Protease inhibitors in chronic hepatitis C liverca 蛋白酶抑制剂在慢性丙型肝炎肝中的作用

EditedbyMorrisShermanMDBChPhDFRCP(C)AssociateProfessorofMedicineUniversityofTorontoProteaseInhibitorsinChronicHepatitisC:

AnUpdateCOMPLETESLIDEDECK(Chapters1–6)November2012RobertP.Myers,MD,MScAssociateProfessor,LiverUnitDivisionofGastroenterologyUniversityofCalgary

ManagementofHepatitisC:

UpdatedGuidelinesfromtheCanadianAssociationfortheStudyoftheLiver(CASL)Objectives:HCVManagementReviewupdatedCASLrecommendationsformanagementofHCVgenotype1*BurdenofHCVinCanadaPre-treatmentassessmentTripletherapyincludingboceprevirandtelaprevirAdverseeffectsDrug-druginteractionsAntiviralresistance*Recommendationsfornon-1genotypesareunchangedfromthe2007CASLHCVguidelines.BurdenofHCVinCanadaSignificantmedicalandeconomicburdenSeroprevalenceunknownRiskGroupPopulationPrevalencePrevalentCasesProportionofCasesIDU,total268,20052%140,00058%CurrentIDU84,40062%52,50022%PreviousIDU183,80048%87,50036%Transfusion3,325,7000.8%25,90011%Hemophilia2,20040%9000.4%Other27,624,3000.27%75,80031%Total31,220,5000.8%243,000100%RemisRS.PHAC2007BurdenofHCVinCanada~8,000incidentcasesannually(80%IDUs)Proportiondiagnosedunclear(<80%)HCV-relatedcomplicationsrisingInsufficientmanpowertotreatallcasesRemisetal.PHAC200780090070060050040030020010001967197219771982198719921997200220072012201720222027YearCirrhosisDecompHCCTransplantModelledincidenceDavisGLetal.Gastroenterology2010;138(2):513-21*Assumes30%Dx&upto25%Rx’din2010.Outcomesat2020.AntiviralTherapyMustbeMaximized

toMakeanImpact3020405060708090100Liver-relateddeathvs.notreatment(%)0Current*25%50%75%100%Proportionofpopulationtreated80%SVRrate60%SVRrate40%SVRrate68%↓34%↓BurdenofHCVinCanada:

CASLRecommendationsAlargepopulation-basedseroprevalencesurveyshouldbeconductedtoaccuratelydefinetheprevalenceofhepatitisCinCanada.ThedesignofthestudyshouldincludepopulationswithanincreasedriskofhepatitisC,particularlyIDUsandimmigrantsfromendemiccountries.IncreasedresourcesarenecessarytoimprovehepatitisCtreatmentcapacityinCanada,includingthetrainingofexperttreatersandpublicfundingfortreatmentnurses.MyersRPetal.CanJGastro2012;26(6):359-75WhoShouldBeTreated?

CASLRecommendationsMyersRPetal.CanJGastro2012;26(6):359-75AllpatientswithchronicHCV,particularlythosewithliverfibrosis,shouldbeconsideredcandidatesforantiviraltherapy.

PatientswithextrahepaticmanifestationsofHCVshouldbeconsideredforantiviraltherapy.

PersistentlynormalALTdoesnotexcludesignificantliverdiseasenorprecludetheneedforantiviraltherapy.WhoShouldBeTreated?

CASLRecommendationsMyersRPetal.CanJGastro2012;26(6):359-75SomefibrosisassessmentnecessaryPrognosisNecessityoftreatmentSurveillanceforHCC&varices

F2thresholdlessimportantwithimprovedtherapiesBiopsyisimperfectSamplingerror;variabilityinpathologicinterpretationNumerousnoninvasivealternativestobiopsyBedossaPetal.Hepatology2003;38(6):1449-57Pre-TreatmentAssessment:IsLiverBiopsyReallyNecessary?Test(Reference)ComponentsCut-offF2-F4vs.F0-F1Sensitivity/specificityF2-F4vs.F0-F1FibroScan(Castera,2005)Liverstiffnessbytransientelastography≥7.1kPa67%/89%APRI(Shaheen,2007)AST/ULNx100Platelets≥0.5≥0.7≥1.581%/50%84%/70%35%/91%FibroTest(Poynard,2004)α2M,haptoglobin,apo-A1,GGT,bilirubin≥0.5856%/83%FibroSpectII(Patel,2004)α2M,HA,TIMP-1≥0.3677%/73%Hepascore(Adams,2005)α2M,HA,GGT,bilirubin≥0.5089%/63%FibroMeter(Leroy,2005)α2M,HA,AST,platelets,PT,urea≥0.5075%/78%Pre-TreatmentAssessment:

Non-invasiveMeasuresofFibrosisAssessmentofDiseaseSeverity

AllpatientswithHCVshouldhaveanassessmentfortheseverityofliverfibrosis.Acceptablemethodsincludeliverbiopsy,TE(FibroScan),andserumbiomarkerpanels(e.g.APRI,FibroTest,Fibrometer),eitheraloneorincombination.Alternatively,cirrhosiscanbeconfidentlydiagnosedinsomepatientswithclearclinicalorradiographicevidence.Pre-TreatmentAssessment:

CASLRecommendationsMyersRPetal.CanJGastro2012;26(6):359-75VirologicTestingHCVRNAandgenotypetestingareessentialtothemanagementofpatientswithchronichepatitisC.HCVRNAtestingshouldbeperformedusingasensitivequantitativeassay(lowerlimitofdetection≤10-15IU/mL)withabroaddynamicrange.StandardizedresultsshouldbeexpressedinIU/mLandbeavailablewithinamaximumof7daysinordertofacilitatemanagementdecisions.Althoughgenotype1bhashigherresponseratesvs.genotype1a,testingforHCVsubtypeisnotindicatedThismaychangewithnewerDAAsavailableinthefuturePre-TreatmentAssessment:

CASLRecommendationsMyersRPetal.CanJGastro2012;26(6):359-75Ge.Nature2009.Suppiah.NatGenet2009.Tanaka.NatGenet2009.Thomas.Nature2009.Single-nucleotidepolymorphisms(SNPs)onchromosome19

EncodesIFN-λ3Associatedwithviralclearance~50%ofethnicvariationinSVRratesStrongestpre-treatmentpredictorofSVR,buton-treatmentresponsemoreimportantInterleukin28B(IL28B)801006040200T/T102T/C433C/C336European-AmericansP=1.06x10-25SVR(%)70T/C91C/C30African-Americans14T/C35C/C26HispanicsP=2.06x10-3P=4.39x10-3P=1.37x10-28186T/C559C/C392Combinedrs12979860SVR(%)Non-SVR(%)NumbersonbarsrepresentnIL28BGenotyping

TheIL28BgenotypemayprovidevaluableinformationregardingthelikelihoodofSVRandtheprobabilityofqualifyingforshortenedtreatmentdurationinpreviouslyuntreatedpatientswithgenotype1.TheroleofIL28Bgenotypingislimitedintreatment-experiencedpatientsandthosewithgenotypesotherthan1and4.Anon-favourableIL28Bgenotypedoesnotprecludeantiviraltherapy.Pre-TreatmentAssessment:

CASLRecommendationsMyersRPetal.CanJGastro2012;26(6):359-75Tripletherapyincludingpeginterferon(PEG-IFN),ribavirin(RBV),andaproteaseinhibitor(telaprevirorboceprevir)isthenewstandardofcareintreatment-naïveandprevioustreatmentfailures.

Boceprevir(800mgevery8hourswithfood)isadministeredaftera4-weeklead-inperiodofPEG-IFNandRBV.Durationoftherapydependsonpatientcharacteristicsandtreatmentresponse.

Telaprevir(750mgevery8hourswithnon-lowfatfood)shouldbestartedsimultaneouslywithPEG-IFNandRBVandgivenfortheinitial12weeksoftherapy.AntiviralTherapyforHCVGenotype1:

CASLRecommendations

MyersRPetal.CanJGastro2012;26(6):359-75RGT-thetailoringoftreatmentdurationbasedonearlyviralkinetics-canbeemployedinselectedpatientsubgroups.Boceprevir:HCVRNAnegativeatweeks8through24Telaprevir:HCVRNAnegativeatweeks4through12SVRratesof~90%havebeenreportedwith24to28weeksoftherapyinpatientsqualifyingforRGT.

Partialresponderstreatedwithtelaprevir,patientswithcirrhosis,andpriornullrespondersshouldnotreceiveRGT.Response-GuidedTherapy(RGT):

CASLRecommendations

MyersRPetal.CanJGastro2012;26(6):359-75Adherencetotreatmentandtofutilityrules,andclosemonitoringofconcomitantdrugsandsideeffectsareparticularlyimportantwithPI-basedtherapy.

Optimalmanagementofthispopulationshouldbeconductedbywell-trained,experiencedpersonnel.AdherencetoAntiviralTherapy:

CASLRecommendations

MyersRPetal.CanJGastro2012;26(6):359-75StrictadherencetofutilityrulesisvitaltolimitexposuretopotentialsideeffectsofthesecostlytherapiesthatwillnotachieveSVR,andtoreduceemergenceofantiviralresistance.Alltherapy–includingPEG-IFNandRBV–mustbediscontinuediffutilityrulesaremet:Boceprevir:HCVRNA≥100IU/mLatweek12ordetectableatweek24Telaprevir:HCVRNA>1,000IU/mLatweek4or12,ordetectableatweek24Identicalfutilityrulesapplytotreatment-naïveandtreatment-experiencedpatients.FutilityRules:

CASLRecommendationsMyersRPetal.CanJGastro2012;26(6):359-751,230SlidecourtesyofDr.J.Feld.1W0W1W2W3W4Iffutilityrulesmet,RNAisrising!Stoptherapy!106105104103102101071,800,00099.9%reduction:Continue?475HCVRNA(IU/mL)FutilityRulesIndicateTreatmentFailure

EveniftheViralLoadHasDeclinedPI-basedtherapyassociatedwithmoreadverseeffectsthanPEG-IFNandRBVdualtherapy

NodatatosupportswitchingfromonePItoanothertomanagetoxicity

MajoradverseeffectsdifferbyPIBoceprevir:anemia(~50%),dysgeusia(~40%)Telaprevir:anemia(~40%),rash(~40%),anorectalsymptoms(~30%)AdverseEffectsoftheProteaseInhibitors(PIs)

MyersRPetal.CanJGastro2012;26(6):359-75TreatmentwithPIsshouldbesupervisedbyexperiencedpersonnelandadverseeffectsmonitoredclosely.

ClosemonitoringofhemoglobinlevelsisessentialduringantiviraltreatmentforHCV,particularlyduringtheadministrationofPIs.

Managementofanemiamayincludeanyofthefollowingstrategies:RBVdosereduction(firstline),transfusionofpackedredbloodcells,and/orerythropoietinadministration.AdverseEffectsoftheProteaseInhibitors(PIs):CASLRecommendationsMyersRPetal.CanJGastro2012;26(6):359-75BoceprevirandtelapreviraresubstratesandinhibitorsofCYP3A4*CYP3A4metabolizesmanycommondrugsPotentialincreaseddrugconcentrationswithPIco-administrationDrugsthatinducedCYP3A4mayreducePIconcentration(i.e.antiviraltreatmentefficacy)NumerouspotentialDDIswithPI-basedtherapyAntiarrhythmics,anticoagulants,anticonvulsants,antihistamines,antibacterials,antiretrovirals,statins,herbalproducts,immunosuppressants,OCPs,phosphodiesteraseinhibitors,andsomesedatives/hypnotics*MinoreliminationpathwaysincludeP-glycoproteinandaldoketoreductase.Drug-DrugInteractions(DDIs)PriortotheinitiationofPIs,potentialDDIsmustbeconsidered,includingthoseattributabletoprescriptionandover-the-counterpharmaceuticalsandherbalpreparations.ReviewproductmonographsandusefulonlineresourcesforpotentialDDIspriortoinitiatingtherapy.//clinpharm/ddis/Drug-DrugInteractions(DDIs):

CASLRecommendationsMyersRPetal.CanJGastro2012;26(6):359-75Allresistancevariantspre-existNotcausedbyPIs,butunmaskedbyselectivepressureReflectinadequateresponsetoPEG-IFN/RBVPredominantcause(80-90%)ofincompleteviralsuppression,breakthrough,orrelapseGenotype1a>1bPawlotskyJM.Hepatology.2011May;53(5):1742-51AntiviralResistance-5-4-3-2-101HCVRNAchangefrombaseline(Log10IU/mL)ModestornullIFNa-ribavirineffectStudytimeResistantHCVWild-type,sensitiveHCVInordertoreducethedevelopmentofantiviralresistancetothePIs,patientswhomeetfutilityrulesindicatingahighlikelihoodoftreatmentfailureshoulddiscontinuetherapyimmediately.Dosagereductionsofboceprevirandtelaprevirshouldnotbeutilizedtomanagetreatment-relatedsideeffects.

Topreventresistance,PIsmustbestoppedifeitherPEG-IFNorRBVarediscontinued.Thereisnoroleforpre-treatmentresistancetesting.MyersRPetal.CanJGastro2012;26(6):359-75AntiviralResistance:

CASLRecommendationsMustmaximizecase-finding,referral,andantiviralRxtoreduceHCVburdeninCanada.Barrierstotreatment(e.g.needforbiopsy)shouldbeminimized.Newtherapies(boceprevirandtelaprevir)markedlyimproveSVRratesingenotype1(treatment-naïveandexperienced),butarecomplexandhaveadditionalsideeffects.Summary:

CASLGuidelinesfortheManagementofHCVImportantHepatitisCProteaseInhibitorDrugInteractionsinMonoand

HIVCoinfectionAliceTseng,Pharm.D.,FCSHP,AAHIVPTorontoGeneralHospitalUniversityofTorontoOutlineReviewprinciplesofdruginteractionsUnderstandhowthepharmacologyofDAAscontributetodruginteractionsHighlightimportantHCVdruginteractionsOutlineastrategyforidentifyingandmanagingdruginteractionsIdentifypertinentHCVdruginteractionresourcesDrugInteractionsPharmacodynamicChangeinpharmacologicaleffectofadrugAdditive,synergistic,orantagonisticactivityortoxicitye.g.,ribavirin+AZT=anemiaPharmacokineticChangeintheamountofdrug(s)inbodyAbsorption,distribution,metabolism,eliminationmay

beaffectedOfteninvolvesCYP450systemortransportersInteractionsAffectingDrugMetabolismMajorityofdrugstransformedtoinactiveformspriortoeliminationthroughPhaseI(oxidation)orPhaseII(conjugation)reactionsPhaseIprimarilyinvolvescytochromeP450systemSuperfamilyofmicrosomalheme-containingenzymesPrimarilylocatedinliver,smallbowel;alsokidney,lung,brainCYP3Aisthemostabundantlyexpressedisoenzyme,isinvolvedinthemetabolismof~50%ofclinicallyuseddrugsothers:CYP2D6,2C9,2B6,1A2,etc.P-glycoproteinEffluxmembranetransporterwhichpreventsdrugaccumulationincells;hasbroadsubstratespecificity,andinhibitingorinducingtheactivityofthisproteincanleadtosignificantalterationsindrugexposureTermsDefinitionInteractionImpactCommonExamplesSubstrateAgentwhichisprimarilyclearedviaacertainenzymaticpathwayRateofdrugbreakdownisaffectedbypresenceofenzymeinhibitorsorenzymeinducersantidepressants,azoles,benzodiazepines,statins,corticosteroids,calciumchannelblockers,macrolides,rifamycins,HIVPIs&NNRTIsInhibitorAgentwhichcompeteswithanotherdrugforbindingatenzymaticsiteDecreasedclearanceofsubstratedrug;quickonset&resolutionofinteractioneffectmacrolides,azoles,HIVproteaseinhibitorsInducerDrugthatstimulatestheproductionofadditionalmetabolicenzymesIncreasedclearanceofsubstratedrug;sloweronsetandresolutionofinteractioneffectanticonvulsants,rifamycins,HIVNNRTIs,St.John’swortBoceprevirandTelaprevirPharmacology=+++potentialforinteractionswithotherdrugscanbeclinicallysignificantsometimesunpredictableBoceprevirTelaprevirDosing800mgq8hwithfood750mgq8hwithfood(20gfat)SubstrateCYP3A4,P-gp,AKRCYP3A4,PgpInhibitor3A4,P-gp3A4,P-gp,renaltransporters(?)InducerNoinducingeffectsinvitro(invivo?)PotentialConsequencesofDAADrugInteractionsInteractionsmayoccurinatwo-waymanner:ConcentrationsofDAAmaybealteredbyotherdrug(s)Concentrationsofconcomitantdrug(s)maybealteredbyDAA

Potentialconsequencesinclude:IncreasedriskoftoxicityDecreasedefficacyStatinInteractionsMoststatinsareP450substratesDAAscansignificantlyincreasestatinlevels:Atorvastatin:130%withboceprevir,

7.88-foldwithtelaprevirPravastatin:60%withboceprevirriskoftoxicity,includingmyopathyandrhabdomyolysisBoceprevirTelaprevirLovastatin,SimvastatinCONTRAINDICATEDAtorvastatinMayneedtoatorvastatindose;donotexceed>20mg/dCONTRA-INDICATEDPravastatinStartwithrecommendeddoseandmonitorfortoxicity.Possibleinstatin;usewithcaution.Rosuvastatin,FluvastatinPossibleinstatin;usewithcaution.[Victrelis&IncivekProductMonographs,2011.FDAHIV/AIDSDrugSafetyCommunication,March1,2012]Atorvastatin40mg+boceprevir:AtorvastatinAUC130%and

Cmax170%vs.atorvastatinaloneSuggestatorvastatindosewithconcomitantBOC;monitorforsymptomsofstatintoxicityifusing>40mg/datorvastatinAtorvastatin20mg+telaprevir:AtorvastatinAUC7.88-foldCombinationiscontraindicatedAtorvastatinInteractions

withBoceprevirandTelaprevirHulskotteEGJetal.HEPDART2011,Koloa,Hawaii,poster122LeeJEetal.AntimicrobAgentsChemother2011,55(10):4569-740.01010203040500.101.0010.0100Nominaltime(hrs)Concentration(ng/mL)Withtelaprevir25,00030,00020,00015,00010,0005,0000081624324048Time(hrs)Atorvastatinconcentration(pg/mL)AtorvastatinaloneAtorvastatin+BoceprevirWithouttelaprevirEffectofSteady-StateTelaprevironthePharmacokineticsofAmlodipine5mgCalciumchannelblockers(CCBs)Amlodipine,diltiazem,felodipine,nifedipine,nicardapine,verapamilareCYP3A4substratesConcentrationsmaybebyboceprevirortelaprevirUsewithcaution,clinicalmonitoringConsiderdosereductionLeeJEetal.AntimicrobAgentsChemother2011,55(10):4569-74AmlodipineAUC179%Monitorfordose-relatedtoxicity0.010250Nominaltime(hrs)Concentration(ng/mL)WithtelaprevirWithouttelaprevir200150100500.050.505.00AntihypertensiveMedicationsClassExamplesPotentialDAAInteractionsACEIEnalapril,lisinopril,ramipril(renal)NotexpectedARBsLosartan(2C9>>3A4toactivemetabolite)Candesartan,irbesartan(2C9)Eprosartan,olmesartan,telmisartan,valsartan(biliary)PossibleeffectLowNotexpectedBeta-blockersPropranolol(2D6,3A4,2C19),carvedilol(2D6,2C9>1A2,2E1,3A4)Acebutolol,labetalol,metoprolol,pindolol(2D6)Atenolol,nadolol(renal)PossibleLowNotexpectedCalciumchannelblockersAmlodipine,diltiazem,felodipine,nifedipine,verapamil(3A4)RiskofCCBexposures;usewithcautionDiureticsHydrochlorothiazide,furosemide,spironolactone(renal)Indapamide(2C9,2D6,3A4)NotexpectedPossibleTreatmentofDepressioninHCVPlaceinTherapyExamples(routeofmetabolism)PotentialDAAInteractionsFirstLineEscitalopram,citalopram(2C19,3A4>>2D6)35%withTVR,nointeractionwithBOCSecondLineParoxetine,fluoxetine(2D6),bupropion(2B6)Sertraline(2B6>2C9/19,3A4,2D6),venlafaxine(2D6>3A4),desvenlafaxine(UGT>>3A4),mirtazapine(2D6,1A3,3A4)LowPossibleThirdLineNortriptyline(2D6)Imipramine(2D6,1A2,2C19,3A>UGT)LowPossibleNoEvidenceModafinil(3A4;induces3A4)Amantadine(notmetabolized)Possible;DAANotexpectedAvoidDuloxetine(1A2,2D6)-CONTRAINDICATEDAdditiveriskofhepatotoxicityMethadoneInteractionsMethadoneismetabolizedbyCYP2B6,CYP2C19&CYP3A,

85%proteinbound;R-isomerisbiologicallyactiveenantiomer

Boceprevirinteraction:Inthepresenceofsteady-stateboceprevir,R-methadoneAUC16%,Cmax10%;noclinicaleffectsnotedincludingopioidwithdrawalBoceprevirexposuresnotaffectedbymethadone

Telaprevirinteraction:Inthepresenceofsteady-statetelaprevir,R-methadoneCmin31%,Cmax21%andAUC21%,butmedianunboundCminof

R-methadonewassimilarbeforeandduringtelaprevircoadministrationandnowithdrawalsymptomswerenoted

ApriorimethadonedoseadjustmentsarenotrequiredwheninitiatingDAAtherapy,butclosemonitoringisrecommended,withmethadonedoseadjustmentsifnecessaryHulskotteetal.2012,VanHeeswijketal.2011.HormonalContraceptiveswithDAAsHormonalcontraceptivesmaynotbeaseffectiveinwomentakingboceprevirortelaprevirBoceprevir(Victrelis):

99%AUCdrospirenone,24%AUCEEUse2alternateeffectivemethodsofcontraceptionduringtreatmentwithBOCandPegIFN/RBVDrospirenone(Yaz®,Yasmin®,Angelique®)iscontraindicatedTelaprevir(Incivek):28%AUC,33%CminofEEUse2additionalnon-hormonalmethodsofeffectivebirthcontrolduringTVRdosingandfor2monthsafterthelastintakeofTVR.BenzodiazepineInteractionsMajorityaresubstratesofCYP3A4Riskforprolonged/excessivesedationOralmidazolam&triazolamarecontraindicatedwithboceprevirandtelaprevirIVmidazolam:considerdose,closemonitoringforrespiratorydepressionorprolongedsedationOtherbenzodiazepines:doseandmonitorConsiderusingbenzodiazepinesthatareglucuronidated:Lorazepam,oxazepam,temazepamInhaledCorticosteroidsCorticosteroidsareCYP3A4substratesPotentialforcorticosteroidconcentrationsresultinginsignificantlyreducedserumcortisolconcentrationsInhaled/nasalfluticasone,budesonide:Avoidco-administrationwithHCVPIsifpossible,particularlyforextendeddurations.Maywishtousecorticosteroidassociatedwithlessadrenalsuppression(e.g.,beclomethasone,ciclesonide)Uselowestpossibledose,considernon-steroidaloptionsVictrelis&Incivek.ProductMonographs,2011PDE5Inhibitors

(sildenafil,tadalafil,vardenafil)PDE5inhibitorsaresubstratesofCYP3A4PotentialforDAAstoconcentrationsDose-relatedsideeffects(headache,vasodilation,dyspepsia,visualdisturbances)ContraindicatedwithDAAsifusingforPAHForerectiledysfunction,usealowerdosewithDAAs:Sildenafil:25mgq48h,tadalafil:10mgq72hDonotusevardenafilInteractionsBetweenHCV&HIVMedicationsChallengesintreatingHIV/HCVco-infectedpatientsAdditivetoxicities:Anemia:ribavirin,zidovudine,DAAsCNS:interferon,efavirenzPotentialfornegative2-wayinteractionsconcentrationsofHIVagentsconcentrationsofHCVDAAsAntiretroviralTreatmentOptionsforPatientsonBoceprevirorTelaprevirBoceprevirTelaprevirProteaseInhibitors(PIs)Avoidwithritonavir-boostedproteaseinhibitorsAvoidritonavir-boosteddarunavir,fosamprenavirandlopinavirAtazanavir/ritonavirOKNon-NucleosideReverseTranscriptaseInhibitors(NNRTIs)AvoidefavirenzDosewithefavirenzEtravirine(?)EtravirineOKNodataRilpivirineOKIntegraseInhibitorRaltegravirOKMaravirocNodata

potential/maraviroc;potentialbenefitonfibrosis?NucleosideReverseTranscriptaseInhibitorsTenofovirOKAvoidAZT(anemia)ManagingDrugInteractions:

1)MedicationReconciliationEnsuremedicationrecordsareuptodateateachvisitPrescription,OTC,vitamins/herbals,recreationaldrugs,inhalers,topical,prnagentsConfirmdoses,prndrugsIncludeallagentsthathavebeenstartedorstoppedPatienteducation:Encouragepatientstoaskbeforetakinganynewprescription/non-prescriptiondrugorsupplementCommunicationwithotherHCP!ManagingDrugInteractions:

2)IdentifyPotentialInteractionsUseasystematicapproachtoidentifycombinationsofpotentialconcernApplyknowledgeofknownPKcharacteristicsOverlappingCYPpathways,substrate,inducer,inhibitorHighindexofsuspicionwithkeyclassesofdrugsUtilizecurrentdruginformationresources:Productmonographs,CPS,literatureConferenceabstracts,specializedHCVdruginteractionwebsitesDrugsContraindicatedwithBoceprevirandTelaprevir(1)1-adrenoreceptorantagonistAlfuzosinHypotension,cardiacarrhythmiaAntiarrhythmicsQuinidine,propafenone,amiodarone.Flecainide(TVR)serious/life-threateningcardiacarrhythmiaAntimycobacterialsRifampinLossofvirologicresponseErgotderivativesAcuteergottoxicityHerbalproductSt.John’swortLossofvirologicresponseStatinsLovastatin,simvastatin.Atorvastatin(TVR)MyopathyincludingrhabdomyolysisNeurolepticPimozideSerious/life-threateningcardiacarrhythmiaVictrelis&Incivek.ProductMonographs,2011DrugsContraindicatedwithBoceprevirandTelaprevir(2)PDE-5inhibitorSildenafil.tadalafil(BOC);vardenafil(TVR)Visualabnormalities,hypotension,prolongederection,syncopeSedatives/hypnoticsOralmidazolam,triazolamIncreasedsedationorrespiratorydepressionOtherCisapride,astemizole,terfenadineSerious/life-threateningcardiacarrhythmiaAnticonvulsants(BOC)Carbamazepine,phenytoin,phenobarbitalLossofvirologicresponseOC(BOC)DrospirenoneHyperkalemiaAldosteroneantagonist(TVR)EplerenoneHyperkalemiaTriptans(TVR)EletriptanCoronaryarteryvasospasm,MI,vent.tachycardia,VFVictrelis&Incivek.ProductMonographs,2011ManagingDrugInteractions:

TherapeuticOptionsDetermineclinicalsignificance

Evaluatetherapeuticoptions:Alterdrugdose/dosingfrequencySubstitutewithalternateagentCananydrugsbepermanentlyortemporarilydiscontinuedwhileonDAAtreatment?Considerpatientconvenienceandcostfactors

Patientcounselling&closemonitoringiscriticalSummaryHighpotentialforpharmacokineticinteractionsbetweendirectlyactingantiviralsandotherdrugclassesConsequencesmayincludetherapeuticfailureandincreasedtoxicityOften,interactionscanbemanaged,butheightenedlevelofawarenessisneededUseasystematicapproachtoidentifyandmanageindividualdrugregimensImportanceofaspecialized,inter-disciplinaryteamincludingpharmacyGeneralHanstenPD.ScienceMed1998;16-25.KashubaADM,BertinoJSJr.DrugInteractionsinInfectiousDiseases,2ndedition,c.2005,pp:13-39.MethenyCJetal.Pharmacotherapy2001;21:778-96.InteractionsinHCVandHIV:KiserJetal.Hepatology2012;55:1620-8.Tseng&Foisy.CurrInfectDisRep2012;14:67-82.InternetTorontoGeneralHospitalImmunodeficiencyClinic;www.hivclinic.caLiverpoolPharmacologyGroup;www.hcvdruginfo.caAdditionalResourcesSideEffectsofAntiviralTherapyforHepatitisCDr.MarkLevstik,FRCP(C)AssociateProfessorMedicineDivisionofGastroenterologyMultiorganTransplantUnitLondonHealthSciencesCentreSideEffectswithBoceprevirandTelaprevirHematological:(commontobothPIs)Anemia,NeutropeniaEffectisadditivewithINFandRBV

GastrointestinalDysgeusia(BOC)Diarrhea(TVR&?BOC)Anorectalirritation(TVR)

DermatologicalTelaprevirspecificrashSideEffectComparisonofPhaseIIIstudiesAdverseEffectPegInterferon/RBVBoceprevir/P/RPegInterferon/RBVTelaprevir/P/RAnemia<100g/dl30%50%17%36%Rash19%17%34%56%Fatigue59%58%50%56%Diarrhoea15%20%17%26%Nausea42%46%28%39%Dysgeusia16%35%3%10%Anorectal7%29%Dysgeusiaandanemiaincreasedwithboceprevir;Rash,anorectalirritationandanemiaincreasedwithtelaprevir.VictrelisProductMonograph,August2012IncivekProductMonograph,June2012PatientsHCVgenotype1infectionCompensatedcirrhosis(ChildPughA)Treatment-experiencedRelapsersPartialresponders(>2log10HCVRNAdeclineatWeek12butnevernegative)NullresponderstheoreticallyexcludedTreatedintheFrenchearlyaccessprogram(FromFebruary2011)SafetyofProteaseInhibitorsinRealLife:CUPICStudyHezodeCetal.EASL2012,Abstract8Peg-IFNα-2a+RBVTVR+Peg-IFNα-2a+RBVFollow-upCUPIC:TreatmentRegimen484160128Weeks72SVRassessmentFollow-upPeg-IFN+RBV36InterimanalysisHezodeCetal.EASL2012,Abstract8BOC:800mg/8h;peg-IFNα-2b:1,5µg/kg/week;RBV:800-1400mg/dBOC+Peg-IFNα-2b+RBVTVR:750mg/8h;peg-IFNα-2a:180µg/week;RBV:1000-1200mg/dCUPIC:Patients