Hepatitis C and CKD: News from KDIGO · Paris, France Marcelo O. Silva, MD Hospital Universitario...

Ali K. Abu-Alfa, MD, FASN, FASH Professor of Medicine

Head, Division of Nephrology & Hypertension Director, Human Research Protection Program

Director for Research Affairs American University of Beirut

Adjunct Faculty

Section of Nephrology Yale School of Medicine

Novosibirsk | September 23rd, 2017

Hepatitis C and CKD: News from KDIGO

Acknowledgement

2

This slide deck was developed based on the draft public-review version of the KDIGO guideline on Hepatitis C in CKD. It is based on a set of slides kindly shared by Dr Michel Jadoul.

KDIGOGuidelinesonHCVinCKD

3

2008 First global comprehensive guidelines on Hepatitis C Virus in nephrology

Global HCV Genotype Distribution

Messina JP et al. HEPATOLOGY 2015; 61:77-87

DAAsPI ProteaseInhibitorDAA Direct-Ac2ngAn2viralAgent

Evolution in HCV Therapy: SVRs

Webster DP et al. Lancet 2015; 385: 1124–1135

SVR in HCV and Long-Term Outcomes

Simmons B et al. Clinical Infectious Diseases 2015; 61: 730–740

31studies(n=33360)includedMedianfollow-up5.4years

DRAFTVERSION:NOTFORCIRCULATION

WORK GROUP MEMBERSHIP

Work Group Co-Chairs

Michel Jadoul, MD Cliniques Universitaires Saint Luc Université Catholique de Louvain

Brussels, Belgium

Paul Martin, MD, FRCP,FRCPI Miller School of Medicine

University of Miami Miami, USA

Work Group

Marina C. Berenguer, MD La Fe University Hospital Valencia, Spain Wahid Doss, MD National Hepatology and Tropical Medicine Research Cairo, Egypt Fabrizio Fabrizi, MD Maggiore Policlinico Hospital Milan, Italy Jacques Izopet, PharmD, PhD Centre de Physiopathologie de Toulouse Purpan Toulouse, France Vivekanand Jha, MBBS, MD, DM, PhD, FRCP George Institute New Delhi, India Nassim Kamar, MD, PhD CHU Rangueil, Toulouse, France

Bertram Kasiske, MD Hennepin County Medical Center Minneapolis, MN, USA Ching-Lung Lai, MD University of Hong Kong Hong Kong, China José M. Morales, MD Hospital Universitario 12 de Octubre Madrid, Spain Priti R. Patel, MD, MPH Centers for Disease Control and Prevention Atlanta, USA Stanislas Pol, MD, PhD Hôpital Cochin Paris, France Marcelo O. Silva, MD Hospital Universitario Austral Pilar, Argentina

KDIGO2017CLINICALPRACTICEGUIDELINEONTHEPREVENTION,DIAGNOSIS,EVALUATION

ANDTREATMENTOFHEPATITISCINCKD

Chapter 1 Detection and Evaluation of HCV in CKD

Chapter 2 Treatment of HCV Infection in Patients with CKD

Chapter 3 Preventing HCV Transmission in HD Units

Chapter 4 Management of HCV-Infected Patients before and after Kidney Transplantation Chapter 5 Diagnosis and Management of Kidney Diseases Associated with HCV Infection


1.1.1 Werecommendscreeningallpa2entsforHCVinfec2onatthe2meofini2alevalua2onofCKD.(1C)

1.1.1.1 Werecommendusingimmunoassayfollowedbynucleicacidtes2ng

(NAT).(1A) 1.1.2 Werecommendscreeningallpa2entsuponini2a2onofin-center

hemodialysisorupontransferringtoanotherdialysisfacilityormodalityforHCVinfec2on.(1A)

1.1.2.1 WerecommendusingNAT,orimmunoassayfollowedbyNAT.(1A) 1.1.3 Wesuggestscreeningallpa2entsuponini2a2onofperitonealdialysis

orhomehemodialysisforHCVinfec2on.(2D)1.1.4 Werecommendscreeningallpa2entsforHCVinfec2onat

the2meofevalua2onforkidneytransplanta2on.(1A)

Chapter 1: Detection and Evaluation of HCV in CKD HCV Screening of Patients with CKD


1.2.1 Werecommendscreeningin-centerhemodialysispa2entsforHCVevery6months.(1B)

1.2.1.1 ReportanynewHCVinfec2oniden2fiedinahemodialysispa2entto

theappropriatepublichealthauthority.(NotGraded)1.2.1.2 IfanewHCVinfec2onisiden2fiedinahemodialysisfacility,we

recommendallpa2entswithinthefacilitywhowereNATnega2vebetestedforHCVinfec2onandthefrequencyofsubsequentHCVtes2ngforthesepa2entsbeincreased.(1A)

1.2.1.3 Werecommendhemodialysispa2entswithresolvedHCVinfec2onundergorepeattes2ngevery6monthsusingNAT.(1B)

1.2.2 We suggest patients have serum alanine aminotransferase (ALT) level

checked upon initiation of in-center hemodialysis or upon transfer to another facility or modality. We suggest NAT-negative hemodialysis patients have serum alanine aminotransferase (ALT) level checked monthly. (2B)

Chapter 1: Detection and Evaluation of HCV in CKD Follow-up HCV Screening of in-Center HD Patients


1.3.1 WerecommendHCV-infectedpa2entswithCKDbeassessedforliverfibrosis.(1A)

1.3.2 Werecommendanini2alnon-invasiveevalua2onofliverfibrosis.(1B)1.3.3 Whenthecauseofliverdiseaseisuncertainornon-invasivetes2ng

resultsarediscordant,considerliverbiopsy.(NotGraded)1.3.4 WerecommendassessmentofportalhypertensioninCKDpa2ents

withsuspectedadvancedfibrosis(F3-4).(1A)

Chapter 1: Detection and Evaluation of HCV in CKD Liver Testing in Patients with CKD and HCV Infection


1.4.1 Werecommendthatallpa2entsbeassessedforkidneydiseaseatthe2meofHCVdiagnosis.(1A)

1.4.1.1 Screenforkidneydiseasewithurinalysisandes2matedglomerular

filtra2onrate(eGFR).(NotGraded)1.4.2 Ifthereisnoevidenceofkidneydiseaseatini2alevalua2on,pa2ents

whoremainNATposi2veshouldundergorepeatscreeningforkidneydisease.(NotGraded)

1.4.3 WerecommendthatallCKDpa2entswithahistoryofHCVinfec2on,

whetherNATposi2veornot,befollowedregularlytoassessforprogressionofkidneydisease.(1A)

1.4.4 WerecommendthatallCKDpa2entswithahistoryofHCVinfec2on,

whetherNATposi2veornot,bescreenedand,ifappropriate,vaccinatedforHAVandHBV,andscreenedforHIV.(1A)

Chapter 1: Detection and Evaluation of HCV in CKD Other Testing of Patients with HCV Infection


DAA for HCV: Site of Action

Pockros PJ et al. Clin Pharmacol Ther 2014; 95:78

NS5A:nonstructuralprotein5A;NS5B:nonstructuralprotein5B;NNPI:non-nucleosidepolymeraseinhibitor

DAA for HCV: Molecular Targets

Majumdar A et al. Drugs 2015: 75:823–834


DAA for HCV: Summary by Class


-PREVIR -ASVIR -BUVIR

SiteofAc2onNS3Protease

inhibitors

NS5A

inhibitors

Nucleos(t)ideNS5B

Polymerase

inhibitors

Non-nucleoside

NS5BPolymerase

inhibitorsPotency High

1stgeneraRon

variablegenotypes

2ndgeneraRon

Increasinglypangenotypic

High

Increasinglypangenotypic

Moderate-High

Pangenotypic

Variable

VariableamongHCVgenotypes

Barrierstoresistance

Low

1a<1b

Low

1a<1b

High

1a=1b

Verylow

1a<1b

Druginterac2onpoten2al

High Lowtomoderate Minimal Variable

Use of DAAs in CKD and ESRD

Kwo PY and Badshah MB Curr Opin Organ Transplant 2015; 20: 235–241

2.1 WerecommendthatallCKDpa2entsinfectedwithHCVbeevaluatedforan2viraltherapy.(1A)

2.1.1 Werecommendaninterferon-freeregimen.(1A)2.1.2 WerecommendchoiceofspecificregimenbebasedonHCVgenotype

(andsubtype),viralload,drug-druginterac2ons,eGFRcategory,stageofhepa2cfibrosis,kidneyandlivertransplantcandidacy,andcomorbidi2es.(1A)

2.1.3 Treatkidneytransplantcandidatesincollabora2onwiththetransplant

centertoop2mize2mingoftherapy.(NotGraded)

Chapter 2: Treatment of HCV Infection in CKD


2.2 Werecommendthatpa2entswitheGFR>30ml/min/1.73m2betreatedwithanylicensedDAA-basedregimen.(1A)



AASLD: HCV Treatment in CKD 1-3

http://hcvguidelines.org/unique-populations/renal-impairment. Accessed September 19, 2017

2.3 Werecommendthatpa2entswitheGFR<30ml/min/1.73m2betreatedwithDAAbasedregimens,preferen2allyribavirin-free(1B),asfollows:

2.3.1 WerecommendforHCVgenotype1subtypeAtheuseof

grazoprevir/elbasvir(1A)andforHCVgenotype1subtypeB,grazoprevir/elbasvir(1A)orthe“PROD”regimen(thecombina2onofritonavir-boostedparitaprevir,ombitasviranddasabuvir)(1B)for12weeks.

2.3.2 WesuggestforHCVgenotype4theuseofgrazoprevir/elbasvirorthe

“2D”regimen(thecombina2onofritonavir-boostedparitaprevir,ombitasvirregimen)for12weeks.(2D)

2.3.3 Treatpa2entswithHCVgenotypes2,3,5,and6onacase-by-case

basis.(NotGraded)Grz/ElbandPRODregimensnotac8veonthesegenotypes

-



AASLD: HCV Treatment in CKD 5, 5D

http://hcvguidelines.org/unique-populations/renal-impairment. Accessed September 19, 2017

(PROD regimen, J Virology 2017)

(C-SURFER regimen, LANCET 2015)

C-SURFER in CKD 4-5/ESRD

Roth D et al. Lancet 2015; 386: 1537–45

GZR100mg/EBR50mg

Placebo(DeferredGroup)

D1 TW4 TW8 TW12 FUW4 FUW8 FUW12

n=111

n=113

GZR100mg/EBR50mg(PK)n=11

R

Follow-up

Follow-up

*GZR100mg/EBR50mg

FUW16

GZR:Grazoprevir EBR:Elbasvir

•  Primaryefficacyoutcomewasacomparisonofsustainedvirologicalresponseat12weeks(SVR12)aiertheendoftherapy

•  HCVGenotype1infecRon(52%1a,48%1b).NoLiverbiopsyrequired.•  Treatment-naiveandtreatment-experiencedpaRents:

–  CKDstage4/5–  Hemodialysis-Dependent(76%)

•  AllHBVandHIVnegaRve.

C-SURFER in CKD 4-5/ESRD: Virologic Response on Treatment


66%

90% 100% 100% 99%

60%

95%100% 99% 98%

0%

20%

40%

60%

80%

100%

TW2 TW4 TW12 FW4 FW12(SVR12)

PaRe

nts(HC

VRN

A<LLoQ),%

Immediatetreatmentgroup

Deferredtreatmentgroup

C-SURFER in CKD 4-5/ESRD: Cure Rates


94.3% 95.1%99.1% 98.0%

0%

25%

50%

75%

100%

Immediatetreatment Deferredtreatment

Fullanalysisset Modifiedfullanalysisset

C-SURFER in CKD 4-5/ESRD: Adverse Event Rates


GZR/EBR (ITG)

(n = 111)

GZR/EBR (DTG)

(n = 102)

Placebo (DTG)

(n = 113)

Difference in % Estimate

ITG vs placebo (95% CI)

AEs,a n (%) 84 (75.7) 61 (59.8) 95 (84.1) –8.3 (–18.9, 2.2)

Headache 19 (17.1) 7 (6.9) 19 (16.8) 0.3 (-9.6, 10.4) Nausea 17 (15.3) 10 (9.8) 18 (15.9) –0.6 (–10.3, 9.1) Fatigue 11 (9.9) 9 (8.8) 17 (15.0) –5.1 (–14.1, 3.7) Insomnia 7 (6.3) 2 (2.0) 12 (10.6) –4.3 (–12.2, 3.2) Dizziness 6 (5.4) 5 (4.9) 18 (15.9) –10.5 (–19.1, -2.6)

Diarrhea 6 (5.4) 5 (4.9) 15 (13.3) –7.8 (–16.1, -0.2)

Serious AEs, n (%) 16b (14.4) 13c (12.7) 19 (16.8) –2.4 (–12.1, 7.3)

Discontinued due to AE, n (%) 0 (0) 3 (2.9) 5 (4.4) –4.4 (10.0, -1.0)

Deaths, n (%) 1 (0.9) 0 (0) 3 (2.7) –1.8 (–6.7, 2.5)

2.4 WerecommendthatallkidneytransplantrecipientsinfectedwithHCVbeevaluatedfortreatment.(1B)

2.4.1 WerecommendtreatmentwithaDAA-basedregimen.(1A)2.4.2 WerecommendthechoiceofregimenbebasedonHCVgenotype(and

subtype),viralload,drug-druginterac2ons,eGFRcategory,stageofhepa2cfibrosis,livertransplantcandidacy,andcomorbidi2es.(1A)

2.4.3 Werecommendthattreatmentwithinterferonbeavoided.(1A)

Chapter 2: Treatment of HCV Infection in CKD Transplantation


RCT: Ledipasvir–Sofosbuvir in Transplant Response Rates

Colombo M et al. Ann Intern Med 2017; 166: 109-117

•  HCVGenotype1or4infecRon•  Medianof10yearsaderkidneytransplantaRon,Cirrhosis15%•  MediancreaRnineclearancebyCG: 56ml/min•  Regimens: Tacrolimus47%,CyclosporinA39%,MMF61%,Steroids98%

RCT: Ledipasvir–Sofosbuvir in Transplant Changes in GFR

Colombo M et al. Ann Intern Med 2017; 166: 109-117

2.5 Werecommendpre-treatmentassessmentfordrug-druginterac2onsbetweentheDAA-basedregimenandotherconcomitantmedica2onsincludingimmunosuppressivedrugsinkidneytransplantrecipients.(1A)

2.5.1 Werecommendthatcalcineurininhibitorlevelsbemonitoredduring

andaierDAAtreatment.(1B)


Chapter 2: Treatment of HCV Infection in CKD Transplantation

Drug-Drug Interactions: Immunosuppressive Medications

Kwo PY and Badshah MB Curr Opin Organ Transplant 2015; 20: 235–241

Drug-Drug Interactions: Immunosuppressive Medications


3.1 Werecommendthathemodialysisfacili2esadheretostandardinfec2on-controlproceduresincludinghygienicprecau2onsthateffec2velypreventtransferofbloodandblood-contaminatedfluidsbetweenpa2entstopreventtransmissionofblood-bornepathogens(1A)3.1.1Werecommendregularobserva2onalauditsofinfec2oncontrolproceduresinhemodialysisunits.(1C)

3.1.2 WerecommendnotusingdedicateddialysismachinesforHCV-infected

pa2ents.(1D)3.1.3 Wesuggestnotisola2ngHCV-infectedhemodialysispa2ents.(2C)3.1.4 WesuggestthatthedialyzersofHCV-infectedpa2entscanbereusedif

thereisadherencetostandardinfec2on-controlprocedures.(2D)


Chapter 3: Preventing HCV Transmission in HD Units

3.2 WerecommendhemodialysiscentersexamineandtrackallHCVtestresultstoiden2fynewcasesofHCVinfec2onsintheirpa2ents.(1B)

3.2.1 Werecommendaggressivemeasuresbetakentoimprovehandhygiene

(andpropergloveuse),injec2onsafety,andenvironmentalcleaninganddisinfec2onwhenanewcaseofHCVisiden2fiedthatislikelytobedialysis-related.(1A)

3.3 StrategiestopreventHCVtransmissionwithinhemodialysisunitsshould

priori2zeadherencetostandardinfec2oncontrolprac2cesandshouldnotprimarilyrelyuponthetreatmentofHCV-infectedpa2ents.(NotGraded)


Chapter 3: Preventing HCV Transmission in HD Units

4.1 Werecommendkidneytransplanta2onasthebesttherapeu2cop2onfor pa2entswithend-stagerenaldisease(ESRD)irrespec2veofpresenceof

HCVinfec2on.(1A)4.2 WesuggestthatallHCV-infectedkidney-transplantcandidatesbe

evaluatedforseverityofliverdiseaseand,ifindicated,portalhypertensionpriortoacceptanceforanisolatedkidneyorcombinedkidney-livertransplanta2on.(2D)

4.2.1 WerecommendthatHCV-infectedpa2entswithcompensatedcirrhosis

(withoutportalhypertension)undergoisolatedkidneytransplanta2on.(1B)

4.2.2 WerecommendtoreferHCV-infectedpa2entswithdecompensated

cirrhosisforcombinedliver-kidneytransplanta2on(1B)andtodeferHCVtreatmentun2laiertransplanta2on.(1D)


Chapter 4: Management of HCV Infected Patients Before and After Kidney Transplantation

4.3 TimingofHCVtreatmentinrela2ontokidneytransplanta2on(beforevs.aier)shouldbebasedondonortype(livingvs.deceaseddonor),waitlist2mesbydonortype,center-specificpoliciesforusingornotkidneysfromHCV-infecteddeceaseddonors,HCVgenotype,andseverityofliverfibrosis.(NotGraded)

4.3.1 ForallHCV-infectedpa2entswhoarecandidatesforkidneytransplanta2on,werecommendtheybeconsideredforan2viraltherapy,eitherbeforeoraiertransplanta2on.(1A)

4.3.2 ForHCV-infectedkidney-transplantcandidateswithalivingkidneydonor,wesuggesttheycanbeconsideredfortreatmentbeforeoraiertransplanta2onaccordingtoHCVgenotypeandan2cipated2mingoftransplanta2on.(2D)

4.3.3 Wesuggestthat,ifreceivingakidneyfromaHCV-posi2vedonorimprovesthechancesfortransplanta2on,theHCVRNA-posi2vepa2entcanundergotransplanta2onwithaHCV-posi2vekidneyandbetreatedforHCVinfec2onaiertransplanta2on.(2D)



4.4.1 WerecommendallkidneydonorsbescreenedforHCVinfec2onwithbothimmunoassayandNAT(ifNATisavailable).(1A)

4.4.2 Werecommendthattransplanta2onofkidneysfromHCVRNA-posi2ve

donorsbedirectedtorecipientswithposi2veNAT.(1A)4.4.3 Aiertheassessmentofliverfibrosis,poten2alHCV-posi2velivingkidney

donorswhodonothavecirrhosisshouldundergoHCVtreatmentbeforedona2on;theycanbeacceptedfordona2oniftheyachieveSVRandremainotherwiseeligibletobeadonor.(NotGraded)

4.5 Wesuggestthatallconven2onalcurrentinduc2onandmaintenance

immunosuppressiveregimenscanbeconsideredforuseinHCV-infectedkidneytransplantrecipients.(2C)

4.6 ManagementofHCV-relatedcomplica?onsinkidneytransplant

recipients(notshown)



5.1 WerecommendthatakidneybiopsybeperformedinHCV-infectedpa2entswithclinicalevidenceofglomerulardisease.(1B)

5.2 Werecommendthatpa2entswithHCV-associatedglomerulardiseasebetreatedforHCV.(1A)

5.2.1 Werecommendthatpa2entswithHCV-relatedglomerulardiseaseshowingstablekidneyfunc2onand/ornon-nephro2cproteinuriabetreatedini2allywithDAA.(1B)

5.2.2 Werecommendthatpa2entswithcryoglobulinemicflare,nephro2csyndrome,orprogressivekidneyfailurebetreatedwithbothDAAandimmunosuppressiveagentsand/orplasma-exchange.(1B)

5.2.3 Werecommendimmunosuppressivetherapyinpa2entswithhistologicallyac2veHCV-associatedglomerulardiseasewhodonotrespondtoan2viraltherapy,par2cularlythosewithcryoglobulinemickidneydisease.(1A)

5.2.3.1 Werecommendrituximabasthefirst-lineimmunosuppressivetreatment.(1B)


Chapter 5: Diagnosis and Management of Kidney Diseases Associated with HCV Infection

Summary •  TherapyforHepaRRsCVirusinfecRoninCKD/ESRDpaRentsand

transplantrecipientshasbeenrevoluRonizedtowardsacurewithneweragentsandregimens.

•  ManyregimensarewelltoleratedbutcauRonshouldbeexercisedgiven:

–  Needtoverifygenotypeforappropriateregimen–  NeedtoavoidcertaindrugsinCKD4-5/ESRD(eg.Sofosbuvir)–  Needtocheckfordrug-druginteracRons,especiallyintransplantpaRents

•  TransplantaRonincontextofHepaRRsCinfecRon,donorand/orrecipient,requiresdeliberaRonandcarefulconsideraRons.

•  CoordinaRonwithhepatologistsandinfecRousdiseasespecialistsiscriRcalforsuccessfulandsafetherapy.

•  UpcomingKDIGOguidelinesofferacomprehensiveup-to-datesummaryandreferenceonHepaRRsCinfecRoninrenalpaRents.

KidneyDisease:ImprovingGlobalOutcomes

/goKDIGO

@goKDIGO

FOLLOW KDIGO

www.kdigo.org

@goKDIGO

Hepatitis C and CKD: News from KDIGO · Paris, France Marcelo O. Silva, MD Hospital Universitario...

Documents

Transcript of Hepatitis C and CKD: News from KDIGO · Paris, France Marcelo O. Silva, MD Hospital Universitario...