TrialenrolmentofLatePresentersnumbersandchallengesfromPROMISEtrial

LyndaStranix-Chibanda,A.Coletti,KMcCarthy,P.Flynn,M.G.FowlerandthePROMISEstudyteam

PROMISEstudy• Randomizedcontrolledtrialbeganin2010• TodetermineoptimalantiretroviralstrategytopreventverticaltransmissionofHIVandmaintainmaternalandinfanthealth

• Acrossdiversecaresettings:– 1077HSwhereARTandformulafeedingstandard– 1077FF/BFwhereotherantiretroviralstrategieswerestandardplusformulafeeding(FF)orbreastfeeding(BF)

70sitesin15countries

StudyDesign• HealthyHIV-infectedwomen• Didnot meetlocalcriteriaforART• Randomlyassignedtodifferentantiretroviralstrategiestoassess:– preventionofverticaltransmissionduringpregnancyandpost-delivery

– infantsafety– maternalhealth

Antepartum Component cessation of breastfeeding

Completefollow-up in

AP Component

Completefollow-up in

PP Component

PostpartumComponent

Maternal Health Component

Antepartum Component

completefollow-up

Late Presenters

During Pregnancy During Breastfeeding After Weaning

Completefollow-up in

MH Component

Labor andDelivery

During PregnancyIMPAACT 1077BF Components

104weeks1550

3400

3650

KeyEligibilityforLPregistration

• HIV infection by rapid testing• No prior ARV exposure in current pregnancy• In labour or within 72 hours after delivery• Infant healthy and alive with birth weight at least 2 kg

(if delivered prior to registration)• Maternal CD4+ cell count not required prior to registration

(but exclude if known to be less than 350)• No other maternal lab values required prior to registration

RationaleforLPregistration

• Estimates were that up to 30% of women delivering in resource limited settings were Late Presenters

• Testing in labour is feasible• ARV prophylaxis reduces transmission even when

started in labour or postpartum• To complete screening procedures in good time for

Postpartum randomization

QuestionsforDiscussion• How many LPs (what proportion) are expected?• What procedures will be put in place to obtain informed

consent and register LPs before delivery? • How feasible will it be to complete the registration process

(using the Subject Enrollment System) before delivery?• What procedures will be put in place to ensure that study

drug kits with corresponding SIDs are available in the labour ward?

• What other operational issues or challenges might you foresee for LP registration?

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4

CumulativeAccrualofLatePresenters

(204in51monthsvs1550– 13%)

ChallengeswithEnrollment

• Primarily operational– Difficult to access Late Presenters– Entry procedures cumbersome– Highly vulnerable psychosocially

• Gained valuable experience (both the sites and protocol writing teams)

ØTop tips from PROMISE with input from P1115 study team and sites

Access• Participants identified in labour ward or postnatal ward

ØStudy staff work offsite• Deliveries 24/7

ØStudy staff work shiftsØProvide ‘talk time’ to labour ward staff

• Obstetric/neonatal complications in those with no ANC– Retained in postnatal ward longer than usual– Medical needs prioritized over studyØ Individualized tracking of timeframe for entry visit, and

follow-up visit (widen study windows)

EntryVisitTimelines30mins-1hour

•Sensitizationofpotentialparticipant•Reviewofmedicalrecordsforpotentialeligibilityà INFORMSTUDYCLINIC

3-5hours

•InformedConsentProcess

35mins•MaternalHIVtest(Sample#1)

40mins•MaternalandNeonatalhistoryandphysicalexamination

15mins•InitialNeonateblooddraw(viralloadandSOEtests)

15mins•ConfirmatoryHIVtestforneonate>1hourafterinitialblooddraw

30-45mins

•Pharmacy

12

Example

ALLDE

PTSONHIGHAL

ERT

EntryProcedures• Not particularly tricky for PROMISE :

– Informed consent for study entry (mother-infant pair)

– Subject Enrolment System (internet based)

– Counselling (infant feeding, HIV pre-test)

– Blood draws (HIV confirmation, baseline CD4 and safety)

– Study drug dispensing• Completed in postnatal ward or at study clinic

ØEngage obstetric team (all stakeholders), baby wagonØFacilitate rapid disclosure to dad/gogo vs very creative

home visit plan

EntryProcedures• Very tricky consenting session and enrolment, at times :

– Hadn’t fully accepted new HIV positive status– Low prior knowledge of HIV and PMTCT– Low literacy– No privacy in postnatal ward– Postpartum exhaustion– Early discharge homeØEngage obstetric team, promote PIHTC for partnersØ Internet connectivity offsite for SES

Vulnerability• Impoverished, underserved communities• Psychologically distraught• Non-disclosure of HIV status and trial participation• No social support• Unwell

– Doubt full comprehension of trial particulars– Doubt consent is truly informed– Doubt ability to comply with trial schedule– Risk of loss to follow-up

Vulnerability• Impoverished, underserved communities

ØReadily mapped for more efficient resource allocation• Psychologically distraught

Ø Intense supportive counselling, and again …ØScreen for depression, and again …ØRevisit IC discussion, and again … ØVisit reminders, and again …

• Non-disclosureØFacilitate the disclosure process (ask about Intimate

Partner Violence)

Vulnerability• No social support

ØSupport groups for study participantsØEngage community for referral structures (psychological

support and income generation)

• Unwell Ø Initiate ARTØMonitor more frequently (risk low adherence, poor infant

health outcomes)

ØFrequent infant HIV testing

Conclusion• A stakeholders/community engagement plan is

invaluableØ Know your population’s needs

• Site operations can be devised to account for difficulties associated with recruitment around the time of deliveryØ Plan aheadØ Look out for obstacles and ethical dilemmasØ Hire ‘on the ball’ recruiters

• Adequate resources must be allocated to recruiting team and to address vulnerability Ø Optimize accrual rateØ Improve retention

IMPAACTP1115VeryEarlyIntensiveTreatmentofHIV-InfectedInfantstoAchieveHIVRemission:APhaseI/IIProofofConcept

Study

Targetedenrollment:n=54infantswithinuteroHIVinfection• 440high-riskmother-infantpairstoidentify22infantswith

inuteroinfection(Cohort1)• 32inuteroinfectedearlyART-treatedinfants(Cohort2)

StudySteps:

1 2 3 4

High-riskinfants

AZT+3TC+NVPwithin48hoursofbirth

HIV-Infected

4-drugART(withLPV/r)

EligibleforARTcessation;monitoringforviralrebound(Age2-4years)

ARTre-initiationwithviralrebound

1 1 3 3 3 3 3 5 8 12 17 2130

4659

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5052 (US)31798 (UG)

4601 (US)5017 (US)5116 (TH)8950 (SA)

30300 (SA) 5113 (US)5115 (TH)

5072 (BR)5073 (BR)

8051 (SA)

Activated Sites

4001 (US)4201 (US)5011 (US)5013 (US)5031 (US)5040 (US)5051 (US)5055 (US)

5092 (US)6501 (US)

5083 (US)

3801 (US)

5030 (US)5048 (US)5071 (BR)5114 (US)

30022 (HAITI)31890 (ZIM)

5074 (BR)8052 (SA)

30293 (UG)

12001 (MW)30301 (MW)

5097 (BR)30303 (ZIM)30306 (ZIM)

30273 (ZAM)

Cohort 2 AccrualCohort 1 Accrual

5117 (BR)5118 (TZ)

5121 (KEN)

P1115 Site Activation and Accrual(similar # accrued in last 12mos vs 51mos)

WithkindpermissionoftheIMPAACTP1115studyteam