TB and Diabetes SNTC Sept25 - 2013

Webinar: TB & Diabetes
Southeastern National TB Center
TuberculosisandDiabetes
EricR.HouptMD,
Professor,DivisionofInfectiousDiseasesIntlHealth
UniversityofVirginia
ScottHeysell MD
JaneMooreVDH
Nodisclosures
Overview
DiabetesincreasestheriskofprogressiontoactiveTBdisease
(odds2.48.3 comparedtonondiabetics)
andlikelyhigherforpoorlycontrolleddiabetics
Diabetes/TBprevalencewillincreaseglobally
WhenadiabetichasTB,treatmentoutcomesareworse(comparedto
nondiabeticsw TB)
DrugconcentrationsaresuboptimalformostDM/TBpatients
9/25/2013 1
Nospecialinsidiousness
ofsignsandsymptomsin
thetuberculous diabetic
TBmorefrequentinthose
withpoordiabetescontrol
Nospecialinsidiousnessofpresentation
Nodifferenceinlocationofdiseaseorlungcavitation
Dooleyetal.LancetID2009
9/25/2013 2
AttributableriskofTBfromDiabetes>HIVinTexas/Mexicoborder
Restrepo etal.BullWHO2011
Diabetesistheleadingidentifiedrisk
factorforTBinVirginia(1015%)
http://www.vdh.state.va.us/epidemiology/diseaseprevention/programs/tuberculosis/do
cuments/annual_final_8_16_2013_revised.pdf
9/25/2013 3
ScreeningfordiabetesinnewTBpatientscanbehighlyeffective
(India)
Overall,numberofTBpatientsneededtoscreen(withHbA1c)in
ordertodetectonenewcaseofdiabeteswasjust4.
Balakrishnan etal.PLoS ONE2012
Basedonstudieslikethis,
ThenationalTBguidelinesinIndiahavechangedto
recommendscreeningfordiabetesinallnewTBcases
9/25/2013 4
Overview
DiabetesincreasestheriskofprogressiontoactiveTBdisease
(odds2.48.3 comparedtonondiabetics)
andlikelyhigherforpoorlycontrolleddiabetics
Diabetes/TBprevalencewillincreaseglobally
WhenadiabetichasTB,treatmentoutcomesareworse(comparedto
nondiabeticsw TB)
DrugconcentrationsaresuboptimalformostDM/TBpatients
OutcomesduringtreatmentforTb
Mostdowell(>90%) Somedont
Death<slowresponse=
persistentsymptoms/smear+
Manypotentialfactors
Extensivedisease
Drugresistance
HIV
Othercomorbidities
Lowdruglevels
Diabetes

9/25/2013 5
DiabeticsinIndonesiamorelikelytobe
culturepositiveat6monthsoftreatment(22%)
14.8%prevalenceofundiagnosedDMinnewTBpatients
TBDMhadgreatersymptomsattimeofdiagnosis
Alisjahbana etal.Clin InfectDis2007
InMaryland,oddsofdeathwere6.5timeshigher(p=0.039)for
diabeticsthannondiabeticswithTB,evenadjustingforHIV,age,
weight,andforeignbirth
ofdeathswerenotTBrelated
Timetosputumcultureconversionwaslonger (49daysfor
diabeticsvs 39daysfornondiabetics,p=0.09)
Dooleyetal.AmJTropMedHyg 2009
9/25/2013 6
AllcausemortalityincreasedindiabeticsduringTBtreatment
Bakeretal.BMCMed2011
Slowercultureconversionindiabetics(withoutcavitary disease)
70%at2mos.
>20%ofdiabeticswithnoncavitary
pulmonaryTBremainsputumpositive
at3monthsoftreatment
Dooleyetal.AmJTropMedHyg 2009
9/25/2013 7
Worseoutcomes..Whatcanwedoaboutit?
TBdisease:
ExtrapulmonaryTB
Extensivelungcavities
Delayedpresentationtocare
Lowplasmadruglevels?
death
Hostfactors:
StartTBtreatment Delayedculture
HIV conversion Acquireddrug
Diabetes resistance
Malnutrition
Silicosis
Relapse
M.tuberculosisstrain:
Drugresistance
Virulence?
OutcomesduringtreatmentforTb
Mostdowell(>90%) Somedont
Death<slowresponse=
persistentsymptoms/smear+
P=NS
Manypotentialfactors
Extensivedisease
Drugresistance
HIV
Othercomorbidities
Lowdruglevels
Diabetes

9/25/2013 8
WehavebeenroutinelycheckingserumantiTBdrugconcentrationsin
slowresponderssince~2007(thankstosomeaddl funding)
~14%ofallTbpatients,definedasnoimprovementinsx orpersistentsmear+
Diabeticswere6.3timesmorelikelyto beslowresponders (p<0.001)

adjustedforage,gender,foreignbirth,priorTBepisodes,cavitary
disease,HIV,alcoholandtobaccouse.
~40%ofdiabetics
Amongslowresponders,diabeticshadsignificantlylowerserum
rifampin levels (estimatedpeakC2h)
Heysell etal.Emerg InfectDis 2010
MajorityofslowrespondershadlowC2hr levels
ofINHandrifampin
82%hadlowlevelstooneofINHorRMP,hardtopredictwhichone
Heyselletal,EmergInfectDis,2010
9/25/2013 9
Druglevels usuallycorrectafterfirstdoseadjustment
RMPdaily/
INHdaily INHbiweekly biweekly
300mg 450mg 900mg 1200mg 600mg 900mg
spansC2hr expectedrange
Heysell etal,Emerg InfectDis 2010
DeterminantsofantiTBdrugpharmacokinetics:
1. mg/kgdosing(weightcategories,pooravailabilityofdrugin
fixeddosecombinationsinsomesettings)
2. Adherence
3. Druginteractions
4. Gastroenteritis
5. Malabsorption
HIV ?
Diabetes
CysticFibrosis
6. Poorsolubility1
7. Hostgenetics
Geneticpolymorphismofgutxenobiotictransport
Metabolism
8. Age
9. Gender
1.Ashokraj etal.Clin ResReg Affairs2008
9/25/2013 10
RifampinexposuresignificantlyreducedindiabeticsfromIndonesia
824ug/mL
expected
Cmax range
(AUC06h),Cmax andoverallrifampinexposurewas53%
lowerindiabeticswithTBcomparedtonondiabeticsin
continuationphase,withsomelinkagetohighbodywt
Nijland etal.Clin InfectDis2006
Lowdruglevelsmatter,atleastinvitro
AmongsubjectswiththelowestTDA(1.5),only2(40%)werecuredat6monthscomparedto
10(91%)withthehigherTDAvalues(p=0.06)
Heysell etal.Antimicrob AgentsChemother 2011
9/25/2013 11
Whatistheright*doseofrifampin?
*In1971thedoseof10mg/kgwasarbitrarilychosenwithoutamaximum
tolerateddosestudy.
PKtesting PKtesting
N=68,smearpositivePTB
randomizedtoRIF Day17 Day814
10,20,25,30,35mg/kg
Isoniazid/Ethambutol/PZA
DailysputumCFUonsolidandTTPinliquidmedia
Dropinculturewasdoserelatedwithmostkillingseenin35mg/kggroup
MeanCmax 10mg/kg7.4mg/L;30mg/kg 33.1mg/L
Adverseevents:mostlygrade1 Boeree etal.

CROI2013
Itwouldnotsurprisemeifeventuallyweuse900mgRIFroutinely.
In2011,aninitiativewasstartedtomeasureisoniazidand
rifampinlevels(these2drugsonly,PZAusuallyfine,EMB
usuallydropped)inalldiabeticsat2weeksofTBtherapy
(insteadofwaitingfor~40%tobeslowresponders)
9/25/2013 12
TheVirginiaAlgorithm
http://www.vdh.state.va.us/epidemiology/diseaseprevention/programs/tuberculosis/document
s/TDMRecommendationsandProceduresRrevised082013Final.pdf
InsteadofonlyselfreportandpriorDMdiagnoses,
wenowrecommendcheckingHbA1Conall
>6.5:education/resourcepacket,referral
<6.5:education/resourcepacket
ImplementationofearlyTDMindiabeticswasoperationallyfeasible
81%ofeligiblediabetics
Characteristic Diabetes Slowresponse Pvalue

(earlyTDM) (standardTDM)
N=21 N=14
Age,meanyearsSD 5717 4612 P=0.04

Gender,male(%N) 15(71) 11(79) P=0.69
PriorepisodeofTB,n(%N) 0 2(14) P=0.17
PulmonaryTBonly,n(%N) 17(81) 8(57) P=0.65
Foreignborn(%Nwithconfirmedstatus) 15(79) 12(92) P=0.63
HIVinfected(%Nwithconfirmedstatus) 0 1(11) P=0.43
Insulindependence,n(%N) 10(48) N/A N/A
DaystoTDMfromtreatmentinitiation, 2316 8854 P=0.003
mediandays(IQR)
Heysell etal.NTCA2013
9/25/2013 13
EarlyTDMindiabeticscorrectedlowdrugconcentrations
inthemajorityandmaylimitslowresponse
Ofthe21diabetics,16(76%)hadaC2hrvaluebelowtheexpectedrangeforisoniazid
(mean2.11.5g/ml;expected35),rifampin (mean6.64.3 g/ml;expected824)orboth
Apropertargetpopulation
15patientshadfollowupconcentrationsafterdoseadjustment,allincreasedand12tothe
expectedrange(includingallforrifampin).
Inpractice,whatouralgorithmdoesisshuntmostdiabeticstoatleast3xweeklytherapy
duringcontinuationphase,withINH900/RIF900,whilekeepingtoa6monthtotalduration
Nomajortoxicitiesreported
88%ofdiabeticswithearlyTDMandpulmonaryTBhadsputumcultureconversion<2mos.
Betterthanexpectednormsfordiabetes/TB
totalstatewideburdenofslowresponsedecreased from1.6patients/mo(40%diabetic)to
1.2patients/mo(12.5%diabetic)
Maylimittheneedforprolongedtreatment
andprogramresources
Heysell etal.NTCA2013
Acknowledgments
UVA
ScottHeysell,TaniaThomas,DorothyBunyan,
SuzanneStroup
VDH
JaneMoore,SuzanneKeller,DebbieStaley,Denise
Dodge
VirginiaTBFoundation
9/25/2013 14
Improving TBDMCare
inthePacific:
Canwemakea
difference?
SoutheasternNationalTBCenter
TBDMWebinar,Sept25,2013
R.Brostrom,MDMSPH
RegionalTBMedicalOfficer,CDCDTBE
HawaiiTBControlBranchChief
CDRUSPHS
ImprovingTBDMCare
QuickUpdateofTBDMLink
EpidemiologyofTBDMinUS
PacificStandards
PacificPlan
Summary Questions
9/25/2013 1
PacificDietaryChangeafter1944
GlobalRisingTideofDiabetes
Millions of Cases in 2000 and Projected Cases for 2030
9/25/2013 2
TBcaseswithDM
60%
Percent Adult TB Patients with Diabetes
50%
40%
30%
20%
10%
0%
*India **Mexico Pacific Islander
*Stephenson, BMC Public Health. 2007; 7: 234 ** Restrepo, Bull WHO, 2011; 89: 352-9
A1c > 7
DM
No DM
A1c < 7
Leung CC, et.al. , Diabetic control and risk of tuberculosis: a cohort study. Am J Epidemiol. 167, 2008
9/25/2013 3
TBDMOutcomes:Relapse
Baker et al. BMC Medicine 2011, 9:81 The impact of diabetes on TB treatment outcomes: A systematic review
TBDMOutcomes:DeathduringTBTx
Baker et al. BMC Medicine 2011, 9:81 The impact of diabetes on TB treatment outcomes: A systematic review
9/25/2013 4
TBDMTeachingPoints
2x riskofremainingculturepositive
3x riskofprogressiontoactiveTB
4x riskofrelapseafterstandardtx
5x riskofdeathduringTBtreatment
Jeon CY, Murray MB, Diabetes mellitus increases the risk of active tuberculosis
A systematic review of 13 observational studies. PLoS Med 5(7): e152
Baker et al. The impact of diabetes on TB treatment outcomes:
A systematic review, BMC Medicine 2011, 9:81
ImprovingTBDMCare
PacificStandards
PacificPlan
Summary Questions
9/25/2013 5
RisingDiabetesRatesintheUS
TBRiskFactorsintheUS 2011
DiabetesMellitus
ContactofInfectiousTB
Immunosuppression
IncompleteLTBITx
EndStageRenalDisease
MissedContact
PostTransplant
TNFAlphaAntagonistTx
ContactofMDRTB
0 500 1,000 1,500 2,000
9/25/2013 6
DMReportedAmongUSAdultswithTB 2011
NHPI
Hispanic
Asian
AIAN
Black/AA
White
UnitedStates
0% 5% 10% 15% 20% 25%
ImprovingTBDMCare
PacificStandards
PacificPlan
Summary Questions
9/25/2013 7
USPacificRegionforTBControl
ScreeningforDMinpersonswithTB
Standard1 EverypersonwithTBovertheageof18shouldbescreenedfor DM
1.1 ThediagnosisofDMmaybemadeusingoneofthefollowingcriteria:
Fastingplasmaglucose126mg/dl
Randomplasmaglucose200mg/dl
HemoglobinA1C 6.5%
1.2 Abnormalglucosevaluesshouldbeverifiedinpatientswhohaveno
symptomsofDM.
1.3 RifampincanelevatebloodglucoseinTBpatients.Glucosetestingshould
berepeatedafter24weeksofTBtreatment,orifsymptomsof
hyperglycemiadevelopduringTBtreatment.
9/25/2013 8
BestPractices:SaipanIsland
PollingQuestion#1
WhenanewsmearpositiveadultTBcaseis
referredtoyourclinicforthefirsttime,doyou:
1. Askthemiftheyhavediabetes?
2. Askandsendthemfordiabetestesting?
3. Askandtesttheminclinicfordiabetes?
4. Wedontusuallyaskaboutdiabetes.
9/25/2013 9
ScreeningforTBinpersonswithDM
Standard2 EverypersonwithDMshouldbescreenedforactiveTBdiseaseand
latentTBinfection
2.1 AtestforTBinfectionshouldbedoneatthetimeofDMdiagnosis.
2.2 ScreeningshouldberepeatedasoftenaslocalTBepidemiologywarrants.
Standard3 PersonswithDMandTBinfectionshouldbeencouragedtotake
preventivetherapy
3.1 IfINHisusedforprevention,giveB6tohelppreventINHinduced
neuropathy(10 25mg/day).*
3.2 Monitorforadherenceandsideeffectsofpreventivetreatment.
*TargetedtuberculintestingandtreatmentoflatentTBinfection,MMWR2000;49.
Standard4 PersonswithDMandTBdiseaseshouldbereferredtothelocalTBProgram
forTBmanagement
BestPractices:RMICommunityClinic
9/25/2013 10
TBScreeninginDiabetesClinic:FindingTB
EbeyeDMClinicRate
EbeyeIsland
RMINTPRate
GlobalTBRate
USTBRate
0 1000 2000 3000 4000 5000

Rate ofTB per100,000
TBScreeninginDiabetesClinic:Results
9/25/2013 11
TreatingTBinpersonswithDM
Standard5 CliniciansmayneedtoadjustTBtreatmentinpersonswithDM
5.1 MakesurethatTBmedicationsareproperlydosed.
Checkcreatinine fordiabeticnephropathy,andifpresent,adjustthe
frequencyofPZAandEMBaccordingtoATSCDCguidelines.*
AdministerB6topreventneuropathy(10 25mg/day).
5.2 ObservecloselyforTBtreatmentfailureinpersonswithDM.
BeawareofpoorabsorptionofsomeTBmedsinDM.
SomeprogramsfollowINHorRIFlevelsinpersonswithDM.
ManagethemanyinteractionsbetweenTBandDMmeds.
5.3 AssuretheCure
Considerextendingtreatmentto9monthsforpersonswithDM,esp.
patientswithcavitarydiseaseordelayedsputumclearance.*
Uponcompletionoftherapy,obtainsputumforsmearandculture.
Evaluatepatientsatoneyearaftertreatmentforevidenceofrelapse.
*TreatmentofTuberculosis,AmericanThoracicSociety,CDC,andISD,MMWR2003;52
ManagingDMinpersonswithTB
Standard6 UseTBclinicvisitstohelpthepatientmanagetheirDM
6.1 ThereshouldbeaglucometerineveryTBclinicformonitoringbloodglucose.
6.2 TBpatientswithDMshouldhavetheirglucosecheckedatleastweeklyforthe
first4weeks,lessfrequentlyifdiabetesiscontrolled.
Monthlyglucosetestingduringtreatmentisrecommended.
6.3 AllclinicstaffshouldreinforceDMlifestylechangesatTBclinicvisits.
6.4 Ifavailable,referpersonswithDMtotheDiabetesClinicforlongtermdiabetes
care.EnsuretheDMclinicianisawareofTBdiagnosisandTBmedications.
Standard7 UseDOTvisitstohelpthepatientmanagetheirDM
7.1 DOTworkersshouldencouragelifestylechangesateverypatientencounter.
DOTworkersshouldusestandardizeddiabeteseducationalmaterials.*
Dietarychangesandphysicalactivityaremostimportant.
7.2 ConsiderdeliveringDMmedswithTBmedsviaDOTforpersonswithpoorly
controlledDMwhohavesuspectednonadherencetodiabeticmedications.
*ARCTBandDMFlipchart: http://www.thearc.org.au/TBandDiabetes.aspx
*NationalDiabetesEducationProgram,USDept ofHealthandHumanServices:http://www.yourdiabetesinfo.org/
9/25/2013 12
BestPractices:TBDMEducationalTool
(PITCA AustralianRespiratoryCouncil)
Standardizedapproach
DOTbasededucation
Weeklytopics:TBandDM
Simplifiedandfocused
BriefIntervention
5minorless
Repeatedmessages
9/25/2013 13
Diabetes?Itsnotmyjob!
ExercisesatBattleCreekSanitarium,Michigan,1911
TBDMNursesTraining:YesWeCan!
AskaboutDMatmonthlycaseconferenceand
quarterlycohortreview(Aug,2010)
ImproveTBDMSurveillance withA1Cforevery
adultcaseonentrytoTBProgram(Dec,2010)
ExpandA1Ctoq3monthswhiletx (June,2012)
InitiateTBClinicGlucometry Training(Oct,2012)
BeginTBClinicA1CTraining(Feb,2013)
StartedTBClinicDiabetesEducationTraining
2Afternoonsessions3/13,4/13
CommunityClinicpartnership
9/25/2013 14
TBDMNursesEducation
DMEducationQuotesfromTBPatients:
CanIcomebacktoclinictomorrowto
talksomemore?
Whataboutmykids,cantheycatchmy
diabetes?
WhatcanIeatatMcDonaldsthatsOK
forme?
IthankGodforyou.
9/25/2013 15
PollingQuestion#2
YoubeginDMscreeningandfindthat20%ofyour
adultcaseshavediabetes.Howmanyofthese
interventionsarerealisticforyourprogram?
1. Referringthemtoprimarycare.
2. ProvidingongoingDMtestinginclinic.
3. ProvidingongoingDMeducationinclinic.
4. ProvidingDMeducationwithDOT.
5. DeliveringDMmedicationswithDOT.
HawaiiTBDMStudy
Measure
MeasureA1ConalladultTBCases and Score
IfDM,thenmeasureA1Cat3mo and6mo
Diabetes
Control
IntegrateStandard6andStandard7intocare
Glucosetestingateachvisit Measure
A1CTestingevery3months and Score
Intervention
RefertoDMCenterforCare Effort
TBDMPatientEducationinClinic
TBDMPatientEducationduringDOT
9/25/2013 16
HawaiiTBDMStudy
ClinicalDiseasevs.LifestyleDisease
130encountersin6months
Maybethepatientsbestopportunity
tobemotivatedforlifestylechanges
TBDMIntegration
NGOs Regional
(Australian Partners Local and
Respiratory (CITC, SPC) External
Council) Diabetes
Programs
External Public Local Private

Partners and Public
(WHO, CDC) Improve Partners
Patient (Clinics)
Care
During TB
Improve Tx
LifeLong Improve
Diabetes TB
Outcomes
Control
9/25/2013 17
Resources
Collaborative framework for care and control
of tuberculosis and diabetes
http://www.who.int/diabetes/publications/
tb_diabetes2011/en/index.html
Pacific Regional Standards for the
Management of TB and DM:
http://www.currytbcenter.ucsf.edu/international/
TBDM_poster_pressquality.pdf
Key Messages for TB and DM (flipchart):
http://www.thearc.org.au/TBandDiabetes.aspx
Acknowledgments
USCentersforDiseaseControlandPrevention
WPRO,WorldHealthOrganization
InternationalUnionAgainstTBandLungDiseases
CurryInternationalTBCenter
SecretariatforthePacificCommunity
AustralianRespiratoryCouncil
CNMIPublicHealthDepartment
PacificIslandsHealthOfficersAssociation
PacificIslandsTBControllersAssociation
9/25/2013 18

TB and Diabetes SNTC Sept25 - 2013

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Webinar: TB & Diabetes

Southeastern National TB Center

Balakrishnan etal.PLoS ONE2012

Diabeticswere6.3timesmorelikelyto beslowresponders (p<0.001)

300mg 450mg 900mg 1200mg 600mg 900mg

Heysell etal,Emerg InfectDis 2010

Nijland etal.Clin InfectDis2006

Heysell etal.Antimicrob AgentsChemother 2011

Adverseevents:mostlygrade1 Boeree etal.

Characteristic Diabetes Slowresponse Pvalue

Age,meanyearsSD 5717 4612 P=0.04

0 500 1,000 1,500 2,000

0% 5% 10% 15% 20% 25%

0 1000 2000 3000 4000 5000

External Public Local Private

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