HCVTreatmentofComplicatedPatients:AdvancedCirrhoticsandPatientswith

SevereRenalImpairment

FredPoordad,MD

HCV-infectedPatientswithRenalImpairment

HCVandtheKidney• HCVisassociatedwithrenalimpairment

• Mixedcryoglobulinemia• Non-glomerularrenaldiseases

• ESRDis7timeshigherinHCVversusnon-HCV-infectedpatients• HCVisassociatedwithahigherrisk(1.5to2.5fold)ofdiabetes

andcardiovascular/cerebrovasculardisease

Corouge M,etal.LiverInt.2016;36(suppl1):28-33.

TimeonDialysisIsCorrelatedwithHCVInfection

DialysispatientsfromtheDialysisOutcomePracticePatternStudy(DOPPS)

Kalantar-Zadeh K,etal.Int Urol Nephrol.2007;39:247-259.

IncreasingprevalenceofHCVinfectionwithgreaterdurationofhemodialysistreatment

HCVandRiskofDeathinLong-TermHemodialysisPatients

Espinosa M, et al. Nephrol Dial Transplant. 2001;16:1669-1674.

Sofosbuvir PharmacokineticsinHCV-NegativePatientsWithRenalImpairment

ResultsAfteraSingle-DoseofSofosbuvir400mgIncreaseinAUCRelativeto

SubjectsWithNormalRenalFunction(%)

Sofosbuvirfullprescribinginformation.

Sofosbuvir AUC GS-3310007eGFR (mL/min/1.73 m2)

>50 to <80 61 55

>30 to <50 107 88

<30 171 451ESRD requiring hemodialysis

Dosed 1 hourBefore hemodialysisAfter hemodialysis

2860

12802070

AASLD-IDSARecommendations:SevereRenalImpairmentorESRDRequiringHemodialysisorPeritonealDialysis

CreatinineClearance<30mL/min(UrgencytoTreatorRetreatIsHighandRenalTransplantisnotanImmediateOption)

CreatinineClearance<30mL/min(TreatmentisNecessaryandTransplantationCannotbePerformed)

AASLD-IDSA.http://www.hcvguidelines.org/full-report-view.March14,2017.

Genotype 1a Elbasvir/grazoprevir (50/100 mg qd) for 12 weeks

Genotype 1b Elbasvir/grazoprevir (50/100 mg qd) for 12 weeksOmbitasvir/paritaprevir/r (25/150/100 mg qd) + dasabuvir (250 mg bid) for 12 weeks

Genotype 4 Elbasvir/grazoprevir (50/100 mg qd) for 12 weeks

Genotype 2, 3, 5, 6 PegIFN and dose-adjusted RBV† at 200 mg/day

Phase3•Placebo-controlled•Genotype1•Treatment-naïveandTreatment-experienced•CKDstage4/5

(+hemodialysis)•Compensatedcirrhosisallowed

C-SURFER:SVR12RatesWith12weeksElbasvir/GrazoprevirinHCVG1,Stage4/5CKD

SVR1

2(%

)

99% 100%

Cirrhosis

Overall(n=116)

SVR12Rates(modifiedfullanalysis)

99%

No(n=110)

99%99%100%

Yes(n=6)

CKDStage

4(n=22)

5(n=94)

Dialysis

No(n=29)

Yes(n=87)

100%

RothD,etal.Lancet.2015;386:1537-1545.

RUBY-1:Ombitasvir/Paritaprevir/r+Dasabuvir + RBVinSevereRenalImpairmentorESRD

VirologicOutcome

Patie

nts(%)

EndofTreatmentResponse

(n=20)

90%

SVR12(n=20)

100%

Pockros PJ,etal.Gastroenterology.2016;Mar11.[Epub aheadofprint].

• RBVdoseinterruption(8/13)• Erythropoietinadministration(n=4)• Nodiscontinuationsduetoadverseevents

• Hemoglobin<8g/dL (n=1)• Noothergrade3/4

laboratoryabnormalities• Noclinicallysignificantchangesinliverorrenalfunctionmarkers

0 24Weeks

G/P36

TreatmentPeriod Post-TreatmentPeriod

SVR12

1612 28

GT1– 6Stage4/5CKD+/- cirrhosisTNorTE

N=104

EXPEDITION-IV:SafetyandEfficacyofGLE/PIBinAdultswithRenalImpairmentandGT1– 6Infection

• GT1:52%,GT2:16%,GT3:11%,GT4-6:21%• Treatmentnaïve:58%• Compensatedcirrhosis:19%• CKDStage4:12%,Stage5:88%,82%onhemodialysis

Gane E,etal.67thAASLD;Boston,MA;November11-15,2016;Abst.LB-11.

mITT=100%SVR12

EXPEDITION-IV:Results– SVR12byIntent-to-treat(ITT)Analysis

Gane E,etal.67thAASLD;Boston,MA;November11-15,2016;Abst.LB-11.

10098

102104SV

R12,

% P

atie

nts

BreakthroughRelapse

DiscontinuationLTFU

0011

80

60

40

20

0ITT

Death(%

) 38%

15%

5% 5%

21%

14%13%

36%

21%

41%

HCV-positiveHCV-negative

Pereira1995

(n=29/72)

29%

14%

33%

0.6%

23%

10%

57%

21%

4%5%

Pereira1995

(n=22/78)

Legendre1998

(n=112/387)

Gentil1999

(n=85/235)

Lee2001

(n=151/326)

Breitenfeldt2002

(n=130/797)

Einollahi2003

(n=41/868)

Bruchfeld2004

(n=51/520)

Morales*2004

(n=488/2801)

Scott2010

(n=140/7432)

*Proportionofdeathsduetoliverdisease.Post-transplantfollow-uprangedfrom57to130months(2studiesdidnotreportfollow-upduration).CarboneM,etal.Transplantation.2013;95:779-786.

DeathRateinHCV+VersusHCV- PatientsAfterKidneyTransplantation

Regimenduration: 12weeks24weeks

Ledipasvir/Sofosbuvir forKidneyTransplantRecipientsWithHCVGenotype1or4

SVR1

2(%

)

100% 100% 100%

Genotype1(n=51|53)

Genotype4(n=6|4)

Overall(n=57|57)

96%

SVR12Rates

96%100%

ColomboM,etal.JHepatol.2016;64(suppl2):S183.AbstractGS13.

• 12vs.24weeks

• Novirologicfailures

• Safety• Discontinuationsduetoadverseevents:

<1%

• eGFR <30mL/minduringtherapy:4%(4/114;relatedtotreatmentin1patient)

• Noepisodesofrejection

• Noclinicallymeaningfulreductionsinrenalfunction

UseofHCV-PositiveDonorKidneys

Sawinski D, et al. Transplantation. 2015;99:2458-2466; Morales JM, et al. Am J Transplant. 2010;10:2453–2462.

• Controversy• Viraltransmissionisinvariable• Genotypesuperinfectioncanoccur• PatientandallograftsurvivalmaybeinferiorcomparedwithHCV-positiverecipientsofHCV-

negativedonorkidneys(basedonhistoricaldatawithIFN-basedtherapy)

• Justification• HCV-positiveESRDpatientsareaffordedalongerlifeexpectancyfromtransplantationwith

anHCV-positivedonorkidneythanremainingondialysis• Doesnotincreasefrequencyofprogressiveliverdiseaseandliverfailure• Increasepoolofdonororgans• Similar10-yearsurvivalratesforHCV-positiveandHCV-negativedonorkidneys• 73%versus77%(P=0.2)

PatientsWithCirrhosis:WhatOptionsExist?

0

10

20

30

40

50

60

70

80

90

100

SVRRa

te(%

)

IFN6 mo

IFN12 mo

IFN+RBV6 mo

IFN+RBV12 mo

PEG12 mo

PEG+RBV12 mo

BOC+PEG+RBV

6-12 mo

SOF+PEG+RBV

3 mo

TVR+PEG+RBV

6-12 mo

SMV+PEG+RBV

6-12 mo

FDV+PEG+RBV

6-12 mo

10-13

17-297-41

4-47 41-42

80-81

21

40-71

5

58-6540-56

LDV/SOFPrOD

GRZ/ELB 3-6 mo

86-100

1986 1998 20022001 2011 2013* 2014 2016

SVRRatesinHCVGT1TNorTEwithBridgingFibrosis-Cirrhosis

LongerdurationortheadditionofRBVmayberequiredtoachievecomparableSVR

99

SOF/VEL3 mo

Stage Definition 1-yearmortality MedianSurvival

1 Compensatedwithoutvarices 1% >12years

2 Compensatedwithvarices 3%

3 Decompensatedwithasciteswithoutvaricealhemorrhage 20% ~2years

4Decompensatedwith/out

asciteswithvaricealhemorrhage

57%

HCV and Cirrhosis | 17

NaturalHistoryofCirrhosis

D’AmicoG,Garcia-Tsao G,Pagliaro L.Naturalhistoryandprognosticindicatorsofsurvivalincirrhosis:asystematicreviewof118studies.JHepatol.2006;44:217-231.

NaturalHistoryandSurvivalofPatientswithAscites

18Planas R,Montoliu S,Ballesté B,RiveraM,MiguelM,Masnou H,Galeras JA,Giménez MD,SantosJ,Cirera I,Morillas RM,Coll S,Solá R.Naturalhistoryofpatientshospitalizedformanagementofcirrhoticascites.Clin GastroenterolHepatol.2006;4:1385-94.

3MonthMortality

19

GuidelinesrecommendreferralforlivertransplantwithaMELD> 10orCTPscore> 7

WiesnerR.Gastroenterology.2003;124:91-6.

DoseAdjustmentsinCirrhosisChildsClass PEG RibavirinDaily Simeprevir PrOD

A Standard 1000-1200mg/day 150mg 75/50/12.5mg+250mg

B No 600mg No No

C No 600mg No No

ChildsClass Elbasvir/grazoprevir

Sofosbuvir/velpatasvir

Ledipasvir/sofosbuvir Daclatasvir

A 50/100mg 400mg/100mg 90mg/400mg 60mg

B No 400mg/100mg 90mg/400mg 60mg

C No 400mg/100mg 90mg/400mg 60mg

Decompensated Cirrhosis:LimitedOptionsChildsClass PEG RibavirinDaily Simeprevir PrOD

A Standard 1000-1200mg/day 150mg 75/50/12.5mg+250mg

B No 600mg No No

C No 600mg No No

ChildsClass Elbasvir/grazoprevir

Sofosbuvir/velpatasvir

Ledipasvir/sofosbuvir Daclatasvir

A 50/100mg 400mg/100mg 90mg/400mg 60mg

B No 400mg/100mg 90mg/400mg 60mg

C No 400mg/100mg 90mg/400mg 60mg

OverallEfficacyPre-TransplantinGT1andGT4SOLAR-1andSOLAR-2:LDV/SOF+RBVinDecompensatedCirrhosis

SVR

12 (%

)

26/30 22/26

SOLAR-1SOLAR-2

24/27 24/25 19/22 17/21 18/20 14/20

LDV/SOF+RBV12wks

LDV/SOF+RBV24wks

LDV/SOF+RBV12wks

LDV/SOF+RBV24wks

CTPB CTPCComparableefficacybetweenSOLAR-1andSOLAR-2studies

CharltonGastroenterology.2015.Volume149,Issue3,Pages 649–659.

LiverFunctionChange:BaselinetoFollow-UpWk 4

23

MELD Score Change ChangeinCTPClass

MajorityshowedimprovementsinMELDandCTPscores

*MissingFU-4:n=24

Pre/Post-Transplant (CTP B and C, n=136*)Baseline CTP

A (5–6)n=73

B (7–9)n=100

C (10–12)n=54

Follow-up Week 4 CTP

A (5–6) 67 (96) 31 (35) 2 (5)

B (7–9) 3 (4) 57 (65) 20 (48)

C (10–12) 0 0 20 (48)

n=95

(-17)

Chan

geinM

ELDScore

(-11)

(+8)

SOLAR-2:LDV/SOF+RBVinDecompensatedandPost-LiverTransplantPatients

noassessment:CTPA,n=3;CTPB,n=12;CTPC,n=12

n=22

n=18

Manns MPetal,LancetInfect Dis.,2016Jun;16(6):685-97.

75/90 82/87 77/90 60/68 65/68 65/71 7/14 11/13 6/12 GT2 4/4GT4 4/4

GT2 4/4GT4 2/2

GT2 3/4GT4 2/2GT6 1/1

SOF/VELinHCVDecompensatedCirrhosis

NEngl JMed.2015.Dec31;373(27):2618-28.

MELDChange(BaselinetoFU12)ASTRAL-4:SubjectswithSVR12,Overall

Nofollow-upWeek12assessmentfor*5patients,†0patients.

BaselineMELD<15

n=208*

ChangeinMELD

BaselineMELD≥15

n=26† Patie

nts(%)

84%Improved 8%Worsened

1 0001027152 4101 1n=1 1174320-1-2-3-5 -4-6-7-11 -8

Patie

nts(%)

52%Improved 27%Worsened

28 114219434132149 4230 0n=

NEngl JMed.2015.Dec31;373(27):2618-28.

Conclusions• HCVremainschallengingtotreatwithchronickidneydisease,especiallyinthosenon-G1/4

• All-oraltherapyhasveryhighefficacyincompensatedcirrhosis

• TreatmentofdecompensatedHCVremainscontroversial