Infant clinical considerations IMPAACT 2010 study-specific Training May 2017

Overview Medical, Medication, and Feeding Histories Physical Examinations Laboratory Evaluations Source Documentation and eCRF Requirements

Overall Approach to Infant Management Infants enrolled in this study should receive ARV prophylaxis and other standard interventions such as cotrimoxazole, isoniazid preventive therapy, and childhood immunizations consistent with local standards of care from non-study sources. Likewise, infants diagnosed with HIV infection should receive ART consistent with local standards of care from non-study sources.

Overall Approach to Infant Management In the event that mothers need to interrupt ART (e.g., due to an adverse event), information and counseling will be provided regarding locally- available options for reducing the risk of perinatal HIV transmission. Such options may include infant ARV prophylaxis during breastfeeding and replacement feeding if determined to be safe and accessible and if the mother’s ART interruption is likely to be prolonged.

Infant Medical and Medication History Required at each scheduled visit Baseline history at Delivery Visit Interval (since the last visit) histories at subsequent visits

Infant Medical and Medication History Birth details should ideally be obtained from medical records Thereafter, history information may be obtained based on maternal report but available medical records should also be obtained when possible to supplement maternal report

Infant Baseline History Assess for and Source Document Enter into eCRFs Date and time of birth Yes Sex, estimated gestational age, length, weight, and head circumference at birth Apgar scores at 1 and 5 minutes On my computer, the whiter font on the green background is very hard to read – maybe could use a slightly darker green?

Infant Baseline History Assess for and Source Document Enter into eCRFs Congenital anomalies and other medical conditions (signs, symptoms, illnesses, other diagnoses) identified between birth and the Delivery Visit Any conditions (adverse events) that meet criteria in protocol Section 7.2 including all suspected congenital anomalies

Infant Baseline History Assess for and Source Document Enter into eCRFs Medications taken between birth and the Delivery Visit All ARVs Any use of: Cotrimoxazole Isoniazid prophylaxis Medications to treat active TB All medications taken at onset of or in response to adverse events that are specified to be entered into eCRFs per Section 7.2 Note: eCRFs will also capture whether traditional medications were taken during follow-up.

Infant Interval History Assess for and Source Document Enter into eCRFs Current status of conditions that were ongoing at the previous visit Any updates of previous entries (e.g., resolution dates) Occurrence of any new conditions (signs, symptoms, illnesses, and other diagnoses) since the last visit Any newly identified adverse events that meet criteria in protocol Section 7.2

Infant Interval History Assess for and Source Document Enter into eCRFs Current status of medications that were ongoing at the last visit Any updates of previous entries (e.g., stop dates)

Infant Interval History Assess for and Source Document Enter into eCRFs Use of any new medications since the last visit All ARVs Any use of: Cotrimoxazole Isoniazid prophylaxis Medications to treat active TB All medications taken at onset of or in response to adverse events that are specified to be entered into eCRFs per Section 7.2 Note: eCRFs will also capture whether traditional medications were taken during follow-up.

Infant Feeding History Required at each scheduled visit At Delivery Visit: feeding history since birth At subsequent scheduled visits: interval (since the last visit) feeding history

Infant Feeding History At this visit, was the infant's feeding method assessed? Since the last visit, has there been a change in the infant's feeding method?

QLW10010: Infant Feeding Method QLW10011: Breastfeeding, Formula, & QLW10010: Infant Feeding Method QLW10011: Breastfeeding, Formula, & Complementary Food Record Has infant been breastfed? Breastfed by mother or someone else? Date and time of first breastfeeding Date of last exposure to breast milk Has infant been formula fed? Date of first formula feeding Has infant received complementary foods? Date of first complementary food

Complete Infant Physical Exam Covered on Day 2 of training as part of Delivery Visit session

Targeted Infant Physical Exam Length Weight Head circumference Fontanel closure Examination of body systems driven by prior and new signs, symptoms, and diagnoses At all visits, additional assessments may be performed at the discretion of the examining clinician

Infant Growth Monitoring Study clinicians are responsible for monitoring infant growth throughout follow-up At all visits, current measurements should be charted and compared to measurements recorded at the last visit to assess for appropriate increases At all visits, weight-for-length should be assessed in relation to WHO growth standards

DAIDS Grading Table Version 2.1 should be weight-for-length z score

Infant Laboratory Evaluations Complete blood count, ALT, creatinine Delivery Visit for all infants Week 26 Visit if currently breastfeeding Additionally if clinically indicated

Recording Test Results on Laboratory eCRFs All creatinine results All Grade 2 or higher ALT results All grade 3 or higher hemoglobin, WBC, ANC, and platelet count results All results that are serious as defined in the DAIDS EAE Manual *Regardless of whether test was protocol-specified or ordered for clinical purposes

Infant Evaluations Adverse Events Exams History Lab Tests I like this slide!

Recording on Adverse Event eCRFs All Grade 3 or higher adverse events All suspected congenital anomalies All SAEs as defined in the DAIDS EAE Manual

Enter Adverse Event eCRF? A few examples Event Enter Value in Lab eCRF? Enter Adverse Event eCRF? Grade 1 creatinine Yes No Grade 2 creatinine Grade 3 creatinine Yes* Grade 4 creatinine

Enter Adverse Event eCRF? A few examples Event Enter Value in Lab eCRF? Enter Adverse Event eCRF? Grade 1 creatinine Yes No Grade 2 creatinine Grade 3 creatinine Yes* Grade 4 creatinine *AE term = increased creatinine

Enter Adverse Event eCRF? A few examples Event Enter Value in Lab eCRF? Enter Adverse Event eCRF? Grade 1 hemoglobin No Grade 2 hemoglobin Grade 3 hemoglobin Yes Yes* Grade 4 hemoglobin

Enter Adverse Event eCRF? A few examples Event Enter Value in Lab eCRF? Enter Adverse Event eCRF? Grade 1 hemoglobin No Grade 2 hemoglobin Grade 3 hemoglobin Yes Yes* Grade 4 hemoglobin *AE term = decreased hemoglobin or anemia if symptomatic

Adverse Event Management All adverse events must be source documented in participant research records, including the severity of each event and its relationship to study drug (infant exposure in utero or through breastfeeding) All adverse events must be followed to resolution (return to baseline) or stabilization, with the frequency of repeat evaluations determined by the clinical significance of each event Grade 3 or higher laboratory tests should be repeated as soon as possible (within three business days) and all grade 3 or higher adverse events should be re-evaluated at least weekly until improvement to grade 2 or lower Protocol Section 8.1

Adverse Event Management Infant adverse events will be managed consistent with the best medical judgment of the site investigator and local clinical practice standards It is not expected that maternal study drug regimens will routinely be modified in response to infant adverse events; site investigators may modify use of infant ARVs and other concomitant medications in response to infant adverse events Protocol Section 8.1

Adverse Event Management Consultation with the CMC is available but not required for most infant adverse events Should an infant experience a grade 3 or higher adverse event assessed as related the mother’s current study drug regimen, the CMC should be consulted Protocol Section 8.1

Infant Laboratory Evaluations HIV Nucleic Acid Test (NAT) Delivery, Week 6, and Week 14 Visits for all infants Week 26 and Week 38 Visits if any exposure to breast milk since the last NAT (“if BF”) Week 50 Visit for all infants

Infant HIV Infection Any infant with a positive HIV NAT result should be recalled for confirmatory testing as soon as possible and within 28 days of specimen collection for the initial test 3 mL of blood should be collected for the testing and residual plasma should be stored If the second test does not confirm the initial result, the CMC should be consulted for guidance on next steps to clarify the infant’s HIV status Pending confirmatory testing, infant prophylaxis should be managed consistent with local standards of care Section 6.8

Infant HIV Infection All infants identified with HIV infection will remain in study follow-up but will be referred to non-study sources of HIV care and treatment as soon as possible Study visits will be conducted as originally scheduled with the exception that no further HIV tests will be performed and stored plasma will be used for antiretroviral resistance testing Study sites may perform additional laboratory testing as needed to facilitate rapid initiation of ART for infected infants Section 6.8 Should we add something about the required post-study contact if the infant’s HIV NAT comes back positive at the Week 50 visit? I was thinking about adding something for the maternal virologic failure in the postpartum scenarios time and could add something about subsequent pregnancies into that section as well?

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