43%female(upfrom30%in2003)• 27%nowinthoseunder30(upfrom5%in2003)
HEPATITISCRISKFACTORS• Riskbehaviors
– Currentorpastinjectiondruguse– Intranasalillicitdruguse
• Riskexposures– Long-termhemodialysis– Unregulatedpercutaneous/parenteralexposure– Healthcareproviderswithneedlesticks ormucosalexposurestoHCV-infectedblood
– ChildrenborntoHCV-infectedwomen– Transfusionspriorto1992,clottingfactorspriorto1987– Incarceratedindividuals
HEPATITISCTESTING
Onetimetestingalsorecommendedforindividualsbornbetween1945-1965,withoutpriorascertainmentofrisk
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
HEPATITISCGENOTYPESINU.S.
• Genotype1A37%• Genotype1B30%• Genotype210%• Genotype36%• Otherormixed9%• Indeterminate5%
NATURALHISTORYOFHCVINFECTION
ExposureAcute Phase
Resolved15%
Chronic85%
Cirrhosis20%
ESLD 6%/yr
HCC4%/yr
Transplantation3-4%/yr
0 yrs 10 yrs 20 yrs 30 yrsDi Bisceglie
HostFactors ViralFactorsNon-Modifiable Co-infectionwithHBVorHIV
FibrosisstageInflammationgradeOlderage attimeofinfectionMalesexOrganTransplant
ModifiableAlcoholconsumptionNonalcoholicfattyliverdiseaseObesityInsulinresistance
FACTORSASSOCIATEDWITHMOREADVANCEDDISEASE
AASLDGuidelines2014
Stage0Stage2 Stage3Stage4
CIRRHOSIS
STAGESOFFIBROSIS
FIBROSCAN
FIBROSCANSCORING
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.
WHOSHOULDPRIMARYCAREPHYSICIANSNOTTREAT?
• Decompensatedcirrhosis• HIV/HCVco-infection• Patientswithrenalimpairment• AcuteHCV• RecurrentHCVafterlivertransplant
HEPATITISCERADICATION:DEFINITION
AbsenceofhepatitisCviralRNAatleast12weeksfollowingcompletionofantiviraltherapy(SVR-sustainedvirological response)
StructuralNon-structural
C E1 E2 NS2 NS3 NS4b NS5a NS5b
HEPATITIS C VIRUS5’UT
Neumann, Science, 1998Rosenberg, J Mol Biology, 2001Lauer, NEJM, 2001
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
HCVGuidelines.org,2017
LEDISPAVIR/SOFOSBUVIR
• Firstapproved11/2014• Canbeusedin
- compensatedcirrhosis- decompensatedcirrhosis- post-livertransplant
• Welltolerated• Fewdrug-drug
interactions
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
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
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.
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
SVR12: Immediate and Deferred Treatment Groups
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
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
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
Sofosbuvir/Velpatasvir (Epclusa)
¨ Velpatasvir, an NS5A inhibitor and Sofosbuvir, an NSEB inhibitor, once daily single tablet regimen¤ FDA approval 2016¤ Pangenotypic
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
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
HCVGuidelines.org,2017
HCVGuidelines.org,2017
HCVGuidelines.org,2017
HCVGuidelines.org,2017
HCVGuidelines.org,2017
HCVGuidelines.org,2017
HCVGuidelines.org,2017
HCVGuidelines.org,2017
Healthline,2016
WHATDRUGSARECHOSENFORHCVTHERAPY?
Medicaidcoverageguidelines:– Genotype1:Zepatier orViekira XR– Genotype2&3:Epclusa– Genotype4:Zepatier orTechnivie
MedicarePartDandCommercialInsurancetrends(eachplanhasadifferentformulary):
– Genotype1:Harvoni– Genotype2:Epclusa– Genotype3:Epclusa orDaklinza+Sovaldi– Genotype4:Harvoni
HCVTHERAPY:RECENTMEDICAIDCHANGES
Summaryofmajorupdates:-Treatmentcoveragewillbeavailabletostage0&1fibrosispatients-Fibroscan/fibrosisstagingisnotrequiredunlessadvancedfibrosis/cirrhosisissuspected-Patientswith“recent”(notdefinedinguideline)drugusemustbeparticipatinginarecoveryprogramandmustnolongerbeactivelyusingIVdrugsforatleast3monthspriortoandduringHCVtherapy-MedicaidwillnowprovideapprovalforthefullcourseofHCVtherapy,andnotrequirerenewals/labsthroughouttreatmentasbefore
HEPATITISCTREATMENT:SUMMARY
• HepatitisCtreatmentishighlyeffectivewithgreaterthan95%sustainedvirological response
• HepatitisCtreatmentiswelltolerated• Currenttreatmentoptionsarecostly• Multiplebarrierstotherapypersistincludingidentifyinginfectedindividualsandperformingappropriatetesting