Maternal Toxicity Management IMPAACT 2010/VESTED Section 8 and Appendix II

Overall Guidelines Page 80 IMPAACT 2010 will use the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 2.1, dated March 2017, with two modifications: Protocol-specific grading for axillary measured fever Grade 1, 37.4 to <38.0°C Grade 2, 38.0 to <38.7°C Grade 3, 38.7 to <39.4°C Grade 4, ≥39.4°C The DAIDS AE Grading Table parameter for weight loss excludes postpartum weight loss. Therefore, maternal weight loss will not be graded in this study. Will be updated Anne – should we say something here about potential updates to the note in this section? “Note: The DAIDS AE Grading Table parameter for weight loss excludes postpartum weight loss. Therefore, maternal weight loss not be graded in this study.” In the draft CM, we added “unintentional” weight loss 2

Page 81 General Guidelines All maternal and infant AEs identified in the study will be source documented in participant research records, including: Severity of each event Relationship to study drug 3

Page 81 General Guidelines All AEs must be followed through resolution (return to baseline) or stabilization Frequency of repeat evaluations determined by the clinical significance of each event Grade 3 or higher AEs should be repeated as soon as possible (within 3 business days) and re-evaluated weekly Additional evaluations may be performed as the site investigator’s discretion 4

Communication IMPAACT 2010 Clinical Management Committee (CMC) will address site management questions When management requires consultation, contact the CMC as soon as possible and within 3 business days of site awareness of the event

Management of Maternal Adverse Events Management Category Appendix Table General Guidelines for Maternal Toxicity Management Table II.1 Rash Table II.2 Asymptomatic ALT or AST elevation Table II.3 Clinical hepatitis Table II.4 Increased creatinine and decreased creatinine clearance Table II.5 Psychiatric events Table II.6 Allergic reaction Table II.7 Switching from TDF or TAF to ZDV or ABC Table II.8 nc = no change 6

Additional Maternal Management Guidelines Maternal HIV viral load Mothers who develop active tuberculosis Mothers who are co-infected with hepatitis B Contraception and management of mothers who become pregnant on study Maternal nervous system and psychiatric symptoms Immune reconstitution syndrome Discussed earlier  We will not go through each of the sections in detail but will point out some notes related to these management considerations 7

Additional Maternal Management Guidelines Maternal HIV viral load Mothers who develop active tuberculosis Mothers who are co-infected with hepatitis B Contraception and management of mothers who become pregnant on study Maternal nervous system and psychiatric symptoms Immune reconstitution syndrome 8

Active Tuberculosis Mothers who develop active TB may need rifampin-containing treatment These mothers may have their study drug regimen modified consistent with package inserts Increase frequency of DTG dosing from 50 mg once daily to 50 mg twice daily TAF should be switched to TDF

Active Tuberculosis Contact the CMC for each TB diagnosis AND to consult on study drug regimen management Conduct an additional study visit (Post-ARV Switch Visit) about 4 weeks after the switch for any mother whose study drug regimen is modified such that DTG or EFV is replaced with another ARV

Additional Maternal Management Guidelines Maternal HIV viral load Mothers who develop active tuberculosis Mothers who are co-infected with hepatitis B Contraception and management of mothers who become pregnant on study Maternal nervous system and psychiatric symptoms Immune reconstitution syndrome 11

Hepatitis B Hepatitis B surface antigen testing is conducted for all women at study entry Mothers who are HepB+ who initiate or discontinue ARVs that are active against Hep B may be at risk of immune reconstitution or rebound hepatitis viremia Monitor closely for symptoms of hepatitis Contact the CMC for any mother who has symptoms of hepatitis

Hepatitis B For infants exposed to hepatitis B, every effort should be made to facilitate access to the best available local standard management for hepatitis B exposure, including the hepatitis B vaccine series, starting at birth Further management in provided in protocol Appendix II, Tables II.3 and II.4

Additional Maternal Management Guidelines Maternal HIV viral load Mothers who develop active tuberculosis Mothers who are co-infected with hepatitis B Contraception and management of mothers who become pregnant on study Maternal nervous system and psychiatric symptoms Immune reconstitution syndrome 14

Contraception counseling Will be done per local standards of care Discussed earlier 

Mothers who become pregnant on study Maintain in follow-up May remain on current study drug regimen but should be provided information and counseled on their current regimen Mothers who choose to receive study drug during a subsequent pregnancy must provide separate informed consent.

Additional Maternal Management Guidelines Maternal HIV viral load Mothers who develop active tuberculosis Mothers who are co-infected with hepatitis B Contraception and management of mothers who become pregnant on study Maternal nervous system and psychiatric symptoms Immune reconstitution syndrome 17

Nervous System and Psychiatric Symptoms EFV and DTG may have nervous system symptoms Mothers will be assessed for postpartum depression, sleeping patterns, and anxiety Discussed earlier  Discussed earlier  Further management in provided in protocol Appendix II, Tables II.1 and II.6.

Additional Maternal Management Guidelines Maternal HIV viral load Mothers who develop active tuberculosis Mothers who are co-infected with hepatitis B Contraception and management of mothers who become pregnant on study Maternal nervous system and psychiatric symptoms Immune reconstitution syndrome 19

Immune Reconstitution Inflammatory Syndrome AEs assessed as secondary to immune reconstitution should not be considered related to study drug Contact the CMC for any mother who has suspected IRIS 20

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