Post on 03-Jun-2020
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