(3HP) 1 2
3 100 80 60 40 759/1674 203/370 2414/3118 20 0 Chest, 2010 Lancet, 1998 AJRCCM, 2003 Studies Halsey,N.A.,etal.,Lancet,1998.351(9105):p.78692. Horsburgh,C.R.,Jr.,etal.,Chest,2010.137(2):p.4019. LoBue,P.A.,etal.,AmJRespir Crit CareMed,2003.168(4):p.4437. 4
RiskofINH induced hepatitis 4175 3263 700 3227 USPHS 13838cases 1971/07~1972/11 2473 Kopanoff DE,etal.AmRevRespir Dis1978;117:9911001. 5 n=28352 (ATS)1356%,68% <13(53%) :0.56 (16/28,353) courtesy ofchanpc.mohw103cdcc315000302 6
n=28352 Rate (%) courtesy ofchanpc.mohw103cdcc315000302 (n=295)3035%,trendtest:p<0.001 (n=187,) <101 201%3024%,trendtest:p<0.001 7 201631 201641 (3HP) once weekly x3months = only12doses 900mgIsoniazid(INH)+ 900mgRifapentine (RPT) 8
3HP 9H 25 2016 INHRMP LTBI(+) 3 10
AgainstMycobacteriabyInhibiting BacterialDNAdependentRNAPolymerase C 43 H 58 N 4 O 12 RMP C 47 H 64 N 4 O 12 RPT RPT/RMPCYP4503A4 2C8/9CYP450 RPT/RMP,, RPT/RMP RPT/RMP 11 RPT RMP (>12hvs 23h) RPT RMP Consumptionwithfood(especiallylipidrichmeal) increasesthepeakserumconcentrationofrpt (4050%Cmax &AUC),incontrasttoRMPthat needstobetakeninafastingstate(alsoinh). Priftin USPI,Dec2014 12
HR:1.34;0.822.18;p=0.23 Benator,D.,etal.,Lancet,2002.360(9332):p.52834. 13 MartinsonNA.NEJM2011 1148HIVinfected,TST+;noHIVTx 6mo.INHdailyselfsupervised IndefiniteINHdailyselfsupervised 3mo.INHRMPtwiceweeklyDOT 3mo.INHRPTweeklyDOT Endpoint:TBfreesurvival Followedupto6yr Martinson,N.A.,etal.,NEngl JMed,2011.365(1):p.1120. 14
78TBcasesoverall Deathrate1.6/100PY 6INH Indef.INH 3INHRMP 3INHRPT TB/death per100py 3.6 2.7 2.9 3.1 Martinson,N.A.,etal.,NEngl JMed,2011.365(1):p.1120. 15 Completion rate (%) AE rate(%) Martinson,N.A.,etal.,NEngl JMed,2011.365(1):p.1120. 16
SterlingTR.NEJM2011 Largesttrial(8000participants) Longestenrollmentperiod Childrenage2yr Spectrumof highrisk predicates Botheffectivenessandefficacy 17 NEJM 18
US CDC 19 SterlingTRetal.NEnglJMed.2011;365:215566 Shepardson Detal.Int JTuberc LungDis.2013;17:15317 Morb MortWkly Rep2011;60:16501653 20
Characteristic 9H (N=3,745) 3HP (N=3,986) Age(median,IQR) 36 (2546) 37(2547) Unemployed 390 (10) 424(11) Hx ofalcoholatenrollment 1888(50) 1929 (48) Jail/prison ever 175(5) 221(6) Hx ofivduat enrollment 135(4) 149(4) Currentsmoker 1034(28) 1112(28) Close contactforltbi 2609 (70) 2857 (72) HCV* 97(3) 99(3) *ExcludedwhenAST>=5xUNL HBV* 60(2) 42(1) 21 3HP9H, 9H(0.43%)vs.3HP(0.19%) LogrankPvalue=0.06 Noninferioritydemonstratedas97.5%upperboundofdiff=0.08%(<0.75%=NImargin) 3HP9H Sterling,T.R.,etal., NEngl JMed,2011.365(23):p.215566. 22
Outcome 9H (N=3,745) 3HP (N=3,986) Pvalue Treatmentcompletion 2,585(69.0%) 3,362(84.3%) <0.0001 Permanentdrug discontinue anyreason 1,160(31.0%) 624(15.7%) <0.0001 Permanentdrug discontinue duetoan adverseevent 135(3.6%) 188(4.7%) 0.004 Death 39(1.0%) 31(0.8%) 0.22 3HP CourtesyofM.ElsaVillarino 23 Hepatotoxicity amongpersonsreceiving> 1dose duringtreatmentorwithin60daysofthelastdose Toxicity 9H N=3,759 3HP N=4,040 Pvalue All hepatotoxicity 113(3.0) 24(0.6) <0.0001 Relatedtodrug 103(2.7) 18(0.4) <0.0001 Notrelated 10(0.3) 6(0.2) 0.319 3HP CourtesyofM.ElsaVillarino 24
PREVENTtrialRMP Abroaddefinitionofwasused a)hypotension,urticaria,angioedema,acute bronchospasm,orconjunctivitisthatoccurredinrelation tostudydrug;or b)>4ofthefollowing(oneofwhichhadtobe>grade2) thatoccurredinrelationtostudydrug: weakness,fatigue,nausea,vomiting,headache,fever,aches, sweats,dizziness,shortnessofbreath,flushing,orchills. Sterling,T.R.,etal., NEngl JMed,2011.365(23):p.215566. 25 Amongpersonsreceiving> 1dose Duringtreatmentorwithin60daysofthelastdose Accountingforattributiontostudydrug HS: hypersensitivity reaction Toxicity 9H N=3,759 3HP N=4,040 Pvalue Relatedtodrug 206(5.5) 332(8.2) <0.001 Rashonly 21(0.6) 31(0.8) 0.26 PossibleHS 17(0.5) 152(3.8) <0.001 Other 65(1.7) 131(3.2) <0.001 Notrelated 410(10.9) 226(5.6) <0.001 9H 26
Apediatriccohortnestedwithinanopen labelrctconductedfromjune11,2001, throughdecember17,2010,withfollowup throughseptember5,2013 in29studysitesintheunitedstates, Canada,Brazil,HongKong(China),and Spain. Participantswerechildren(aged217years) whowereeligiblefortreatmentofltbi Villarino,M.E.,etal.,JAMAPediatr,2015. 169(3):p.24755. 27 TolerabilityandEffectivenessinChildren TBTCS26+IMPAACT Study26amendedtoenroll352additionalchildren;1,058total& 908forefficacyevaluation Nohepatotoxicity,grade4events,ordeaths Endpoint 3HP N=471 9H N=434 Pvalue Treatment 88% 81% 0.003 completion D/C adversedrug 1.7% 0.5% 0.11 reaction TB 0(0%) 3(0.78%) Upperboundof difference:0.44% 28
3HP8 3influenzalikeAEs(grade2) 3cutaneous(allwithpruriticrash[2weregrade2],1 withoralblistersandfever[grade3]) 2gastrointestinalreactions(1wasgrade1and1was grade2) 9H2 1cutaneousAE(grade2)and1gastrointestinal reaction(grade3) :9H3HP alternative 29 INH: 15mg/kgforchildren12yearsold 25mg/kgforthose211years themaximumweeklydosewas900mg RPT: Notadjustedforage,adoseperweightband table BlakeMJetal.Pharmacokineticsofrifapentine inchildren.pediatr InfectDisJ.2006;25(5):405409. Peloquin CAetal.Stabilityofantituberculosis drugsmixedinfood.clin InfectDis.2007;45(4):521. 30
HIV Outcome 9H (N=193) 3HP (N=206) Pvalue Tuberculosis 6(3.5%) 2(1.0%) ns Treatmentcompletion 63.7% 88% <0.0001 Permanentdrug discontinue duetoan adverseevent Drugrelated hepatotoxicity Drugrelated PossibleHS 8(4%) 7(4%) 0.8 11(6%) 3(2%) 0.03 0(0%) 1(0.5%) 0.99 SterlingTR.CROI2013 31 Study/Arms TBcases INHresistant RMP resistant HR resistant MartinsonNA RPTINH 24 1 2 1 6INH 22 Cont.INH 8 1 1 1 RMPINH 24 0 0 0 SterlingTR RPTINH 15 1 9INH 7 1 Martinson,N.A.,etal.,NEngl JMed,2011.365(1):p.1120. Sterling,T.R.,etal., NEngl JMed,2011.365(23):p.215566. 32
3HP Drug Duration Dose (>12yearold) Frequency Total doses Isoniazid (INH) 300mg 3# 3months 15mg/kgroundedupto thenearest50or100mg (12yearsold); 25mg/kgforthose211 years 900mgmaximum Once weekly 12 Rifapentine (RPT) 150mg 6# 3months 10.0 14.0kg300mg 14.1 25.0kg450mg 25.1 32.0kg600mg 32.1 49.9kg750mg 50.0kg900mg maximum Once weekly 12 USCDCLatentTuberculosisInfection:AGuideforPrimaryHealthCareProviders http://www.cdc.gov/tb/publications/ltbi/ 33 WHORecommendationforLTBI Management 34
(3HP): once weekly x3months = only12doses 900mgIsoniazid(INH)+ 900mgRifapentine (RPT) 2016 35 MONITORANDSURVEILLANCEOF ADVERSEEVENTS 36
SystemicDrugReaction Sterling,T.R.,etal., ClinInfectDis,2015.61(4):p.52735. hypersensitivityrptprevent Trial PREVENTTrial NYC Stennis,N.L.,etal.,ClinInfectDis,2016.62(1):p.539. 37 SystemicDrugReactioninthePREVENT TuberculosisStudy 138(3.5%)3HP(n=3893)systemic drugreaction(sdr) Symptomsoccurredafteramedianof3doses, and4hoursafterthedose;mediantimeto resolutionwas24hours. 4/3893(0.1%)admission 13/3893(0.3%)severereactions 8:Grade4toxicity(including1syncope) 6:hypotensive 6:syncope(noadmission,lossconsciousness) Nodeathreported Sterling,T.R.,etal., ClinInfectDis,2015.61(4):p.52735. 38
3HP Flulikesyndrome (2.2%),, 0.15% 3HP(n=138) 9H(n=15) Cutaneous 23(17%) 9(60%) Severe 3 1 nonsevere 20 8 Flulike 87(63%) 2(13%) Severe 6 0 nonsevere 81 2 Gastrointestinal 7(5%) 1(7%) Severe 2 0 nonsevere 5 1 Respiratory 5(4%) 0(0%) Severe 1 0 nonsevere 4 0 Notdefined 16(12%) 3(20%) Severe 1 0 nonsevere 15 3 39 Frequencyofsignsandsymptomsin153casesof systemicdrugreactions(sdr),stratifiedbyarm Fatigue Headache Nausea Weakness Chills Myalgia Fever Dizziness Joint pain Rash Abdominal Pain Flushing Conjunctivitis Vomiting Itching 3HP,,,; 9H,, Sterling,T.R.,etal., ClinInfectDis,2015.61(4):p.52735. 40
2013 13HP LTBI,,5033HP, Stennis,N.L.,etal.,ClinInfectDis,2016.62(1):p.539. 41 SideEffectsExperiencedbyNewYorkCityHealthDepartment TuberculosisClinicPatientsTreatedWith3HP 32 (10.6%), :,,. syncope, 5, 1.7%. Stennis,N.L.,etal.,ClinInfectDis,2016.62(1):p.539. 42
/ LTBI 3HP :,, 3HP Stennis,N.L.,etal.,ClinInfectDis,2016.62(1):p.539. 43 TheTreatmentCompletionRateandSideEffectsof9Hand3HP RegimensPopulation(courtesy of 9H(n=590) 3HP(n=101) Resultsoftreatment n % n % pvalue completed 515 87.29% 98 97.03% p<0.001 discontinued 75 12.71% 3 2.97% Reasonofdiscontinued sideeffects 28 4.75% 3 2.97% * p<0.001 reject 44 7.46% 0 0% death 1 0.17% 0 0% TB 2 0.34% 0 0% 3HPcompletionratewassignificantlyhigherthan9H Lowdiscontinueratein3HP 44
HepatotoxicityandDiscontinue (courtesy of) 3HP 9H N=104 N=90 pvalue Hepatotoxicity 1(0.9%) 4(4.3%) 0.184 AST/ALT>10ULN 0 1 AST/ALT5~10ULN 1 3 TBil >3mg/dL 0 0 Discontinuation 11(9.6%) 18(20.0%) 0.066 Notsupervised 0 11 DuetoAE 9(8.6%) (4.4%) Tx notnecessary 2 2 Familyagainst 0 1 MOHW103CDCC114112301 45 AnyAEDuringthetreatment (courtesy of 3HP(n=104) 9H(n=90) pvalue Any AE 48(46.2%) 26(28.9%) 0.014 Flulikesymptoms 22(21.2%) 16(17.8%) 0.555 Malaise 22(21.2%) 13(14.4%) 0.226 Fever/Flush 20(19.2%) 4(4.4%) 0.002 GIupset 14(13.5%) 8(8.9%) 0.316 CutaneousAE 6(5.8%) 3(3.3%) 0.508 Blurvision 1(1.0%) 1(1.1%) >0.999 Irregular menstruation 1(1.0%) 0(0.0%) >0.999 MOHW103CDCC114112301 46
PostMarketingSurveillance byuscdc Vigilancefordrughypersensitivityreactions, particularlyhypotensionorthrombocytopenia Nofurtheralarmsignalwasdetectedfor syncope(hypotensiveinnatureandsuspect associatedwithconcomitant medications HTN/CNSdepressivedrugs CurtseyofChristineS.Ho,18thAnnualConferenceoftheUnionNAR,2014 46 th IUATLDworldconference,2015 47 (3HP)9H (ALT,total bilirubin) 9H 9H () CBC/DC 48
() 9H 49 flulikesyndrome, ; flulikesyndrome () 9Hrechallenge rechallenge 9H 50
RPT DOPT (prophyria) RMP RPT RPT, 51 RPTCYP4503A4 2C8/9CYP450 RPT,, RPT4, RPT14 :coumadin,methadone,phenytoin proteaseinhibitors NRTIsAzole 52
RPT 53 ExamplesofDrugsWithinClass Antiarrhythmics Disopyramide,mexiletine,quinidine,tocainide Antibiotics Chloramphenicol,clarithromycin,dapsone,doxycycline; Fluoroquinolones(suchasciprofloxacin) OralAnticoagulants Warfarin Anticonvulsants Phenytoin Antimalarials Quinine AzoleAntifungals Fluconazole,itraconazole,ketoconazole Antipsychotics Haloperidol Barbiturates Phenobarbital Benzodiazepines Diazepam BetaBlockers Propanolol CalciumChannelBlockers Diltiazem,nifedipine,verapamil CardiacGlycosidePreparations Digoxin Corticosteroids Prednisone Fibrates Clofibrate OralHypoglycemics Sulfonylureas(e.g.,glyburide,glipizide) HormonalContraceptives/Progestins Ethinyl estradiol,levonorgestrel Immunosuppressants Cyclosporine,tacrolimus Methylxanthines Theophylline Narcoticanalgesics Methadone Phophodiesterase5(PDE5)Inhibitors Sildenafil Thyroidpreparations Levothyroxine Tricyclicantidepressants Amitriptyline,nortriptyline 54 Sterling,T.R.,etal.,NEngl JMed,2011.365(23):p.215566. (supplementaryprotocol)
3HP 9H 3HP 4doses 3HP+ 6H 55 56
3HP 57 : ()1922 58
59 60
12() 9H3HPINHsusceptible(9H)INH &RMPsusceptible(3HP) 211 9HINHsusceptible 2 3HP9HINHsusceptible USCDCLatentTuberculosisInfection:AGuideforPrimaryHealthCareProviders http://www.cdc.gov/tb/publications/ltbi 61 IneligiblePatients ( Pregnantandthose expectingtobecome pregnantduring treatment INH RMP SourcecaseisINHor RMPresistant 2 <2yearsofage ARTsHIV (proteaseinhibitors) 211(9H3HP) coumadin,methadone,phenytoin 62
SterlingTR,etal.NEngl JMed2011;365:215566. ClinInfectDis.2015;61(4):52735. 63 64