treatment transplant kdigo of hcv recipients in kidney · • 21% dropout due to side effects...

TREATMENTOFHCVINKIDNEYTRANSPLANTRECIPIENTS

Dr.KaiMingChow,PrinceofWalesHospital,ChineseUniversityofHongKong

KDIGO

DISCLOSURES

•  Noconflictofinterest

KDIGO

LECTUREOUTLINES

Candidates- HCVpatientseligibilityforkidneytransplantTransplant- Timingofkidneytransplantandantiviraltreatment

forHCVpatientsRecipients- Choiceofimmunosuppressionfortransplant

recipientsDonors- HCVkidneydonor

KDIGO

Hepatitis C infection

Kidney Transplant Eligibility

KDIGO

• AreHCVpatientshavingworseoutcomeafterkidneytransplant?

• ShouldHCVstatusaffecttheeligibilityofkidneyfailurepatientsforkidneytransplantwaitinglist?

SHOULDKIDNEYTRANSPLANTBEOFFERED?

KDIGO

• OrganProcurementandTransplantationNetworkdatabase• 33357adultprimarykidneytransplantrecipients,1470(4.4%)wereHCV-positive

• 1364HCV-positiveand-negativepairsselectedbypropensityscorematching

HCVANDKIDNEYTRANSPLANTOUTCOMES

Heo NY, Mannalithara A, Kim D, Udompap P, Tan JC, Kim WR. Long-term patient and graft survival of kidney transplant recipients with hepatitis C virus infection in the United States. Transplantation 2018;102:454-460

KDIGO

WORSETRANSPLANTOUTCOMES

WhenHCV-positiveand-negativekidneytransplantrecipientswerecarefullymatched,HCVwasassociatedwith:•  Lowerlong-termrecipientsurvival(attributabletoinfectionandliverfailure)

•  Lowerlong-termdeath-censoredgraftsurvival

(similarfordeceaseddonorandlivedonorrecipients)

Heo NY, Mannalithara A, Kim D, Udompap P, Tan JC, Kim WR. Long-term patient and graft survival of kidney transplant recipients with hepatitis C virus infection

in the United States. Transplantation 2018;102:454-460

KDIGO

COMPARETRANSPLANTWITHDIALYSIS

WhataboutsurvivalofHCVpatientsondialysisandthatafterkidneytransplant?RecentUSanalysisof442,171dialysispatients(7.2%HCVseropositive)from2004to2014

Sawinski D, Forde KA, Lo Re V 3rd, Goldberg DS, Cohen JB, Locke JE, Bloom RD, Brensinger C, Weldon J, Shults J, Reese PP. Mortality and kidney transplantation outcomes among hepatitis C virus-seropositive maintenance dialysis patients: a

retrospective cohort study. Am J Kidney Dis 2019;73:815-826

KDIGO

SURVIVALBENEFITOFTRANSPLANTOUTCOMES

Lesslikelihoodofentrytotransplantwaitlist(HR,0.67;95%CI,0.61-0.74)

Andyet…

HCV-seropositivepatientslivedlongerwithtransplantation(aHRat3years,0.42;95%CI,0.27-0.63)comparedtoremainingonthewaitlist

Sawinski D, Forde KA, Lo Re V 3rd, Goldberg DS, Cohen JB, Locke JE, Bloom RD, Brensinger C, Weldon J, Shults J, Reese PP. Mortality and kidney transplantation outcomes among hepatitis C virus-seropositive maintenance dialysis patients: a

retrospective cohort study. Am J Kidney Dis 2019;73:815-826

KDIGO

SURVIVALBENEFITOFTRANSPLANTOUTCOMES

Sawinski D, Forde KA, Lo Re V 3rd, Goldberg DS, Cohen JB, Locke JE, Bloom RD, Brensinger C, Weldon

J, Shults J, Reese PP. Mortality and kidney transplantation outcomes among hepatitis C virus-

seropositive maintenance dialysis patients: a retrospective cohort study. Am J Kidney Dis

2019;73:815-826

Hazardratiofordeath

kidney transplantation compared to remaining on

the waiting list

KDIGO

KDIGORecommendation

4.1.1:Werecommendkidneytransplantationasthebesttherapeutic

optionforpatientswithCKDG5,irrespectiveofpresenceofHCVinfection(1A).

KDIGO

Hepatitis C treatment

Kidney transplant

KDIGO

TRANSPLANTCANDIDATES

2008KDIGOguidelines:• TreatHCVinpatientswaitlistedfortransplanttoeradicateinfectionwhileondialysis

• ButIFN-basedtherapyispoorlytolerated

Gordon CE, Balk EM, Becker BN et al. KDOQI US commentary on the KDIGO clinical practice guideline for the prevention, diagnosis, evaluation, and treatment of hepatitis C in CKD. Am J Kidney Dis 2008;52:811–825

KDIGO

TRANSPLANTRECIPIENTS

• InterferonIFNlinkedtoacutegraftrejection(evenwithnonfunctioninggrafts)

• Notrecommendedforkidneytransplantrecipientsby2008KDIGOguidelines(unlesspressingindicationssuchasclinicallyandhistologicallyworseningliverdisease)

• Ribavirinalsocausesanaemiabyprovokinghaemolysis

Gordon CE, Balk EM, Becker BN et al. KDOQI US commentary on the KDIGO clinical practice guideline for the prevention, diagnosis, evaluation, and treatment of hepatitis C in CKD. Am J Kidney Dis 2008;52:811–825

KDIGO

IFNANDREJECTIONRISK

• Meta-analysisof12studiescovering140kidneytransplantrecipients

• 21%dropoutduetosideeffects(graftdysfunctionthemostfrequentreason)

• Rejectionrate:10outof140treatedpatients

Wei F, Liu J, Liu F, Hu H, Ren H, Hu P. Interferon-based anti-viral therapy for hepatitis C virus infection after renal transplantation: an updated meta-analysis. PLoS One 2014;9:e90611

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CHANGINGLANDSCAPE

AfterDAA BeforeDAA

KDIGO

Pol S, Parlati L, Jadoul M. Hepatitis C virus and the kidney. Nat Rev Nephrol 2019;15:73-86

KDIGO

KDIGORecommendation4.1.3:WerecommendthatallHCV-infectedpatientswhoarecandidates

forkidneytransplantationbeconsideredforDAAtherapy,eitherbeforeoraftertransplantation(1A).

KDIGO

DAA:CHANGETHESCENE

Canwaituntilafterkidneytransplantation KDIGO

TRANSPLANTCANDIDATES

Factorstoconsiders(fortimingofHCVtreatment):• severityofliverdiseaseorextrahepaticmanifestations• eligibilityforantiviralregimenswithestablishedsafetyinsevererenalimpairment

• estimatedwaitingtimeontherenaltransplantlistKDIGO

BEFOREORAFTERTRANSPLANT?

Chute DF, Chung RT, Sise ME. Direct-acting antiviral therapy for hepatitis C virus infection in the kidney transplant recipient. Kidney Int 2018;93:560–567

KDIGO

HOWLONGTOWAITAFTERTRANSPLANT

• Case-by-casedecision

• Don’twanttowaitfortoolong,orpost-transplantcomplicationwillensue

• Don’twanttotreattooearly(first6months),whenCNIdosageneedsadjustment(druginteraction)

KDIGO

Antiviral agents Calcineurin inhibitors Mammalian target of rapamycin inhibitors

Cyclosporine Tacrolimus Sirolimus Everolimus

Sofosbuvir Nodoseadjustmentrequired Nodoseadjustmentrequired Nodoseadjustmentrequired

Nodoseadjustmentrequired

Simeprevir ↑CsAandSMVlevels MonitorTAClevels MonitorSRLlevels MonitorEVLlevels

Notrecommended

Ombitasvir/ Paritaprevir/ ritonavir+Dasabuvir

↑CsAlevels ↑TAClevels MonitorSRLlevels Notrecommended

AdjustCsAdose AdjustTACdose

Daclatasvir Nodoseadjustmentrequired Nodoseadjustmentrequired Nodoseadjustmentrequired

MonitorEVLlevels

Ledipasvir Nodoseadjustmentrequired Nodoseadjustmentrequired MonitorSRLlevels MonitorEVLlevels

Elbasvir/ Grazoprevir

↑GZVlevels ↑TAClevels

AdjustTACdose

MonitorSRLlevels MonitorEVLlevels

Notrecommended

Glecaprevir/ Pibrentasvir

↑G/Plevels ↑TAClevels

MonitorSRLlevels

MonitorEVLlevels

Notrecommended(unlessdailydose<100mg)

AdjustTACdose

KDIGO

CONSULTTHEWEBSITE

• HepatitisDrugInteractionswebsitefromtheUniversityofLiverpool

• http://www.hep-druginteractions.org

• Checkforthelatestguidanceonpotentialdrug–druginteractionspriortoDAAuse

KDIGO

PROSANDCONS

•  TextPre-transplant HCV treatment Post-transplant HCV treatment

Pros

•  Limitriskofprogressiveliverinjuryinpre-transplantperiod

•  AvoidriskofprogressiveHCVliverdiseaseandfibrosingcholestatichepatitisfollowingtransplant

•  Providesoptimumuseandtimingofalivedonorgraft

•  AcceptHCV-positivedonors•  Shorterwait-listtime•  Increasekidneydonorpool

Cons

•  PotentiallyprecludeuseofHCV-positiveorgans

•  Longerwait-listtimeandriskofdeathondialysis

•  Stillatriskofprogressiveliverdisease•  Stillatriskofhepatocellularcarcinoma•  LongerwaitfortreatmentofHCVpost-

transplantmayleavethematriskofdiabetes,graftfailure,decreasedsurvival

KDIGO

Hepatitis C treatment

Kidney transplant Immunosuppression KDIGO

WHATIMMUNOSUPPRESSIONTOUSE

• ConcernsofincreaseinHCVviralloadaftertransplantation

• Anycautionwithimpactofinductionandhighdosemaintenanceimmunosuppression?

KDIGO

INDUCTIONANDSTEROIDIMMUNOSUPPRESSION

• Anyconcernwithtransplantsurvival?

• AntibodyinductionhasnotbeenlinkedtoworsesurvivalinHCV-positivepatientswithpost-transplantationchronicliverdisease

• LimiteddataoninfluenceofsteroidsinkidneytransplantpatientswithHCVinfection,butnodifferenceinmortalityinaUSstudy

KDIGO

HCVANDMETABOLICCOMPLICATIONS

• IncreasedinsulinresistanceafterchronicHCVinfection

• Meta-analysis(>30,000kidneytransplantrecipients):relativeriskofpost-transplantdiabetesmellitusis2.73-foldhigher

• Cantheriskbemodifiedbyimmunosuppression?

Fabrizi F, Messa P, Martin P, Takkouche B. Hepatitis C virus infection and post-transplant diabetes mellitus among renal transplant patients: a meta-analysis. Int J Artif Organs 2008;318:675-682

KDIGO

CALCINEURININHIBITORIMMUNOSUPPRESSION

• NosignificantdifferenceinoutcomeswithcyclosporinesversustacrolimusinHCV-infectedtransplantrecipients

• Higherriskofpost-transplantdiabetesmellitusintacrolimus-treatedpatients

Bloom RD, Rao V, Weng F, Grossman RA, Cohen D, Mange KC. Association of hepatitis C with posttransplant diabetes in renal transplant patients on tacrolimus. J Am Soc Nephrol 2002;13:1374-1380

KDIGO

COXREGRESSIONMODELOFNODAT/PTDM

Santos AH Jr, Chen C, Casey MJ, Womer KL, Wen X. New-onset diabetes after kidney transplantation: can the risk be modified by choosing immunosuppression regimen based on pretransplant viral serology? Nephrol Dial Transplant 2018;33:177-184

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ear)

Adult transplant recipients (n = 97 644)

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CONVERSIONOFFKTOCYCLOSPORIN

• Single-centerstudy:10HCV-positiverenaltransplantrecipientswithOGTTbeforeandthreemonthsaftertheconversion

• Significantlyimprovedglucose-stimulatedinsulinsensitivityandoverallglucosetolerance

Handisurya A, Kerscher C, Tura A, Herkner H, Payer BA, Mandorfer M, Werzowa J, Winnicki W, Reiberger T, Kautzky-Willer A, Pacini G, Säemann M, Schmidt A.

Conversion from tacrolimus to cyclosporine A improves glucose tolerance in HCV-positive renal transplant recipients. PLoS One 2016;11:e0145319

§  priortoconversion(fullsymbols)

q  3monthsafterconversion(blanksymbols)KDIGO

CALCINEURININHIBITORIMMUNOSUPPRESSION

• CyclosporineinhibitsHCVreplicationonculturedhepatocytes

Watashi K, Hijikata M, Hosaka M, Yamaji M, Shimotohno K. Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes. Hepatology 2003;38:1282-1288

KDIGO

OTHERIMMUNOSUPPRESSION• ChangetoMMF(n=14):increasedserumHCVRNAfrom5.2±0.7to5.8±0.5logcopies/ml(P=0.01)

Rostaing L, Izopet J, Sandres K, Cisterne JM, Puel J, Durand D. Changes in hepatitis C virus RNA viremia concentrations in long-term renal transplant patients after introduction of mycophenolate mofetil. Transplantation 2000;69:991–994

KDIGO

OTHERIMMUNOSUPPRESSION

• Dataonsirolimusandeverolimus:limitedinpatientswithHCVinfection

KDIGO

KDIGORecommendation4.3.1:Wesuggestthatallconventionalcurrentinductionand

maintenanceimmunosuppressiveregimenscanbeusedinHCV-infectedkidneytransplantrecipients(2C).

KDIGO

Hepatitis C Kidney Donor KDIGO

TRANSPLANTDONORS

CantransplantHCV-positivekidneysintoHCV-negativerecipients?

KDIGO

THINKERTRIAL

• TransplantingHepatitisCKidneysintoNegativeKidneyRecipients

• KidneysfromHCVgenotype1–viraemicdonorsinto10HCV-negativepatients

• RecipientsmonitoredforHCVviraemiastartingatpostoperativeday3

• OnceHCVRNAdetected:elbasvir–grazoprevir(Zepatier)treatmentfor12weeks

Goldberg DS, Abt PL, Blumberg EA, Van Deerlin VM, Levine M, Reddy KR, Bloom RD, Nazarian SM, Sawinski D, Porrett P, Naji A, Hasz R, Suplee L, Trofe-Clark J, Sicilia A, McCauley M, Farooqi M, Gentile C, Smith J, Reese PP. Trial of transplantation of HCV-

infected kidneys into uninfected recipients. N Engl J Med 2017;376:2394-2395

KDIGO

THINKERTRIAL

• Donor-to-recipientHCVtransmission:100%

• TwocasesofelevatedALT

• AllrecipientswerecuredofHCV(sustainedvirologicresponseSVR12)

Goldberg DS, Abt PL, Blumberg EA, Van Deerlin VM, Levine M, Reddy KR, Bloom RD, Nazarian SM, Sawinski D, Porrett P, Naji A, Hasz R, Suplee L, Trofe-Clark J, Sicilia A, McCauley M, Farooqi M, Gentile C, Smith J, Reese PP. Trial

of transplantation of HCV-infected kidneys into uninfected recipients. N Engl J Med 2017;376:2394-2395

KDIGO

THINKERTRIAL–12MONTHRESULT

• First10recipients–12monthdata(THINKER-1)• Additional10recipients–6monthdata(THINKER-2)

• Primaryoutcome–allachievedcureofHCV

Reese PP, Abt PL, Blumberg EA, Van Deerlin VM, Bloom RD, Polturi VS, Levine M, Porrett P, Sawinski D, Nazarain SM, Naji A, Hasz R, Suplee L, Trofe-Clark J, Sicilia A, McCauley M, Gentile C, Smith J, Niknam BA, Bleicher M, Reddy KR, Goldberg DS. Twelve-Month outcomes after transplant of hepatitis C-infected kidneys into uninfected recipients:

a single-group trial. Ann Intern Med 2018;169:273-281

KDIGO

THINKERTRIAL–12MONTHRESULT

•  MeanPhysicalComponentSummary(PCS)andMentalComponentSummary(MCS)quality-of-lifescoresdecreasedat4weeks

•  PCSscoresthenincreasedabovepretransplantvalues

•  MCSscoresreturnedtobaselinevalues



KDIGO

SIMILARGFR(6AND12MO)WITHMATCHEDSUBJECTS



KDIGO

FURTHEREXPANSIONOFDONORPOOL

• EXPANDER• ExploringRenalTransplantsUsingHepatitisCInfectedDonorsforHCVNegativeRecipients

Durand CM, Bowring MG, Brown DM, Chattergoon MA, Massaccesi G, Bair N, Wesson R, Reyad A, Naqvi FF, Ostrander D, Sugarman J, Segev DL, Sulkowski M, Desai NM. Direct-acting antiviral prophylaxis in kidney

transplantation from hepatitis C virus–infected donors to noninfected recipients: an open-label nonrandomized trial. Ann Intern Med 2018;168:533-540

KDIGO

EXPANDER:IMPLICATIONSOFSTUDYDESIGN

• AlloworganfromHCVinfecteddonorswithanyHCVgenotype• Notrequirevirologicorgenotypicassayatthetimeoforganofferandallocation



KDIGO

EXPANDER

• Industry-fundedpilotstudyinJohnHopkinsUniversity• 10HCVD+/R−kidneytransplantcandidateswithoutlivingdonors• Deceaseddonorsaged13to50yearswithpositiveHCVRNAandHCVantibodytest

• TestingtolerabilityandfeasibilityofprophylacticDAAforrecipients



KDIGO

RECIPIENTSWITHHCV-INFECTEDDONORS

• Medianwaittime1month• GPZ-EBRregime:Grazoprevirandelbasvirimmediatelybeforesurgeryanddailyfor12weeksaftersurgery

• Donorswithgenotype2or3HCV:additionalsofosbuvir(GPZ-EBR+SOF)aftertransplant



KDIGO

OUTCOMESOFHCVD+/R-KIDNEYTRANSPLANT

• 12weeks'follow-up• Notreatment-relatedadverseevents• NorecipientbecameinfectedwithchronicHCV• OverhalfofrecipientshadHCVRNAlevelsbelowthelowerlimitofquantification(LLOQ)

Durand CM, Bowring MG, Brown DM, Chattergoon MA, Massaccesi G, Bair N, Wesson R, Reyad A, Naqvi FF, Ostrander D, Sugarman J, Segev DL, Sulkowski M, Desai NM. Direct-acting antiviral prophylaxis in kidney transplantation from hepatitis

C virus–infected donors to noninfected recipients: an open-label nonrandomized trial. Ann Intern Med 2018;168:533-540

KDIGO

HCVRNATRENDINTRANSPLANTRECIPIENTS

Durand CM, Bowring MG, Brown DM, Chattergoon MA, Massaccesi G, Bair N, Wesson R, Reyad A, Naqvi FF, Ostrander D, Sugarman J, Segev DL, Sulkowski M, Desai NM. Direct-acting antiviral prophylaxis in kidney transplantation from hepatitis C

virus–infected donors to noninfected recipients: an open-label nonrandomized trial. Ann Intern Med 2018;168:533-540

KDIGO

CONCLUSION

HCVINKIDNEYTRANSPLANT

KDIGO

CONCLUSION

q  KidneytransplantationisthebesttherapeuticoptionforpatientswithCKDG5,irrespectiveofpresenceofHCVinfection

q  AllHCV-infectedpatientswhoarecandidatesforkidneytransplantationtobeconsideredforDAAtherapy,eitherbeforeoraftertransplantation

q  AllconventionalcurrentinductionandmaintenanceimmunosuppressiveregimenscanbeusedinHCV-infectedkidneytransplantrecipients

KDIGO

Candidateswaitingfortransplant

Transplantrecipients

HCVkidneydonors

KDIGO

treatment transplant kdigo of hcv recipients in kidney · • 21% dropout due to side effects...

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