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