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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
28 GLE/PIB -- GLE/PIB‡
12 SOF/VEL GLE/PIB, SOF/VEL --
38 GLE/PIB -- GLE/PIB‡
12 SOF/VEL GLE/PIB, SOF/VEL§ --
4
8 GLE/PIB -- GLE/PIB‡
12GZR/EBR, SOF/LDV, SOF/VEL,
GLE/PIB, GZR/EBR,SOF/LDV, SOF/VEL GZR/EBR
5, 6
8 GLE/PIB -- GLE/PIB‡
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