Accessing MDR-TB exposed Households: the PHOENiX MDR-TB ... · Accessing MDR-TB exposed Households: the PHOENiX MDR-TB Feasibility Study Gavin Churchyard (MBBCh, FCP (SA), FRCP (Edin),

AccessingMDR-TBexposedHouseholds:thePHOENiXMDR-TB

FeasibilityStudy

GavinChurchyard

(MBBCh,FCP(SA),FRCP(Edin),MMED,PhD)Co-ChairofPHOENIxFeasibilityStudyandMainTrial

MDRTBinHouseholdContacts�  ContactsofMDRTBpa0entshaveahighriskofTBinfec0onanddisease

�  VastmajorityofMDRTBinchildrenarisesfromhouseholdtransmission

•  Systema0creviewofobserva0onalstudiesofcontactsofdrug-resistantindexcases•  4–8%propor0onwithincidentTB•  44–72%ofincidentTBaredrug-resistant

Shahetal.ClinInfectDis2014CainKPetal.IntJTubercLungDis2010

�  Treatmentofpresump0veMDRTBinfec0onnotrecommended�  Qualityofevidenceisseriouslylimited

�  Recommendstrictclinicalobserva0onandclosemonitoringforTBdiseaseforatleasttwoyears

�  ThereremainsanurgentneedfortrialsofTBpreven0vetherapyforHHcontactsofMDRTBpa0ents,par0cularlyforthoseathighriskincludingHIV-infected,TST+andyoungchildrentoinforminterna0onalevidence-basedrecommenda0ons

WHO2014GuidelinesforPrevenNveTherapyforMDRTBContacts

Recommenda)onsandResearchGaps

ProtecNngHouseholdsOnExposuretoNewlyDiagnosedIndexMulNdrug-ResistantTuberculosisPaNents

(A5300B/I2003B/PHOENIx)StudyHypothesis�  Trea0ngHIV-infectedandotherchild,adolescentandadulthouseholdcontactsofMDRTBpa0ents,includingpre-XDRTBandXDRTB,whoareathighriskofdevelopingTBwithdelamanidwillsubstanNallyreducetheriskofdevelopingTB,comparedtoisoniazid

PHOENIxFeasibilitystudy

ObjecNves�  Todescribethefeasibilityofiden0fying,recrui0ng,andcharacterizingadultMDRTBindexcasesandtheiradultandchildhouseholdcontacts

�  TodescribetheprevalenceofLTBI,TBdiseaseandHIVinfec0onamongadultandchildhouseholdcontacts

Design�  Cross-sec0onalstudywith1yearfollow-up

Samplesize�  300adultMDRindexcasesandalleligiblehouseholdcontacts

PopulaNon�  IndexCase:Anadult(18yearsorolder)withpulmonaryMDRTB�  Householdcontact:Apersonwholivesinthesamedwellingunitandsharesthesamehousekeepingarrangementsastheindexcase,andwhoreportsexposurewithin6monthspriortotheindexcasestar0ngMDRTBtreatment

Methods

Site-level�  MDRTBcaseload�  Resourceu0liza0onsurvey

IndexCases�  Medicalhistory�  Documenta0onofchestimagingandHIVstatus

�  Sputumfordrug-suscep0bilitytes0ng

EvaluaNons

HouseholdContacts�  Householdenumera0on�  Medicalhistory�  Documenta0onofHIVstatus(HIVtes0ng,ifunknown)

�  LatentTBinfec0ontes0ng�  Chestx-ray�  RespiratorysamplesforTBdiagnosis�  Knowledge,a_tudeandprac0ces(KAP)survey

PHOENIxFeasibilityStudySites

Botswana(1)Brazil(1)Hai0(1)Kenya(1)India(2)Peru(2)SouthAfrica(8)Tanzania(1)Thailand(2)Zimbabwe(1)

16sitesacNvated4sitesnotacNvated

MDRTBIndexCaseEnrollmentIndexCasesApproached

(Oct2015–Mar2014)410

IndexCasesScreened396(97%)

IndexCasesEnrolled308(78%)

3(3%)doesnothaveMDRTB2(2%)hasnotstartedMDRTBtreatment1(1%)illnessthatwouldinterfere1(1%)nohouseholdmember1(1%)duplicatescreeningnumber69(78%)Otherreason11(13%)unknown

Reasonsfornon-enrollment(n=88)

HouseholdContactsEnrollment

HHCreasonsfornotenrolling(n=308)HouseholdContacts

Enumerated*(*basedonn=305household)

1317

HouseholdContactsEnrolled**

(**basedonn=308households)

1018(77%)

28(9%)unabletocontact39(13%)notwilling,noreasongiven57(19%)donotwanttopar0cipateinresearch65(21%)toobusy1(<1%)fearofs0gma20(6%)ineligible63(20%)otherreasons35(11%)missingdata

ParNcipantCharacterisNcsCharacterisNc

Index(N=308)

HHC(N=1018)

Medianage,years(range) 36(18-74) 26Female 133(43%) 600(59%)*Countries(#sites)Botswana(1)Brazil(1)HaiN(1)India(2)Kenya(1)Peru(2)SouthAfrica(7)Thailand(1)

10(3%)10(3%)16(5%)58(19%)8(3%)63(20%)133(43%)10(3%)

38(4%)17(2%)52(5%)206(20%)12(1%)203(20%)460(45%)30(3%)

*14pregnantwomen

Indexcasesn=308

�  Iden0fiedat� Communityclinics 53%� Generalhospital 16%� CRS 13%� ReferraltoCRS 11%� Other 1%

� Documenta0onofDSTfromlocallab� All308rifampinresistance� Only232(75%)hadINHresistancedocumented

MDRTBIndexCaseCharacterisNcs

CharacterisNc

Index(N=308)

HIV-infected 112(36%)

Diabetes 25(8%)

Currentorformersmoking 133(43%)

PreviousTB 147(48%)Chestx-raycavitaNon 201(65%)AFBsmearposiNve(n=211) 148(70%)

MDRTBtreatmentduraNon(median) 6.2weeks

AgeDistribuNonofHouseholdContacts

1%9%

25%

48%

17%

0%

10%

20%

30%

40%

50%

60%

0

100

200

300

400

500

600

<1 1-<5 5-<18 18-<50 >=50

Pediatriccapacityvariable:2-50%enrolmentofchildren<5yrsacrosssites

HIVTesNng� Overall

� 78%ofHHChadunknownHIVstatuspriortostudyentry� 71%ofHHCagreedtoHIVtes0ng� 26(5%)newinfec0onsiden0fied

� VariableuptakeofHIVtes0ngacrosssites� 9siteswith>80%uptakevs.4siteswith<50%uptake� Loweruptakeinage2-17yo(52-65%)vs.<2yrs(77%)andadults(78%)

� ReasonsfornotofferingorrefusingHIVtes0ng:�  Parent/guardiannotavailabletoconsentorParent/guardianrefusal� NoIRBapprovalforHIVtes0nginchildren

�  ParentsofchildHIVnega0ve(riskpercep0on)

LatentTBInfecNonLTBITesNng n(%)

NoTSTdone* 300(30%)

TSTtested 705(64%)

TST+ 392(56%)

TST- 304(43%)

Testedbutnoresult 9(1%)

NoIGRAdone 26(3%)

IGRAtested 973(97%)

IGRA+ 629(65%)

IGRA- 330(34%)

Testedbutnoresult 14(1%)

LTBI N(%)

TST+orIGRA+ 708(70%)

TST-andIGRA- 272(27%)

Unknown 27(3%)

LTBIstatuswithcombinedtesNng

*TSTnotdoneat3of16sites(2Peruand1SouthAfrica)

LatentTBInfecNonLTBITesNng n(%)

NoTSTdone* 300(30%)

TSTtested 705(64%)

TST+ 392(56%)

TST- 304(43%)

Testedbutnoresult 9(1%)

NoIGRAdone 26(3%)

IGRAtested 973(97%)

IGRA+ 629(65%)

IGRA- 330(34%)

Testedbutnoresult 14(1%)

LTBI N(%)

TST+orIGRA+ 708(70%)

TST-andIGRA- 272(27%)

Unknown 27(3%)

LTBIstatuswithcombinedtesNng

*TSTnotdoneat3of16sites(2Peruand1SouthAfrica)

LatentTBInfecNonLTBITesNng n(%)

NoTSTdone* 300(30%)

TSTtested 705(64%)

TST+ 392(56%)

TST- 304(43%)

Testedbutnoresult 9(1%)

NoIGRAdone 26(3%)

IGRAtested 973(97%)

IGRA+ 629(65%)

IGRA- 330(34%)

Testedbutnoresult 14(1%)

LTBI N(%)

TST+orIGRA+ 708(70%)

TST-andIGRA- 272(27%)

Unknown 27(3%)

LTBIstatuswithcombinedtesNng

*TSTnotdoneat3of16sites(2Peruand1SouthAfrica)

TST+andIGRA+byCountry�  TST+ �  IGRA+

8%

78%

35%

60%

50%

0

65%

13%

56%

0% 20% 40% 60% 80% 100%

Botswana

Brazil

HaiN

India

Kenya

Peru

SouthAfrica

Thailand

Overall

Notdone

55%

76%

73%

74%

70%

56%

80%

47%

72%

0% 20% 40% 60% 80% 100%

Botswana

Brazil

HaiN

India

Kenya

Peru

SouthAfrica

Thailand

Overall

YieldofContactTracingn=1016contacts

� Signs/symptomsrelatedtoTB� 23%HHCs<15yearsand24%of>=15years

� CXR� 971(96%)gotCXR� 169(17%)abnormal

� 130(13%)prevalentTBcases� Possible71,7%� Probable33,3%� Confirmed26,3%

� Yieldvariedbysite

PotenNallyEligibleHighRiskHouseholdContacts

CharacterisNc N(%)

Ineligible(hadprevalentTBornothighrisk) 350(34%)

PotenNallyeligible<5years≥5yearsandHIV+≥5yearsandTSTorIGRA+

666(66%)66(10%)60(9%)540(81%)

Median#ofeligiblecontactsperhousehold 2(IQR1–3)

WillingnesstotakePrevenNvetherapy

•  HHCwillingnesstotakepreven0vetherapywashigh(79%)withsignificantsite-levelvaria0on

n=741HHCsmedianage3362%women42%primaryorlesseduca0on

Suryavanshi,MurilletalPosteratAmericanThoracicSociety2017

ResourceuNlizaNon

� 16sitesmade512aoemptstoevaluate308households� upto5aoemptsperhousehold

� MedianHHsizewas4peopleplusindexcase� Range1–21persons

� Median0mespentbysitestaffperaoemptwas4hours

� Range1to24hours

InfecNoncontrolHousehold&faciliNes� N95respiratorswerewornbystudystaffin15/16sites�  Indexcasesworesurgicalmasksinallsites� SputumcollectedinaseparateareainallclinicsTransportaNonofparNcipants� Par00onedvehicleavailableathalfthesites� N95respiratorswornbydriversat82%ofsites� Surgicalmaskswornbypar0cipantsatallsites� Windowsopenwhentranspor0ngpar0cipantsatallsites

Sitechallenges�  TSTaccess� UptakeofHIVtes0ng�  Recruitmentofchildren�  Sufficientstaffing�  Travel/logis0cs

� Safetyofoutreachteams� Needformul0plevisits,flexibilityinhours/loca0on

� Occupa0onalexposurerisk/infec0oncontrol� Challengesofwearingpersonalprotec0veequipment� Transpor0nghouseholdcontactstothesite� Needforseparatesputumsamplingareas

�  S0gma

Conclusion� EnrollingMDRTBindexcasesandhouseholdcontactsisfeasible� StrategiestoimproveHIVtes0ngbyHHCisrequired� Contactinves0ga0onofchildrenrequiresstrengthening� Householdcontactinves0ga0onsprovideahighyieldbutarelaborintensiveandrequiremul0pleresources

� Highwillingnesstopar0cipateintrialofpreven0vetherapy

ProtocolTeam�  Co-Chairs:GavinChurchyard,AmitaGupta,AnnekeHesseling,SusanSwindells�  ClinicalRepresentaNves:DanielJohnson,RohanHazra,ElizabethSmith�  ClinicalTrialsSpecialists:LindaG.Naini,LaraHosey�  StaNsNcians:MichaelHughes,SoyeonKim�  DataManager:LynneJones�  DAIDSPharmacist:ThucumaSise�  Pharmacologists:KellyDooley,KimberlyK.Scarsi�  InvesNgators:RichardE.Chaisson,MarkHarrington,SharonNachman,SaritaShah�  ConsultantCardiologist:RichardFriedman�  ConsultantMicrobiologist:Anne-MarieDemers�  FieldRepresentaNves:SavitaM.Kanade,JanetNicotera�  LaboratoryTechnologists:PatriciaAnthony,ChristopherLane�  CommunityScienNficSubcommipeeRepresentaNves:UjwalAmarKadam,RonaldSsenyonga�  InternaNonalSiteSpecialist:AkbarShahkolahi�  LaboratoryDataManager:AdamManzella�  IndustryRepresentaNve:JeffreyHavin

SiteInvesNgatorsandStudyTeams�  RodneyDawsonandKimNarunsky-UniversityofCapeTownLungInsNtuteSouthAfrica(Site31792)Fund110205�  AlbertoMendozaandFannyRosas-BarrancoCRSPeru(Site11301)Grant5UM1AI069438-10

�  JessicaRiosandLilianaVallejos-SanMiguelCRSPeru(Site11302)Grant110199�  VidyaMaveSushantMeshram-ByramjeeJeejeebhoyGovernmentMedicalCollegeCRS(Site31441)GrantU01AI069497

�  NKumarasamyandEasterThamburaj-ChennaiAnNviralResearchandTreatment(CART)CRS(Site11701)GrantUM01A1069432

�  KylaCominsandVictoireTicha-TASKCRS(Site31718)GrantUM1AI069521�  FrancescaConradieandRalinahMaepa-WitsHelenJosephHospitalCRS(Site11101)GrantAI069463

�  MarkHatherillandJus0nShenje-SouthAfricanTuberculosisVaccineIniNaNve(SATVI)(Site31793)Grant5UM1AI068636-10

�  SandyNereoeFontainandStalzCharlesVilbrun-GHESKIOCentersIMIS(Site31730)Grant5UM1AI069421�  AnthonyGarcia-PratsandPetraDeKoker-DesmondTutuTBCentre-StellenboschUniversity(DTTC-SU)(Site31790)

�  AidaAsmelashandAyotundeOmozoarhe-GaboroneCRS(Site12701)GrantUM1AI069456�  SupalertNedsuwanandTimRCressey-PHPT-ChiangraiPrachanukrohHospital(Site5116)GrantHHSN275201300003C

�  DebraPetersandBreoMansfield-SowetoACTGCRS(Site12301)Grant5UM1AI069453

�  UmeshGLallooandRosieMngqibisa-DurbanInternaNonalCRS,EnhancingCareFoundaNon(Site11201)Grant2UM1AI069432-08�  AnaCris0naGarciaFerreiraandMariaReginaRocha-InsNtutoNacionaldeInfectologia-INI/Fiocruz(Site12101)Grant5UM1AI069476-09

�  ChristopherMugahandElishaOkeyo-Kisumu(KEMRI/CDC)CRS(Site31460)Grant5UM1A1068636-09