Post on 09-Oct-2020
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