1. Infant clinical considerations

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

3. 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.

4. 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.

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

6. 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

7. 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

8. Infant length is listed in the protocol to be measured as part of each scheduled physical examination. Are there standardized procedures that should be followed when measuring length?
All sites should establish SOPs for infant anthropomorphic measurements (length, weight, and head circumference), so that consistent methods are used across infants and across visits for a given infant. Site SOPs are generally expected to follow WHO guidelines, which are available at:

9. 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

10. 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.
Updated Per
CM #2

11. 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

12. 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)

13. 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.
Updated Per
CM #2

14. 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

15. 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

16. Complete Infant Physical Exams Including Surface Exams: Procedures, Source Documents, Photos, and eCRFs

17. Purpose
To establish each infant’s physical condition at the Delivery Visit (as soon as possible after birth)
To complete a systematic and standardized assessment for congenital anomalies (i.e., birth defects, congenital defects, congenital malformation)

18. What is a congenital anomaly?
Abnormalities that are present at birth:
Structural  the way the body looks (inside or outside)
Functional  the way the body performs

19. Why do congenital anomalies occur?
About half of the time, the reason is unknown
Other reasons include
Genetics
Infections, like syphilis or rubella
Nutritional deficiencies, like iodine or folate
Exposures from alcohol, smoking, or chemicals
Medications (potentially efavirenz, cotrimoxazole, fluconazole, tetracycline, enalapril?)

20. Before Dolutegravir was rolled out the investigators completed a 2-year analysis from Tsepamo, which were presented earlier this year at CROI, showed that Efavirenz/TDF/FTC, which is the first-line WHO recommended regimen and the most common regimen used in pregnancy in high-burden countries, is safer than older ART regimens in pregnancy. Here you can see the prevalence of any adverse birth outcome in the light bars, and any severe adverse outcome in the dark bars, among HIV-uninfected and women on 5 different ART regimens from conception. The absolute differences between these outcomes was large, with 6-12% lower prevalence for any adverse outcome and 6-11% lower prevalence for any severe adverse outcome among women on TDF-FTC-EFV. All of these differences were significant in adjusted analysis..

21. Here are theirr main results
Here are theirr main results. The total % of adverse birth outcomes, seen here in the lighter bars was 34% in DTG compared with 35% in EFV. In the darker bars, you can see the % of total severe adverse outcomes was 11% for both regimens. In adjusted analysis the relative risk of both any adverse and any severe adverse birth outcome was 1
Total HIV negatives 29%, TDF/FTC at conception 36%
Severe HIV negatives 10% and TD/FTC/EFV 12%

22. Although this is very preliminary, because they had just a small number of first-trimester ART exposures, 116 DTG and 396 EFV, they only found 1 major congenital abnormality which was skeletal dysplasia in an EFV-exposed infant

23. Infant Exam at Delivery Visit
This slide highlights the physical examination performed for infants at the Delivery Visit

24. Added “Skin”
CM #2
Procedures
Per protocol Section 6.16, complete exams are required at the Delivery Visit
Newborn step-wise surface exam is a required part of the complete exam
This slide shows procedural text from protocol Section 6.16 related to these exams.
A “newborn step wise surface examination” is required at this visit, with the expectation that WHO standard procedures for performing these exams will be followed at all sites.

25. Now available on the IMPAACT 2010/VESTED Study Page

27. Procedures
All elements of the surface exam should be performed for purposes of assessing for congenital anomalies, with the exception of:
Intra-oral system
Cardiac system
Genitourinary system
These should be included in the general exam but will not be routinely assessed for presence of congenital anomalies

28. Procedures Face (including mouth) Neck
Head (including fontanels & circumference)
Face (including mouth)
Neck
Chest
Physical appearance, length, weight, & skin
Spine
Hips & Genitalia
Abdomen & Anus
Arms, legs, fingers, & toes

29. Procedures Face Neck Physical appearance, length, weight, & skin Chest
Head (including fontanels & circumference)
Face
Neck
Chest
Physical appearance, length, weight, & skin
Spine
Hips & Genitalia
Abdomen & Anus
Arms, legs, fingers, & toes

30. Procedures
If any potential congenital anomalies are identified on examination of any body system, these should be photographed by the examining clinician and a site pediatrician should ideally examine the infant as soon as possible

31. Who will take photographs at your site?
Procedures
Who will take photographs at your site?

32. All exam findings should be source documented
Documentation
All exam findings should be source documented
Speaker can say that the sample source document is intended for use at the delivery visit to capture all aspects of the Complete Physical Exam required per protocol, which includes the newborn surface exam as well as other exam components (auscultation of chest, neurologic assessment).

33. Entering into the database
Any suspected congenital anomaly in any body system should be entered into eCRFs
DXW10000, IMPAACT 2010 Congenital Anomalies
ADE10002, Adverse Events Log

34. Entering into the database
We can defer detailed discussion of AE reporting to Day 3, but state that, per protocol Section 7.2.2, all suspected congenital anomalies must be reported on Adverse Event eCRFs
If anyone brings up EAE reporting, can use that as an opportunity to look protocol Section

35. Entering into the database

36. Entering into the database
DXW10000: Congenital Anomalies
Provide a detailed narrative about the anomaly
Enter the date the anomaly was first identified
Indicate the number of photographs uploaded to the File Exchange Utility (on FSTRF portal)
Emphasize to include all available descriptive information in the narrative (no issues with number of characters allowed to be entered)

37. Entering into the database
Photos will be securely uploaded to the DMC to permit review and evaluation by the CMC (including an expert on birth defects)
Descriptive data and photos will be reviewed in near real time to determine whether the abnormality meets the protocol definition of “major congenital anomaly”

38. 1. During the surface exam, the site clinician identifies polydactyly
1. During the surface exam, the site clinician identifies polydactyly. This should be source documented.
True
False

39. 1. During the surface exam, the site clinician identifies polydactyly
1. During the surface exam, the site clinician identifies polydactyly. This should be entered into eCRFs.
True
False

40. 2. A suspected cardia congenital anomaly is identified by an attending clinician in the hospital where the infant was born. This should be source documented.
True
False

41. 2. A suspected cardiac congenital anomaly is identified by an attending clinician in the hospital where the infant was born. This should be entered into eCRFs.
True
False

42. 2. A suspected cardiac congenital anomaly is identified by an attending clinician in the hospital where the infant was born. This should be entered into eCRFs.
Yes No
Maybe

45. Privacy and Confidentiality
If any photographs are taken, standard precautions will be followed to protect participant privacy and confidentiality
Photographs that may be transmitted off-site will be identified by PID only
Protocol Section 12.7

46. Privacy and Confidentiality
How will your site maintain privacy and confidentiality of infants who are photographed?

47. Privacy and Confidentiality
Does your site IRB/EC mandate a separate form for obtaining informed consent for photographs?

48. Privacy and Confidentiality
“If we take photos of abnormalities seen when your baby is examined, we will not photograph your baby’s face unless the abnormality is on the face. In that case, we will make every effort to hide details that could identify your baby. Photos will be labeled only with a code number (not with your or your baby’s name). Photos will be kept securely with other information collected for the study. Photos also may be shared with other doctors working on the study. The other doctors may be here at [site name] or in other countries. These doctors will not be given your or your baby’s name, and they will be required to keep the photos private and confidential. When the study is completed, the photos will be destroyed.”
From sample ICF, Item 24 “There could be risks of disclosure of your and your baby’s information”

49. What are your questions about Infant Surface Exams?

50. 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

51. Infant Growth Monitoring
At all visits:
Current measurements should be charted and compared to measurements recorded at the last visit to assess for appropriate increases
Weight-for-length should be assessed in relation to WHO growth standards

52. DAIDS Grading Table Corrected Version 2.1
Updated Per
CM #2
DAIDS Grading Table Corrected Version 2.1

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

54. 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

55. Infant Evaluations
Adverse Events
Lab Tests
History
Exams

56. 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

57. Enter Adverse Event eCRF?
Some 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

58. Enter Adverse Event eCRF?
Some 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

59. 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 3 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

60. 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

61. 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

62. 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]
Week 50 Visit for all infants

63. Infant Event Driven Visit Scenario

64. 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

65. 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

66. 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
This is one of three events that would require follow-up if identified at the last study visit at postpartum Week 50 per protocol Section 6.10
Section 6.10

67. What are your questions?