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

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

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

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

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

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

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

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

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

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

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)

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)

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.

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

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

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

What are your questions about maternal histories?

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)

Role Play

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?

Standardized Questionnaires

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.

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.

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.

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.

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

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

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

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

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

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?

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 2017. 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).

Would you conduct a Confirmation of Virologic Failure Visit based on the Week 8 result? Yes No 29 of 29

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

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.

Would you conduct a Confirmation of Virologic Failure Visit based on the Week 14 result? Yes No 29 of 31

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 29 of 32

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 27 of 32

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 27 of 32

What procedures and/or evaluations would you perform at this visit?

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

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?

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

Any questions?

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

Maternal Laboratory Evaluations ALT, AST, Creatinine, CrCl (Screening; antepartum Weeks 4, 12, 24; Delivery; postpartum Weeks 14, 26, 50; and Post ARV switch) Grade 1 Grade 2 Grade 3 Grade 4

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

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

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.

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

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 7.2.1 and 7.2.2)

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

What are your questions?