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PharmacologyforallHCVClinicians

ParyaSaberi,PharmD,MASAssistantProfessor,UCSFCenterforAIDSPreventionStudies

MedicalManagementofHIV/AIDSandHepatitisDecember2016

Disclosure

• Ihavenothingtodisclose.

Resources

• AASLD/IDSA:www.hcvguidelines.org• EASL:www.easl.eu/medias/cpg/HCV-recommendations/English-report.pdf

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Resources• UniversityofLiverpool:– HEPiChart:play.google.com/store/apps– HCVdrug-druginteractions:www.hep-druginteractions.org

– HIVdrug-druginteractions:www.hiv-druginteractions.org

• TorontoGeneralHospital’sHCVdrug-druginteractiontables&news:www.hcvdruginfo.ca/

• IndianaUniversity’sCYPdruginteractiontable:Medicine.iupui.edu/clinpharm/ddis

• Packageinserts

Selecting&RefiningHCVTreatmentOptions

PatientsbeingconsideredforHCVtherapy

DetermineallpossibleDAAoptionsbasedongenotype,presenceofcirrhosis,treatment-naïveor-experienced,&drugresistance

Reviewallprescription&OTCmeds&herbalsupplements

Screenforinteractionsusingresources&packageinserts

RefineDAAoptionsbasedoninteractions,priorAEs,&patientpreferences

Case#1A52year-oldAfricanAmericanwomancomesinforherappointmentwiththeclinicalpharmacisttostartSOF/VEL(Epclusa).• HCV:Tx-naïve,Gt1a,stage2fibrosis,nocirrhosis(APRI=0.3)

• Labs:Normalliverfunction,Cr=0.9(CrCl=63)• Meds:– TDF/FTC/EFV:1tabletonce-daily– Omeprazole:20mgonce-daily

Regimens Dose Duration

EBR/GZR* QDfixed-dosecomboEBR(50mg)/GZR (100mg) x12weeks

SOF/LDV QDfixed-dosecomboSOF(400mg)/LDV(90mg) x12weeks

SOF/VEL QDfixed-dosecomboSOF(400mg)/VEL(100mg) x12weeks

DCV+SOF QDDCV(60mg**)+SOF(400mg) x12weeks

SMV+SOF QDSMV(150mg)+SOF(400mg) x12weeks

PTV/RTV/OBV+DSV+RBV(“PrOD”)

QDfixed-dosecomboPTV(150mg)/RTV(100mg)/OBV(25mg)+BIDDSV(250mg)+wt-basedRBV

x12weeks

Case#1TreatmentOptions:Tx-Naïve,HCVGt1a,notcirrhotic

*IfnobaselineNS5ARAVsdetected(forEBR)**DCVdose↑to90mgQDwhenwithEFVor↓to30mgQDwhenwithATV/rorATV/c

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Question#1:WhichARVshaveamajordrug-druginteractionwithSOF/VEL?

a. Efavirenzb. Darunavir/rc. Tenofovir disoproxil fumarated. Elvitegravir/ce. Alloftheabove

MechanismofSOF/VELDrug-DrugInteractions

• SOF:substrateforP-gp &BCRPVEL:substrateforP-gp,BCRP,OATP,CYP3A4,CYP2C8,&CYP2B6

P-glycoprotein:effluxenzymethat“pushes”drugsoutofGIbloodstreambackintoGIlumen;alsoinliver,kidneys,&blood-brain

barrier

BreastCancerResistanceProtein:expressedinsmallintestine,liver,

kidneys,&blood-brainbarrier&playsimportantroleindrug

disposition&tissueprotection

Organicaniontransportingpolypeptide:involvedinsecretionor

reabsorptionofdrugs(organic

anions);acrosscellmembranein

kidneys,brain,&liver

CytochromeP450Enzymes:>50

enzymesessentialformetabolismof

2/3ofmedsclearedbymetabolism.

Primarycauseofdrug-drug&drug-foodinteractions

MechanismofSOF/VELDrug-DrugInteractions

• SOF:substrateforP-gp &BCRPVEL:substrateforP-gp,BCRP,OATP,CYP3A4,CYP2C8,&CYP2B6

• InducersofP-gp,CYP2B6,CYP2C8,orCYP3A4(e.g.,rifampin,St.John’swort)maydecreaseplasmaconcentrationsofSOForVEL– Notrecommended

• VELisinhibitorofP-gp,BCRP,&OATP– Co-administrationofsubstratesofthesetransportersmayincreaseexposureofsuchdrugs

VEL-EFVInteraction• VEL:substrateofP-gp,BCRP,OATP,CYP2B6,-2C8,&-3A4

• VEL+EFV:~50%decreaseinVELexposure

Mogalian E,Leutkemeyer A,etal.AIDS2016;Durban,Sourth Africa.

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Summary:SOF/VEL-ARVInteractions

DrugClass DrugName RecommendationNNRTIs RPV Nodoseadjustmentsneeded

EFV,ETR NotrecommendedPIs DRV/r,ATV/r,LPV/r NodoseadjustmentsneededInSTI RAL Nodoseadjustmentsneeded

EVG/COBI/FTC/TDF NodoseadjustmentsneededDTG Nodoseadjustmentsneeded

N(t)RTI TDF/FTC NodoseadjustmentsneededABC/3TC Nodoseadjustmentsneeded

Case#1:OTCInteractions

YouaskheraboutanyOTCs&sheremindsyouthatsheistakingomeprazole20mgoncedailyforreflux.

52y/owoman,tx-naïve,Gt1a,nocirrhosis,CrCl=63,onTDF/FTC/EFV

Question#2:Whatshouldyoutellheraboutomeprazole?a. Nothingb. TellhertotakeSOF/VELwithfood&4

hoursbeforeomeprazolec. Tellhertonottakedoseshigherthan

40mgoncedailyd. Tellhertotakefamotidineinsteade. Optionsb &c

VEL-OMPInteraction• ↑pHresultsin↓VELsolubility&↓VELconcentration

• Proton-pumpinhibitors:Ifnecessary,SOF/VELcanbegivenwithfood&taken4hrs beforePPI(atmaxdosecomparabletoomeprazole20mg)

• H2-receptorantagonists:Givensimultaneouslywithor12hoursapartfromSOF/VELat≤famotidine40mgBID

• Antacid:Separateby4hours

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Case#1:Options1. ChangeARTtonon-EFV-containing

regimen(e.g.,DTG)– ShetriedABC/3TC/DTGbefore&hadsevere

insomnia,sosherefusestochangeART2. ChangeDAAtoSOF/LDV,EBR/GZR,etc.– EBR/GZRisalsonotcompatiblewithEFV• GZR&EBR:CYP3A&P-gp substrates

– DecidetotrySOF/LDV(Harvoni)

MechanismofSOF/LDVDrug-DrugInteractions

• SOF/LDV:substratesofdrugtransportersP-gp&BCRP

• P-gp inducers(e.g.,rifampin,St.John’swort):may↓SOF/LDVplasmaconcentrations– notrecommended

• ClinicallysignificantinteractionsmediatedbyCYP450orUGT1A1enzymesarenotexpected

Question#3:WhichARVregimenshavesignificantdrug-druginteractionswithSOF/LDV?a. DTG/ABC/3TCb. AnyTDF-containingregimensc. AnyHIVPI/r-basedregimensd. AnyTAF-containingregimense. AnyNNRTI-basedregimens

TDF&SOF/LDVPossiblemechanism:• LDVinhibitseffluxtransporters(P-gp&BCRP)leadingtohigher

tenofovirexposure• Invitro,SOF/LDVincreasetenofovirabsorption

GermanP,etal.AbstractO_06.15thInternationalWorkshoponClinicalPharmacologyofHIVandHepatitisTherapy.2014;Washington,DC. /GermanP,etal.Abstract82.22ndCROI.2015;Seattle,WA. /MathiasA.16thInternationalWorkshoponClinicalPharmacologyofHIVandHepatitisTherapy.2015;Washington,DC.

ARV TFVPKINSTI • TFVAUC↑1.7-foldinDTG+TDF/FTCNNRTI • TFVAUC↑98%inEFV/TDF/FTC

• TFVAUC↑40%inRPV/TDF/FTCPI/r • TFVAUC↑50%inDRV/r+TDF/FTC

• Unchangedwith12-hourstaggeringofdoseAUC:areaundertheconcentrationdrugconcentration-timecurve;DRV:darunavir;FTC:emtricitabine;PK:pharmacokinetics;r:ritonavir;TDF:tenofovir

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69patientsonSOF/LDVandeitherTDF+boosted (N=25)orTDF+non-boosted (N=44)ARVregimen

– SOF/LDVdidnotsignificantlyworsenrenalfunctioninthoseonTDF+boosted ARVregimens

– OnepatientonTDF+boosted ARVregimenstoppedTDFduetorenalimpairment(baselineGFR=89)

TDF&SOF/LDV

Vivancos-Gallego,M.J.,etal.Real-liferenalsafetyof“boostedTDF”inHIV/HCV-patientsonSOF/LDV.CROI2016,Boston.Abstract:452.

TAF&SOF/LDVSOF/LDVdoesnotsignificantly impactTAFortenofovirPK

Custodio JM,etal.IDSA/IDWeek 2015;SanDiego,CA.

SideNote:SOF/VEL+TDForTAF

• SOF/VEL+TDF:increasedTFVAUCby20-81%– Recommend:monitorrenalfunctionorchangeART

• SOF/VEL+TAF:noclinicallysignificantimpactonTFV

Mogalian E,Leutkemeyer A,etal.AIDS2016;Durban,Sourth Africa.

Summary:SOF/LDV-ARVInteractions

DrugClass DrugName RecommendationNNRTIs EFV,ETR,NVP,RPV NodoseadjustmentsneededPIs ATV/r,DRV/r,LPV/r Nodoseadjustmentsneeded

TPV NotrecommendedInSTI ELV/COBI MonitorforTDF-associatedrenaldysfunction

COBIlevels↑(possible ↑AEs)DTG,RAL Nodoseadjustmentsneeded

N(t)RTI TDF+EFV MonitorforTDF-associatedrenaldysfunctionTDF+(ATV/rorDRV/rorLPV/r)

↑TDFconcentrations.Consideralternativetherapy;monitorforTDF-associatedrenaldysfunction

TAF Nodoseadjustmentsneeded3TC,ABC,FTC,ZDV Nodoseadjustmentsneeded

CCR5Inhibitor MVC Potentialinteraction

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LDV-OMPInteraction• ↑pHresultsin↓LDVsolubility.Drugsthat↑pHwill↓LDVconcentration.

• Proton-pumpinhibitors:– Whenomeprazole20mg/daygiven2hrspriortoLDV,↓LDVAUCby42%&↓LDVCmax by48%

– GivePPIsimultaneously withSOF/LDV,underfastedconditions,&atdosecomparabletoomeprazole≤20mg/day

• H2-receptorantagonists:Givesimultaneouslywithor12hrsapartfromSOF/LDV;at≤famotidine40mgBID

• Antacid:Separateby4hrs

SOF/LDV+PPIs• HCV-Target:Evaluatesafety/efficacyofSOF/LDVinreal-worldcohortandimpactofbaselinefactorsontreatmentoutcomes

• PPIuseassociatedwithhigherrateofvirological failure

Terrault N.,etal.HCV-TARGET.66thAnnualMeetingoftheAmericanAssociationfortheStudyofLiverDiseases.Boston,MA.2015

SOF/LDV+PPIs• TRIO:DatafromspecialtypharmaciesonPPIusein2,034patientwithGt1&on8,12,or24weeksofSOF/LDV+/- RBVbetween10/2014-3/2015

• 23%onPPIs,62%onlowdosePPIs,majorityonPPIsthroughoutHCVtherapy

• Findings:– PPIusewasnotpredictiveofSVR– NoeffectofPPItype,dose,orduration– TwicedailyPPImayhavereducedSVR– Onlyfibrosisscore&HCVtx durationpredictiveofresponse

Afdhal N.,etal.NoEffectofProtonPumpInhibitor(PPI)UseonSVRwithLDV/SOF:Real-WorldDatafrom2034Genotype1PatientsintheTRIONetwork.EASL2016.Barcelona.

SOF/LDV+PPIs

Afdhal N.,etal.NoEffectofProtonPumpInhibitor(PPI)UseonSVRwithLDV/SOF:Real-WorldDatafrom2034Genotype1PatientsintheTRIONetwork.EASL2016.Barcelona.

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Case#1:Options

1. ChangeTDFtoavoidTDF+SOF/LDVinteraction– TDF/FTCtoABC/3TC(ifHLA-b5701negative)– TDF/FTCtoTAF/FTC

2. ContinueTDF/FTC/EFV+SOF/LDV&monitorrenalfunctionveryclosely(pt’sCrCl=63)- e.g.,every2weeksatleastinitially(Cr,electrolytesw/phosphorus,&urinaryprotein&glucose)

3. UseotherDAAregimen:issueswithcost/access,pillburden,AEs

52y/owoman,tx-naïve,Gt1a,nocirrhosis,CrCl=63,onTDF/FTC/EFV&Omeprazole

Case#1:Conclusion

• PtwillingtotryTAF/FTC+EFV,soyouchangeherARVs.–Recommendmonitoringx1-2monthsonnewARTbeforestartingDAAs

• ShedoesverywellonSOF/LDV&hasattainedSVR12.

Case#2

A35year-oldmalepatientisbeingseenattheclinicalpharmacyofficetogetstartedonEBR/GZR(Zepatier).• HCV:Tx-naïve,Gt1b,cirrhotic(Child-Pugh

scoreA)• InsurancestronglyrecommendsEBR/GZR• Meds:TAF/FTC/EVG/c,Rosuvastatin (10mg

oncedaily)

Regimens Dose Duration

EBR/GZR* QDfixed-dosecomboEBR(50mg)/GZR (100mg) x12weeks

SOF/LDV QDfixed-dosecomboSOF(400mg)/LDV(90mg) x12weeks

SOF/VEL QDfixed-dosecomboSOF(400mg)/VEL(100mg) x12weeks

PTV/RTV/OBV+DSV+RBV(“PrOD”)**

QDfixed-dosecomboPTV(150mg)/RTV(100mg)/OBV(25mg)+BIDDSV(250mg)+wt-basedRBV

x12weeks

Case#2TreatmentOptions:Tx-Naïve,HCVGt1b,cirrhotic

*NS5aresistancetestingrecommendedforGt1a**FDAwarningregardingtheuseofPrOD orPrO inpatientswithcirrhosis

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Question#4:WhatARVisEBR/GZRcompatiblewith?

a. Atazanavir,Darunavir,&Lopinavirb. Elvitegravirc. Efavirenz &Etravirined. Noneoftheabove

Summary:EBR/GZR-ARVInteractions

DrugClass DrugName Recommendation

NNRTIs RPV Nodoseadjustmentsneeded

EFV,ETR Notrecommended

PIs DRV/r,ATV/r,LPV/r Notrecommended

InSTI RAL Nodoseadjustmentsneeded

DTG Nodoseadjustmentsneeded

ELV/c Notrecommended

N(t)RTI TDF, TAF Nodoseadjustmentsneeded

GZR&EBR:CYP3A&P-gp substrates

• GZR/EBRinhibitintestinalBCRP;↑absorptionBCRPsubstrates

• Rosuvastatin– Cmax ↑5.49x,AUC↑2.68x– Donotexceed10mg/d

• Atorvastatin:donotexceed20mg/d

• Pravastatin&Pitavastatin:Usew/odoseadjustment

Case#2:Drug-DrugInteractions

L.Caro,etal.16thInternationalWorkshoponClinicalPharmacologyofHIVandHepatitisTherapy.WashingtonDC,2015

Case#2:Options

1. ChangeART– Suggestions:DTG/ABC/3TCorRPV/TAF/FTC

2. ChangeHCVtreatment– SOF/LDVx12weeks– SOF/VELx12weeks

35y/omanstartingEBR/GZR.Gt1b,cirrhotic,Tx-naïve;TAF/FTC/ELV/c,Rosuvastatin

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Case#2:Conclusion

• DuetoinsurancecoverageofEBR/GZR,wedecidetochangeARTtoDTG/ABC/3TC.– Recommendmonitoringx1-2monthsonnewARTbeforestartingDAAs

• PatientrecentlystartedHCVtreatment&isdoingwell.

Case#3You’reseeinga45year-oldWhitemalepatientwhowouldliketostartHCVtreatment.ProviderinconsideringSOF/VEL(Epclusa)butworriedaboutPPIinteraction.PatientisHIVtx-experienced,sowehavestrongpreferencenottochangeART.– HCV:Tx-naïve,Gt3,nocirrhosis– Labs:CrCl=90–Meds:• DRV/r+ETR+TDF/FTC• Omeprazole:20mgBID

Reminder:SOF/VEL-ARVInteractions

DrugClass DrugName RecommendationNNRTIs RPV Nodoseadjustmentsneeded

EFV,ETR NotrecommendedPIs DRV/r,ATV/r,LPV/r NodoseadjustmentsneededInSTI RAL Nodoseadjustmentsneeded

EVG/COBI/FTC/TDF NodoseadjustmentsneededDTG Nodoseadjustmentsneeded

N(t)RTI TDF/FTC NodoseadjustmentsneededABC/3TC Nodoseadjustmentsneeded

Case#3GeneralOptions:Tx-Naïve,Gt3,nocirrhosis

Regimens Dose DurationSOF/VEL QDfixed-dosecomboSOF

(400mg)/VEL(100mg)x12weeks

DCV+SOF DCV(60mg)+SOF(400mg)QD x12weeks

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Question#5:WithwhichARVsdoweneedtomodifythedoseofDCV?

a. OnlyEFV,ETR,&NVPb. OnlyEVG/COBI,ATV/r,&fos-APV/rc. OnlyDRV/r&RPVd. a&be. a,b,&c

Summary:DCV+SOF-ARVInteractions

DrugClass DrugName RecommendationNNRTIs RPV Nodoseadjustmentsneeded

EFV,ETR,NVP ↑DCVto90mgQDPIs ATV/r,fos-APV/r ↓DCVto30mgQD

DRV/r,LPV/r MonitorforDCVadverseeffects(keepdoseat60mgQD)

InSTI ELV/COBI ↓DCVto30mgQDRAL,DTG Nodoseadjustmentsneeded

N(t)RTI 3TC,ABC,FTC,TDF,ZDV NodoseadjustmentsneededCCR5Inhibitor MVC Nodoseadjustmentsneeded

Case#3:Conclusion

• HecontinuedDRV/r+ETR+TDF/FTCandinitiatesDCV+SOF–AdjustdoseofDCVto90mgdailywithSOFatstandarddoseof400mgdaily

• Hedoesverywell&hasSVRat12weeks

NewAgentsSOF/VEL/Voxilaprevir MK-3682/Grazoprevir

/MK-8404(Ruzasvir)Glecaprevir (ABT-493)/Pibrentasvir (ABT-530)

MOA NS5Bnucleotideinhibitor+NS5Ainhibitor+NS3/4Aproteaseinhibitor

NS5Bnucleotideinhibitor+NS3/4Aproteaseinhibitor+NS5Ainhibitor

Proteaseinhibitor+NS5A

Dose Once-daily,fixed-dosecombo,tripletx

2tabsonce-daily,fixed-dosecombo,tripletx

Once-daily,fixed-dosecombo

Indication Tx-naïveandexperienced,Gt1-6Prior DAA failureAnticipate8weeksfortx-naïve

PossiblyGt1-3for8weeksInthosewithGt1,cirrhoticandnon-cirrhotic,priorDAAfailure

GT1,priorDAAfailureNoNDAyetPossibly8weeksinnon-cirrhotics

ART Compatibility Compatiblewith:RPV,DTG,EVG/cNotcompatiblewith:EFV,ETR

Compatiblewith:RPV,RAL,DTGNotcompatiblewith:PI/r,EVG/c,EFV,ETR

CompatiblewithRAL,RPV,DTGNotcompatiblewithPIs&EFV

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Summary:ImportantPoints• SOF/VELcannotbeusedwithEFVorETR.• ELB/GZRcannotbeusedwithPI/r,EVG/COBI,EFV,&ETR.

• DCVrequiresdoseadjustmentwithATV/rorEVG/c(↓30mgdaily)andEFVorETR(↑90mgdaily).

• LDV↑TFVlevels(esp.withTDF+PI/r&EVG/c),eitheravoidcombobychangingTDFtoTAForotherARVsormonitorrenalfunctionclosely.

• LDVandVELinteractwithPPIs.• WhenmakingARTmodifications,considerimpactonothermedications(i.e.,de-inductionorde-inhibition).

Acknowledgements

• AnnieLuetkemeyer,MD• MegNewman,MD,FACP• DianeV.Havlir,MD