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PharmacologyforallHCVClinicians

ParyaSaberi,PharmD,MAS

AssistantProfessor,UCSFCenterforAIDSPreventionStudiesMedicalManagementofHIV/AIDSandHepatitis

December2017

Disclosure

• Ihavenothingtodisclose.

Resources

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

https://www.hcvguidelines.org/

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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

QuickDAARecapBrand Generic MOA Gt HD Decomp.

CirrhosisEFV/ETR PI/r

/cEpclusa sofosbuvir (SOF)+

velpatasvir (VEL)NS5Binhibitor+NS5Ainhibitor

1,2,3,4,5,6

√ √

Harvoni sofosbuvir (SOF)+ledipasvir (LDV)

NS5Binhibitor+NS5Ainhibitor

1,4,5,6

√ √ √

Mavyret glecaprevir (GLE)+pibrentasvir (PIB)

NS3/4Aproteaseinhibitor+NS5Ainhibitor

1,2,3,4,5,6

√ (√)

Vosevi sofosbuvir (SOF)+velpatasvir (VEL)+voxilaprevir (VOX)

NS5Binhibitor+NS5Ainhibitor+NS3/4Aproteaseinhibitor

1,2,3,4,5,6 (√)

Zepatier elbasvir (EBR)+grazoprevir (GZR)

NS5Ainhibitor+NS3/4Aproteaseinhibitor

1,4√

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

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

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Regimens Dose DurationEBR/GZR* QDfixed-dosecomboEBR(50mg)/GZR (100mg) x12weeks

GLE/PIB QDfixed-dosecomboGLE(300mg)/PIB (120mg) x8 weeks

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

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

Case#1RecommendedTreatmentOptions:

Tx-Naïve,HCVGt1a,notcirrhotic

*IfnobaselineNS5ARAVsdetected(forEBR)

Question#1:WhichARVshaveamajordrug-druginteractionwithSOF/VEL?

a. Efavirenzb. Darunavir/rc. Tenofoviralafenamided. 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-brainbarrier

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,EFV)↓plasmaconcentrationsofSOForVEL– Notrecommended

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

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VEL-EFVInteraction• VEL:substrateofCYP3A4• VEL+EFV:~50%decreaseinVELexposure

Mogalian E,LuetkemeyerA,etal.AIDS2016;Durban,SouthAfrica.

Summary:SOF/VEL-ARVInteractions

DrugClass DrugName RecommendationNNRTIs RPV Nodoseadjustmentsneeded

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

EVG/c/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. Trytoavoidacidblockersbut,ifyoumust,

takeSOF/VELwithfood&4hoursbeforeOMPc. Trytoavoidacidblockersbut,ifyoumust,

takeOMP40mgoncedailyd. TakefamotidineorantacidsinsteadofOMP,

givenlackofinteractions

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VEL-OMPInteraction• ↑pHresultsin↓VELsolubility&↓VELconcentration

• Trytoavoidacidblockersaltogether…– PPIs:SOF/VELwithfood&4hrs beforePPI(atmaxdosecomparabletoomeprazole20mg)

– H2-RAs:Givensimultaneouslywithor12hoursapartfromSOF/VELat≤famotidine40mgBID

– Antacid:Separateby4hours

Case#1:Options1. ChangeARTtonon-EFV-containing

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

insomnia,sosherefusesanyARTchangeOR

2. ChangeDAA– EBR/GZR&GLE/PIB (substratesofCYP3A&

P-gp):incompatiblewithEFV– 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:WhichARVregimenshavedrug-druginteractionswithSOF/LDV?a. DTG/ABC/3TCb. AnyTDF-containingregimensc. AnyHIVPI/r-basedregimensd. AnyTAF-containingregimense. AnyNNRTI-basedregimens

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TDF&SOF/LDV• Possiblemechanism:

– LDVinhibitseffluxtransporters(P-gp&BCRP)leadingto↑TFVexposure– Invitro,SOF/LDVincreaseTFVabsorption

• ↑TFVnotbeenshowntobeclinicallysignificant.Options:– SwitchtoTAF(especiallyifpreexistingrenaldysfunction)– MonitorrenalfunctionmorecloselyifcontinueTDF

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

TAF&SOF/LDV

SOF/LDVdoesnotsignificantly impactTAForTFVPK

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

SideNote:SOF/VEL+TDForTAF

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

• SOF/VEL+TAF:noclinicallysignificantimpactonTFV

Mogalian E,LuetkemeyerA,etal.AIDS2016;Durban,SouthAfrica.

Summary:SOF/LDV-ARVInteractionsDrugClass DrugName Recommendation

NNRTIs EFV,ETR,NVP,RPV NodoseadjustmentsneededPIs ATV/r,DRV/r,LPV/r Nodoseadjustmentsneeded

TPV NotrecommendedInSTI ELV/c 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 Nodata

OnlyDAAcompatiblewithEFV(&likelywithETR)

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

• PPIs:– Whenomeprazole20mg/daygiven2hrspriortoLDV,↓LDVAUCby42%&↓LDVCmax by48%

– Trytoavoidacidblockers.Ifnecessary,givePPIsimultaneously withSOF/LDV,underfastedconditions,&atdosecomparabletoomeprazole≤20mg/day

• H2-RA:Givesimultaneouslywithor12hrsapartfromSOF/LDV;atfamotidine≤40mgBID

• Antacid:Separateby4hrs

Case#1:Options

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

2. ContinueTDF/FTC/EFV+SOF/LDV&monitorrenalfunctionveryclosely- 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

A45year-oldmalepatientisbeingseenattheclinicalpharmacyofficetogetstartedonGLE/PIB(Mavyret).• HCV:Tx-naïve,Gt1b,cirrhotic(Child-Pugh

scoreA)• Meds:TAF/FTC/EVG/c,rosuvastatin,

omeprazole

Reminder:GLE/PIBcan’tbe

usedindecompensatedcirrhosis(i.e.,Child-PughB/C)

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Regimens Dose DurationGLE/PIB QDfixed-dosecomboGLE (300mg)/PIB(120mg) x12weeks

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

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

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

Case#2RecommendedTreatmentOptions:

Tx-Naïve,HCVGt1b,compensatedcirrhosis

Question#4:WhichARVisGLE/PIBcompatiblewith?

a. Atazanavir/rb. Elvitegravir/cc. Efavirenz orEtravirined. Raltegravir orDolutegravire. Alloftheabove

Question#4:WhichARVisGLE/PIBcompatiblewith?

a. Atazanavir/rb. Elvitegravir/cc. Efavirenz orEtravirined. Raltegravir orDolutegravire. Alloftheabove

GLE/PIB↑ELV/cCmax by29-36%,

AUCby42-47%.GLECmax &AUC2.5- &3.1-foldhigher,respectively,vs.

GLE/PIBalone;PIBAUCwas57%higher.NoclinicaldataforELV/c+GLE/PIB,socautionwhenusing

together.

EffectofInhibitorsonGLE/PIB

• GLE/PIBcontraindicatedwithATV/r• GLE/PIBmaybeokaywithDRV/r,LPV/r,andELV/cbutnotrecommendedduetolackofclinicaldata

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Summary:GLE/PIB-ARVInteractions

DrugClass DrugName Recommendation

NNRTIs RPV Nodoseadjustmentsneeded

EFV,ETR Notrecommended

PIs ATV/r Notrecommended

DRV/r,LPV/r Notrecommended(fornow)

InSTI RAL Nodoseadjustmentsneeded

DTG Nodoseadjustmentsneeded

ELV/c Notrecommended(fornow)

N(t)RTI TDF, TAF Nodoseadjustmentsneeded

GLE/PIB:CYP3A&P-gp substrates • GLE/PIBinhibitBCRP,P-gp,OATP• Rosuvastatin (substrateforBCRP&OATP)– Cmax ↑462%,AUC↑115%– Donotexceed10mg/d

• Pravastatin:reduceddoseby50%• Atorvastatin:donotco-administer

Case#2:Drug-DrugInteractions

SOF/LDV SOF/VEL EBR/GZR GLE/PIB SOF/VEL/VOXAtorvastatin ND 20mg Pitavastatin ND ND Lowestdose Pravastatin ↓doseby50% 40mgRosuvastatin 10mg 10mg 10mg

Case#2:DAA+PPIInteractionsNostatisticallysignificantdifferenceinSVR12betweenhigh&lowPPIdoseswithGLE/PIBacrossgenotypes,butcautionwithhighdosePPIsuntilmoredataavailable

SOF/LDV SOF/VEL EBR/GZR GLE/PIB SOF/VEL/VOXAntacids Separateby4hrs Separateby4hrs Separateby4hrsH2RA Togetheror12hrs

apart;FAM40mgBIDTogetheror12hrsapart;FAM40mgBID

Togetheror12hrsapart;FAM40mgBID

PPIs TogetherwithOMP20mg

Withfood,4hrsbeforeOMP20mg

Withfood,4hrsbeforeOMP20mg

Flamm S,etal.WorldCongressofGastroenterologyatACG2017;2017;Orlando,FL.P1435.

SideNote:Warfarin

• UpdatedSOF,SOF/LDV,SOF/VEL,SOF/VEL/VOX:“FluctuationsinINRvaluesmayoccurinpatientsreceivingwarfarinconcomitantwithHCVtreatment...FrequentmonitoringofINRvaluesisrecommendedduringtreatmentandpost-treatment...”

• Interactionmoresignificantwithribavirin&PrOD• Interactionusually resultsindecreasedINR,needingan↑Warfarindose(≥15%)

• MechanismunclearbuteradicationofHCVimprovesliverfunctiontoincreaseclottingfactorsynthesis&/orwarfarinmetabolism

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Case#2:Options

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

2. ChangeDAA– SOF/LDVx12weeks– SOF/VELx12weeks

45y/omanstartingGLE/PIB.Gt1b,cirrhotic,Tx-naïve;TAF/FTC/EVG/c,rosuvastatin,omeprazole

ContraindicatedwithPPIs

Case#2:Conclusion

• DuetoinsurancecoverageofGLE/PIB,wedecidetochangeARTtoDTG/ABC/3TC.– Recommendmonitoringx1-2monthsonnewARTbeforestartingDAAs

• PatientrecentlystartedHCVtreatment&isdoingwell.

Case#3

You’reseeinga58year-oldWhitemaleonhemodialysiswhowouldliketostartHCVtreatment.Providerisnotsurewhattousegivenpatient’srenalfunction.–HCV:Tx-naïve,Gt3,nocirrhosis–Meds:DTG+ABC+3TC(renally-dosed)

Question#5:WhichDAAagentsareokaytouseinthosewitheGFR <30mL/min?

1. EBR/GZR(Zepatier)2. GLE/PIB(Mavyret)3. SOF/LDV(Harvoni)4. SOF/VEL(Epclusa)5. 1&26. Alloftheabove

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CKD DAA Nodoseadjustment Duration1-3 EBR/GZR QDEBR(50mg)/GZR (100mg) x12weeks

GLE/PIB QDGLE(300mg)/PIB (120mg) X8-16 weeksSOF/LDV QDSOF(400mg)/LDV(90mg) x12weeksSOF/VEL QDSOF(400mg)/VEL(100mg) x12weeksDCV+SOF QDDCV(60mg**)+SOF(400mg) x12weeksSMV+SOF QDSMV(150mg)+SOF(400mg) x12weeksSOF/VEL/VOX QDSOF(400mg)/VEL(100mg)/VOX (100mg) x12weeks

4-5EBR/GZR QDEBR(50mg)/GZR (100mg) x12weeksGLE/PIB QDGLE(300mg)/PIB (120mg) X8-16 weeks

Case#3 TreatmentOptions:RenalImpairment

ChronicKidneyDisease(CKD)stages:1=normal(eGFR >90mL/min);2=mildCKD(eGFR 60-89mL/min);3=moderateCKD(eGFR 30-59ml/min)4=severeCKD(eGFR 15-29mL/min);5=end-stageCKD(eGFR <15mL/min)

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

Regimens Dose DurationSOF/VEL QDfixed-dosecomboSOF

(400mg)/VEL(100mg)x12weeks

GLE/PIB QDfixed-dosecomboGLE(300mg)/PIB(120mg)

x8weeks

Case#3:Conclusion

• HeinitiatesGLE/PIB• Hedoesverywell&hasSVRpost-treatment

ImportantPoints• SOF/LDVcanbeusedwithEFVorETR.• SOF/LDV&SOF/VELcanbeusedwithPI/r &EVG/c.• LDV&VEL↑TFVlevels(esp.withTDF+PI/r&EVG/c),either

avoidcombobychangingTDFtoTAForotherARVsormonitorrenalfunctionclosely.

• EBR/GZR&GLE/PIBseemokaywithPPIs(cautionw/highdoses).• PravastatinseemsokaywithmostDAAs.• EBR/GZR&GLE/PIBcanbeusedinESRD.• SOF/VEL&SOF/LDVcanbeusedindecompensatedcirrhosis– GLE/PIB,EBR/GZR,&SOF/VEL/VOXshouldnotbeusedinthosewithChild-PughB&C.

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Acknowledgements

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