Download - Disclosures Advanced HCV management12/8/17 1 Advanced HCV management Annie Luetkemeyer, MD Division of HIV, ID and Global Medicine ZSFG, UCSF Disclosures •Research Grant support

12/8/17

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AdvancedHCVmanagement

AnnieLuetkemeyer,MDDivisionofHIV,IDandGlobalMedicine

ZSFG,UCSF

Disclosures

• ResearchGrantsupporttoUCSFfrom• AbbVie• Gilead• Merck• Proteus• NIH

Overview

• Renalfailure• AcuteHCV• Retreatment• Resistancetesting• Decompensatedcirrhotics• HCVtreatmentforchildrenandpregnantwomen

Renalfailure

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HCVcanworsenrenalfailure(andviceversa)

TranAASLD2017

• Glecaprevir/pibrentasvir– Durationaspernon-cirrhoticprescribingrecommendations

• Grazoprevir/Elbasvir x12weeks– C-SurfertrialdidnotgiveRBV(N=111,52%GT1a)(RothLancet2015)

VAevaluationofGLE/PIBinCKD

KramerAASLD2017

Whatifpatientcan’ttakeHCVPI?

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SOFinrenalfailure• SOFnotapprovedforuseatCrCl<30duetoincreasedmetabolite

• Smallstudiesofsimprevir +SOF(regularor½dose)– OverallhighSVR,generallywelltolerated

• Target:SOF+RBV,SIM,PEG

– Similarcurerates– HOWEVER,worseanemia(RBV),progressionofrenaldz(?causality)

Saxena LiverInt 2016

<30 30-45 45-60 >60

Sofosbuvir-basedregimensinESRD• NumberofsmallstudiesdemonstratingsafetyandefficacyofSOF-basedregimensinCKD– 18 GT1patientswithGFR<30butnotondialysis,12weeksSOF/LDVwithout

RBV

Lawitz E, et al. AASLD 2017. Abstract 1587.

• NOclinicallymeaningfulchangeineGFR

Sofosbuvir-basedregimensinESRD• NumberofsmallstudiesdemonstratingsafetyandefficacyofSOF-basedregimensinCKD– 18 GT1patientswithGFR<30butnotondialysis,12weeksSOF/LDVwithout

RBV

Lawitz E, et al. AASLD 2017. Abstract 1587.

• NOclinicallymeaningfulchangeineGFR

TakeHome:StickwithapprovedregimenswhenfeasiblebutSOF-basedregimensareanalternative,particularlyifcanavoidRBV

AcuteHCVConsiderations• NoindicationforHCVPEP• Considermonitoringfor

spontaneousclearance• Considerearlytreatment:

– HCVtransmissionprevention– Reduceriskofclinicalcomplications(ex:alreadycirrhotic)

– ConcernforLTFUin3-6months

• IFHCVRNA<LLOD,repeatatleast12weekslatertoconfirmclearance

AdaptedfromEACSGuidelinesversion9.0,www.eacsguidelines.org

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SWIFT-C

Naggie #196AASLD2017

• 100%SVRwith8weeksofSOF/LDVinHIV(+)menwithacuteHCV

• AcuteHCVdefinedas<24ofweekofinfectionorreinfectionafterclearance,newHCVRNA+and

• ALT>5xULNifpreviouslynormalwithin12months• ALT>10XULNifnoALTbaseline• DocumentationofnewHCVAb(+)orRNA(+)w/inpast6months

OrtreatthesameaschronicHCV- nowhave8weekoption

ShortenedRegimens?

TreatingDAAfailures

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FirststepsafterNS5afailure2016Message:• Identifyanypatientrelatedissuesthatcontributedtofailure:pooradherence,treatmentinterruption,drug-druginteractions,intolerance

• Resistancetesting:– AtleastNS5a&considerNS3a/4(HCVPI)– LowutilitytotestforNS5b(nucleotide)resistance

FirststepsafterNS5afailure2016Message:• Identifyanypatientrelatedissuesthatcontributedtofailure:pooradherence,treatmentinterruption,drug-druginteractions,intolerance

• Resistancetesting:– AtleastNS5a&considerNS3a/4(HCVPI)– LowutilitytotestforNS5b(nucleotide)resistance

PrinciplesoftreatingDAAfailures

• Typeofpriortreatmentimportant,i.e.NS5aorNS3alone,vsNS5a&NS3together(EBR/GRZorGLE/PIB)

• PEG/RBV+/- SOFfailurestreatedastreatmentnaïve,exceptforGT3treatedwithGLE/PIB

• Ribavirin&treatmentextensionto24weeksgenerallyunnecessary

• Resistancetestinggenerallyunnecessary

Improvedresistanceprofileof“NextGeneration”NS5As

WangC.AAC2012.WangC.AAC2014.ChengG,etal.EASL2012.Abstract1172.ZhaoY,etal.EASL2012.AbstractA845.YangG,etal.EASL2013.Abstract1199.NgT,etal.CROI2014.Abstract639.Asante-AppiahE,etal.AASLD2014.Abstract1979.NgT.THU-305EASL2017.LawitzE.AAC2016.

Fold Change Genotype1a Genotype 1b GT3a

M28T Q30R L31M/V Y93H/N L31V Y93H Y93H

Ledipasvir 20x >100x >100x/>100x

>1000x/>10,000 >100x N/A

Ombitasvir >1000x >100x<3x >10,000x/

>10,000x <10x 20x N/A>100x

Daclatasvir >100x >1000x >100x/>1000x

>1,000x/>10,000x <10x 20x >1000x

Elbasvir 20x >100x>10x >1000x/

>1000x <10x >100x N/A>100x

Velpatasvir <10x <3x 20x/50x >100x/>1000x <3x <3x >100x

Pibrentasvir <3x <3x <3x 7x/7x <3x <3x <3x

Ruzasvir <10x <10x <10x <10x <10x <10x

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SOF/VEL/VOX• HasbecomemainstayforretreatmentofNS5afailureaswellasotherDAAfailures

•

Vosevi Packageinsert

TripleDAAtherapyforre-treatment

SVR12:96%GT1a;100%GT1b;95%GT3

POLARIS-1(n=263)NS5Aexperienced

46%cirrhosis

POLARIS-4(n=182)NONS5Aexposure

46%cirrhosis97%SVRvs90%SOF/VEL

Nocirrhosis CirrhosisSOF/VEL/VOX:98%GT1a;96%GT1b;94%GT3

Bourliere M.NEJM2017.

96 99 93

0

20

40

60

80

100

All NoCirrhosis Cirrhosis

SOF/VEL:89%GT1a;95%GT1b;85%GT3

Regimen:SOF/VEL/VOXfor12weeks

4/101GT1anon-SVR2LTFU

1relapse1BT(non-compliance)

Noimpactofpre-treatmentRASs

SarrazinC.etal.#THU-248EASL2017.

POLARIS-1 POLARIS-4

NoimpactbygenotypeorVELandVOXspecificRASs

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Non-NS5a,treatmentexperienced,+/- cirrhosis

GT3Cirrhotic,Treatmentnaïveorexperienced(non-DAAfailures)

ZeuzemAASLD2016,Bourliere NEJM2017,FosterNEJM2016

GLE/PIBforretreatment• Magellan-1:DAAexperiencedwithorwithoutcirrhosis,GT1and4only,GLE/PIBx12or16weeks

Poodad EASL2017

Poordad EASL2017Mavyret packageinsert

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• PRS=PriorPEG/RBV+/- SOF• EssentiallythesameastreatmentnaïveexceptforGT3

patients- extendto16weeks

Mavyret packageinsert KrishnanAASLD2017

C-ISLE

Foster2017EASL

• Treatmentexperienced,cirrhoticGT3patients• ELB/GRZ/SOFwithorw/oRBV

SOF/VEL/VOX&GLE/PIBfailures??

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GLE/PIBfailures

Pilot-MatiasT.SAT-204.EASL2017.

• In2256Phase2/3participants,<1%developedviralresistance• BUT,whenpatientsDOfail,thepatternsarecomplexwithsubstantialresistance

LackofadditionalRASselectioninfailures

SarrazinC.etal.#THU-248EASL2017.BourliereAASLD2007

AllPOLARIS-1relapsesalsohadcirrhosis

POLARIS-1Deferredtreatment

SOF/VEL/VOX&GLE/PIBfailures

• ConsiderresistancetestingofNS3andNS5a• Nodata(yet)toguideretreatmentConsider:• GLE/PIBfailures->SOF/VEL/VOX+/- RBVorGLE/PIB/SOF(dataforthcomingfromMagellan-3)

• SOF/VEL/VOXfailures->SOF/VEL/VOXx24weeks+RBV

• Expertconsultation

Drugresistancetesting

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When(ifever)isdrugresistancetestingindicatedin2017?Scenario Action

GT1a, EBR/GRZplanned • NS5aRAStesting• IfEBRRASpresent,extend

treatment to16weekwithRBV

GT3,cirrhotic,SOF/VEL planned • NS5aRAStesting• If Y93Hpresent,consider

addingRBVSOF/VEL/VOXorGLE/PIB failure • ?NS5a andNS3RAStestingto

helpguidetherapy

DecompensatedCirrhosis

HCVcurereducesdeathindecompensatedcirrhosis • Alwaysbesttoproceedinconsultationwith

hepatologist andtransplantteam,ifapplicable• Stabilizemedicalconditionbeforetreating• AvoidHCVproteaseinhibitors– levelscanbemarkedlyelevated– ThisincludesGlecaprevir/Pibrenstasvir andSofosbuvir/Velpatasvir/Voxilaprevir

• IncludelowdoseRibavirinifpossible– 600mg,titrateupastolerated

DAA Genotype ConsiderationsSOF/LDV/RBVx12weeks GT1,4 Extend therapyto24

weeksifcannotincludeRBV

SOF/VEL/RBVx12weeks GT1-6DCV/SOF/RBVx 12weeks GT1-4

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DecompensatedCirrhotics:RetreatmentafterNS5aand/orSOFfailure

Pregnancy&Children

HCVinpregnancy• Riskoftransmission≈5%

– HigherinHIV(+)women• Vaginaldeliveryok,butshouldavoidfetalscalpmonitorsandforcepsdelivery

• Breastfeedingnotariskfortransmission,butnursingwithbloody/crackednipplesnotrecommended

• Noapprovedtreatmentduringpregnancy– TreatHCVbefore seekingpregnancyifpossible

• PKstudyofSOF/LDVx12weeksstartedat24weeksgestationongoing(NCT02683005)

HCVinchildren

• Rateoffibrosisprogressioninchildrenislow• Generallyrecommendedtowaittotreatuntilage12

• SOF/LDVapprovedfor≥12years• GLE/PIBandSOF/VELstillonlyfor≥18years

• DAA’sunderevaluationfortreatmentofchildrenages3-11

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Conclusions• Goodoptionsforrenalfailure,decompensatedcirrhotics,andNS5afailures

• Drugresistancetestingincreasinglyunnecessary

• WeneeddatatoinformsafeandeffectiveHCVtreatmentinpregnantwomen,childrenandadolescents.

Thankyou!

Additionalslides

GT Wks No Cirrhosis Compensated Cirrhosis eGFR < 30 mL/min

1

8 GLE/PIB -- GLE/PIB‡

12GZR/EBR,*SOF/LDV,†SOF/VEL

GLE/PIB, GZR/EBR,*SOF/LDV, SOF/VEL GZR/EBR


12 SOF/VEL GLE/PIB, SOF/VEL --


12 SOF/VEL GLE/PIB, SOF/VEL§ --

4


12GZR/EBR, SOF/LDV, SOF/VEL,

GLE/PIB, GZR/EBR,SOF/LDV, SOF/VEL GZR/EBR

5, 6


12 SOF/LDV, SOF/VEL GLE/PIB, SOF/LDV, SOF/VEL --

*IfGT1awithBLNS5ARASsforEBR,12wksnotrecommended;canincreasedurationto16wkswithRBV(alternative).†Somedatatosupport8wks,but8wks notrecommendedinHIV/HCVcoinfection.‡Ifalsocirrhotic,increasedurationto12wks.§IfBLY93HRASpresent,addRBVorconsiderSOF/VEL/VOX.

AASLD/IDSAGUIDELINES9/17www.hcvguidelines.org

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GT Wks NS3+PegIFN/RBVExperience

Non-NS5A,SOF-ContainingExperience

NS5AExperience

1 12 GLE/PIB,SOF/LDV,*SOF/VEL

GLE/PIB,SOF/VEL,†SOF/VEL/VOX‡ SOF/VEL/VOX

2 12 GLE/PIB,SOF/VEL

3 12 SOF/VEL/VOX§ SOF/VEL/VOX§ SOF/VEL/VOX§

4-6 12 SOF/VEL/VOX SOF/VEL/VOX SOF/VEL/VOX

*Notrecommendedifalsocirrhotic.†Forgenotype1bonly.‡Forgenotype1aonly.§IfalsocirrhoticwithpriorNS5Afailure,addRBV.

DAAexperienced

2017Dvory-Sobol AASLD

Download - Disclosures Advanced HCV management12/8/17 1 Advanced HCV management Annie Luetkemeyer, MD Division of HIV, ID and Global Medicine ZSFG, UCSF Disclosures •Research Grant support

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