TreatingHepatitisC-HIVCoinfected Patients

WelcometotheRealWorldH.NinaKim,MDMSc

AssociateProfessorofMedicineUniversityofWashington

DivisionofAllergy&InfectiousDiseasesApril21,2017

LearningObjectivesUponcompletionofthispresentation,learnersshouldbebetterableto:

• Discusssomereal-worldHCVtreatmentissuesrelatedtochoiceofdirect-actingantiviral(DAA)therapyinHIV-HCVcoinfectedpatients

• Identifyrelevantdruginteractions withDAAsandantiretroviraltherapy

• Recognizethepotentialforadverseevents inselectedpatientsundergoingDAAtherapy

• HighlighttheimportanceofHCCsurveillance evenafterHCVclearanceinpatientswithcirrhosis

MilestonesinHCVTreatment

3544

75

85

96

1827

74

85

96

0

20

40

60

80

100

IFN/RBV PegIFN/RBV Telaprevir or Boceprevir + PR

SMV or SOF + PR IFN-free DAAs

Patie

nts

with

SVR

12

(%)

HCV HIV/HCV

HIV-HCVCoinfected ResponsestoDAATherapyComparabletoHCVMonoinfected

Regimen(12weeks)

Genotype1

HIV-HCVCoinfected HCVMonoinfected

Study SVR Study SVR

Daclatasvir +Sofosbuvir ALLY-2 97% AI444040 100%

Ledipasvir-Sofosbuvir ION-4 96% ION-1 99%

Paritaprevir-ritonavir-ombitasvir +Dasabuvir TURQUOISE-I 94% PEARL-III, IV 96%

Elbasvir-Grazoprevir C-EDGECoinf 95% C-EDGETN 95%

HCVTargetsforDirect-ActingAntivirals(DAAs)

Translationandpolyproteinprocessing

NS3/4proteaseinhibitors

Receptorbindingandendocytosis Transport

andrelease

Virionassembly

RNAreplication

Fusionanduncoating

(+)RNA

Membranousweb

NS5Bpolymeraseinhibitors

Nucleos(t)ideNon-nucleoside

NS5Ainhibitors

replicationandassembly

Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

CurrentlyAvailableDAAsClass Drug Dosing Activity FDA

Approved

NS5Binhibitor Sofosbuvir (Solvadi) QD Pangenotypic 2013

NS3Aproteaseinhibitor(PI) Simeprevir (Olysio) QD GT1,2,4,5,6 2013

NS5A-NS5Binhibitorcombo

Ledipasvir-Sofosbuvir(Harvoni) QD GT1 2014

NS5A,NS5BinhibitorswithPI(“3D”)

Paritaprevir/ritonavir/ombitasvir +dasabuvir (Viekira Pak)

BID GT1 2014

NS5Ainhibitor+PIOmbitasvir-

paritaprevir/ritonavir(Technivie)

QD GT4 2015

NS5Ainhibitor Daclatasvir(Daclinza) QD Pangenotypic 2015

NS5Ainhibitor+PI Elbasvir-Grazoprevir (Zepatier) QD GT1,4(pangenotypic) 2016

NS5A-NS5Binhibitorcombo

Sofosbuvir-Velpatasvir(Epclusa) QD Pangenotypic 2016

Case1A52year-oldHIV-infectedmanpresentstoyourclinicforroutinefollow-up.On emtricitabine/tenofovir (FTC/TDF),ritonavirandatazanavir witharecentCD4count560cells/mm3 andHIVRNA<40copies/mL. HehaschronichepatitisC,withHCVRNAlevelof1.5millionIU/mL,genotype1A,treatmentnaïve.

Hisexamisnotableforafirmliveredgeandscatteredspiderangiomata.LabsshowALT50,AST60,platelets110K;hisCrCl is75.Hisultrasounddemonstratesanodularcontouredliverandnormal-sizedspleen.

HewantstreatmentforhishepatitisCinfection.

Whichofthefollowingwouldyoudonext?

A. Sethimupforaliverbiopsyfordiseasestaging.B. Considerswitchinghisantiretroviralregimenin

anticipationoftreatmentwithledipasvir-sofosbuvir.C. Startelbasvir-grazoprevir oncedaily.D. Startledipasvir-sofosbuvir plusribavirin(weight-

baseddosing).

FactorstoConsiderinChoiceofDAARegimen

• Genotype (andsubtype:1Avs 1B)• Cirrhosis?

– Decompensatedorcompensated?

• Treatmentexperience?– Failurewithpeginterferon/ribavirinorpriorDAAs?

• IfHIV-coinfected:whatistheirantiretroviraltherapy?

DAARegimens:Genotype1EBR-GRZ LDV-SOF PrOD SOF-VEL SMV+SOF DCV+SOF

GT1ANocirrhosis

12 weeks(*16weeks+RBVif+NS5ARAV)

12weeks 12weeks+RBV 12weeks 12weeks 12weeks

GT1ACirrhosis,Naïve

12weeks(*16weeks+RBVif+NS5ARAV)

12weeks --- 12weeks --- ---

GT1ACirrhosis, PRExperienced

12weeks(*16weeks+RBVif+NS5ARAV)

12weeks+RBV(or24weeksalone)

(24weeks+RBV) 12weeks

(24weeks(+RBVifQ80K))

(24weeks+/- RBV)

GT1BNocirrhosis 12weeks 12weeks 12weeks 12weeks --- ---

GT1BCirrhosis,Naïve

12weeks 12weeks 12weeks 12weeks --- ---

GT1BCirrhosis, PRExperienced

12weeks(*16weeks+RBVif+NS5ARAV)

12weeks+RBV(or24weeksalone)

12weeks 12weeks (24weeks+/- RBV)

(24weeks+/- RBV)

Ledipasvir-Sofosbuvir (Harvoni)• IndicationsandUsage

- HCVgenotypes1,4,5,and6inadults- Patientsco-infectedwithHIVandHCV

• Class&Mechanism- Ledipasvir:NS5Ainhibitor- Sofosbuvir:NucleotideanalogNS5Bpolymeraseinhibitor

• Dosing:Ledipasvir-Sofosbuvir (fixeddose90mg/400mg):1tabletorallyoncedailywithorwithoutfood

• DrugInteractions: Yes,buttoalesserextentthanHCVproteaseinhibitors

• AdverseEffects(AE):Fatigue,headache

• WholesaleCost: $94,500fora12-weekcourse

Source:Harvoni PrescribingInformation.GileadSciences

DrugInteractions:ARTandDAAs

Ledipasvir-Sofosbuvir &Tenofovir DF• Ledipasvir increasestenofovir DF

exposureby30-60%whencoadministered withboostedPI(whichindependentlyincreasesTDFlevels).

• Avoid LDVandTDFif– CrCl <60– Co-administeredwithr/PI

• Renaltoxicitymonitoring:– CrandUAatweek2,4and

furtherasindicated• ConsiderswitchtoTAF/FTC

Source:Harvoni PrescribingInformation.GileadSciencesGermanP,CROI2015,Abstract82.

Case2A60year-oldHIV-infectedmanpresentstoyourclinic.Onabacavir,dolutegravir andrilpivirine witharecentCD4count350cells/mm3 andHIVRNA<40copies/mL. PMH:Burkitt’slymphomain2008inremission.Hx TDFnephrotoxicity,hxM184V,andunabletotoleratePIs.

HehaschronichepatitisC,withHCVRNAlevelof800,000IU/mL,genotype1A,treatmentnaïve.FibroScan revealsF2fibrosis.Hehasanisolatedhep BcoreAbandisimmunetohepatitisA.

Youplantoprescribeledipasvir-sofosbuvir (LDV/SOF).HisinsurancedeniesauthorizationofLDV-SOFbuthaselbasvir-grazoprevir (EBR-GRZ) onformulary.

Elbasvir-Grazoprevir (Zepatier)• IndicationsandUsage

- ChronicHCVgenotypes1or4inadults- PatientswithHIV-HCVcoinfection

• Class&Mechanism- Elbasvir:HCVNS5Ainhibitor- Grazoprevir:HCVNS3/4Aproteaseinhibitor

• Dosing:Elbasvir-Grazoprevir (fixeddose50mg/100mg)Onetabletorallyoncedaily,withorwithoutfood

• DrugInteractions: Yes – substrateofCYP3A4andPgP

• AdverseEffects(AE):- Fatigue,headache,nausea,rash(4%)- IncreaseinALT>5xnormalin1%ofsubjects

• WholesaleCost: $54,600fora12-weekcourse

Source:Zepatier PrescribingInformation.Merck&Co.,Inc.

DrugInteractions:ARTandDAAs

EBR-GRZ LDV-SOF PrOD SOF-VEL SMV+SOF DCV+SOFGT1ANocirrhosis

12 weeks(*16weeks+RBVif+NS5ARAV)

12weeks 12weeks+RBV 12weeks 12weeks 12weeks

GT1ACirrhosis,Naïve

12weeks(*16weeks+RBVif+NS5ARAV)

12weeks --- 12weeks --- ---

GT1ACirrhosis, PRExperienced

12weeks(*16weeks+RBVif+NS5ARAV)

12weeks+RBV(or24weeksalone)

(24weeks+RBV) 12weeks

(24weeks(+RBVifQ80K))

(24weeks+/- RBV)

GT1BNocirrhosis 12weeks 12weeks 12weeks 12weeks --- ---

GT1BCirrhosis,Naïve

12weeks 12weeks 12weeks 12weeks --- ---

GT1BCirrhosis, PRExperienced

12weeks(*16weeks+RBVif+NS5ARAV)

12weeks+RBV(or24weeksalone)

12weeks 12weeks (24weeks+/- RBV)

(24weeks+/- RBV)

DAARegimens:Genotype1

ImpactofBaselineNS5ARAVsinGT1aHCVtreatedwithEBR-GRZ

Jacobson I, et al. Gastroenterology. 2017, E-pub ahead of print.

98 98 98 98

58

86

72

91

PatientswithoutRAVs PatientswithRAVs

SVR

12 (%

)

EBR RAVs NS5A RAVs EBR RAVs NS5A RAVs

405/414

14/24

345/352

74/86

389/396

31/43

284/289

136/150

Population Sequencing Next Generation Sequencing

Case2 continuedYousendNS5Agenotype1resistancetesting.ItreturnsshowingY93Hmutation.

Youdecidetostart EBR-GRZ+ribavirin600mgBID foraplanneddurationof16weeks.

Patientmisseshisweek2CBCandreturns4weeksintotherapywithcomplaintoffatigue,irritabilityandmalaise.

Week4Labs:

Hemoglobin 10 g/dl(fromabaselineof14).Totalbilirubinis3.2,ALThasrisento365(from55)andAST250(from40).

Whichwouldyoudonext?

A. Reducetheribavirinfrom1200mgto800mgdaily.B. Discontinuetheribavirinandcontinueelbasvir-

grazoprevir.C. SendHBVDNAlevel.Considerstoppingtherapy

pendingtheseresults.D. WaitforHCVRNAresultstoreturnbeforedeciding

whattodo.

FactorstoConsiderinChoiceofDAARegimen

• Genotype (andsubtype:1Avs 1B)• Cirrhosis?

– Decompensatedorcompensated?

• Treatmentexperience?– Failurewithpeginterferon/ribavirinorpriorDAAs?

• IfHIV-coinfected:theirantiretroviraltherapy?• Cantheytolerateribavirin?• Whatistheirinsurance?

FDAWarningOct2016HBVReactivationonDAATherapy

• UnexpectedALTandASTelevations4-8weeks(mean53days)fromDAAinitiation.

• MultiplekindsofDAA.

• Hospitalizationinatleast6patients.Severeclinicaldecompensationin3casesà 2deathsand1livertransplantation.

• Amongthe29casesofHBVreactivation,13(45%)werechronicHBVcarriers(+HBsAg).

• SomehadabsentHBsAg andanti-HBs,i.e.anisolatedanti-HBcoreprofile.

https://www.fda.gov/Drugs/DrugSafety/ucm522932.htm

VACohortHBVReactivationonDAATherapy

Belperio,Hepatology.2017.E-publishedaheadofprint.

ALTpeaknotnormal

HBVreactivation(>3log10 ↑)

HBVDNAtestedon

DAA

Hep Bstatus

DAAtreatment

62,920

HBsAg+377 (0.7%)

84 (22%) 7 (8%) 6

Isolatedcore7295*

173 (2.4%) 1 (0.6%) 0

*18%ofthe62%testedforcoreAb(aswellassAg/Ab)

Case2A60year-oldHIV-infectedmanpresentstoyourclinic.Onabacavir,dolutegravir andrilpivirine witharecentCD4count350cells/mm3 andHIVRNA<40copies/mL. PMH:Burkitt’slymphoma in2008inremission.Hx TDFnephrotoxicityandunabletotoleratePIs.

HehaschronichepatitisC,withHCVRNAlevelof800,000IU/mL,genotype1A,treatmentnaïve.FibroScan revealsF2fibrosis.Hehasanisolatedhep BcoreAb andisimmunetohepatitisA.

Youplantoprescribeledipasvir-sofosbuvir (LDV/SOF).HisinsurancedeniesauthorizationofLDV-SOFbuthaselbasvir-grazoprevir (EBR-GRZ) onformulary.

Paritaprevir-Ritonavir-Ombitasvir +Dasabuvir (“3D”, Viekira Pak)• Indication: HCVGenotype1infection,includingcompensated

cirrhosis• Class&Mechanism

- Ombitasvir:NS5Ainhibitor- Paritaprevir:NS3/4Aproteaseinhibitor- Ritonavir:HIVPIusedasbooster- Dasabuvir:NS5Binhibitor

• Dose:2tabletsOmbitasvir-Paritaprevir-RitonavironcedailywithfoodplusDasabuvir 1tablettwice dailywithfood

• AdverseEffects(AE):Fatigue,pruritus,andinsomnia• WholesaleCost:$83,319for12-weekcourse

Source:Viekira PakPrescribingInformation.Abbvie,Inc.

Coformulated DAAsforGT1HCVDrug Pros Cons

Ledipasvir-sofosbuvir(LDV-SOF)(Harvoni)

• Simplicity,evenforcirrhotics• Canusewithout RBVinmost• Few druginteractions• Dataindecompensated

cirrhotics

• Cost• Restrictivedrugaccessprogram• Approvedonlyvs GT1

Paritaprevir-ritonavir-ombitasvir +dasabuvir(PrOD)(Viekira Pak)

• Activityvs GT4(Technivie)• DatainESRD

• Pillburden(esp +RBV)• BIDdosingw/food• Druginteractions• NecessityofRBVwithGT 1A• Hepatoxicity (rare)– avoidin

decompensatedpts

Elbasvir-grazoprevir(EBR-GRZ)(Zepatier)

• Simplicityinmostpatients• Extensive datainESRD• Activityvs GT4• Lowercost• WorksforPI-experiencedpts

• Druginteractions• NS5A resistancetestinginGT1A• 16weekdurationinsome• Hepatotoxicity(rare)– avoidin

decompensatedpts

RBV = ribavirin, IDUs = injection drug users, ESRD = end-stage renal disease

Case3

A45year-oldHIV-infectedmanpresentstoyourclinicforroutinefollow-up.On FTC/TDF,ritonaviranddarunavir witharecentCD4count560cells/mm3 andHIVRNA<40copies/mL.

PastMedicalHx:Diabetesmellitus,type2– A1C7%onmetforminandGERDwellcontrolledonomeprazole20mgBID

ChronichepatitisC,genotype1A,stage2fibrosis onrecentfibroScan.Hashx viralnon-responsetopeginterferon +ribavirinin2004.

EBR-GRZ LDV-SOF PrOD SOF-VEL SMV+SOF DCV+SOFGT1ANocirrhosis

12 weeks(*16weeks+RBVif+NS5ARAV)

12weeks 12weeks+RBV 12weeks 12weeks 12weeks

GT1ACirrhosis,Naïve

12weeks(*16weeks+RBVif+NS5ARAV)

12weeks --- 12weeks --- ---

GT1ACirrhosis, PRExperienced

12weeks(*16weeks+RBVif+NS5ARAV)

12weeks+RBV(or24weeksalone)

(24weeks+RBV) 12weeks

(24weeks(+RBVifQ80K))

(24weeks+/- RBV)

GT1BNocirrhosis 12weeks 12weeks 12weeks 12weeks --- ---

GT1BCirrhosis,Naïve

12weeks 12weeks 12weeks 12weeks --- ---

GT1BCirrhosis, PRExperienced

12weeks(*16weeks+RBVif+NS5ARAV)

12weeks+RBV(or24weeksalone)

12weeks 12weeks (24weeks+/- RBV)

(24weeks+/- RBV)

DAARegimens:Genotype1

Case3

A45year-oldHIV-infectedmanpresentstoyourclinicforroutinefollow-up.On FTC/TDF,ritonaviranddarunavir witharecentCD4count560cells/mm3 andHIVRNA<40copies/mL.

PastMedicalHx:Diabetesmellitus,type2– A1C7%onmetforminandGERDwellcontrolledonomeprazole20mgBID

ChronichepatitisC,genotype1A,stage2fibrosis onrecentfibroScan.Hasviralnon-responsetopeginterferon +ribavirin in2004.

Youdecidethat ledipasvir-sofosbuvir isthesimplesttreatmentoptionforpatientatthistime.

QuestionWhatmedicationchangeswouldyouwanttomakebeforestartingledipasvir-sofosbuvir inthispatient?

A. Nochanges– currentmedicationsarefine.B. Discontinuemetforminandswitchtosulfonylurea.C. Reducehisomeprazoleto20mgoncedailyor

discontinue.D. Discontinuehisritonavir,darunavir andstart

dolutegravir.E. CandD.

Ledipasvir-Sofosbuvir &ProtonPumpInhibitors

98 98

93 93

80

85

90

95

100

8wksLDV-SOF 12wksLDV-SOF

SVR1

2(%

)

NoPPI

PPI

Terrault,Netal.HCV-TARGET.Gastroenterol 2016;151:1131.

Tapper,Netal.TRIONetwork.Hepatology 2016;64:1893.

Case3 (continued)A45year-oldHIV-infectedmanpresentstoyourclinicforroutinefollow-up.On FTC/TDF,ritonaviranddarunavir witharecentCD4count560cells/mm3 andHIVRNA<40copies/mL.

PastMedicalHx:Diabetesmellitus,type2– A1C7%onmetforminandGERDwellcontrolledonomeprazole20mgBID

ChronichepatitisC,genotype1A,stage2fibrosisonrecentfibroScan.Hasviralnon-responsetopeginterferon +ribavirinin2004.

Startsondolutegravir (DTG),FTC/TDF.Omeprazolereducedto20mgoncedailytobetakenonemptystomachwithLDV-SOF.

Metforminwasdosereducedforcoadministration withDTGàA1C10%onrepeattesting.

Case4A50year-oldHIV-infectedmancomesinforroutinecareaftermissingafewintervalvisits.HehasbeenonFTC/TDFanddolutegravir,lastCD4count630cells/mm3 andHIVundetectablein2016.

PMH:ObesityBMI35kg/m2.Hx chronichepatitisCgenotype3,stage4fibrosiswhocleared withsofosbuvir +daclatasvir in2015.

Atthisvisit,heisfoundtohaveALT200andAST350(ALTandASTin20sinJan2016).Henotessomefatigue,anorexiaandnausea.Deniesanyalcoholuse,IVDUorsexualactivity.HishepatitisAAb(total)andHep BsurfaceAb werebothpositiveonentryintocare.

Forthispatient,whichofthefollowingwouldyoudonext?

A. CounselpatientthatheshouldstophisARTgivenlikelyhepatotoxicity.

B. Obtainultrasoundandserumalpha-fetoprotein.C. ArrangeforCTorMRIliverprotocol.D. SendhepatitisCantibodywithreflexiveRNAlevel.E. SendhepatitisAIgM antibody.

HCC incirrhoticHCVpatientsMaintainsurveillanceafterHCVclearance

• RiskofHCCinHCVcirrhoticsà 1-3%peryear.

• SVRassociatedwith76%reductioninHCCriskinlong-termstudies.

• ButreductioninHCCriskisnotimmediate post-SVR

• Possible↑riskintumorrecurrenceormorediffuse/aggressiveHCCpost-DAAsuggestedbyafewrecentEuropeanseries.

Morgan,AnnInternMed. 2013;158:329-37.Reig,JHepatol.2016;65:719–26.Conti, J Hepatol. 2016;65:727-33.

Beste,Gastro.2015;149:1471-82.

HCC incirrhoticHCVpatientsRiskFactors• Age• Severityofcirrhosis• Diabetes,metabolicsyndrome,obesityà NASH/NAFLD• Malegender• Alcohol• ChronichepatitisBcoinfection• HIVinfection(lowCD4)

AASLD2011HCCPractice Guidelines.Akuta,Oncology.2016;91:341-47.Gjaerde, Clin Infect Dis. 2016;63:821-9.

www.hepatitisc.uw.edu

Questions?

NinaKim,MDMScUniversityofWashingtonHarborviewLiverClinichyangkim@uw.edu