1. Maternal clinical considerations1
Maternal clinical considerations
IMPAACT 2010 study-specific Training
May 2017

2. Overview 2 Medical and Medication Histories
Standardized Questionnaires (role play)
Physical Examinations
Laboratory Evaluations
Source Documentation and eCRF Requirements

3. Maternal Medical and Medication History
Required at each scheduled visit
Baseline history at Screening and Entry
Establishes condition at study entry for comparison with condition during follow-up
Interval (since the last visit) histories at subsequent visits

4. Maternal Medical and Medication History
All history information may be obtained based on maternal self-report but available medical records should be obtained when possible to supplement self-reported information

5. Maternal Baseline History
Assess for and
Source Document
Enter into eCRFs
Date of birth and socio-demographics
Yes
HIV diagnosis, WHO clinical staging, and treatment history (including all ARV use prior to enrollment)
Section 6.11, Table 3
DOB in eligibility checklist
HIV diagnosis on medical history eCRF
ARVs on con meds eCRF

6. Maternal Baseline History
Assess for and
Source Document
Enter into eCRFs
Reproductive & obstetrical history
Dates and outcomes of all prior pregnancies
Date of LMP prior to the current pregnancy
Complications in the current pregnancy as listed in the Perinatal/Pregnancy section of Diagnosis Appendix 100
Other targeted conditions potentially associated with adverse pregnancy outcomes in the current pregnancy
Yes
Study specific forms for these - obstetrical history and targeted pregnancy diagnoses

7. Complete at Entry Visit to record all conditions diagnosed in the
index pregnancy before Entry

8. Maternal Baseline History
Assess for and
Source Document
Enter into eCRFs
History of allergy and hypersensitivity (including to ARVs)
Yes
History of bone fracture
(traumatic and non-traumatic
History of depression and/or suicidality
History of tobacco smoking and alcohol use
Medical history eCRF and study-specific smoking and alcohol eCRF

9. Maternal Baseline History
Assess for and
Source Document
Enter into eCRFs
Medical conditions (signs, symptoms, illnesses, and other diagnoses) occurring during the 28 days prior to enrollment and/or ongoing at enrollment
Yes
Medications taken within the 28 days prior to enrollment and/or ongoing at enrollment
Any other information needed to determine eligibility for the study ─
Medical conditions eCRF, con meds eCRF

10. Maternal 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

11. Maternal 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)

12. Maternal Interval History
Assess for and
Source Document
Enter into eCRFs
Use of any new medications
since the last visit
All ARVs taken from time of enrollment through completion of follow-up (including timing of dosing at the Delivery and Week 6 Postpartum Visits)
continued on next slide
Record DTG, FTC/TAF, FTC/TDF, EFV/FTC/TDF taken after enrollment on Treatment Log (TXW10001)
Record all other ARVs taken after enrollment on Con Meds Log (CMW10001)

13. Maternal Interval History
Assess for and
Source Document
Enter into eCRFs
Use of any new medications
since the last visit
Any use of:
Cotrimoxazole
Isoniazid prophylaxis
Medications to treat active TB
Hormonal contraceptives
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.

14. Additional History at Delivery Visit
Complications of pregnancy identified following enrollment
Other targeted conditions potentially associated with adverse pregnancy outcomes identified following enrollment
Date and time of onset of labor
Type of labor (spontaneous or induced)
Mode of delivery
Complications of delivery
Outcome of delivery
Corticosteroids taken for fetal lung maturity at any time during pregnancy

15. Complete at Delivery to record all conditions diagnosed in the
index pregnancy after Entry

16. Forthcoming in the MOP
Mapping of protocol-specified history elements to eCRFs

17. What are your questions about maternal histories?

18. Standardized Questionnaires
QLW10000: IMPAACT 2010 Edinburgh Postnatal Depression Scale (Week 6 postpartum, Week 50 postpartum)
QLW10005: IMPAACT 2010 Pittsburgh Sleep Quality Index Questionnaire (Entry, Week 8 antepartum, Week 38 postpartum)
QLW10006: IMPAACT 2010 Generalized Anxiety Disorder 7-Item Scale (Entry, Week 8 antepartum, Week 38 postpartum)

19. Role Play

20. Standardized Questionnaires
Who will administer each questionnaire?
After the questionnaire is completed, who will evaluate responses with respect to needs for further evaluation, treatment, documentation, and/or reporting of reported symptoms?
Who will determine ARV management?

21. Standardized Questionnaires

22. Mental Health Management Guidelines
Table II.6, Management of Maternal Psychiatric Events (Insomnia, Psychiatric Disorders, Suicidal Ideation or Attempt)
Grade 1
Mild sleep disturbance and/or symptoms of psychiatric disorder with no or minimal interference with usual social and functional activities. May include preoccupation with thoughts of death but no suicidal ideation or intent:
The current study drug regimen may be continued (with referral to non-study sources of mental health services at the discretion of the site investigator). Consultation with the CMC is available but not required.

23. Table II.6, Management of Maternal Psychiatric Events (Insomnia, Psychiatric Disorders, Suicidal Ideation or Attempt)
Grade 2 without suicidal ideation
Moderate sleep disturbance and/or symptoms of psychiatric disorder causing greater than minimal interference with usual social and functional activities without suicidal ideation: The current study drug regimen may be continued (with referral to non-study sources of mental health services at the discretion of the site investigator). Consultation with the CMC is available but not required.
Grade 2 with suicidal ideation
Moderate sleep disturbance and/or symptoms of psychiatric disorder causing greater than minimal interference with usual social and functional activities with suicidal ideation: Consult the CMC about the frequency of ongoing monitoring, timing of study drug resumption, and the choice of study drug regimen:
If the event is assessed as related to EFV, EFV should generally be switched to an alternative ARV (e.g., to DTG or a PI)
If the event is assessed as related to DTG, consideration may be given to replacing DTG (e.g., with a PI)
The participant should be referred to non-study sources of mental health services.

24. Table II.6, Management of Maternal Psychiatric Events (Insomnia, Psychiatric Disorders, Suicidal Ideation or Attempt)
Grade 3
Consult the CMC about the frequency of ongoing monitoring, timing of study drug resumption, and the choice of study drug regimen:
If the event is limited to sleep disturbance only, consideration may be given to continuing the current study drug regimen in consultation with CMC. For all other grade 3 psychiatric events, if assessed as related to study drug (any agent), the entire study drug regimen should be held.
If the event is assessed as related to EFV or DTG, these drugs should be permanently discontinued.
The participant should be referred to non-study sources of mental health services.

25. Table II.6, Management of Maternal Psychiatric Events (Insomnia, Psychiatric Disorders, Suicidal Ideation or Attempt)
Grade 4
Hold the entire study drug regimen. Consult the CMC about the frequency of ongoing monitoring, timing of study drug resumption, and the choice of study drug regimen. If the event is assessed as related to EFV or DTG, these drugs should be permanently discontinued.
The participant should be referred to non-study sources of mental health services as soon as possible.

26. What are your questions about maternal questionnaires?
Plan to take a break after this slide

27. Complete Maternal Physical Exam
Height (screening)
Weight
Blood pressure
Auscultation of chest
Obstetric exam (antepartum)
Examination of
Skin
Head
Mouth
Neck
Abdomen
Extremities
Required at Screening and at Entry (Katie will talk from here after the break)
additional assessments may be performed
at the discretion of the examining clinician

28. Targeted Maternal Physical Exam
Weight
Blood pressure
Obstetric exam (antepartum)
Examination of body systems driven by prior and new signs, symptoms, and diagnoses
additional assessments may be performed
at the discretion of the examining clinician

29. Maternal Laboratory Evaluations
HIV-1 RNA
Entry
Weeks 4, 8, 12, 24 antepartum
Delivery
Weeks 14, 26, 38, 50 postpartum
Confirmation of virologic failure
Post ARV switch

30. Maternal Virologic Monitoring
Refer to protocol Sections 6.7 and 8.3
Closely monitor trends in viral load over time, conduct Confirmation of Virologic Failure Visits when indicated, and consult CMC on management of participants with confirmed virologic failure

31. What would be the next step in evaluating the laboratory result?
Scenario: While reviewing lab results from 21 June 2017, the study clinical notes that a maternal viral load of 653 copies/mL.
What would be the next step in evaluating the laboratory result?

32. Scenario: While reviewing lab results from 21 June 2017, the study clinical notes that a maternal viral load of 653 copies/mL. Review of this mother’s history indicates that she was randomized to Arm 1 on 26 April Her viral load at Entry was 12,842 copies/mL. She started study drug (DTG+FTC/TAF) per protocol at Entry and has been well with no clinical complaints. At her antepartum Week 4 visit, her viral load was 6,748 copies/mL. The result noted in #1 above was obtained at the Week 8 visit (on 21 June 2017).

33. Would you conduct a Confirmation of Virologic Failure Visit based on the Week 8 result?
Yes No
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34. What clinical management action would you take?
Would you conduct a Confirmation of Virologic Failure Visit based on the Week 8 result?
What clinical management action would you take?
Yes No

35. The mother delivers on 19 July 2017 without complications
The mother delivers on 19 July 2017 without complications. Her viral load at the Delivery Visit was <40 copies/mL. She continued to be well, with no clinical complaints, and with a suppressed viral load at her postpartum Week 6 Visit. She and her infant return to the clinic for the postpartum Week 14 visit on 25 October 2017; upon review of her results from this visit, the viral load is 253 copies/mL.

36. Would you conduct a Confirmation of Virologic Failure Visit based on the Week 14 result?
Yes No
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37. Suppose the mother discloses that she has had difficulty with adherence to her ARVs between Week 6 and Week 14 visits. Would you still need to conduct a Confirmation of Virologic Failure Visit based on the Week 14 result?
Yes No
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38. Suppose the mother had switched from DTG+FTC/TAF to a different regimen at antepartum Week 8 because of intolerability. Would you still need to conduct a Confirmation of Virologic Failure Visit based on the Week 14 result?
Yes No
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39. When would you conduct a Confirmation of Virologic Failure Visit for this mother?
As soon as possible and within 28 days of the date of the first result
As soon as possible and within 28 days of the date of specimen collection for the initial test
As soon as possible and within 28 days of the date of site awareness of the first result
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40. What procedures and/or evaluations would you perform at this visit?

41. Procedures Specified in Protocol Section 6.7
Clinical
Obtain interval medical and medications history (targeted physical exam may be performed if clinically indicated)
Identify/review/update adverse events
Perform additional evaluations per Section 8 and/or if clinically indicated (consult CMC if indicated)
Study Drug
Administer adherence questionnaire
Assess adherence in relation to HIV-1 RNA test result and provide adherence counseling as needed
Laboratory (Blood)
Collect blood for:
HIV-1 RNA (real-time; store residual plasma)
Stored plasma for resistance testing

42. What steps would you take if discussion with the mother indicated that she was not adherent to her ART regimen? Who is responsible for each step?

43. What clinical management action would you take based on the results obtained at the Confirmation of Virologic Failure Visit?

44. Any questions?

45. Maternal Laboratory Evaluations
Complete blood count (Screening and postpartum Weeks 26 and 50)
CD4+ cell count (Entry and postpartum Weeks 26 and 50)
Refer to protocol Appendix II.1 for (general) management guidance

46. Maternal Laboratory Evaluations
ALT, AST, Creatinine, CrCl
(Screening; antepartum Weeks 4, 12, 24; Delivery; postpartum Weeks 14, 26, 50; and Post ARV switch)
Grade Grade Grade Grade 4

47. Chemistry Management Guidelines
Refer to protocol Appendix II.3 for asymptomatic ALT and AST elevations
Refer to protocol Appendix II.4 for clinical hepatitis
Refer to protocol Appendix II.5 for increased creatinine and decreased creatinine clearance

48. Recording Test Results on Laboratory eCRFs
All creatinine and CrCl results
All Grade 1 or higher LFT results
All grade 3 or higher hemoglobin, WBC, ANC, and platelet count results
All results that lead to a change of ART regimen
All results that are serious as defined in the DAIDS EAE Manual
All results that are relevant to events that meet criteria for reporting as EAEs
Change of ART regimen = any hold, discontinuation, switch/replacement, dose or frequency modification.
*Regardless of whether test was protocol-specified or ordered for clinical purposes

49. Maternal Evaluations Adverse Events Exams History Lab Tests
This slide is similar to one presented previously for infants, but in this case, the history icon includes medical and history reported to clinicians in follow-up to questionnaire administration, when applicable.

50. Recording on Adverse Event eCRFs
All Grade 3 or higher adverse events
All Grade 2 or higher rashes
All Grade 2 or higher psychiatric events
All suspected or confirmed diagnoses of clinical hepatitis
All adverse events that lead to a change of ART regimen
All SAEs as defined in the DAIDS EAE Manual

51. For both mothers and infants
When available, a diagnosis should be reported as the adverse event term
In addition, signs and symptoms associated with the diagnosis must also be reported if the signs and symptoms meet protocol criteria for adverse event reporting (per protocol Sections and 7.2.2)

52. Example Grade 3 malaria Report diagnosis of malaria
Additionally report fever if grade 3 or higher
Additionally report decreased hemoglobin if grade 3 or higher

53. What are your questions?