Impact of a Daily SMS Medication Reminder System on Tuberculosis Treatment Outcomes

13 Pages·2016·1.6 MB·English

RESEARCHARTICLE
Impact of a Daily SMS Medication Reminder
System on Tuberculosis Treatment
Outcomes: A Randomized Controlled Trial
ShamaMohammed1*,RachelGlennerster2,AamirJ.Khan1
1 InteractiveResearchandDevelopment,Karachi,Pakistan,2 AbdulLatifJameelPovertyActionLab,
MassachusettsInstituteofTechnology,Cambridge,MA,UnitedStatesofAmerica
*[email protected]
a11111
Abstract
Importance
Therapiduptakeofmobilephonesinlowandmiddle-incomecountriesoverthepast
decadehasprovidedpublichealthprogramsunprecedentedaccesstopatients.Whilepro-
OPENACCESS
gramshaveusedtextmessagestoimprovemedicationadherence,therehavebeenno
Citation:MohammedS,GlennersterR,KhanAJ
high-poweredtrialsevaluatingtheirimpactontuberculosistreatmentoutcomes.
(2016)ImpactofaDailySMSMedication
ReminderSystemonTuberculosisTreatment
Outcomes:ARandomizedControlledTrial.PLoS
Objective
ONE11(11):e0162944.doi:10.1371/journal.
pone.0162944 TomeasuretheimpactofZindagiSMS,atwo-waySMSremindersystem,ontreatment
Editor:LeiGao,ChineseAcademyofMedical successofpeoplewithdrug-sensitivetuberculosis.
SciencesandPekingUnionMedicalCollege,
CHINA
Design
Received:May9,2016
Weconductedatwo-arm,paralleldesign,effectivenessrandomizedcontrolledtrialinKara-
Accepted:August26,2016
chi,Pakistan.IndividualparticipantswererandomizedtoeitherZindagiSMSorthecontrol
Published:November1,2016 group.ZindagiSMSsentdailySMSreminderstoparticipantsandaskedthemtorespond
Copyright:©2016Mohammedetal.Thisisan throughSMSormissed(unbilled)callsaftertakingtheirmedication.Non-respondents
openaccessarticledistributedunderthetermsof weresentuptothreeremindersaday.
theCreativeCommonsAttributionLicense,which
permitsunrestricteduse,distribution,and
reproductioninanymedium,providedtheoriginal Setting
authorandsourcearecredited.
PublicandprivatesectortuberculosisclinicsinKarachi,Pakistan.
DataAvailabilityStatement:Datacanbeaccessed
athttps://dataverse.harvard.edu/dataset.xhtml?
Participants
persistentId=doi:10.7910/DVN/HVJ2CM.
Funding:Thisstudywasfundedbythe Newly-diagnosedpatientswithsmearorbacteriologicallypositivepulmonarytuberculosis
InternationalInitiativeforImpactEvaluation(http:// whowereontreatmentforlessthantwoweeks;15yearsofageorolder;reportedhaving
www.3ieimpact.org/),grantnumberOW1.48.The
accesstoamobilephone;andintendedtoliveinKarachithroughouttreatmentwereeligi-
fundershadnoroleinstudydesign,datacollection
bletoparticipate.Weenrolled2,207participants,with1,110randomizedtoZindagiSMS
andanalysis,decisiontopublish,orpreparationof
themanuscript. and1,097tothecontrolgroup.
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ImpactofaDailySMSMedicationReminderSystemonTuberculosisTreatmentOutcomes
CompetingInterests:Theauthorshavedeclared MainOutcome
thatnocompetinginterestsexist.
Theprimaryoutcomewasclinicallyrecordedtreatmentsuccessbaseduponintention-to-
treat.
Results
WefoundnosignificantdifferencebetweentheZindagiSMSorcontrolgroupsfortreatment
success(719or83%vs.903or83%,respectively,p=0(cid:1)782).Therewasnosignificantpro-
grameffectonself-reportedmedicationadherencereportedduringunannouncedvisitsdur-
ingtreatment.
Conclusion
Inthislarge-scalerandomizedcontrolledeffectivenesstrialofSMSmedicationreminders
fortuberculosistreatment,wefoundnosignificantimpact.
TrialRegistration
ThetrialwasregisteredwithClinicalTrials.gov,NCT01690754.
Introduction
Tuberculosisisthesecond-leadingcauseofdeathfrominfectiousdiseasesglobally,withnine
millionpeopleinfectedand1.5milliondeathsin2013[1].Treatment fordrug-sensitivetuber-
culosislastssixtoeightmonthsandcanresultindifficultsideeffects.Failuretoadheretotreat-
mentcanresultincontinuedtransmission,thedevelopmentofmultidrug-resistant
tuberculosis,ordeath.TheWorld HealthOrganizationrecommendsdirectlyobservedtherapy
topromoteadherence,whereapre-assignedtreatmentsupporterwatcheseachpatienttake
his/herdailymedication.However,evidencefortheeffectivenessofthismethodisinconclusive
[2].
Therapiduptakeofmobilephonesinlow-andmiddle-incomecountrieshasprovidedpub-
lic-healthprogramsunprecedentedaccesstopatients.Mobilephone-basedinterventionsto
improvemedicationadherencehavebeenadoptedformanydiseases,withmixedresults[3–6].
Mosttrialsareinadequatelydesigned,insufficientlypowered,orarerestrictedtohigh-income
countries[3–6].Themostrigoroustrialsevaluatingmobilephone-usefortreatmentcompli-
anceindevelopingcountriesexistforadherencetoantiretroviraltherapy(ART)forpeopleliv-
ingwithHumanImmunodeficiencyVirus(HIV).Meta-analysisthatcombinestwopositive
trialsinKenya[7,8]andonenullresultfromCameroon[9]foundanoverallpositiveimpactof
weeklyShortMessageService(SMS,ortextmessage)reminders[10–12].Amorerecentstudy
ofinteractiveautomatedvoiceremindersandpictorialmessagesinIndia,foundnoimpacton
adherencetoART[13].
Whilethereisconsiderableinterestinthepotentialofmobilephone-basedinterventionsto
improvetuberculosistreatmentadherence,rigorousevidenceontheirimpactislimited[14–
17].Recently,alimitedclusterrandomizedtrialinChinafoundthat,whilemedicationmonitor
remindersledtoimproveddrugcompliancefortuberculosispatients,dailytwo-waySMS
remindersdidnot[18].Oureffectivenesstrialgaugedtheimpactofatwo-wayinteractiveSMS
medicationremindersystem(ZindagiSMS)onthetreatmentsuccessofpeoplewithdrug-sen-
sitivetuberculosis.
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ImpactofaDailySMSMedicationReminderSystemonTuberculosisTreatmentOutcomes
Methods
StudyDesignandParticipants
Participantswererecruitedintotherandomizedcontrolledtrialthroughalargetertiarycenter
(theIndusHospital),ninepublicfacilities,andanetworkofprivateGeneralPractitioner(GP)
clinicsandprivatelaboratoriesinKarachi.
To beeligible,participantshadtobenewlydiagnosedwithsmearorbacteriologicallyposi-
tivepulmonarytuberculosis;15yearsofageorolder;reporthavingaccesstoamobilephone;
andintendtoliveinKarachithroughouttreatment.To allowZindagiSMStohelpestablish
habitsearly,participantshadtobeontreatmentforlessthantwoweeks.To minimizespill-
overs,patientswithanotherhouseholdmemberinthestudywereineligible.Enrolmentcontin-
ueduntilthepredeterminedsamplesizewasmet.
Eligibleparticipantswereconsentedusinganoralconsentform,acopyofwhichwasgiven
totheparticipant.Oralconsentwassolicitedinsteadofwrittenconsent,asoursamplewasa
low-literatepopulation.Thetrialandoralconsentprocedurewasapprovedbytheresearcheth-
icsboardsatInteractiveResearchandDevelopment(IRD)inKarachi,PakistanandtheMassa-
chusettsInstituteofTechnology(MIT)inCambridge,USA.Thetrialwasregisteredwith
ClinicalTrials.gov,NCT01690754.
RandomizationandMasking
Onceapatientconsentedtoparticipate,astudyrepresentativeenteredidentifyinginformation
onamobilephone-basedenrolmentform.Individualparticipantswererandomizedtoeither
theZindagiSMSorcontrolgroups,usingpredeterminedlistonthestudyserverthatwasgen-
eratedusingsimplerandomization.Theresearchteamwasblindedtotheallocationsequence
generated.Ifmobiledataconnectivitywasinterrupted(10%ofenrolments),thestudyrepre-
sentativecalledtheirsupervisor,whoenteredtheidentifyinginformationintoMicrosoftExcel
andgeneratedthegroupassignmentusingtherandomizationfunction.Inbothcasesfieldstaff
whointeracteddirectlywithpatientshadnoabilitytoinfluencetherandomizedallocation.
Therandomizationstatusofindividualparticipantswasnotsharedwithtreatingclinicsbythe
researchteam.
Procedures
Allstudyparticipantsreceivedthestandardofcareprovidedbytheirclinic.Initially,partici-
pantsreceivedNTP’s recommendedeight-monthtreatmentregimen.However,NTPguide-
lineschangedinthesecondquarterof2012toasix-monthregimen.
ZindagiSMSusedtwo-wayreminderstoencouragepatientstoactivelyengagewithremind-
ers,ratherthanpassivelyreadandpotentiallyignorethem.Itenabledthestudyteamtoidentify
non-responsivepatientsforphonecallstoencourageparticipation.ZindagiSMSsentenrolled
patientsdailyremindersatatimeoftheirchoosing.MessageswereinUrduusingEnglish
scriptandincludedadailymotivationalmessagefollowedbyaremindertorespondviaSMS
or,afterSeptember2011,amissed(unbilled)calltoindicatetheyhadtakentheirmedication.
Fourteenmessageswererandomizedandsenttoparticipants.Basedonfeedbackfromour
pilot,tuberculosiswasnotmentionedinthemessagesduetostigma[19].Forexample,one
messagesaid,“Your healthisinyourhands.Take yourmedicationandremembertorespondby
SMSoramissedcall.”SMSresponseswerenotverifiedforcontent.Participantswereoffered
PKR60(USD0.60)permonthtocoverthecostsofresponding.Initially,theparticipantswere
askedtopickupreimbursementsattheirclinic,butfromOctober2013,reimbursementswere
transferreddirectlytoparticipants’phones.
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ImpactofaDailySMSMedicationReminderSystemonTuberculosisTreatmentOutcomes
OnceZindagiSMSreceivedaresponseoramissedcall,aconfirmatorySMSmessagewas
senttotherespondent.Ifthepatientdidnotrespondwithintwohours,asecondreminderwas
sent.Athirdandfinalreminderforthedaywassentaftertwoadditionalhoursofnon-respon-
siveness.Membersofourstudyteamphonedparticipantswhodidnotrespondforsevendays.
Participantswereinterviewedattheirhouseholdforamoreextensivebaseline.Ninetyper-
centofcompletedbaselinesurveyswereconductedwithin30daysofenrolment.Oncea
month,studyenumeratorsattemptedsurprisevisitstoparticipants’householdstoconducta
midlinesurvey.Sputumsamples,independentfromthosecollectedbythetreatingclinics,were
collectedforpatientsatvariouspointsintheirtreatment.Giventhedifficultiesinfindingpar-
ticipantsathomeandthattheycouldnotalwaysproducesputum,thereisconsiderablevaria-
tioninthesputumsamplesavailableperpatient.Anendlinesurveywasconductedafterthe
completionofparticipants’treatmentperiod.Participantswhowerereportedashaving
defaultedortransferredoutfromtreatmentweresurveyedagainbetweenSeptemberand
November2014torecordwhethertheycontinuedtheirtreatment.
Theenrolmentformwasenteredonmobilephones,withpaperformsasbackup.Othersur-
veyswerecollectedonpaperanddouble-enteredintoaMicrosoftAccessdatabase.
Outcomes
Theprimaryoutcomewasprogrammaticallydefinedtreatmentsuccessasrecordedinclinic
registersprovidedbytheNTP, theglobalstandardforassessingtuberculosisprograms.Treat-
mentsuccessisdefinedasthesumofpatientsclinicallyreportedascured(i.e.patientwhose
sputumsmearorculturewaspositiveatthebeginningoftreatmentbutwhowassmear-orcul-
ture-negativeinthelastmonthoftreatmentandonatleastonepreviousoccasion)ortreat-
mentcompleted(i.e.apatientwhocompletedtreatmentbutwhodoesnothaveanegative
sputumsmearorcultureresultinthelastmonthortreatmentandonatleastoneprevious
occasion).Inoursecondaryanalysis,weexploredthefullrangeofclinicallyrecordedtreatment
outcomes(cured,treatmentcompleted,default,died,treatmentfailureandtransferredout).In
particular,ZindagiSMSmighthaveincreasedsuccessbyreducingdefault(i.e.apatientwhose
treatmentwasinterruptedfortwoconsecutivemonthsormore).Thelimitationofthisout-
comeisthatbecauseregistersofNTP-reportingclinicsinPakistanarenotlinked,patientswho
arereportedashavingdefaultortransferredoutcouldhavecontinuedtreatmentelsewhere.As
arobustnesscheckwethereforeexploredadjustedtreatmentoutcomesfortreatmentsuccess
anddefault,substitutingself-reportedforclinicallyrecordedoutcomesfortheparticipants
interviewed.
To explorepotentialmechanismsofimpact(orlackofimpact),wealsogaugedadherence
asasecondaryoutcomebyaskingparticipantswhethertheyhadtakentheirmedicationinthe
last24hoursduringhomevisits.Whileself-reportedadherencecanbeunreliable,thereisno
reasontobelievemisreportingissystematicallydifferentamongthoseassignedtoZindagiSMS
orthecontrolgroup.DuringsurveyvisitsbetweenFebruaryandApril2012,weconductedIso-
Screentests,whichdetectisoniazidmetabolitesinurinesamplestogaugewhethertuberculosis
drugsweretakenwithinthepast24hours.Isoniazidisalwaysincludedinfirst-linetuberculosis
treatment.We comparedIsoScreenresultswithself-reportedadherenceonthesamevisit.
WhileIsoScreentestswereconductedonanon-randomsample,theygiveusanindicationof
thereliabilityofself-reportedadherence.
Finally,wecollectedself-reportedpsychologicalandphysicalhealthmeasuresassecondary
outcomes.We usedafour-pointLikertscaleforpatients’difficultyincompletingarangeof
physicaltasksandhowsupportedtheyfeltduringtreatment,apictureofafive-rungladder
withsixcompartmentsbetweenrungsforlikelihoodofbeingcured,andimagesoffivefaces
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ImpactofaDailySMSMedicationReminderSystemonTuberculosisTreatmentOutcomes
forhowhealthytheyfelt.Questionsonparticipants’abilitytocompletetasksandself-reported
healthwereaskedatbaseline,midline,andendline;thelikelihoodofbeingcuredaskedatbase-
lineandmidline;andhowsupportedparticipantsfeltaskedatendline.
StatisticalAnalysis
We calculatedaminimumsamplesizeof1,094participantsineachstudyarm,usingpowerof
80%,minimumdetectableeffectsize(MDE)offivepercentagepoints,andtreatmentsuccess
rateinthecontrolgroupof75%.AnMDEof5percentagepointswaschosenbecauseasmaller
impactwasconsideredunlikelytomotivatepolicychange.Datawereanalyzedusingintention-
to-treat,i.e.allocationtotreatmentnotactualtakeup.We usedtheχ2testfordifferencesin
proportionsfortheanalysisoftheprimaryoutcome.Incomparingsputumsamples,weran
ordinaryleastsquaresregressions,aftercontrollingfordaysinthestudyandregimentype.
We alsoassessedwhetherZindagiSMShaddifferentialimpactsontreatmentsuccessby
gender,indicatorsofqualityofcare,andmobilephoneaccess.Inanalyzingoursecondaryout-
comes,weranordinaryleastsquaresregressionsoneachoutcometotestforprogrameffects,
aftercontrollingfordayssinceenrollmentandregimentype.To adjustformultiplehypotheses
testingweusedtheBonferronicorrectionandthelessconservativeWestfallandYoung free
step-downresamplingmethod[20].
StatisticalanalysiswasconductingusingSTATA/IC version12.0.Ap-valueof<0.05was
consideredstatisticallysignificant.
Results
We enrolled2,207participantsintothestudybetweenMarch18,2011andFebruary25,2014
(Fig1).Bothgroupshadsimilarbaselinecharacteristics(Table 1).
Asaneffectivenesstrialwesoughttoreplicateimplementationconditions,asitwouldexist
atscale.TheZindagiSMSsystemsentremindersorreceivedresponsesfor174,284patientdays
toparticipantsduringtheirestimatedtreatmentduration(180daysforthesix-monthregimen
or240daysfortheeight-monthregimen).Withperfectimplementation,remindersshould
havebeensentforatotalof220,560patientdays,suggestingthesystemwassuccessfullyimple-
mentedfor79%ofpatientdays.Missedreminderswereduetosystemfailures,administrative
shortfalls,orGPRSoutagesinthecitymobile(14%);participantsaskingtoleavethesystemor
dying(3%);participantsoptingoutofreceivingremindersatenrolment(2%);andparticipants
notknowingtheirphonenumberatenrolmentandfailingtosharetheirnumbersubsequently
(2%).Ofthe1,069participantswhoweresentmessages,912(85%)respondedatleastonce.Of
theparticipantsthatwereonthesystemthroughouttheirtreatment,themeanresponserate
(calculatedasthenumberofresponsesreceivedoverthenumberofreminderssentperpatient)
was29%,rangingfrom0to99%.Overthecourseoftreatment,averageresponseratesfellfrom
48%inthefirsttwoweeksto24%(eight-monthregimen)and20%(six-monthregimen)inthe
lasttwoweeks(SeeFig2).
Therewerenosignificantdifferencesintreatmentoutcomesbetweenparticipantsinthe
ZindagiSMSgroupandthecontrolgroup(Table 2).Asarobustnesscheck,wesubstitutedthe
clinicallyrecordedoutcomeswithself-reportedoutcomesforparticipantswhodefaultedor
transferredoutoftreatmentthatwewereabletointerview,orwhosefamilymembersreported
theparticipanthaddied.Ofthe283participantsthatwerereportedashavingdefaultedor
transferredout,weinterviewed130(46%);49participants(17%)haddied;22(8%)refusedto
beinterviewed;andwewereunabletolocate82(29%).Self-reportedoutcomeswerecatego-
rizedusingthecriteriainFig3.Whenweadjustedtreatmentoutcomestoreflecttheself-
reportedoutcomes,thedefaultratereducedinbothgroupsbuttherewerestillnosignificant
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Fig1.TrialProfile.
doi:10.1371/journal.pone.0162944.g001
differencesinoutcomesbetweenthetwogroups(Table 2).We alsoexaminedindependent
sputumsamplesbetweenthegroups.We collected1191sputumsamplesforparticipants(603
intheZindagiSMSgroupand588inthecontrolgroup).Ofthese,onehundredandninety
sampleswereexcludedbecausetheywereprimarilysaliva,ratherthansputum(104intheZin-
dagiSMSgroupand86inthecontrolgroup).Therewasnostatisticallysignificantdifference
betweensputumresultsforbothgroups(p=0.762).
Therewasnosignificantprogrameffectinsubgroupsforgender,anyoftheindicatorsrelat-
ingtoqualityofcare,oraccesstoamobilephoneafteradjustingformultiplesubgroupsusing
theBonferronicorrection(adjustedp-valueof0.003for17subgroups)ortheWestfalland
Young freestep-downresamplingcorrection(Table 3).We alsocreatedasingleindexof
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ImpactofaDailySMSMedicationReminderSystemonTuberculosisTreatmentOutcomes
Table1. Demographiccharacteristicsofparticipantsenrolledinthetrial(2011–2014,Karachi,Paki-
stan).*
SMSGroup(n=1110) ControlGroup(n=1097)
n(%) n(%)
Female 561(51%) 518(47%)
Age(mean/SD)† 33(16) 33(16)
Urduismothertongue 529(48%) 549(50%)
Clinictype
IndusHospital 404(36%) 385(35%)
GPclinic/private‡laboratory 190(17%) 193(18%)
Publictuberculosisclinic 516(46%) 519(47%)
6Monthtreatmentregimen 764(69%) 777(71%)
Assignedatreatmentsupporter 102(10%) 106(10%)
Ownmobilephone 540(49%) 565(52%)
Schooling
Noschool 517(49%) 475(47%)
Primary(class1–5) 108(10%) 115(11%)
Secondary(class6–10) 325(31%) 307(30%)
Tertiary(aboveclass10) 77(7%) 101(10%)
Religiousschool 15(1%) 16(2%)
*Thereare138missingvaluesforassignedatreatmentsupporter,145missingvaluesforage;146missing
valuesfornoschoolandreligiousschool;and151missingvaluesforprimary,secondary,andtertiary.
†SD=standarddeviation
‡GP=privategeneralpractitioner
doi:10.1371/journal.pone.0162944.t001
qualityofcarefromrelevantvariablesandanotherformobilephoneaccesstotestforsubgroup
effectbutagainfoundnosignificanttreatmenteffectsforsubgroups.(S1Appendix)
We comparedtheresultsof159IsoScreentestswithself-reportedadherenceduringthe
samestudyvisit.IsoScreentestsindicatedthat17%ofthosewhosaidtheyhadtakentheir
drugsinthepast24hourshadnot,indicatingover-reporting.However,theseresultswerenot
statisticallydifferentbytreatmentarm.
Therewerenosignificantprogrameffectsinself-reportedmedicationadherenceoranyof
ourothersecondaryoutcomes,afteradjustingformultiplehypothesesusingtheBonferroni
correction(p-valueof0.001forfivehypotheses)ortheWestfallandYoung correction
(Table 4).
Discussion
We foundnosignificantimpactofSMSmedicationremindersontreatmentsuccess,other
treatmentoutcomes,self-reportedadherence,orself-reportedphysicalandpsychological
health.Therewerenostatisticallysignificantimpactsofremindersontreatmentsuccesswithin
avarietyofsubgroupsafteradjustingformultiplehypothesistesting.
Withanattritionrateoflessthan1%,similaracrossarms,onourprimaryoutcomevariable,
theresultsareveryrobust.Theinclusionofparticipantsfrompublicclinics,privateGPclinics,
laboratories,andalargephilanthropichospitalcontributestoitsexternalvalidity.
Alimitationofourtrialwasthelackofanobjectiveadherencemeasure.Adherencewas
self-reported,which,IsoScreentestsindicated,isanoverestimateofactualadherence.How-
ever,evenifparticipationinZindagiSMSgeneratedincreasedadherence,notreflectedinself-
reports,itdidnottranslateintoimprovedtreatmentoutcomes.Inaddition,IsoScreentests(on
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Fig2.Responseratesovertimeintreatment.
doi:10.1371/journal.pone.0162944.g002
anonrandomsample)indicatedthatmisreportingwassimilarintheZindagiSMSandcontrol
groups.
Anotherpotentiallimitationisthatclinicscouldincorrectlyrecordtreatmentoutcomesto
meetexpectedsuccessratesencouragedbytheNTP. However,sinceclinicswereblindtoallo-
cation,thereisnoreasonanymisreportingwassystematicallydifferentbetweentreatment
arms.Moreover,inoursub-studyonparticipantsreportedashavingdefaultedortransferred
out,self-reportedoutcomesweresimilarintheinterventionandcontrolgroups.Another
Table2. Clinically-recordedtreatmentsuccessbetweenZindagiSMSandcontrolgroups(2011–2014,Karachi,Pakistan).
Clinicallyrecordedtreatmentsuccess Clinicallyrecordedtreatmentsuccessadjustedforself-
reportedoutcomes
ZindagiSMS ControlGroup ZindagiSMS ControlGroup
n % N % p-value n % n % p-value
Treatmentsuccess 917 83% 903 83% 0.782 923 84% 911 83% 0.871
Treatmentcomplete 332 30% 325 30% 0.863 339 31% 333 30% 0.903
Cured 585 53% 578 53% 0.960 584 53% 578 53% 0.994
Default 108 10% 103 9% 0.775 74 7% 80 7% 0.572
Died 19 2% 19 2% 0.975 38 3% 29 3% 0.282
TreatmentFailure 27 2% 29 3% 0.758 26 2% 29 3% 0.655
TransferOut 33 3% 39 4% 0.446 43 4% 44 4% 0.875
Total 1104 1093 1104 1093
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Fig3.Criteriafordeterminingself-reportedoutcomes.
doi:10.1371/journal.pone.0162944.g003
potentiallimitationisthatourtrialtookplaceinPakistan,whichreportshightreatmentsuc-
cessratesof91%in2012[1].Resultsmaydifferincountriesreportinglowersuccessrates.
OurresultsweresimilartothefindingsofLiuandcolleaguesinChinathattwo-waySMS
remindershadnoimpactonmedicationadherencefortuberculosispatients,thoughweare
abletoruleoutmuchsmallereffectsofSMSreminders[15].Meta-analysisofstudiesonHIV
andSMSremindersshowpositiveresultsonofweeklySMSremindersonadherenceandclini-
caloutcomes(Finitsisetal2014[10],Mbuagbawetal2013[11],Horvathetal2012)[12].
Thesereviewsdrawmainlyonthreelargehighqualitystudies(Finitsisetalalsoincludemany
smallpoorqualitystudiesandHorvathetalonlyincludesLesterandcolleagues’[7]andPop-
Elechesandcolleagues’[8]trials)andconcludeweeklyremindersaremoreeffectivethandaily
reminders.ThethreekeystudiesareMbuagbawandcolleagues,whotestweeklySMSremind-
ersinCameroonandfindnoimpact[9]Pop-Elechesandcolleagueswhotestedmultiplever-
sionsofSMSremindersandonlyfoundonlyshortmessagessentweeklyimproveadherence
[8],andLesterandcolleaguesfindapositiveimpactofweeklyremindersinKenya[7].Impor-
tantly,inLesterandcolleagues,participantsalsoreceivedoff-siteclinicianfollow-upifthey
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Table3. Sub-groupanalysisusingtreatmentsuccessastheoutcome(2011–2014,Karachi,Pakistan).
ZindagiSMS Control ZindagiSMS naive FWER‡-adjusted
Group Group
Sub-group N % n % coefficient p-value* p-value
Sex
Male 438 80% 468 81% -0.012 0.618 0.999
Female 479 86% 435 84% 0.019 0.394 0.974
Qualityofcare
IndusHospital 317 79% 301 78% 0.005 0.872 1
GPClinic/PrivateLab 180 95% 167 87% 0.082 0.006† 0.069
PublicTBClinic 420 82% 435 84% -0.023 0.331 0.954
Assignedatreatmentsupporter 89 87% 84 79% 0.080 0.124 0.698
Notassignedatreatmentsupporter 793 84% 768 84% -0.004 0.815 1
Remindedtotakemedication(withonemonthafterenrolment) 355 82% 324 83% -0.011 0.689 1
Notremindedtotakemedication(withinonemonthafterenrolment) 436 87% 446 84% 0.022 0.318 0.953
Accesstoamobilephone
Ownmobilephone 450 84% 474 84% -0.005 0.806 1
Don’townmobilephone 467 82% 429 81% 0.016 0.502 0.994
Noschooling 416 81% 381 80% 0.004 0.875 1
Anyschooling 461 88% 469 87% 0.006 0.758 1
Atleastoneliteratepersoninthehousehold 753 85% 744 84% 0.008 0.629 0.999
Noliteratepeopleinthehousehold 129 80% 108 81% -0.016 0.736 1
CansendSMS(withinmonthofenrolment) 263 88% 232 87% 0.014 0.624 0.999
CannotsendSMS(withinfirstmonthofenrolment) 528 83% 538 82% 0.001 0.958 1
*Bonferronicorrectionp-value(with17subgroups):0.003
†p<0.05
‡Family-wiseerrorrate20
doi:10.1371/journal.pone.0162944.t003
reportedaproblemordidnotrespondtotheSMS[7,21].NotincludedinthereviewsisShet
andcolleagueswhotestweeklyautomatedtelephoneremindersinIndiaandfindnosignificant
effect[13].
Table4. SecondaryoutcomesbetweentheZindagiSMSandcontrolgroups(2011–2014,KarachiPakistan).
Tookmedication Perceptionsonlikelihoodof Howhealthytheyfelt† Easeofcompleting Howmuchsupportwas
inthelast24 beingcured†(6=verylikely, (5=veryhealthy, tasks†(4=nodifficulty, received†(4=lotof
hours† 1=notlikely) 1=veryunhealthy) 1=lotofdifficulty) support,1=nosupport)
Zindagi 0.002 -0.008 -0.012 -0.017 0.020
Naïvep- 0.772 0.473 0.423 0.036‡ 0.521
value*
FWER§ 0.89 0.89 0.89 0.162 0.89
adjustedp-
value
N(surveys) 11,301 9,560 11,324 11,235 1658
N(patients) 2091 2068 2091 2088 1658
*Bonferronicorrectionp-value(with5hypotheses):0.001
†Controllingforthelengthoftheregimen,daysinthestudy,anddaysinthestudy-squared.
‡p<0.05
§Family-wiseerrorrate[20]
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