Clinical trial NCT03048422
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2018-01-19; Completion date: 2020-10-03
Enrollment: 643 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to compare the virologic efficacy and safety of three antiretroviral (ARV) regimens, dolutegravir plus emtricitabine/tenofovir alafenamide, dolutegravir plus emtricitabine/tenofovir disoproxil fumarate, and efavirenz/emtricitabine/tenofovir disoproxil fumarate in pregnant women living with HIV-1 and to compare the safety of these regimens for their infants.

Detailed description:
This study compared the virologic efficacy and safety of three ARV regimens in pregnant women living with HIV: dolutegravir (DTG) plus emtricitabine/tenofovir alafenamide (FTC/TAF), DTG plus emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), and efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF). The study also compared the safety of these regimens for their infants.

At study entry, mothers were randomly assigned to either receive DTG plus FTC/TAF (Arm 1), DTG plus FTC/TDF (Arm 2), or EFV/FTC/TDF (Arm 3) during pregnancy, through delivery, and for 50 weeks postpartum.

Mothers completed study visits at study entry and every four weeks during pregnancy. Study visits for mothers and their infants occurred at delivery and at 6, 14, 26, 38, and 50 weeks postpartum. Visits for mothers and infants included physical examinations and blood collection. Select study visits also included breast milk collection from mothers who breastfed, hair and urine collection, ultrasound scans, pregnancy testing, contraception counseling, and, for a subset of participants, dual energy x-ray absorptiometry (DXA) scans for mothers and their infants.

For pregnancy outcome measures, mothers and infants were evaluated together as mother-infant pairs, with any outcome between the two counting as an event (for example, if an infant was born small for gestational age, this would be a pregnancy outcome event for the mother-infant pair). For all other outcome measures, women and infants were evaluated separately.

Arms: arm 1: Mothers randomized to receive dolutegravir (DTG) plus emtricitabine/tenofovir alafenamide (FTC/TAF) during pregnancy, through delivery, and for 50 weeks postpartum. arm 2: Mothers randomized to receive DTG plus emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) during pregnancy, through delivery, and for 50 weeks postpartum. arm 3: Mothers randomized to receive efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) during pregnancy, through delivery, and for 50 weeks postpartum. arm 4: Infants born to women in Arm 1. Infants did not directly receive study intervention, but may have been exposed to the randomized treatment through placental or breastmilk transfer. arm 5: Infants born to women in Arm 2. Infants did not directly receive study intervention, but may have been exposed to the randomized treatment through placental or breastmilk transfer. arm 6: Infants born to women in Arm 3. Infants did not directly receive study intervention, but may have been exposed to the randomized treatment through placental or breastmilk transfer.
Interventions: intervention 1: Dolutegravir intervention 2: Emtricitabine/tenofovir alafenamide intervention 3: Emtricitabine/tenofovir disoproxil fumarate intervention 4: Efavirenz/emtricitabine/tenofovir disoproxil fumarate
Intervention descriptions: intervention 1: One 50 mg DTG tablet was administered orally once daily intervention 2: One fixed-dose combination tablet (FTC 200 mg/TAF 25 mg) was administered orally once daily intervention 3: One fixed-dose combination tablet (FTC 200 mg/TDF 300 mg) was administered orally once daily intervention 4: One fixed-dose combination tablet (EFV 600 mg/FTC 200 mg/TDF 300 mg) was administered orally once daily

Protocol documents:
Prot_ICF_000.pdf: 
IMPAACT 2010 
 
Phase III Study of the Virologic Efficacy and Safety of  
Dolutegravir-Containing versus Efavirenz-Containing Antiretroviral Therapy 
Regimens in HIV-1-Infected Pregnant Women and their Infants 
 
“VESTED” 
Virologic Efficacy and Safety of ART Combinations with TAF/TDF, EFV, and DTG 
 
A Multisite Study of the  
International Maternal Pediatric Adolescent  
AIDS Clinical Trials Network 
 
 
Sponsored by: 
National Institute of Allergy and Infectious Diseases 
Eunice Kennedy Shriver 
National Institute of Child Health and Human Development 
National Institute of Mental Health 
 
 
Study Drugs Provided by: 
Gilead Sciences 
Mylan 
ViiV Healthcare Ltd 
 
 
DAIDS Study ID #30129 
IND # 133,438 Held by DAIDS 
 
 
 
Protocol Co-Chairs: 
Shahin Lockman, MD, MSc 
Lameck Chinula, MBBS, MMED, FCOG 
 
NIAID Medical Officer:  
Patrick Jean-Philippe, MD 
 
NICHD Medical Officer: 
Nahida Chakhtoura, MD, MsGH 
 
Clinical Trials Specialists: 
Anne Coletti, MS 
Katie McCarthy, MPH 
 
 
 
Final Version 2.0 
8 December 2017


IMPAACT 2010, FINAL Version 2.0 
Page 2 of 163 
8 December 2017 
IMPAACT 2010 
Phase III Study of the Virologic Efficacy and Safety of  
Dolutegravir-Containing versus Efavirenz-Containing Antiretroviral Therapy 
Regimens in HIV-1-Infected Pregnant Women and their Infants 
 
TABLE OF CONTENTS 
 
ABBREVIATIONS AND ACRONYMS ....................................................................................... 6 
PROTOCOL TEAM ROSTER .................................................................................................... 9 
SITE REPRESENTATIVES ROSTER .......................................................................................13 
SCHEMA ..................................................................................................................................18 
1 
INTRODUCTION ...........................................................................................................21 
1.1 
Background ..................................................................................................................................... 21 
1.2 
Prior Research on Dolutegravir (DTG, Tivicay®)............................................................................. 22 
1.3 
Prior Research on Tenofovir Alafenamide (TAF) ............................................................................. 26 
1.4 
Prior Research on Dolutegravir + Emtricitabine/Tenofovir Alafenamide (DTG + FTC/TAF) in Non-
Pregnant Adults ............................................................................................................................... 29 
1.5 
Prior Research on Emtricitabine (FTC, EmtrivaTM) .......................................................................... 30 
1.6 
Prior Research on Tenofovir Disoproxil Fumarate (TDF, Viread®) ................................................. 32 
1.7 
Prior Research on Emtricitabine and Tenofovir Disoproxil Fumarate Fixed-Dose Combination 
Tablet (FTC/TDF, Truvada®) .......................................................................................................... 35 
1.8 
Prior Research on Efavirenz (EFV, Sustiva®, Stocrin®) ................................................................. 36 
1.9 
Rationale for the Study and its Objectives ....................................................................................... 40 
1.10 
Hypotheses ..................................................................................................................................... 44 
2 
OBJECTIVES ................................................................................................................45 
2.1 
Primary Objectives .......................................................................................................................... 45 
2.2 
Secondary Objectives ...................................................................................................................... 45 
2.3 
Exploratory Objectives ..................................................................................................................... 46 
3 
STUDY DESIGN ...........................................................................................................47 
4 
STUDY POPULATION ..................................................................................................48 
4.1 
Inclusion Criteria .............................................................................................................................. 48 
4.2 
Exclusion Criteria............................................................................................................................. 50 
4.3 
Co-Enrollment Considerations ......................................................................................................... 50 
4.4 
Recruitment, Screening, and Enrollment Process ........................................................................... 51 
4.5 
Participant Retention ....................................................................................................................... 52 
4.6 
Participant Withdrawal from the Study ............................................................................................ 52 
5 
STUDY DRUG CONSIDERATIONS ..............................................................................53 
5.1 
Study Drug Regimens ..................................................................................................................... 53 
5.2 
Study Drug Administration ............................................................................................................... 53 
5.3 
Study Drug Formulation ................................................................................................................... 54 
5.4 
Study Drug Supply........................................................................................................................... 54 
5.5 
Study Drug Accountability ............................................................................................................... 55 
5.6 
Final Disposition of Study Drug ....................................................................................................... 55 
5.7 
Study Drug Adherence Assessment and Counseling ...................................................................... 55 
5.8 
Concomitant Medications ................................................................................................................ 55 
5.9 
Prohibited Medications .................................................................................................................... 56 
5.10 
Precautionary Medications .............................................................................................................. 56 
6 
STUDY VISITS AND PROCEDURES ...........................................................................56 
6.1 
Screening Visits ............................................................................................................................... 57 
6.2 
Entry Visit ........................................................................................................................................ 59 


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6.3 
Maternal Antepartum Follow-Up Visits ............................................................................................ 60 
6.4 
Maternal and Infant Delivery Visit .................................................................................................... 62 
6.5 
Maternal and Infant Postpartum Follow-Up Visits ............................................................................ 64 
6.6 
Additional Procedures Following Maternal ARV Switch .................................................................. 69 
6.7 
Additional Procedures for Confirmation of Maternal Virologic Failure ............................................. 69 
6.8 
Modified Procedures for Infants Identified as HIV-Infected ............................................................. 70 
6.9 
Early Discontinuation Visit ............................................................................................................... 71 
6.10 
Post-Study Contacts ........................................................................................................................ 72 
6.11 
Maternal Medical and Medication History ........................................................................................ 72 
6.12 
Maternal Physical Examinations ...................................................................................................... 75 
6.13 
Fetal Ultrasound .............................................................................................................................. 75 
6.14 
Infant Medical and Medication History ............................................................................................. 76 
6.15 
Infant Feeding History ..................................................................................................................... 76 
6.16 
Infant Physical Examinations ........................................................................................................... 78 
6.17 
Maternal and Infant DXA Scans ...................................................................................................... 79 
6.18 
Additional Considerations for Laboratory Procedures ..................................................................... 79 
7 
SAFETY ASSESSMENT, MONITORING, AND REPORTING ......................................81 
7.1 
Safety-Related Roles and Responsibilities ...................................................................................... 81 
7.2 
Safety-Related Data Collection ....................................................................................................... 82 
7.3 
Expedited Adverse Event (EAE) Reporting ..................................................................................... 84 
8 
PARTICIPANT MANAGEMENT ....................................................................................86 
8.1 
Maternal and Infant Adverse Events ............................................................................................... 86 
8.2 
Management of Maternal Adverse Events....................................................................................... 87 
8.3 
Monitoring and Management of Maternal HIV Viral Load ................................................................ 87 
8.4 
Management of Mothers who Develop Active Tuberculosis ............................................................ 88 
8.5 
Management of Mothers who are Co-Infected with Hepatitis B ....................................................... 88 
8.6 
Contraception and Management of Mothers who Become Pregnant on Study ............................... 89 
8.7 
Management of Maternal Nervous System and Psychiatric Symptoms .......................................... 89 
8.8 
Management of Immune Reconstitution Inflammatory Syndrome (IRIS) ......................................... 90 
8.9 
Infant Management.......................................................................................................................... 91 
9 
STATISTICAL CONSIDERATIONS ..............................................................................91 
9.1 
General Design Issues .................................................................................................................... 91 
9.2 
Outcome Measures ......................................................................................................................... 93 
9.3 
Enrollment/Randomization .............................................................................................................. 95 
9.4 
Sample Size and Accrual ................................................................................................................ 95 
9.5 
Monitoring ...................................................................................................................................... 104 
9.6 
Analyses ........................................................................................................................................ 106 
10 
DATA HANDLING AND RECORD KEEPING ............................................................. 111 
10.1 
Data Management Responsibilities ............................................................................................... 111 
10.2 
Essential and Source Documents and Access to Source Data ..................................................... 111 
10.3 
Quality Control and Quality Assurance .......................................................................................... 112 
11 
CLINICAL SITE MONITORING ................................................................................... 112 
12 
HUMAN SUBJECTS PROTECTIONS......................................................................... 112 
12.1 
Institutional Review Board/Ethics Committee Review and Approval ............................................. 112 
12.2 
Vulnerable Participants .................................................................................................................. 113 
12.3 
Informed Consent .......................................................................................................................... 113 
12.4 
Potential Benefits........................................................................................................................... 114 
12.5 
Potential Risks ............................................................................................................................... 115 
12.6 
Reimbursement/Compensation ..................................................................................................... 115 
12.7 
Privacy and Confidentiality ............................................................................................................ 115 
12.8 
Communicable Disease Reporting ................................................................................................ 116 


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12.9 
Management of Incidental Findings ............................................................................................... 116 
12.10 
Management of New Information Pertinent to Study Participation ................................................ 116 
12.11 
Post-Study Access to Study Drug ................................................................................................. 116 
13 
ADMINISTRATIVE PROCEDURES ............................................................................ 117 
13.1 
Regulatory Oversight ..................................................................................................................... 117 
13.2 
Protocol Registration ..................................................................................................................... 117 
13.3 
Study Implementation .................................................................................................................... 118 
13.4 
Protocol Deviation Reporting ......................................................................................................... 118 
13.5 
Critical Event Reporting ................................................................................................................. 118 
13.6 
ClinicalTrials.gov ........................................................................................................................... 118 
14 
PUBLICATIONS ......................................................................................................... 119 
15 
REFERENCES ............................................................................................................ 119 
Appendix I Schedule of Evaluations .............................................................................................. 128 
Appendix II Maternal Toxicity Management Guidelines ..................................................................... 131 
Appendix III Sample Informed Consent Form .................................................................................. 142 
Appendix IV Sample Informed Consent Form for Specimen Storage and Future Use.............................. 157 
Appendix V Sample Informed Consent Form for Use of Study Drug during Subsequent Pregnancy ......... 161 
 
 
LIST OF FIGURES 
 
Figure 1 Overview of Study Design .............................................................................................................................. 20 
Figure 2 Absorption of TAF and TDF in Gut, Plasma, and Lymphoid Cells ................................................................. 26 
 
 
LIST OF TABLES 
 
Table 1 Reported Congenital Anomalies in IMPAACT P1026s Dolutegravir Arm ........................................................ 24 
Table 2 Plasma TAF AUC in Non-Pregnant Adults ...................................................................................................... 27 
Table 3 Documentation Requirements for Maternal Medical and Medication Histories ............................................... 73 
Table 4 Documentation Requirements for Infant Medical and Medication Histories .................................................... 77 
Table 5 Expedited Adverse Event Reporting Requirements for IMPAACT 2010 ......................................................... 84 
Table 6 Historical Evidence of Sensitivity to Drug Effects ............................................................................................ 97 
Table 7 95% CI for M1: The Estimated IMPAACT 2010 EFV-Containing Arm Effect Relative to Placebo .................. 98 
Table 8 Viral Suppression (HIV-1 RNA <200) Primary Non-Inferiority Efficacy Analysis  Comparing the DTG-
containing Arms Versus the EFV-containing Arm ...................................................................................................... 100 
Table 9 Viral Suppression (HIV-1 RNA <200) Secondary Superiority Efficacy Analysis  Comparing the DTG-
containing Arms Versus the EFV-containing Arm ...................................................................................................... 101 
Table 10 Power Analysis for Primary Composite Adverse Pregnancy Outcome Objective (All Pairwise Comparisons)
 ................................................................................................................................................................................... 101 
Table 11 Power Analysis for Primary Composite Maternal Adverse Event Objective (All Pairwise Comparisons) .... 102 
Table 12 Power Analysis for Primary Composite Infant Adverse Event Objective (All Pairwise Comparisons) ......... 102 
 
 
 
 


IMPAACT 2010, FINAL Version 2.0 
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IMPAACT 2010 
Phase III Study of the Virologic Efficacy and Safety of  
Dolutegravir-Containing versus Efavirenz-Containing Antiretroviral Therapy 
Regimens in HIV-1-Infected Pregnant Women and their Infants 
 
DAIDS Study ID #30129 
 
 
Version 2.0 
Protocol Signature Page 
 
 
 
 
I will conduct this study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with United States (US) Health and 
Human Service regulations (45 CFR 46); applicable US Food and Drug Administration regulations; 
standards of the International Conference on Harmonization Guideline for Good Clinical Practice (E6); 
Institutional Review Board/Ethics Committee determinations; all applicable in-country, state, and local 
laws and regulations; and other applicable requirements (e.g., US National Institutes of Health, Division 
of AIDS) and institutional policies. 
 
 
 
 
 
 
 
Signature of Investigator of Record 
 
Date 
 
 
 
 
 
Name of Investigator of Record 
 
 
(printed) 
 
 
 
 


IMPAACT 2010, FINAL Version 2.0 
Page 6 of 163  
8 December 2017 
IMPAACT 2010 
Phase III Study of the Virologic Efficacy and Safety of  
Dolutegravir-Containing versus Efavirenz-Containing Antiretroviral Therapy 
Regimens in HIV-1-Infected Pregnant Women and their Infants 
 
ABBREVIATIONS AND ACRONYMS 
 
3TC 
lamivudine 
ABC 
abacavir 
ACTG 
AIDS Clinical Trials Group 
AE 
adverse event 
AIDS 
acquired immune deficiency syndrome 
ALT 
alanine aminotransferase 
APR 
Antiretroviral Pregnancy Registry 
ART 
antiretroviral therapy 
ARV 
antiretroviral 
AST 
aspartate aminotransferase 
ATV/r 
ritonavir-boosted atazanavir 
AUC 
area under the curve 
BID 
twice a day 
BMC 
bone mineral content 
CFR 
(US) Code of Federal Regulations 
CHAI 
Clinton Health Access Initiative 
CI 
confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CMC 
clinical management committee 
CNS 
central nervous system 
COBI 
cobicistat 
CrCl 
creatinine clearance 
CRF 
case report form 
CRMS 
Clinical Research Management System 
CRPMC 
Clinical Research Products Management Center 
d4T 
staduvine 
DAERS 
DAIDS Adverse Experience Reporting System 
DAIDS 
Division of AIDS 
DHHS 
(US) Department of Health and Human Services 
DILI 
drug-induced liver injury 
DMC 
Data Management Center 
DNA 
deoxyribonucleic acid 
DRV/r 
ritonavir-boosted darunavir 
DSMB 
Data and Safety Monitoring Board 
DTG 
dolutegravir 
DXA 
dual-energy x-ray absorptiometry 
EAE 
expedited adverse event 
EC 
ethics committee 
eCRF 
electronic case report form 
EFV 
efavirenz 
EIA 
enzyme immunoassay 
EPDS 
Edinburgh Postnatal Depression Scale 
EUROCAT 
European Surveillance of Congenital Anomalies 


IMPAACT 2010, FINAL Version 2.0 
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EVG 
elvitegravir 
FDA 
(US) Food and Drug Administration 
FDAAA 
(US) Food and Drug Administration Amendments Act 
FDC 
fixed-dose combination 
FTC 
emtricitabine 
GCLP 
good clinical laboratory practice 
HBV 
hepatitis B virus 
HDL 
high-density lipoprotein 
HESDE 
Historical Evidence of Sensitivity to Drug Effects  
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
IMPAACT 
International Maternal Pediatric Adolescent AIDS Clinical Trials Network 
INR 
international normalized ratio 
IRB 
institutional review board 
IRIS 
immune reconstitution inflammatory syndrome 
ITT 
intention to treat 
LDMS 
laboratory data management system 
LFT 
liver function test 
LPC 
laboratory processing chart 
LPV/r 
ritonavir-boosted lopinavir 
MOP 
manual of procedures 
NAT 
nucleic acid test 
NIAID 
National Institute of Allergy and Infectious Diseases 
NICHD 
National Institute of Child Health and Human Development 
NIH 
(US) National Institutes of Health 
NNRTI 
non-nucleoside reverse-transcriptase inhibitor 
NRTI 
nucleoside reverse-transcriptase inhibitor 
NVP 
nevirapine 
PACTG 
Pediatric AIDS Clinical Trials Group 
PCR 
polymerase chain reaction 
PI 
protease inhibitor 
PID 
participant identification number 
PK 
pharmacokinetic 
PRO 
(DAIDS) Protocol Registration Office 
PT 
prothrombin time 
QD 
once a day 
QTc 
corrected QT interval 
RAL 
raltegravir 
RNA 
ribonucleic acid 
RR 
relative risk 
RSC 
(DAIDS) Regulatory Support Center 
SAE 
serious adverse event 
SDMC 
Statistical and Data Management Center 
SES 
subject enrollment system 
SID 
study identification number 
SOP 
standard operating procedure 
SRG 
safety review group 
SUSAR 
suspected unexpected serious adverse reaction 
TAF 
tenofovir alafenamide 
TB 
tuberculosis 
TDF 
tenofovir disoproxil fumarate 


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TFV-DP 
tenofovir diphosphate 
ULN 
upper limit of normal 
UN 
United Nations 
UNAIDS 
Joint United Nations Programme on HIV/AIDS 
US 
United States 
VL 
viral load 
VQA 
Virology Quality Assurance 
WHO 
World Health Organization 
ZDV 
zidovudine 
  
 


IMPAACT 2010, FINAL Version 2.0 
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IMPAACT 2010 
Phase III Study of the Virologic Efficacy and Safety of  
Dolutegravir-Containing versus Efavirenz-Containing Antiretroviral Therapy 
Regimens in HIV-1-Infected Pregnant Women and their Infants 
 
PROTOCOL TEAM ROSTER 
 
Protocol Co-Chairs 
Shahin Lockman, MD, MSc 
Department of Immunology and Infectious 
Diseases  
Harvard T.H. Chan School of Public Health 
FXB Building, 651 Huntington Avenue 
Boston, MA 02115 USA 
Phone: (617) 432-4767 
Email: slockman@hsph.harvard.edu  
 
Lameck Chinula, MBBS, MMED, FCOG 
Tidziwe Center 
100 Mzimba Road 
Kamuzu Central Hospital 
Private Bag A-104  
Lilongwe, Malawi 
Phone: (265) 888-248-3220 
Email: lameck_chinula@med.unc.edu  
 
NIAID Medical Officer 
Patrick Jean-Philippe, MD 
Maternal Adolescent Pediatric Research 
Branch, DAIDS/NIAID/NIH 
5601 Fishers Lane, Room 8B49  
MSC 9831  
Rockville, MD 20852-9831 USA 
Phone: (240) 292-4790 
Email: jeanphilippep@niaid.nih.gov  
 
NICHD Medical Officer 
Nahida Chakhtoura, MD, MsGH 
Maternal and Pediatric Infectious Disease 
Branch 
Eunice Kennedy Shriver National Institute of 
Child Health and Human Development 
National Institutes of Health 
6710B Rockledge Drive, Room 2155D 
MSC 7002 
Bethesda, MD 20817 USA 
Phone: (301) 435-6872 
Email: nahida.chakhtoura@nih.gov  
 
Clinical Trials Specialist 
Anne Coletti, MS 
IMPAACT Operations Center, FHI 360 
359 Blackwell St., Suite 200 
Durham, NC 22701 USA 
Phone: (919) 544-7040 x11238 
Email: acoletti@fhi360.org  
 
Katie McCarthy, MPH 
IMPAACT Operations Center, FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701 USA 
Phone: (919) 544-7040 x11439 
Email: kmccarthy@fhi360.org 
 
Protocol Statisticians 
Sean Brummel, PhD 
Statistical and Data Analysis Center 
Harvard T.H. Chan School of Public Health 
651 Huntington Avenue 
Boston, MA 02115-6017 USA 
Phone: (617) 432-2817 
Email: sbrummel@sdac.harvard.edu  
 
Lauren Ziemba, MS 
Statistical and Data Analysis Center 
Harvard T.H. Chan School of Public Health 
651 Huntington Avenue 
Boston, MA 02115-6017 USA 
Phone: (617) 432-3254 
Email: lziemba@sdac.harvard.edu 
 
Protocol Pharmacist 
Lynette Purdue, PharmD 
PAB, DAIDS, NIAID, NIH 
5601 Fishers Lane, Room 9E28 
Rockville, MD 20852 USA 
Phone: (240) 627-3061 
Email: lpurdue@niaid.nih.gov 
 
 
 
 
 


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8 December 2017 
Protocol Virologist 
Lisa Frenkel, MD 
Seattle Children’s Research Center and 
University of Washington 
1900 Ninth Avenue  
Box 359300/JMB-8 
Seattle, WA 98101 USA 
Phone: (206) 987-5140 
Email: lfrenkel@uw.edu 
 
Protocol Investigators 
K. Rivet Amico, PhD 
University of Michigan 
Department of Health Behavior and Health 
Education 
3830 School of Public Health 
1415 Washington Heights 
Ann Arbor, Michigan 48109-2029 
Phone: (810) 360-8716 
Email: ramico@umich.edu  
 
Judith Currier, MD, MS 
UCLA Center for AIDS Research and Education 
11075 Santa Monica Blvd, Suite 100 
Los Angeles, CA 90025 USA 
Phone: (310) 825-6689 
Email: jscurrier@mednet.ucla.edu  
 
Lee Fairlie, MD  
SMACHC 2nd Floor  
Hillbrow Health Precinct 
Corner Esselen St. and Klein St.  
Hillbrow  
Johannesburg, Gauteng 2001  
South Africa  
Phone: +27-11-3585317  
Email: lfairlie@wrhi.ac.za  
 
Risa Hoffman, MD, MPH 
UCLA Center for AIDS Research and Education 
10833 Le Conte Ave 37-121 CHS 
Los Angeles, CA 90095 USA 
Phone: (310) 825-7225 
Email: RHoffman@mednet.ucla.edu  
 
Lewis Ball Holmes, MD 
Massachusetts General Hospital 
55 Fruit Street 
Boston, MA 02114 
Phone: (617) 726-1742 
Email: lholmes@partners.org  
Gaerolwe Masheto, MD 
Gaborone Prevention & Treatment CRS 
Botswana Harvard AIDS Institute  
Private Bag BO320 
Gaborone, Botswana 
Phone: +267-393-0335 
Email: gmasheto@bhp.org.bw  
 
Mark Mirochnick, MD 
Section of Neonatal Medicine 
Boston Medical Center 
One Boston Medical Center Place 
Boston, MA 02118 USA 
Phone: (617) 414-3754 
Email: mark.mirochnick@bmc.org  
 
Jeremiah Momper, PharmD, PhD 
University of California San Diego 
9500 Gilman Drive, MC 0719 
La Jolla, CA 92093-0719 USA 
Phone: (858) 822-0913 
Email: jmomper@ucsd.edu 
 
Kevin Robertson, PhD 
University of North Carolina at Chapel Hill 
170 Manning Drive, CB#7025 
Chapel Hill, NC 27599 USA 
Phone: (919) 966-4401 
Email: robertsonkevin@neurology.unc.edu 
 
Paul Sax, MD  
Brigham and Women's Hospital, PBBA4 
75 Francis Street 
Boston, MA 02115 USA 
Phone: 617-732-8881 
Fax: 617-732-6829 
Email: psax@partners.org  
 
Roger Shapiro, MD, MPH  
Department of Immunology and Infectious 
Diseases  
Harvard T.H. Chan School of Public Health 
FXB Building, 651 Huntington Avenue 
Boston, MA 02115 USA 
Phone: 617-432-2334 
Email: rshapiro@hsph.harvard.edu  
 


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Lynda Stranix-Chibanda, MBChB, MMED 
University of Zimbabwe College of Health 
Sciences – Clinical Trials Unit (UZCHS-CTU) 
Department of Paediatrics and Child Health 
15 Phillips Avenue, Belgravia 
Harare, Zimbabwe 
Phone: 263 4704890 
Email: stranix@uzchs-ctu.org 
 
Jeffrey Stringer, MD 
UNC Global Women’s Health 
111 Mason Farm Rd. 
Suite 4300 MBRB, CB#7577 
Chapel Hill, NC 27599-7577 USA 
Email: jeffrey_stringer@med.unc.edu  
 
Protocol Data Managers 
Benjamin Johnston, BS 
Frontier Science & Technology Research 
Foundation (FSTRF) 
4033 Maple Road  
Amherst, NY 14226-1056 USA 
Phone: (716) 834-0900 x7407 
Email: johnston@fstrf.org  
 
Chelsea Krotje, MPH 
Frontier Science & Technology Research 
Foundation (FSTRF) 
4033 Maple Road  
Amherst, NY 14226-1056 USA 
Phone: (716) 834-0900 x7368 
Email: krotje@fstrf.org 
 
Protocol Laboratory Data Manager 
Andee Fox, MPH 
Frontier Science & Technology Research 
Foundation (FSTRF) 
4033 Maple Road 
Amherst, NY 14226-1056 USA 
Phone: (716) 834-0900 x7276 
Email: fox@fsrtf.org  
 
Laboratory Center Representative 
William Murtaugh, MPH 
IMPAACT Laboratory Center 
Children’s Hospital of Los Angeles 
4650 Sunset Blvd., MS #51 
Los Angeles, CA 90027 USA 
Phone: (323) 361-8502 
Email: wmurtaugh@impaactlabcenter.org  
 
Protocol Laboratory Technologist 
Sikhulile Moyo, MSc, MPH 
Botswana Harvard AIDS Institute  
Princess Marina Hospital  
Private Bag 320 
Gaborone, Botswana  
Phone: +267 390 2671 
Email: sikhulilemoyo@gmail.com 
Westat Clinical Research Associate 
Rita Patel, MS 
Westat, Inc. 
1441 W. Montgomery Ave. 
Rockville, MD 20850 USA 
Phone: (240) 453-2693 
Email: ritapatel@westat.com  
 
Community Program Manager 
Cheryl D. Blanchette, BS  
IMPAACT Operations Center, FHI 360 
359 Blackwell St., Suite 200 
Durham, NC 22701 USA 
Phone: (919) 544-7040 x11359  
Email: ccokley@fhi360.org  
 
Community Advisory Board Member 
Nagawa Jaliaah 
Block 5 Mulago Hospital 
PO Box 72052, Clock Tower 
Kampala, Uganda 
Phone: +256 782292819 
Email: jaaliahnagawa@gmail.com  
 
Pharmaceutical Representatives 
Scott McCallister, MD 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 USA 
Phone: (650) 372-7031 
Email: scott.mccallister@gilead.com  
 
James Rooney, MD 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 USA 
Phone: (650) 522-5708 
Email: jim.rooney@gilead.com 
 


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Jean van Wyk, MBChB, MFPM 
ViiV Healthcare 
980 Great West Road 
Brentford, Middlesex, TW8 9GS, 
United Kingdom 
Phone: +44 208 380 6200 
Email: jean.x.andre-van-
wyk@viivhealthcare.com 
 
Navdeep Thoofer, PhD 
ViiV Healthcare 
980 Great West Road 
Brentford, Middlesex, TW8 9GS,  
United Kingdom 
Phone: +44 208 380 6200 
Email: navdeep.k.thoofer@viivhealthcare.com  
 
 
 


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IMPAACT 2010 
Phase III Study of the Virologic Efficacy and Safety of  
Dolutegravir-Containing versus Efavirenz-Containing Antiretroviral Therapy 
Regimens in HIV-1-Infected Pregnant Women and their Infants 
 
SITE REPRESENTATIVES ROSTER 
 
Pediatric Perinatal HIV Clinical Trials Unit, 
CRS 4201 
Gwendolyn Scott, MD 
University of Miami Miller School of Medicine 
BCRI Room 286 
1580 NW Tenth Avenue 
Miami, Florida 33136 USA 
Phone: (305) 243-6522 
Email: gscott@med.miami.edu 
 
Charles Mitchell, MD 
University of Miami Miller School of Medicine 
BCRI Room 286 
1580 NW 10th Avenue 
Miami, Florida 33136 USA 
Phone: (305) 243-2700 
Email: cmitchel@med.miami.edu  
 
Univ. of Florida Jacksonville NICHD,  
CRS 5051 
Mobeen Rathore, MD, CPE 
653-1 West 8th Street, LRC 3rd Floor 
Jacksonville, Florida 32209 USA 
Phone: (904) 798-4179 
Email: mobeen.rathore@jax.ufl.edu  
 
Saniyyah Mahmoudi, MSN, ARNP, AGPCNP 
653-1 West 8th Street, LRC 3rd Floor 
Jacksonville, Florida 32209 USA 
Phone: (904) 244-5331 
Email: saniyyah.mahmoudi@jax.ufl.edu  
 
Instituto de Puericultura e Pediatria Martagao 
Gesteira – UFRJ NICHD, CRS 5071 
Elizabeth S. Machado, MD, PhD  
Rua Bruno Lobo, 50 - Ilha do Fundao 
Rio de Janeiro 21941-912 Brazil 
Phone: +55 21 3148-2255 
Email: emachado@infolink.com.br  
 
Maria Chermont Sapia, MD 
Rua Bruno Lobo, 50 - Ilha do Fundao 
Rio de Janeiro 21941-912 Brazil 
Phone: +55 21 3148-2255 
Email: macher.rlk@terra.com.br  
 
Hospital Federal dos Servidores do Estado 
NICHD, CRS 5072 
Esaú C. João, MD, PhD 
Hospital Federal dos Servidores do Estado 
Rua Sacadura Cabral, 178, Anexo IV, 4 andar 
CEP 20221-903, Rio de Janeiro, Brasil 
Phone: +55 21 2233-0018 
Email: esaujoao@gmail.com  
 
SOM Federal University Minas Gerais Brazil 
NICHD, CRS 5073 
Jorge A. Pinto, MD, DSc 
Avenida Alfredo Balena 190, Room # 161 
Belo Horizonte, Minas Gerais, 30130-100, 
Brasil 
Phone: (55 31) 3409 9822 
Email: jpinto@medicina.ufmg.br  
 
Flavia Gomes Faleiro Ferreira, MD, DSc 
Avenida Alfredo Balena 190, Room # 144 
Belo Horizonte, Minas Gerais, 30130-100, 
Brasil 
Phone: (55 31) 3409 9111 
Email: ffaleiroferreira@gmail.com  
 
 


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8 December 2017 
Hosp. Geral De Nova Igaucu Brazil NICHD, 
CRS 5097 
Jose Henrique Pilotto, MD, PhD 
Raul Pompeia 66 Apt 101 
Copacabana. Rio de Janeiro 
CEP:22080-002, Brazil 
Phone: +55(21) 98182-9797 
Email: jhpilotto@gmail.com  
 
Gisely Falco, RN 
Avenida Henrique Duque Estrada Mayer, 953 
Alto da Posse. Nova Iguaçu 
Rio de Janeiro. CEP: 26030-380, Brazil 
Phone: +55(21) 99634-7239  
Email: gisely.falco@gmail.com  
 
Siriraj Hosp., Mahidol Univ. NICHD, CRS 5115 
Kulkanya Chokephaibulkit, MD 
2 Wanglang Road 
Bangkok-noi, Bangkok 10700 Thailand  
Phone: +66-2-418-0545 
Email: kulkanya.cho@mahidol.ac.th  
 
Watcharee Lermankul 
2 Wanglang Road 
Bangkok-noi, Bangkok 10700 Thailand  
Phone: +66-2-866-0225 
Email: watchareeped@gmail.com  
 
Chiangrai Prachanukroh Hospital NICHD,  
CRS 5116 
Jullapong Achalapong, MD 
1039 Sathanpayaban Rd., Muang  
Chiang Rai 57000 Thailand 
Phone: +66 (0) 53 711 300  
Email: jullapongachalapong@gmail.com 
 
Tim Cressey  
187/10 Changklan Road 
Changklan, Muang 
Chiang Mai 50100 Thailand 
Phone: +66 (0) 5381 9125-9  
Email: tim.cressey@phpt.org 
 
Kilimanjaro Christian Medical Centre,  
CRS 5118 
Blandina Mmbaga, MD, MMed, PhD 
P.O. Box 3010, Moshi, Tanzania 
Phone: +255768435116 
Email: blaymt@yahoo.com 
 
James Ngocho, MD, MSc 
P.O. Box 3010, Moshi, Tanzania 
Phone: +255784640164 
Email jamesngocho08@gmail.com 
 
Shandukani Research, CRS 8051 
Lee Fairlie, MD  
SMACHC 2nd Floor  
Hillbrow Health Precinct 
Corner Esselen St. and Klein St.  
Hillbrow, Johannesburg, Gauteng 2001  
South Africa  
Phone: +27-11-3585317  
Email: lfairlie@wrhi.ac.za  
 
Hermien Gous, PharmD 
SMACHC 2nd Floor  
Hillbrow Health Precinct 
Corner Esselen St. and Klein St.  
Hillbrow, Johannesburg, Gauteng 2001  
South Africa  
Phone: +27 11 358 5502 
Email: hgous@wrhi.ac.za  
 
Soweto IMPAACT, CRS 8052 
Haseena Cassim, MBChB 
Chris Hani Baragwanath Academic Hospital 
P.O. Box 114 
Diepkloof, Soweto 
Johannesburg, South Africa 
Phone: +27-11-989-9772 
Email: cassimh@phru.co.za  
 
Nasreen Abrahams, MBA 
Chris Hani Baragwanath Academic Hospital 
P.O. Box 114 
Diepkloof, Soweto 
Johannesburg, South Africa 
Phone: +27-11-989-9742 
Email: abrahamsn@phru.co.za 
 


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Family Clinical Research Unit, CRS 8950 
Gerhard Theron, MD 
Department of Obstetrics and Gynaecology 
Faculty of Health Sciences, Stellenbosch 
University 
Francie van Zijl Ave, Parow Valley, 7505 
South Africa  
Phone: +27 21 938 9216 
Email: gbth@sun.ac.za  
 
Jeanne Louw, MSc 
FAMCRU, Ward J8, Tygerberg Hospital 
Francie van Zijl Ave, Parow Valley, 7505 
South Africa 
Phone: +27 21 938 4290 
Email: jeannes@sun.ac.za  
 
Malawi, CRS 12001 
Lameck Chinula, MBBS, MMED, FCOG 
Tidziwe Center 
100 Mzimba Road 
Kamuzu Central Hospital 
Private Bag A-104  
Lilongwe, Malawi 
Phone: (265) 888-248-3220 
Email: lameck_chinula@med.unc.edu 
 
Portia Kamthunzi, MBBS, MSc 
Tidziwe Center 
100 Mzimba Road 
Kamuzu Central Hospital 
Private Bag A-104,  
Lilongwe, Malawi 
Phone: +265 1 750 610 
Email: pkamthunzi@unclilongwe.org 
 
Gaborone, CRS 12701, and Molepolole,  
CRS 12702 
Gaerolwe R. Masheto, MD, PGDipFamMed 
Botswana Harvard AIDS Institute Partnership 
Princess Marina Hospital 
Plot 1836 North Ring Road 
Gaborone, Botswana 
Phone: +267 3975999 
Email: gmasheto@bhp.org.bw  
 
Tebogo J. Kakhu, RN, BSN 
Botswana Harvard AIDS Institute Partnership 
Princess Marina Hospital 
Plot 2731 Hospital Way 
Gaborone, Botswana 
Phone: +267 3931353 
Email: tkakhu@bhp.org.bw 
 
Les Centres GHESKIO Clinical Research Site 
(GHESKIO-INLR), CRS 30022 
Jean William Pape, MD 
33, Blvd. Harry Truman,  
Port-au-Prince, Haïti 
Phone: +011-509-2940-1431 
Email: jwpape@gheskio.org  
 
Marie Flore Pierre, MD 
33, Blvd Harry Truman,  
Port-au-Prince, Haïti 
Phone: +011-509-2222-2241 
Email: mfpvanity_76@yahoo.fr  
 
MU-JHU Research Collaboration, CRS 30293 
Deo Wabwire, MBChB, MMed 
Upper Mulago Hill Road 
P.O. Box 23491 
Kampala, Uganda 
Phone: +256-41-454044 
Email: dwabwire@mujhu.edu 
 
Maxensia Owor, MBChB, MMED, MPH 
Upper Mulago Hill Road 
P.O. Box 23491 
Kampala, Uganda 
Phone: +256-41-454044 
Email: maxowor@mujhu.org 
 


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8 December 2017 
Umlazi, CRS 30300 
Sherika Hanley, MBChB, MFamMed, FCFP 
Nelson R. Mandela School of Medicine 
University of KwaZulu-Natal 
Private Bag X7, Durban 4013 
South Africa 
Phone: +27-31-260-1935 
Email: Hanley@ukzn.ac.za  
 
Vani Chetty, BScHons 
Nelson R. Mandela School of Medicine 
University of KwaZulu-Natal 
Private Bag X7, Durban 4013 
South Africa  
Phone: +27-31-260-1935 
Email: Chettyv1@ukzn.ac.za  
 
Blantyre, CRS 30301 
Luis Gadama, MBBS, FCOG 
P.O. Box 1131 
Blantyre, Malawi 
Phone: +265 1 875 129 
Email: lgadama@jhu.medcol.mw  
 
Rachel Kawalazira, MBBS 
P.O. Box 1131 
Blantyre, Malawi 
Phone: +265 1 875 159 
Email: rkawalazira@jhu.medcol.mw 
 
St. Mary’s, CRS 30303 
Tsungai Chipato, MBChB, FRCOG, MCE 
UZCHS-CTU 
15 Phillips Avenue, Belgravia 
Harare, Zimbabwe 
Phone: +263 470-1717 
Email: tchipato@zol.co.zw 
 
Emmie Marote, RGN/SCN, BAEd, BSN 
UZCHS-CTU 
15 Phillips Avenue, Belgravia 
Harare, Zimbabwe 
Phone: +263 470-4890 
Email: emarote@uzchs-ctu.org 
 
Seke North, CRS 30306 
Patricia Mandima, MBChB, DipHIVMan 
UZCHS-CTU 
15 Phillips Avenue, Belgravia 
Harare, Zimbabwe 
Phone: +263 470-4890 
Email: pmandima@uzchs-ctu.org 
 
Suzen Maonera, RGN/SCN, BSN, MSN 
UZCHS-CTU 
15 Phillips Avenue, Belgravia 
Harare, Zimbabwe 
Phone: +263 470-4890 
Email: smaonera@uzchs-ctu.org 
 
Byramjee Jeejeebhoy Medical College,  
CRS 31441 
Pradep Sambarey, MD, PhD 
Jai Prakash Narayan Road 
Pune, Maharastra, 411001 India  
Phone: 020 21628000 x2311 
Email: drsambarey@yahoo.co.in  
 
Nishi Suryavanshi, PhD 
Jai Prakash Narayan Road 
Pune, Maharastra, 411001 India 
Phone: 91 98 232 48979 
Email: nishisuryavanshi@hotmail.com  
 
Chiang Mai University HIV Treatment,  
CRS 31784 
Linda Aurpibul, MD, MPH 
Research Institute for Health Sciences (RIHES),  
Chiang Mai University 
110 Intavaroros Road, Muang, 
Chiang Mai, 50200 Thailand 
Phone: +66 5393 6148 x445 
Email: lindaa@rihes.org  
 
Chintana Khamrong, MSc 
Research Institute for Health Sciences (RIHES), 
Chiang Mai University 
110 Intavaroros Road, Muang, 
Chiang Mai, 50200 Thailand 
Phone: +66 5393 6148 x446 
Email: chintanak@rihes.org 
 


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Baylor-Uganda, CRS 31798 
Violet Korutaro, MBChC, MScPH 
Block 5 Mulago Hospital 
PO Box 72052, Clock Tower 
Kampala, Uganda 
Phone: +256 4171 19200 
Email: vkorutaro@baylor-uganda.org  
 
Sarah Nanyunja, BSN 
Block 5 Mulago Hospital 
PO Box 72052, Clock Tower 
Kampala, Uganda 
Phone: +256 4171 19200 
Email: snanyunja@baylor-uganda.org  
 
Harare Family Care, CRS 31890 
Tichaona Vhembo, DipHIVMan, MBChB, MPH 
UZCHS-CTU 
15 Phillips Avenue, Belgravia 
Harare, Zimbabwe 
Phone: +263 4 791946 
Email: tichaona@uzcrc.co.zw  
 
Sukunena Maturure, Dip Comm. Health, RGN 
UZCHS-CTU 
15 Phillips Avenue, Belgravia 
Harare, Zimbabwe 
Phone: +263 4 791946 
Email: sjmaturure@uzcrc.co.zw 


IMPAACT 2010, FINAL Version 2.0 
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8 December 2017 
IMPAACT 2010 
Phase III Study of the Virologic Efficacy and Safety of  
Dolutegravir-Containing versus Efavirenz-Containing Antiretroviral Therapy 
Regimens in HIV-1-Infected Pregnant Women and their Infants 
 
SCHEMA 
 
 
Purpose: 
To compare the virologic efficacy and safety of three antiretroviral regimens for 
HIV-1-infected pregnant women and to compare the safety of these regimens for 
their infants 
 
Design: 
Phase III, three-arm, randomized, open-label study  
 
Study Population: 
HIV-1-infected pregnant women initiating antiretroviral therapy at 14-28 weeks 
gestation, and their infants 
 
Sample Size: 
639 mother-infant pairs (approximately 213 per arm) with possible adjustment 
at first interim analysis 
 
Study Drug: 
Arm 1: Maternal dolutegravir plus emtricitabine/tenofovir alafenamide  
[DTG+FTC/TAF] 
 
Arm 2: Maternal dolutegravir plus emtricitabine/tenofovir disoproxil fumarate  
[DTG+FTC/TDF] 
 
Arm 3: Maternal efavirenz/emtricitabine/tenofovir disoproxil fumarate  
[EFV/ FTC/TDF] 
 
In the objectives below, “a DTG-containing regimen” refers to the combination 
of both DTG-containing arms (i.e., Arm 1+Arm 2). “Any pairwise regimen 
comparison” refers to comparisons of Arm 1 to Arm 2, Arm 2 to Arm 3, and Arm 
1 to Arm 3. 
 
Study Duration: 
Up to approximately 31 months total. Accrual is expected to require 
approximately 12 months (from the date of first enrollment) and enrolled 
participants will be followed through pregnancy and for approximately 50 
weeks postpartum. 
 
Primary Objectives 
To determine the following among HIV-1-infected pregnant women and their infants:  
 
Whether treatment initiated during pregnancy with a DTG-containing regimen is non-inferior to 
EFV/FTC/TDF with regard to virologic efficacy (HIV-1 RNA <200 copies/mL) at delivery 
 
Whether rates of the following safety outcomes differ for any pairwise regimen comparison 
– 
Adverse pregnancy outcomes (spontaneous abortion, fetal death, preterm delivery, or small for 
gestational age)  
– 
Maternal grade 3 or higher adverse events through 50 weeks postpartum 
– 
Infant grade 3 or higher adverse events through 50 weeks postpartum 
 


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8 December 2017 
Secondary Objectives 
To evaluate the following among HIV-1-infected pregnant women and their infants:  
 
Whether treatment initiated during pregnancy with a DTG-containing regimen is superior to 
EFV/FTC/TDF with regard to virologic efficacy (HIV-1 RNA <200 copies/mL) at delivery  
 
Whether the following differ when comparing a DTG-containing regimen initiated during pregnancy 
to EFV/FTC/TDF:  
– 
Proportion of mothers with HIV-1 RNA <50 copies/mL at delivery 
– 
Proportion of mothers with HIV-1 RNA <200 copies/mL at 50 weeks postpartum  
– 
Time to maternal HIV-1 RNA <200 copies/mL through delivery 
 
Whether the following differs for any pairwise regimen comparison: 
– 
Proportion of mothers with HIV-1 RNA <200 copies/mL at delivery and at 50 weeks postpartum 
using the standardized FDA snapshot algorithm 
 
Whether rates of the following differ when comparing a DTG-containing regimen to EFV/FTC/TDF: 
– 
Adverse pregnancy outcomes (spontaneous abortion, fetal death, preterm delivery, or small for 
gestational age)  
– 
Maternal grade 3 or higher adverse events through 50 weeks postpartum 
– 
Infant grade 3 or higher adverse events through 50 weeks postpartum 
 
Whether rates of the following differ for any pairwise regimen comparison: 
– 
A composite outcome of spontaneous abortion, fetal death, preterm delivery, small for gestational 
age, or major congenital anomaly 
– 
A ranked composite infant safety outcome measure through 50 weeks postpartum 
– 
Infant HIV infection through 50 weeks postpartum 
– 
Infant mortality through 50 weeks postpartum 
– 
Infant bone toxicity at 26 weeks postpartum 
– 
Maternal bone toxicity at 50 weeks postpartum 
– 
Markers of maternal and infant renal toxicity through 50 weeks postpartum  
– 
Antiretroviral drug resistance observed with each maternal ART regimen: 
• Among mothers who experience virologic failure (at baseline and time of virologic failure)  
• Among HIV-infected infants (at time of HIV diagnosis) 
 
Whether treatment initiated during pregnancy with each regimen is non-inferior with regard to 
preterm delivery and, separately, small for gestational age, for any pairwise regimen comparison 
 
Exploratory Objectives 
To: 
 
Evaluate the following with treatment initiated in pregnancy with a DTG-containing regimen 
compared to EFV/FTC/TDF: 
–Maternal postpartum depression through 50 weeks postpartum 
–Adverse outcomes of subsequent pregnancies occurring during maternal follow-up 
 
Evaluate potential immunologic and hormonal predictors of adverse pregnancy outcomes and 
postpartum maternal health outcomes and the association of these factors with maternal ART 
regimens 
 
Assess for associations between maternal antepartum adverse events and adverse pregnancy outcomes 
 
Assess for associations between maternal antiretroviral drug levels and maternal and infant adverse 
events 
 
Assess for mother-to-infant transfer of antiretrovirals during pregnancy and breastfeeding 
 
Assess adherence to maternal ART regimens in the antenatal and postnatal periods and describe 
barriers and facilitators of adherence during these periods 
 
 
 


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8 December 2017 
IMPAACT 2010 
Phase III Study of the Virologic Efficacy and Safety of  
Dolutegravir-Containing versus Efavirenz-Containing Antiretroviral Therapy 
Regimens in HIV-1-Infected Pregnant Women and their Infants 
 
Figure 1 
Overview of Study Design 
 
 
 
 
 


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Page 21 of 163  
8 December 2017 
1 
INTRODUCTION  
 
1.1 
Background 
 
Approximately 1.5 million HIV-infected women deliver annually, with nearly 90% of these births 
occurring in sub-Saharan Africa (1). Efavirenz/(lamivudine or emtricitabine)/tenofovir disoproxil 
fumarate [EFV/(3TC or FTC)/TDF] is the preferred first-line antiretroviral treatment (ART) 
regimen recommended by the World Health Organization (WHO) for adults, including pregnant 
women (2, 3). For pregnant women who are not able to take EFV, the WHO-recommended 
alternative first-line regimen includes nevirapine (NVP), which carries known safety concerns 
when initiated at higher CD4 counts and is not available in fixed-dose combination formulations 
with TDF/FTC or 3TC. Other alternatives (abacavir (ABC)) or ritonavir-boosted protease 
inhibitors (PIs)) are often not available or would not be considered by programs due to cost or 
other concerns. Finding a feasible, safe, and effective alternative first-line regimen to EFV/(3TC 
or FTC)/TDF during pregnancy is of significant importance, because: 
 
a) Not all women will tolerate (or be ideal candidates for) EFV/(3TC or FTC)/TDF, including 
women with a history of (or at risk of developing) depression or other psychiatric illness. 
EFV has been associated with hepatotoxicity (4) and higher rates of suicidal ideation 
compared with non-EFV based ART (5), and little is known about its potential to exacerbate 
postpartum depression.  
b) An increasing number of women are conceiving while taking ART. Slight concern remains 
regarding the potential teratogenic effects of first-trimester EFV exposure (6), although EFV 
is a component of WHO-recommended first-line ART for pregnant women and women of 
childbearing potential. 
c) TDF can cause renal and bone toxicity in a subset of patients taking TDF-containing ART, 
and may (7) or may not (8) be associated with bone toxicity in perinatally exposed infants.  
 
In addition, it is very important to obtain timely pregnancy efficacy and safety data for 
antiretrovirals that are currently taken or likely to be taken by large numbers of women of 
childbearing potential globally within the relatively near future. Unfortunately, pregnancy safety 
and efficacy data are often late or lacking, leading either to use of suboptimal regimens in 
pregnant women (or women of childbearing potential), or use in pregnancy of antiretroviral 
regimens for which minimal pregnancy data exist. Most antiretroviral combinations used thus far 
have not been demonstrated to result in adverse maternal health, pregnancy, or child health 
outcomes. However, some ART regimens (e.g., regimens containing lopinavir/ritonavir [LPV/r]) 
may be associated with increased adverse maternal low grade toxicity and preterm delivery/low 
birth weight compared to zidovudine (ZDV) plus single dose nevirapine (sdNVP) (9).  
 
It is anticipated that two newer antiretroviral drugs, dolutegravir (DTG) and tenofovir 
alafenamide (TAF), will be recommended and widely used as first-line in both resource-rich and 
resource-constrained settings over the next several years because of their favorable potency, 
safety, and cost profiles. In fact, a modeling exercise undertaken by the Clinton Health Access 
Initiative (CHAI) suggested that DTG and TAF will replace current ARVs in ≥90% of patients by 
2025, and that this may be associated with more than $3 billion in cost savings during that time 
period (10, 11).  
 


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8 December 2017 
DTG, a once-daily integrase inhibitor, is highly efficacious and generally well tolerated. It 
appears to have a very high barrier to development of HIV drug resistance. In a head-to-head 
study comparing DTG combined with ABC and 3TC to EFV/FTC/TDF, the DTG combination 
had superior virologic activity at 48 weeks (described below) (12). DTG is included in two of the 
preferred first-line regimens recommended for adults by the US DHHS (13) and is used with 
increasing frequency in well-resourced settings. DTG was also recently included in WHO 
guidelines as an alternative first-line agent in non-pregnant adults (3) and is being incorporated 
into new national program guidelines for first-line use in some resource-limited countries. In 
2015, CHAI, UNAIDS, and UNITAID announced a new agreement under which generically-
manufactured DTG will be available for $44 /patient per year (a price that is comparable to that 
of EFV) (14). Hence, it is expected that DTG may soon become a cornerstone of preferred first-
line ART treatment globally. 
 
Tenofovir alafenamide fumarate (TAF) is as efficacious as TDF in ART regimens studied thus 
far, and is associated with less toxicity than TDF as a component of ART (15). Given its 
favorable toxicity profile, it is likely that TAF will replace TDF in adult ART regimens, assuming 
that it is competitively priced (16). TAF/FTC received United States Food and Drug 
Administration (FDA) approval in April 2016 (as Descovy®). TAF/FTC (like DTG) has already 
been sub-licensed with the Medicines Patent Pool, and TAF is cheaper to manufacture than TDF 
(requiring fewer raw materials). It will therefore fortunately be possible for generic 
pharmaceutical producers to manufacture a single combination pill of DTG/TAF/FTC (or 3TC) to 
be taken once daily that would be affordable and accessible in resource-limited settings.  
 
In sum, it is very likely that both DTG and TAF will be used with increasing frequency in the 
future, potentially as components of first-line recommended ART globally. The WHO 2015 
guidelines update noted that neither DTG nor TAF had been studied in pregnancy (both were 
pregnancy Category B); however, as described in Sections 1.2.2 and 1.3.2, data from studies in 
pregnancy are emerging. If DTG and TAF are included in future WHO-recommended first-line 
regimens in resource-limited settings as anticipated, it will be important to have data regarding 
their efficacy and safety in pregnancy (given the desire to use the same first-line ART regimens in 
pregnant and non-pregnant patients, for programmatic simplicity). These data will also be of 
relevance in the US and other well-resourced settings. 
 
1.2 
Prior Research on Dolutegravir (DTG, Tivicay®) 
 
1.2.1 
Dolutegravir: Studies in Non-Pregnant Adults 
 
Superior virologic efficacy has been observed in randomized trials of DTG-containing versus 
EFV- or PI-containing three-drug ART regimens among treatment-naïve adults, in three out of 
four trials (12, 17-19).  
 
In the SINGLE trial, 833 ART-naive adults (16% women) with HIV-1 RNA ≥1,000 copies/mL 
were randomized in double-blind fashion to start ART with DTG+ABC/3TC versus 
EFV/TDF/FTC (and received at least one dose). At week 48, 88% of participants in the DTG arm 
versus 81% in the EFV arm had HIV-1 RNA <50 copies/mL (per FDA snapshot algorithm) 
(p=0.003, meeting superiority criterion) (12). A low and similar percentage of participants in both 
arms had virologic failure; however, 10% of participants in the EFV arm and 2% of the DTG arm 
discontinued study drug due to adverse events (AEs). No resistance to DTG nor to NRTIs was 
detected in virus from SINGLE trial participants randomized to DTG and experiencing virologic 
failure (while five participants in the EFV arm developed drug-resistant virus) (17). In the Phase 
IIb SPRING-1 trial in ART-naive adults, 205 patients were randomized to start DTG (10 mg, 25 


IMPAACT 2010, FINAL Version 2.0 
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8 December 2017 
mg, or 50 mg) or EFV (20). Week 16 response rates (HIV-1 RNA ≤50 copies/mL) were 93% for 
all doses of DTG and 60% (30 of 50) for EFV. Week 48 response rates were 87% (139 of 155) 
for all doses of DTG and 82% (41 of 50) for EFV. 
 
In another randomized trial among ART-naive adults (the open-label FLAMINGO study, 15% of 
participants female), once-daily DTG was found to be superior to once-daily darunavir/ritonavir 
(DRV/r, each in combination with either TDF/FTC or ABC/3TC) at 48 weeks (per FDA snapshot 
algorithm). Four hundred eighty-four participants were included in the analysis (242 in each arm); 
217 (90%) participants in the DTG arm and 200 (83%) in the DRV/r arm had HIV-1 RNA <50 
copies/mL (adjusted difference 7.1%, 95% CI 0.9-13.2) (18). DTG was therefore deemed non-
inferior (and superior, on pre-specified secondary analysis). Virologic failure occurred in two 
participants (<1%) in each arm, while a slightly higher proportion of patients in the DRV/r arm 
discontinued drug (4%) compared with the DTG arm (2%) due to AEs or stopping criteria. No 
new primary drug resistance mutations were detected in participants in either arm. Ninety-six-
week data from the FLAMINGO study showed higher rates of virologic suppression to <50 
copies/mL in the DTG arm (80%) compared with the DRV/r arm (68%, p=0.002), with the 
greatest difference in patients with high viral load at baseline (17). 
 
In the ARIA randomized trial conducted among 495 treatment-naive women, DTG/ABC/3TC had 
superior virologic efficacy to ritonavir-boosted atazanavir (ATV/r) + TDF/FTC at 48 weeks (19). 
Using the FDA snapshot algorithm with HIV-1 RNA<50 copies/mL, 82% in the DTG arm versus 
71% in the ATV/r arm were deemed to have virologic success at 48 weeks (p=0.005). Two 
percent versus 6% had virologic non-response due to HIV-1 RNA above threshold, and 4% 
versus 7% had no virologic data due to an adverse event or death in the DTG and ATV/r arms, 
respectively. 
 
DTG was also found to be non-inferior to raltegravir (RAL) in the double-blind SPRING-2 Study 
conducted in North America, Australia, and Europe (21). In this trial, 822 ART-naive adults with 
HIV-1 RNA ≥1,000 copies/mL were randomized to start ART with DTG or RAL and received at 
least one dose (each in combination with either investigator-selected TDF/FTC or ABC/3TC. At 
96 weeks, 81% of participants in the DTG arm and 76% of participants in the RAL arm had HIV-
1 RNA <50 copies/mL (adjusted difference 4.5%, 95% CI -1.1% to 10.0%). Virologic non-
response occurred in fewer participants in the DTG arm versus the RAL arm (5% versus 10% 
respectively). Only 2% of participants in each arm discontinued study drug due to AEs (most of 
which occurred by week 48). At 48 weeks, no new drug resistance mutations were found in 
participants failing DTG. 
 
The most common adverse events reported with DTG-containing ART are insomnia, headache, 
dizziness, abnormal dreams, and depression (in 6-11% of patients) (22-24); anxiety, transaminitis, 
diarrhea, and rash (in less than 5% of patients); hypersensitivity and drug-induced liver injury 
(DILI) are very rare. DTG inhibits the tubular excretion of creatinine, and may thus cause a small 
(~0.1-0.15 mg/dL), non-pathologic increase in serum creatinine within the first few weeks of 
DTG initiation that does not reflect renal injury. 
 


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1.2.2 
Dolutegravir: Studies in Pregnancy 
 
DTG was classified as FDA pregnancy Category B (when this classification scheme was used).  
 
Thus far, limited safety or efficacy data for DTG in pregnancy in humans have been published or 
presented. In the most recent version of the Antiretroviral Pregnancy Registry report (issued 30 
June 2017), 2/77 women with first trimester exposure to DTG had a live-born child with a 
reported birth defect and 2/56 women with second or third trimester exposure had a live-born 
child with a reported birth defect (25). 
 
IMPAACT P1026s has reported pharmacokinetic outcomes in 13 women taking DTG during 
pregnancy, and their neonates, with these data more recently updated for 21 women, all enrolled 
in the United States (26, 27). Median third trimester DTG levels were somewhat lower than 
second trimester (or postpartum) levels in these 11 participants. However, second and third 
trimester DTG Cmin concentrations (0.86 mcg/mL in both cases) exceeded the IC90 for the drug 
(which is approximately 0.064 mcg/mL), and third trimester AUC and trough levels were similar 
to those in non-pregnant adults. Infant DTG drug levels at birth (Cmax was approximately 2 
mcg/mL) were also well above the IC90. DTG pregnancy pharmacokinetic data are still being 
collected in additional participants in P1026s (9 of whom are already enrolled). Maternal HIV-1 
RNA was <50 copies/mL at delivery in 15 of 15 women (100%) in whom it was measured. In 
sum, data from P1026s thus far suggest that while third trimester DTG levels may be lower, 
reasonable DTG levels (and transplacental transfer of DTG) will nevertheless be achieved in 
pregnancy with standard dosing, although final data are awaited. It is anticipated that sufficient 
DTG pregnancy pharmacokinetic data will be available prior to the opening of IMPAACT 2010 
(these data will be reviewed by the 2010 Protocol Team prior to study initiation, to verify that it is 
appropriate to move forward with the study as planned). Of note, as of June 2016, five babies 
were reported to have congenital anomalies (and two babies with findings deemed to be “normal 
variants”) of approximately 15 born (see Table 1).  
 
Table 1 
Reported Congenital Anomalies in IMPAACT P1026s Dolutegravir Arm 
Anomaly
Other Findings
Gestational Age 
DTG Started
Relatedness
Multicystic dysplastic right kidney
Cystic fibrosis
11 4/7 weeks
Possibly related
Cyst left kidney
None
12 2/7 weeks
Possibly related
Total anomalous pulmonary 
venous return
None
16 6/7 weeks
Not related
Congenital filum terminale 
fibrolipoma
Normal conus, 
sacral dimple
18 3/7 weeks
Not related
Hereditary chin tremors
None
28 6/7 weeks
Resolved
Two vessel umbilical cord
None
Prior to conception
Normal variant
Post-axial supernumerary digit
None
9 weeks
Normal variant
 
Based on the nature of the anomalies and the timing of first exposure in pregnancy, possible 
association with DTG can be ruled out for all but two of the five anomalies (the renal cysts). 
Given the gestational age at which DTG was initiated and the nature of the renal cysts, they are 
also unlikely to be related to exposure to DTG (of note, in both instances the renal cysts were 
incidentally detected during routine antenatal fetal ultrasound, rather than due to any clinical 
concern or finding – because of this, and because they are not likely to have medical or surgical 


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significance, these renal cysts would not generally be described as major congenital 
malformations). 
 
An observational surveillance study of birth outcomes in women starting ART during pregnancy 
(in the context of the national HIV treatment program) showed similar rates of adverse pregnancy 
outcomes (stillbirth, neonatal death, preterm or very preterm birth, small for gestational age or 
very small for gestational age) among 845 women initiating DTG/TDF/FTC (at median 19 weeks 
gestation) compared with 4593 women initiating EFV/TDF/FTC (at median 21 weeks gestation) 
in pregnancy. Among 512 women initiating ART in the first trimester of pregnancy (116 
DTG/TDF/FTC, 396 EFV/TDF/FTC), one major congenital abnormality was identified (skeletal 
dysplasia in an EFV-exposed infant). (28) 
 
Several smaller studies of DTG in pregnancy are planned. The DolPHIN1 study in Uganda 
(NCT02245022) will evaluate DTG pharmacokinetics in pregnancy. This study will enroll 60 
women, 30 in the DTG arm and 30 in standard of care arm (NVP or EFV + 2 NRTI). The planned 
DolPHIN2 study will enroll 250 women late in pregnancy (approximately half of whom will take 
DTG-containing ART) and will evaluate maternal HIV-1 RNA at delivery, safety and tolerability. 
In addition, women who become pregnant while taking the DTG/ABC/3TC fixed dose 
combination tablet while participating in the ARIA trial (described in Section 1.2.1) will have 
DTG PK testing (NCT02075593). 
 
1.2.3 
Animal Studies of Dolutegravir  
 
The following information was obtained from the US DHHS Perinatal Guidelines, last updated 
6 August 2015 (13). 
 
Carcinogenicity 
 
DTG was not genotoxic or mutagenic in vitro. No carcinogenicity was detected in 2-year long-
term studies in mice at exposures up to 14-fold higher than that achieved with human systemic 
exposure at the recommended dose, or in rats at exposures up to 10-fold higher in males and 15-
fold higher in females than human exposure at the recommended dose.  
 
Reproduction/Fertility 
 
DTG did not affect fertility in male and female rats and rabbits at exposures approximately 27-
fold higher than human clinical exposure, based on area under the curve, at the recommended 
dose. 
 
Animal Teratogenicity/Developmental Toxicity 
 
Studies in rats and rabbits have shown no evidence of developmental toxicity, teratogenicity, or 
effect on reproductive function with DTG. 
 
Placental and Breast Milk Passage 
 
Studies in rats have demonstrated that DTG crosses the placenta in animal studies and is excreted 
into breast milk in rats. 
 


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1.3 
Prior Research on Tenofovir Alafenamide (TAF) 
 
1.3.1 
Tenofovir Alafenamide: Studies in Non-Pregnant Adults 
 
TDF, a prodrug of tenofovir (TFV), is associated with renal and bone toxicity in adults (29, 30) 
and may be associated with bone toxicity in perinatally exposed infants (8). The PROMISE trial 
did not find that TDF-containing ART was associated with lower newborn bone mineral content 
compared with non-TDF (ZDV) containing ART, when NRTIs were used in combination with 
LPV/r during pregnancy, but did find that both of these ART regimens were associated with 
significantly lower bone mineral content than ZDV+sdNVP (7). The PROMISE results also 
revealed the puzzling finding of higher rates of severe adverse pregnancy outcomes and 14-day 
infant mortality among women who received LPV/r+TDF/FTC compared with LPV/r+ZDV/3TC 
during pregnancy, although the rates of severe adverse pregnancy outcomes did not differ 
significantly between women who received LPV/r+TDF/FTC versus ZDV/sdNVP (9). 
Reassuringly, a different (observational) study did not demonstrate higher rates of adverse 
pregnancy outcomes with use of EFV/TDF/FTC compared with other 3-drug ART (or with ZDV) 
during pregnancy (31).  
 
Tenofovir alafenamide fumarate, another prodrug of TFV, results in approximately 10-fold lower 
plasma concentration of drug but at least 4-fold higher intracellular drug concentration (32), and 
requires a smaller quantity of raw materials to produce. This is because after absorption from the 
gut, only a small fraction of TAF is metabolized in the plasma to TFV (Figure 2). Instead, the 
TAF prodrug is predominantly metabolized intracellularly into TFV, which is then 
phosphorylated to become the active drug tenofovir diphosphate (TFV-DP). In contrast, after gut 
absorption, the majority of the TDF prodrug is converted to TFV in the plasma; TFV is then taken 
up into cells, and converted into the active TFV-DP intracellularly. It is thought that the ~90% 
lower systemic exposure to TFV leads to its lower toxicity (as TFV levels have been associated 
with renal and bone toxicity). 
 
Figure 2 
Absorption of TAF and TDF in Gut, Plasma, and Lymphoid Cells  
 
 


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The virologic efficacy of ART with elvitegravir (EVG)/cobicistat (COBI)/FTC/TAF is non-
inferior to that of EVG/COBI/FTC/TDF in several large trials (15, 33). In two controlled, double-
blind Phase III studies conducted in 1,744 ART-naive HIV-infected adults from 16 countries 
(15% women), participants were randomly assigned (1:1) to receive once-daily 
EVG/COBI/FTC/TAF or EVG/COBI/FTC/TDF with matching placebo. At 48 weeks, 92% of 
866 patients in the TAF group and 90% of 867 patients in the TDF group had plasma HIV-1 RNA 
<50 copies/mL (per FDA snapshot algorithm)—adjusted difference 2.0%, 95% CI -0.7 to 4.7 
(15). Patients in the TAF arm had significantly smaller mean serum creatinine increases than 
those in the TDF arm (0.08 versus 0.12 mg/dL; p <0.0001), significantly less proteinuria (median 
percent change -3 versus. 20; p <0.0001), and a significantly smaller decrease in bone mineral 
density at spine (mean % change, -1.30 versus -2.86; p <0.0001) and hip (-0.66 versus -2.95; 
p<0.0001) (15).  
 
In a Phase II study, 103 ART-naive adults were randomized to start darunavir/COBI/FTC/TAF 
and 50 were randomized to start darunavir/COBI/FTC/TDF once daily with matched placebos. At 
week 48, the proportions with HIV-1 RNA <50 copies/mL were similar (77% in the TAF versus 
84% in the TDF arms); the difference was driven by higher rate of discontinuations in TAF 
(6.8%) versus TDF (2%) (33). The safety profiles of both arms (TAF versus TDF) were similar, 
with 92% versus 94% of participants reporting any treatment-emergent adverse events, and 7% 
versus 8% reporting a grade 3 or 4 adverse event (33). The TAF arm had significantly better renal 
and bone safety parameters than the TDF arm: less proteinuria and less change in hip and spine 
bone mineral density. 
 
Of note, TAF appears to have similar activity against hepatitis B as TDF (34, 35), although Phase 
III trial results are not yet published. 
 
TAF PK in Non-Pregnant Adults 
 
Standard TAF dosing results in at least four-fold higher intracellular concentrations of the active 
TFV-DP drug compared with standard TDF dosing (32). Based on existing data, plasma TAF 
levels can be used to accurately predict intracellular TFV-DP levels in non-pregnant individuals 
and it is unlikely that pregnancy would affect this relationship (36). Adherence preceding the 
observed TAF dose (prior to PK testing in P1026s) should not substantially affect plasma TAF 
levels, given its short plasma half-life. The IC90 from 10-day monotherapy studies for TAF is 
<50 ng*h/mL. 
 
Table 2 shows plasma TAF area under the curve (AUC) in non-pregnant adults from Phase III 
studies of TAF (36). Both TAF 25 mg and TAF 10 mg with COBI yield similar AUC parameters. 
  
Table 2 
Plasma TAF AUC in Non-Pregnant Adults 
Genvoya + Descovy (TAF 10 & 25 mg)
AUC (ng*h/mL)  
N=831 (292-0104, 292-0111, 311-1089)
Descovy only (TAF 25 mg)
AUC (ng*h/mL)  
N=161 (311-1089)
Mean
182
167
Median
167
158
Min
30.3
77.6
Max
1869
406
10% percentile
74.30
111.7
 


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1.3.2 
Tenofovir Alafenamide: Studies in Pregnancy 
 
TAF was classified as FDA pregnancy Category B (when this classification scheme was used). 
 
Thus far, minimal safety or efficacy data for TAF in pregnancy have been published or presented. 
In the most recent version of the Antiretroviral Pregnancy Registry report (issued 30 June 2017), 
1/8 women with first trimester exposure to TAF had a live-born child with a reported birth defect 
and 0/10 women with second or third trimester exposure had a live-born child with a reported 
birth defect. (25) 
 
The Phase IV WAVES study of EVG/COBI/FTC/TAF versus ATV/r + TDF/FTC 
(NCT01705574) enrolled only women (n=583). The extension phase of the study randomizes 
those in the ATV/r arm to remain on their current regimen or switch to EVG/COBI/FTC/TAF. 
Women who become pregnant in this study are encouraged to remain on their study drugs, and 
pregnancy outcomes are captured. Among 14 women with pregnancy in the 
EVG/COBI/FTC/TAF arm thus far, three had a live birth, four had an elective abortion, five had 
a spontaneous abortion, and two were pending their pregnancy outcome (37). Among six women 
with pregnancy in the ATV/r + FTC/TDF arm thus far, three had a live birth, one had an elective 
abortion, one had a spontaneous abortion, and one was pending her pregnancy outcome (37). 
These numbers are too small to permit meaningful interpretation of findings; it is also important 
to note that spontaneous abortion rates in women followed prospectively from conception, as in 
this study, are not available for most ART regimens, and that spontaneous abortion may occur in 
up to one third of the general population) (38). 
 
As noted in Section 1.6.2, tenofovir (the metabolite of both TAF and TDF) crosses the placenta 
well. Given approximately 10-fold higher plasma concentrations of tenofovir with the use of TDF 
(compared with TAF), placental concentrations of tenofovir may well be lower with TAF than 
with TDF. However, no data on this exist to date. 
 
TAF PK in Pregnancy 
 
IMPAACT P1026s is currently evaluating TAF PK in pregnancy. As of November 2017, 65 
women taking TAF during pregnancy had enrolled in P1026s (27 taking 25 mg unboosted, 8 
taking 25 mg boosted with COBI or RTV, and 30 taking 10 mg boosted with COBI).  
 
Version 1.0 of this protocol specified that TAF pregnancy PK data from IMPAACT P1026s 
would be reviewed to determine whether standard TAF dosing in pregnancy yields drug 
exposures exceeding a minimum level above which the drug is likely to maintain efficacy in 
pregnancy. Plasma TAF AUC in second and third trimesters was specified as the PK parameter of 
interest, to be reviewed when six or more women in P1026s had TAF PK data available through 
pregnancy outcome (with either the 25 mg TAF doing or the 10 mg TAF dosing boosted with 
COBI). Pre-specified decision rules for this data review were as follows:  
 
 
If at least 50% of women had TAF AUC >10th percentile (i.e., >74 ng*hr/mL) on all 
measurements, IMPAACT 2010 would be permitted to open. The IMPAACT 2010 team, in 
collaboration with the IMPAACT P1026s team, would summarize the TAF PK results and 
the decision to open IMPAACT 2010 to enrollment in a memorandum to the study sites.  
 


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 
If <50% of women reach this AUC target, the IMPAACT 2010 team would discuss next 
steps, which might include waiting for additional TAF pregnancy PK data. The team would 
also review any available virologic suppression data from P1026s participants taking TAF-
containing regimens. 
 
As documented in a protocol Clarification Memorandum issued under protocol Version 1.0, the 
protocol-specified review of data from IMPAACT P1026s was completed in mid-June 2017. The 
review included data from 11 women, seven of whom were receiving 25 mg TAF (unboosted) 
and four of whom were receiving 10 mg TAF boosted with COBI. Among the 11 women, two 
had PK samples collected only in the second trimester of pregnancy, four had samples collected 
in both the second trimester and the third trimester, and five had samples collected only in the 
third trimester. The resulting fifteen AUC values during pregnancy ranged from 119 to 524 
ng*hr/mL, with a median of 152 ng*hr/mL in the second trimester and a median of 176 ng*hr/mL 
in the third trimester. All AUC values were greater than 74 ng*hr/mL. Based on these results, the 
TAF PK criteria for opening IMPAACT 2010 to accrual were met.  
 
1.3.3 
Animal Studies of Tenofovir Alafenamide 
 
Embryonic fetal development studies of TAF have been performed in rats and rabbits. These 
revealed no evidence of impaired fertility or harm to the fetus due to TAF. The embryo-fetal 
studies showed no observed adverse effect levels in rats and rabbits occurred at TAF exposures 
similar to and 53 times higher than, respectively, the exposure in humans at the recommended 
daily dose. TAF is rapidly converted to tenofovir. The observed tenofovir exposure in rats and 
rabbits were 59 and 93 times higher than human tenofovir exposures at the recommended daily 
doses, respectively. The information above was obtained from the Genvoya® package insert (39). 
 
Although there are no preclinical data available regarding the penetration of TAF into the 
placenta or breast milk, data from animal (rat) and in vitro models suggest that it is unlikely that 
intact TAF-prodrug crosses the placental barrier at significant levels, due to the expression of 
efflux transporters (40), as is the case with TDF, also a prodrug of tenofovir (41). 
 
1.4 
Prior Research on Dolutegravir + Emtricitabine/Tenofovir Alafenamide (DTG + FTC/TAF) in 
Non-Pregnant Adults 
 
DTG and FTC/TAF have not yet been studied in combination. However, two studies have 
evaluated DTG/3TC as two-drug therapy in ART-naïve adults, given the high potency and high 
barrier to emergence of resistance with DTG:  
 
a. A pilot study of DTG/3TC as initial therapy in 20 ART-naive adults with baseline HIV-1 
RNA ≤100,000 copies/mL and CD4 count ≥200 cells/mm3 (the PADDLE study, 
NCT02211482). Results were encouraging: after 8 weeks of DTG/3TC, all 20 study 
participants had a viral load below 50 copies/mL, all 20 maintained HIV-1 RNA below 50 
copies through week 24, and 18 of 20 had HIV-1 RNA <50 copies/mL at 48 weeks (one had 
low-level viremia, one died) (12, 42). 
 
b. The AIDS Clinical Trials Group (ACTG) conducted A5353, a Phase II single-arm open-label 
study of two-drug treatment with DTG/3TC in 120 ART-naive adult men and women with 
HIV-1 RNA ≥1,000 copies/mL and <500,000 copies/mL (at entry, median HIV-1 RNA was 
4.6 log10 copies/mL and CD4 count was 387 cells/mm3). At 24 weeks, 108/120 (90%, CI 
[83%, 95%]) had HIV-1 RNA <400 copies/mL, with no significant difference in suppression 


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rates between persons with entry HIV-1 RNA <100,000 copies/mL versus >100,000 
copies/mL: 90% [82%, 96%] and 89% [75%, 97%], respectively. In the as-treated population, 
108/112 (96% [91%, 99%]) had HIV-1 RNA < 50 copies/mL at 24 weeks, with no difference 
between the HIV-1 RNA strata (99% [93%, 100%] versus 92% [78%, 98%], p=0.10). The 
three participants (two in low, one in high HIV-1 RNA strata) with virologic failure had 
plasma DTG levels below the limit of quantification around the time of failure, and no 
integrase mutations were detected (M184V was detected in one participant). (43) 
 
The fact that DTG/3TC alone (without a third drug such as TAF) may be sufficiently potent ART 
in first-line treatment of adults provides some further assurance of the potency of three-drug ART 
with DTG+FTC/TAF in pregnant women, although there are insufficient data on DTG/3TC alone 
in non-pregnant adults to warrant testing this approach in pregnant women. 
 
1.5 
Prior Research on Emtricitabine (FTC, EmtrivaTM) 
 
1.5.1 
Emtricitabine: Studies in Non-Pregnant Adults 
 
Emtricitabine (FTC) is a synthetic nucleoside analogue with activity against HIV reverse 
transcriptase. FTC is widely used globally, and is included in the first-line recommended regimen 
by the WHO for adults, including pregnant women (2, 3). It is also included in recommended 
agents to be used during pregnancy by the US DHHS (13). 
 
Two Phase III controlled studies (FTC-301A and FTC-303) provide the most information 
concerning the safety and efficacy of FTC in HIV-infected adults treated for extended periods 
with combinations of ART (44). 
 
Study FTC-301A was a 48 week, double-blind, active-controlled, multicenter study comparing 
FTC (200 mg) once daily to d4T in combination with once daily open-label didanosine and EFV 
in 571 ARV-naïve patients with plasma HIV RNA >5,000 copies/mL. At week 48, FTC was 
statistically superior to d4T with 81% of the patients in the FTC treatment group achieving and 
maintaining plasma HIV RNA <400 copies/mL compared with 68% of the patients in the d4T 
treatment group. Likewise, the proportion of patients who achieved and maintained plasma HIV 
RNA <50 copies/mL was statistically significantly different with 78% of patients in the FTC 
treatment group compared with 59% of patients in the d4T treatment group. Additionally, FTC-
treated patients had a statistically greater increase in CD4 cell count at Week 48 with a mean 
increase from baseline of +168 cells/mm3 for the FTC group and +134 cells/mm3 for the d4T 
group. The proportion of patients with virologic failure was 3% in the FTC group and 11% in the 
d4T group. A statistically greater proportion of patients in the d4T group experienced an AE that 
led to study drug discontinuation through Week 48 than in the FTC group (13% versus 7%). 
 
Study FTC-303 was a 48 week, open-label, active-controlled, multicenter study comparing FTC 
to 3TC in combination with d4T or ZDV and a PI or NNRTI in 440 patients who were on a 3TC- 
containing triple-ARV regimen for at least 12 weeks prior to study entry and had plasma HIV 
RNA <400 copies/mL (44). Patients were randomized 1:2 to continue therapy with 3TC (150 mg 
BID) or to switch to FTC (200 mg QD). All patients were maintained on their stable background 
regimen. Through 48 weeks of therapy, there was no statistically significant difference between 
treatment groups in efficacy outcomes. The proportion of patients with virologic failure was 7% 
in the FTC arm and 8% in the 3TC arm. Through 48 weeks of therapy, the proportion of patients 
who achieved and maintained plasma HIV RNA <400 copies/mL was 77% in the FTC arm and 
82% in the 3TC arm. The difference was largely attributed to attrition from the study and not loss 
of virologic activity. Likewise, the proportion of patients who achieved and maintained plasma 


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HIV RNA <50 copies/mL was 67% in the FTC arm and 72% in the 3TC arm. The mean increase 
from baseline in CD4 cell counts was +29 cells/mm3 in the FTC arm and +61 cells/mm3 in the 
3TC arm. These findings support equivalent efficacy of FTC 200 mg once daily and 3TC 150 mg 
administered twice daily (45). 
 
More than 2,000 adult patients with HIV infection have been treated with FTC alone or in 
combination with other ARVs for periods of 10 days to 200 weeks in Phase I-III clinical trials. 
Assessment of AEs is based on data from studies FTC-301A and FTC-303 in which 571 
treatment naïve (FTC-301A) and 440 treatment experienced (FTC-303) patients received FTC 
200 mg (n=580) or comparator drug (n=431) for 48 weeks. 
 
The most common adverse events that occurred in patients receiving FTC with other ARVs in 
clinical trials were headache, diarrhea, nausea, and rash event, which were generally mild to 
moderate in severity. Approximately 1% of patients discontinued participation in the clinical 
studies due to these events. All AEs were reported with similar frequency in FTC and control 
treatment groups with the exception of skin discoloration, which was reported with higher 
frequency in the FTC-treated group. Skin discoloration, manifested by hyperpigmentation on the 
palms and/or soles was generally mild and asymptomatic. Laboratory abnormalities in these 
studies occurred with similar frequency in the FTC and comparator groups. 
 
1.5.2 
Emtricitabine: Studies in Pregnancy 
 
FTC was classified as FDA pregnancy Category B (when this classification scheme was used). 
There are sufficient data in the Antiretroviral Pregnancy Registry to rule out at least a 1.5-fold 
increase in overall birth defects and a 2-fold increase in the risk of cardiovascular and 
genitourinary birth defects with FTC (46). 
 
In a study of 35 pregnant women given a dose of 400 mg FTC at the onset of labor, median 
cord/maternal drug ratio was 0.73, indicating significant placental transfer. Median AUC after a 
400 mg dose in labor was 15.5 mg*h/L, similar to levels in non-pregnant adults after a 200 mg 
dose. Among 18 women receiving standard FTC dosing (200 mg/day) during the third trimester, 
median AUC of 8.6 μg*h/mL was above the target of >7 μg*h/mL, but only 12 of 18 women 
were above the target (47). Mean cord/maternal blood ratio at delivery was 1.17. 
 
Emtricitabine is excreted into human breast milk, achieving median minimal and maximal breast 
milk concentrations of 177 and 679 ng/mL, well above the estimated emtricitabine IC50 for HIV-
1. The median dose of FTC that was estimated to be delivered by breast milk represented only 2% 
of the recommended infant treatment dose. (48) 
 
1.5.3 
Animal Studies of Emtricitabine 
 
Carcinogenicity 
 
In long-term oral carcinogenicity studies of FTC, no drug-related increases in tumor incidence 
were found in mice at doses up to 750 mg/kg/day (26 times the human systemic exposure at the 
therapeutic dose of 200 mg/day) or in rats at doses up to 600 mg/kg/day (31 times the human 
systemic exposure at the therapeutic dose). Emtricitabine was not genotoxic in the reverse 
mutation bacterial test (Ames test), mouse lymphoma, or mouse micronucleus assays. (49) 
 


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Reproduction/Fertility 
 
FTC did not affect fertility in male rats at approximately 140-fold or in male and female mice at 
approximately 60-fold higher exposures (AUC) than in humans given the recommended 200 mg 
daily dose. Fertility was normal in the offspring of mice exposed daily from before birth (in 
utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than 
human exposures at the recommended 200 mg daily dose. (49) 
 
Teratogenicity/Developmental Toxicity 
 
The incidence of fetal variations and malformations was not increased in embryofetal toxicity 
studies performed with FTC in mice at exposures (AUC) approximately 60-fold higher and in 
rabbits at approximately 120-fold higher than human exposures at the recommended daily dose. 
(49) 
 
Placental and Breast Milk Passage  
 
FTC has been shown to cross the placenta in mice and rabbits; the average fetal/maternal drug 
concentration was 0.4 in mice and 0.5 in rabbits (47). 
 
1.5.4 
Emtricitabine and Hepatitis B Infection 
 
Exacerbations of hepatitis B (HBV) have been reported after discontinuation of FTC (50, 51). 
Patients who are co-infected with HBV and HIV may have increased values on liver function 
tests (LFTs) and exacerbation of hepatitis symptoms when FTC is stopped. Usually these 
symptoms are self-limiting; however, serious complications have been reported. The threshold for 
stopping antiretrovirals with activity against HBV (including FTC) should be high, and patients 
co-infected with HBV and HIV should be closely monitored with both clinical and laboratory 
assessments for several months after stopping FTC treatment. 
 
1.6 
Prior Research on Tenofovir Disoproxil Fumarate (TDF, Viread®) 
 
1.6.1 
Tenofovir Disoproxil Fumarate: Studies in Non-Pregnant Adults 
 
TDF is one of the most widely-used antiretrovirals globally, and is included in the first-line 
recommended regimen by the WHO for adults, including pregnant women (2, 3).  
 
Although TDF is a nucleotide analogue, it has the same mechanism of action and resistance 
pattern as NRTIs. Therefore, for simplification of discussion, TDF will be referred to as an NRTI 
in this study. 
 
Efficacy in Treatment Naïve Patients 
 
Study 903 was a 144-week randomized, double-blind trial designed to compare the efficacy and 
safety of a treatment regimen of TDF, 3TC, and EFV to a regimen of d4T, 3TC and EFV in 600 
ART-naive adults with HIV infection. Following the completion of the double blind portion of 
the trial, there was an additional two-year single arm open-label portion of the trial in selected 
sites, wherein all patients received TDF, 3TC and EFV as once daily regimen. (Patients originally 
randomized to the d4T arm switched to receive TDF.) 
 


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In a 144-week analysis, when missing observations in the intent to treat (ITT) analysis were 
treated as having plasma HIV RNA concentrations greater than 400 copies/mL, 76% of 
participants in the TDF group and 72% of participants in the d4T active control group achieved 
plasma HIV RNA concentrations <400 copies/mL. Plasma HIV RNA concentrations 
<50 copies/mL at week 144 were seen in 73% and 69% of participants in the TDF and d4T active 
control groups, respectively. The mean increases in CD4 cell count from baseline to week 144 
were 263 cells/mm3 and 283 cells/mm3 for the TDF and d4T active control groups, respectively. 
The assessments of safety and tolerability indicate that the safety profile of TDF 300 mg/day was 
similar to that of the d4T active control (52). 
 
FTC-TDF compared to 3TC-ZDV 
 
Study 934 was a Phase III, randomized, open-label, multicenter study designed to compare a 
regimen of EFV with either TDF 300 mg/FTC 200 mg once daily or ZDV 300 mg/3TC 150 mg 
twice daily as fixed dose combination (FDC) Combivir® (52). Interim analysis at 48 weeks 
revealed discontinuation occurred more frequently in the 3TC-ZDV group (9%) than FTC-TDF 
(4%), mostly because of AEs such as anemia and nausea. The 48-week data demonstrated that, 
using the time to loss of virologic suppression as the primary analysis in which missing or 
switching is counted as a failure, the proportion of participants with plasma HIV RNA levels less 
than 400 copies/mL in an ITT analysis (n=487) was 84% in the FTC-TDF group compared to 
73% in the 3TC-ZDV-treated participants (p=0.002). The proportion of participants with plasma 
HIV RNA levels <50 copies/mL was 80% in the FTC-TDF group versus 70% in the 3TC-ZDV 
group (p=0.021). These results are supported by 96-week data (53). 
 
Tenofovir and TDF administered in toxicology studies to rats, dogs, and monkeys at exposures 
(based on AUCs) between 6- and 12-fold higher than observed in humans caused bone toxicity. 
In monkeys, the bone toxicity was diagnosed as osteomalacia, and appeared to be reversible upon 
dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as 
reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown. Studies to 
assess loss of bone density among patients receiving tenofovir are described below. 
 
More than 1,200 patients have received TDF 300 mg once daily alone or in combination with 
other ARVs in Phase I-III clinical trials. Over 11,000 patients have received TDF in expanded 
access programs. The cumulative patient exposure to marketed TDF from first approval to 
31 December 2003 is estimated to be approximately 200,000 patient-years of treatment.  
 
In clinical trials in treatment-experienced patients (Studies 902 and 907), the safety profile of 
TDF 300 mg/day was similar to that of placebo. There were no clinically significant AEs 
attributable to TDF 300 mg once daily other than a slightly higher incidence of mild to moderate 
gastrointestinal AEs (nausea, diarrhea, vomiting, and flatulence). Few adverse laboratory events 
were documented other than mild or moderate transient hypophosphatemia. Clinically significant 
events considered by the investigators to be related to TDF were uncommon and none suggested 
potential adverse drug reactions or drug-drug interactions (54, 55). 
 
Study 910 was initiated to observe the long-term safety effects of TDF, in combination with other 
ARVs, in participants who have completed prior TDF studies 901, 902, and 907. The long-term 
safety and tolerability of TDF were monitored using periodic assessments of concomitant 
medications, AEs, serial laboratory tests, and bone densitometry (in select participants). A total of 
687 participants received TDF 300 mg either initially or through rollover. Long-term follow up 
shows that the incidence of AEs or laboratory abnormalities leading to discontinuation of TDF 
remained low despite mean treatment duration of more than two years, and extending to nearly 


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four years in some participants. None of the AEs or laboratory abnormalities that led to study 
drug discontinuation had a reported incidence of more than 1%. Furthermore, there was no 
indication of nephrotoxicity in this highly treatment-experienced population (56). In a large 
cohort of HIV-infected adults in Zambia, only 0.25% of patients with no or mild renal 
dysfunction at pre-ART baseline experienced severe renal dysfunction after 12 months of TDF-
containing ART (and 1.8% developed moderate or severe renal dysfunction) (57). 
 
1.6.2 
Tenofovir Disoproxil Fumarate: Studies in Pregnancy 
 
TDF was classified as FDA pregnancy Category B based on animal and clinical data (when this 
classification scheme was used). 
 
In the Antiretroviral Pregnancy Registry, sufficient numbers of first trimester TDF exposures 
have been monitored to detect at least a two-fold increase in risk of overall birth defects but no 
such increase in birth defects has been observed. The prevalence of birth defects after first 
trimester TDF exposure was 2.3% (60 of 2,608 births; 95% CI, 1.8%-3.0%), which is within the 
range of congenital anomalies reported in the general US population (46). 
 
TDF pharmacokinetics during pregnancy among 19 pregnant women was assessed in P1026s in 
the last trimester between weeks 30-36 and also at 6-12 weeks post-delivery. The proportion of 
pregnant women with AUC exceeding the target of 2 µg hour/mL was slightly lower in the third 
trimester (74%) than postpartum (86%) but trough levels were comparable at both time points. A 
recent case series found TDF to be well tolerated among 76 pregnant women, with two stopping 
therapy, one for rash and one for nausea. All 78 infants were healthy with no signs of toxicity, 
and all were HIV-uninfected (58). 
 
In three studies of pregnant women, the cord-to-maternal blood ratio ranged from 0.60 to 0.99, 
indicating high placental transfer (59-61). A dose of 600 mg of TDF in labor resulted in levels in 
the women similar to levels in non-pregnant adults after a 300 mg dose, suggesting higher doses 
are required for adequate levels during labor in term pregnant women (62). 
 
Tenofovir does not penetrate well into human breast milk (breast milk/maternal plasma 
ratio = 0.08) (63). 
 
An observational study of 74 TDF-exposed (DXA at median 13 days) and 69 TDF-unexposed 
infants (DXA at median 19 days) showed that the mean (standard deviation) bone mineral content 
(BMC) of TDF-exposed infants was 12% lower than for TDF-unexposed infants (56.0 [11.8] 
versus 63.8 [16.6] g; p=0.002); and that the adjusted mean bone mineral content was 5.3 g lower 
(95% CI, -9.5, -1.2; p=0.013) in the TDF-exposed infants (8).  
 
The P1084s substudy of the PROMISE trial sought to compare newborn BMC by randomized 
exposure to maternal ZDV+sdNVP with brief TDF/FTC tail; LPV/r+ZDV/3TC or 
LPV/r+TDF/FTC. Infant DXA was performed from 0-21 days of life. Mean infant whole body 
BMC was significantly lower in both LPV/r arms compared to the ZDV arm, but was not 
significantly worse in the TDF/FTC arm compared with the ZDV/3TC arm (in the context of 
LPV/r exposure in both of these arms). Lumbar spine BMC did not differ significantly between 
regimens. (7) 
 


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1.6.3 
Animal Studies of Tenofovir Disoproxil Fumarate 
 
Chronic dosing of rats in pregnancy noted no growth or reproductive problems when TDF was 
administered at doses not associated with maternal toxicity. At high doses of exposure (25 times 
the AUC achieved with therapeutic dosing), no fetal structural changes were seen. 
 
Chronic exposure of fetal monkeys to TDF at a high dose of 30 mg/kg (25 times the AUC levels 
achieved with therapeutic doses in humans) from days 20-150 of gestation was associated with 
maternal monkey toxicity but did not result in gross structural abnormalities (64). However, 
significantly lower fetal circulating insulin-like growth factor levels were reported and were 
associated with body weights 13% lower than untreated controls. A slight reduction in fetal bone 
porosity was also observed within two months of maternal treatment. However, a macaque 
treated for over 10 years with 10 mg/kg/day of TDF has given birth over several years to three 
infant macaques, all of whom were normal and had no bone abnormalities at birth (65). 
 
Studies of intravenous TDF administration in pregnant cynomolgus monkeys reported a 
fetal/maternal concentration of 17% indicating some placental transfer (64).  
 
1.6.4 
Tenofovir Disoproxil Fumarate and Hepatitis B Infection 
 
Exacerbations of HBV have been reported in patients after discontinuation of TDF (66). Patients 
who are co-infected with HBV and HIV may have increased values on LFTs and exacerbation of 
hepatitis symptoms when TDF is stopped. Usually these symptoms are self-limiting; however, 
serious complications have been reported. The threshold for stopping antiretrovirals with activity 
against HBV (including TDF) should high, and patients co-infected with HBV and HIV should be 
closely monitored with both clinical and laboratory assessments follow-up for several months 
after stopping TDF. 
 
1.7 
Prior Research on Emtricitabine and Tenofovir Disoproxil Fumarate Fixed-Dose 
Combination Tablet (FTC/TDF, Truvada®) 
 
Gilead Sciences developed Truvada, a product containing FTC 200 mg and TDF 300 mg in a 
fixed-dose combination (FDC) tablet formulation that was approved by the FDA in August 2004. 
As a component of the New Drug Application, two Phase I studies evaluating the 
pharmacokinetics of co-administered FTC and TDF tablet formulation were completed. 
 
Overall, Study GS-US-104-172 demonstrated bioequivalence between the FTC-TDF combination 
tablet and the FTC capsule and TDF tablet formulations when administered separately. 
Administration of the FTC-TDF combination tablet with either a high-fat meal or light meal 
increased tenofovir exposure by approximately 30% compared with fasted-state administration. 
Clinical experience with TDF indicates that the effect of food on tenofovir exposure is not of 
clinical relevance. FTC and TDF, either administered as a combination tablet (containing FTC 
200 mg/ TDF 300 mg) or co-administered as FTC 200 mg capsule and TDF 300 mg tablet were 
well tolerated. 
 
Among women becoming pregnant while taking part in pre-exposure prophylaxis trials, no 
significant difference in adverse pregnancy outcomes (including preterm delivery or congenital 
anomalies) were observed between the TDF, TDF/FTC, and placebo arms (67, 68). 
 


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1.8 
Prior Research on Efavirenz (EFV, Sustiva®, Stocrin®) 
 
1.8.1 
Efavirenz: Studies in Non-Pregnant Adults 
 
EFV is a potent NNRTI that is approved by the FDA and that has been widely used in 
combination with other antiretroviral agents for the treatment of HIV-1 infection throughout the 
world. It is included in the first-line preferred regimen by the WHO for adults, including pregnant 
women and women of childbearing age (2, 3). The US HHS perinatal guidelines also include 
EFV among recommended agents for use in pregnancy, but starting after 8 weeks’ gestation. 
 
Clinical Experience with EFV 
 
EFV is a once daily NNRTI that has been shown to be effective in the treatment of HIV disease, 
demonstrating high and durable levels of virologic suppression (in combination with two NRTIs) 
in multiple large studies conducted among ART-naive patients. EFV was superior to LPV/r in the 
ACTG A5142 trial (69), but comparable to ATV/r in the ACTG A5202 study (70). In the 2NN 
study, NVP did not meet non-inferiority criteria when compared to EFV (71). In the ECHO and 
THRIVE studies, EFV was non-inferior to RPV; EFV was associated with lower rates of 
virologic failure (particularly among participants with pre-ART HIV-1 RNA >100,000 
copies/mL) (72). 
 
In more recent studies, some regimens have been found to be superior to EFV, primarily due to 
fewer discontinuations because of AEs in non-EFV regimens. As noted earlier, the SINGLE trial 
showed that a DTG-based regimen was superior to EFV for the primary endpoint of viral 
suppression at Week 48 (12). In the STARTMRK trial, raltegravir was superior to EFV at 4 and 5 
years (73, 74). 
 
Safety Profile 
 
The most significant side effects associated with EFV are central nervous system (CNS) 
symptoms and rash. CNS symptoms include, but are not limited to, dizziness, impaired 
concentration, somnolence, abnormal dreams, and insomnia. Symptoms usually begin during the 
first or second day of therapy and generally resolve after the first 2 to 4 weeks of therapy. 
Symptoms may also be less noticeable if EFV is taken at bedtime. Potential for additive 
symptoms may occur if used concomitantly with alcohol or psychoactive drugs.  
 
In multi-study comparisons of EFV-treated versus controls, severe acute depression (1.6% versus 
0.6%) and suicidal ideation (0.6% versus 0.3%) were reported. Patients with a history of 
psychiatric disorder are at greater risk. There have been occasional post-marketing reports of 
delusions and aberrant behavior, predominantly in those with a history of mental illness or 
substance abuse. An analysis including data from four ACTG trials showed a higher rate of 
suicidality (reported suicidal ideation or attempted or completed suicide) among patients taking 
EFV-containing regimens compared with non-EFV comparator regimens (5), although this 
association was not found in two large observational cohorts (75, 76). 
 
Rash is usually mild to moderate and occurs within the first two weeks of initiating therapy. In 
most participants, rash resolves with continuing EFV therapy within one month. However, EFV 
can be associated with erythema multiforme/Stevens-Johnson syndrome. Among approximately 
2,200 treated individuals in studies and expanded access programs, the incidence of grade 4 rash 
(e.g., erythema multiforme and Stevens-Johnson syndrome) was 0.14%. The median time to onset 
of rash in adults was 11 days, and the median duration was 16 days. EFV should be permanently 


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discontinued in persons developing severe rash associated with blistering, desquamation, mucosal 
involvement, or fever. Appropriate antihistamines and/or corticosteroids may improve the 
tolerability and hasten the resolution of rash. (77) 
 
Other side effects associated with EFV include upset stomach, diarrhea, anorexia, headache, 
tiredness, pancreatitis, elevated cholesterol (including HDL), elevated triglycerides, and elevated 
transaminases. EFV has also been associated with severe drug-induced liver injury in South 
Africa, with higher CD4 count at ART initiation, younger age, and possibly female gender 
associated with these liver events (4). Finally, EFV has been associated with prolonged QTc, 
particularly in individuals with slower EFV metabolism (78). 
 
More information can be found in the most recent Sustiva or Stocrin package insert (77). 
 
1.8.2 
Efavirenz: Studies in Pregnancy 
 
The following section has been taken from the US DHHS Guidelines, Panel on Treatment of 
HIV-Infected Pregnant Women and Prevention of Perinatal Transmission (13). 
 
The FDA advises women to avoid becoming pregnant while taking EFV and health care 
providers to avoid administration in the first trimester of pregnancy as potential fetal harm may 
occur. However, EFV remains a cornerstone of the preferred first-line antiretrovirals 
recommended by the WHO, regardless of trimester (and for women of childbearing potential), 
and is used by millions of women globally. 
 
Pharmacokinetics  
 
A recent review of an intensive pregnancy PK study plus four others that measured single EFV 
concentrations in pregnant women found that EFV concentrations were not significantly affected 
by pregnancy and that high rates of HIV RNA suppression at delivery were achieved with EFV-
containing regimens (79). 
 
Placental and Breast Milk Passage 
 
In a study of 25 mother-infant pairs, median EFV cord blood/maternal blood concentration was 
0.49 (range 0.37–0.74) (80). In a study of 13 women in Rwanda, EFV concentration was 
significantly higher in maternal plasma than skim breast milk (mean breast milk to mean maternal 
plasma concentration ratio 0.54) and higher in skim breast milk than in infant plasma (mean skim 
breast milk to mean newborn plasma concentration ratio 4.08) (81). Mean infant plasma EFV 
concentrations were 860 ng/mL; the mean infant plasma EFV concentration was 13.1% of 
maternal plasma concentrations. All infants had detectable plasma concentrations of EFV, and 
eight of 13 newborns had plasma EFV concentrations below the minimum therapeutic 
concentration of 1,000 ng/mL recommended for treatment of HIV-infected adults. In a study of 
plasma and hair drug concentration in 56 mother-infant pairs receiving EFV-based therapy during 
pregnancy and breastfeeding, infant plasma levels at delivery and hair levels at age 12 weeks 
suggested moderate in utero transfer during pregnancy and breastfeeding, with approximately 
one-third of transfer occurring postpartum (40% cumulative with 15% during breastfeeding) (82). 
All mothers and infants had detectable EFV plasma levels at 0, 8, and 12 weeks and mean infant-
to-maternal-hair concentration at 12 weeks postpartum was 0.40 for EFV. 
 


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Teratogenicity Data 
 
This section is adapted from the US DHHS Recommendations for Use of Antiretroviral Drugs in 
Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV 
Transmission in the United States (13). 
 
In pregnancies with prospectively reported exposure to EFV-based regimens in the Antiretroviral 
Pregnancy Registry through January 2016, birth defects were observed in 21 of 883 live births 
with first-trimester exposure (2.4%, 95% confidence interval [CI], 1.5% to 3.6%) (46). Although 
these data provide sufficient numbers of first-trimester exposures to rule out a two-fold or greater 
increase in the risk of overall birth defects, the low incidence of neural tube defects in the general 
population means that a larger number of exposures are still needed to be able to definitively rule 
out an increased risk of this specific defect. Prospective reports to the Antiretroviral Pregnancy 
Registry of defects after first-trimester EFV exposure have documented one neural tube defect 
case (sacral aplasia, myelomeningocele, and hydrocephalus with fetal alcohol syndrome) and one 
case of bilateral facial clefts, anophthalmia, and amniotic band. Among retrospective cases, there 
are six reports of CNS defects, including three cases of meningomyelocele in infants born to 
mothers receiving EFV during the first trimester. Retrospective reports can be biased toward 
reporting of more unusual and severe cases and are less likely to be representative of the general 
population experience. 
 
In an updated meta-analysis of 23 studies (including the Antiretroviral Pregnancy Registry data) 
reporting on birth outcomes among women exposed to EFV during the first trimester, there were 
44 infants with birth defects among 2,026 live births to women receiving first-trimester EFV (rate 
of overall birth defects (1.63%, 95% CI, 0.78% to 2.48%) (83). The rate of overall birth defects 
was similar among women exposed to EFV-containing regimens and non-EFV-containing 
regimens during the first trimester (pooled relative risk [RR] 0.78, 95% CI, 0.56–1.08). Across all 
births, one neural tube defect (myelomeningocele) was observed, giving a point prevalence of 
0.05% (95% CI, <0.01 to 0.28), within the range reported in the general population. The number 
of reported first-trimester EFV exposures (>2000) are sufficient to rule out more than a 2-3 fold 
increase in neural tube defects (83) (the incidence of neural tube defects in the general U.S. 
population is very low — 0.02% to 0.2% — so the incidence of defects even with a 2-3 fold 
increase would still be well under 1%). 
 
A French study of 13,124 live births between 1994 and 2010 included an analysis of 372 infants 
born after first-trimester EFV exposure (6). In the primary analysis using the European 
Surveillance of Congenital Anomalies (EUROCAT) classification system, no increase in birth 
defects after first trimester EFV exposure was detected compared to those without EFV exposure 
in pregnancy (adjusted odds ratio 1.16, 95% CI, 0.73–1.85). In a secondary analysis using the 
modified Metropolitan Atlanta Congenital Defect Program classification used by the 
Antiretroviral Pregnancy Registry, an association was found between first-trimester EFV 
exposure and neurologic defects. However, none of the four defects (i.e., ventricular dilatation 
with anomalies of the white substance, partial agenesis of the corpus callosum, subependymal 
cyst, and pachygyria) were neural tube defects, and none of the defects had common embryology 
(84). First-trimester EFV exposure was not associated with an increased risk of defects in a 
Pediatric HIV/AIDS Cohort Study analysis that included 2,580 live births, 94 after first-trimester 
EFV exposure (85) or an analysis of a national cohort in Italy that included 1,257 pregnancies, 80 
after first-trimester EFV exposure (86). 
 


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Although two small studies (Pediatric AIDS Clinical Trials Group [PACTG] protocol 219/219C 
and PACTG protocol P1025) reported a higher rate of birth defects among infants with first-
trimester exposure to EFV compared with those without exposure, the number of exposures was 
small (35 exposures in PACTG 219/219C and 42 in P1025) and there is overlap in defect cases 
between the two studies (87-89). Thus, additional data are needed on first-trimester EFV 
exposures to more conclusively determine if risk of neural tube defects is elevated. 
 
The FDA advises women to avoid becoming pregnant while taking EFV and health care 
providers to avoid administration in the first trimester of pregnancy. However, given that the risk 
of neural tube defects is restricted to the first 5 to 6 weeks of pregnancy (the neural tube closes at 
36 to 39 days after last menstrual period), pregnancy is rarely recognized before 4 to 6 weeks of 
pregnancy, and ARV drug changes in pregnancy may be associated with loss of viral control, 
EFV can be continued in pregnant women receiving EFV-based antiretroviral therapy who 
present for antenatal care in the first trimester (as recommended in the US perinatal ARV 
guidelines (90)). Since 2012, the British HIV Guidelines recommend that EFV can be used 
regardless of the trimester of pregnancy, stating that “...efavirenz can be used in pregnancy 
without additional precautions and considerations over and above those of other antiretroviral 
therapies” (91). 
 
1.8.3 
Animal Studies of Efavirenz 
 
This section is adapted from the US DHHS Recommendations for Use of Antiretroviral Drugs in 
Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV 
Transmission in the United States (13). 
 
Carcinogenicity 
 
EFV was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening 
tests. A study evaluating genotoxicity of EFV in mice noted DNA damage in brain cells after 
daily dosing for 36 days; no damage was seen in liver, heart, or peripheral blood cells (92). Long-
term animal carcinogenicity studies with EFV have been completed in mice and rats. At systemic 
drug exposures approximately 1.7-fold higher than in humans receiving standard therapeutic 
doses, no increase in tumor incidence above background was observed in male mice, but in 
female mice, an increase above background was seen in hepatocellular adenomas, carcinomas, 
and pulmonary alveolar/bronchiolar adenomas. No increase in tumor incidence above background 
was observed in male and female rats with systemic drug exposures lower than that in humans 
receiving therapeutic doses. 
 
Reproduction/Fertility 
 
No effect of EFV on reproduction or fertility in rodents has been seen. 
 
Teratogenicity/Developmental Toxicity 
 
An increase in fetal resorption was observed in rats at EFV doses that produced peak plasma 
concentrations and area under the curve (AUC) values in female rats equivalent to or lower than 
those achieved in humans at the recommended human dose (600 mg once daily). EFV produced 
no reproductive toxicities when given to pregnant rabbits at doses that produced peak plasma 
concentrations similar to and AUC values approximately half of those achieved in humans 
administered EFV (600 mg once daily). Central nervous system (CNS) malformations and cleft 
palate were observed in 3 of 20 infants born to pregnant cynomolgus monkeys receiving EFV 


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from gestational days 20 to 150 at a dose of 60 mg/kg/day (resulting in plasma concentrations 1.3 
times that of systemic human therapeutic exposure, with fetal umbilical venous drug 
concentrations approximately 0.7 times the maternal values) (93). The malformations included 
anencephaly and unilateral anophthalmia in one fetus, microphthalmia in another fetus, and cleft 
palate in a third fetus. 
 
Placental and Breast Milk Passage 
 
EFV readily crosses the placenta in rats, rabbits, and primates, producing cord blood 
concentrations similar to concentrations in maternal plasma. Maternal and fetal blood 
concentrations in pregnant rabbits and cynomolgus monkeys are equivalent, while fetal 
concentrations in rats exceeded maternal concentrations. 
 
1.9 
Rationale for the Study and its Objectives 
 
1.9.1 
Overall Rationale 
 
While current ART regimens achieve very low rates of perinatal HIV transmission when started 
early enough in pregnancy and adhered to, there is need for a safe, effective, and affordable 
alternative to EFV-containing ART for pregnant HIV-infected women in resource-constrained 
settings. Furthermore, it is very important to obtain pregnancy efficacy and safety data for 
antiretroviral regimens that are being adopted in newer first-line treatment regimens due to their 
better potency, tolerability, and resistance profiles. This study aims to ascertain the safety and 
virologic efficacy of DTG-containing ART during pregnancy and to obtain data on the efficacy 
and safety of DTG+FTC/TAF. These data will be relevant to well-resourced as well as resource-
constrained settings.  
 
1.9.2 
Rationale for Studying Virologic Efficacy 
 
Studies powered to detect differences in risk of perinatal HIV transmission require very large 
sample sizes. Maternal HIV-1 RNA at delivery is the strongest predictor of perinatal HIV 
transmission measured in studies thus far (94-96) and much of the transmission risk reduction 
associated with use of maternal ART regimens is achieved through reducing maternal viral 
burden. Therefore, virologic suppression at delivery, a surrogate for perinatal transmission rates, 
was chosen as the primary virologic efficacy outcome for this study. While it is acknowledged 
that there may be residual transmission risk not captured through measurement of maternal 
virologic suppression, virologic efficacy outcomes from this study will provide randomized 
clinical trial data needed to optimize choice of ART regimen during pregnancy. 
 
An HIV-1 RNA threshold of <200 copies/mL was chosen for the primary virologic endpoint 
(rather than <50 copies/mL) due to more reliable (and less variable) detection at 200 copies/mL, 
particularly when HIV-1 RNA is being tested at multiple different laboratories (even using the 
same testing platform). Use of the <200 copies/mL threshold (rather than <50 copies/mL) is also 
expected to lead to fewer “false calls” for clinical management of virologic failure and optimize 
the likelihood of correctly defining virologic success versus failure for statistical analysis. The 
primary virologic efficacy analysis will therefore use 200 copies/mL as the threshold, based upon 
testing that will be run in real time at each site. For a secondary objective, batched testing at one 
centralized VQA-certified laboratory will be performed to assess virologic suppression at 
delivery using a threshold of 50 copies/mL. 
 


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Non-inferiority was hypothesized for the primary virologic study objective, in order to establish 
that DTG-based ART does not have appreciably worse virologic efficacy in pregnant women 
compared with the current most frequently-used ART regimen globally. 
 
1.9.3 
Rationale for Studying Adverse Pregnancy Outcomes 
 
HIV-infected women, particularly women starting three-drug ART, experience higher rates of 
adverse pregnancy outcomes (preterm delivery, small for gestational age, and stillbirth) than 
HIV-uninfected women (9, 31, 97, 98). Certain antiretroviral drugs may be associated with 
specific adverse birth outcomes (e.g., PIs have been associated with preterm delivery in some 
studies, including one randomized controlled trial (99), but not in others (100-102)). However, 
observational data can be potentially misleading (e.g., due to residual confounding), and data 
from large randomized trials reflecting pregnancy outcomes by antiretroviral regimen are scarce. 
In the PROMISE trial, rates of preterm delivery (<37 weeks) were not significantly different 
between TDF/LPV/r and ZDV/LPV/r (19.7% versus 18.5%); rates of very preterm delivery (<34 
weeks) were higher with TDF/LPV/r than ZDV/LPV/r (6.0% versus 2.6%, p=0.04) but not when 
compared with ZDV/sdNVP (3.2%, p=0.10) (9). 
 
In sum, it is possible that particular regimens or drug classes (and/or timing of ART use during 
pregnancy) are associated with adverse pregnancy outcome, but insufficient data exist to predict 
which antiretrovirals will be associated with lower/higher risk. It is important to ascertain rates of 
adverse pregnancy outcomes with new regimens that may be used in a widespread fashion in 
pregnant women (and women of childbearing potential). 
 
The upper gestational age limit specified for this study (28 weeks) was selected for appropriate 
evaluation of adverse pregnancy outcomes, as women enrolled at later gestational ages may be at 
lower risk for these outcomes (i.e., some women who already experienced these adverse 
pregnancy outcomes would not enroll in the study if enrollment at later gestational age were 
permitted). Women with known multiple pregnancies (e.g., twins) will be excluded from the 
study because of association of such pregnancies with fetal growth restriction, preterm delivery, 
and fetal demise, which are components of the primary adverse pregnancy outcome for this study.  
 
Congenital anomalies are excluded from the primary composite endpoint of adverse pregnancy 
outcomes because events that are associated with chromosomal abnormalities or with 
organogenesis (collectively, the vast majority of major congenital anomalies) cannot be related to 
study drug due to timing of first drug exposure. Thus, inclusion of these "pre-randomization" 
events may bias us toward not being able to detect a difference between arms. Secondary analyses 
will include congenital anomalies, however. 
 
The outcomes of any new pregnancies that occur during maternal follow-up will also be 
evaluated in this study. Although the number of new pregnancies is expected to be small, the 
planned exploratory analyses will provide some data on the outcomes that follow exposure to the 
study ART regimens during the first trimester of pregnancy. 
 


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1.9.4 
Rationale for Comparing Toxicity/Tolerability 
 
In the only trial to directly compare treatment with EFV-based versus DTG-based ART thus far 
(the SINGLE study), 10% of participants in the EFV arm and 2% in the DTG arm discontinued 
study drug due to AEs (although rates of serious adverse events did not differ between arms) (12). 
Based upon this (and upon other data from other trials showing DTG to be well tolerated (17, 
21)), it is anticipated that DTG will be at least as well tolerated as EFV in pregnant women. 
However, a higher proportion of patients stopped DTG in a clinical setting than in the trials 
published thus far (103), and data do not yet exist on the safety/tolerability of DTG in pregnant 
women. The safety and tolerability of DTG (and TAF) in pregnant women, compared to the 
current global standard of care regimen, EFV/FTC/TDF, will be important for decisions to be 
made by policy makers, clinicians and patients around the use of these drugs in pregnancy. 
 
Similarly, it is important to ascertain the general safety of newer maternal ART regimens for 
infants. For example, in the PROMISE trial, mortality among infants through one week of age 
was found (unexpectedly) to differ between randomized ARV arms: 1-week infant mortality was 
4.4% in TDF/LPV/r-exposed infants, 3.2% in ZDV/sdNVP-exposed infants (p=0.43) and 0.6% in 
ZDV/LPV/r-exposed infants (p=0.001 versus TDF/LPV/r); most infant mortality was likely 
mediated through preterm birth (9). Data are inconclusive regarding effects of in utero exposure 
to different ART combinations on infant growth (104, 105), neurodevelopment (106, 107), and 
hematological outcomes (with most data being reassuring) (108-110). 
 
Chronic treatment with TDF-containing ART is associated with more renal and bone toxicity than 
TAF is, in non-pregnant adults (15, 33). As noted earlier, the effects (if any) of in utero TDF 
exposure on infant bone development, growth, and renal function remain unclear. No data exist 
on the relative bone and renal toxicities of TDF versus TAF in postpartum women nor their 
newborns. This randomized trial represents an important opportunity to learn more about the 
effects of the 3 regimens on maternal and infant bone and renal outcomes. The rationale for 
conducting DXA once in infants at 26 weeks of age is to assess bone mineral density/content 
(BMD/BMC) at the latest time point on-study at which it is still practicable to perform high-
quality infant DXA, in order to capture potential longer-term effects of exposure to each regimen 
on infant BMD/BMC while minimizing infant radiation exposure. The rationale for conducting 
maternal DXA once at 50 weeks postpartum is to assess maternal BMD after the longest possible 
period of exposure to ART on-study.  
 
1.9.5 
Rationale for a Three-Arm Trial 
 
It is anticipated that DTG+FTC/TAF will be one of the most commonly used first-line ART 
regimens within the next few years, globally. One option would be to conduct a two-arm trial, 
comparing this new regimen (DTG+FTC/TAF) with the current global standard first-line regimen 
(EFV/FTC/TDF). The primary rationale for including the third arm (DTG+FTC/TDF) is to 
investigate effect modification of DTG in the presence of either TAF or TDF. This analysis will 
be highly informative in the event that there is an unexpected excess of safety events associated 
with exposure to DTG. Without the DTG+FTC/TDF arm, if there is an unexpected excess of 
safety events, it would be impossible to assess whether DTG+FTC/TAF is safer than 
DTG+FTC/TDF and it would be difficult to determine whether the safety signal was due to the 
DTG or the TAF. 
 
Inclusion of the DTG+FTC/TDF arm will also provide data on this specific regimen in 
pregnancy. These data may be important if FTC/TAF is not adopted as rapidly or widely in HIV 
treatment guidelines as currently expected (or as rapidly as DTG). 


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1.9.6 
Rationale for Exploratory Objectives 
 
Maternal Postpartum Depression 
 
EFV (and less commonly DTG) can be associated with development of depression; however, 
very little is known about the interplay between treatment with EFV and postpartum depression, 
and no data exist regarding the incidence of depression in postpartum women taking DTG-based 
regimens. This study offers an important opportunity to assess rates of postpartum depression by 
randomized regimen (with referral of women with possible signs/symptoms of depression for 
further evaluation/treatment). The study will also assess sleep disturbances and anxiety, as these 
are fairly common side effects of both EFV and DTG. 
 
Predictors of Adverse Pregnancy Outcomes 
 
Progesterone is a critical hormone in pregnancy that maintains the pregnancy state and works as 
an anti-inflammatory, smooth muscle relaxer and vasodilator (111). Murine and human studies 
have shown a relationship between progesterone levels and birth weight in the presence of 
antiretrovirals (112). At present, it is unknown whether specific ART regimens impact 
progesterone directly or via other regulatory hormones including prolactin (113); whether all 
ART regimens can impact progesterone levels or if this is restricted to PIs (112); or whether the 
timing of ART exposure in pregnancy matters. It is also unknown whether low progesterone 
levels impact birth outcomes directly (at the level of the cervix and placenta) or by allowing 
immunologic shifts away from a Th2-dominated environment (leading to systemic effects and 
possible placental damage). In addition, HIV-infected pregnant and postpartum women have been 
shown to have higher mortality than HIV-uninfected women, with higher reported rates of 
malaria, tuberculosis, and bacterial infections (114, 115). Many of these studies have been 
observational and performed in the era prior to the use of three-drug ART during pregnancy and 
postpartum, and the majority of data on chronic inflammation in HIV have focused on men. 
Levels of inflammation and associations with infectious morbidity and pregnancy complications 
have not been well described, particularly in resource-limited settings. Understanding the nature 
of residual inflammation in this unique population can provide targets for interventions designed 
to optimize clinical outcomes. 
 
Stored samples will be used to characterize ante- and postpartum inflammation, including IDO-1, 
monocyte activation, and other plasma markers of inflammation, and to evaluate the relationship 
between progesterone/prolactin/markers of inflammation and pregnancy outcomes. The study will 
evaluate changes over time and will compare women receiving the three different ART regimens. 
The primary analyses will be designed to understand the extent to which residual inflammation in 
women on ART is associated with infectious morbidity, pregnancy and delivery complications, 
and non-infectious morbidity. Analyses will advance our understanding of possible targets for 
anti-inflammatory clinical therapies that can reduce morbidity and optimize outcomes in pregnant 
and postpartum women. 
 


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Mother-to-Infant Transfer of ARVs during Pregnancy and Breastfeeding 
 
Studies such as IMPAACT P1026s provide maternal pregnancy and postpartum PK data (as well 
as data on neonatal elimination of some ARVs). However, P1026s does not assess penetration of 
ARVs into breast milk, nor levels of ARVs acquired by breastfeeding infants. This study provides 
the opportunity to collect samples that will permit assessment of DTG and TAF levels in breast 
milk (and in breastfeeding infants). Analysis of ARV levels in maternal and infant hair samples 
collected at delivery/birth will permit comparison of degree of maternal-infant ARV transfer (for 
the different ARVs). 
 
Maternal ART Adherence 
 
Maternal adherence to ARVs during the antepartum period tends to be very high, but some 
studies (particularly in programmatic settings) have reported loss to follow-up and/or drop-off in 
ART adherence in the postpartum period (116-118). Little is known about reasons for (and 
interventions to prevent) this decline in postpartum adherence (119). This study offers an 
opportunity to assess adherence overall, by antepartum versus postpartum periods, and by ARV 
regimen and study site. Hair levels of ARVs reflect drug uptake from the systemic circulation 
over weeks to months (120), reflecting cumulative exposure to medications over time (and 
therefore serving as an objective biomarker of antiretroviral adherence during pregnancy) (121). 
Adherence will be assessed in this study by HIV-1 RNA level, maternal and infant hair levels, 
and maternal self-report (122).  
 
1.10 
Hypotheses 
 
Among HIV-1-infected pregnant women initiating ART between 14 and 28 weeks gestation, and 
their infants: 
 
 
A DTG-containing regimen will be non-inferior to EFV/FTC/TDF with regard to virologic 
efficacy at delivery 
 
Rates of adverse pregnancy outcomes will not significantly differ between the three study 
ART regimens 
 
Rates of maternal and infant grade 3 or higher adverse events will not significantly differ 
between the three study ART regimens 
 
 
 
 


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2 
OBJECTIVES 
 
Note: In the objectives below, “a DTG-containing regimen” refers to the combination of both 
DTG-containing arms (i.e., Arm 1+Arm 2). “Any pairwise regimen comparison” refers to 
comparisons of Arm 1 to Arm 2, Arm 2 to Arm 3, and Arm 1 to Arm 3.  
 
2.1 
Primary Objectives 
 
The primary objectives of this study are to determine the following among HIV-1-infected 
pregnant women and their infants:  
 
2.1.1 
Whether treatment initiated during pregnancy with a DTG-containing regimen is non-
inferior to EFV/FTC/TDF with regard to virologic efficacy (HIV-1 RNA <200 
copies/mL) at delivery 
 
2.1.2 
Whether rates of the following safety outcomes differ for any pairwise regimen 
comparison:  
 
Adverse pregnancy outcomes (spontaneous abortion, fetal death, preterm delivery, or 
small for gestational age)  
 
Maternal grade 3 or higher adverse events through 50 weeks postpartum 
 
Infant grade 3 or higher adverse events through 50 weeks postpartum 
 
2.2 
Secondary Objectives 
 
The secondary objectives of this study are to evaluate the following among HIV-1-infected 
pregnant women and their infants:  
 
2.2.1 
Whether treatment initiated during pregnancy with a DTG-containing regimen is superior 
to EFV/FTC/TDF with regard to virologic efficacy (HIV-1 RNA <200 copies/mL) at 
delivery 
 
2.2.2 
Whether the following differ when comparing a DTG-containing regimen initiated during 
pregnancy to EFV/FTC/TDF:  
 
Proportion of mothers with HIV-1 RNA <50 copies/mL at delivery 
 
Proportion of mothers with HIV-1 RNA <200 copies/mL at 50 weeks postpartum  
 
Time to maternal HIV-1 RNA <200 copies/mL through delivery 
 
2.2.3 
Whether the following differs for any pairwise regimen comparison:  
 
Proportion of mothers with HIV-1 RNA <200 copies/mL using the standardized FDA 
snapshot algorithm at delivery and at 50 weeks postpartum 
 
2.2.4 
Whether rates of the following differ when comparing a DTG-containing regimen to 
EFV/FTC/TDF: 
 
Adverse pregnancy outcomes (spontaneous abortion, fetal death, preterm delivery, or 
small for gestational age)  
 
Maternal grade 3 or higher adverse events through 50 weeks postpartum 
 
Infant grade 3 or higher adverse events through 50 weeks postpartum 
 


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2.2.5 
Whether rates of the following differ for any pairwise regimen comparison: 
 
A composite outcome of spontaneous abortion, fetal death, preterm delivery, small 
for gestational age, or major congenital anomaly 
 
A ranked composite infant safety outcome measure through 50 weeks postpartum 
 
Infant HIV infection through 50 weeks postpartum 
 
Infant mortality through 50 weeks postpartum 
 
Infant bone toxicity at 26 weeks postpartum 
 
Maternal bone toxicity at 50 weeks postpartum  
 
Markers of maternal and infant renal toxicity through 50 weeks postpartum 
 
Antiretroviral drug resistance observed with each maternal ART regimen: 
– 
Among mothers who experience virologic failure (at baseline and time of 
virologic failure)  
– 
Among HIV-infected infants (at time of HIV diagnosis) 
 
2.2.6 
Whether treatment initiated during pregnancy with each regimen is non-inferior with 
regard to preterm delivery and, separately, small for gestational age for any pairwise 
regimen comparison 
 
2.3 
Exploratory Objectives 
 
The exploratory objectives of this study are to: 
 
 
2.3.1 
Evaluate the following with treatment initiated in pregnancy with a DTG-containing 
regimen compared to EFV/FTC/TDF: 
 
Maternal postpartum depression through 50 weeks postpartum 
 
Adverse outcomes of subsequent pregnancies occurring during maternal follow-up 
 
2.3.2 
Evaluate potential immunologic and hormonal predictors of adverse pregnancy outcomes 
and postpartum maternal health outcomes and the association of these factors with 
maternal ART regimens 
 
2.3.3 
Assess for associations between maternal antepartum adverse events and adverse 
pregnancy outcomes 
 
2.3.4 
Assess for associations between maternal antiretroviral drug levels and maternal and 
infant adverse events 
 
2.3.5 
Assess for mother-to-infant transfer of antiretrovirals during pregnancy and breastfeeding 
 
2.3.6 
Assess adherence to maternal ART regimens in the antenatal and postnatal periods and 
describe barriers and facilitators of adherence in these periods 
 
 


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3 
STUDY DESIGN 
 
This is a Phase III, three-arm, randomized, open-label study to compare the virologic efficacy and 
safety of three antiretroviral regimens for HIV-1-infected pregnant women and their infants.  
Refer to Figure 1 for an overview of the study design and to Section 4 for the study eligibility 
criteria. A total of 639 mother-infant pairs are expected to be enrolled at study sites in Botswana, 
Brazil, Haiti, India, Malawi, South Africa, Thailand, Uganda, the United States, Tanzania, and 
Zimbabwe.  
 
Mother-infant pairs will be screened for eligibility during pregnancy and enrolled at 14-28 weeks 
gestation. Mothers will be ART-naïve, defined as having not received prior antiretroviral therapy, 
other than ARVs received during previous pregnancies or previous periods of breastfeeding 
(stopped at least six months prior to study entry). Mothers will be permitted to have taken ARVs 
during previous pregnancies and/or periods of breastfeeding to optimize the generalizability of 
study findings to the relevant population of interest. Mothers will be permitted (but not required) 
to receive up to 14 days of non-study ART in the current pregnancy prior to study entry as part of 
local standard management. This period of non-study ART use was selected to ensure that 
initiation of ART is not delayed while mothers are being screened for the study while also 
keeping the period of non-study ART exposure as short as is feasible to minimize potential 
impacts on study outcomes. 
 
Upon enrollment, mothers will be randomly assigned in a 1:1:1 ratio to receive either 
DTG+FTC/TAF (Arm 1), DTG+FTC/TDF (Arm 2), or EFV/FTC/TDF (Arm 3) during 
pregnancy, through delivery, and postpartum. Infants will not receive ARVs as part of the study 
but are expected to receive non-study ARV prophylaxis consistent with local standards of care. 
Mothers will be counseled on infant feeding options consistent with local standards of care; both 
breastfeeding and formula feeding mother-infant pairs may take part in the study. 
 
Mothers will complete study visits every four weeks during pregnancy; mothers and infants will 
complete study visits at delivery and at 6, 14, 26, 38, and 50 weeks postpartum. Study-specific 
visits and procedures will be performed as described in Section 6 and the Schedule of Evaluations 
in Appendix I. Safety outcomes will be assessed throughout follow-up, with standard evaluations 
performed at all sites; at selected sites, infant DXA scans will additionally be performed at 26 
weeks postpartum, and maternal DXA scans will be performed at 50 weeks postpartum. Primary 
and secondary virologic efficacy outcomes will be assessed at delivery and at 50 weeks 
postpartum, using a single HIV-1 RNA testing platform at all sites. All HIV-1 RNA assays 
performed at site laboratories will be performed in real time. For the secondary objective 
evaluating viral suppression to less than 50 copies/mL at delivery, however, the assay will be 
performed centrally (batched) after all specimens have collected.  
 
Safety and efficacy will be routinely monitored by an independent data and safety monitoring 
board (DSMB) as described in Section 9.5.3. The DSMB will also re-evaluate the study sample 
size and make recommendations regarding potential sample size adjustments following a pre-
specified algorithm. Primary virologic efficacy analyses will compare participants randomized to 
either DTG-containing regimen (Arm 1 + Arm 2 combined) to participants randomized to the 
EFV-containing regimen (Arm 3). Primary safety analyses will compare participants randomized 
to each DTG-containing regimen to participants randomized to the EFV-containing regimen and 
to participants randomized to the other DTG-containing regimen. Refer to Section 9 for a 
complete description of statistical considerations, data monitoring, and data analysis plans. 
 
 


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4 
STUDY POPULATION 
 
This study will be conducted among approximately 639 mother-infant pairs who will be selected 
for the study according to the criteria in Sections 4.1 and 4.2 and the guidelines in Section 4.3. 
The study-specific approach to recruitment, screening, and enrollment is described in Section 4.4. 
Considerations related to participant retention and withdrawal from the study are provided in 
Sections 4.5 and 4.6, respectively. 
 
4.1 
Inclusion Criteria 
 
All of the criteria listed below must be met in order for mother-infant pairs to be included in this 
study.  
 
4.1.1 
Mother is at least 18 years of age and willing and able to provide written informed 
consent for her and her infant’s participation in this study  
 
4.1.2 
Mother has confirmed HIV-1 infection based on documented testing of two samples 
collected at different time points:  
 
Sample #1 may be tested using any of the following:  
 
Two rapid antibody tests from different manufacturers or based on different 
principles and epitopes  
 
One enzyme immunoassay (EIA) OR Western blot OR immunofluorescence assay 
OR chemiluminescence assay 
 
One HIV DNA PCR  
 
One quantitative HIV RNA PCR (above the limit of detection of the assay)  
 
One qualitative HIV RNA PCR 
 
One total HIV nucleic acid test  
 
Sample #2 may be tested using any of the following:  
 
One rapid antibody test. If this option is used in combination with two rapid tests for 
Sample #1, at least one of the three rapid tests must be FDA-approved and the third 
rapid test must be from a third manufacturer or based on a third principle or epitope.  
 
One EIA OR Western blot OR immunofluorescence assay OR chemiluminescence 
assay 
 
One HIV DNA PCR  
 
One quantitative HIV RNA PCR (above the limit of detection of the assay)  
 
One qualitative HIV RNA PCR  
 
One total HIV nucleic acid test  
 
If both samples are tested using antibody tests, at least one of the samples must be tested 
in a laboratory setting that operates according to Good Clinical Laboratory Practice 
(GCLP) guidelines and participates in an appropriate external quality assurance program. 
If nucleic acid testing is used, at least one test must be performed in a CLIA-certified (for 
US sites) or VQA-certified (for non-US sites) laboratory. For tests performed in other 
settings, adequate source documentation including the date of specimen collection, date 
of testing, test performed, and test result must be available. FDA-approved testing 
methods should be used when possible.  
 


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4.1.3 
At screening, mother is ART-naïve, defined as having not received prior antiretroviral 
therapy other than ARVs received during prior pregnancies or prior periods of 
breastfeeding (i.e., receipt of any single, dual, or triple ARV regimen during prior time-
limited periods of pregnancy and breastfeeding is permitted). Receipt of up to 14 days of 
ARVs during the current pregnancy is permitted prior to study entry so that initiation of 
ARVs during the current pregnancy is not delayed during the study screening period. 
 
Note: Non-study ART may be initiated in the current pregnancy prior to initiation of the 
study screening process. For eligible participants, enrollment must occur within 14 days 
of non-study ART initiation.  
 
Note: Consistent with criterion 4.2.4, receipt of ARVs during a prior pregnancy or prior 
period of breastfeeding must have concluded at least six months prior to study entry. 
Receipt of TDF or FTC/TDF for pre-exposure prophylaxis at any time in the past is not 
exclusionary (even if received within six months prior to study entry). 
 
4.1.4 
At screening, mother has the following laboratory test results (based on testing of 
samples collected within 14 days prior to study entry): 
 
 
Grade 1 or lower (<2.5 x ULN) ALT and AST 
 
Grade 2 or lower (≤1.8 x ULN) creatinine 
 
Grade 2 or lower (≥60 mL/min) estimated creatinine clearance (CrCl; Cockcroft-
Gault formula) 
 
See Section 7.3.3 for guidance on severity grading. Laboratory tests may be repeated 
during the study screening period, with the latest result used for eligibility determination. 
 
4.1.5 
At screening and at study entry, no evidence of multiple gestation or fetal anomalies, as 
assessed by best available method  
 
4.1.6 
At study entry, gestational age of 14-28 weeks, defined as greater than 13 weeks plus six 
days and less than 28 completed weeks gestation, estimated by best available method  
 
Note: For criteria 4.1.5 and 4.1.6, fetal ultrasound is preferred but not required for 
purposes of eligibility determination. If ultrasound cannot be performed during the study 
screening period prior to study entry, it must be performed within 14 days after study 
entry. As further explained in Section 6.1, enrolled participants will not be withdrawn 
from the study based on ultrasound findings obtained after study entry. 
 
4.1.7 
At study entry, mother expects to remain in the geographic area of the study site during 
pregnancy and for 50 weeks postpartum 
 


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4.2 
Exclusion Criteria 
 
Mother-infant pairs must be excluded from the study if any of the following are identified at any 
time prior to study entry:  
 
4.2.1 
Mother is currently incarcerated or involuntarily confined in a medical facility 
 
4.2.2 
Mother is currently receiving: 
 
A psychoactive medication for treatment of a psychiatric illness 
 
Treatment for active tuberculosis 
 
Treatment for active hepatitis C infection 
 
4.2.3 
Mother is expected to require treatment with interferon and/or ribavirin for hepatitis C 
infection during the study follow-up period 
 
4.2.4 
Mother has a history of any of the following, as determined by the site investigator or 
designee based on maternal report and available medical records:  
 
Hypersensitivity or clinically significant adverse reaction to any of the ARVs 
included in the three study drug regimens (ever) 
 
Antiretroviral drug resistance mutations that would impact selection of ART regimen 
(ever) 
 
Clinically significant heart disease and/or known prolonged QTc interval (ever) 
 
Suicidal ideation or attempt (ever) 
 
HIV-2 infection (ever) 
 
Zika virus infection, diagnosed or suspected, during the current pregnancy 
 
Receipt of any antiretroviral medication within six months prior to study entry, with 
two exceptions: receipt of any duration of TDF or FTC/TDF for pre-exposure 
prophylaxis or receipt of up to 14 days of ARVs during the current pregnancy 
 
Receipt of any prohibited medication within 14 days prior to study entry (see Section 
5.9)  
 
Clinically significant acute illness requiring systemic treatment and/or hospitalization 
within 14 days prior to study entry 
 
Unstable liver disease (defined by the presence of ascites, encephalopathy, 
coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent 
jaundice) or known biliary abnormalities (with the exception of Gilbert’s syndrome 
or asymptomatic gallstones) within 14 days prior to study entry 
 
4.2.5 
Mother or fetus has any other condition that, in the opinion of the site investigator or 
designee, would make participation in the study unsafe, complicate interpretation of 
study outcome data, or otherwise interfere with achieving the study objectives 
 
4.3 
Co-Enrollment Considerations 
 
Co-enrollment in other studies is not precluded, although careful consideration must be given to 
visit burden, blood draw volumes, and interpretation of outcome data across studies. Given these 
considerations, requests for co-enrollment must be approved in advance by the Protocol Teams of 
both studies. Requests for such approval should be emailed to the Clinical Management 
Committee (CMC; refer to Sections 7.1.2 and 9.5.1 for more information regarding the role of the 
CMC for this study).  
 


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4.4 
Recruitment, Screening, and Enrollment Process 
 
Recruitment methods for this study may vary across sites but are expected to rely on active 
identification and referral of HIV-1-infected pregnant women who are not taking ART at the time 
of presenting for antenatal care. Based on current standards of care, it is expected that many such 
women will be started on a non-study ART regimen at the time of presenting for antenatal care. 
This is permitted by the study eligibility criteria. However, recruitment and eligibility screening 
procedures will need to be performed in a timely manner to ensure that eligible women are 
enrolled within 14 days of starting non-study ART. Upon enrollment, women will discontinue 
their non-study ART regimen (if they had started a non-study regimen) and initiate a study drug 
regimen.  
 
Upon identification of a potentially eligible pregnant woman, study staff will provide information 
about the study to her. Women who express interest in learning more about the study will be 
provided additional information, education, and counseling as part of the study informed consent 
process. The process may be initiated at any time during pregnancy but — based on the required 
timing of study entry described above — is generally not expected before approximately 12 
weeks gestation or after approximately 26 weeks gestation. The process will include detailed 
review of the study informed consent form, time to address any questions or concerns the woman 
may have, and an assessment of the woman’s understanding before proceeding to her informed 
consent decision. The process will be fully documented and only women who are able to 
demonstrate understanding will be asked to provide written informed consent for study screening 
and enrollment.  
 
Eligibility screening will be initiated after written informed consent is provided. Each site must 
establish standard operating procedures (SOPs) for eligibility determination that describe where 
and when screening procedures will be performed; roles and responsibilities for performing the 
required procedures; roles and responsibilities for assessing and confirming eligibility; and 
procedures for documenting the process, taking into consideration the required timing of 
enrolment. Screening evaluations must be performed within 14 days prior to enrollment and 
enrollment must occur within 14 days of (non-study) ART initiation during the current pregnancy 
(for example, a woman who starts (non-study) ART on the first day of the month must be 
enrolled by the fourteenth day of the month). Screening evaluations may be repeated during the 
14-day screening period, with the latest outcome used for eligibility determination. In the event 
that the 14-day screening period is exceeded, the screening process may be repeated, provided the 
mother is still within 14 days of non-study ART initiation; in this case, most but not all screening 
evaluations must be repeated, as specified in Section 6.1. 
 
Women who are found to meet the study eligibility criteria will be enrolled in the study in pairs 
with their infants. The IMPAACT Data Management Center (DMC) Subject Enrollment System 
(SES) will be used to assist with tracking the screening and enrollment process. When informed 
consent is obtained, participant identification numbers (PIDs) will be assigned to the mother and 
(unborn) infant, and a study-specific screening number will be obtained for the pair through the 
SES. For pairs found to be eligible, enrollment will occur upon successful entry of required 
eligibility data into the SES. Successful entry into the SES will generate study identification 
numbers (SIDs) for the mother and infant and prescribing information for the maternal study drug 
regimen. For pairs who are screened and found to be ineligible, or who do not otherwise enroll in 
the study for any reason, an electronic case report form (eCRF) will be entered to record the 
screening outcome. Refer to Section 9.5 for more information on monitoring participant accrual 
in this study.  
 


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Successful entry into the SES will result in generation of SIDs as well as generation the random 
assignment for the pair; for these pairs, generation of the SIDs with the random assignment is the 
effective point of enrollment in the study. The prescribing information generated by the SES will 
detail the randomly assigned regimen — DTG+FTC/TAF, DTG+FTC/TDF, or EFV/FTC/TDF — 
consistent with Sections 5.1 and 5.2, below. For all mother-infant pairs, the relevant study drug 
regimen will be prescribed and dispensed on the day of enrollment, with the first dose expected to 
be taken on the day of enrollment or the following day.  
 
4.5 
Participant Retention 
 
Once a mother-infant pair is enrolled, study staff will make every effort to retain both mother and 
infant for the protocol-specified duration of follow-up (through 50 weeks postpartum), thereby 
maximizing statistical power and minimizing potential biases associated with loss to follow-up. 
Refer to Section 9.5 for more information on monitoring participant retention in this study. 
 
4.6 
Participant Withdrawal from the Study 
 
Regardless of the participant retention procedures referenced above, mothers may voluntarily 
withdraw themselves and/or their infants from the study. Participants may also be withdrawn 
from the study by the site investigator or designee under the following circumstances: 
 
 
Participant re-locates away from the study site and cannot be transferred to another site or is 
otherwise determined to be lost-to-follow-up 
 
Site investigator or designee determines that continued participation in the study would be 
unsafe or otherwise not in the best interest of the participant  
 
The study is stopped or canceled by the sponsors, government or regulatory authorities, or 
site IRBs/ECs 
 
Mother-infant pairs in which the mother discontinues use of study drug for any reason will not be 
withdrawn from the study; any such pairs should ideally be retained through the scheduled 
duration of follow-up. Likewise, any mother who does not deliver a live born infant or whose 
infant dies during follow-up should ideally be retained through the scheduled duration of follow-
up. 
 
Should the consenting mother of an enrolled infant die or no longer be available for any reason, 
all applicable IRB/EC policies and procedures should be followed; however, no further study-
specific infant evaluations should be performed until informed consent for continued study 
participation is obtained from the infant’s authorized guardian, as defined locally. Study sites may 
continue to provide care for the infant as needed and appropriate (outside of the study), consistent 
with local standards of care, but no study-specific procedures (outside of the standard of care) 
may be performed. If an authorized guardian cannot be identified, or if the authorized guardian 
does not consent to continued study participation, the infant must be withdrawn from the study. 
Refer to Section 12.3 for further guidance on guardian consent for infant study participation. 
 
For any participant who is withdrawn from the study prior to scheduled completion of follow-up, 
study staff will document the reason for the withdrawal in detail and will make every effort to 
complete final evaluations as described in Section 6.9. In the event that the circumstances that led 
to a participant’s withdrawal change (e.g., he or she returns to the study site area after having re-
located previously), the site investigator or designee should contact the CMC to discuss options 
for resumption of follow-up. 


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5 
STUDY DRUG CONSIDERATIONS 
 
Site pharmacists should consult the Pharmacy Guidelines and Instructions for DAIDS Clinical 
Trials Networks for standard pharmacy operations.  
 
Study drug is defined for this study as the ARVs included in the maternal regimens specified in 
Section 5.1. Mothers will be exposed to study drug through direct ingestion; infants may be 
exposed to study drug in utero and through breastfeeding. Refer to the relevant Package Inserts 
for each of the ARVs and fixed dose combinations thereof for more information about these 
drugs.  
 
5.1 
Study Drug Regimens 
 
Mother-infant pairs will be randomly assigned in a 1:1:1 ratio to receive one of the following 
maternal ART regimens during pregnancy, through delivery, and for 50 weeks postpartum:  
 
Arm 1 
Dolutegravir (DTG) + emtricitabine/tenofovir alafenamide (FTC/TAF)  
during pregnancy, through delivery, and for 50 weeks postpartum 
 
Arm 2 
Dolutegravir (DTG) + emtricitabine/tenofovir disoproxil fumarate (FTC/TDF)  
during pregnancy, through delivery, and for 50 weeks postpartum 
 
Arm 3 
Efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF)  
during pregnancy, through delivery, and for 50 weeks postpartum 
 
As noted in Section 4.4, the first dose of each regimen is expected to be taken on the day of 
enrollment or the following day.  
 
5.2 
Study Drug Administration  
 
Dolutegravir (DTG) will be administered orally as one 50 mg tablet once daily, with or without 
food.  
 
Refer to the IMPORTANT INTERACTION sub-section of Section 5.8.1 for additional 
information on administration of DTG for mothers who require cation-containing antacids or 
laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications.  
 
Refer to Section 8.4 for additional information on management of DTG dosing for mothers who 
require rifampin-containing treatment for active tuberculosis. 
 
Emtricitabine/tenofovir alafenamide (FTC/TAF) will be administered orally as one fixed-dose 
combination tablet (FTC 200 mg/TAF 25 mg) once daily, with or without food.  
 
Refer to Section 8.4 for additional information on management of FTC/TAF dosing for mothers 
who require rifampin-containing treatment for active tuberculosis. 
 
Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) will be administered orally as one fixed-dose 
combination tablet (FTC 200 mg/TDF 300 mg) once daily, with or without food.  
 


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Efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) will be administered orally, as 
one fixed-dose combination tablet (EFV 600 mg/FTC 200 mg/TDF 300 mg) once daily, on an 
empty stomach, preferably at bedtime.  
 
5.3 
Study Drug Formulation  
 
Dolutegravir (DTG): 50 mg tablets. Store at 25°C (77°F) with excursions between 15° and 30°C 
(59°-86°F) permitted (see USP Controlled Room Temperature). 
 
Emtricitabine/tenofovir alafenamide (FTC/TAF): Fixed-dose combination tablets (FTC 200 mg/TAF 
25 mg). Must be dispensed in original bottle; keep container tightly closed. Store below 30°C 
(86°F). 
 
Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF): Fixed-dose combination tablets (FTC 200 
mg/TDF 300 mg). Must be dispensed in original bottle with the desiccant provided. Store at 20°-
25°C (68°-77°F) with excursions between 15° and 30°C (59°-86°F) permitted. 
 
Efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF): Fixed-dose combination 
tablets (EFV 600 mg/FTC 200 mg/TDF 300 mg). Store per manufacturer’s storage instructions.  
 
5.4 
Study Drug Supply 
 
DTG will be supplied by ViiV Healthcare Ltd.  
 
FTC/TAF and FTC/TDF will be supplied by Gilead Sciences. 
 
EFV/FTC/TDF will be supplied by Mylan.  
 
All of the above-listed study drugs will be made available to study sites through the NIAID 
Clinical Research Products Management Center (CRPMC). Upon successful completion of 
protocol registration procedures, these study drugs may be obtained by the site pharmacist 
following instructions provided in the Pharmacy Guidelines and Instructions for DAIDS Clinical 
Trials Networks.  
 
Study-supplied study drugs are expected to be provided to mothers in Arms 1, 2, and 3 consistent 
with their random assignments as specified in Section 5.1. However, for mothers in all arms, 
ART regimens may be modified as specified in Section 8 and Appendix II. As indicated in these 
sections, all regimen changes involving DTG, EFV, TAF, or TDF should be made in consultation 
with the CMC.  
 
All available study-supplied study drugs, as well as ARVs available from non-study sources, may 
be used when constructing regimens for mothers in all arms. In the event that study supplies of 
DTG, FTC/TAF, FTC/TDF, or EFV/FTC/TDF are not available, these ARVs may be provided 
from non-study supplies, with approval in advance from the CMC. If non-study-supplied ARVs 
are provided, the ARVs should ideally be dispensed through study site pharmacies. If this is not 
possible, other options may be considered in consultation with the CMC; CMC review and 
approval of the operational plan is required. Any ARV supplied from non-study sources must 
comply with the DAIDS policy on use of drug products not marketed in the US, which is 
available at: https://www.niaid.nih.gov/research/daids-clinical-research-pharmacy-and-study-
products-management. 
 


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5.5 
Study Drug Accountability 
 
Site pharmacists must maintain complete records of all study drugs received from the CRPMC 
and subsequently dispensed.  
 
5.6 
Final Disposition of Study Drug 
 
Any unused study drug remaining at US sites after the study is completed or terminated will be 
returned to the CRPMC (unless otherwise directed by the sponsor). At non-US sites, any unused 
study drug will be destroyed. Site pharmacists will follow the relevant instructions for return or 
destruction of unused study products provided in the Pharmacy Guidelines and Instructions for 
DAIDS Clinical Trials Networks.  
 
5.7 
Study Drug Adherence Assessment and Counseling 
 
Study staff will provide adherence counseling to enrolled mothers throughout the period of study 
participation. Counseling may be provided by clinic and/or pharmacy staff consistent with local 
standards of care and site SOPs; site SOPs must also meet for minimum requirements specified in 
the study-specific Manual of Procedures (MOP) with respect to initial and ongoing counseling 
and support. Counseling should be provided in a client-centered manner, tailored as needed to the 
information, skills building, and support needs of each mother. Information on correct use of 
study drugs will be provided, particularly at the time of enrollment and in the early stages of 
follow-up, as well as at the time of any regimens changes. Counseling will also address 
challenges to consistent use of study drug over time, with the aim of supporting mothers in 
identifying strategies to address any such challenges. 
 
Adherence to the maternal study drug regimen will be assessed by questionnaire as indicated in 
the Schedule of Evaluations in Appendix I. These data will not be used as a basis for adherence 
counseling. The results of HIV viral load testing performed throughout follow-up provide a 
biologic measure of adherence and may be used to guide feedback to mothers and associated 
adherence counseling. Refer to Section 8.3 for more information on virologic monitoring and 
management.  
 
5.8 
Concomitant Medications  
 
The term concomitant medications is used in this study to refer to medications other than the 
study drugs that comprise the maternal ART regimens listed in Section 5.1.  
 
5.8.1 
Maternal Concomitant Medications 
 
All concomitant medications received by enrolled mothers throughout the duration of study 
participation must be source documented as part of the medical and medication histories obtained 
at each study visit (see Section 6.11). This includes prescription and non-prescription (over-the-
counter) medications; vaccines and other preventive medications; contraceptives; antacids, 
antenatal vitamins and other nutritional supplements; and alternative, complementary, and 
traditional medications and preparations. Requirements for entering maternal concomitant 
medications into eCRFs are specified in Section 6.11.  
 


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IMPORTANT INTERACTIONS WITH COMMONLY USED CONCOMITANT MEDICATIONS  
 
Mothers who have not initiated cotrimoxazole or isoniazid prophylaxis prior to study entry should 
preferably defer initiation of these medications until at least two weeks after initiation of their 
study drug regimen, if eligible to initiate such prophylaxis per local standards of care.  
 
Mothers in Arms 1 and 2 (i.e., the DTG-containing arms) who require cation-containing antacids 
or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications will 
be counseled to take these medications at least six hours before or at least two hours after taking 
DTG. Alternatively, DTG and supplements containing calcium or iron can be taken together with 
food. 
 
Refer to Section 8.4 for additional information on management of mothers who require rifampin-
containing treatment for active tuberculosis. 
 
5.8.2 
Infant Concomitant Medications 
 
All concomitant medications received by enrolled infants must be source documented as part of 
the medical and medication histories obtained at each study visit (see Section 6.14). This includes 
prescription and non-prescription (over-the-counter) medications; vaccines and other preventive 
medications; therapeutic foods and nutritional supplements; and alternative, complementary, and 
traditional medications and preparations. Requirements for entering infant concomitant 
medications into eCRFs are specified in Section 6.14.  
 
5.9 
Prohibited Medications  
 
Any mother who requires a medication considered prohibited while on study drug must have the 
study drug held or permanently discontinued. A list of prohibited medications will be posted on 
the study-specific website: http://impaactnetwork.org/studies/IMPAACT2010.asp. Upon 
identification of the need for a prohibited medication, the site investigator should consult the 
CMC for further guidance on study drug management.  
 
5.10 
Precautionary Medications  
 
A list of medications that should be used with caution while on study drug will be posted on the 
study-specific website: http://impaactnetwork.org/studies/IMPAACT2010.asp.  
 
 
6 
STUDY VISITS AND PROCEDURES 
 
An overview of the maternal and infant schedule of study visits and evaluations is provided in 
Appendix I; blood draw volumes for each visit are also detailed in Appendix I. Presented in this 
section is additional information on visit-specific study procedures. Information related to 
scheduled visits is presented in Sections 6.1-6.5; information related to event-driven visits for 
maternal ARV switches, maternal virologic failure, and infant HIV infection is presented in 
Sections 6.6-6.8; and information on early discontinuation and post-study contacts is presented in 
Sections 6.9-6.10. Additional details related to study-specific procedures, such as physical exams, 
ultrasound scans, and DXA scans are provided in Sections 6.11-6.17. Additional considerations 
for laboratory procedures are provided in Section 6.18.  
 


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All visits and procedures must be performed at the approved clinical research site or approved 
associated facilities. All visits should be conducted as close as possible to the specified target visit 
dates and within the specified allowable visit windows. Unless otherwise specified, visits may be 
split, with required procedures performed on more than one day within the allowable visit 
window if necessary. Some visit windows overlap by a period of one day; the day of overlap 
should be prioritized, when applicable, for completion of the earlier of the two visits. For 
example, there is one day of overlap between the allowable windows for the Antepartum Week 4 
and Week 8 Visits. If a participant were to present to the study site on this day, the Antepartum 
Week 4 Visit should be conducted on this day, if not previously conducted; otherwise, the 
Antepartum Week 8 Visit may be conducted on this day. In the event that a scheduled visit is 
missed (i.e., not completed within the allowable window), the missed evaluations should be 
completed, if possible, at the next scheduled visit. For example, if the Antepartum Week 12 Visit 
is missed, the ALT, AST, creatinine, creatinine clearance, and HIV-1 RNA evaluations specified 
for that visit should be performed, if possible, at the Antepartum Week 16 Visit. Further 
operational guidance on prioritization of evaluations is provided in the study-specific MOP.  
 
All visits and procedures must be documented in accordance with the NIAID Division of AIDS 
(DAIDS) policies for source documentation; refer to Section 10 for more information on 
documentation and data management requirements. Refer to Section 7 for information on 
expedited adverse event (EAE) reporting, which may be required at any time during follow-up.  
 
In addition to the protocol-specified procedures listed in this section, study staff may complete 
other tasks consistent with site SOPs, including but not limited to collecting, reviewing, and 
updating demographic and locator information; reviewing elements of informed consent; 
providing contraception counseling (see Section 8.6) and other relevant types of counseling; 
scheduling telephone contacts and visits; providing instructions for contacting study staff between 
visits; providing visit reminders; and following up on missed visits. All such tasks should be 
documented consistent with site SOPs. Study staff may also perform additional evaluations if 
required per the participant management guidance in Section 8, if clinically indicated, and/or if 
such evaluations would otherwise be expected according to local standards of care. Study staff 
should inform mothers of clinically meaningful physical examination findings and laboratory test 
results when available. 
 
6.1 
Screening Visits 
 
Refer to Section 4.4 for a description of the study recruitment, screening, and enrollment process.  
 
Screening may be initiated after written informed consent is obtained. Screening procedures may 
be performed on multiple days, including on the date of enrollment (see Section 6.2). Further 
operational guidance for the required screening procedures is as follows: 
 
 
Maternal HIV testing may or may not be required to meet the eligibility criteria in Section 
4.1.2. One of the required maternal HIV tests must be performed in an appropriately certified 
laboratory setting; the other required test may be performed in other (non-certified) settings.  
 
 
Maternal pregnancy testing may or may not be required to meet the eligibility criteria in 
Section 4.1.6. If available maternal medical records document a positive pregnancy test 
result, or if pregnancy is confirmed by ultrasound scan prior to enrollment, no pregnancy 
testing is required. Otherwise, a blood or urine pregnancy test should be performed, with 
results available for eligibility determination prior to enrollment.  
 


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 
Maternal ALT, AST, and creatinine testing is required in relation to the eligibility criteria in 
Section 4.1.4; as soon as the screening creatinine test result is obtained, the mother’s 
estimated CrCl rate should be calculated using the Cockcroft-Gault formula, and all results 
should be graded for severity as specified in Section 7.3.3.  
 
 
Every effort should be made to perform fetal ultrasound to estimate gestational age and assess 
for multiple gestation and fetal anomalies prior to study entry. However, if this is not 
possible, the best available method should be used to perform these assessments for eligibility 
determination. In these cases, ultrasound must be performed as soon as possible and within 
14 days after study entry and the ultrasound findings will subsequently be used in algorithms 
to calculate gestational age at study entry and gestational age at delivery. If ultrasound is 
performed prior to study entry, results must be considered for purposes of eligibility 
determination. For example, if ultrasound performed prior to study entry indicates multiple 
gestation, the mother (and her fetuses) should not be enrolled. However, if ultrasound is 
performed after study entry, enrolled participants will not be withdrawn from the study if the 
ultrasound identifies an exclusionary condition.  
 
Note: In the event that fetal ultrasound was performed prior to the study screening period, 
and a result report meeting all requirements specified in Section 6.13 is available, it is not 
necessary to perform another scan for study purposes.  
 
 
Screening evaluations may be repeated, with the latest outcome used for eligibility 
determination.  
 
For potential participants who do not meet eligibility criteria, screening should be discontinued 
once ineligibility is determined (enter the relevant eCRF to record the screening outcome).  
 
Screening Visit Procedures (within 14 days prior to study entry) 
Administrative 
and Regulatory 
 Obtain written informed consent for IMPAACT 2010 
 Assign PIDs to mother and (unborn) infant 
 Obtain screening number from SES 
 Obtain available documentation of mother’s HIV status 
Clinical 
 Obtain available maternal medical records and maternal 
medical and medications history  
 Assess documentation of HIV infection and of current 
pregnancy in relation to study requirements 
 Assess maternal ARV history in relation to study 
requirements 
 Perform complete maternal physical exam 
 Perform fetal ultrasound if possible (and if not performed 
prior to the study screening period)  
 Assess current gestational age based on best available 
method
Laboratory
Blood 
Collect maternal blood for: 
 Confirmatory HIV testing if needed per Section 4.1.2 
 ALT, AST, creatinine, CrCl  
 Complete blood count 
 Stored plasma for antiretroviral resistance testing
Blood or 
Urine 
Collect blood or urine for:  
 Pregnancy test if needed per Section 4.1.6 (see above for 
further guidance) 


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All screening procedures are expected to be performed within 14 days prior to study entry. In the 
event that the 14-day screening period is exceeded, the screening process may be repeated, 
provided that adequate time remains to permit enrollment within 14 days of non-study ART 
initiation. In this case, all of the screening procedures listed above must be repeated, with the 
exception that: 
 
 
New PIDs should not be assigned 
 
Confirmatory HIV testing need not be repeated 
 
Fetal ultrasound need not be repeated 
 
Previously documented medical and medications history information should be reviewed and 
updated through the date of re-screening (it is not necessary to re-record history information 
that was previously documented)  
 
6.2 
Entry Visit 
 
Refer to Section 4.4 for a description of the study recruitment, screening, and enrollment process.  
 
For eligible mother-infant pairs, enrollment must occur at 14-28 weeks gestation and within 14 
days of the mother initiating ART in the current pregnancy.  
 
All Entry Visit procedures are expected to be performed on the day of enrollment; procedures that 
may provide information relevant to eligibility for the study (e.g., medical history, physical 
examination) should be performed first, prior to final eligibility determination. In the event that a 
mother-infant pair is found to be ineligible on the scheduled day of entry, enrollment must not 
occur.  
 
Additional guidance for sequencing of procedures at the Entry Visit is as follows: 
 
 
Final eligibility determination and confirmation must precede enrollment 
 
Enrollment must precede prescribing of study drug 
 
Prescribing must precede dispensing of study drug 
 
Blood collection must precede ingestion of the first dose of study drug  
 
As noted in Section 6.1, fetal ultrasound should be performed prior to study entry if possible. If 
this is not possible, ultrasound must be performed as soon as possible and within 14 days after 
study entry. Participants will not be withdrawn from the study if ultrasound performed after entry 
identifies an exclusionary condition (i.e., multiple gestation, fetal anomaly, or gestational age 
outside of the allowable range of 14-28 weeks). For any multiple gestation identified after 
enrollment, pregnancy outcomes will be ascertained for all fetuses and all live born infants will be 
followed per the Schedule of Evaluations.  
 
Note: In the event that fetal ultrasound is not performed prior to or within 14 days after study 
entry, the CMC must be informed immediately. The mother-infant pair will be retained in follow-
up and available information will be used to estimate gestational age at study entry; this will be 
done by the site investigator or designee in consultation with the CMC. Please refer to Section 
9.5.1 for more information on monitoring for completeness and timeliness of ultrasound and 
actions to be taken in response to missed or delayed ultrasound scans.  
 


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Entry Visit Procedures (Day 0) 
Administrative 
and Regulatory 
 Complete final eligibility determination and confirmation* 
 Complete paper-based eligibility checklist*, enter checklist 
data into SES to enroll the mother-infant pair, print and file 
a copy of the confirmation file
Clinical
 Update medical and medications history since last visit* 
 Perform complete maternal physical exam* 
 Perform fetal ultrasound if not done previously and if 
possible prior to enrollment (if not done prior to 
enrollment, must be done within 14 days after enrollment) 
 Administer Pittsburgh Sleep Quality Index (PSQI) 
 Administer Generalized Anxiety Disorder 7-Item Scale 
(GAD-7)
Study Drug 
 Prescribe and dispense ARVs 
 Provide ARV use instructions and adherence counseling 
Laboratory 
Blood 
Collect blood for: 
 Hepatitis B surface antigen 
 CD4+ cell count 
 HIV-1 RNA (real-time; store residual plasma) 
 Stored plasma and cell pellets for immunologic and 
hormonal markers of adverse pregnancy outcomes
Urine 
Collect urine for: 
 Storage for markers of renal toxicity
 *Perform prior to enrollment 
 
6.3 
Maternal Antepartum Follow-Up Visits 
 
After study entry, mothers will complete scheduled follow-up visits every four weeks prior to 
delivery. Between scheduled visits, particularly in the first month of study participation, study site 
staff are encouraged to contact mothers to address any issues or questions about their study 
participation, clarify instructions for use of study drugs, and/or provide adherence counseling as 
needed.  
 
Given that mother-infant pairs will be enrolled at 14-28 weeks gestation, up to seven or eight 
antepartum visits may be completed by each mother, depending on the gestational age at entry 
and the gestational age at delivery. For example, a mother who enrolls at 14 weeks gestation and 
delivers at 40 weeks gestation would be expected to complete antepartum visits at 18, 22, 26, 30, 
34, and 38 weeks gestation; the corresponding study weeks for these visits would be Antepartum 
Follow-Up Weeks 4, 8, 12, 16, 20, and 24. Mothers who enroll in the study later, or deliver 
earlier, would have fewer visits than in this example. 
 
The target dates for all maternal antepartum follow-up visits are counted from the date of 
enrollment as Day 0, with an allowable window of ± 2 weeks. There is no required sequencing of 
procedures at these visits.  
 
Maternal creatinine and CrCl evaluations are required at Antepartum Follow-Up Weeks 4, 12, 
and 24. As soon as the creatinine results from these visits are obtained, the estimated CrCl rate 
should be calculated using the Cockcroft-Gault formula, graded for severity, and assessed for 
clinical significance concurrent with all other laboratory test results.  
 


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6.3.1 
Antepartum Follow-Up Week 4 Visit 
 
Antepartum Follow-up Week 4 Visit Procedures (Day 28 ± 2 weeks) 
Clinical 
 Obtain interval medical and medications history 
 Perform targeted physical exam 
 Identify/review/update adverse events 
 Perform additional evaluations per Section 8 and/or if 
clinically indicated (consult CMC if indicated)
Study Drug
 Administer routine adherence questionnaire 
 Prescribe and/or dispense ARVs as needed 
 Provide ARV use instructions, adherence counseling, and 
support as needed
Laboratory 
Blood 
Collect blood for: 
 ALT, AST, creatinine, CrCl 
 HIV-1 RNA (real-time; store residual plasma)
 
6.3.2 
Antepartum Follow-Up Week 8 Visit 
 
Antepartum Follow-up Week 8 Visit Procedures (Day 56 ± 2 weeks) 
Clinical
 Obtain interval medical and medications history 
 Administer PSQI 
 Administer GAD-7 
 Perform targeted physical exam 
 Identify/review/update adverse events 
 Perform additional evaluations per Section 8 and/or if 
clinically indicated (consult CMC if indicated)
Study Drug 
 Administer routine adherence questionnaire and barriers 
and facilitators questionnaires 
 Prescribe and/or dispense ARVs as needed 
 Provide ARV use instructions, adherence counseling, and 
support as needed
Laboratory
Blood
Collect blood for: 
 HIV-1 RNA (real-time; store residual plasma) 
 Stored plasma and cell pellets for immunologic and 
hormonal markers of adverse pregnancy outcomes
 
6.3.3 
Antepartum Follow-Up Week 12 Visit 
 
Antepartum Follow-up Week 12 Visit Procedures (Day 84 ± 2 weeks) 
Clinical
 Obtain interval medical and medications history 
 Perform targeted physical exam 
 Identify/review/update adverse events 
 Perform additional evaluations per Section 8 and/or if 
clinically indicated (consult CMC if indicated)
Study Drug 
 Administer routine adherence questionnaire 
 Prescribe and/or dispense ARVs as needed 
 Provide ARV use instructions, adherence counseling, and 
support as needed
Laboratory 
Blood 
Collect blood for: 
 ALT, AST, creatinine, CrCl 
 HIV-1 RNA (real-time; store residual plasma)
 


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6.3.4 
Antepartum Q4 Week Follow-Up Visits 
 
After completion of the Antepartum Follow-up Week 12 visit, mothers will continue to complete 
scheduled follow-up visits every four weeks (Q4) prior to delivery. Depending on the date of 
delivery, these visits may take place at Antepartum Follow-up Weeks 16, 20, 24, and 28. For 
example, a mother enrolled at 14 weeks gestation who delivers at 40 weeks gestation would 
complete the Week 4, 8, and 12 visits described above, as well as Q4 visits at study Weeks 16, 
20, and 24 prior to delivery. In contrast, a mother enrolled at 24 weeks gestation who delivers at 
37 weeks gestation would complete the Week 4, 8, and 12 visits described above, but would not 
completed any Q4 visits prior to delivery. 
 
Antepartum Follow-up Week 16 (Day 112 ± 2 weeks), Week 20 (Day 140 ± 2 weeks), Week 
24 (Day 168 ± 2 weeks), and Week 28 (Day 196 ± 2 weeks) Visit Procedures
Clinical
 Obtain interval medical and medications history 
 Perform targeted physical exam 
 Identify/review/update adverse events 
 Perform additional evaluations per Section 8 and/or if 
clinically indicated (consult CMC if indicated)
Study Drug
 Administer routine adherence questionnaire 
 Prescribe and/or dispense ARVs as needed 
 Provide ARV use instructions, adherence counseling, and 
support as needed
Laboratory 
Blood 
At Week 24 only, collect blood for: 
 ALT, AST, creatinine, CrCl  
 HIV-1 RNA (real-time, store residual plasma)
 
6.4 
Maternal and Infant Delivery Visit 
 
Mothers and infants should complete a study visit as soon as possible after delivery, and within 
a targeted window of 14 days after delivery.  
 
In addition to other evaluations, the primary study outcomes are ascertained at this visit. As such, 
every effort should be made to conduct this visit within the targeted window. If the visit 
cannot be conducted within the targeted window, it may be conducted within an allowable 
window of 27 days after delivery. The timeliness of visit completion at each site will be closely 
monitored and corrective actions taken when needed, as described in Section 9.5.1. 
 
In the event that an enrolled mother does not deliver a live born infant, or that a live born infant 
dies soon after delivery, the mother should still complete the Delivery Visit and all subsequent 
postpartum visits if she is willing to do so.  
 


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Maternal Delivery Visit Procedures 
(as soon as possible and within 14 (targeted) or 27 (allowable) days after delivery or other 
pregnancy outcome)
Clinical 
 Obtain interval medical and medications history 
 Perform targeted physical exam 
 Identify/review/update adverse events 
 Perform additional evaluations per Section 8 and/or if 
clinically indicated (consult CMC if indicated)
Study Drug 
 Administer routine adherence questionnaire and record 
details of last two ARV doses 
 Prescribe and/or dispense ARVs as needed 
 Provide ARV use instructions, adherence counseling, and 
support as needed
Laboratory 
Blood 
Collect blood for: 
 ALT, AST, creatinine, CrCl 
 HIV-1 RNA (real-time; store residual plasma) 
 Stored plasma for HIV-1 RNA at central laboratory 
 Stored plasma and cell pellets for immunologic and 
hormonal markers of adverse pregnancy outcomes 
 Only if mother is at risk for Zika virus infection (due to 
local transmission, travel, or other exposure) and maternal 
Zika virus infection during the current pregnancy is 
suspected: stored serum for Zika diagnostic testing
Hair
Collect hair for: 
 Storage for ARV drug levels
 
Infant Delivery Visit Procedures 
(as soon as possible and within 14 (targeted) or 27 (allowable) days after birth)
Clinical 
 Obtain birth history, interval medical and medications 
history since birth, and feeding history since birth 
 Perform complete physical exam 
 Identify/review/update adverse events 
 Perform additional evaluations per Section 8 and/or if 
clinically indicated (consult CMC if indicated)
Laboratory 
Blood 
Collect blood for: 
 HIV NAT (store remnant samples) 
 ALT and creatinine  
 Complete blood count 
 Only if mother is at risk for Zika virus infection (due to 
local transmission, travel, or other exposure) and maternal 
Zika virus infection during the current pregnancy is 
suspected: stored serum for Zika diagnostic testing
Hair
Collect hair for: 
 Storage for ARV drug levels
 
As soon as the maternal creatinine result from this visit is obtained, the estimated CrCl rate 
should be calculated using the Cockcroft-Gault formula, graded for severity, and assessed for 
clinical significance concurrent with all other laboratory test results.  
 
In the event that the infant HIV NAT performed at this visit is positive, the infant should be 
recalled to the clinic as soon as possible for confirmatory testing. See also Section 6.8. 
 


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6.5 
Maternal and Infant Postpartum Follow-Up Visits 
 
Following delivery, mothers and infants will complete scheduled follow-up visits at 6, 14, 26, 38, 
and 50 weeks postpartum. For both mothers and infants, the target dates for all postpartum visits 
are counted from the date of delivery (or other pregnancy outcome) as Day 0. The Week 6 Visit 
may be conducted within an allowable window of ± 2 weeks. For all other visits, the allowable 
window is ± 6 weeks. There is no required sequencing of procedures at these visits.  
 
All infants will undergo HIV testing at Weeks 6, 14, and 50, regardless of feeding method. 
Breastfed infants will additionally undergo testing at Weeks 26 and 38 if they were exposed to 
breast milk since the date of their last test. In the event of any positive test, the infant should be 
recalled to the clinic as soon as possible for confirmatory testing. See also Section 6.8. 
 
Maternal creatinine and CrCl evaluations are required at Postpartum Follow-Up Weeks 14, 26, 
and 50. As soon as the creatinine results from these visits are obtained, the estimated CrCl rate 
should be calculated using the Cockcroft-Gault formula, graded for severity, and assessed for 
clinical significance concurrent with all other laboratory test results.  
 
6.5.1 
Postpartum Follow-Up Week 6 Visit 
 
Maternal Postpartum Follow-up Week 6 Visit Procedures (Day 42 ± 2 weeks) 
Clinical 
 Obtain interval medical and medications history 
 Administer Edinburgh Postnatal Depression Scale (EPDS) 
 Perform targeted physical exam 
 Identify/review/update adverse events 
 Perform additional evaluations per Section 8 and/or if 
clinically indicated (consult CMC if indicated)
Study Drug 
 Administer adherence routine questionnaire and record 
details of last two ARV doses 
 Prescribe and/or dispense ARVs as needed 
 Provide ARV use instructions, adherence counseling, and 
support as needed
Laboratory
Blood
Collect blood for: 
 Stored plasma for ARV drug levels
Breast milk 
If currently breastfeeding, collect breast milk for: 
 Storage for ARV drug levels
 
Infant Week 6 Visit Procedures (Day 42 ± 2 weeks) 
Clinical
 Obtain interval medical, medications, and feeding history  
 Perform targeted physical exam with growth evaluation 
 Identify/review/update adverse events 
 Perform additional evaluations per Section 8 and/or if 
clinically indicated (consult CMC if indicated)
Laboratory 
Blood 
Collect blood for: 
 HIV NAT (store remnant samples) 
 Stored plasma for ARV drug levels
 


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6.5.2 
Postpartum Follow-Up Week 14 Visit 
 
Maternal Postpartum Follow-Up Week 14 Visit Procedures (Day 98 ± 6 weeks) 
Clinical 
 Obtain interval medical and medications history 
 Perform targeted physical exam 
 Identify/review/update adverse events 
 Perform additional evaluations per Section 8 and/or if 
clinically indicated (consult CMC if indicated)
Study Drug
 Administer routine adherence questionnaire 
 Prescribe and/or dispense ARVs as needed 
 Provide ARV use instructions, adherence counseling, and 
support as needed
Laboratory 
Blood 
Collect blood for: 
 ALT, AST, creatinine, CrCl 
 HIV-1 RNA (real-time; store residual plasma)
 
Infant Week 14 Visit Procedures (Day 98 ± 6 weeks) 
Clinical 
 Obtain interval medical, medications, and feeding history 
 Perform targeted physical exam with growth evaluation 
 Identify/review/update adverse events 
 Perform additional evaluations per Section 8 and/or if 
clinically indicated (consult CMC if indicated)
Laboratory 
Blood 
Collect blood for: 
 HIV NAT (store remnant samples)
 


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6.5.3 
Postpartum Follow-Up Week 26 Visit 
 
Maternal Postpartum Follow-Up Week 26 Visit Procedures (Day 182 ± 6 weeks) 
Clinical 
 Obtain interval medical and medications history 
 Perform targeted physical exam 
 Identify/review/update adverse events 
 Perform additional evaluations per Section 8 and/or if 
clinically indicated (consult CMC if indicated)
Study Drug
 Administer routine adherence questionnaire 
 Prescribe and/or dispense ARVs as needed 
 Provide ARV use instructions, adherence counseling, and 
support as needed
Laboratory 
Blood 
Collect blood for: 
 ALT, AST, creatinine, CrCl 
 Complete blood count 
 CD4+ cell count 
 HIV-1 RNA (real-time; store residual plasma)
 
Infant Week 26 Visit Procedures (Day 182 ± 6 weeks) 
Clinical
 Obtain interval medical, medications, and feeding history 
 Perform targeted physical exam with growth evaluation 
 Identify/review/update adverse events 
 Perform additional evaluations per Section 8 and/or if 
clinically indicated (consult CMC if indicated)
Laboratory 
Blood 
If ever exposed to breast milk, collect blood for: 
 HIV NAT (store remnant samples) 
 ALT and creatinine 
 Complete blood count
Radiology (at selected sites) 
At DXA sites only, DXA scan of whole body and lumbar spine 
 
 
 


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6.5.4 
Postpartum Follow-Up Week 38 Visit 
 
Maternal Postpartum Follow-Up Week 38 Visit Procedures (Day 266 ± 6 weeks) 
Clinical 
 Obtain interval medical and medications history 
 Administer PSQI 
 Administer GAD-7 
 Perform targeted physical exam 
 Identify/review/update adverse events 
 Perform additional evaluations per Section 8 and/or if 
clinically indicated (consult CMC if indicated) 
 Provide information, counseling, and referrals (as needed) 
in preparation for study exit at Week 50
Study Drug
 Administer routine adherence questionnaire and barriers 
and facilitators questionnaires 
 Prescribe and/or dispense ARVs as needed 
 Provide ARV use instructions, adherence counseling, and 
support as needed
Laboratory 
Blood 
Collect blood for: 
 HIV-1 RNA (real-time; store residual plasma)
 
Infant Week 38 Visit Procedures (Day 266 ± 6 weeks) 
Clinical 
 Obtain interval medical, medications, and feeding history 
 Perform targeted physical exam with growth evaluation 
 Identify/review/update adverse events 
 Perform additional evaluations per Section 8 and/or if 
clinically indicated (consult CMC if indicated)
Laboratory
Blood
If ever exposed to breast milk, collect blood for: 
 HIV NAT (store remnant samples)
 
At this visit, information and counseling should be provided to the mother to begin to prepare for 
study exit at the Week 50 Visit. Referrals to non-study care and treatment should be discussed as 
needed, with emphasis on the importance of retention in care following study completion.  
 
 
 


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6.5.5 
Postpartum Follow-Up Week 50 Visit 
 
The Week 50 Visit is the final scheduled study visit for mothers and infants.  
 
Maternal Postpartum Follow-Up Week 50 Visit Procedures (Day 350 ± 6 weeks) 
Clinical 
 Obtain interval medical and medications history 
 Administer EPDS  
 Perform targeted physical exam 
 Identify/review/update adverse events 
 Perform additional evaluations per Section 8 and/or if 
clinically indicated (consult CMC if indicated) 
 Provide information, counseling, and/or referrals (as 
needed) in relation to study exit at this visit
Study Drug
 Administer routine adherence questionnaire 
 Collect any remaining study drug supplies
Laboratory
 
Blood
Collect blood for: 
 ALT, AST, creatinine, CrCl 
 Complete blood count 
 CD4+ cell count 
 HIV-1 RNA (real-time; store residual plasma) 
 Stored plasma and cell pellets for immunologic and 
hormonal markers of adverse pregnancy outcomes
Urine 
Collect urine for: 
Storage for markers of renal toxicity
Blood or 
Urine 
At DXA sites only, collect blood or urine for: 
 Pregnancy test on same day (preferably) or within 14 days 
prior to DXA scan
Radiology (at selected sites) 
At DXA sites only, DXA scan of lumbar spine and hip  
 
Infant Week 50 Visit Procedures (Day 350 ± 6 weeks) 
Clinical 
 Obtain interval medical, medications, and feeding history 
 Perform targeted physical exam with growth evaluation 
 Identify/review/update adverse events 
 Perform additional evaluations per Section 8 and/or if 
clinically indicated (consult CMC if indicated)
Laboratory 
Blood 
Collect blood for: 
 HIV NAT (store remnant samples)
 
At this visit, prior discussions of transition to non-study care and treatment should be reviewed, 
with information, counseling, and/or referrals provided as needed. Study drug cannot be 
dispensed to mothers at or after this visit; therefore, operational plans must be in place to permit 
transition to non-study care and treatment at this visit. Arrangements should be made to provide 
the infant’s HIV NAT result and all other clinically meaningful results to the mother. The mother 
should also be informed of how to contact study staff with any post-study questions and how to 
learn about the results of the study when available.  
 


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6.6 
Additional Procedures Following Maternal ARV Switch  
 
For any mother whose study drug regimen is modified such that DTG or EFV is replaced with 
another ARV, an additional study visit should be conducted approximately four weeks after the 
switch, according to the “Post ARV Switch” column of the Schedule of Evaluations, to assess 
tolerance and monitor virologic response to the modified regimen. In addition to the procedures 
listed below, other evaluations may be performed at the discretion of the site investigator and/or if 
recommended by the CMC. These procedures may be combined with regularly scheduled visit 
procedures if they are performed within the allowable window of a regularly scheduled visit. 
 
Post Maternal ARV Switch Visit Procedures (Four Weeks after Switch ± 1 week) 
Clinical
 Obtain interval medical and medications history  
 Administer EPDS  
 Administer PSQI  
 Administer GAD-7 
 Perform targeted physical exam 
 Identify/review/update adverse events 
 Perform additional evaluations per Section 8 and/or if 
clinically indicated (consult CMC if indicated)
Study Drug 
 Administer routine adherence questionnaire 
 Prescribe and/or dispense ARVs as needed 
 Provide instructions and adherence counseling as needed
Laboratory
Blood
Collect blood for: 
 ALT, AST, creatinine, CrCl 
 HIV-1 RNA (real-time; store residual plasma)
 
As soon as the maternal creatinine test result for this visit is obtained, the estimated CrCl 
rate should be calculated using the Cockcroft-Gault formula, graded for severity, and 
assessed for clinical significance concurrent with all other laboratory test results. 
 
6.7 
Additional Procedures for Confirmation of Maternal Virologic Failure 
 
Refer to Section 8.3 for more information on monitoring maternal HIV viral load and managing 
virologic failure.  
 
Maternal virologic failure is defined as two successive plasma HIV-1 RNA test results ≥200 
copies/mL, with specimen collection for the first test occurring at or after 24 weeks on study 
(counted from the date of enrollment).  
 
In the event that a mother has an HIV viral load ≥200 copies/mL at or after at least 24 weeks on 
study, the mother should be recalled to the clinic for confirmatory HIV-1 RNA testing as soon as 
possible and ideally within 28 days of the date of specimen collection for the initial test. Other 
procedures should also be performed according to the “Confirmation of Virologic Failure” 
column of the Schedule of Evaluations, and clinical management should proceed consistent with 
Section 8.3. All procedures should be performed regardless of reported adherence to study drug 
and any other factors that may affect HIV-1 RNA test results. These procedures may be combined 
with regularly scheduled visit procedures if they are performed within the allowable window of a 
regularly scheduled visit.  
 


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It is generally not expected that mothers will meet the criteria for confirmation of virologic failure 
(≥200 copies/mL at or after at least 24 weeks on study) during antepartum follow-up; however, if 
these criteria are met prior to delivery, the Confirmation of Virologic Failure evaluations should 
be performed.  
 
Maternal Confirmation of Virologic Failure Visit Procedures 
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 routine adherence questionnaire 
 Assess adherence in relation to HIV-1 RNA test results and 
provide adherence counseling as needed
Laboratory 
Blood 
Collect blood for: 
 HIV-1 RNA (real-time; store residual plasma) 
 Antiretroviral resistance testing (real-time if virologic 
failure is confirmed, with storage of residual plasma; 
otherwise store plasma)
 
6.8 
Modified Procedures for Infants Identified as HIV-Infected 
 
Any infant with a positive HIV NAT result should be recalled to the clinic for confirmatory 
testing as soon as possible and within 28 days of specimen collection for the initial test. As is the 
case at other visits when HIV NAT is performed, 3 mL of blood should be collected for the 
testing and remnant samples will be stored; an additional 3 mL should also be collected and 
stored for antiretroviral resistance testing. In the event that 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 ARVs should be managed consistent with local 
standards of care.  
 
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. 
 
 


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6.9 
Early Discontinuation Visit 
 
Refer to Section 4.6 for criteria for withdrawal from the study. For any mother or infant who is 
withdrawn or terminated from the study prior to the scheduled completion of follow-up at Week 
50, every effort should be made to perform a final series of study evaluations, if possible, 
according to the “Early D/C” column of the Schedule of Evaluations. However, any evaluations 
performed within the 28 days prior to the Early Discontinuation Visit need not be repeated at the 
visit.  
 
Maternal Early Discontinuation Visit Procedures 
Clinical 
 
 Obtain interval medical and medications history 
 Perform targeted physical exam 
 Identify/review/update adverse events 
 Perform additional evaluations per Section 8 and/or if 
clinically indicated (consult CMC if indicated)
Study Drug 
 
 Administer routine adherence questionnaire 
 Collect any remaining study drug supplies
Laboratory 
Blood 
Collect blood for: 
 ALT, AST, creatinine, CrCl 
 HIV-1 RNA (real-time; store residual plasma)
Urine
Collect urine for: 
 Storage for markers of renal toxicity
 
Infant Early Discontinuation Visit Procedures 
Clinical 
 Obtain interval medical, medications, and feeding history 
 Perform targeted physical exam with growth evaluation 
 Identify/review/update adverse events 
 Perform additional evaluations per Section 8 and/or if 
clinically indicated (consult CMC if indicated)
Laboratory 
Blood 
Collect blood for: 
 HIV NAT (store residual plasma)
 
As soon as the maternal creatinine test result for this visit is obtained, the estimated CrCl 
rate should be calculated using the Cockcroft-Gault formula, graded for severity, and 
assessed for clinical significance concurrent with all other laboratory test results. 
 
Arrangements should be made to provide the mother clinically meaningful test results from the 
Early Discontinuation Visit. The mother should be provided information on how to remain in 
contact with study staff (if desired) and learn about the results of the study when available. The 
mother should also be provided information, counseling, and referrals to non-study sources of 
care and treatment for herself and her infant, as applicable.  
 


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6.10 
Post-Study Contacts 
 
As indicated in Sections 6.5.4 and 6.5.5, planning for transition to non-study care and treatment 
should begin at the Week 38 Visit, and the transition should be implemented at the Week 50 
Visit. Following the Week 50 Visit, study staff will complete a final study contact with each 
mother to confirm her transition and, in particular, confirm her access to non-study ARVs. 
Mothers will also be asked to report their non-study ARV regimen, their adherence to non-study 
ARVs, any potential intolerance or side effects associated with their non-study ARVs, and any 
other problems with accessing or taking their non-study ARVs. This contact should take place 
within four weeks after the Week 50 Visit and should be documented in each mother’s study 
chart. These contacts are not expected to be entered into eCRFs. However, eCRF data collection 
is required after the Week 50 Visit in the following scenarios:  
 
 
If a mother is pregnant at the Week 50 Visit: Refer to Section 8.6; in this scenario, the 
pregnancy outcome must be ascertained and the relevant eCRFs entered after the Week 50 
Visit to record the pregnancy outcome. Relevant eCRFs will also be entered to capture any 
ARV changes during the pregnancy (after the Week 50 Visit). 
 
 
If confirmation of maternal virologic failure is pending after the Week 50 Visit: Refer to 
Section 6.7; in this scenario, the confirmatory HIV-1 RNA PCR assay must be performed and 
the relevant eCRFs entered to record the result of the assay. 
 
 
If confirmation of infant HIV infection is pending after the Week 50 Visit: Refer to Section 
6.8; in this scenario, the confirmatory HIV NAT must be performed and the relevant eCRFs 
entered to record the result of the test. 
 
6.11 
Maternal Medical and Medication History  
 
Collection of medical and medication history information is required at each scheduled maternal 
visit. A baseline history is established at Screening and Entry, and interval (since the last visit) 
histories are obtained at subsequent follow-up visits. 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.  
 
Documented medical conditions will be assessed for severity as described in Section 7.3.3, and 
new conditions occurring during follow-up will also be assessed for relationship to study drug as 
described in Section 8.1. Relevant dates will be recorded for all conditions and medications; see 
Section 5.8 for more information on concomitant medications.  
 
Table 3 specifies the baseline and interval medical and medications history elements that must be 
source documented for mothers, as well as associated eCRF entry requirements.  


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Table 3 
Documentation Requirements for Maternal Medical and Medication Histories 
Assess for and 
Source Document
Enter into 
eCRFs
Maternal Baseline Medical and Medication History Elements
Date of birth and other socio-demographics 
Yes (all) 
HIV diagnosis, WHO clinical staging, and 
treatment history (including all ARV use prior to 
enrollment)
Yes (all) 
Reproductive and obstetrical history: 
 Dates and outcomes of all prior pregnancies 
 Date of last menstrual period prior to the current 
pregnancy 
 Complications in the current pregnancy 
 Other targeted conditions potentially associated 
with adverse pregnancy outcomes in the current 
pregnancy
Yes (all) 
History of allergy and/or hypersensitivity 
(including to ARVs)
Yes (all) 
History of bone fracture  
(traumatic and non-traumatic)
Yes (all) 
History of depression and/or suicidality 
Yes (all) 
History of tobacco smoking and alcohol use 
Yes (all) 
Medical conditions (signs, symptoms, illnesses, 
and other diagnoses) occurring during the 28 days 
prior to enrollment and/or ongoing at enrollment
Yes (all) 
Medications taken within the 28 days prior to 
enrollment and/or ongoing at enrollment
Yes (all) 
Any other information needed to determine 
eligibility for the study
— 
 


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Table 3 
Documentation Requirements for Maternal Medical and Medication Histories 
Assess for and 
Source Document
Enter into 
eCRFs
Maternal Interval Medical and Medication History Elements
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 Section 7.2 
Current status of medications that were ongoing at 
the previous visit
Any updates of previous entries  
(e.g., stop dates)
Use of any new medications since the last visit  
(see Section 5.8.1 for more information on concomitant 
medications) 
 All ARVs taken from time of 
enrollment through completion of 
follow-up (including timing of dosing 
at the Delivery and Week 6 
Postpartum Visits) 
 Any new use of: 
– Cotrimoxazole 
– Isoniazid prophylaxis 
– Medications to treat active 
tuberculosis 
– 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  
corticosteroids were taken for fetal lung 
maturity at any time during pregnancy.
 
In addition to the above, at the Delivery Visit, all of the following should be source documented 
and entered into eCRFs:  
 
 
Complications of pregnancy identified following enrollment and before delivery, regardless 
of severity grade  
 
Other targeted conditions potentially associated with adverse pregnancy outcomes identified 
following enrollment and before delivery, regardless of severity grade 
 
Date and time of onset of labor 
 
Type of labor (spontaneous or induced) 
 
Mode of delivery 
 
Complications of delivery 
 
Outcome of delivery 
 


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6.12 
Maternal Physical Examinations  
 
A physical examination is required at each scheduled maternal visit. Complete exams are required 
at the Screening and Entry Visits; targeted exams are required at all other visits. 
 
Complete exams should include the following: 
 
 
Height measurement (at screening only) 
 
Weight measurement 
 
Blood pressure measurement 
 
Obstetric exam (at antepartum visits)  
 
Auscultation of chest (heart and lung exam) 
 
Examination of:  
– 
Skin 
– 
Head 
– 
Mouth 
– 
Neck 
– 
Abdomen 
– 
Extremities 
 
Targeted exams should include the following: 
 
 
Weight measurement 
 
Blood pressure measurement 
 
Obstetric exam (at antepartum visits)  
 
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.  
 
All exam findings should be source documented and the following should be entered into eCRFs: 
height (only at screening exam), weight, blood pressure, and fundal height (only at antepartum 
exams). Abnormal findings identified prior to enrollment will be entered into medical history 
eCRFs. Abnormal findings identified after enrollment will be entered into adverse events eCRFs 
as specified in Section 7.2. 
 
6.13 
Fetal Ultrasound 
 
A fetal ultrasound scan is required to permit more accurate calculation of gestational age at entry 
into the study and gestational age at delivery. Scans should be performed prior to study entry if 
possible, but may be performed within 14 days after study entry if necessary. When scans are 
performed prior to study entry, results must be used to estimate gestational age and assess for 
evidence of multiple gestation and fetal anomalies for purposes of eligibility determination. When 
scans are performed after study entry, any findings that indicate multiple gestation, fetal anomaly, 
or gestational age outside of the allowable range of 14-28 weeks will be recorded but will not be 
considered eligibility violations and will not result in withdrawal from the study. 
 
Ultrasound scans may be performed at the study site or at off-site facilities. In the event that a 
scan is performed prior to the study screening period, and a result report meeting all requirements 
specified below is available, it is not necessary to perform another scan for study purposes.  


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A result report that minimally documents the following must be obtained for filing in participant 
study charts and entry into eCRFs; if more than one result report that meets these requirements is 
available, the earliest available results should be entered into eCRFs for estimation of gestational 
age: 
 
 
Date of scan 
 
Number of fetuses 
 
Estimated fetal weight if greater than 20 completed weeks gestation 
 
Biometry measures 
– 
If less than 14 weeks gestation: 
 
Crown-rump length 
– 
If 14 or more weeks gestation:  
 
Femur length 
 
Abdominal circumference 
 
Biparietal diameter and/or head circumference 
 
Ultrasound-based gestational age on the date of the scan or ultrasound-based estimated date 
of delivery  
 
If any fetal anomalies are identified, these should also be documented in the result report. 
 
6.14 
Infant Medical and Medication History  
 
Collection of medical and medication history information is required at each scheduled infant 
visit. A baseline history is established at the Delivery Visit and interval (since the last visit) 
histories are obtained at subsequent follow-up visits. Infant birth details should ideally be 
obtained from available 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.  
 
The infant baseline medical and medication history will consist of information recorded at birth 
as well as information obtained at the Delivery Visit. The Delivery Visit should take place as 
soon as possible after birth and within the targeted window of up to 14 days after birth; if the visit 
cannot be conducted within the targeted window, it may be conducted within the allowable 
window of up to 27 days after delivery. As such, information recorded at birth may differ from 
information obtained at the Delivery Visit.  
 
Table 4 specifies the baseline and interval medical and medications history elements that must be 
source documented for infants, as well as associated eCRF entry requirements.  
 
6.15 
Infant Feeding History  
 
An infant feeding history is required at each scheduled visit. At the Delivery Visit, feeding 
history since birth (including date and time of first breastfeeding, if applicable) will be collected. 
Thereafter, interval (since the last visit) histories will be collected. At each time point, data will 
be collected (source documented and entered into eCRFs) on feeding method, including whether 
the infant has been breastfed or formula fed, and date of last exposure to breast milk. Any 
therapeutic foods received will be recorded as concomitant medications (see Section 5.8.2).  
 


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Table 4 
Documentation Requirements for Infant Medical and Medication Histories 
Assess for and 
Source Document
Enter into 
eCRFs
Infant Baseline Medical and Medication History Elements
Date and time of birth 
Yes (all) 
Sex, estimated gestational age, length, 
weight, and head circumference at birth 
(obtain from medical records; 
measurements will also be performed by 
study staff at the infant Delivery Visit)
Yes (all) 
Apgar scores at 1 and 5 minutes  
(obtain from medical records)
Yes (all) 
Congenital anomalies and other medical 
conditions (signs, symptoms, illnesses, 
and other diagnoses) identified between 
birth and the Delivery Visit
Any conditions (adverse events) 
that meet criteria in Section 7.2 
including all suspected  
congenital anomalies
Medications taken between birth and the 
Delivery Visit 
 All ARVs 
 Any use of: 
– Cotrimoxazole 
– Isoniazid prophylaxis 
– Medications to treat active tuberculosis 
 All medications taken at onset of or in response 
to adverse events that are specified to be entered 
into eCRFs per Section 7.2
Infant Interval Medical and Medication History Elements
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 Section 7.2 
Current status of medications that were 
ongoing at the previous visit
Any updates of previous entries  
(e.g., stop dates)
Use of any new medications since the 
last visit 
(see Section 5.8.2 for more information 
concomitant medications) 
 All ARVs 
 Any new use of: 
– Cotrimoxazole 
– Isoniazid prophylaxis 
– Medications to treat active tuberculosis 
 All medications taken at onset of or in response 
to adverse events that are specified to be entered 
into eCRFs per Section 7.2
 
 


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6.16 
Infant Physical Examinations  
 
A physical examination is required at each scheduled infant visit. A complete exam is required at 
the Delivery Visit; targeted exams are required at all other scheduled visits.  
 
Complete exams should include the following: 
 
 
Newborn step-wise surface examination of: 
– 
Physical appearance 
– 
Length  
– 
Weight 
– 
Skin 
– 
Head (including fontanels and circumference) 
– 
Face (including mouth) 
– 
Neck 
– 
Chest 
– 
Abdomen and anus 
– 
Hips and genitalia 
– 
Arms, legs, fingers, and toes 
– 
Spine 
 
Auscultation of chest 
 
Neurologic assessment 
 
The newborn step-wise surface examination will be performed consistent with WHO 
guidelines (available on the study-specific website: http://impaactnetwork.org/studies/ 
IMPAACT2010.asp). The purpose of this examination is to establish each infant’s physical 
condition at the Delivery Visit and to complete a systematic and standardized assessment for 
congenital anomalies. All elements of the surface examination should be performed for 
purposes of assessing for congenital anomalies in all infants, with the exception of the intra-
oral, cardiac, and genitourinary systems (which will be included in the general examination 
but will not be routinely assessed for presence of congenital anomalies). 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.  
 
Targeted exams should include the following: 
 
 
Length measurement 
 
Weight measurement 
 
Head circumference measurement 
 
Assessment of fontanel closure 
 
Auscultation of chest 
 
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. Also at all visits, the measurements listed above will be used to determine weight-for-
length z-scores, which will be assessed in relation to WHO growth standards; measurements 
may also be charted on standard infant growth charts. 


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All exam findings should be source documented and the following should be entered into eCRFs: 
length, weight, head circumference, fontanel closure. Abnormal findings — including any 
suspected congenital anomaly in any body system — will be entered into adverse events eCRFs 
as specified in Section 7.2; photographs of abnormal findings may be securely uploaded to the 
DMC upon request to permit review and evaluation of findings by the CMC. 
 
Note: Suspected congenital anomalies identified in body systems that are not part of the 
systematic surface examination (i.e., the intra-oral, cardiac, and genitourinary systems) or that 
may not be included in analyses of major congenital anomalies (e.g., polydactyly), should still be 
source documented and entered into eCRFs.  
 
6.17 
Maternal and Infant DXA Scans  
 
At selected sites, mothers will undergo DXA scans of the lumbar spine and hip at Week 50 
postpartum and infants will undergo DXA scans of the whole body and lumbar spine at Week 26 
postpartum. Scans will be performed according to standardized procedures described in the study-
specific MOP. Scan images will be transferred electronically for centralized reading and results 
will be transmitted electronically from the central readers to the DMC. The centralized readings 
of all scans will be made available to the study sites after the last scan has been read centrally. 
However, in the event that an infant experiences a bone fracture subsequent to his or her scan, the 
result of his or her scan will be provided to the site as soon as available.  
 
6.18 
Additional Considerations for Laboratory Procedures 
 
Each study site and laboratory involved in this study will comply with the DAIDS policy on 
Requirements for DAIDS Funded and/or Sponsored Laboratories in Clinical Trials Policy, which 
is available at: https://www.niaid.nih.gov/research/daids-clinical-research-policies-standard-
procedures. 
 
6.18.1 Specimen Collection 
 
Specimens will be collected for this study as indicated in the Schedule of Evaluations and per 
detailed guidance provided in the Laboratory Processing Chart (LPC), which will be posted on 
the study-specific webpage at: http://impaactnetwork.org/studies/IMPAACT2010.asp. 
 
In accordance with US National Institutes of Health (NIH) recommendations, adult (maternal) 
blood collection will not exceed 10.5 mL/kg or 550 mL, whichever is smaller, over any eight-
week period; pediatric (infant) blood collection will not exceed 5 mL/kg in a single day or 9.5 
mL/kg in any eight-week period.  
 
In the event that maternal blood collection must be limited, available specimens should be 
prioritized for use in the following order: (1) confirmatory HIV testing (if needed at Screening 
Visit), (2) HIV-1 RNA, (3) chemistry, (4) hepatitis B surface antigen (at Entry Visit only), (5) 
hematology, (6) CD4+ cell count, and (7) plasma, cell pellet, and serum storage for purposes 
other than HIV-1 RNA. 
 
In the event that infant blood collection must be limited, available specimens should be 
prioritized for use in the following order: (1) HIV NAT, (2) chemistry, (3) hematology, and 
(4) serum storage. 
 


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6.18.2 Specimen Preparation, Testing, Storage, and Shipping 
 
All specimens collected for this study will be labeled, transported, processed, tested, stored and/or 
shipped in accordance with the DAIDS policy referenced in Section 6.18, site and local 
laboratory SOPs, and the LPC. The frequency of specimen collection and testing will be directed 
by the Schedule of Evaluations and specifications for clinical management provided in Section 8. 
The Laboratory Data Management System (LDMS) will be used to document specimen 
collection, testing, storage, and shipping as specified in LPC. Any specimens stored at the 
Screening Visit for mothers who do not subsequently enroll in the study will be destroyed.  
 
At each study site, all maternal plasma HIV-1 RNA assays must be performed in real time in a 
VQA-certified laboratory using the testing platform specified in the LPC. For mothers who 
experience virologic failure, antiretroviral resistance testing will be performed in real time at 
designated VQA-certified laboratories. Blood collected for resistance testing at Confirmation of 
Virologic Failure Visits will be processed locally, with plasma retained at the site laboratory 
pending HIV-1 RNA testing to confirm virologic failure. If failure is confirmed, aliquots of 
plasma stored for resistance testing at the Screening Visit and the Confirmation of Virologic 
Failure Visit will be shipped to a designated VQA-certified testing laboratory (residual plasma 
aliquots will be stored at the site laboratory); if failure is not confirmed, all plasma aliquots will 
remain stored at the site laboratory.  
 
Infant HIV NAT must be performed in a VQA-certified laboratory (for non-US sites) or a CLIA-
certified laboratory (for US sites). Whenever these tests are performed, any plasma remaining 
after the assay is completed should be stored.  
 
Most specimens collected and stored at site laboratories per the Schedule of Evaluations are 
expected to be requested for centralized testing after all participants have completed follow-up 
(through Week 50 postpartum). However, an interim shipment is planned when all enrolled 
mothers have delivered. At this time, all specimens stored for centralized HIV-1 RNA testing will 
be requested for shipment to the designated testing laboratory. These specimens will then be 
tested as needed to evaluate outcomes through the delivery time point. Interim shipments may 
also be required for urine samples stored for evaluation of markers of renal toxicity. Alternative 
shipping arrangements may be specified by the Protocol Team as needed; detailed shipping 
instructions will be provided in the LPC. 
 
After all protocol-specified laboratory testing has been performed, residual specimens may be of 
interest for future research use. Mothers will be asked to provide written informed consent for 
future research use of these specimens, if permitted by site IRBs/ECs and other applicable review 
bodies. Mothers may choose to provide or to decline informed consent for future research use of 
residual specimens — for themselves and for their infants — with no impact on other aspects of 
participation in the study. If mothers initially provide informed consent for future research use of 
residual specimens but subsequently change their mind and withdraw that consent, all remaining 
residual samples will be destroyed. 
 


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6.18.3 Biohazard Containment 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact with 
contaminated needles, blood, and blood products, appropriate blood and secretion precautions 
will be employed by all personnel in the drawing of blood and shipping and handling of all 
specimens for this study as currently recommended by the US Centers for Disease Control and 
Prevention, NIH, and other applicable agencies. All specimens will be shipped using packaging 
that meets requirements specified by the International Air Transport Association Dangerous 
Goods Regulations for UN 3373, Biological Substance, Category B, and Packing Instruction 650. 
Culture isolates, if obtained in this study, are to be shipped as specified for UN 2814 Category A 
Infectious Substances. 
 
 
7 
SAFETY ASSESSMENT, MONITORING, AND REPORTING 
 
Participant safety will be carefully assessed, monitored, and reported at multiple levels 
throughout this study. Sections 7.1-7.3 describe safety-related roles, responsibilities, and 
procedures. The safety monitoring roles of the study-specific Safety Review Group (SRG) and 
DSMB are briefly referenced in Section 7.1 and described in greater detail in Sections 9.5.2 and 
9.5.3. 
 
7.1 
Safety-Related Roles and Responsibilities 
 
7.1.1 
Site Investigators 
 
Site investigators are responsible for monitoring of all study participants and for alerting the 
Protocol Team if unexpected concerns arise. Site investigators and their designees will enter 
safety-related data into eCRFs as indicated in Section 7.2 and complete expedited adverse event 
(EAE) reporting as indicated in Section 7.3. Site investigators are also responsible for prompt 
reporting to their IRBs/ECs and other applicable review bodies of any unanticipated problems 
involving risks to participants or others. 
 
7.1.2 
Clinical Management Committee (CMC) 
 
The following Protocol Team members comprise the CMC: Protocol Co-Chairs, selected Protocol 
Investigators, Medical Officers, Statisticians, Data Managers, and Clinical Trial Specialists. The 
CMC will provide guidance as needed to site investigators regarding all aspects of participant 
management, including but not limited to questions of participant eligibility, management of AEs, 
and management of antiretroviral regimens.  
 
7.1.3 
Safety Review Group (SRG) 
 
An SRG comprised of the Protocol Medical Officers, Protocol Statisticians, Protocol Data 
Managers, and other designated individuals with expertise in adult HIV medicine, obstetrics, and 
pediatrics who are independent of the Protocol Team will monitor participant safety through 
routine review of study data reports as described in Section 9.5.2.  
 


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7.1.4 
Data and Safety Monitoring Board (DSMB)  
 
An independent DSMB will monitor participant safety through routine and as needed reviews of 
study data. Refer to Section 9.5.3 for more information on the role of the DSMB in monitoring of 
this study.  
 
7.2 
Safety-Related Data Collection 
 
Note: This section describes eCRF data collection for pre-existing conditions and adverse events. 
As part of this description, reference is made to severity grading and criteria for EAE reporting; 
refer to Sections 7.3.3 and 7.3.2, respectively, for detailed information on these topics.  
 
The definition of the term adverse event provided in Version 2.0 of the Manual for Expedited 
Reporting of Adverse Events to DAIDS (DAIDS EAE Manual) will be used in this study. This 
definition will be applied to all mothers and infants, beginning at the time of enrollment, 
regardless of subsequent administration of or exposure to study drug. Any untoward medical 
conditions (including abnormal laboratory test results, signs, symptoms, or diseases) identified 
prior to enrollment will be considered pre-existing conditions. Refer to Section 4.4 for more 
information on defining the effective point of enrollment in the study.  
 
Pre-existing conditions and adverse events will be entered into eCRFs as specified in Sections 
7.2.1 (for mothers) and 7.2.2 (for infants).  
 
7.2.1 
Safety-Related Data Collection for Mothers 
 
Pre-Existing Conditions 
 
All pre-existing conditions identified among mothers during the 28 days prior to study entry will 
be entered into maternal medical history eCRFs.  
 
Adverse Events 
 
The following adverse events — inclusive of abnormal laboratory test results and clinical signs, 
symptoms, and diagnoses except as specified in the IMPAACT Do Not Report List — will be 
entered into maternal adverse events eCRFs: 
 
 
All grade 3 or higher adverse events 
 
All grade 2 or higher rashes  
 
All grade 2 or higher psychiatric events 
 
All events involving suicidal ideation or attempt 
 
All suspected or confirmed diagnoses of clinical hepatitis 
 
All suspected or confirmed diagnoses of immune reconstitution inflammatory syndrome 
(IRIS) 
 
All adverse events that lead to any change of ART regimen (i.e., any hold, discontinuation, 
switch/replacement, dose or frequency modification)  
 
All serious adverse events (SAEs) as defined in Version 2.0 of the DAIDS EAE Manual 
 


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In addition to the above specifications for entry into adverse events eCRFs, further detailed 
eCRFs will be entered for hepatic events resulting in discontinuation of DTG or EFV; suicide-
related events that meet criteria for reporting as EAEs (see Section 7.3.2); and serious 
hypersensitivity reactions to ABC that occur among mothers who switch from TDF or TAF to 
ABC.  
 
Laboratory Test Results 
 
In addition to the recording specified above, the following laboratory test results will be entered 
into the relevant maternal laboratory eCRFs, regardless of whether the test was protocol-specified 
or ordered by the site investigator for clinical purposes: 
 
 
All creatinine and creatinine clearance results 
 
All grade 1 or higher LFT results 
 
All grade 3 or higher hemoglobin, white blood cell count, absolute neutrophil count, and 
platelet count results 
 
All results that lead to a change of ART regimen (i.e., any hold, discontinuation, 
switch/replacement, dose or frequency modification)  
 
All results that are serious as defined in Version 2.0 of the DAIDS EAE Manual 
 
All results that are relevant to events that meet criteria for reporting as EAEs (see Section 
7.3.2)  
 
7.2.2 
Safety-Related Data Collection for Infants 
 
Pre-Existing Conditions 
 
Because infants will be exposed to study drug in utero, all abnormal conditions identified during 
and after birth will be considered adverse events. No pre-existing conditions will be entered into 
eCRFs for infants.  
 
Adverse Events 
 
The following adverse events — inclusive of abnormal laboratory test results and clinical signs, 
symptoms, and diagnoses except as specified in the IMPAACT Do Not Report List — will be 
entered into infant adverse events eCRFs: 
 
 
All grade 3 or higher adverse events 
 
All suspected congenital anomalies 
 
All SAEs as defined in Version 2.0 of the DAIDS EAE Manual  
 


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Laboratory Test Results 
 
In addition to the recording specified above, the following laboratory test results will be entered 
into the relevant infant laboratory eCRFs, regardless of whether the test was protocol-specified or 
ordered by the site investigator for clinical purposes: 
 
 
All creatinine results 
 
All grade 2 or higher ALT results 
 
All grade 3 or higher hemoglobin, white blood cell count, absolute neutrophil count, and 
platelet count results 
 
All results that are serious as defined in Version 2.0 of the DAIDS EAE Manual 
  
7.3 
Expedited Adverse Event (EAE) Reporting 
 
7.3.1 
EAE Reporting to DAIDS 
 
Requirements, definitions, and methods for expedited reporting of adverse events are outlined in 
Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE 
Manual), which is available on the DAIDS RSC website at: http://rsc.tech-
res.com/safetyandpharmacovigilance. 
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based reporting 
system, must be used for EAE reporting to DAIDS. In the event of system outages or technical 
difficulties, EAEs may be submitted using the DAIDS EAE Form. This form is available on the 
DAIDS RSC website at: http://rsc.tech-res.com/safetyandpharmacovigilance. 
 
For questions about DAERS, please contact NIAID CRMS Support at 
CRMSSupport@niaid.nih.gov. Queries may also be sent from within the DAERS application 
itself. 
 
For questions about expedited reporting, please contact the DAIDS RSC Safety Office at 
DAIDSRSCSafetyOffice@tech-res.com. 
 
7.3.2 
EAE Reporting Requirements for this Study 
 
As indicated in Table 5, below, both the SAE (serious adverse event) and SUSAR (suspected 
unexpected serious adverse reaction) reporting categories, as defined in Version 2.0 of the 
DAIDS EAE Manual, will be used for this study. The SUSAR category is used for participants in 
Arm 3, who will be exposed to an approved regimen at approved doses for an approved 
indication. 
 
Table 5 
Expedited Adverse Event Reporting Requirements for IMPAACT 2010 
 
Study Entry through
Week 14 Postpartum
After Week 14 Postpartum
through Study Exit
Study Drugs for which 
Expedited Reporting 
is Required 
 
Mothers 
Infants 
Mothers 
Infants 
Arm 1 
SAEs 
SAEs 
SAEs 
SUSARs 
DTG, FTC, TAF 
Arm 2 
SAEs 
SAEs 
SAEs 
SUSARs 
DTG, FTC, TDF 
Arm 3 
SUSARs 
SUSARs 
SUSARs 
SUSARs 
EFV, FTC, TDF 


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For mothers in Arm 1 or Arm 2, the EAE reporting categories listed above will be remain 
unchanged regardless of ART regimen changes. For mothers in Arm 3 who switch to a DTG-
containing or TAF-containing regimen, the EAE reporting category will also be switched to the 
SAE reporting category, from the date of the switch through study exit.  
 
In addition to the above, the following must also be reported in an expedited manner (i.e., as 
EAEs) for mothers in Arm 1 or Arm 2 and for mothers in Arm 3 who switch to a DTG-containing 
or TAF-containing regimen:  
 
 
Pregnancy complications that result in medically indicated and/or elective termination of the 
pregnancy 
 
Spontaneous abortions and fetal deaths 
 
In addition to the above, the following must also be reported in an expedited manner (i.e., as 
EAEs) for mothers in all arms: 
 
 
Hepatic toxicities that result in discontinuation of DTG or EFV 
 
Serious ABC hypersensitivity reactions in mothers switching from TDF or TAF to ABC 
 
7.3.3 
Grading Severity of Events (applies to EAEs and all other adverse events) 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
(DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017, will be used in this study. 
This table is available on the RSC website at http://rsc.tech-res.com/clinical-research-sites/safety-
reporting/daids-grading-tables. In addition, the following protocol-specific grading scheme for 
axillary measured fever will be used in this study: 
 
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 
 
Note: The DAIDS AE Grading Table parameter for unintentional weight loss excludes 
postpartum weight loss. Therefore, maternal weight loss will not be graded in this study.  
 
7.3.4 
EAE Reporting Period 
 
The EAE reporting period for this study is the protocol-specified period of follow-up, beginning 
at the time of randomization and ending on the date of the final follow-up visit.  
 
After the above-specified period, only SUSARs will be reported if study staff become aware of 
such events on a passive basis (e.g., from publicly available information). 
 
 


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8 
PARTICIPANT MANAGEMENT 
 
8.1 
Maternal and Infant Adverse Events 
 
All maternal and infant adverse events identified in this study will be source documented in 
participant research records, consistent with the policies and procedures referenced in Section 10. 
Among other details, source documentation will include the severity of each event (graded as 
described in Section 7.3.3) and its relationship to study drug, assessed according to the following 
categories and definitions: 
 
Related 
There is a reasonable possibility that the adverse event may be related to 
study drug.  
 
Not related 
There is not a reasonable possibility that the adverse event may be related 
to study drug.  
 
Further standardized guidance on determining whether there is a reasonable possibility of a 
relationship is available in the DAIDS EAE Manual (referenced in Section 7.3.1). Note that 
adverse events assessed as secondary to immune reconstitution should not be considered related 
to study drug (refer to Section 8.8 for further information on management of IRIS). 
 
For mothers, relationship should be assessed for each study drug received (ingested). 
 
For infants, relationship should be assessed for study drug received by the mother to which the 
infant may have been exposed 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. Additional evaluations may be performed at the discretion of the site 
investigator to determine the etiology of an event and/or further assess its severity or relationship 
to study drug. Clinical management of all adverse events should be consistent with the best 
medical judgment of the site investigator and local clinical practice standards. Adverse events that 
are ongoing at the time of the final study visit, particularly those of Grade 3 or higher severity, 
should generally be followed to resolution or stabilization by the site investigator; if this is not 
possible, the site investigator should actively facilitate referral to local non-study sources of 
appropriate medical care and treatment.  
 
Please refer to Section 8.2 for further guidance on management of maternal adverse events; infant 
management is addressed in Section 8.9. When management of an adverse event requires 
consultation with the CMC, the CMC should be contacted as soon as possible and within three 
business days of site awareness of the event. 
 


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8.2 
Management of Maternal Adverse Events 
 
Maternal adverse events will be managed based on their severity and assessed relationship to 
study drug, as described in the remainder of this section. Please refer to the management tables in 
Appendix II for detailed guidance on management of maternal 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), and allergic reaction 
(Table II.7). All other adverse events should be managed as shown in Table II.1. For any mother 
whose study drug regimen is modified such that DTG or EFV is replaced with another ARV, an 
additional study visit should be conducted approximately four weeks after the switch as described 
in Section 6.6. Refer to Table II.8 for further guidance when switching from TAF or TDF to ZDV 
or ABC. 
 
8.3 
Monitoring and Management of Maternal HIV Viral Load 
 
Monitoring 
 
Maternal HIV-1 RNA (viral load) will be monitored closely with frequent testing as specified in 
the Schedule of Evaluations. All maternal HIV-1 RNA assays must be performed in a VQA-
certified laboratory using the testing platform specified in the LPC. Site investigators should 
review the results of each test as well as trends over time and consult with the CMC regarding 
any individual test results or trends of concerns. As noted in Section 5.7, viral load results should 
be provided to participants and may be used to guide adherence counseling.  
 
Definition of Virologic Failure 
 
Virologic failure is defined as two successive plasma HIV-1 RNA test results ≥200 copies/mL, 
with specimen collection for the first test occurring at or after 24 weeks counted from the date of 
randomization. For mothers who switch ARVs within the first 24 weeks on study, the counting of 
weeks for purposes of defining virologic failure is generally not expected to be altered by the 
switch (i.e., the counting of 24 weeks would generally not be re-started at the time of the switch). 
However, treatment interruption for a period of 14 days or longer may require alternative 
management. The CMC should be consulted regarding any mother who interrupts treatment for 
14 or more days for any reason.  
 
Confirmation of Virologic Failure 
 
Any mother with a plasma HIV-1 RNA level ≥200 copies/mL at or after 24 weeks on study 
should be recalled to the clinic for confirmatory testing as soon as possible and within 28 days of 
the date of specimen collection for the initial test. As indicated in Section 6.7, specimen 
collection for antiretroviral resistance testing will also be performed at the time of specimen 
collection for confirmatory HIV-1 RNA testing. All procedures should be performed regardless 
of reported adherence to study drug or any other factors that may affect HIV-1 RNA results.  
 
Management of Confirmed Virologic Failure 
 
The CMC should be consulted regarding management of all participants with confirmed virologic 
failure.  
 
For mothers with confirmed virologic failure, upon receipt of the confirmatory HIV-1 RNA test 
result, specimens collected for antiretroviral resistance testing at the Screening Visit and the 


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Confirmation of Virologic Failure Visit should be shipped to a designated VQA-certified testing 
laboratory. Resistance test results will be provided in real time to help guide ART regimen 
management, as described below. 
 
If the virologic failure is assessed as likely due to non-adherence, the current ART regimen may 
be continued, with enhanced adherence support per site SOPs (see Section 5.7) and continued 
virologic monitoring. Likewise, if the failure is assessed as due to intercurrent illness or other 
factors not associated with the current regimen, the current regimen may be continued. Otherwise, 
the regimen should generally be modified in consultation with the CMC. Recommendations for 
alternative regimens should take into consideration the participant’s preferences and medical 
history, current regimen, current local standard guidelines for first- and second-line regimens, and 
resistance test results. For any mother whose regimen is modified such that DTG or EFV is 
replaced with another ARV, an additional study visit should be conducted approximately four 
weeks after the switch as described in Section 6.6. 
 
8.4 
Management of Mothers who Develop Active Tuberculosis 
 
Mothers who develop active tuberculosis and need rifampin-containing treatment during follow-
up may have their study drug regimen modified consistent with the relevant Package Inserts and 
guidelines for co-administration of ARVs and TB treatment medications. Such modifications will 
include increasing the frequency of DTG dosing from 50 mg once daily to 50 mg twice daily. In 
addition, TAF should be switched to TDF. The CMC should be informed of each TB diagnosis 
and consulted on study drug regimen management on a case-by-case basis. After the period of 
rifampin treatment is completed, the original ART regimen should be resumed.  
 
For any mother whose study drug regimen is modified such that DTG or EFV is replaced with 
another ARV, an additional study visit should be conducted approximately four weeks after the 
switch as described in Section 6.6. 
 
8.5 
Management of Mothers who are Co-Infected with Hepatitis B 
 
Hepatitis B surface antigen testing will be performed at study entry so that hepatitis B infection 
status can be taken into account when evaluating maternal adverse events and managing study 
drug regimens. Hepatitis B testing is not required after study entry per the Schedule of 
Evaluations but may be performed at any time during follow-up if clinically indicated.  
 
Hepatitis B co-infected mothers who initiate or discontinue ARVs that are active against hepatitis 
B may be at risk of immune reconstitution or rebound hepatitis viremia (respectively) and 
subsequent transaminitis. These mothers should be closely monitored for any symptoms of 
hepatitis; should any such symptoms occur, the CMC should be consulted regarding further 
management. Periodic monitoring of liver function tests and markers of hepatitis B virus 
replication should also be considered. Further guidance on management of elevated ALT and 
AST values and symptomatic hepatitis is provided in Tables II.3 and II.4. 
 
For infants of mothers who are co-infected with hepatitis B, every effort should be made to 
facilitate access to the best available local standard management for hepatitis B exposure, 
including (but not limited to) the hepatitis B vaccine series, ideally beginning at birth.  
 


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8.6 
Contraception and Management of Mothers who Become Pregnant on Study 
 
Mothers should be provided with contraception counseling as needed during their participation in 
the study. Counseling should be provided per site SOPs, which should reflect WHO guidelines 
for HIV-infected women as well as local standards of care. Counseling should begin during 
pregnancy and continue postpartum as needed for each mother, and should reflect the ARVs that 
mothers are currently taking and the potential interactions between these ARVs and available 
contraceptive methods. Study sites should ideally integrate provision of contraceptive methods 
with other services offered to study participants and should provide referrals to non-study sources 
of methods that cannot be provided at the study site.  
 
Pregnancy testing is not required per the study Schedule of Evaluations. Nonetheless, testing may 
be performed when clinically indicated at any time during maternal follow-up. 
 
Mothers who become pregnant will be maintained in follow-up and may remain on their current 
ART regimen during the new pregnancy. When the new pregnancy is identified, mothers will be 
provided information and counseling on their current regimen and what is known about the safety 
of the ARVs that comprise the regimen during pregnancy. Mothers who wish to change regimens 
based on this counseling will be permitted to do so, and site clinicians may consult with the CMC 
regarding any mothers for whom a regimen change may be clinically indicated or otherwise 
considered in the best interest of the mother or fetus. For any mother whose study drug regimen is 
modified such that DTG or EFV is replaced with another ARV, an additional study visit should 
be conducted approximately four weeks after the switch as described in Section 6.6. Mothers who 
choose to receive study drug during a subsequent pregnancy must provide separate informed 
consent to do so (refer to Section 12.3 and Appendix V).  
 
All pregnancies and pregnancy outcomes should be ascertained and entered into eCRFs. For 
mothers who are pregnant at the time of study exit, additional post-study contacts should be 
completed to ascertain their pregnancy outcomes as well as any ART regimen changes after study 
exit (see Section 6.10). These data may be ascertained based on maternal report but medical 
records should be obtained whenever possible to supplement maternal reports. 
 
Study sites are strongly encouraged to prospectively register participants with subsequent 
pregnancies in the Antiretroviral Pregnancy Registry (APR) prior to pregnancy outcome by 
calling the following number in the US: +1-800-258-4263. Outside of the US, please see the APR 
website (www.apregistry.com) for additional toll-free numbers.  
 
8.7 
Management of Maternal Nervous System and Psychiatric Symptoms 
 
As described in Section 1.8, use of EFV is commonly associated with nervous system symptoms 
(e.g., dizziness, impaired concentration, somnolence, abnormal dreams, and insomnia) that 
usually begin on the first or second day of therapy and resolve within 2-4 weeks on therapy. To 
minimize these possible effects, mothers receiving EFV in this study will be encouraged to take 
EFV at bedtime; mothers will also be informed of the potential for exacerbation of these 
symptoms associated with use of alcohol and psychoactive drugs.  
 
Insomnia, headache, and anxiety have been reported with DTG. Participants who experience 
insomnia with evening dosing of DTG may have resolution of insomnia after switching to 
morning dosing (123). 
 


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Mothers who experience nervous system symptoms should generally be managed consistent with 
the guidance provided in Table II.1. For any mothers who experience persistent symptoms that 
cannot be tolerated, the CMC should be consulted regarding a change of study drug regimen.  
 
Serious psychiatric adverse events, including severe depression and suicidal ideation or attempts, 
have also been observed with use of EFV (and rarely with DTG). Patients with a history of 
psychiatric disorder are a highest risk for these events; for this reason, mothers with a history of 
suicidality or psychiatric illness that requires treatment with psychoactive medication will be 
excluded from this study.  
 
Mothers who enroll in the study will be assessed for sleep disturbances, anxiety, and depression 
through collection of medical history information at each scheduled visit as well as through 
administration of the Pittsburgh Sleep Quality Index (PSQI), Generalized Anxiety Disorder 7-
Item Scale (GAD-7), and Edinburgh Postnatal Depression Scale (EPDS). Further information on 
administering these standardized questionnaires is provided in the study-specific MOP.  
 
The PSQI, GAD-7, and EPDS are not intended to be — and should not be — used for diagnostic 
purposes or to make decisions regarding study drug changes. However, responses to these 
questionnaires may prompt further evaluation for neuropsychiatric problems. For participants 
with questionnaire responses indicating possible neuropsychiatric symptoms of concern, a 
designated study staff member will continue discussion with the participant to determine whether 
she may require additional support, evaluation, and/or treatment, following site SOPs.  
 
The DAIDS AE Grading Table provides guidance on grading the severity of insomnia, 
psychiatric disorders (including anxiety and depression) and suicidal ideation or attempt. Study-
specific guidance for management of these conditions is provided in Table II.6. As indicated this 
table, any participant identified with a grade 1 or grade 2 condition accompanied by suicidal 
ideation, or any grade 3 or 4 condition, should be referred to appropriate mental health services. 
 
8.8 
Management of Immune Reconstitution Inflammatory Syndrome (IRIS) 
 
Inflammatory syndromes with manifestations of opportunistic or other infections have been 
reported shortly after initiation of ART (usually within three months). While these syndromes 
may appear as a recurrence or worsening of disease, they more likely reflect improvement in the 
body's ability to control infection as the immune system recovers on ART. IRIS can have various 
manifestations, including lymph node inflammation associated with Mycobacterium avium 
intracellulare, eye inflammation associated with cytomegalovirus, worsening of tuberculosis, 
cryptococcosis, or toxoplasmosis symptoms, and elevated liver enzymes in people with hepatitis 
B or C co-infection. There have also been case reports of temporary worsening of Pneumocystis 
pneumonia, progressive multifocal lymphadenopathy, herpes simplex and varicella zoster 
(shingles), warts due to human papillomavirus, and other skin conditions. Autoimmune disorders 
(such as Graves’ disease, polymyositis, and Guillain-Barre syndrome) have also been reported to 
occur in the setting of immune reconstitution; however, the time to onset is more variable and can 
occur many months after initiation of treatment and sometimes can be an atypical presentation. 
 


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As noted in Section 8.1, adverse events assessed as secondary to immune reconstitution should 
not be considered related to study drug; the rationale for this is that although IRIS is related to 
ART initiation, assessment of relationship of IRIS to a specific ART regimen is not meaningful 
for a given event. In addition, the DAIDS EAE Manual specifies that IRIS events should not be 
reported as EAEs, as IRIS is considered an anticipated event for antiretroviral therapies. 
 
When IRIS is suspected, the following management guidelines should be followed in consultation 
with the CMC: 
 
 
Continue ART 
 
Confirm diagnosis of the infection 
 
Continue or initiate specific therapy for the infection 
 
Evaluate the participant clinically to exclude a new infectious process if the participant was 
already receiving therapy for the infection 
 
Anti-inflammatory agents — initially nonsteroidal anti-inflammatory medications or 
corticosteroids if needed — may be initiated at the discretion of the site investigator in 
consultation with the CMC. 
 
8.9 
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.  
 
 
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 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. Consultation with the CMC is available but not required for most infant adverse events. 
However, should an infant experience a grade 3 or higher adverse event that is assessed by the 
site investigator as related the mother’s current study drug regimen, the CMC should be 
consulted.  
 
 
9 
STATISTICAL CONSIDERATIONS 
 
9.1 
General Design Issues 
 
This is a Phase III, three-arm, randomized, open-label study to compare the virologic efficacy and 
safety of three antiretroviral regimens — DTG+FTC/TAF, DTG+FTC/TDF, and EFV/FTC/TDF 
— for HIV-1-infected pregnant women and their infants. Mother-infant pairs will be randomized 
at 14-28 weeks gestation in a 1:1:1 ratio to receive either DTG+FTC/TAF (Arm 1), 


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DTG+FTC/TDF (Arm 2), or EFV/FTC/TDF (Arm 3). The primary objectives are to compare the 
DTG-containing arms (Arms 1 and 2) to the EFV-containing arm (Arm 3) with respect to 
maternal viral suppression at delivery; to compute all pairwise regimen comparisons for a 
composite adverse pregnancy outcome (spontaneous abortion, fetal death, preterm delivery, or 
small for gestational age); and to compute all pairwise regimen comparisons for maternal and 
infant grade 3 or higher adverse events through 50 weeks postpartum. All mothers and infants are 
planned to be followed through 50 weeks postpartum. The total sample size is 639 mother-infant 
pairs (approximately 213 per arm) and accrual is expected to be completed within 12 months after 
the first pair is enrolled. The sample size will be re-evaluated as further described in Section 
9.4.2, with the possibility of adjustment prior to the closure of participant accrual. 
 
The primary virologic efficacy analysis will combine the two DTG-containing randomized arms 
for comparison to EFV/FTC/TDF. The DTG-containing arms will be combined because viral 
load at delivery is not expected to vary between these arms. This combined analysis also weighs 
feasibility against the need to provide information on the possibility of effect modification of 
DTG in the presence of TDF or TAF. Powering the study for all three pairwise comparisons 
would be ideal scientifically; however, this would require an infeasible sample size.  
 
Viral suppression at delivery was chosen as the primary efficacy endpoint because of the 
importance of maintaining high viral suppression to minimize perinatal HIV transmission. A 
conclusion for superiority in viral suppression of a DTG-containing regimen relative to 
EFV/FTC/TDF might hasten the adoption of a DTG-containing regimen for use during pregnancy 
and postpartum. However, a conclusion of non-inferiority might allow for an increase in the 
options available to pregnant and postpartum women. Because of these two important possible 
conclusions at the end of the study, the primary analysis will be an analysis of non-inferiority 
while a superiority comparison is specified as an important secondary analysis. Testing both 
superiority and non-inferiority does not constitute multiple testing (124); however, non-inferiority 
must be established before a conclusion of superiority can be made. 
 
A conclusion of non-inferiority will be predicated on the following considerations: 
 
The 95% CI for the difference excludes the non-inferiority margin. 
 
There is a high degree of consistency with the protocol plans. For example, the levels of 
protocol deviations and loss to follow-up will need to be similar to those in previous studies 
in which superiority has been shown (e.g., PROMISE, PROMOTE). 
 
The EFV-containing arm shows its usual efficacy. 
 
The ITT and the per-protocol analyses show similar results. 
 
All three pairwise regimen comparisons will be conducted for the adverse pregnancy and 
maternal adverse event primary objectives. The DTG-containing arms (Arm 1 and Arm 2) will 
not be combined for these primary analyses because little is known about safety in pregnancy 
through one year postpartum between these two arms. 
 
An open-label study design was selected because the number of pills per day and instructions for 
administration vary between treatment arms. Potential sources of bias with an open-label study 
include increased attribution and reporting of specific toxicities in a treatment arm. Site 
investigators may be more likely to change antiretroviral therapy if a treatment arm is perceived 
as suboptimal. Efforts will be made to minimize these biases by establishing standard criteria and 
guidelines for toxicity and ARV regimen management (Section 8), safety-related data recording 
and reporting (Section 7), and inadequate virologic response (Section 8.3).  
 


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9.2 
Outcome Measures 
 
Note: The numbering of the outcome measures in this section corresponds to the numbering of 
the objectives in Section 2.  
 
The primary and secondary outcome measures listed in Sections 9.2.1 and 9.2.2 below will be 
addressed in the study’s primary statistical analysis plan, which will define the content of the 
primary analysis report. This report will form the basis for the primary study publication and 
results reporting to ClinicalTrials.gov. Other outcomes of interest for secondary objectives 
(intended for subsequent publications) are listed as other outcome measures. Outcomes of interest 
for exploratory objectives are listed in Section 9.2.3. 
 
9.2.1
Primary Outcome Measures
9.2.1.1
Efficacy  
 
HIV-1 RNA <200 copies/mL at delivery (up to 14 days postpartum), using 
real-time test results obtained at site laboratories
9.2.1.2
Safety 
 
Composite outcome of spontaneous abortion (occurring at <20 weeks 
gestation), fetal death (occurring at ≥20 weeks gestation), preterm delivery 
(<37 completed weeks), or small for gestational age (<10th percentile)  
 
Maternal grade 3 or higher adverse events, including events resulting in 
death due to any cause, through 50 weeks postpartum (refer to Section 7.3.3 
for severity grading) 
 
Infant grade 3 or higher adverse events, including events resulting in death 
due to any cause, through 50 weeks postpartum (refer to Section 7.3.3 for 
severity grading)
9.2.2
Secondary Outcome Measures
9.2.2.1
 
HIV-1 RNA <200 copies/mL at delivery (up to 14 days postpartum) using 
real-time test results obtained at site laboratories
9.2.2.2
 
HIV-1 RNA <50 copies/mL at delivery (up to 14 days postpartum) using 
batched test results obtained from central laboratory 
 
HIV-1 RNA <200 copies/mL at 50 weeks postpartum using real-time test 
results obtained from site laboratories 
 
Time to first HIV-1 RNA <200 copies/mL through delivery (up to 14 days 
postpartum) using real-time results obtained from site laboratories
9.2.2.3
 
HIV-1 RNA <200 copies/mL at delivery (up to 14 days postpartum) using 
real-time test results obtained from site laboratories and FDA snapshot 
algorithm 
 
HIV-1 RNA <200 copies/mL at 50 weeks postpartum using real-time results 
obtained from site laboratories and FDA snapshot algorithm
9.2.2.4
 
Composite outcome of spontaneous abortion (occurring at <20 weeks 
gestation), fetal death (occurring at ≥20 weeks gestation), preterm delivery 
(<37 completed weeks), or small for gestational age (<10th percentile)  
 
Maternal grade 3 or higher adverse events, including events resulting in 
death due to any cause, through 50 weeks postpartum (refer to Section 7.3.3 
for severity grading) 
 
Infant grade 3 or higher adverse events, including events resulting in death 
due to any cause, through 50 weeks postpartum (refer to Section 7.3.3 for 
severity grading)


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9.2.2.5
 
Composite outcome of spontaneous abortion (occurring at <20 weeks 
gestation), fetal death (occurring at ≥20 weeks gestation), preterm delivery 
(<37 completed weeks), or small for gestational age (<10th percentile) or 
major congenital anomaly* 
 
Ranked composite infant safety outcome (defined in Section 9.6.2) through 
50 weeks postpartum 
 
Infant HIV infection at delivery and through 50 weeks postpartum 
 
Infant death due to any cause through 50 weeks postpartum 
 
Maternal serum creatinine and creatinine clearance rate (Cockcroft-Gault 
formula) 
 
Infant serum creatinine and creatinine clearance rate (Schwartz formula) 
 
HIV-1 antiretroviral drug resistance mutations at the time of maternal 
virologic failure (and at screening for mothers with resistance detected at 
the time of virologic failure to determine if the resistance was present prior 
to enrollment or occurred post-enrollment) using the Stanford algorithm 
 
HIV-1 antiretroviral drug resistance mutations at the time HIV diagnosis for 
HIV-infected infants
9.2.2.6
 
Preterm delivery (<37 completed weeks) 
 
Small for gestational age (<10th percentile)
Other Outcome Measures
 
The other outcome measures below correspond to secondary objective 2.2.5: 
 
Maternal urine protein:creatinine ratio, urine beta 2 microglobulin: 
creatinine ratio, and urine retinol binding protein:creatinine ratio 
 
Maternal lumbar spine and hip BMD Z-scores based on DXA scan at 50 
weeks postpartum 
 
Infant whole body and lumbar spine BMC Z-scores based on DXA scan at 
26 weeks postpartum
9.2.3
Exploratory Outcome Measures
9.2.3.1
 
Maternal postpartum depression as indicated by EPDS score at 6 weeks and 
50 weeks postpartum 
 
Composite of the following outcomes of subsequent pregnancy: 
spontaneous abortion (occurring at <20 weeks gestation), fetal death 
(occurring at ≥20 weeks gestation), preterm delivery (<37 completed 
weeks), small for gestational age (<10th percentile), or major congenital 
anomaly*
9.2.3.2
 
Immunologic and hormonal predictors of adverse pregnancy outcomes and 
postpartum maternal health outcomes (potential predictors will be further 
defined by the Protocol Team after the study is completed, based on 
available scientific information and state-of-the-art assays at that time; these 
outcomes may include but are not limited to: IDO, K/T ratio, IL-6, D-dimer, 
hsCRP, sCD14/sCD163, TNFRI/II, progesterone, prolactin)
9.2.3.3
 
Composite outcome of spontaneous abortion (occurring at <20 weeks 
gestation), fetal death (occurring at ≥20 weeks gestation), preterm delivery 
(<37 completed weeks), or small for gestational age (<10th percentile)  
 
Preterm delivery (<37 completed weeks)
9.2.3.4
 
Antiretroviral drug concentrations in maternal hair at delivery 
 
Maternal and infant grade 3 or higher adverse events through delivery and 
from delivery through 6 weeks postpartum (refer to Section 7.3.3 for 
severity grading)


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9.2.3.5
 
Antiretroviral drug concentrations in maternal and infant hair, and ratio 
thereof as a measure of transfer from mother-to-infant, at delivery 
 
Antiretroviral drug concentrations in maternal plasma, breast milk, and 
infant plasma at 6 weeks postpartum
9.2.3.6
 
Antiretroviral drug concentrations in maternal hair at delivery  
 
Self-reported adherence to maternal ART regimens through 50 weeks 
postpartum 
 
Self-reported barriers and facilitators of adherence to maternal ART 
regimens at 50 weeks postpartum
 
*Major congenital anomaly will be defined for this study consistent with the definition of 
malformation provided by Holmes and Westgate, i.e., a structural abnormality with surgical, 
medical, or cosmetic importance (125). The following will not be considered major congenital 
anomalies: genetic disorders, chromosome abnormalities, minor anomalies, birth marks, 
positional deformities, prematurity related findings, prenatal ultrasound-only findings (i.e., 
findings only identified by ultrasound and not by the examining pediatrician), and polydactyly 
(postaxial, type B). Findings consistent with the definition of malformation will be included in 
analyses as major congenital anomalies. All suspected congenital anomalies will be entered into 
eCRFs and a small group of study investigators (blinded to randomized study arm), including an 
expert on birth defects, will review all suspected anomalies in near real time to determine whether 
they meet the study-specific definition of major congenital anomaly.  
 
9.3 
Enrollment/Randomization 
 
A dynamic permuted block system will be used to randomize mother-infant pairs in 
approximately equal numbers to DTG+FTC/TAF (Arm 1) or DTG+FTC/TDF (Arm 2) or 
EFV/FTC/TDF (Arm 3). To ensure balance in the three arms, the randomization will be stratified 
by gestational age at enrollment (14-18 weeks or 19-23 weeks or 24-28 weeks) and by country. 
There will be no limit on the number of pairs in each stratum. The rationale for stratifying by 
gestational age is that mothers who enter the study later in gestation will be less likely to achieve 
the desired viral load decrease but will be exposed to study drug for a shorter period of time 
compared with mothers who enroll earlier in gestation.  
 
9.4 
Sample Size and Accrual 
 
The sample size of 639 mother-infant pairs was set using the primary virologic efficacy objective 
and adjusting for two interim analyses assumed (O’Brien-Fleming like error spending function 
(126)) to maintain a two-sided Type I error rate (α) of 0.05. No adjustment for interim analyses 
was made for the primary safety comparisons: composite adverse pregnancy safety objective, 
maternal adverse event safety objective, or infant adverse event safety objective. For the sample 
size calculations, it was assumed that 10% of the data for the primary outcomes would be missing 
due to loss to follow-up, insufficient specimens, invalid results, or other reasons for being non-
evaluable. Therefore, with a sample size of 639 pairs, it was assumed that there would be 575 
(90%) evaluable pairs. SAS 9.4 proc seqdesign was used for the power calculations. The tables 
below display power analyses for efficacy (Table 8 and Table 9) and safety outcomes (Table 10, 
Table 11, and Table 12).  
 


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Because there is some uncertainty in assumptions underlying the sample size calculation (as is 
very often the case), the study design includes checks on assumptions at each DSMB review, and 
a formal re-evaluation of sample size once at least 192 women have HIV-1 RNA data at delivery 
(approximately 33% of the expected information). The re-evaluation will be undertaken earlier if 
accrual is expected to be completed before the next scheduled DSMB meeting. DSMB reviews 
are described in more detail in Section 9.5.3, below. 
 
The sample size of 639 pairs was chosen to provide 80% power for a 10% non-inferiority margin 
for virologic efficacy (<200 copies/mL) at delivery when comparing the combined DTG-
containing arms to the EFV-containing arm. The sample size was adjusted for two interim 
analyses (O’Brien-Fleming like error spending function (126)), with interim analyses at 33% and 
66% of the maximal information to maintain a two-sided Type I error rate (α) of 0.05. The 
variance of the estimated difference was computed under the alternative hypothesis that the 
combined DTG-containing arms and the EFV-containing arm are equivalent. The percent 
suppressed at delivery was assumed to be 80% for the combined DTG-containing arms and 80% 
for the EFV-containing arm. A non-inferiority margin of 10% was selected because a difference 
smaller than 10% is not thought to be of clinical importance, is expected to have similar perinatal 
transmission risk, and 10% is expected to retain much of the efficacy of the EFV-containing arm. 
Further considerations on the choice of the 10% margin are discussed below. 
 
Eighty percent suppression was chosen to power the study as this is the lowest expected viral 
suppression percent at delivery, and this assumption will lead to a conservative sample size that 
will maintain at least 80% power for non-inferiority if viral suppression percentages are higher 
than 80%. The PROMOTE study showed that women who initiated an EFV based regimen at 12-
28 weeks of gestation can achieve a delivery suppression percentage of 97.6% at 400 copies/mL 
(127). In the Phase IIb SPRING-1 trial of 205 treatment-naive adults (14% women), participants 
were randomized to start DTG (10 mg, 25 mg, or 50 mg) or EFV (20). Week 16 suppression 
percentages (for <50 copies/mL) were 93% for all doses of DTG and 60% for EFV. The 
PROMOTE study used a higher viral suppression cutoff (<400 copies/mL at an approximate 
average of 19 weeks of EFV exposure) than will be used in IMPAACT 2010, while the SPRING-
1 trial used a lower cutoff (<50 copies/mL at 16 weeks of EFV exposure). The average result 
across these two studies for EFV-containing regimens is 79% suppressed, similar to the 80% 
assumed for the EFV-containing arm in IMPAACT 2010. 
 
9.4.1 
Justification of the Non-Inferiority Margin 
 
The non-inferiority margin was set to 10%. This section highlights how a 10% margin is expected 
to retain much of the efficacy of the EFV-containing regimen based on the Historical Evidence of 
Sensitivity to Drug Effects (HESDE).  
 
To statistically justify the non-inferiority margin it is common to set the margin as a percentage of 
the efficacy for the active comparator (EFV-containing arm) (128). The data that the efficacy for 
the active comparator are based on is called HESDE, which is defined in the FDA guidance 
entitled, Non-Inferiority Clinical Trials to Establish Effectiveness: 
 
“HESDE means that prior studies, which were appropriately designed and conducted 
trials in the past and that used a specific active treatment (generally the one that is to be 
used in the new NI study or, in some cases, one or more pharmacologically closely 
related drugs), regularly showed this treatment to be superior to placebo (or some other 
treatment). Consistent findings in past studies allow for a reliable estimate of the drug’s 
effect compared to placebo.” 


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Five trials were considered to estimate the efficacy of the EFV-containing arm (M1): PACTG 
076, which demonstrated that ZDV was superior to placebo for perinatal transmission (129); 
PACTG 185, from which estimates of viral suppression at delivery for women receiving ZDV are 
available (94); the PROMISE trial, in which two triple ART regimens (ZDV/3TC+LPV/r and 
FTC/TDF+LPV/r) were found to be superior to ZDV+sdNVP+FTC/TDF tail for prevention of 
perinatal transmission (9); the SPRING Phase IIb study, which demonstrated that DTG was 
superior to EFV; and the PROMOTE study, in which an EFV-based regimen was found to be 
superior to LPV/r-based regimens for virologic suppression at delivery. These studies imply that 
ZDV/3TC+LPV/r and FTC/TDF+LPV/r are superior to placebo for prevention of perinatal 
transmission. However, the superiority of the EFV-based regimen over LPV/r-based regimens for 
viral suppression implies that an EFV-based regimen is highly likely to be superior to placebo for 
perinatal transmission. With the exception of the SPRING Phase IIb study, all of the studies were 
conducted in HIV-positive, pregnant women. IMPAACT 2010 will be conducted at many of the 
same sites as PROMISE, so the conduct of IMPAACT 2010 is expected to be similar to 
PROMISE. The gestational age at entry for IMPAACT 2010 is most similar to the PROMOTE 
study. Unlike PROMISE, IMPAACT 2010 and PROMOTE do not include a CD4 threshold in the 
study entry criteria. Summary data for these trials are shown in Table 6. 
 
Table 6 
Historical Evidence of Sensitivity to Drug Effects 
Study  
Gestational Age 
at 
Randomization
Control 
Group 
Experimental 
Group 
Percent Suppressed
Perinatal Transmission
Control Experimental Control Experimental
PACTG 0761 
(N=409)
14-34 weeks 
(median=26)
Placebo 
ZDV 
Not 
available
Not  
available
25.5% 
8.3% 
PACTG 1851 
(N=451) 
20-30 weeks 
(median=26) 
ZDV + 
immune 
globulin 
without HIV-
1 antibody
ZDV +  
immune  
globulin with 
HIV-1 antibody
24%  
(presented across arms) 
4.8% 
4.7% 
PROMISE 
Period 1 & 21 
(N=3,084)
>14 weeks 
(median=25) 
ZDV alone 
ZDV/3TC + 
LPV/r 
16% 
68% 
1.8% 
0.5% 
PROMOTE1 
(N=389)
12-28 weeks 
(median=21)
LPV/r-based 
ART
EFV-based 
ART
86% 
97.7% 
0.56% 
0.00% 
SPRING IIb2 
(N=205)
NA (16 week 
response rate)
EFV only 
DTG only 
60% 
87% 
NA 
NA 
1Study in HIV-positive, pregnant women; 2Study in treatment naïve adults
Note: PACTG 185 used a lower viral load limit of 500 copies/mL; both PROMOTE and PROMISE used a lower viral 
load limit of 400 copies/mL. 
Note: The gestational age at entry will be 14-28 weeks for IMPAACT 2010.
 
One possible way to estimate the efficacy for the active comparator is to use the imputed placebo 
approach in which data from historical trials are combined (128). The imputed placebo approach 
estimates the suppression rate of placebo that would have occurred if placebo was present in a 
trial compared to the EFV-containing arm. The ZDV arms displayed in Table 6 were used to 
stand in for placebo, a conservative and necessary approach. This approach is conservative (will 
give smaller values for M1) because ZDV alone can reduce viral load. This approach is necessary 
because viral load at delivery is not available from PACTG 076. For example, an estimated M1 
with PROMISE as the target trial is given by: 
 


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8 December 2017 
𝑀1
෢= ቆ
𝑝𝐸𝐹𝑉௉ோைெை்ா
෣
𝑝𝐿𝑃𝑉+ 𝑅𝑇𝑉௉ோைெை்ா
෣
ቇ∗𝑝𝐿𝑃𝑉+ 𝑅𝑇𝑉௉ோைெூௌா
෣
−𝑝𝑍𝐷𝑉௉௥௢௠ప௦௘
෣
 
= ൬. 977
. 86 ൰∗.68 −.16 = .62. 
 
This formula effectively discounts the EFV PROMOTE estimate by the ratio of the PROMOTE 
and PROMISE LPV/r arms. 
 
Table 7 
95% CI for M1: The Estimated IMPAACT 2010 EFV-Containing Arm Effect Relative to Placebo 
Target Trial 
Data Used 
95% CI for M1 
Average of PACTG 185 
and PROMISE
All data in Table 6 
(46%, 57%) 
PROMISE
PROMISE and PROMOTE
(54%, 66%)
Average of PROMOTE 
and SPRING IIb
All data in Table 6 
(64%, 73%) 
PROMOTE
PROMISE and PROMOTE
(77%, 84%)
ZDV in PACTG 185, EFV in 
SPRING IIb, and PROMOTE
PACTG 185 (ZDV), SPRING IIb 
(EFV), PROMOTE (EFV)
(47%, 63%) 
 
To account for uncertainty in the estimate of M1, the bootstrap was used to compute 95% CIs. 
The lower bound of the bootstrap 95% CI with PROMISE as the target trial is 54%, a 
conservative estimate of M1. Furthermore, five scenarios were considered. The results for these 
scenarios are displayed in Table 7. The smallest lower limit of the 95% CI is 46%. This estimate 
used the ZDV suppression probabilities from PROMISE and PACTG 185, and the EFV 
suppression percentages from PROMOTE and SPRING IIb. 
 
Clinical Justification 
 
Ten percent was chosen by the Protocol Team as an acceptable level of difference because a 
difference of 10% with high levels of suppression is not expected to confer a large difference in 
perinatal transmission. In the PROMOTE study (Table 6), the suppression difference was 11.7% 
but the difference in perinatal transmission was 0.56%. Similarly, the difference in suppression 
for PROMISE was 52% but the difference in perinatal transmission was 1.3%. Importantly, the 
perinatal transmission probability was lower, in all arms of PROMOTE and PROMISE, than the 
World Health Organization’s targets of 5% in breastfeeding populations and 2% in non-
breastfeeding populations (130). This implies that a difference smaller than 10% is unlikely to 
confer large differences in perinatal transmission. 
 
Percent of Efficacy Retained 
 
Assuming that M1 is 0.46, a 10% margin will preserve at least 64% ((.46-.10)/.55) of the efficacy 
of an EFV-based regimen. This is a conservative estimate of M1, using the lowest lower bound of 
the 95% confidence interval for M1 (Table 7). Preserving this percentage of efficacy was 
considered acceptable to the Protocol Team. 
 


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Constancy Assumption 
 
The constancy assumption is expected to hold because there have been no advancements of 
standard clinical care in the field of HIV treatment that would affect viral load in the absence of 
receipt of ART. Similarly, the effect of ART on viral load is expected to remain the same. Table 6 
provides indirect evidence of a constant treatment effect across studies by comparing PACTG 
185 to PROMISE for the ZDV arm. Both studies had a median gestational age of 26 at 
randomization. PACTG 185 was conducted between October 1993 and March 1997, while 
PROMISE was conducted between April 2011 and October 2014. Even still, the suppression rates 
for ZDV are similar, and differences are likely due to different participant populations: 
PROMISE enrolled healthy women, while PACTG 185 enrolled a relatively sicker participant 
population. 
 
Assay Sensitivity 
 
According to the FDA guidance, assay sensitivity means that had the non-inferiority study 
included a placebo arm, a control drug-placebo difference of at least M1 would have been 
present. IMPAACT 2010 will have assay sensitivity due to the following reasons: 
 
1) Many of the IMPAACT 2010 sites are the same sites from the PROMISE study. 
2) The difference observed in PROMISE (52%) was larger than the conservative estimate of 
M1. 
3) The PROMOTE EFV -based ART regimen was shown to be superior to the LPV/RTV -based 
ART regimen that was used in PROMISE. 
4) IMPAACT 2010 will have adequate power for a 10% difference, much smaller than the 
estimated value for M1 (see Table 8). 
 
Power 
 
The power for a conclusion of non-inferiority with a sample size of 639 is 80% with a non-
inferiority margin of 10%, assuming that the EFV-containing arm and the DTG-containing arms 
have an 80% suppression percentage, and 90% evaluable (Table 8). To account for the possibility 
that the percentage of viral suppression at delivery might deviate from 80% in the EFV-
containing arm, Table 8 also includes scenarios in which the suppression percentage varies from 
60% to 90%. If the true suppression percentage is 85% in both the DTG-containing and the EFV-
containing arms then the power is 88%, while a suppression percentage of 90% in both the DTG-
containing and the EFV-containing arms results in 96% power. Suppression percentages of 95% 
and 85% provide high power, and these percentages could have reasonably been selected to size 
the study. If the percent suppressed in the EFV-containing arm is lower than expected, the power 
is reduced: 60% versus 60% results in 63% power and 70% versus 70% results in 69% power. In 
addition, a small increase in the true rate of suppression for the combined DTG-containing arms 
results in a significant increase in power: 83% suppressed results in 96% power assuming an 80% 
true percentage of suppression in the EFV-containing arm. Assuming 85% evaluable, the power 
is reduced by 1-3%. With a sample size of 639 pairs, the half-lengths of the 95% CI for the 
difference in percentages range from 5% to 9%. 
 


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Table 8 
Viral Suppression (HIV-1 RNA <200) Primary Non-Inferiority Efficacy Analysis  
Comparing the DTG-containing Arms Versus the EFV-containing Arm 
Percent Suppressed  
N 
Assuming 90% 
Evaluable
Assuming 85% 
Evaluable
DTG-
containing 
arms
EFV-
containing 
arm
DTG-
containing 
arms
EFV-
containing 
arm
95% CI 
Half-
Length*
Power** 
95% CI 
Half-
Length*
Power** 
60%
60%
426
213
8.5%
63%
8.7%
60%
70%
70%
426
213
8.0%
69%
8.2%
66%
80%
80%
426
213
6.9%
80%
7.1%
78%
81%
80%
426
213
6.9%
87%
7.1%
85%
83%
80%
426
213
6.8%
96%
7.0%
95%
85%
85%
426
213
6.2%
88%
6.4%
86%
90%
90%
426
213
5.2%
96%
5.4%
95%
*Half-length was computed for the difference in percentages.
**Power for a non-inferiority design (10% margin) testing a two sample difference in binomial proportions 
comparing the combined DTG-containing arms relative to the EFV-containing arm. The power was adjusted to 
account for two interim analyses with an O’Brien-Fleming like error spending function and 85%-90% evaluable at 
delivery.
 
This study was powered for non-inferiority, not superiority. However, superiority is an important 
secondary analysis. Under the assumptions stated above, there will be 86% power to detect a 10% 
difference in the percent suppressed between the combined DTG-containing arms relative to the 
EFV-containing arm (Table 9). To account for the possibility that the percent of viral suppression 
at delivery might deviate from 80% in the EFV-containing arm, Table 9 includes scenarios in 
which the suppression percentage varies from 60% to 90%. If the percent suppressed is higher 
than 80% in the EFV-containing arm the power ranges from 85% to 94%. If the percent 
suppressed in the EFV-containing arm is lower than expected, the power is reduced: 80% versus 
70% results in 72% power and 70% versus 60% results in 65% power. Power will also be reduced 
if more than the assumed 10% are not evaluable. Assuming 15% non-evaluability, the power is 
reduced by 2-3%. With a sample size of 639 pairs, the half-lengths of the 95% CI for the 
difference in percentages range from 5% to 9%. 
 


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Table 9 
Viral Suppression (HIV-1 RNA <200) Secondary Superiority Efficacy Analysis  
Comparing the DTG-containing Arms Versus the EFV-containing Arm 
Percent Suppressed  
N 
Assuming 90% 
Evaluable
Assuming 85% 
Evaluable
DTG-
containing 
arms
EFV-
containing 
arm
DTG-
containing 
arms
EFV-
containing 
arm
95% CI 
Half-
Length*
Power** 
95% CI 
Half-
Length*
Power** 
70%
60%
426
213
8.3%
65%
8.6%
62%
80%
70%
426
213
7.6%
72%
7.8%
70%
90%
80%
426
213
6.4%
86%
6.6%
84%
94%
85%
426
213
5.6%
85%
5.8%
83%
97%
90%
426
213
4.6%
86%
4.7%
84%
91%
80%
426
213
6.3%
93%
6.5%
92%
95%
85%
426
213
5.5%
93%
5.7%
92%
98%
90%
426
213
4.5%
94%
4.6%
93%
*Half-length was computed for the difference in percentages. 
**Power for a non-inferiority design (10% margin) testing a two sample difference in binomial proportions 
comparing the combined DTG-containing arms relative to the EFV-containing arm. The power was adjusted to 
account for two interim analyses with an O’Brien-Fleming like error spending function and 90% evaluable at 
delivery.
 
Table 10 contains a power analysis for the primary adverse pregnancy outcome. All pairwise 
comparisons will be conducted for this analysis; hence, power was calculated using a sample size 
of 213 in each comparison group. The composite adverse pregnancy outcome event percentage 
was assumed to be 27% for the EFV-containing arm (31). The upper and lower alternative was 
calculated to give 80% and 90% power. With 213 in each comparison group, 41% versus 27% 
and 15% versus 27% results in 80% power; 43% versus 27% and 14% versus 27% results in 90% 
power. The half-lengths of the 95% CI for the difference in percentages range from 8% to 10%. 
 
Table 10 
Power Analysis for Primary Composite Adverse Pregnancy Outcome Objective 
(All Pairwise Comparisons) 
Percent with a 
Composite Outcome 
N 
Assuming 90% 
Evaluable
Assuming 85% 
Evaluable
Comparison 
Group 1 
Comparison 
Group 2 
Comparison 
Group 1 
Comparison 
Group 2 
95% CI 
Half-
Length
Power* 
95% CI 
Half-
Length
Power* 
41%
27%
213
213
9.4%
80%
9.6%
78%
43%
27%
213
213
9.4%
90%
9.7%
88%
15%
27%
213
213
8.1%
80%
8.3%
78%
14%
27%
213
213
8.0%
90%
8.2%
88%
*Power for two sided alpha 0.05 test difference in binomial proportions. Power was NOT adjusted interim analyses. 
Ninety percent and 85% evaluable was assumed. This table can also be used to judge power for each pairwise 
comparison. 
 
This study is not powered to detect differences in infant mortality (67% power for a difference of 
4.4% versus 0.6%, as was observed in the PROMISE trial). 
 


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Table 11 contains a power analysis for the primary maternal safety objective. All pairwise 
comparisons will be conducted for this analysis; hence, power was calculated using a sample size 
of 213 mothers in each comparison group. The outcome event percentage was assumed to be 15% 
for the EFV-containing arm (127). The upper and lower alternative was calculated to give 80% 
and 90% power. With 213 mothers in each comparison group, 27% versus 15% and 6% versus 
15% results in 80% power; 29% versus 15% and 5% versus 15% results in 90% power. The half-
lengths of the 95% CI for the difference in percentages range from 6% to 8%.  
 
Table 11 
Power Analysis for Primary Composite Maternal Adverse Event Objective 
(All Pairwise Comparisons) 
Percent with a 
Composite Outcome 
N 
Assuming 90% 
Evaluable
Assuming 85% 
Evaluable
Comparison 
Group 1 
Comparison 
Group 2 
Comparison 
Group 1 
Comparison 
Group 2 
95% CI 
Half-
Length
Power* 
95% CI 
Half-
Length
Power* 
27%
15%
213
213
8.1%
80%
8.3%
78%
29%
15%
213
213
8.2%
90%
8.4%
89%
6%
15%
213
213
6.1%
80%
6.3%
78%
5%
15%
213
213
5.9%
90%
6.0%
88%
*Power for two sided alpha 0.05 test difference in binomial proportions. Power was NOT adjusted interim analyses. 
Ninety percent and 85% evaluable was assumed. This table can also be used to judge power for each pairwise 
comparison. 
 
Table 12 contains a power analysis for the primary infant safety objective. All pairwise 
comparisons will be conducted for the analysis; hence, power was calculated using a sample size 
of 213 infants in each comparison group. The outcome event percentage was assumed to be 25% 
for the EFV-containing arm (127). The upper and lower alternative was calculated to give 80% to 
90% power. With 213 infants in each comparison group, 38% versus 25% and 14% versus 25% 
results in 80% power; 40% versus 25% and 12% versus 25% results in 90% power. The half-
lengths of the 95% CI for the difference in percentages range from 8% to 10%. 
 
Table 12 
Power Analysis for Primary Composite Infant Adverse Event Objective 
(All Pairwise Comparisons) 
Percent with a 
Composite Outcome
N 
Assuming 90% 
Evaluable
Assuming 85% 
Evaluable
Comparison 
Group 1 
Comparison 
Group 2 
Comparison 
Group 1 
Comparison 
Group 2 
95% CI 
Half-
Length
Power* 
95% CI 
Half-
Length
Power* 
38%
25%
213
213
9.2%
80%
9.5%
78%
40%
25%
213
213
9.3%
90%
9.5%
89%
14%
25%
213
213
7.9%
80%
8.1%
78%
12%
25%
213
213
7.7%
90%
7.9%
88%
*Power for two sided alpha 0.05 test difference in binomial proportions. Power was NOT adjusted interim analyses. 
Ninety percent and 85% evaluable was assumed. This table can also be used to judge power for each pairwise 
comparison. 
 


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DXA scans will be performed measured in a subset of approximately 213 (71 per arm) mothers 
and infants. Two hundred and thirteen DXA measurements will provide 80% power to detect at 
least one half a standard deviation difference which the team assessed as clinically relevant 
(difference of approximately 0.40 g for spine bone mineral content and 2.75 g for whole body 
bone mineral content for infants (7) and 0.07 g lumbar spine for mothers).  
 
9.4.2 
Re-Evaluation of Sample Size 
 
The main purpose of the sample size re-evaluation is to use the observed data to inform the 
following parameters used in the sample size calculations: the percent of participants with 
evaluable data and the percent of mothers with HIV-1 RNA <200 copies/mL at delivery. This is 
to evaluate whether a sample size increase is needed to achieve the desired statistical power for 
the primary efficacy objective of the study. The sample size re-evaluation will take place at one 
interim analysis, once sufficient information is available to estimate the proportion of mothers 
with HIV-1 RNA <200 copies/mL at delivery. To maintain power for the primary safety analyses, 
the maximal sample size should not be decreased. 
 
The re-evaluation will be undertaken by a statistician who is blinded to the randomized treatment 
arms. The statistician will be given study datasets without access to the randomized treatment 
arms. The re-evaluated sample size will be computed for the DSMB at the interim analysis in 
which at least 192 women have delivery HIV-1 RNA data available (approximately 33% of the 
expected information) or at the scheduled DSMB review before accrual is completed, whichever 
comes first. If accrual of 639 mother-infant pairs is expected to be completed before the next 
scheduled DSMB meeting, accrual may be paused when 639 pairs have been enrolled but accrual 
would not formally close until the DSMB has reviewed the sample size adjustment. The DSMB 
will review the sample size re-evaluation based on a pre-specified algorithm and make 
recommendations concerning sample size.  
 
Further guidelines for the DSMB in considering sample size re-evaluation include the following: 
 
 
The sample size should not increase because the percent of non-evaluable women at delivery 
is higher than 15%. The primary rationale for this guideline is that the percent could 
potentially be so high relative to the anticipated percent suppressed that the results of the 
study may be difficult to interpret. Thus, the main point of considering the percent evaluable 
is because a rate lower than 15% may be relevant in offsetting any increase in sample size 
needed due a lower than expected suppression percentage at delivery.  
 
 
The DSMB will be provided with estimated primary outcome rates by arm at each interim 
efficacy analysis. A concern, however, with sample size re-evaluation is that it may affect the 
Type I error rate and introduce bias in estimates of the difference in outcomes between arms 
(and associated CIs). This is generally avoided if the interim information used to re-evaluate 
the sample size is pooled over randomized treatment arms (131).  
 
 
A sample size re-evaluation algorithm will be followed. To re-power the study, the amount of 
information will be fixed to the amount used to calculate the sample size of 639 pairs. The 
maximal amount of information for this study is: 
 
Ι=(. 8 ∗(1 −.8)/(.9 ∗639 ∗
ଶ
ଷ) + .8 ∗(1 −.8)/(.9 ∗639 ∗
ଵ
ଷ))^ −1 ≈797.2. 
 


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Maximal information was computed from the inverse of the variance of the estimate of the 
difference in binomial proportions calculated under the alternative hypothesis. At the time of 
the sample size re-evaluation, the observed pooled binomial proportion (𝑃෠) will be used to 
compute the re-evaluated sample size. If we let ɛ be the proportion evaluable, after solving 
the information formula for N, the formula to re-compute the total sample size is: 
 
𝑁= Ι
ɛ ∗൤9
2 𝑃෠൫1 −𝑃෠൯൨. 
 
Following this procedure (132) will aid in maintaining 80% power for a non-inferiority 
margin of 10% assuming that the comparison groups have the same but arbitrary suppression 
probabilities.  
 
9.4.3 
Accrual 
 
Accrual of 639 mother-infant pairs is expected to be completed within approximately 12 months 
after the first pair is enrolled. Monthly accrual rates are expected to be low initially, as sites 
obtain approvals and are activated to initiate the study. Once all sites are activated, accrual rates 
of up to 90-100 pairs per month are expected. 
 
If the sample size re-evaluation described in Section 9.4.2 results in a recommendation to increase 
the sample size, the accrual period may be extended beyond 12 months. 
 
9.5 
Monitoring 
 
Implementation of this study will be monitored at multiple levels, consistent with standard 
procedures described in the IMPAACT Manual of Procedures. Included in these standard 
procedures is monthly review of participant accrual and retention by the IMPAACT Management 
Oversight Group. A study monitoring plan that details monitoring roles and responsibilities and 
data to be reviewed at each level will be prepared before the study opens to accrual. Sections 10 
and 11 provide more information on on-site monitoring and quality management at the site level. 
Further information on monitoring of study progress, quality of study conduct, and participant 
safety, and virologic efficacy across sites is provided below. 
 
9.5.1 
Monitoring by the Protocol Team 
 
All reports prepared for Protocol Team review will provide data pooled across the three 
randomized study arms. 
 
Study Progress and Quality of Study Conduct 
 
The Protocol Team is responsible for continuous monitoring of study progress, including timely 
achievement of key milestones and quality of study conduct.  
 
The Protocol Team will closely monitor participant accrual based on reports that will be 
generated at least monthly by the SDMC. The team has developed a study accrual plan that 
includes site-specific and total enrollment projections over the course of the accrual period, and 
actual accrual will be monitored relative to these projections. The team will monitor the timing of 
site-specific study activation, which will determine when each site will begin accruing 
participants, and actual accrual following activation. For any site that is delayed in completing the 


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study activation process, or that falls short of its accrual projections, the team will communicate 
with the site to identify the barriers the site has encountered and the operational strategies and 
action plans to address these.  
 
The Protocol Team will monitor participant retention in a manner similar to participant accrual.  
 
On behalf of the Protocol Team, the CMC will monitor other key indicators of the quality of 
study conduct (e.g., data completeness, data and specimen completeness) based on reports 
generated by the SDMC and will take action with study sites as needed to ensure high quality 
study conduct throughout the period of study implementation. This routine monitoring will 
include real-time assessment of the completeness and timeliness of performing fetal ultrasound 
scans as specified in Sections 6.1 and 6.2. In the event of any missed or delayed ultrasound scan, 
the CMC will communicate with the site investigator and coordinator (e.g., via conference call) to 
discuss the problem(s) encountered and operational strategies to address these. If ultrasound scans 
are missed or delayed for more than approximately 10% of participants at a given site, the CMC 
will consider whether to pause accrual at that site until sufficient corrective actions have been 
taken to assure that the problems have been fully resolved (as judged by the CMC). The CMC 
will also monitor the timeliness of maternal and infant Delivery Visits at each site in a similar 
manner. Sites that do not consistently complete these visits within the targeted window will be 
required to implement appropriate corrective action plans; consideration may also be given to 
pausing accrual at such sites while corrective action is being taken.  
 
9.5.2 
Monitoring by the SRG 
 
The SRG will monitor participant safety through routine review of safety data reports generated 
by the SDMC. These reports will provide tabulations of the maternal and infant adverse events 
specified for entry into eCRFs in Section 7.2 pooled across the three randomized study arms. The 
SRG will review these reports via conference call or other meeting at least monthly. At the time 
of each review, the DAIDS Medical Officer will also review any EAEs reported to the DAIDS 
Safety Office that are not yet reflected in the data reports. The SRG will continually evaluate the 
pattern and frequency of reported events and assess for any individual occurrences or trends of 
concern. If the SRG identifies a potential safety concern, the Protocol Statisticians or Medical 
Officers will notify the DSMB and request further DSMB review and recommendations; among 
the recommendations requested will be whether the CMC should be informed of the SRG and/or 
DSMB review findings. 
 
9.5.3 
Monitoring by the DSMB 
 
The study will be monitored by a NIAID-convened Data and Safety Monitoring Board (DSMB), 
which will perform its monitoring functions consistent with the NIAID Policy on Data and Safety 
Board Operations, available at: https://www.niaid.nih.gov/research/data-and-safety-monitoring-
boards.  
 
Interim analyses of study progress and conduct as well as participant safety will be reviewed at 
least every six months starting within 12 months after the first mother-infant pair is randomized. 
Two interim efficacy analyses will be performed when approximately 33% and 66% of the 
anticipated information on viral suppression at delivery have been observed, unless otherwise 
requested by the DSMB. Assuming participant accrual as described in Section 9.4.3 and that the 
average gestational age at entry is 24 weeks, it is projected that 33% of the total information will 
be available 10 months after the first mother-infant pair is enrolled in the study.  
 


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The DSMB will be provided with masked by-arm study data reports. Based on any of its reviews, 
the DSMB may recommend that the study proceed as currently designed, proceed with design 
modifications, or be discontinued. The DSMB may also provide operational recommendations to 
address any study implementation challenges that may be identified.  
 
Statistical Stopping Guidelines for Evaluating Efficacy 
 
Efficacy decision boundary guidelines will be based on the group sequential Lan-DeMets 
O’Brien-Fleming like error spending approach. The Z test statistic for the difference in 
proportions when comparing the DTG-containing arms to the EFV-containing arm will be 
compared to the z-value decision boundary guideline computed from the Lan-DeMets O’Brien-
Fleming like error spending approach. The z-value decision boundary guideline is approximately 
±3.7 at 33% of information and ±2.5 at 66% of information. As the decision boundary guidelines 
change depending on the amount of information at the interim analysis, these boundaries are only 
given for illustrative purposes. If the Z test statistic is larger in magnitude than the z-value 
decision boundary guideline, in either direction, then early termination of the study may be 
considered. A conclusion for non-inferiority of the combined DTG-containing arms relative to the 
EFV-containing arm at an interim analysis in the absence of superiority would not warrant 
stopping for efficacy. Because a conclusion for superiority will be predicated on the existence of 
non-inferiority, the ability for the study to conclude non-inferiority should also be considered by 
the DSMB.  
 
Assessment of Futility for the Efficacy Comparisons 
 
IMPAACT 2010 should not be stopped at an interim analysis for futility if it appears unlikely that 
that a conclusion of superiority or non-inferiority can be made at the maximal sample size. There 
are two reasons why futility of the primary efficacy comparisons should not be considered at 
interim analyses: 1) the study will be quite advanced in its conduct by the time a reasonable 
number of participants have outcome information for the futility analyses, and 2) it will be 
important to collect as much safety data as possible for the 3 primary safety objectives.  
 
Timing of Data Release Should the Study Continue to the Maximal Sample Size 
 
The primary outcomes can be measured at two different study times. Efficacy and pregnancy 
outcomes are measured at the delivery visit, whereas maternal and infant adverse events are 
measured through Week 50. Due to this difference, and so that the study results can have 
maximum impact, the primary virologic efficacy and maternal safety results (through delivery), 
including the adverse pregnancy outcomes endpoint, may be analyzed and presented while 
postpartum and infant follow-up are ongoing. 
 
9.6 
Analyses 
 
Further details of the proposed analyses will be described in a statistical analysis plan that will be 
developed before the first enrollment in the study. 
 
All of the primary and secondary analyses will be performed with the principle of ITT. For the 
analyses testing the null hypothesis of no difference, the ITT analysis is the primary analysis. 
 


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There are two secondary non-inferiority objectives (see Section 2.2.6) and one primary non-
inferiority analysis objective (see Section 2.1.1). Non-inferiority analyses typically require 
additional considerations relative to an analysis of superiority, including the congruence between 
an ITT analysis and a per-protocol analysis. Thus, the non-inferiority analyses, ITT and per-
protocol, should be given equal weight in the non-inferiority analyses. Further requirements for a 
conclusion of non-inferiority are described in Section 9.1. 
 
Per-protocol analyses will censor or exclude participants’ data who do not remain on the 
randomized regimen up to the time of the measured outcome. Any change, defined as the first 
switch, first addition, or first removal of any of the ARVs in the randomized regimen will be 
considered a change from the randomized regimen, with the exception of switches made due to a 
requirement for other concomitant medications. 
 
The unit of analysis for infant and pregnancy outcomes will be the mother-infant pair. Analysis 
summaries will use the most extreme (worst) infant or pregnancy outcome for each pregnancy. 
For example, if one infant of a multiple birth becomes HIV-infected but the other does not, this 
will count as one event in the analyses. If both infants become infected, this will count as one 
event for the mother-infant pair in the analysis, not two. This is a conservative approach and 
addresses the fact that data on infants from multiple births may be related. 
 
Summaries and regimen comparisons will not be adjusted for the two stratification factors. By-
arm regimen comparisons of the primary outcomes for each stratum of gestational age at study 
entry will be included in the final study report. P-values for these treatment comparisons will be 
provided if there is a statistically significant interaction between the treatment arm and gestational 
age at study entry. 
 
There are ten primary comparisons to be made, including one efficacy comparison and nine 
safety comparisons. All ten comparisons are described in Section 9.6.1. There will be no 
adjustments for multiple comparisons. Type I error rates (α) will be controlled at the comparison 
level where a statistical difference will be declared if the p-value is less than 0.05. The p-value for 
the primary efficacy comparison will be adjusted for the repeated interim analyses, and the safety 
analyses will use an unadjusted nominal p-value. The safety analyses will not be adjusted for 
multiple comparisons or interim analyses to minimize the chance of a Type II error (β). The trial-
wise Type I error will be larger than 5%. 
 
9.6.1 
Primary Outcome Analyses 
 
Efficacy: Viral Suppression 
 
Analyses will compare the DTG-containing arms to the EFV-containing arm. 
 
Viral suppression will be summarized using a difference in binomial proportions with a success 
defined as HIV-1 RNA <200 copies/mL at delivery. The denominator for this analysis will 
include women who have an HIV-1 RNA measurement within the delivery visit window (+14 
days). A two-sided, two-sample test for the difference in proportions will be used for this 
analysis. CIs and p-values for the difference in proportions will be adjusted for the interim 
analyses to maintain a two-sided Type 1 error rate of 0.05 using the time ordered calculations. 
Ninety-five percent repeated confidence intervals (RCIs) will be computed at interim analyses to 
aid the determination of non-inferiority. A p-value less than 0.05 testing the equality of 
proportions will be considered statistically significant and a p-value testing the equality of the 
proportions will be provided only if non-inferiority is established. Similarly, a 95% CI (or RCI at 


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interim analyses) that excludes a difference of 10% in favor of the EFV-containing regimen will 
be considered statistically significant for the non-inferiority analysis. Sensitivity analyses will be 
carried out using multiple imputation for women missing the HIV-1 RNA measurement within 
the delivery visit window.  
 
Safety: Spontaneous Abortion, Fetal Death, Preterm Delivery, and Small for Gestational Age  
 
Analyses will compare DTG+FTC/TDF (Arm 2) to DTG+FTC/TAF (Arm 1), DTG+FTC/TDF 
(Arm 2) to EFV/FTC/TDF (Arm 3), and DTG+FTC/TAF (Arm 1) to EFV/FTC/TDF (Arm 3). 
 
The analyses of the composite adverse pregnancy outcomes will be summarized as differences in 
proportions. A two-sided, two-sample test for the equality of the difference in proportions will be 
used for the by arm comparisons. A nominal (not adjusted for interim analyses) p-value less than 
0.05 will be considered statistically significant. The Type I error rate for each comparison will be 
5%. Two important separate sensitivity analyses will be conducted: 1) by including mothers who 
are lost to follow-up before experiencing any one of these pregnancy outcomes as failures to 
account for the possibility of informative missingness, and 2) by stratifying by the presence of a 
major congenital anomaly. The analysis stratifying by the presence of a major congenital anomaly 
will be conducted to investigate effect modification if there is a by-arm imbalance in major 
congenital anomalies. Conclusions based on the analysis stratified by the presence of a major 
congenital anomaly should be interpreted with care as some major congenital anomalies may 
have occurred after randomization. 
 
Safety: Maternal Grade 3 or Higher Adverse Events  
 
Analyses will compare DTG+FTC/TDF (Arm 2) to DTG+FTC/TAF (Arm 1), DTG+FTC/TDF 
(Arm 2) to EFV/FTC/TDF (Arm 3), and DTG+FTC/TAF (Arm 1) to EFV/FTC/TDF (Arm 3). 
 
The primary maternal safety analysis will use a Kaplan-Meier estimate of the event probability 
through 50 weeks postpartum. The proportion experiencing an event for each group will be 
computed from the Kaplan-Meier survival curve and Greenwood’s formula will be used to 
compute the variance of the difference. A Z score will be computed by taking the difference in 
the estimated probabilities and dividing this difference by the square root of the sum of variances 
as estimated by Greenwood’s formula. Since the time from randomization to a pregnancy 
outcome will vary among the mothers, the Week 50 event probability estimate will be taken from 
the average time from randomization to the mother’s pregnancy outcome plus 50 weeks. The Z 
score will then be compared to the standard normal curve to compute a p-value. A nominal (not 
adjusted for interim analyses) p-value less than 0.05 will be considered statistically significant. 
The Type 1 error rate for each comparison will be 0.05. Important sensitivity analyses will be 
conducted by including mothers who drop out of the study early as failures to account for the 
possibility of informative missingness. 
 


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Safety: Infant Grade 3 or Higher Adverse Events  
 
Analyses will compare DTG+FTC/TDF (Arm 2) to DTG+FTC/TAF (Arm 1), DTG+FTC/TDF 
(Arm 2) to EFV/FTC/TDF (Arm 3), and DTG+FTC/TAF (Arm 1) to EFV/FTC/TDF (Arm 3). 
 
The primary infant safety analysis will use a Kaplan-Meier estimate of the event probability 
through Week 50. The proportion experiencing an event for each group will be computed from 
the Kaplan-Meier survival curve and Greenwood’s formula will be used to compute the variance 
of the difference. A Z score will be computed by taking the difference in the estimated 
probabilities and dividing this difference by the square root of the sum of variances as estimated 
by Greenwood’s formula. The Z score will then be compared to the standard normal curve to 
compute a p-value. A nominal (not adjusted for interim analyses) p-value less than 0.05 will be 
considered statistically significant. The Type 1 error rate for each comparison will be 0.05. 
Important sensitivity analyses will be conducted by including infants who drop out of the study 
early as failures to account for the possibility of informative missingness. 
 
9.6.2 
Secondary and Other Outcome Analyses 
 
Section 2.2 lists how the three arms will be used for the secondary regimen comparisons.  
 
Analyses to test the equality of differences in event probabilities at delivery will be performed 
using a similar approach as for the primary analyses. This includes estimates of the probability of 
mothers with HIV-1 RNA <50 copies/mL at delivery, the probability of HIV-1 RNA <200 
copies/mL at delivery and through 50 weeks postpartum as defined by the FDA snapshot 
algorithm, the probability of mothers with adverse pregnancy outcomes, HIV drug resistance 
mutations acquired post-randomization as defined by the Stanford algorithm, and the probability 
of infant HIV infection at delivery. A two-sided, two-sample test for the equality of the difference 
in proportions will be used for the by-arm comparisons. A nominal (not adjusted for interim 
analyses) p-value less than 0.05 will be considered statistically significant. The Type I error rate 
for each of these analyses will be 5%. 
 
A non-inferiority analysis of preterm delivery and small for gestational age will be conducted as a 
secondary analysis. The non-inferiority analysis will be conducted because the Protocol Team 
believes that is important to set a predefined decision rule for a conclusion of non-inferiority 
before the data are observed. A non-inferiority margin of 10% will be used. This margin reflects 
the judgment of the Protocol Team. The non-inferiority analysis will be conducted to test if 
DTG+FTC/TDF is non-inferior to EFV/FTC/TDV, if DTG+FTC/TAF is non-inferior to 
EFV/FTC/TDF, and if DTG+FTC/TAF is non-inferior to DTG+FTC/TDF. For the non-inferiority 
analyses, a p-value will not be computed; instead, statistical significance for non-inferiority will 
be determined by the appropriate limit of a 95% CI rejecting the non-inferiority margin. This 
procedure for the non-inferiority analyses controls a one-sided Type I error rate of 0.025. Further 
guidance on the requirements for a conclusion of non-inferiority is discussed in Section 9.1. 
 
Week 50 postpartum cumulative event probabilities will be estimated using the Kaplan-Meier 
method. This analysis will estimate the probability of a confirmed infant HIV infection through 
50 weeks postpartum and the probability of infant mortality through 50 weeks postpartum. 
Greenwood’s formula will be used to compute the standard error of the difference between the 
estimated probabilities. 
 


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Time to viral suppression (first HIV-1 RNA <200 copies/mL) through delivery will be compared 
using a log-rank test, and will be displayed graphically using the Kaplan-Meier estimate of the 
survival curve. An important sensitivity analysis will be conducted by considering deaths and loss 
to follow-up as a competing risk. 
 
Continuous outcomes, which include infant DXA outcomes and markers of maternal and infant 
renal toxicity, will be analyzed by using two sample t-tests and multivariable linear regression.  
 
Infants and pregnancy outcomes will be classified into the worst group using the following 
hierarchy: 
 
1. Infant death 
2. Spontaneous abortion (<20 weeks gestation) or fetal death (≥20 weeks gestation) 
3. Infant HIV infection  
4. Extremely and very early preterm (<32 completed weeks) 
5. Major congenital anomaly 
6. Preterm delivery (<37 completed weeks) 
7. Small for gestational age (<10th percentile) 
8. Hospitalization  
9. Grade 3 or 4 adverse event 
10. None of the above 
 
Proportions of participants in each classified group will summarized and all three pairwise 
regimen comparisons will be compared using ordinal logistic regression.  
 
9.6.3 
Exploratory Outcome Analyses 
 
A detailed analysis plan will be written before the exploratory analyses are conducted.  
 
The DTG-containing arms will be compared to the EFV-containing arm for the maternal 
postpartum depression score using a two-sample t-test to test the equality of means.  
 
The composite outcome of the subsequent pregnancies will be tested using Fisher’s exact test 
with the mid-p option. Three Fisher’s exact tests will be conducted, one for each pairwise 
regimen comparison.  
 
Generalized linear models and Cox regression models will be used to investigate immunologic 
and hormonal predictors of adverse pregnancy outcomes and postpartum maternal health 
outcomes while adjusting for potential confounders.  
 
The adjusted relative risk of a primary composite pregnancy outcome and, separately, preterm 
delivery (<37 completed weeks) will be estimated using multivariable log-linear models 
comparing mothers who experienced any grade 3 or 4 clinical adverse event (i.e., excluding 
isolated abnormal laboratory test results), pregnancy complication, or targeted condition that may 
be associated with adverse pregnancy outcome to mothers who did not experience any of these 
events. Clinical adverse events, pregnancy complications, and targeted conditions that overlap 
with the outcome for the adjusted analysis will be excluded. 
 
Generalized linear models will be used to test antiretroviral drug concentrations in maternal and 
infant hair, drug concentrations in maternal breast milk, drug concentrations in infant plasma, and 
self-reported barriers and facilitators of adherence while adjusting for potential confounders.  


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Analyses that associate adverse events with antiretroviral drug concentrations will be conducted 
using two disjoint time periods for the adverse event outcomes: 1) adverse events that occurred 
up to and including the delivery visit, and 2) adverse events that occurred after the delivery visit 
and up to and including the week 6 postpartum visit while adjusting for the events observed at 
delivery. These two time periods were selected because hair will only be collected at the delivery 
visit.  
 
 
10 
DATA HANDLING AND RECORD KEEPING 
 
10.1 
Data Management Responsibilities 
 
As described in Section 4.4, data on screening and enrollment in this study will be collected using 
the DMC SES.  
 
Study sites must maintain adequate and accurate research records containing all information 
pertinent to the study for all screened and enrolled mother-infant pairs, including paper-based 
CRFs (if used), eCRFs, and supporting source data. In maintaining these records, sites must 
comply with the standards of source documentation specified in the DAIDS policy on 
Requirements for Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials 
(available on the website referenced in Section 10.2). 
 
eCRFs and an eCRF completion guide will be made available to study sites by the DMC. Study 
site staff will enter required data into eCRFs, with system checks applied and data queries 
generated immediately upon saving the entered data. Data must be entered within timeframes 
specified by the DMC; queries must also be resolved in a timely manner. Selected laboratory data 
will be transferred electronically to the DMC through the LDMS.  
 
Further information on eCRFs and IMPAACT data management procedures will be provided by 
the DMC. A User Manual for the Subject Enrollment System is available on the DMC portal at: 
https://www.frontierscience.org. 
 
10.2 
Essential and Source Documents and Access to Source Data 
 
All DAIDS policies referenced in this section are available at: 
https://www.niaid.nih.gov/research/daids-clinical-research-policies-standard-procedures.  
 
Study sites must comply with DAIDS policies on Requirements for Essential Documents at 
Clinical Research Sites Conducting DAIDS Funded and/or Sponsored Clinical Trials and 
Requirements for Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials. In 
its policy on Requirements for Manual of Operational Procedures, DAIDS requires sites to 
establish SOPs for maintaining essential and source documents in compliance with these policies. 
Site SOPs should be updated and/or supplemented as needed to describe roles, responsibilities, 
and procedures for this study, and site SOPs should be followed throughout the study.  
 


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Per the DAIDS policy on Storage and Retention of Clinical Research Records, study records must 
be stored in a manner that ensures privacy, confidentiality, security, and accessibility during the 
conduct of the study and after the study is completed. Records must be retained for a minimum of 
three years after the completion of the study. Per 21 CFR 312.62, records must be maintained for 
two years after the date a marketing application is approved for one or more of the study products 
for the indication for which it is evaluated in this study; or, if no application is filed, or if the 
application is not approved for this indication, records must be retained two years after the study 
is discontinued and the FDA is notified.  
 
All study records must be accessible for inspection, monitoring, and/or auditing during and after 
the conduct of the study by authorized representatives of the study sponsors and their contracted 
monitors, IMPAACT, Gilead Sciences, Mylan, ViiV Healthcare Ltd, the FDA, site drug 
regulatory authorities, site IRBs/ECs, OHRP, and other US, local, and international regulatory 
entities. Records must be kept on-site throughout the period of study implementation; thereafter, 
instructions for off-site storage may be provided by NIAID or NICHD. No study records may be 
removed to an off-site location or destroyed prior to receiving approval from NIAID or NICHD.  
 
10.3 
Quality Control and Quality Assurance 
 
Study sites must ensure that essential documents and participant research records are subject to 
continuous quality control and quality assurance procedures consistent with the DAIDS policy on 
Requirements for Clinical Quality Management Plans, which is available at: 
https://www.niaid.nih.gov/research/daids-clinical-research-policies-standard-procedures. 
 
 
11 
CLINICAL SITE MONITORING 
 
Site monitors under contract to NIAID or NICHD will visit study sites to inspect study facilities 
and review participant study records including consent forms, paper-based CRFs (if used), 
eCRFs, medical records, laboratory records, and pharmacy records, to ensure protection of study 
participants, compliance with the IRB/EC approved protocol, and accuracy and completeness of 
records. The monitors also will review essential document files to ensure compliance with all 
applicable regulatory requirements. Site investigators will make study facilities and documents 
available for inspection by the monitors.  
 
 
12 
HUMAN SUBJECTS PROTECTIONS 
 
12.1 
Institutional Review Board/Ethics Committee Review and Approval  
 
Prior to study initiation, site investigators must obtain IRB/EC review and approval of this 
protocol and site-specific ICFs in accordance with 45 CFR 46; subsequent to initial review and 
approval, IRBs/ECs must review the study at least annually. Site investigators must also promptly 
report to the IRB/EC any changes in the study and any unanticipated problems involving risks to 
participants or others. 
 


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All IRB/EC policies and procedures must be followed and complete documentation of all 
correspondence to and from the IRBs/ECs must be maintained in site essential document files. 
Sites must submit documentation of both initial review and approval and continuing review to the 
DAIDS Protocol Registration Office (PRO) in accordance with the DAIDS Protocol Registration 
Manual (see also Section 13.2). 
 
12.2 
Vulnerable Participants 
 
The NIH is mandated by law to ensure that pregnant women and children be included in clinical 
research when appropriate (133, 134). This study responds to that mandate and will provide 
clinical research data to inform HIV treatment guidelines for pregnant women. Nonetheless, the 
pregnant women, fetuses, and children who take part in this study are considered vulnerable 
participants per the US Code of Federal Regulations, and site IRBs/ECs must consider the 
potential risks and benefits to maternal, fetal, and infant participants as described in 45 CFR 46 
Subpart B (for pregnant women, fetuses, and neonates) and 45 CFR 46 Subpart D (for children). 
 
With respect to 45 CFR 46 Subpart B, the specifications of 45 CFR 46.204 (d) are considered to 
apply; therefore, maternal participants will be asked to provide written informed consent for their 
own and their children’s study participation. 
 
With respect to 45 CFR 46 Subpart D, IRBs/ECs must determine the level of risk to children in 
the categories specified in 45 CFR 46.404-407. Documentation of this determination is required 
to complete the DAIDS protocol registration process described in Section 13.2, and the risk 
category assigned by the IRB/EC further determines the parental informed consent requirements 
for the study at each site.  
 
Per 45 CFR 46.408 (b), the IRB/EC may find that the consent of one parent is sufficient for 
research to be conducted under 46.404 or 46.405. If the IRB/EC finds that the research is covered 
by 46.406 or 46.407, both parents must give their consent, unless one parent is deceased, 
unknown, incompetent, or not reasonably available or when only one parent has legal 
responsibility for the care and custody of the child (as determined locally). IRBs/ECs must 
document their risk determination, and study sites should adapt the signature pages of their site-
specific ICFs as needed to accommodate the parental consent requirements associated with the 
IRB/EC determination. 
 
Study sites must comply with all IRB/EC requirements and the requirements of the DAIDS policy 
on Enrolling Children (including Adolescents) in Clinical Research, which is available at:  
https://www.niaid.nih.gov/research/daids-clinical-research-policies-standard-procedures. 
  
12.3 
Informed Consent 
 
Refer to Section 4.4 and the study-specific MOP for further information on informed consent 
procedures for this study. 
 
Written informed consent for maternal and infant study participation will be obtained before any 
study-specific procedures are performed (see Appendix III). The informed consent process will 
include information exchange, detailed discussion, and assessment of understanding of all 
required elements of informed consent, including the potential risks, benefits, and alternatives to 
study participation. The process will emphasize the randomized nature of the study and the 
differences in care and treatment that mothers and infants may experience as part of the study 
relative to current local standards of care. 


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Mothers will be asked to provide written informed consent for storage and future research testing 
(including genetic testing) of biological specimens remaining after protocol-specified testing has 
been completed (see Appendix IV). This consent is optional; mothers may decline storage and all 
future testing of residual samples, or may decline genetic testing only, with no impact on other 
aspects of study participation. While the mother’s consent is optional, conduct of an informed 
consent process to determine the mother’s consent decision is not. This consent process must be 
conducted, but need not be conducted prior to study entry. It may be conducted at any time during 
study participation but ideally as soon as possible and within three months after study entry.  
 
Mothers who become pregnant during postpartum follow-up will be provided with information 
and counseling on their current study drug regimen and what is known about the potential risks of 
the ARVs that comprise the regimen during pregnancy. Mothers who wish to change regimens 
based on this counseling will be permitted to do so, and all mothers who choose to receive one or 
more study drugs during the pregnancy will provide written informed consent to do so (see 
Appendix V).  
 
As indicated above, it is generally expected that mothers will provide informed consent for their 
own and their infant’s participation in this study. However, parental consenting requirements at 
each site will depend on the IRB/EC risk determination described in Section 12.2; all IRB/EC 
requirements must be followed.  
 
Should the consenting mother of an enrolled infant die or no longer be available for any reason, 
all applicable IRB/EC policies and procedures should be followed; however, no further study-
specific infant evaluations should be performed until informed consent for continued study 
participation is obtained from the infant’s authorized guardian, as defined locally. Study sites may 
continue to provide care for the infant as needed and appropriate (outside of the study), consistent 
with local standards of care, but no study-specific procedures (outside of the standard of care) 
may be performed. If an authorized guardian cannot be identified, or if the authorized guardian 
does not consent to continued study participation, the infant must be withdrawn from the study. In 
accordance with the DAIDS policy on Enrolling Children (including Adolescents) in Clinical 
Research (available at the website referenced in Section 12.2), all sites must establish and 
maintain written procedures describing the standards that will be followed to identify who may 
serve as guardian for an enrolled infant, reflective of applicable IRB/EC guidance for conduct of 
human subjects research within the context of available local law, regulation, or government 
policy. 
 
12.4 
Potential Benefits 
 
There may be no direct benefit to mothers and infants who take part in this study. However, 
information learned in this study may be of benefit to participants and others in the future, 
particularly information that may lead to optimized treatment guidelines for HIV-infected 
pregnant women and their infants. Mothers may also appreciate the opportunity for themselves 
and their infants to contribute to HIV-related research. 
 


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12.5 
Potential Risks  
 
The potential risks of participation in this study include risks associated with study procedures 
and risks associated with the study drugs. 
 
Most study procedures are routine medical procedures that are associated with minimal to no risk 
in participants. Blood collection may cause pain, bruising, or swelling. There is a very small 
chance of infection where the needle is inserted. There is also a very small chance of cutting the 
skin when hair is collected with scissors. It may be uncomfortable to express breast milk.  
 
DXA scans involve exposure to radiation. Assuming that three attempts may be required to 
complete scans of the lumbar spine and hip, mothers who undergo DXA scans will be exposed to 
a maximum of 2.04 mrem (0.22 mrem for each scan of the spine, 0.46 mrem for each scan of the 
hip). This is comparable to the dose of radiation received from naturally occurring sources over a 
2-3 day period at sea level (approximately 0.8 mrem per day). Assuming that three attempts may 
be required to complete scans of the whole body and lumbar spine, infants who undergo DXA 
scans will be exposed to a maximum of 4.08 mrem (0.89 mrem for each scan of the whole body, 
0.47 mrem for each scan of the spine). This is comparable to the dose of radiation received from 
naturally occurring sources over a 5-day period at sea level. For both mothers and infants, the 
exposure to radiation associated with the DXA scans is well below limits set forth by the FDA in 
21 CFR 361.1(b)(3).  
 
Please refer to Sections 1.2-1.8 and the Package Inserts for the study drugs for a complete 
description of the potential risks associated with use of these drugs.  
 
Please refer to Section 12.7 for further information on privacy and confidentiality. Despite all 
efforts to maintain confidentiality, involvement in the study could become known to others, 
possibly leading to unfair treatment, discrimination, or other social impacts. Mothers may become 
worried, stressed, or anxious in relation to the results of the infant HIV test performed for the 
study. Trained study staff will be available to assist mothers who may experience these issues and 
problems.  
 
12.6 
Reimbursement/Compensation 
 
Pending IRB/EC approval, participants will be reimbursed for costs associated with completing 
study visits (e.g., transport costs). Reimbursement amounts will be specified in site-specific ICFs 
or other materials if applicable per IRC/EC policies and procedures.  
 
12.7 
Privacy and Confidentiality 
 
All study procedures will be conducted in private and every effort will be made to protect 
participant privacy and confidentiality to the extent possible. Participant information will not be 
released without written permission to do so except as necessary for review, monitoring, and/or 
auditing as described in Section 10.2. If any photographs of physical exam findings are taken, 
standard precautions will be followed to protect participant privacy and confidentiality.  
 


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All study-related information will be stored securely. Participant research records will be stored 
in locked areas with access limited to study staff. All laboratory specimens, CRFs, and other 
documents that may be transmitted off-site (e.g., EAE report forms, photographs of exam 
findings) will be identified by PID only. Likewise, communications between study staff and 
Protocol Team members regarding individual participants will identify participants by PID only.  
 
Study sites are encouraged but not required by DAIDS policies to store study records that bear 
participant names or other personal identifiers separately from records identified by PID. All local 
databases must be secured with password protected access systems. Lists, logbooks, appointment 
books, and any other documents that link PID numbers to personal identifying information should 
be stored in a separate, locked location in an area with limited access.  
 
In addition to the above, a Certificate of Confidentiality has been obtained for this study from the 
US DHHS. This certificate protects study staff from being compelled to disclose study-related 
information by any US federal, state, or local civil, criminal, administrative, legislative, or other 
proceedings. It thus serves to protect the identity and privacy of study participants. Because the 
certificate cannot be enforced outside of the US, however, it applies only to US sites and 
participants. 
 
12.8 
Communicable Disease Reporting 
 
Study staff will comply with local requirements to report communicable diseases including HIV 
infection identified among study participants to health authorities. Participants will be made 
aware of all applicable reporting requirements as part of the study informed consent process. 
 
12.9 
Management of Incidental Findings 
 
Site clinicians will provide mothers with clinically meaningful maternal and infant physical exam 
findings and laboratory test results. When applicable, site clinicians will also provide referrals to 
non-study sources of medical care for further evaluation and/or treatment of these findings. 
 
12.10 Management of New Information Pertinent to Study Participation 
 
Study staff will provide mothers with any new information learned over the course of the study 
that may affect their willingness to continue receiving study drug and/or remain in follow-up.  
 
12.11 Post-Study Access to Study Drug 
 
It is expected that DTG will be registered in all of the study site countries by the end of the study. 
In the event that DTG is not available locally as women on a DTG-based regimen complete their 
study participation, women will be switched to the best available standard of care regimen. While 
it may be preferable for women to continue a DTG-based regimen if they have been tolerating the 
regimen well and are virologically suppressed, adverse consequences are not anticipated when 
switching to an alternate first-line regimen (e.g., to an EFV- or a PI-based regimen).  
 
TAF may be registered in many participating sites by the time the study is completed. If TAF is 
not available locally, women can be switched from TAF to TDF when coming off-study. TDF is 
currently available in all participating study site countries and adverse consequences are not 
anticipated when switching from TAF to TDF. 
 


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13 
ADMINISTRATIVE PROCEDURES 
 
13.1 
Regulatory Oversight 
 
This study is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), 
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), 
and National Institute of Mental Health (NIMH), which are part of the United States National 
Institutes of Health (NIH). Gilead Sciences, Mylan, and ViiV Healthcare Ltd will provide study 
drugs for this study but are not involved in sponsorship or regulatory oversight of the study. 
 
Within the NIAID, DAIDS is responsible for regulatory oversight of this study. DAIDS will 
distribute safety-related information pertaining to the study drugs prior to and during the conduct 
of the study, in accordance with its sponsor obligations. As the convening authority of the DSMB, 
NIAID is the single entity with authority and responsibility to act upon the recommendations of 
the DSMB. 
 
NIAID and NICHD provide funding to the clinical research sites at which this study will be 
conducted. Each institute contracts with independent clinical site monitors who will perform 
monitoring visits as described in Section 11. As part of these visits, monitors will inspect study-
related documentation to ensure compliance with all applicable US and local regulatory 
requirements. 
 
13.2 
Protocol Registration 
 
Prior to implementation of this protocol, and any subsequent full version amendments, each site 
must have the protocol and the protocol ICFs approved, as appropriate, by their local IRBs/ECs 
and any other applicable regulatory entity. Upon receiving final approval, sites will submit all 
required protocol registration documents to the DAIDS PRO at the RSC. The DAIDS PRO will 
review the submitted protocol registration packet to ensure that all of the required documents 
have been received.  
 
Site-specific ICFs will be reviewed and approved by the DAIDS PRO and sites will receive an 
Initial Registration Notification from the DAIDS PRO that indicates successful completion of the 
protocol registration process. A copy of the Initial Registration Notification should be retained in 
the site's regulatory files. 
 
For any future protocol amendments, upon receiving final IRB/EC and any other applicable 
regulatory entity approvals, sites should implement the amendment immediately. Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the RSC. The DAIDS 
PRO will review the submitted protocol registration packet to ensure that all the required 
documents have been received. Site-specific ICFs will not be reviewed and approved by the 
DAIDS PRO and sites will receive an Amendment Registration Notification when the DAIDS 
PRO receives a complete registration packet. A copy of the Amendment Registration Notification 
should be retained in the site's regulatory files. 
 


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For additional information on the protocol registration process and specific documents required 
for initial and amendment registrations, refer to the current version of the DAIDS Protocol 
Registration Manual, which is available on the RSC website at: http://rsc.tech-res.com/clinical-
research-sites/protocol-registration. 
 
13.3 
Study Implementation 
 
 
This study will be conducted in accordance with the protocol, international good clinical practice 
guidelines, and all applicable US and local regulations. Study implementation will also be guided 
by the IMPAACT Manual of Procedures, study-specific MOP, LPC, and other study 
implementation materials that will be available on the IMPAACT website at:  
www.impaactnetwork.org. 
 
Study implementation at each site will also be guided site-specific SOPs. The DAIDS policy on 
Requirements for Manual of Operational Procedures specifies the minimum set of SOPs that must 
be established at sites conducting DAIDS funded and/or sponsored clinical trials (available on the 
website referenced in Section 10.2). These SOPs should be updated and/or supplemented as 
needed to describe roles, responsibilities, and procedures for this study. 
 
13.4 
Protocol Deviation Reporting 
 
Per the policy for Requirements for Source Documentation in DAIDS Funded and/or Sponsored 
Clinical Trials (available at the website referenced in Section 10.2), all protocol deviations must 
be documented in participant research records. Reasons for the deviations and corrective and 
preventive actions taken in response to the deviations should also be documented.  
 
Deviations should be reported to site IRBs/ECs and other applicable review bodies in accordance 
with the policies and procedures of these review bodies. Serious deviations that are associated 
with increased risk to one or more study participants and/or significant impacts on the integrity of 
study data must also be reported within IMPAACT, following procedures specified in the 
IMPAACT Manual of Procedures. 
 
13.5 
Critical Event Reporting 
 
Per the DAIDS policy on Identification and Classification of Critical Events, a critical event is 
defined as an unanticipated study-related incident that is likely to cause harm or increase the risk 
of harm to participants or others or has a significant adverse impact on study outcomes or 
integrity. All such events must be reported following procedures specified in the DAIDS Critical 
Events Manual, which is available at: 
https://www.niaid.nih.gov/sites/default/files/documents/criticaleventsmanual.pdf. 
 
13.6 
ClinicalTrials.gov 
 
This protocol is subject to the United States Food and Drug Administration Amendments Act of 
2007 (FDAAA), including registration in ClinicalTrials.gov. 
 
 


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14 
PUBLICATIONS 
 
All presentations and publications of data collected in this study are governed by IMPAACT 
policies, which are available in the IMPAACT Manual of Procedures.  
 
 
15 
REFERENCES 
 
1. 
UNAIDS. Global report: UNAIDS report on the global AIDS epidemic 2013. 2013. 
2. 
World Health Organization. Consolidated Guidelines on the Use of Antiretroviral Drugs 
for Treating and Preventing HIV Infection: Recommendations for a Public Health 
Approach. Second Edition. June 2016. 
3. 
World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for 
treating and preventing HIV infection: What's New. 2015. 
4. 
Sonderup MW, Maughan D, Gogela N, Setshedi M, Wainwright H, Meintjes G, et al. 
Identification of a novel and severe pattern of efavirenz drug-induced liver injury in 
South Africa. AIDS. 2016;30(9):1483-5. 
5. 
Mollan KR, Smurzynski M, Eron JJ, Daar ES, Campbell TB, Sax PE, et al. Association 
between efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal 
ideation or attempted or completed suicide: an analysis of trial data. Annals of internal 
medicine. 2014;161(1):1-10. 
6. 
Sibiude J, Mandelbrot L, Blanche S, Le Chenadec J, Boullag-Bonnet N, Faye A, et al. 
Association between prenatal exposure to antiretroviral therapy and birth defects: an 
analysis of the French perinatal cohort study (ANRS CO1/CO11). PLoS medicine. 
2014;11(4):e1001635. 
7. 
Siberry G, Tierney C, Stranix-Chibanda L, Marr C, Shepherd JA, Browning R, et al. 
Impact of Maternal Tenofovir Use on HIV-Exposed Newborn Bone Mineral. Conference 
on Retroviruses and Opportunistic Infections Boston, MA2016. 
8. 
Siberry GK, Jacobson DL, Kalkwarf HJ, Wu JW, DiMeglio LA, Yogev R, et al. Lower 
newborn bone mineral content associated with maternal use of tenofovir disoproxil 
fumarate during pregnancy. Clinical infectious diseases : an official publication of the 
Infectious Diseases Society of America. 2015;61(6):996-1003. 
9. 
Fowler MG, Qin M, Fiscus SA, Currier J, Makanani B, Martinson F, et al. PROMISE: 
efficacy and safety of 2 strategies to prevent perinatal HIV transmission [Abstract 31LB]. 
Conference on Retroviruses and Opportunistic Infections; Seattle, WA2015. 
10. 
Prabhu VR, Wong C, Jenkins S, Nizami S, Catlin K, Domanico P, editors. New ARVs 
could represent over USD 3 billion in cost savings through 2025. Conference on 
Retroviruses and Opportunistic Infections; 2016; Boston, MA. 
11. 
Ripin D, Prabhu VR. A cost-savings analysis of a candidate universal antiretroviral 
regimen. Current opinion in HIV and AIDS. 2017;12(4):403-7. 
12. 
Walmsley SL, Antela A, Clumeck N, Duiculescu D, Eberhard A, Gutierrez F, et al. 
Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. The New 
England journal of medicine. 2013;369(19):1807-18. 
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Dryden-Peterson S, Shapiro RL, Hughes MD, Powis K, Ogwu A, Moffat C, et al. 
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110. 
Ziske J, Kunz A, Sewangi J, Lau I, Dugange F, Hauser A, et al. Hematological changes 
in women and infants exposed to an AZT-containing regimen for prevention of mother-
to-child-transmission of HIV in Tanzania. PloS one. 2013;8(2):e55633. 
111. 
Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B, Moawad AH, et al. 
Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. The 
New England journal of medicine. 2003;348(24):2379-85. 
112. 
Papp E, Mohammadi H, Loutfy MR, Yudin MH, Murphy KE, Walmsley SL, et al. HIV 
protease inhibitor use during pregnancy is associated with decreased progesterone levels, 
suggesting a potential mechanism contributing to fetal growth restriction. The Journal of 
infectious diseases. 2015;211(1):10-8. 
113. 
Papp E, Balogun K, Banko N, Mohammadi H, Loutfy M, Yudin MH, et al. Low Prolactin 
and High 20-alpha-Hydroxysteroid Dehydrogenase Levels Contribute to Lower 
Progesterone Levels in HIV-Infected Pregnant Women Exposed to Protease Inhibitor-
Based Combination Antiretroviral Therapy. The Journal of infectious diseases. 
2016;213(10):1532-40. 
114. 
Zaba B, Calvert C, Marston M, Isingo R, Nakiyingi-Miiro J, Lutalo T, et al. Effect of 
HIV infection on pregnancy-related mortality in sub-Saharan Africa: secondary analyses 
of pooled community-based data from the network for Analysing Longitudinal 
Population-based HIV/AIDS data on Africa (ALPHA). Lancet. 2013;381(9879):1763-71. 
115. 
Calvert C, Ronsmans C. The contribution of HIV to pregnancy-related mortality: a 
systematic review and meta-analysis. Aids. 2013;27(10):1631-9. 
116. 
Phillips T, McNairy M, Zerbe A, Myer L, Abrams EJ. Postpartum transfer of care among 
HIV-infected women initiating antiretroviral therapy during pregnancy. Journal of 
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117. 
Okawa S, Chirwa M, Ishikawa N, Kapyata H, Msiska CY, Syakantu G, et al. 
Longitudinal adherence to antiretroviral drugs for preventing mother-to-child 
transmission of HIV in Zambia. BMC pregnancy and childbirth. 2015;15:258. 
118. 
Ngarina M, Kilewo C, Karlsson K, Aboud S, Karlsson A, Marrone G, et al. Virologic and 
immunologic failure, drug resistance and mortality during the first 24 months postpartum 
among HIV-infected women initiated on antiretroviral therapy for life in the Mitra plus 
Study, Dar es Salaam, Tanzania. BMC infectious diseases. 2015;15:175. 
119. 
Kim MH, Zhou A, Mazenga A, Ahmed S, Markham C, Zomba G, et al. Why Did I Stop? 
Barriers and Facilitators to Uptake and Adherence to ART in Option B+ HIV Care in 
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Beumer J, Bosman I, Maes R. Hair as a biological specimen for therapeutic drug 
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Koss CA, Natureeba P, Mwesigwa J, Cohan D, Nzarubara B, Bacchetti P, et al. Hair 
concentrations of antiretrovirals predict viral suppression in HIV-infected pregnant and 
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Participants in Research Involving Human Subjects. 1998 March 6. Report No. 
 


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Appendix I Schedule of Evaluations 
Antepartum 
 
 
Weeks During Pregnancy 
Post
Study Visit 
Screen 
Entry 
Week 4 
Week 8 
Week 12 
Q4 Weeks1 
ARV 
Early 
Visit Window 
up to -14 d 
Day 0 
±2 wks 
±2 wks 
±2 wks 
±2 wks 
Switch2 
D/C3 
MATERNAL EVALUATIONS
 
 
Informed consent 
X 
 
 
 
 
 
 
Maternal medical history 
X 
X 
X 
X 
X 
X 
X 
X 
ARV adherence questionnaire4 
 
 
X 
X 
X 
X 
X 
X 
Sleep and anxiety questionnaires 
 
X 
 
X 
 
 
X
 
Depression questionnaire 
 
 
 
 
 
 
X
 
Physical examination 
X 
X 
X 
X 
X 
X 
X
X 
Fetal ultrasound 
prior to or 
within 14 days after entry 
 
 
 
 
 
Confirmatory pregnancy testing5 
X 
 
 
 
 
 
 
 
Confirmatory HIV testing  
0-6 mL 
 
 
 
 
 
 
 
Hepatitis B surface antigen 
 
3 mL 
 
 
 
 
 
 
AST, ALT, creatinine, CrCl 
4 mL 
 
4 mL 
 
4 mL 
4 mL Wk 24 
4 mL 
4 mL 
Complete blood count 
3 mL 
 
 
 
 
 
 
 
CD4+ cell count 
 
3 mL 
 
 
 
 
 
HIV-1 RNA (store residual plasma)6 
 
6 mL 
6 mL 
6 mL 
6 mL 
6 mL Wk 246 
6 mL
6 mL 
Stored plasma 
6 mL 
 
 
 
 
 
 
Stored plasma and cell pellets 
 
10 mL 
 
10 mL 
 
 
 
Stored urine  
 
15 mL 
 
 
 
 
15 mL 
Total blood volume 
13-20 mL 
22 mL 
10 mL 
16 mL 
10 mL 
0-10 mL 
10 mL 
10 mL 
 
1Refer to Section 6.3.4. After antepartum study Week 12, mothers will complete scheduled follow-up visits every four weeks (Q4) prior to delivery. 
Depending on the date of delivery, these visits may take place at antepartum study Weeks 16, 20, 24, and 28.  
2Refer to Section 6.6.  
3Refer to Section 6.9. 
4Routine questionnaire at all indicated visits; barriers and facilitators questionnaires at Antepartum Week 8. 
5Refer to Section 6.1. If available medical records document a positive pregnancy test result, or if pregnancy is confirmed by ultrasound scan prior to 
entry, no pregnancy testing is required. Otherwise, a blood (1 mL) or urine (5 mL) pregnancy test should be performed, with results available for final 
eligibility determination prior to entry. The total blood volume shown in the Screen column above accommodates collection of 1 mL of blood if needed. 
6It is generally not expected that mothers will meet the criteria for confirmation of virologic failure (≥200 copies/mL at or after at least 24 weeks on study) 
during antepartum follow-up; however, if these criteria are met prior to delivery, the Confirmation of Virologic Failure evaluations shown on the next page 
and further described in Section 6.7 should be performed.  
 


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Appendix I Schedule of Evaluations 
Delivery and Postpartum
Delivery 
Weeks Postpartum 
Post 
Confirmation 
 
Study Visit 
up to 14/27 d* 
6 
14 
26 
38 
50 
ARV 
of Virologic  
Early 
Visit Window 
New Day 0 
±2 wks 
±6 wks 
±6 wks 
±6 wks 
±6 wks 
Switch1 
Failure2 
D/C3 
MATERNAL EVALUATIONS
 
 
 
Maternal medical history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ARV adherence questionnaire4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sleep and anxiety questionnaires 
 
 
 
 
X 
 
X 
 
 
Depression questionnaire 
 
X 
 
 
 
X 
X 
 
 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
[X] 
X 
AST, ALT, creatinine, CrCl 
4 mL 
 
4 mL 
4 mL 
 
4 mL 
4 mL 
 
4 mL 
Complete blood count 
 
 
 
3 mL 
 
3 mL 
 
 
 
CD4+ cell count 
 
 
 
3 mL 
 
3 mL 
 
 
 
HIV-1 RNA (store residual plasma) 
6 mL 
 
6 mL 
6 mL 
6 mL 
6 mL 
6 mL 
6 mL 
6 mL 
ARV resistance testing  
(store residual plasma)
 
 
 
 
 
 
 
6 mL 
 
Stored plasma 
6 mL 
6 mL 
 
 
 
 
 
 
 
Stored plasma and cell pellets 
10 mL 
 
 
 
 
10 mL 
 
 
 
Stored serum5 
0-4 mL5 
 
 
 
 
 
 
 
 
Stored breast milk  
 
20 mL if BF 
 
 
 
 
 
 
 
Stored urine  
 
 
 
 
 
15 mL 
 
 
15 mL 
Stored hair 
X 
 
 
 
 
 
 
 
 
DXA scan (at selected sites)6 
 
 
 
 
 
X6 
 
 
 
Total blood volume 
26-30 mL 
6 mL 
10 mL 
16 mL 
6 mL 
26-27 mL 
10 mL 
12 mL 
10 mL 
INFANT EVALUATIONS 
 
 
 
 
 
 
 
 
 
Infant medical and feeding history 
X 
X 
X 
X 
X 
X 
 
 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
 
 
X 
HIV NAT (store remnant samples)7,8 
3 mL 
4 mL8 
3 mL 
3 mL if BF 
3 mL if BF 
3 mL 
 
 
3 mL 
ALT and creatinine9 
1 mL 
 
 
1 mL if BF 
 
 
 
 
 
Complete blood count9 
1 mL 
 
 
1 mL if BF 
 
 
 
 
 
Stored serum5 
0-1 mL5 
 
 
 
 
 
 
 
 
Stored hair 
X 
 
 
 
 
 
 
 
 
DXA scan (at selected sites) 
 
 
 
X 
 
 
 
 
 
Total blood volume 
5-6 mL 
4 mL 
3 mL 
0-5 mL 
0-3 mL 
3 mL 
 
 
3 mL 
 
 


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Appendix I Delivery and Postpartum Footnotes: 
 
*The Delivery Visit should be conducted as soon as possible after delivery and within a targeted window of 14 days after delivery. If the visit cannot be 
conducted within the targeted window, it may be conducted within an allowable window of 27 days after delivery. The timeliness of visit completion at each 
site will be closely monitored and corrective actions taken when needed, as described in Sections 6.4 and 9.5.1. 
1Refer to Section 6.6.  
2Refer to Sections 6.7 and 8.3. 
3Refer to Section 6.9. 
4Routine questionnaire at all indicated visits; barriers and facilitators questionnaires at Postpartum Week 38. 
5At Delivery, collect maternal and infant blood for serum storage only if the mother is at risk for Zika virus infection (due to local transmission, travel, or other 
exposure) and maternal Zika virus infection during the current pregnancy is suspected.  
6Maternal DXA scan must be preceded by a pregnancy test. A blood (1 mL) or urine (5 mL) pregnancy test may be performed on the day of the scan 
(preferably) or within 14 days prior to the scan. The total blood volume shown in the Week 50 column above accommodates collection of 1 mL of blood if 
needed. 
7For infants ever exposed to breast milk, perform HIV NAT at Delivery and Weeks 6, 14, 26, 38, and 50. For infants never exposed to breast milk, perform 
HIV NAT at Delivery and Weeks 6, 14, and 50. Also refer to Section 6.8. Any infant with an initial positive HIV NAT result should be recalled to the clinic as 
soon as possible for confirmatory testing.  
8At Week 6, 4 mL is required to provide sufficient plasma for HIV NAT and testing of ARV drug levels. 
9At Week 26, perform testing (ALT, creatinine, complete blood count) for infants ever exposed to breast milk. 
 


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Appendix II 
Maternal Toxicity Management Guidelines 
 
 
Refer to Section 8 for comprehensive information on participant management and Section 8.1 for an 
overview of guidance applicable to all adverse events.  
 
Maternal adverse events will be managed based on their severity and assessed relationship to study drug, 
as specified in the tables provided in this appendix. Table II.1 provides general guidelines. Tables II.2 
through II.8 provide specific guidelines for the following types of events: 
 
Table II.2 
Rash 
Table II.3 
Asymptomatic ALT or AST elevation 
Table II.4 
Clinical hepatitis  
Table II.5 
Increased creatinine and decreased creatinine clearance  
Table II.6 
Psychiatric events 
Table II.7 
Allergic reaction 
Table II.8 
Switching from TDF or TAF to ZDV or ABC 
 
Each of the above-listed types of events should be managed according to the corresponding table; all 
other events should be managed according to Table II.1.  
 
When management of an adverse event requires consultation with the CMC, the CMC should be 
contacted as soon as possible and within three business days of site awareness of the event. 
 
As a general principle, unless stated otherwise, it is preferable to avoid stopping an entire ARV regimen 
during pregnancy or while breastfeeding (to reduce the chance of viremia and therefore of HIV 
transmission to the infant), and instead to substitute a new ARV for the drug that is suspected of causing 
toxicity. 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. 
 
If DTG or EFV are held due to suspected hypersensitivity, elevated LFTs, and/or clinical hepatitis, then 
DTG or EFV should be permanently discontinued and the participant should not be re-challenged with the 
same drug, as detailed further below. For any mother whose study drug regimen is modified such that 
DTG or EFV is replaced with another ARV, an additional study visit should be conducted approximately 
four weeks after the switch as described in Section 6.6. 
 
For any mother who experiences an adverse event that results in holding or permanently discontinuing 
use of EFV, FTC/TDF should be given for seven days after stopping EFV to minimize the risk of 
resistance, unless the reason for hold or discontinuation involves possible FTC/TDF toxicity.  
 
 


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Table II.1
General Guidelines for Maternal Toxicity Management 
The guidance provided in this table applies to adverse events other than  
those for which event-specific guidance is provided in Tables II.2-II.7.
Grade 1 or
Grade 2 
 
Regardless of assessed relationship to study drug, the current study drug regimen may 
be continued; consultation with the CMC is available but not required.  
Grade 3
If assessed as not related to study drug, the current study drug regimen may be 
continued. Re-evaluation should continue at least weekly until improvement to grade 2 or 
lower, then resume the frequency of evaluation specified in the SoE unless more frequent 
monitoring is clinically indicated. 
If assessed as related to study drug, the suspect study drug should be replaced or the 
entire regimen held unless the site investigator assesses that continuation of the current 
regimen is in the best interest of the participant. The CMC must be informed of the grade 
3 event and consulted on the site investigator’s proposed clinical and ARV management 
plan, with any change of any ARV in the regimen approved by the CMC. Re-evaluate at 
least weekly until improvement to grade 2 or lower, then resume the frequency of 
evaluation specified in the SoE unless more frequent monitoring is clinically indicated. 
The suspect study drug (or entire regimen) may be resumed when the event has improved 
to grade 2 or lower. Following resumption, if the event recurs at grade 3 or higher, the 
suspect study drug should be permanently discontinued.  
Grade 4
If assessed as not related to study drug, the current study drug regimen may be 
continued. The CMC must be informed of the grade 4 event and the site investigator’s 
proposed clinical and ARV management plan. Re-evaluation should continue at least 
weekly until improvement to grade 2 or lower. 
If assessed as related to study drug, the entire study drug regimen should be held. The 
CMC must be informed of the grade 4 event and the site investigator’s proposed clinical 
and ARV management plan. The participant should be re-evaluated at least weekly until 
improvement to grade 2 or lower, at which time study drug may be resumed. When 
resuming study drug, the suspect study drug should be replaced, with any change of any 
ARV in the regimen approved by the CMC. On a case-by-case basis, the CMC may also 
approve resumption of the prior regimen with close monitoring for potential recurrence; in 
this case, should the event recur at grade 3 or higher, the suspect study drug should be 
permanently discontinued.  
 
 
 
 


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Management of Maternal Rash 
 
Mild to moderate rash is an expected adverse reaction for DTG-containing ART. Rash generally occurs 
within the first ten weeks of treatment, rarely require interruptions or discontinuations of therapy and 
usually resolves within two to three weeks (even with continuation of DTG). The index case of 
hypersensitivity with DTG involved a profuse, purpuric and coalescing leukocytoclastic vasculitis as well 
as clinically significant liver chemistry elevations. Other than this case, no other instances of serious skin 
reaction, including Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and erythema 
multiforme, have been reported for DTG in clinical trials. 
 
Mild to moderate rash is also occurs frequently after initiation of EFV-containing ART. In controlled 
clinical trials, 26% (266/1008) of adults treated with EFV 600 mg experienced new skin rash (versus 17% 
of patients treated with non-EFV regimens). Rashes are usually mild-to-moderate maculopapular skin 
eruptions that occur within the first two weeks of initiating EFV (median time to onset of rash in adults 
was 11 days). Rash resolves within one month (median 16 days) in most patients continuing EFV. Severe 
or life-threatening rash occurred in 0.9% (9/1008) of patients treated with EFV (with grade 4 rash 
occurring in 0.1%). (77) 
 
Table II.2
Management of Maternal Rash
All grades
Assess for signs and symptoms of clinical hepatitis, as listed in Table II.4, and of 
hypersensitivity, as listed in Table II.7. Reinforce participant awareness of these 
signs and symptoms. Instruct participant to contact the site clinician should any such 
signs or symptoms occur and follow appropriate guidance tables. Assess for alternative 
causes of the rash and manage alternative causes, consistent with local standards of care 
(e.g., discontinue suspected concomitant medications if possible). 
Grade 1 or
Grade 2 
 
 If the rash is not generalized, or there is a definitive alternative explanation for the rash 
(other than study drug), the current study drug regimen may be continued with no 
additional evaluations required. 
 If the rash is generalized and there is no definitive alternative explanation for the rash, 
perform liver function tests (LFTs)* within three business days. 
– If the participant has no suspected hypersensitivity reaction or signs/symptoms of 
clinical hepatitis, study drug may be continued pending receipt of LFT results. If 
LFT results are grade 1 or lower, the current study drug regimen may be continued 
with close monitoring and instruction to return to the study site in the event of new 
symptoms or worsening rash. 
– If the participant has suspected hypersensitivity reaction or clinical hepatitis or any 
grade 2 or higher LFT result, all ARVs should be held and the CMC should be 
consulted on change of regimen. DTG or EFV should be permanently discontinued. 


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Table II.2
Management of Maternal Rash
Grade 3
 Hold all ARVs. 
 Perform LFTs* and CBC with differential within three business days. If the participant 
has suspected hypersensitivity reaction or clinical hepatitis or any grade 2 or higher 
LFT result, EFV or DTG should be permanently discontinued. 
 If there is an alternative explanation for the rash (and no signs/symptoms of 
hypersensitivity or hepatitis), the current study drug regimen may be resumed with 
close follow-up at the discretion of the investigator, in consultation with the CMC. The 
timing of resumption of antiretroviral treatment and the choice of regimen to be 
initiated should be determined in consultation with the CMC.  
 Follow the participant closely until the rash resolves to grade 2 or lower. 
Grade 4
  
 Hold all ARVs and permanently discontinue DTG or EFV. 
 The timing of resumption of antiretroviral treatment and the choice of regimen to be 
initiated should be determined in consultation with the CMC.  
 Follow the participant closely until the rash resolves to grade 2 or lower. 
*Signs and symptoms of potential hypersensitivity reaction are provided in Table II.7. Signs and symptoms of 
clinical hepatitis are provided in Table II.4. LFTs should minimally include ALT and AST; additional tests may 
be ordered at the discretion the site investigator and/or at the recommendation of the CMC. 
 
 


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Table II.3
Management of Maternal Asymptomatic ALT/AST Elevations 
If participant becomes symptomatic, follow management for symptomatic hepatitis.
All grades
Assess for signs and symptoms of clinical hepatitis, as listed in Table II.4, and of 
hypersensitivity, as listed in Table II.7. Reinforce participant awareness of these 
signs and symptoms. Instruct participant to contact the site clinician should any such 
signs or symptoms occur and follow appropriate guidance tables. Assess for 
alternative causes of the ALT/AST elevation and manage alternative causes 
consistent with local standards of clinical practice (e.g., diagnose and treat 
concomitant illness*, discontinue suspect concomitant medications if possible).  
Grade 1 
Regardless of assessed relationship to study drug, the current study drug regimen 
may be continued; consultation with the CMC is available but not required. Repeat 
ALT/AST within 14 business days. If repeat ALT/AST result is grade 1 or lower, 
resume the frequency of monitoring specified in the SoE. If repeat ALT/AST result is 
grade 2 or higher, follow management for the relevant grade.  
Grade 2
 If the participant has suspected clinical hepatitis (Table II.4) or hypersensitivity 
(Table II.7), all ARVs should be held and the CMC informed within three business 
days. DTG or EFV should be permanently discontinued. 
 If the participant does not have suspected clinical hepatitis or hypersensitivity, then 
repeat ALT/AST within three to four business days (at most within one week) and 
also check total and direct bilirubin**. If repeat ALT/AST result is grade 1, 3, or 4, 
follow management for the relevant grade. If repeat ALT/AST result is grade 2, 
inform the CMC and: 
– If total bilirubin ≥2 x ULN and direct bilirubin >35% of total bilirubin, all ARVs 
should be held. DTG or EFV should be permanently discontinued. 
– If total bilirubin <2 x ULN and the participant remains asymptomatic, ARVs may 
be continued at the discretion of the site investigator. In these instances, the 
participant should be re-evaluated after one to two weeks (clinically and with 
ALT/AST). If repeat ALT/AST is grade 2 or lower, resume the frequency of 
evaluation specified in the SoE. If repeat ALT/AST is grade 3 or higher, follow 
management for the relevant grade. 
 If study drugs are held, the timing of resumption of antiretroviral treatment and the 
choice of regimen to be initiated should be determined in consultation with the 
CMC. 
 


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Table II.3
Management of Maternal Asymptomatic ALT/AST Elevations 
If participant becomes symptomatic, follow management for symptomatic hepatitis.
Grade 3
 If the participant has suspected clinical hepatitis (Table II.4) or hypersensitivity 
(Table II.7), all ARVs should be held and the CMC informed within three business 
days. DTG or EFV should be permanently discontinued. 
 If the participant does not have suspected clinical hepatitis or hypersensitivity, then 
repeat ALT/AST within three business days and also check total and direct 
bilirubin**. If repeat ALT/AST result is grade 1, 2, or 4, follow management for the 
relevant grade. If repeat ALT/AST result is grade 3, inform the CMC and: 
– If total bilirubin ≥2 x ULN and direct bilirubin >35% of total bilirubin, all ARVs 
should be held. DTG or EFV should be permanently discontinued. 
– If total bilirubin <2 x ULN and the participant remains asymptomatic, ARVs may 
be continued at the discretion of the site investigator. In these instances, the 
participant should be re-evaluated approximately weekly (clinically and with 
ALT/AST) until improvement to grade 2 or lower (then resume the frequency of 
evaluation specified in the SoE). If improvement to grade 2 or lower does not 
occur within 14 days of the initial elevated result, the CMC should be consulted 
about potentially discontinuing DTG or EFV. 
 If study drugs are held, the timing of resumption of antiretroviral treatment and the 
choice of regimen to be initiated should be determined in consultation with the 
CMC. 
Grade 4
 
 If the participant has suspected clinical hepatitis (Table II.4) or hypersensitivity 
(Table II.7), all ARVs should be held and the CMC informed within three business 
days. DTG or EFV should be permanently discontinued. 
 If the participant does not have suspected clinical hepatitis or hypersensitivity, then 
repeat ALT/AST within three business days and also check total and direct 
bilirubin**. If repeat ALT/AST result is grade 1, 2, or 3, follow management for the 
relevant grade. If repeat ALT/AST result is grade 4, all ARVs should be held and 
DTG or EFV should be permanently discontinued; inform the CMC. 
 The participant should be re-evaluated approximately weekly until improvement to 
grade 2 or lower (then resume the frequency of evaluation specified in the SoE).  
 The timing of resumption of antiretroviral treatment and the choice of regimen to be 
initiated should be determined in consultation with the CMC. 
*Careful assessments should be done to assess/rule out pregnancy-related causes (e.g., HELLP), the use of 
alcohol, non-study drug-related drug toxicity, viral hepatitis, or other potential causes of LFT elevations. Consider 
the following additional tests as clinically indicated to further evaluate the liver event:  
– Viral hepatitis serologies (e.g., hepatitis A IgM antibody; HBsAg and hepatitis B core antibody [IgM]; 
hepatitis C RNA; hepatitis E IgM antibody; cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen 
IgM antibody or, if unavailable, obtain heterophile antibody or monospot testing) 
– Syphilis screening 
– Complete blood count with differential to assess eosinophilia 
– Liver imaging (e.g., ultrasound or computerized tomography) 
 
**Events of a pure drug-induced liver injury (DILI) leading to jaundice, without a liver transplant, have a case 
fatality rate of 10-50%. Increased ALT or total bilirubin are relatively common (particular in HIV/AIDS) but the 
combination of ALT >3 x ULN and total bilirubin >2 x ULN is rare and raises concerns for DILI. 
 


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Table II.4
Management of Maternal Clinical Hepatitis
 See also Section 8.6 for management of mothers who are co-infected with Hepatitis B. 
 Signs and symptoms of clinical hepatitis include unexplained anorexia, nausea or vomiting, right 
upper quadrant tenderness (i.e., liver tenderness or hepatomegaly), acholic stools, bilirubinuria, 
scleral icterus, and jaundice. Malaise and new or worsening fatigue are common in pregnancy but 
should also be assessed in relation to potential acute hepatotoxicity. All mothers should be instructed 
contact the site clinician should they experience any of these signs or symptoms. 
 For mothers with signs or symptoms of clinical hepatitis, immediately test ALT and AST as well 
as total and direct bilirubin (and PT/INR if available) and inform the CMC. All ARVs should be held 
for grade 2 or higher ALT/AST if accompanied by signs/symptoms of clinical hepatitis. DTG or 
EFV should be permanently discontinued. 
 Participants should be evaluated approximately weekly or more frequently, until signs/symptoms are 
grade 2 or lower*. 
 The timing of resumption of antiretroviral treatment and the choice of regimen to be initiated should 
be determined in consultation with the CMC. 
*Careful assessments should be done to assess/rule out pregnancy-related causes (e.g., HELLP), the use of 
alcohol, non-study drug-related drug toxicity, viral hepatitis, or other potential causes of LFT elevations. Consider 
the following additional tests as clinically indicated to further evaluate the liver event:  
– Fractionated bilirubin 
– Viral hepatitis serologies (e.g., hepatitis A IgM antibody; HBsAg and hepatitis B core antibody [IgM]; 
hepatitis C RNA; hepatitis E IgM antibody; cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen 
IgM antibody or, if unavailable, obtain heterophile antibody or monospot testing) 
– Syphilis screening 
– Complete blood count with differential to assess eosinophilia 
– Liver imaging (e.g., ultrasound or computerized tomography) 
 
**Events of a pure drug-induced liver injury (DILI) leading to jaundice, without a liver transplant, have a case 
fatality rate of 10-50%. Increased ALT or total bilirubin are relatively common (particular in HIV/AIDS) but the 
combination of ALT >3 x ULN and total bilirubin >2 x ULN is rare and raises the concerns for DILI. 
 
 
 
 
 


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Management of Maternal Increased Creatinine and Decreased Creatinine Clearance 
 
DTG can inhibit the tubular secretion of creatinine and can therefore be associated with a slight increase 
in serum creatinine and apparent decrease in the estimated glomerular filtration rate (GFR, generally by 
10% or less). This type of change occurs within the first four weeks of treatment with DTG (remaining 
stable thereafter) and is not associated with renal damage nor with true decline in renal function. At the 
same time, pregnancy can affect creatinine: normal creatinine ranges are slightly higher in non-pregnant 
adults (0.5-0.9 mg/dL) compared with during the first trimester (0.4-0.7 mg/dL), second trimester (0.4-0.8 
mg/dL), or third trimester (0.4-0.9 mg/dL) of pregnancy (and estimated GFR is higher during pregnancy). 
TDF and TAF can cause renal insufficiency. 
 
Table II.5
Management of Maternal Increased Creatinine and Decreased Creatinine Clearance 
All grades 
Assess participant for other potential causes of decreased renal function. 
Make appropriate renal dosing adjustments of all ARVs (and other 
concomitant medications if possible), consistent with Package Inserts. 
Management, below, should be based on the worst result (CrCl or 
creatinine).  
Estimated CrCl ≥90 mL/min 
OR Grade 1 creatinine 
Monitor as per SoE. 
Estimated CrCl <90 to 
50 mL/min  
OR Grade 2 creatinine
Monitor creatinine at least every two weeks until establish that creatinine 
and estimated CrCl are stable to improving. 
 
Estimated CrCl <50 mL/min 
OR Grade 3 or higher 
creatinine 
If the participant is on TDF or TAF, consult the CMC and: 
 Repeat creatinine and estimated CrCl within three business days. 
 Evaluate for potential causes of decreased renal function. TDF or TAF 
should be substituted with another ARV (e.g., ZDV or ABC) while the 
etiology of the decreased renal function is investigated.  
 If est. CrCl <50 mL/min or grade 3 or higher creatinine are confirmed, 
then TDF or TAF should be held (or switched to another ARV). 
 In women known to be co-infected with hepatitis B virus who develop 
renal toxicity on TDF, TAF may be substituted for TDF in consultation 
with the CMC and with close follow-up 
 Re-evaluate approximately weekly until improvement in creatinine and 
estimated creatinine clearance to grade 2 or lower (est. CrCl 
≥60 mL/min). 
– If improvement of estimated creatinine clearance to grade 2 or lower 
(est. CrCl ≥60 mL/min) and if TDF or TAF was held but an alternate 
etiology was identified, consideration can be given to resuming TDF 
or TAF in consultation with the CMC, with close monitoring of renal 
function.  
– If no alternate etiology can be identified, TDF or TAF should be 
permanently discontinued. 
 Close monitoring should include approximately weekly evaluation for 
one month followed by monthly re-evaluation for three months. 
If the participant is not on TDF or TAF: 
Evaluate for potential causes of decreased renal function and consult the 
CMC on study drug regimen and frequency of re-evaluation. 


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Management of Maternal Psychiatric Events 
 
Prior psychiatric history or postnatal depression may be risk factors for psychiatric events (which have 
also been observed with use of EFV and DTG). 
 
Table II.6
Management of Maternal Psychiatric Events  
(Insomnia, Psychiatric Disorders, Suicidal Ideation or Attempt)
Grade 1 
without 
suicidal 
ideation 
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. 
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 1 or 
Grade 2  
with  
suicidal 
ideation  
Mild or 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. 
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.  
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. 
 
 


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Table II.7
Management of Maternal Allergic Reactions
Signs and symptoms of potential hypersensitivity reaction may include rash, fever, general malaise, 
fatigue, muscle or joint aches, facial edema, eosinophilia, angioedema, and difficulty breathing. 
Malaise and new or worsening fatigue are common in pregnancy but should also be assessed in relation 
to potential hypersensitivity reaction. All mothers should be instructed to contact the site clinician 
should they experience any of these signs or symptoms. For participants receiving ABC, refer to 
Table II.8. 
Grade 1 or
Grade 2 
 
 Study drug may be continued at the discretion of the site investigator. The 
participant should be advised to contact site staff immediately if there is any 
worsening of symptoms or if further systemic signs or symptoms develop. 
Antihistamines, topical corticosteroids, or antipruritic agents may be prescribed. 
 If the participant has suspected clinical hepatitis (Table II.4) or Grade 2 or higher 
ALT/AST, all ARVs should be held. DTG or EFV should be permanently 
discontinued. Inform the CMC. 
Grade 3 or 
Grade 4 
If the grade 3 or 4 allergic reaction is assessed as related to DTG or EFV, DTG or 
EFV should be should permanently discontinued. Consult the CMC on the frequency 
of ongoing monitoring, timing of study drug resumption, and choice of regimen. 
 
 
 


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Table II.8
Management of Participants Switching from TDF or TAF to ZDV or ABC 
To ZDV from 
TDF or TAF 
 
ZDV should be initiated with caution in participants with known anemia (hemoglobin 
concentration <7.5 g/dL) or neutropenia (absolute neutrophil count <750/mm3), and 
alternative causes for anemia and/or neutropenia should be sought and treated prior to 
starting ZDV if possible (or a drug other than ZDV should be selected). 
To ABC from 
TDF or TAF 
 Where HLA-B*5701 screening is considered standard of care, it is recommended 
that site investigators screen for presence of the HLA-B*5701 allele in any 
participant starting if their HLA-B*5701 status is unknown (even if the participant 
has previously tolerated ABC). ABC should not be used in participants known to 
carry HLA-B*5701. 
 Where HLA-B*5701 screening is not considered standard of care, site investigators 
must obtain a complete history of: any previous exposure to ABC-containing 
products; and any events surrounding the discontinuation of this previous exposure, 
and evaluate for the possibility of a clinically suspected hypersensitivity reaction. If 
the possibility of a clinically suspected ABC HSR cannot be ruled out then 
treatment with any ABC-containing product should not be started, due to the risk 
for a potential life threatening and sometimes fatal re-challenge reaction. Where 
participants have previously tolerated treatment with ABC, restarting ABC should 
be done in a setting where medical assistance is readily available, and the site staff 
and participant should be vigilant for signs/symptoms of possible ABC 
hypersensitivity reaction. 
 In the event of clinically suspected ABC hypersensitivity reaction, treatment 
with ABC must be promptly and permanently discontinued, regardless of the 
participant’s HLA-B*5701 status. Such events should then be managed 
appropriately as outlined in the local prescribing information. 
Note: In some countries (e.g., the USA), the use of ABC in participants known to carry HLA-B*5701 is 
contraindicated; investigators must initiate treatment with ABC in accordance with relevant recommendations and 
any restrictions included in the local product labeling. 
 
 
 


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Appendix III 
Sample Informed Consent Form 
 
IMPAACT 2010 
Phase III Study of the Virologic Efficacy and Safety of  
Dolutegravir-Containing versus Efavirenz-Containing Antiretroviral Therapy  
Regimens for HIV-1-Infected Pregnant Women and their Infants 
 
Version 2.0, [date] 
 
Introduction 
 
You and your baby are being asked to take part in the research study named above. 
 
This form gives information about the study. Please read it, or have it read to you, and ask any questions 
you may have. We will take as much time as needed for you to fully understand the study. We will ask 
you questions to see if we have explained the study clearly. 
 
After you understand the study, if you decide that you and your baby will participate, you will be asked to 
sign or make your mark on this form. You will be offered a copy to keep. 
 
 
About the Study 
 
The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) and [insert 
site name] are doing this study to test anti-HIV medicines (ARVs) for pregnant women who have HIV. 
HIV is the virus that causes AIDS. 
 
You are being asked to join this study with your baby because you are pregnant and have HIV. The study 
will include about 640 mothers and babies from Botswana, Brazil, Haiti, India, Malawi, South Africa, 
Thailand, Uganda, the United States, Tanzania, and Zimbabwe. Each mother and baby will be in the study 
during pregnancy and for about 1 year after the baby is born. 
 
The person in charge of the study at [insert site name] is [insert name of IoR]. The United States National 
Institutes of Health is paying for the study. 
 
1. The study is testing different combinations of ARVs in pregnant women and their babies. 
 
People with HIV usually take a combination of 3 or more ARVs. This study will test 3 different 
combinations of ARVs. The ARVs that will be tested are: [sites may substitute locally appropriate drug 
names here and throughout this form] 
 
 
Dolutegravir (DTG) 
 
Tenofovir alafenamide (TAF) 
 
Tenofovir disoproxil fumarate (TDF) 
 
Efavirenz (EFV) 
 
Emtricitabine (FTC) 
 


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All of these ARVs are approved in the United States and Europe. [Sites to modify as needed: EFV, TDF, 
and FTC are approved in [site country]. DTG and TAF are not currently approved in [site country]].  
 
EFV, TDF, and FTC have been used widely throughout the world. DTG and TAF are newer ARVs that 
have not yet been used as widely. DTG and TAF are as safe and effective for controlling HIV as other 
ARVs. As a result, use of DTG and TAF is becoming more common. However, there is little information 
available as of now on use of DTG and TAF in pregnant women.  
 
This study will test combinations of DTG, TAF, and the other ARVs listed above in pregnant women. 
The study will look at the safety of the ARVs and whether they cause any bad effects for mothers and 
babies. The study will also look at how well the ARVs control the amount of HIV in mothers’ blood.  
 
More information about the study and the ARVs is given in the rest of this form. The combinations of 
ARVs that will be tested are given in #8 (see below).  
 
2. Only mothers and babies who qualify can participate in the study. 
 
If you decide to join the study with your baby, we will first do some tests to find out if you qualify. More 
information about the tests is given in #4 (see below). If you qualify, you and your baby will be entered in 
the study. If you do not qualify, you and your baby cannot be entered in the study.  
 
3. It is your decision whether or not to join the study. 
 
Deciding to join the study with your baby is voluntary (your choice). You are free to join or not join. If 
you join, you can change your mind and leave the study. Your decisions will have no effect on the 
medical care that you and your baby would normally receive. Your access to services, and the benefits 
and rights you normally have, will not be affected. 
 
Take your time and consider your decision carefully. If you wish, you can talk to other people about the 
study. You can also bring other people here to learn about the study with you. 
 
No matter what you decide about the study, it is important for you to take ARVs. Taking ARVs is the best 
known way to maintain your health and avoid passing HIV to your baby.  
 
 
Finding Out if You and Your Baby Qualify 
 
4. We will ask questions, examine you, and discuss the study requirements with you. 
 
To find out if you and your baby qualify for the study, we will: 
 
 
Review your medical records. 
 
Ask about your health and the medicines you take. 
 
Ask about ARVs you have taken in the past. 
 
Talk with you about the study requirements and if you are able to meet the requirements. 
 
Give you a physical examination. This will include an obstetric exam [here and below, sites may use 
locally appropriate terminology to refer to this exam] that will check on how long you have been 
pregnant and whether you may be pregnant with more than one baby.  


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 
Draw your blood (up to 20 mL or about 4 teaspoons) for tests. The tests will:  
– 
Check your blood cells.  
– 
Check how well your liver and kidneys are working.  
– 
Confirm that you have HIV. There are certain HIV tests that are required for this study. If the 
required tests are not in your medical records, we will do the tests that are needed. 
Some blood will not be tested right away. It will be saved for later testing for resistance to ARVs. 
This test shows whether different ARVs may work against the HIV in your blood. 
 
We may also do a test to confirm that you are pregnant. If there is no pregnancy test in your medical 
records, we will use some of your blood or collect urine for a pregnancy test.  
 
These procedures will take about 2 hours [here and throughout this form, sites may modify the expected 
visit duration as needed].  
 
5. We will do an ultrasound scan. 
 
The study requires an ultrasound scan of your baby [sites may use locally appropriate terminology to 
refer to the scan]. The scan uses sound waves to check the size of your baby, which shows how long you 
have been pregnant. Ultrasound scans are commonly done among pregnant women. If you have already 
had this type of scan done (outside the study), we may be able to use that scan for the study. If not, we 
will do the scan as part of the study. 
 
To do the scan, gel is placed on your belly. Then a small device is moved back and forth on your belly to 
send and receive sound waves. The scan will show a picture of your baby. Depending on how long you 
have been pregnant, you might be able to see the baby’s hands, arms, or legs. However, you should not 
worry if you cannot see the baby in the picture. The person who does the scan will explain what can be 
seen in the picture. 
 
[Sites to modify first three sentences as needed:] The scan will be done at [insert clinic name and/or 
location]. It will take less than 30 minutes. We will arrange for you to have the scan at a scheduled time. 
The scan should ideally be done before entering the study. If this is not possible, we will arrange for you 
to have the scan within 2 weeks after entering the study. There is no cost to you for transport or having 
the scan done.  
 
6. We will tell you if you and your baby qualify. 
 
We will give you the results of all procedures and explain the results to you. While waiting for the results, 
it is important for you to keep taking any ARVs that you been given (outside of the study). 
 
If you or your baby have any medical problems, or you do not qualify for the study for any reason, we 
will tell you this. You will not be entered in the study. 
 
If you and your baby do qualify for the study, and you agree to join, you will be entered in the study.  
 
If you do not qualify for the study, or you decide not to join, we will tell you where you can go for ARVs 
and other care you and your baby may need. [Sites may insert locally appropriate information as 
needed:] There are programs available for pregnant women with HIV and their babies. You have the 
option to receive services from these programs as an alternative to being in this study. If you do not join 
the study, the blood drawn at your first visit will not be kept for later testing (it will be destroyed).  
 
 
 


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Entering the Study 
 
7. If you and your baby qualify, you will enter the study within 2 weeks of your first visit. 
 
On the day you enter the study, we will: 
 
 
Ask about your health, ARVs, and other medicines. 
 
Give you a physical examination, including an obstetric exam. 
 
Draw your blood (22 mL or about 4-5 teaspoons) for tests. These tests will check: 
– 
If you have hepatitis B. Hepatitis B is a disease of the liver. 
– 
The amount of HIV in your blood. This is called your HIV viral load. Your HIV viral load should 
decrease over time as you take ARVs. 
– 
Your CD4 cells. These cells help your body fight infections. HIV attacks CD4 cells. The number 
of CD4 cells should increase over time as you take ARVs. 
Some blood will be saved for later testing. The later tests will look at factors in the blood that may 
predict pregnancy outcomes. For example, the tests may look for factors that predict why some 
women deliver their babies too early. 
 
Collect urine (15 mL or about 3 teaspoons) to save for later testing. The later testing will check on 
your kidneys.  
 
If you have not already had an ultrasound scan of your baby, we will arrange for you to have the scan 
within 2 weeks after entering the study (see #5 above).  
 
At this visit, you will be told which combination of ARVs you will take during the study. We will give 
you the ARVs and show you how to take them. You will need to take either 1 or 2 tablets once a day 
every day. It is very important that you take the ARVs as instructed. We will take as much time as needed 
for you to understand the instructions and come up with plans to help you take the ARVs as instructed. 
 
These procedures will take about 4 hours.  
 
 
Being in the Study 
 
8. Mothers and babies will be placed in different groups that receive different ARVs. 
 
Mothers and babies will be placed in 1 of 3 groups. The ARVs given to mothers in the study will depend 
on the group they are in. The combinations are shown below using abbreviations for the ARV names (see 
#1 for full names). Some of the ARVs in the groups are the same, some are different. 
 
EFV 
+
TDF 
+
FTC 
The ARVs in this group are most commonly 
given to pregnant women worldwide. 
DTG 
+
TDF 
+
FTC 
The ARVs in this group differ from the first 
group because DTG is given instead of EFV. 
DTG 
+
TAF 
+
FTC 
The ARVs in this group differ from the first 
group because DTG is given instead of EFV  
and TAF is given instead of TDF. 


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To test each combination of ARVs, the mothers and babies in each group will be compared to the mothers 
and babies in the other groups.  
 
Each mother and baby is placed in a group at random, [like flipping a coin; sites may insert a different 
example if preferred]. Each mother and baby has a 1-in-3 or 33% chance of being placed in each group. 
We have no say in which group each mother and baby are placed. Mothers also cannot choose. Mothers 
must be willing to take the combination of ARVs assigned to their group. Mothers who are not willing to 
take the assigned combination of ARVs should not join the study. 
 
9. Mothers will have visits every 4 weeks while pregnant. 
 
The number of visits during pregnancy will depend on when each mother enters the study and when her 
baby is born. Most mothers will have about 5 visits while pregnant. Some may have 1-2 visits; others may 
have up to 7 visits.  
 
Each visit will take about 1-2 hours. At these visits we will:  
 
 
Review your medical records. 
 
Ask about your health, ARVs, and other medicines. 
 
Give you a physical examination, including an obstetric exam. 
 
Draw your blood (up to 16 mL or about 3 teaspoons) for tests. At different visits, the tests will check:  
– 
How well your liver and kidneys are working. 
– 
Your HIV viral load.  
Some blood will be saved for later tests of factors that may predict pregnancy outcomes.  
 
Give you supplies of ARVs as needed. 
 
10. Mothers and babies will have a visit soon after delivery. Then they will have 5 more visits over 1 year.  
 
We will stay in contact with you as you get close to your delivery date. We will ask you to contact us 
when your labor begins. We will arrange for your first mother-baby visit as soon as possible after 
delivery. It is important for this visit to take place close to the baby’s birth. At the latest, the visit must be 
within 14 days of the baby’s birth. This visit will take up to 4 hours. 
 
After your first mother-baby visit, you and your baby will have a visit when your baby is about 6 weeks 
of age. After that, visits will be scheduled when your baby is about 3, 6, 9, and 12 months of age. Each 
visit will take about 2 hours.  
 
Different procedures will be done at these visits for mothers and babies. Some procedures will be done for 
both mothers and babies. Other procedures will be done only for mothers or only for babies. 
 
For mothers and babies, at these visits we will: 
 
 
Review your and your baby’s medical records. 
 
Ask about your and your baby’s health, ARVs, and other medicines. 
 
Ask about how you are feeding your baby. 
 
Give you and your baby a physical examination. If any abnormalities are seen when your baby is 
examined, we may take a photo of the abnormality. The photo will help the doctors working on the 
study look at the abnormality and decide if it is important for your baby’s health. We will tell you the 
doctors’ opinion within about 3 months. [Here and in #24, sites may modify text regarding 
photographs if IRBs/ECs mandate a separate form for obtaining informed consent for photographs.] 


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 
Collect hair from you and your baby (only at the first mother-baby visit). We will cut about 100 
strands of hair from the back of your and your baby’s head to be saved for later testing. The later 
testing will look at the amount of ARVs that can be found in the hair. 
 
[To be included at DXA sites only:] Mothers and babies will also have DXA scans of their bones. DXA 
stands for a kind of x-ray called dual energy x-ray absorptiometry. DXA scans check how hard and strong 
the bones are. When having the scan, mothers lie on a table while a machine passes over their body. 
Babies are held on a table while the machine passes over their body. The machine does not touch the body 
and the scan does not hurt. The scan may take up to 15 minutes. Babies scans will be done at 6 months of 
age. Mothers scans will be done when their babies are about 12 months of age. Mothers must have a 
pregnancy test to confirm they are not pregnant before having the scan. The results of the scans will not 
be available while the study is ongoing. We will tell you how to contact us if you would like to receive 
your and your baby’s results after the study is done. 
 
For mothers, we also will: 
 
 
Draw blood for tests. The amount of blood drawn will range from 6 to 30 mL (about 1-6 teaspoons) at 
different visits. At different visits, the tests will check:  
– 
Your blood cells.  
– 
How well your liver and kidneys are working. 
– 
Your HIV viral load.  
– 
Your CD4 cells. 
Some blood will be saved for later testing. These later tests may look at your HIV viral load and 
factors that may predict pregnancy outcomes. The tests may also look for a virus called Zika. Zika 
may cause problems during pregnancy and birth defects in babies.  
 
Collect breast milk. If you are breastfeeding when your baby is 6 weeks of age, you will express 20 
mL (about 5 teaspoons) of milk for later testing. The later tests will look at the amount of ARVs that 
can be found in the milk.  
 
Collect urine (15 mL or about 3 teaspoons) to be saved for later testing. This will be done when your 
baby is 12 months of age. The later testing will check on your kidneys. 
 
Give you supplies of ARVs as needed.  
 
For babies, we also will: 
[Sites may modify the text in this section consistent with current guidelines for infant feeding. In 
particular, sites at which breastfeeding is not recommended may modify the wording related to 
breastfeeding consistent with local, regional, and/or national standards.] 
 
Draw blood (up to 6 mL or about 1 teaspoon) for tests. The tests done at each visit will depend on 
whether the baby is breastfeeding.  
– 
All babies will have an HIV test at the first mother-baby visit and at 6 weeks, 3 months, and 12 
months of age. Babies who are breastfeeding will also have HIV tests at 6 and 9 months of age.  
– 
At the first mother-baby visit, all babies will have tests of their blood cells, liver, and kidneys. For 
babies who are breastfeeding, these tests will also be done at 6 months of age.  
Some blood will be saved for later testing. The later tests will look at the amount of ARVs in the 
blood. The tests may also look for Zika virus. 
 
If any test done for the study shows that your baby has HIV, we will ask you to bring your baby to the 
clinic as soon as possible for another test. We will collect about 3 mL (less than 1 teaspoon) of blood for 
HIV testing and for later testing for resistance. Whether your baby has HIV or not, you and your baby 
will stay in the study as originally planned. The study cannot provide care and treatment for babies who 
have HIV, but we will tell you where you can go for the care and treatment your baby may need. 


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11. We will ask questions about how you have been sleeping and feeling. 
 
At some visits, we will ask questions about how well you have been sleeping and how you have been 
feeling (for example, if you have felt happy or sad or scared). Sometimes mothers feel abnormally sad 
after having their babies. This is called postpartum depression. If the questions show that you have been 
sadder than normal, we will talk with you about this. We will also talk with you about problems with 
sleep or feeling anxious. If you have these types of feelings or problems, we will tell you about other 
services outside the study that might help you.  
 
12. Mothers will have extra visits if their ARVs are changed or if their HIV is not controlled.  
 
Mothers may have their ARVs changed at any time in the study. If DTG or EFV is changed to another 
ARV, mothers will have an extra visit about 4 weeks after the change. More information about why 
ARVs may be changed is given in #16 (see below). 
 
Mothers will have viral load tests at most visits. After being in the study for about 6 months, a mother’s 
viral load should be very low. If tests show that the viral load is higher than expected, mothers will have 
an extra visit.  
 
These extra visits will take about 1 hour. At these visits we will: 
 
 
Review your medical records. 
 
Ask about your health, ARVs, and other medicines. 
 
Give you a physical examination. 
 
Draw your blood (up to 12 mL or about 2-3 teaspoons) for tests. The tests will check your HIV viral 
load. If you changed ARVs, the tests will also check how well your liver and kidneys are working. If 
your HIV is not controlled, the tests will check for resistance. Some blood will be saved for later 
testing.  
 
Give you additional supplies of ARVs as needed. 
 
13. Mothers and babies may have extra visits if they are sick. 
 
Mothers and babies may have extra visits if they are sick or need more tests to check on their health. 
Additional blood or urine may be collected at these visits if needed. Please contact us if you or your baby 
become sick. 
 
14. Mothers who become pregnant again may have extra procedures. 
 
Mothers could become pregnant again while in the study. We will talk with you about family planning. If 
you wish to become pregnant again, or think you may be pregnant, please tell us right away. We will test 
your blood or urine to find out if you are pregnant.  
 
If you become pregnant again, you and your older baby will stay in the study as originally planned (until 
your older baby is about 12 months of age). If you are pregnant at your last study visit, we will contact 
you after that to find out the outcome of your pregnancy. 
 


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The study cannot provide medical care related to a new pregnancy or delivery of a new baby. If you have 
another baby, that baby will not be in the study. Therefore, it is important to receive medical care for a 
new pregnancy outside the study. We will tell you where you can go for the care you need. [Sites may 
modify or add to the preceding sentence to provide site-specific details on provision and/or referral for 
care.]  
 
We will talk with you about your choices for taking ARVs during a new pregnancy. We will ask you to 
sign a separate consent form to record your choices.  
 
15. Tests will be done at different laboratories. 
 
We will do most tests of your and your baby’s blood at our laboratory. We will give you the results of 
these tests at the next scheduled visit, or sooner if necessary. We will explain the results to you. If the 
results show that you or your baby may need medical care or treatment that cannot be provided by the 
study, we will tell you where you can go for this care. 
 
Other tests will be done at laboratories in the United States and other countries. This includes: 
 
 
Some tests of your HIV viral load 
 
Some tests of your kidney 
 
Tests for resistance to ARVs 
 
Tests for factors that may predict pregnancy outcomes 
 
Tests of the amount of ARVs that can be found in blood, breast milk, and hair 
 
Tests for Zika virus 
 
The results of most of these tests will not be available while the study is ongoing. If any of the results 
may be important for your or your baby’s health, we will tell you about them. Otherwise, the results will 
not be given to you.  
 
16. We may change or stop your ARVs. 
 
At all of your visits, we will check whether the ARVs you are taking may be causing bad effects. If so, 
the ARVs may be changed or stopped. The ARVs may be changed if you have certain illnesses or need to 
take other medicines that cannot be taken with ARVs. We will always discuss ARV changes with you. 
Please tell us about any problems you may have with taking your ARVs.  
 
We may stop all the ARVs you are receiving from the study if: 
 
 
You are not able to come to study visits. 
 
You are not able to take the ARVs. 
 
Taking the ARVs may be harmful to you. 
 
You ask to stop taking the ARVs.  
 
If we stop all your ARVs, we will talk with you about options for receiving ARVs from outside the study. 
You and your baby will stay in the study as originally planned. 
 


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17. We may take you and your baby off the study early. 
 
Each mother and baby is expected to stay in the study until the baby is about 12 months old. However, we 
may take you and your baby off the study if: 
 
 
The study is stopped for any reason. 
 
We determine that you and your baby cannot meet the study requirements (for example, if you move 
away and cannot come to the clinic). 
 
We determine that staying in the study might harm you or your baby. 
 
18. Please tell us if you want to leave the study. 
 
You and your baby are free to leave the study at any time for any reason. The care that you and your baby 
would normally receive will not be affected, but it is important that we know your decision. We will ask 
you and your baby to come to the clinic for one last visit. At this visit, we will do the same types of 
procedures listed in #10 (see above). We will answer any questions you may have and tell you how to 
contact us in the future, if you wish. 
 
19. We will contact you after your last visit.  
 
After your last study visit, the study cannot keep giving you ARVs. We will talk with you about this and 
help make sure you can get ARVs from outside the study after your last visit. We will also contact you 
within the month after your last visit to confirm that you are getting ARVs from outside the study. 
 
 
Risks of the Study 
 
20. There is little risk from the study procedures. 
 
Most procedures done in this study are routine medical procedures, with little risk to you and your baby. 
Drawing blood can cause pain, swelling, bruising, or bleeding where the needle is inserted. Rarely, 
drawing blood can cause fainting or infection. You or your baby could be cut when hair is collected with 
scissors. Expressing breast milk could be uncomfortable. There is no risk from ultrasound. 
 
Your baby will be tested for HIV while in this study. You may become worried or anxious about your 
baby’s test results. We will explain all tests to you and provide counseling to help with feelings you may 
have about the tests and your baby’s results.  
 
[To be included at DXA sites only:] For mothers and babies who have DXA scans, there is a small risk 
from x-rays, also known as radiation. Radiation is energy in the form of waves. All people are exposed to 
a low level of natural radiation from the sun. This is called background radiation. High levels of radiation 
can cause cancer. However, the level of radiation from a DXA scan is much lower than the level that 
causes cancer. The level from DXA scans for this study is also about the same as the background 
radiation every person normally has over 5 days. The study staff have been trained to do DXA scans 
using the smallest amount of radiation possible.  
 
21. There are risks from ARVs.  
 
All ARVs can cause side effects. This includes any ARVs that you would receive outside the study. Some 
side effects are minor; others can be severe. Some side effects are common, others are rare. Some people 
who take ARVs have some of the side effects. Other people have no side effects.  


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Some of the most common and most serious side effects of ARVs are listed below. Until you join the 
study, we will not know what specific ARVs you will take. Therefore, this form gives information about 
all the ARVs that may be given in the study (see #1 and #8 above).  
 
This form does not list all possible side effects for all ARVs. If you join the study, we will tell you more 
specific information about the ARVs that you will be taking. At each study visit, we will check on 
whether the ARVs you are taking may be causing side effects. If you have questions or concerns about 
side effects at any time, please tell us.  
 
22. Some side effects can be severe.  
 
First, you should know about the possible severe side effects of ARVs. These effects are rare, but they 
can cause serious health problems and can result in death. Please contact us if you have any of these 
symptoms or if you feel sick at any time.  
 
 
Severe rash. This can be caused by EFV and DTG. Please contact us or go to the nearest hospital 
immediately if you have a rash and any of the following symptoms:  
– 
Fever  
– 
Feel very ill or without energy 
– 
Muscle or joint aches  
– 
Blisters or sores in mouth  
– 
Blisters or peeling of the skin  
– 
Redness or swelling of the eyes  
– 
Swelling of the mouth or face  
– 
Problems breathing  
 
 
Liver problems. The liver is an organ near the stomach. If you get liver problems, you might have 
yellowing of the skin or whites of the eyes; dark or tea-colored urine; pale colored stools; upset 
stomach or vomiting; loss of appetite; pain, aching or tenderness of the right side below the ribs; or 
itchy skin. This can be caused by EFV and DTG. The risk of these problems may be higher during 
pregnancy and the 3 months after giving birth while taking EFV. 
 
 
Pancreas problems. The pancreas is an organ near the stomach. If your pancreas becomes inflamed, 
you may have stomach pain, upset stomach or vomiting, or more fats in the blood. This can be caused 
by EFV. 
 
 
Kidney problems. The kidneys are organs near the middle of your back (one on each side). Doctors 
usually find out about kidney problems from tests of the blood. This can be caused by TDF, TAF, and 
DTG.  
 
 
Severe depression, including thoughts or acts of hurting or killing oneself. People with a history of 
psychiatric problems may be at greater risk for these serious psychiatric problems. This can be caused 
by EFV and DTG. Please contact us or go to the nearest hospital immediately if you have any 
thoughts of hurting yourself. 
 
 
Other severe mental problems, including aggressive behavior or psychosis-like symptoms, such as 
abnormal thinking, paranoia, and delusions. This can be caused by EFV. 
 


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23. Other side effects are more common.  
 
You should also know about the more common side effects of ARVs, which are not usually severe. These 
are listed below. 
 
Overall Body Effects
 
Changes in the placement of body fat 
(increasing around the stomach, neck, or 
breast or decreasing in the arms, legs, or 
cheeks) 
 
Overall weakness or tiredness 
 
Allergic reaction 
 
Numbing, tingling, or pain in the hands and 
feet 
 
Fever 
Effects on Your Blood
 
More fats in the blood that may increase the 
risk of heart problems 
 
More acid in the blood that may be related to 
liver problems  
 
Other changes in blood tests that may show 
problems with the muscles, liver, kidneys, or 
pancreas. The blood tests may show how well 
these organs are working, or they may look 
for substances made by the organs, or they 
may look for fats in the blood.
Effects on Your Muscles and Bones
 Aches and pains 
 Loss of muscle 
 Bone thinning or softening (which could 
increase the chance of breaking a bone)  
Effects on Your Head
 
Headache 
 
Yellowing of the eyes 
 
Runny nose 
 
Swelling of the face, lips, or tongue
Effects on Your Skin
 Itching 
 Rash 
 Darkening of the palms and soles of feet 
Effects on Your Mind or Mental Function
 Drowsiness 
 Trouble sleeping 
 Abnormal dreams 
 Dizziness 
 Confusion 
 Difficulty concentrating 
 Hallucinations 
 Feeling of strangeness and losing touch with 
reality 
 Exaggerated feeling of well-being 
 Agitation or anxiety 
 Feeling of deep sadness or unworthiness 
(depression) 
Effects on Your Stomach
 
Pain or upset stomach 
 
Loose or watery stools 
 
Nausea 
 
Vomiting 
 
Gas
Effects on Your Chest
 
Cough 
 
Shortness of breath 
 
Changes seen in tests of heart rhythm 
 
24. There are other possible risks from ARVs. 
 
Possible effects on pregnancy, unborn babies, and breastfeeding babies 
 
Taking ARVs is the best known way for a mother who has HIV to maintain her health and avoid passing 
HIV to her baby during pregnancy and breastfeeding. However, HIV and ARVs may cause some 
pregnancy complications, like early delivery or low weight of the baby at birth. We do not know if some 
ARVs are more likely to cause these effects than others.  
 
[Sites to modify as needed to reflect local standards: The combination of ARVs with EFV is 
recommended (outside of the study) for women with HIV.] This combination with EFV also seems to be 
safe in pregnancy, especially when taken after the first 3 months of pregnancy. EFV may cause harm to 


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the baby when taken in the first 3 months of pregnancy. We do not yet know if DTG or TAF are safe in 
pregnancy. Some studies done in animals showed that the ARVs were safe in animals. 
 
In this study, ARVs are given after the first 3 months of pregnancy. The ARVs are continued through 
pregnancy and after delivery. After delivery, mothers who become pregnant again may be taking ARVs 
during the first 3 months of their new pregnancy. If you become pregnant again, we will talk with you 
about your choices for taking ARVs during your new pregnancy (see also #14 above). 
 
Babies who breastfeed may receive the ARVs taken by their mothers through breast milk. We do not 
know how much of the ARVs go into breast milk or what effects this may have on babies.  
 
We are doing this study to learn more about safety of the ARVs given in the study for pregnant women 
and their babies. We will also learn how much of the ARVs are passed to babies and what effects this 
may have.  
 
Immune reconstitution syndrome 
 
In some people with advanced HIV infection, signs and symptoms from other infections or certain 
diseases can occur soon after starting ARVs. Some of these symptoms may be life threatening. If you start 
having new symptoms, or if any existing symptoms get worse after starting ARVs, please tell us 
immediately. 
 
Hepatitis B 
 
Some ARVs are active against hepatitis B. For women who have hepatitis B, and take ARVs that are 
active against hepatitis B, stopping the ARVs could cause the hepatitis B to worsen. If this happens, most 
women get better quickly without treatment, but in rare cases this has resulted in death. 
 
Risk of resistance 
 
If ARVs are not taken as instructed, this can cause resistance. Resistance means that an ARV may no 
longer work against HIV. To avoid resistance, it is important to take ARVs instructed and avoid missing 
doses.  
 
25. There could be risks of disclosure of your or your baby’s information. 
 
We will make every effort to keep your and your baby’s information private and confidential. Study 
records and specimens will be kept in secure locations. All specimens and most records will be labeled 
only with a code number. However, your and your baby’s names will be written on some records.  
 
[Sites may modify this paragraph if IRBs/ECs mandate a separate form for obtaining informed consent 
for photographs.] 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.  
 


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Despite our best efforts to keep your and your baby’s information private, it is possible that the 
information could be obtained by someone who should not have it. If this were to happen, you or your 
baby could be treated badly or unfairly. You could feel stress or embarrassment.  
 
[To be included at US sites:] To help us protect your privacy, we have obtained a Certificate of 
Confidentiality that protects us from being forced to release information that may identify you or your 
baby, such as by the courts or police. The certificate cannot be used in all situations, but it can be used to 
resist demands for information that would identify you or your baby. The certificate does not protect 
against requests for information from the US federal government or from the US Food and Drug 
Administration. Regardless of the certificate, you can release information about your and your baby’s 
participation in the study to others, if you wish. 
 
 
Benefits of the Study 
 
26. There may be no benefit from being in the study. 
 
By joining the study, you and your baby will be part of the search for new treatments for pregnant women 
with HIV. However, being in the study may not benefit you or your baby in any way.  
 
You and your baby will have regular visits here and frequent checks on your health. It is possible that the 
procedures done may help you and your baby stay healthy. If these procedures show that you or your 
baby may need medical care that cannot be provided through the study, we will tell you where you can go 
for the care you or your baby may need.  
 
 
Other information about the study 
 
27. There are no costs to you for being in the study. 
 
There are no costs to you for study visits or procedures or the ARVs that are given by the study.  
 
[Insert information about compensation/reimbursement here, e.g., You will be reimbursed for the cost of 
transport to study visits. For each visit, you will be given (specify amount).] 
 
28. Study records may be reviewed by study staff and groups that oversee the study. 
 
Groups that oversee the study include: 
 
 
[insert name of site IRB/EC] 
 
[insert name of site drug regulatory authority] 
 
[insert name of other site regulatory entities] 
 
The United States National Institutes of Health and its study monitors 
 
The United States Food and Drug Administration 
 
The United States Office for Human Research Protections 
 
Other US, local, and international regulatory entities 
 
The IMPAACT Network that is coordinating the study 
 
The companies that make the ARVs given in the study: Gilead Sciences, Mylan, and  
ViiV Healthcare Ltd 
 


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The study staff and these groups are required to keep study records private and confidential. 
 
The results of the study may be presented publicly or published. However, no presentation or publication 
will use your name or your baby’s name or identify you or your baby personally.  
 
A description of this study will be available on ClinicalTrials.gov as required by United States law. This 
website will not include information that can identify you or your baby. At most, the website will include 
a summary of the results of the study. You can search this website at any time. 
 
Your and your baby’s study information may be disclosed to other authorities if required by law.  
 
29. If you or your baby gets sick or injured, contact us immediately. 
 
Your and your baby’s health is important to us. We will make every effort to protect your well-being and 
minimize risks. It is possible, however, that you or your baby could have an illness or injury that is study-
related. This means the illness or injury occurred as a direct result of being in the study.  
 
[Sites may modify this paragraph to reflect local institutional policies; information regarding coverage 
available through clinical trial insurance obtained by the site should be included if applicable; the 
statement regarding no program for compensation through the NIH may not be removed.] If a study-
related illness or injury occurs, we will treat you or your baby or tell you where you can get the treatment 
you or your baby need. The cost for this treatment may be charged to you or your health insurance. There 
is no program to pay money or give other forms of compensation for study-related illness or injury 
through [site name or] the United States National Institutes of Health.  
 
 
Who to Contact 
 
30. If you have questions, concerns, or problems at any time, use these contacts. 
 
 
If you have questions about the study:  
[insert name and telephone number of investigator or other study staff] 
 
 
If you have questions about your rights or your baby’s rights as research participants or concerns 
about how you or your baby are being treated in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate 
person/organization] 
 
 
If you or your baby have any health or other problems that may be related to study participation:  
[insert name and telephone number of investigator or other study staff] 
 
 
If you want to leave the study:  
[insert name and telephone number of investigator or other study staff] 
 
 


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Signatures 
 
If you decide to join this study with your baby, sign or make your mark below. 
 
Before deciding whether to join this study with your baby, make sure you have read this form, or had it 
read to you, and that all of your questions have been answered. You should feel that you understand the 
study, its risks and benefits, and what is expected of you and your baby if you decide to join.  
 
We will tell you any new information from this study or other studies that may affect your willingness for 
you and your baby to stay in the study. You can ask questions or request more information at any time.  
 
You do not give up any rights by signing this form. 
 
[Insert signature blocks as required by site IRB/EC policies.] 
 
 
 
 
 
 
 
 
 
Name of Mother (print)  
 
Signature of Mother 
  
Date 
 
 
 
 
 
 
 
 
Name of Study Staff Conducting 
Signature of Study Staff 
 
Date 
Consent Process Name (print) 
 
 
 
 
 
 
 
 
Name of Witness 
 
Signature of Witness  
 
Date 
(as appropriate; print) 
 
 
 
 


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Appendix IV 
Sample Informed Consent Form for Specimen Storage and Future Use 
 
IMPAACT 2010 
Phase III Study of the Virologic Efficacy and Safety of  
Dolutegravir-Containing versus Efavirenz-Containing Antiretroviral Therapy  
Regimens in HIV-1-Infected Pregnant Women and their Infants 
 
Version 2.0, [date] 
 
You have decided to join the study named above with your baby. As part of the study, you will have 
blood, urine, and hair collected. You may have breast milk collected if you breastfeed your baby. Your 
baby will have blood and hair collected. After these samples are tested for the study, some samples may 
be left over. We call these extra samples. The IMPAACT Network would like to keep these extra samples 
and use them for other research in the future. 
 
This form gives information about use of extra samples. Please read it, or have it read to you, and ask any 
questions you may have. After we discuss the information with you, you will record your decisions on use 
of extra samples at the end of the form.  
 
1. It is your decision whether or not to allow the extra samples to be used.  
 
You are free to say yes or no, and to change your mind at any time. Your decision will not affect your or 
your baby’s participation in the study. If you say no, all extra samples will be destroyed.  
 
2. If you agree, your and your baby’s extra samples will be kept in a repository.  
 
[Sites should insert one of the two options shown below. Choose/adapt the second option if local 
regulations do not permit storage of samples for future research use in the United States.] 
 
A repository is a secure facility that is used to store samples. The IMPAACT Network repository is in the 
United States. If you agree to have extra samples stored, the samples will be kept in this repository. There 
is no limit on how long the samples will be kept [sites may insert time limits or additional site-specific 
requirements here if required by local authorities]. 
 
A repository is a secure facility that is used to store samples. The IMPAACT Network has a repository in 
the United States. However, our local regulations require that extra samples be stored in our country. 
Therefore, we will keep the samples here at our laboratory. There is no limit on how long the samples will 
be kept [sites may insert time limits or additional site-specific requirements here if required by local 
authorities]. 
 
3. Extra samples could be used for different types of research.  
 
Extra samples may be used for research on HIV, pregnancy, the immune system, and other diseases. The 
research may be done in the United States or in other locations.  
 


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If you agree, the extra samples could also be used for research that looks at your or your baby’s genes. 
Genes are passed to children from their birth parents. They affect how people look and how their bodies 
work. Differences in people’s genes can help explain why some people get a disease while others do not. 
Your and your baby’s samples would only be used to look at genes related to HIV, how the body 
responds to ARVs, pregnancy, and the immune system. 
 
Any research done with the extra samples must be reviewed and approved by the IMPAACT Network. 
The research must also be approved by an ethics committee. The role of an ethics committee is to review 
the research plan and protect the rights and well-being of the people whose samples will be used.  
 
The research done with extra samples is not expected to give any information relevant to your or your 
baby’s health. Therefore, the results will not be given to the study staff or to you. The results also will not 
be placed in your or your baby’s study records. 
 
4. There is little risk to you or your baby.  
 
When extra samples are used for research, they are labeled with a code number only. To protect your and 
your baby’s privacy, no names are used. However, information such as age, gender, HIV status, and other 
health information may be linked to the samples. Information on the ARVs you received in the study may 
also be linked to the samples.  
 
There may be some risks from tests of your or your baby’s genes. If others found out the results of these 
tests, they could treat you or your baby badly or unfairly. However, this is almost impossible because the 
results will not be given to the study staff or to you, and will not be in your or your baby’s study records. 
 
5. There may be no benefit to you or your baby.  
 
By allowing your extra samples to be used for research, you and your baby will be part of the search for 
new information that may benefit people with HIV in the future. However, the research done with the 
extra samples is not expected to directly benefit you or your baby in any way.  
 
6. You will not be paid for use of your or your baby’s samples. 
 
There is no cost to you for use of your or your baby’s extra samples. The samples will not be sold, and 
you will not be paid for use of the samples. It is possible that research done with the samples could lead to 
a new discovery or a new product. If this happens, there is no plan to share any money with you or your 
baby.  
 
7. Information from research using extra samples may be reviewed by groups that oversee the research. 
 
These groups include:  
 
 
The IMPAACT Network  
 
The ethics committees that review and approve the research  
 
Government and other agencies that pay for the research  
 
Government and other agencies that monitor the research 
 
Other US, local, and international regulatory entities 
 
The people who do research with the extra samples and the groups listed above are required to make 
efforts to keep information private and confidential. 


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8 December 2017 
 
The results of research done with the extra samples may be presented publicly or published. However, no 
presentation or publication will use your or your baby’s name or identify you or your baby personally.  
 
8. If you have questions, concerns, or problems at any time, use these contacts. 
 
 
If you have questions about use of your or your baby’s extra samples:  
[insert name and telephone number of investigator or other study staff].  
 
 
If you later change your mind about use of your or your baby’s extra samples:  
[insert name and telephone number of investigator or other study staff].  
 
 
If you have questions about your or your baby’s rights as a research participant or concerns about 
how you are being treated in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate 
person/organization].  
 
 


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Signatures 
 
Before deciding whether to allow your and your baby’s extra samples to be used for research, make sure 
you have read this form, or had it read to you. Make sure all of your questions have been answered. You 
should feel that you understand your options and the possible risks and benefits before making your 
decision. 
 
You do not give up any rights by signing this form. 
 
[Insert initial and signature blocks as required by site IRB/EC policies and the IRB/EC determination if 
the level of risk to children in the categories specified in 45 CFR 46.404-407. Separate consent decisions 
must be documented for genetic testing]. 
 
For YOUR extra samples, write your initials or make your mark next to your choice. 
 
__________ 
I allow my extra samples to be used for research on HIV, pregnancy, the immune system, 
ARVs, and other diseases. I also allow my samples to be used for tests of my genes.  
 
__________ 
I allow my extra samples to be used for research on HIV, pregnancy, the immune system, 
ARVs and other diseases. I do not allow my samples to be used for tests of my genes.  
 
__________ 
I do not allow my extra samples to be used for any research.  
 
 
For YOUR BABY’s extra samples, write your initials or make your mark next to your choice. 
 
__________ 
I allow my baby’s extra samples to be used for research on HIV, pregnancy, the immune 
system, ARVs, and other diseases. I also allow my baby’s samples to be used for tests of 
his or her genes.  
 
__________ 
I allow my baby’s extra samples to be used for research on HIV, pregnancy, the immune 
system, ARVs, and other diseases. I do not allow my baby’s samples to be used for tests 
of his or her genes.  
 
__________ 
I do not allow my baby’s extra samples to be used for any research.  
 
 
 
 
 
 
 
 
 
 
Name of Mother (print)  
 
Signature of Mother 
  
Date 
 
 
 
 
 
 
 
 
Name of Study Staff Conducting 
Signature of Study Staff 
 
Date 
Consent Process Name (print) 
 
 
 
 
 
 
 
 
Name of Witness 
 
Signature of Witness  
 
Date 
(as appropriate; print) 
 


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Appendix V 
Sample Informed Consent Form for Use of Study Drug during Subsequent Pregnancy 
 
IMPAACT 2010 
Phase III Study of the Virologic Efficacy and Safety of  
Dolutegravir-Containing versus Efavirenz-Containing Antiretroviral Therapy  
Regimens in HIV-1-Infected Pregnant Women and their Infants 
 
Version 2.0, [date] 
 
You are taking anti-HIV medicines (ARVs) from the study named above. Because you are pregnant 
again, it is important for you to choose whether to keep taking ARVs from the study.  
 
This form gives information about taking ARVs while you are pregnant. Please read it, or have it read to 
you, and ask any questions you may have. After we discuss the information with you, you will record 
your decision on taking ARVs from the study at the end of the form.  
 
1. It is your decision whether to take ARVs from the study while you are pregnant.  
 
When you first joined the study, you were assigned to receive a combination of ARVs. You were given 
information about these ARVs, and you agreed to take these ARVs while pregnant. Now that you are 
pregnant again, you have a choice of whether to keep taking ARVs from the study.  
 
You are free to say yes or no, and to change your mind at any time. Your decision will not affect your or 
your baby’s participation in the study. No matter what you decide, you and your baby will still stay in the 
study as originally planned.  
 
2. We will discuss your choice of ARVs with you.  
 
We will talk with you about the ARV you are currently taking and how these compare to the ARVs that 
are usually given to pregnant women. If you are doing well on the ARVs you are currently taking, we 
may recommend that you keep taking the same ARVs during your new pregnancy. If we have any 
concerns, or if you have any concerns, we will discuss changing your ARVs. If you wish to consider 
changing your ARVs, we will tell you about the ARVs that are available from the study and the ARVs 
that are available outside the study.  
 
No matter what you decide, it is important that you take ARVs during your new pregnancy. Taking ARVs is 
the best known way to maintain your health and avoid passing HIV to your baby. 
 
3. The risks and benefits of taking ARVs from the study in your new pregnancy are the same as in your 
previous pregnancy.  
 
If you are past the first three months in your new pregnancy, there is no change in the possible risks and 
benefits of taking ARVs from the study now compared to when you first joined the study. If you are in 
the first three months, it is possible that the risks and benefits could be different. We do not yet know 
much about this at this time. 
 
We will review what is known about the risks and benefits with you. If any new information about the 
risks and benefits becomes available later, we will give you that information and again discuss your 
choice of ARVs. You can ask questions or request more information at any time.  


IMPAACT 2010, FINAL Version 2.0 
Page 162 of 163  
8 December 2017 
4. There is no cost to you for taking ARVs from the study.  
 
If you choose to keep taking ARVs from the study, you will receive the ARVs here at the study clinic free 
of charge.  
 
If you choose to take ARVs from outside the study, there may be costs to you [or your health insurance], 
depending on whether the ARVs are available free of charge outside the study. [Sites may modify the 
preceding sentence as needed to reflect the local context.] 
 
5. Your ARVs could be changed or stopped.  
 
No matter what you decide about taking ARVs from the study, you will keep having the same clinic 
visits, examinations, and tests to check on your health while you are in the study. If we find that the 
ARVs could be causing problems, we will make recommendations to change or stop the ARVs if needed. 
This is no different from what would be done in the study if you were not pregnant again.  
 
6. The study cannot provide medical care for your new pregnancy.  
 
The study cannot provide medical care related to your new pregnancy or delivery of a new baby. If you 
have another baby, that baby will not be in the study. Therefore, it is important for you to receive medical 
care related to your pregnancy outside the study. We will tell you where you can go for this care. [Sites 
may modify or add to the preceding sentence to provide site-specific details on provision and/or referral 
for care.] 
 
7. If you get sick or injured, contact us right away. 
 
Your and your baby’s health is important to us. We will make every effort to protect your well-being and 
minimize risks. It is possible, however, that you or your baby could have an illness or injury that is study-
related. This means the illness or injury occurred as a direct result of being in the study.  
 
[Sites may modify this paragraph to reflect local institutional policies; information regarding coverage 
available through clinical trial insurance obtained by the site should be included if applicable; the 
statement regarding no program for compensation through the NIH may not be removed.] If a study-
related illness or injury occurs, we will treat you or your baby or tell you where you can get the treatment 
you or your baby need. The cost for this treatment may be charged to you or your health insurance. There 
is no program to pay money or give other forms of compensation for study-related illness or injury 
through [site name or] the United States National Institutes of Health.  
 
8. If you have questions, concerns, or problems at any time, use these contacts. 
 
 
If you have questions about the study or your choice of ARVs:  
[insert name and telephone number of investigator or other study staff].  
 
 
If you have questions about your rights as a research participant or concerns about how you are being 
treated in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate 
person/organization].  
 


IMPAACT 2010, FINAL Version 2.0 
Page 163 of 163  
8 December 2017 
 
If you have any health or other problems that may be related to your study participation:  
[insert name and telephone number of investigator or other study staff].  
 
 
If you want to leave the study:  
[insert name and telephone number of investigator or other study staff]. 
 
 
Signatures 
 
Before deciding whether to take ARVs from the study during your new pregnancy, make sure you have 
read this form, or had it read to you. Make sure all of your questions have been answered. You should feel 
that you understand your options and the possible risks and benefits before making your decision. 
 
You do not give up any rights by signing this form. 
 
[Insert initial and signature blocks as required by site IRB/EC policies.] 
 
Write your initials or make your mark next to your choice. Then sign or make your mark below. 
 
 
__________ 
I choose to take ARVs from the study during my new pregnancy.  
 
 
__________ 
I choose to not take ARVs from the study during my new pregnancy.  
 
 
 
 
 
 
 
 
 
 
Name of Mother (print)  
 
Signature of Mother 
  
Date 
 
 
 
 
 
 
 
 
Name of Study Staff Conducting 
Signature of Study Staff 
 
Date 
Consent Process Name (print) 
 
 
 
 
 
 
 
 
Name of Witness 
 
Signature of Witness  
 
Date 
(as appropriate; print) 
 
 

SAP_004.pdf: 
 
 
IMPAACT 2010 
 
Phase III Study of the Virologic Efficacy and Safety of 
Dolutegravir-Containing versus Efavirenz-Containing Antiretroviral Therapy 
Regimens in HIV-1-Infected Pregnant Women and their Infants 
 
“VESTED” 
Virologic Efficacy and Safety of ART Combinations with TAF/TDF, EFV, and 
DTG 
 
 
DAIDS Study ID #30129 
IND # 133,438 Held by DAIDS 
ClinicalTrials.gov ID: NCT03048422 
 
 
Statistical Analysis Plan 
 
Version 5.0 
 
October 26, 2020 
 
 
 
 
 
Statistical Data Analysis Center 
Harvard T.H. Chan School of Public Health 
 
 
 
 
This is the IMPAACT 2010 SAP Version 5.0 with names of authors, names of publication writing team 
members, and analysis timeline redacted. 
 
 
 
 
 
 
 
 
 
 
 


 
 
IMPAACT 2010 Primary Statistical Analysis Plan version 5.0 
October 26, 2020 
Page 2 of 24 
 
 
Table of Contents 
 
Table of Contents ...................................................................................................................................... 2 
1. 
Introduction ...................................................................................................................................... 3 
2. 
Core Manuscript Writing Team ........................................................................................................ 3 
3. 
Study Overview ................................................................................................................................. 3 
3.1 
Study Design .............................................................................................................................. 3 
3.2 
Hypotheses ................................................................................................................................ 5 
3.3 
Study Objectives and Outcome Measures ................................................................................. 5 
3.3.1 Primary Objectives and Outcome Measures............................................................................ 5 
3.3.2 Secondary Objectives and Outcome Measures ....................................................................... 6 
3.4 Visit and Evaluation Schedule .......................................................................................................... 9 
4. 
Monitoring and Re-Evaluation of Sample Size ................................................................................ 10 
4.1 
DSMB ....................................................................................................................................... 10 
4.2 
Re-Evaluation of Sample Size ................................................................................................... 10 
5. 
Analyses .......................................................................................................................................... 12 
6. 
Primary Outcome Measures ........................................................................................................... 13 
7. 
Secondary Outcome Measures ....................................................................................................... 16 
8. 
Other Outcome Measures .............................................................................................................. 19 
9. 
Summaries to Investigate the Impact of SARS-COV-2 ................................................................... 20 
10. Outline of Report Contents ............................................................................................................ 20 
11. Protocol History .............................................................................................................................. 21 
12. Appendix ............................................................................................................................................ 24 
SAP Version History ............................................................................................................................. 24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
IMPAACT 2010 Primary Statistical Analysis Plan version 5.0 
October 26, 2020 
Page 3 of 24 
 
1. Introduction 
 
This document describes the proposed content for the primary statistical analysis of IMPAACT 2010, 
focusing on analyses that address the major randomized comparisons for key safety, tolerability and 
efficacy outcome measures. This includes the key analyses that will form the core of any 
presentation or publication used to disseminate the primary conclusions of the study. It is 
recognized that this statistical analysis plan (SAP) may be modified by the Study Team as new 
information becomes available or to reflect recommendations made by the DSMB. 
 
The primary outcomes can be measured at two different study times: at pregnancy outcome and 
through visit week 50 postpartum. In order for the study results to have maximum impact, the 
study data results will be released once all women have had a pregnancy outcome instead of 
waiting until all participants complete follow-up through visit week 50. The final primary analysis 
results will be described in two separate reports after all pregnancy outcomes and after all follow- 
up is completed; analyses for both timepoints will be described throughout this document. 
 
Major changes to the previous SAP are noted in bold throughout the document. 
 
 
2. Core Manuscript Writing Team 
 
Core writing team names were redacted from this version of the SAP.  
 
3. Study Overview 
3.1 Study Design 
 
IMPAACT 2010 is a Phase III, three-arm, randomized, open-label study to compare the virologic 
efficacy and safety of three antiretroviral regimens — 1) dolutegravir(DTG)+ emtricitabine(FTC)/ 
tenofovir alafenamide(TAF)(DTG+FTC/TAF), 2) dolutegravir(DTG)+ emtricitabine(FTC)/tenofovir 
disoproxil fumarate (TDF)(DTG+FTC/TDF), and 3) efavirenz (EFV)/emtricitabine(FTC)/tenofovir 
disoproxil fumarate (TDF) (EFV/FTC/TDF) — for HIV-1-infected pregnant women and their infants. 
Mother-infant pairs will be randomized at 14-28 weeks gestation in a 1:1:1 ratio to receive either 
DTG+FTC/TAF (Arm 1), DTG+FTC/TDF (Arm 2), or EFV/FTC/TDF (Arm 3). The primary objectives are 


 
 
IMPAACT 2010 Primary Statistical Analysis Plan version 5.0 
October 26, 2020 
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to compare the DTG-containing arms (Arms 1 and 2) to the EFV-containing arm (Arm 3) with respect 
to maternal viral suppression at delivery; to compute all pairwise regimen comparisons for a 
composite adverse pregnancy outcome (spontaneous abortion, fetal death, preterm delivery, or 
small for gestational age); and to compute all pairwise regimen comparisons for maternal and infant 
grade 3 or higher adverse events through 50 weeks postpartum. All mothers and infants are  
planned to be followed through 50 weeks postpartum. The total sample size is 639 mother-infant 
pairs (approximately 213 per arm) and accrual is expected to be completed within 12 months after 
the first pair is enrolled. The total study duration will be approximately 31 months. The sample size 
will be re-evaluated with the possibility of adjustment prior to the closure of participant accrual. 
Mother-infant pairs will be stratified at randomization by gestational age (14-18 weeks, 19-23 
weeks, 24-28 weeks) and by country. 
 
The primary virologic efficacy analysis will combine the two DTG-containing randomized arms for 
comparison to EFV/FTC/TDF. The DTG-containing arms will be combined because viral load at 
delivery is not expected to vary between these arms. This combined analysis also weighs feasibility 
against the need to provide information on the possibility of effect modification of DTG in the 
presence of TDF or TAF. Powering the study for all three pairwise comparisons would be ideal 
scientifically; however, this would require an infeasible sample size. 
 
Viral suppression at delivery was chosen as the primary efficacy endpoint because of the importance 
of maintaining high viral suppression to minimize perinatal HIV transmission. A conclusion for 
superiority in viral suppression of a DTG-containing regimen relative to EFV/FTC/TDF might hasten 
the adoption of a DTG-containing regimen for use during pregnancy and postpartum. However, a 
conclusion of non-inferiority might allow for an increase in the options available to pregnant and 
postpartum women. Because of these two important possible conclusions at the end of the study, 
the primary analysis will be an analysis of non-inferiority while a superiority comparison is specified 
as an important secondary analysis. Testing both superiority and non-inferiority does not constitute 
multiple testing; however, non-inferiority must be established before a conclusion of superiority can 
be made. 
 
A conclusion of non-inferiority will be predicated on the following considerations: 
• 
The 95% confidence interval for the difference excludes the non-inferiority margin. 
• 
There is a high degree of consistency with the protocol plans. For example, the levels of 
protocol deviations and loss to follow-up will need to be similar to those in previous studies 
in which superiority has been shown (e.g., PROMISE, PROMOTE). 
• 
The EFV-containing arm shows its usual efficacy. 
• 
The ITT and the per-protocol analyses show similar results. 
 
All three pairwise regimen comparisons will be conducted for the adverse pregnancy and maternal 
adverse event primary objectives. The DTG-containing arms (Arm 1 and Arm 2) will not be 
combined for these primary analyses because little is known about safety in pregnancy through 1 
year postpartum between these two arms. 
 
An open-label study design was selected because the number of pills per day and instructions for 
administration vary between treatment arms. Potential sources of bias with an open-label study 
include increased attribution and reporting of specific toxicities in a treatment arm. Site 
investigators may be more likely to change antiretroviral therapy if a treatment arm is perceived as 
suboptimal. Efforts to minimize these biases are determined in the study protocol by establishing 


 
 
IMPAACT 2010 Primary Statistical Analysis Plan version 5.0 
October 26, 2020 
Page 5 of 23 
 
standard criteria and guidelines for toxicity and ARV regimen management, safety-related data 
recording and reporting, and inadequate virologic response. 
 
Missing data will be handled using three strategies: complete case analysis, multiple imputation, and 
sensitivity analyses. The complete case analysis will remove records with missing data. Since the 
amount of missing data is expected to be low in IMPAACT 2010, the complete case analysis will be 
the principal analysis. Multiple imputation and sensitivity analyses will be used to measure the 
robustness of the study findings. Congruence, as measured by the differences in the estimated point 
estimates and 95% CIs, between the complete case analyses and the missing data methods will be 
used to measure robustness of the analysis to the incomplete records. Multiple imputation and 
sensitivity analyses will be used for all of the four primary analyses. Multiple imputation and 
sensitivity analyses will be used for the secondary analyses if the percentage of missing data is 
unacceptably high (e.g. >10%). The details on which missing data methods will be used for each 
outcome is described in the analysis sections below. 
 
 
3.2 Hypotheses 
 
Among HIV-1-infected pregnant women initiating ART between 14 and 28 weeks gestation, and 
their infants: 
• 
A DTG-containing regimen will be non-inferior to EFV/FTC/TDF with regard to virologic 
efficacy at delivery 
• 
Rates of adverse pregnancy outcomes will not significantly differ between the three study 
ART regimens 
• 
Rates of maternal and infant grade 3 or higher adverse events will not significantly differ 
between the three study ART regimens 
 
 
3.3 Study Objectives and Outcome Measures 
3.3.1 Primary Objectives and Outcome Measures 
 
The primary and secondary objectives are per protocol version 2.0, LOA #3. Outcome measures 
presented in the final postpartum analysis report will be summarized as defined in protocol version 
2.0, LOA #3. Primary outcome measures that will be presented in the final primary pregnancy 
outcome analysis report are identified below with the following superscripts based on definition of 
delivery: 
†Includes data up to 14 days postpartum (post-birth) in primary pregnancy analysis report 
‡Includes data through 28 days postpartum (post-birth) in primary pregnancy analysis report 
††Includes data reported on study through 50 weeks postpartum (post-birth) as of data freeze 
date in primary pregnancy analysis report 
‡‡Includes measurements up to but not including post-delivery. 


 
 
IMPAACT 2010 Primary Statistical Analysis Plan version 5.0 
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Primary Objectives and Outcome Measures 
• 
Whether treatment initiated during pregnancy with a DTG-containing regimen is non- 
inferior to EFV/FTC/TDF with regard to virologic efficacy (HIV-1 RNA <200 copies/mL) at 
delivery 
Outcome Measure: HIV-1 RNA <200 copies/mL at delivery (up to 14 days postpartum), using 
real-time test results obtained at site laboratories† 
 
• 
Whether rates of the following safety outcomes differ for any pairwise regimen comparison: 
 
o Adverse pregnancy outcomes (spontaneous abortion, fetal death, preterm delivery, 
or small for gestational age) 
Outcome Measure: Composite outcome of spontaneous abortion (occurring at <20 
weeks gestation), fetal death (occurring at ≥20 weeks gestation), preterm delivery1 
(<37 completed weeks), or small for gestational age2 (<10th percentile)† 
 
o Maternal grade 3 or higher adverse events through 50 weeks postpartum 
Outcome Measure: Maternal grade 3 or higher adverse events, including events 
resulting in death due to any cause, through 50 weeks postpartum (refer to 
Protocol Section 7.3.3 for severity grading; for this outcome measure, grade 3 or 
higher creatinine levels and creatinine clearance rates will be defined based on 
absolute values (>1.8 x ULN for creatinine, <60 mL/min for creatinine clearance 
rate)† 
 
o Infant grade 3 or higher adverse events through 50 weeks postpartum 
Outcome Measure: Infant grade 3 or higher adverse events, including events 
resulting in death due to any cause, through 50 weeks postpartum‡ 
 
1 The estimation of gestational age at delivery and study entry will follow the guidance from the American College of 
Obstetricians and Gynecologists (ACOG). The ACOG algorithm determines an estimated due date (EDD) by combining 
information from the estimated due date from ultrasound measurements and the self-reported last menstrual period 
("Methods for Estimating Due Date." The American College of Obstetricians and Gynecologists, no. 700, May 2017). 
 
To account for missing data, the following hierarchy will be used to estimate gestational age: 
 
1) 
ACOG algorithm using the ultrasound biometry measurements calculated by the INTERGROWTH-21 formulas 
2) 
ACOG algorithm using ultrasound EDD (Missing biometry measurements) 
3) 
Ultrasound biometry measurements calculated by the INTERGROWTH-21 formulas (Missing LMP) 
4) 
Ultrasound EDD (Missing LMP and the biometry measurements) 
5) 
Last menstrual period (Missing ultrasound measurement) 
6) 
Site-determined gestational age at study entry (Applicable to interim analyses in which missing data have yet to 
be queried, missing LMP and ultrasound data) 
 
2Infants will be classified as small for gestational age based on methods from the INTERGROWTH-21st Project. Birthweight, 
sex, and gestational age at delivery will be used to calculate the infant percentile of size for gestational age at delivery. 
Villar, et.al. "International Standards for Newborn Weight, Length, and Head Circumference by Gestational Age and Sex: 
the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project." The Lancet, vol. 384, 6 Sept. 2014. More 
information on the INTERGROWTH-21st Project can also be found at intergrowth21.tghn.org. 
 
3.3.2 Secondary Objectives and Outcome Measures 
 
The secondary objectives of this study are to evaluate the following among HIV-1-infected pregnant 
women and their infants: 


 
 
IMPAACT 2010 Primary Statistical Analysis Plan version 5.0 
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 
Whether treatment initiated during pregnancy with a DTG-containing regimen is superior to 
EFV/FTC/TDF with regard to virologic efficacy (HIV-1 RNA <200 copies/mL) at delivery 
Outcome Measure: HIV-1 RNA <200 copies/mL at delivery using real-time test results 
obtained at site laboratories (superiority analysis) † 
 
 
Whether the following differ when comparing a DTG-containing regimen initiated during 
pregnancy to EFV/FTC/TDF: 
o Proportion of mothers with HIV-1 RNA <50 copies/mL at delivery 
Outcome Measure: HIV-1 RNA <50 copies/mL at delivery (up to 14 days 
postpartum) using batched test results obtained from central laboratory 
o Proportion of mothers with HIV-1 RNA <200 copies/mL at 50 weeks postpartum 
Outcome Measure: HIV-1 RNA <200 copies/mL at 50 weeks postpartum using real- 
time test results obtained from site laboratories 
o Time to maternal HIV-1 RNA <200 copies/mL 
Outcome Measure: Time to first HIV-1 RNA <200 copies/mL through delivery (up to 
14 days postpartum) using real-time results obtained from site laboratories† 
 
 
Whether the following differs for any pairwise regimen comparison: 
o Proportion of mothers with HIV-1 RNA <200 copies/mL using the standardized FDA 
snapshot algorithm at delivery and at 50 weeks postpartum 
Outcome Measures: 
 
HIV-1 RNA <200 copies/mL at delivery (up to 14 days postpartum) using 
real-time test results obtained from site laboratories and FDA3 snapshot 
algorithm† 
 
HIV-1 RNA <200 copies/mL at 50 weeks postpartum using real-time results 
obtained from site laboratories and FDA snapshot algorithm 
 
 
Whether rates of the following differ when comparing a DTG-containing regimen to 
EFV/FTC/TDF: 
o Adverse pregnancy outcomes (spontaneous abortion, fetal death, preterm delivery, 
or small for gestational age) 
Outcome Measure: Composite outcome of spontaneous abortion (occurring at <20 
weeks gestation), fetal death (occurring at ≥20 weeks gestation), preterm delivery 
(<37 completed weeks), or small for gestational age (<10th percentile) † 
o Maternal grade 3 or higher adverse events through 50 weeks postpartum 
Outcome Measure: Maternal grade 3 or higher adverse events, including events 
resulting in death due to any cause, through 50 weeks postpartum† 
o Infant grade 3 or higher adverse events through 50 weeks postpartum 
Outcome Measure: Infant grade 3 or higher adverse events, including events 
resulting in death due to any cause, through 50 weeks postpartum‡ 
 
 
Whether rates of the following differ for any pairwise regimen comparison: 
o A composite outcome of spontaneous abortion, fetal death, preterm delivery, small 
for gestational age, or major congenital anomaly 
Outcome Measure: Composite outcome of spontaneous abortion (occurring at <20 
weeks gestation), fetal death (occurring at ≥20 weeks gestation), preterm delivery 
(<37 completed weeks), or small for gestational age (<10th percentile) or major 
congenital anomaly4 †† 


 
 
IMPAACT 2010 Primary Statistical Analysis Plan version 5.0 
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o A ranked composite infant safety outcome measure through 50 weeks postpartum 
Outcome Measure: Ranked composite infant safety outcome through 50 weeks 
postpartum 
o Infant HIV infection through 50 weeks postpartum 
Outcome Measure: Infant HIV infection at delivery and through 50 weeks 
postpartum† 
o Infant mortality through 50 weeks postpartum 
Outcome Measure: Infant death due to any cause through 50 weeks postpartum‡ 
o Infant bone toxicity at 26 weeks postpartum 
Other Outcome Measure: Infant whole body and lumbar spine BMC values based 
on DXA scan at 26 weeks postpartum 
o Maternal bone toxicity at 50 weeks postpartum 
Other Outcome Measure: Maternal lumbar spine and hip BMD Z-scores based on 
DXA scan at 50 weeks postpartum 
o Markers of maternal and infant renal toxicity through 50 weeks postpartum 
Outcome Measures: 
 
Maternal serum creatinine and creatinine clearance rate (Cockcroft-Gault 
formula) † 
 
Infant serum creatinine and creatinine clearance rate (Schwartz formula) 
Other Outcome Measure: Maternal serum creatinine and creatinine clearance rate 
(Cockcroft-Gault formula), urine protein creatinine ratio, beta 2 microglobulin, and 
retinol binding protein 
o Antiretroviral drug resistance observed with each maternal ART regimen: 
 
Among mothers who experience virologic failure (at baseline and time of 
virologic failure) 
Secondary Outcome Measure: HIV-1 antiretroviral drug resistance 
mutations at the time of maternal virologic failure (and at screening for 
mothers with resistance detected at the time of virologic failure to 
determine if the resistance was present prior to enrollment or occurred 
post-enrollment) using the Stanford algorithm 
 
Among HIV-infected infants (at time of HIV diagnosis) 
Secondary Outcome Measure: HIV-1 antiretroviral drug resistance 
mutations at the time HIV diagnosis for HIV-infected infants 
 
 
Whether treatment initiated during pregnancy with each regimen is non-inferior with regard 
to preterm delivery and, separately, small for gestational age for any pairwise regimen 
comparison 
Outcome Measures: 
o Preterm delivery (<37 completed weeks)† 
o Small for gestational age (<10th percentile)† 
 
 
Whether changes in maternal weight differ for any pairwise comparison or when 
comparing a DTG-containing regimen to EFV/FTC/TDF 
Other Outcome Measures: 
o Change in maternal weight antepartum (from study entry to delivery) ‡‡ 
o Change in maternal weight postpartum (from delivery to 50 weeks postpartum) 
o Change in maternal weight overall (from study entry to 50 weeks postpartum) 


 
 
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Other outcome measures are not submitted to ClinicalTrials.gov. 
 
3FDA’s Guidance for Industry, “The Human Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs for 
Treatment”, Appendix A, November 2015. 
 
4Major congenital anomaly will be defined for this study consistent with the definition of malformation provided by 
Holmes LB, Westgate MN. Inclusion and exclusion criteria for malformations in newborn infants exposed to potential 
teratogens. Birth defects research Part A, Clinical and molecular teratology. 2011;91(9):807-12, i.e., a structural 
abnormality with surgical, medical, or cosmetic importance. The following will not be considered major congenital 
anomalies: genetic disorders, chromosome abnormalities, minor anomalies, birth marks, positional deformities, 
prematurity related findings, prenatal ultrasound-only findings (i.e., findings only identified by ultrasound and not by the 
examining pediatrician), and polydactyly (postaxial, type B). Findings consistent with the definition of malformation will be 
included in analyses as major congenital anomalies. All suspected congenital anomalies will be entered into eCRFs and a 
small group of study investigators (blinded to randomized study arm), including an expert on birth defects, will review all 
suspected anomalies in near real time to determine whether they meet the study-specific definition of major congenital 
anomaly. 
 
 
3.4 Visit and Evaluation Schedule 
 
Throughout this document, analysis timeframes described as “at week X”, includes the study visit 
window. Antepartum clinic visits are scheduled every 4 weeks (± 2 weeks) prior to delivery. 
Participants will complete a delivery clinic visit as soon as possible after delivery, within a targeted 
window of 14 days after the pregnancy outcome. If the visit cannot be conducted within the targeted 
window, it may be conducted within an allowable window of 27 days after delivery. Viral               
load results will only be considered as delivery measurements if tested within 14 days after the 
pregnancy outcome. Both the mother and infant are scheduled to return at 6 weeks postpartum (± 2 
weeks) and then continue follow-up visits every 12 weeks (±6 weeks) until 50 weeks postpartum. 
 
If a mother’s study drug regimen is modified by switching DTG or EFV to another ARV, an additional 
study visit should be scheduled approximately 4 weeks (± 1 week) after the switch. If a maternal 
participant has an HIV viral load ≥ 200 copies/mL at or after at least 24 weeks on the study or an 
infant receives a positive HIV NAT result, additional HIV-1 RNA testing should be conducted within 
28 days of the date of specimen collection for the initial test. 
 
If a mother is pregnant at the visit week 50 postpartum visit, the pregnancy outcome and ARV 
changes during the subsequent pregnancy must be recorded. If confirmation of a maternal virologic 
failure or infant HIV infection is pending after the visit week 50 postpartum visit, the confirmatory 
test and result must be recorded as well. 
 
Baseline for Mothers and Birth Data for Infants 
Maternal baseline values are the measurements closest to or on study entry date. 
Ultrasound measurements used to estimate gestational age are prioritized to the earliest values 
available during the current pregnancy. Ultrasounds are permitted up to 14 days after 
randomization. 
 
Infant birth values are the measurements closest to or on their birthdate. Values will be considered 
as birth data up to 14 days after delivery. 


 
 
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4. Monitoring and Re-Evaluation of Sample Size 
4.1 DSMB 
 
The study will be monitored by a NIAID-convened Data and Safety Monitoring Board (DSMB), which 
will perform its monitoring functions consistent with the NIAID Policy on Data and Safety Board 
Operations. 
 
Interim analyses of study progress and conduct as well as participant safety will be reviewed at least 
biannually starting within 12 months after the first mother-infant pair is randomized. Two interim 
efficacy analyses will be performed when approximately 33% and 66% of the anticipated   
information on viral suppression at delivery have been observed, unless otherwise requested by the 
DSMB. Assuming participant accrual as described in Section 3.8 of the protocol and that the average 
gestational age at entry is 24 weeks, it is projected that 33% of the total information will be available 
10 months after the first mother-infant pair is enrolled in the study. 
 
The DSMB will be provided with masked by-arm study data reports. Based on any of its reviews, the 
DSMB may recommend that the study proceed as currently designed, proceed with design 
modifications, or be discontinued. The DSMB may also provide operational recommendations to 
address any study implementation challenges that may be identified. 
 
Statistical Stopping Guidelines for Evaluating Efficacy 
Efficacy decision boundary guidelines will be based on the group sequential Lan-DeMets O’Brien- 
Fleming like error spending approach. The Z test statistic for the difference in proportions when 
comparing the DTG-containing arms to the EFV-containing arm will be compared to the z-value 
decision boundary guideline computed from the Lan-DeMets O’Brien-Fleming like error spending 
approach. The z-value decision boundary guideline is approximately ±3.7 at 33% of information and 
±2.5 at 66% of information. As the decision boundary guidelines change depending on the amount 
of information at the interim analysis, these boundaries are only given for illustrative purposes. If 
the Z test statistic is larger in magnitude than the z-value decision boundary guideline, in either 
direction, then early termination of the study may be considered. A conclusion for non-inferiority of 
the combined DTG-containing arms relative to the EFV-containing arm at an interim analysis in the 
absence of superiority would not warrant stopping for efficacy. Because a conclusion for superiority 
will be predicated on a decision for non-inferiority, the non-inferiority analyses should also be 
considered by the DSMB. 
 
Assessment of Futility for the Efficacy Comparisons 
IMPAACT 2010 should not be stopped at an interim analysis for futility if it appears unlikely that a 
conclusion of superiority or non-inferiority can be made at the maximal sample size. There are two 
reasons why that futility of the primary efficacy comparisons should not be considered at interim 
analyses: 1) the study will be quite advanced in its conduct by the time a reasonable number of 
participants have outcome information for the futility analyses, and 2) it will be important to collect 
as much safety data as possible for the 3 primary safety objectives. 
 
 
4.2 Re-Evaluation of Sample Size 


 
 
IMPAACT 2010 Primary Statistical Analysis Plan version 5.0 
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The main purpose of the sample size re-evaluation is to use the observed data to inform the 
following parameters used in the sample size calculations: the percent of participants with evaluable 
data and the percent of mothers with HIV-1 RNA <200 copies/mL at delivery. This is to evaluate 
whether a sample size increase is needed to achieve the desired statistical power for the primary 
efficacy objective of the study. The sample size re-evaluation will take place at one interim analysis, 
once sufficient information is available to estimate the proportion of mothers with HIV-1 RNA <200 
copies/mL at delivery. To maintain power for the primary safety analyses, the sample size should not 
be decreased. 
 
The re-evaluation will be undertaken by a statistician who is blinded to the randomized treatment 
arms. The statistician will be given study datasets without access to the randomized treatment arms.  
The re-evaluated sample size will be computed for the DSMB at the interim analysis in which at    
least 192 women have delivery HIV-1 RNA data available (approximately 33% of the expected 
information) or at the scheduled DSMB review before accrual is completed, whichever comes first. If 
accrual of 639 mother-infant pairs is expected to be completed before the next scheduled DSMB 
meeting, accrual may be paused when 639 pairs have been enrolled but accrual would not formally 
close until the DSMB has reviewed the sample size adjustment. The DSMB will review the sample 
size re-evaluation based on a pre-specified algorithm and make recommendations concerning  
sample size. 
 
Further guidelines for the DSMB in considering sample size re-evaluation include the following: 
 
 
The sample size should not increase because the percent of non-evaluable women at 
delivery is higher than 15%. The primary rationale for this guideline is that the percent 
could potentially be so high relative to the anticipated percent suppressed that the results 
of the study may be difficult to interpret. Thus, the main point of considering the percent 
evaluable is because a rate lower than 15% may be relevant in offsetting any increase in 
sample size needed due a lower than expected suppression percentage at delivery. 
 
 
The DSMB will be provided with estimated primary outcome rates by arm at each interim 
efficacy analysis. A concern, however, with sample size re-evaluation is that it may affect 
the Type I error rate and introduce bias in estimates of the difference in outcomes between 
arms (and associated confidence intervals). This is generally avoided if the interim 
information used to re-evaluate the sample size is pooled over randomized treatment arms. 
 
 
A sample size re-evaluation algorithm will be followed. To re-power the study, the amount 
of information will be fixed to the amount used to calculate the sample size of 639 pairs. 
The maximal amount of information for this study is: 
 
Ι = [. 8 ∗(1 −.8)/(.9 ∗639 ∗2
3) + .8 ∗(1 −.8)/(.9 ∗639 ∗1
3)]
−1
≈797.2


 
 
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Maximal information was computed from the inverse of the variance of the estimate of the 
difference in binomial proportions calculated under the alternative hypothesis. At the time of the 
sample size re-evaluation, the observed pooled binomial proportion (𝑃̂) will be used to compute 
the re-evaluated sample size.  If we let ɛ be the proportion evaluable, after solving the information 
formula for N, the formula to re-compute the total sample size is: 
 
𝑁= Ι
ɛ ∗[9
2 𝑃̂(1 −𝑃̂)]. 
 
 
Following this procedure will aid in maintaining 80% power for a non-inferiority margin of 10% 
assuming that the comparison groups have the same but arbitrary suppression probability. 
 
The sample size was re-evaluated and presented to the DSMB in January 2019. The DSMB 
recommended on February 4, 2019 that the study continue as planned with no alteration in study 
size. 
 
 
5. Analyses 
 
All of the primary and secondary analyses will be performed with the principle of ITT. For the 
analyses of superiority, the ITT analysis is the primary analysis. Per-protocol analyses of non- 
inferiority will also be conducted. 
 
There are two secondary non-inferiority objectives and one non-inferiority analysis for the primary 
efficacy objective. Non-inferiority analyses typically require additional considerations relative to an 
analysis of superiority, including the congruence between an ITT analysis and a per-protocol 
analysis. Thus, the non-inferiority analyses, ITT and per-protocol, should be given equal weight in 
the non-inferiority analyses. 
 
Per-protocol analyses will censor or exclude participants’ data who do not remain on the 
randomized regimen up to the time of the measured outcome. Any change, defined as the first 
switch, first addition or first removal of any of any of the ARVs in the randomized regimen will be 
considered a change from the randomized regimen, with the exception of switches made due to a 
requirement for other concomitant medications. 
 
The unit of analysis for infant and pregnancy outcomes will be the mother-infant pair. Analysis 
summaries will use the most extreme (worst) infant or pregnancy outcome for each pregnancy. For 
example, if one infant of a multiple birth becomes HIV-infected but the other does not, this will 
count as one event in the analyses. If both infants become infected, this will count as one event for 
the mother-infant pair in the analysis, not two. This is a conservative approach and addresses the 
fact that data on infants from multiple births may be related. Analyses of live born infants will be 
conducted on the unique participant level (twins will be treated as independent). 
 
Summaries and regimen comparisons will not be adjusted for the two stratification factors. By arm 
regimen comparisons for each stratum of gestational age at study entry (14-18 weeks, 19-23 weeks, 
or 24-28 weeks) will be included in the final study report. P-values for these treatment comparisons 
will be provided if there is a statistically significant difference (p-value <0.05) between the 


 
 
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treatment arm and gestational age at study entry. 
 
There are ten primary comparisons to be made, including one efficacy comparison and nine safety 
comparisons. There will be no adjustments for multiple comparisons. Type I error rates (α) will be 
controlled at the comparison level where a statistical difference will be declared if the p-value is 
less than 0.05. The p-value for the primary efficacy comparison will be adjusted for the repeated 
interim analyses using the error spending approach mentioned above, and the safety analyses will 
use an unadjusted nominal p-value. The safety analyses will not be adjusted for multiple 
comparisons or interim analyses to minimize the chance of a Type II error (β). The trial-wise Type I 
error will be larger than 5%.  
 
Per NIH policy for Phase III and pivotal Phase II and IV studies, NIH requires primary analyses of 
treatment comparisons to be summarized by sex and by race and treatment interactions with sex 
and race to be tested. These analyses are required so do not represent multiple comparisons and 
will be presented in the primary study analysis regardless of power issues. Analyses restricted to 
one sex or race will present the appropriate data (analyses including only mothers need to be 
presented by race, not by sex). 
 
Women with no post-baseline follow-up will be excluded from post-baseline analyses. Visits after 
the date of randomization will be considered post-baseline visits.  
 
6. Primary Outcome Measures 
 
Efficacy: Viral Suppression 
 
Purpose: to address whether the DTG-containing regimen is non-inferior to EFV/FTC/TDF with 
regard to virologic efficacy at delivery when initiated during pregnancy 
 
Primary Efficacy Outcome Measure 
 
HIV-1 RNA <200 copies/mL at delivery (up to 14 days postpartum), using real-time test 
results obtained at site laboratories 
 
Statistical Methods 
Analyses will compare the DTG-containing arms to the EFV-containing arm. Viral suppression will be 
summarized using a difference in binomial proportions with a success defined as HIV-1 RNA <200 
copies/mL at delivery. The denominator for this analysis will include women who have an HIV-1 RNA 
measurement within the delivery visit window (+14 days). A two-sided, two-sample test in 
proportions will be used for this analysis with normal approximation. Confidence intervals and p- 
values for the difference in proportions will be adjusted for the interim analyses to maintain a two- 
sided Type 1 error rate of 0.05 using the time ordered calculations. Ninety-five percent repeated 
confidence intervals (RCI) will be computed at interim analyses. A 10% non-inferiority margin will be 
used for the primary analysis. A p-value less than 0.05 testing the equality of proportions will be 
considered statistically significant, and a p-value testing the equality of the proportions will be 
provided if non-inferiority is established. Similarly, a 95% CI (or RCI at interim analyses) that 
excludes a difference of 10% in favor of the EFV-containing regimen will be considered to be 
statistically significant for the non-inferiority analysis. 
 
After collecting baseline data, the observed percent of women with a baseline viral load <200 


 
 
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copies/mL was higher than expected. A descriptive analysis to describe the impact that this 
observation has on the analysis conclusion will be conducted by re-computing the primary delivery 
viral load analysis among women with a baseline viral load of <200 copies/mL and women with ≥ 
200 copies/mL separately. An interaction between the study arm and baseline viral will be tested 
using logistic regression. 
 
Sensitivity analyses will be carried out using multiple imputation for women missing the HIV-1 RNA 
measurement within the delivery visit window. A linear mixed effect model will be used to impute 
missing delivery viral loads. The predictor will be time on study with the outcome of the log viral load 
before or on the delivery visit. Viral load measurements below the limit of quantification will            
be set to the limit of quantification. This model will include all participants that have at least one 
viral load measurement before or on delivery. Viral load will not be imputed for mothers with no 
viral load measurements. Natural splines will be used to model the viral load trajectories over time. 
Bayesian information criteria (BIC) will be used to select the degrees of freedom of the spline model. 
Furthermore, a random intercept and random slope(s) (multiple slopes if BIC selects a non-linear 
term) will be fit at the participant level. These participant level random effects will be used to impute 
the missing VL data. Because the VL trajectory might vary by arm, three imputation models              
will be used, one for each arm. 
 
For interim analyses, the efficacy data will be presented to the DSMB when approximately 33% and 
66% of participants have viral suppression data at delivery. A masked by-arm analysis will be given. 
See section 4.1 for stopping guidelines based on efficacy decision boundary guidelines. 
 
Safety 
 
Purpose: to address whether safety outcome rates differ between the three regimens initiated 
during pregnancy. 
 
Primary Safety Outcome Measures 
 
Composite outcome of spontaneous abortion (occurring at <20 weeks gestation), fetal death 
(occurring at ≥20 weeks gestation), preterm delivery (<37 completed weeks), or small for 
gestational age (<10th percentile) 
 
Maternal grade 3 or higher adverse events, including events resulting in death due to any 
cause, through 50 weeks postpartum (refer to Protocol Section 7.3.3 for severity grading; 
for this outcome measure, grade 3 or higher creatinine levels and creatinine clearance rates 
will be defined based on absolute values (>1.8 x ULN for creatinine, <60 mL/min for 
creatinine clearance rate) 
 
Infant grade 3 or higher adverse events, including events resulting in death due to any 
cause, through 50 weeks postpartum 
 
The protocol requires grading of events according to Version 2.1 of the Division of AIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table). 
 
Statistical Method 
Safety data will be presented to the DSMB every six months. All primary safety analyses will 
compare DTG+FTC/TDF (Arm 2) to DTG+FTC/TAF (Arm 1), DTG+FTC/TDF (Arm 2) to EFV/FTC/TDF 
(Arm 3), and DTG+FTC/TAF (Arm 1) to EFV/FTC/TDF (Arm 3). 
 


 
 
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Spontaneous Abortion, Fetal Death, Preterm Delivery, and Small for Gestational Age 
The analyses of the composite adverse pregnancy outcomes will be summarized as differences in 
proportions. A two-sided, two-sample test for the equality of the difference in proportions will be 
used for the by arm comparisons. A nominal (not adjusted for interim analyses) p-value less than 
0.05 will be considered statistically significant. The Type I error rate for each comparison will be 5%. 
Two important separate sensitivity analyses will be conducted: 1) by including mothers who 
withdrew (i.e. lost to follow-up) before experiencing any one of these pregnancy outcomes as failures 
to account for the possibility of informative missingness, and 2) by stratifying by the presence of a 
major congenital anomaly. The analysis stratifying by the presence of a major congenital anomaly 
will be conducted to investigate effect modification if there is a by-arm imbalance in major 
congenital anomalies. 
Conclusions based on the analysis stratified by the presence of a major congenital anomaly should 
be interpreted with care as some major congenital anomalies may have occurred after 
randomization. At interim analyses, a sensitivity analysis will be conducted by restricting the 
analysis to women that with an expected due date four weeks before the date the data were frozen. 
This sensitivity analysis will be conducted because early events are likely to be selected at interim 
analyses, and without this restriction the prevalence of these events might be overestimated. 
 
Maternal Grade 3 or Higher Adverse Events 
The primary maternal safety analysis will use a Kaplan-Meier estimate of the event probability 
through 50 weeks postpartum. At the final analysis through 50 weeks postpartum, the proportion 
experiencing an event for each group will be computed from the Kaplan-Meier survival curve and 
Greenwood’s formula will be used to compute the variance of the difference. A Z score will be 
computed by taking the difference in the estimated probabilities and dividing this difference by the 
square root of the sum of variances as estimated by Greenwood’s formula. Since the time from 
randomization to a pregnancy outcome will vary among the mothers, the visit week 50 event 
Kaplan-Meier probability estimate will be taken from the time at the average time from 
randomization to the mother’s pregnancy outcome plus 50 weeks. The Z score will then be 
compared to the standard normal curve to compute a p-value. For the primary pregnancy analysis 
report, a log rank test of the equality of survival curves will be presented. A nominal (not adjusted 
for interim analyses) p-value less than 0.05 will be considered statistically significant. The Type 1 
error rate for each comparison will be 0.05. Important sensitivity analyses will be conducted by 
including mothers who drop out of the study early as failures to account for the possibility of 
informative missingness. At interim analyses the log-rank of the equality of survival curves will be 
presented to the DSMB. 
 
Grade 3 and 4 creatinine clearance adverse events reported due to a percent decrease from 
baseline or creatinine adverse events reported due to an increase from baseline will be excluded 
from the primary maternal safety analysis. Only women with a calculated creatinine clearance value 
of <60 mL/min or mL/min/1.73m2 (grade 3 or higher creatinine clearance) or >1.8 x ULN creatinine 
(grade 3 or higher creatinine) will be counted as failures in the primary maternal safety analysis. See 
Section 9 for further details regarding creatinine clearance and creatinine grading. 
 
Infant Grade 3 or Higher Adverse Events 
The primary infant safety analysis will use a Kaplan-Meier estimate of the event probability from 
birth through visit week 50. The proportion experiencing an event for each group will be computed 
from the Kaplan-Meier survival curve and Greenwood’s formula will be used to compute the 
variance of the difference. A Z-score will be computed by taking the difference in the estimated 


 
 
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probabilities and dividing this difference by the square root of the sum of variances as estimated by 
Greenwood’s formula. The Z score will then be compared to the standard normal curve to compute 
a p-value. For the primary pregnancy analysis report, a log rank test of the equality of survival 
curves will be presented through the first 28 days after birth. A nominal (not adjusted for interim 
analyses) p-value less than 0.05 will be considered statistically significant. The Type 1 error rate for 
each comparison will be 0.05. Important sensitivity analyses will be conducted by including infants 
who drop out of the study early as failures to account for the possibility of informative missingness. 
At interim analyses the log-rank test testing the equality of survival curves will be presented to the 
DSMB.  
 
7. Secondary Outcome Measures 
 
Secondary Outcome Measures 
 
HIV-1 RNA <200 copies/mL at delivery (up to 14 days postpartum) using real-time test 
results obtained at site laboratories 
 
HIV-1 RNA <50 copies/mL at delivery (up to 14 days postpartum) using batched test results 
obtained from central laboratory 
 
Time to first HIV-1 RNA <200 copies/mL through delivery (up to 14 days postpartum) 
using real-time results obtained from site laboratories  
 
HIV-1 RNA <200 copies/mL at 50 weeks postpartum using real-time test results obtained 
from site laboratories 
 
HIV-1 RNA <200 copies/mL at delivery using real-time test results obtained from site 
laboratories and FDA snapshot algorithm 
 
HIV-1 RNA <200 copies/mL at 50 weeks postpartum using real-time results obtained from 
site laboratories and FDA snapshot algorithm 
 
Composite outcome of spontaneous abortion (occurring at <20 weeks gestation), fetal death 
(occurring at ≥20 weeks gestation), preterm delivery (<37 completed weeks), small for 
gestational age (<10th percentile) or major congenital anomaly 
 
Ranked composite infant safety outcome through 50 weeks postpartum 
 
Infant HIV infection at delivery and through 50 weeks postpartum 
 
Infant death due to any cause through 50 weeks postpartum 
 
Maternal serum creatinine and creatinine clearance rate (Cockcroft-Gault formula) 
 
Infant serum creatinine and creatinine clearance rate (Schwartz formula) 
 
HIV-1 antiretroviral drug resistance mutations at the time of maternal virologic failure (and 
at study entry for mothers with resistance detected at the time of virologic failure to 
determine if the resistance was present at enrollment or occurred post-enrollment) using 
the Stanford algorithm 
 
HIV-1 antiretroviral drug resistance mutations at the time HIV diagnosis for HIV-infected 
infants 
 
Preterm delivery (<37 completed weeks) 
 
Small for gestational age (<10th percentile) 
 
Change in maternal weight antepartum (from study entry to delivery)   
 
Change in maternal weight postpartum (from delivery to 50 weeks postpartum)  
 
Change in maternal weight overall (from study entry to 50 weeks postpartum) 
 
Analyses to test the equality of differences in event probabilities at delivery will be performed using 
the same approach as for the primary analyses. This includes estimates of the probability of mothers 
with HIV-1 RNA <50 copies/mL at delivery, the probability of HIV-1 RNA <200 copies/mL at delivery 


 
 
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and through 50 weeks postpartum as defined by the FDA snapshot algorithm the probability of 
mothers with adverse pregnancy outcomes, HIV drug resistance mutations acquired post- 
randomization as defined by the Stanford algorithm, and the probability of infant HIV infection at 
delivery. A two-sided, two-sample test for the equality of the difference in proportions will be used 
for the by-arm comparisons. 
 
A non-inferiority analysis of preterm delivery and small for gestational age will be conducted as a 
secondary analysis. The non-inferiority analysis will be conducted because the protocol team 
believes that is important to set a predefined decision rule for a conclusion of non-inferiority before 
the data are observed. A non-inferiority margin of 10% will be used. This margin reflects the 
judgment of the protocol team. The non-inferiority analysis will be conducted to test if 
DTG+FTC/TDF is non-inferior to EFV/FTC/TDF, if DTG+FTC/TAF is non-inferior to EFV/FTC/TDF, and if 
DTG+FTC/TAF is non-inferior to DTG+FTC/TDF. For the non-inferiority analyses, a p-value will not be 
computed; instead, statistical significance for non-inferiority will be determined by the appropriate 
limit of a 95% confidence interval rejecting the non-inferiority margin. This procedure for the non- 
inferiority analyses controls a one-sided Type I error rate of 0.025. 
 
Visit week 50 postpartum cumulative event probabilities will be estimated using the Kaplan-Meier 
method. This analysis estimates confirmed infant HIV infection through 50 weeks postpartum, and 
infant mortality through 50 weeks postpartum. Greenwood’s formula will be used to compute the 
standard error of the difference between the estimated probabilities. For the analysis of neonatal 
deaths, a log rank test for the equality of survival curves will be used. 
 
Time until viral suppression (first plasma HIV RNA viral load <200 copies/mL) from study entry 
through delivery will be compared using a log-rank test, and will be displayed graphically using the 
Kaplan-Meier estimate of the survival curve. 
 
Continuous outcomes, which include markers of maternal and infant renal toxicity, will be analyzed 
using two sample t-tests. A linear mixed effects model with a robust variance estimator will also be 
used to estimate the rate and change between arms of creatinine clearance over time. 
 
Infants and pregnancy outcomes will be classified into the worst group using the following 
hierarchy: 
1. Infant death 
2. Spontaneous abortion (<20 weeks gestation) or fetal death (≥20 weeks gestation) 
3. Infant HIV infection 
4. Extremely and very early preterm (<32 completed weeks) 
5. Major congenital anomaly 
6. Preterm delivery (<37 completed weeks) 
7. Small for gestational age (<10th percentile) 
8. Hospitalization 
9. Grade 3 or 4 adverse event 
10. None of the above 
 
Proportions of participants in each classified group will be summarized and all three pairwise 
regimen comparisons will be compared using ordinal logistic regression. In addition to the standard 
ordinal logistic regression analysis, a weighted ordinal logistic regression will be employed to give 
each outcome type the same weight, using the following equation,  
 


 
 
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# 𝑜𝑓 𝑝𝑎𝑟𝑡𝑖𝑐𝑖𝑝𝑎𝑛𝑡𝑠
(# 𝑜𝑓 𝑝𝑎𝑟𝑡𝑖𝑐𝑖𝑝𝑎𝑛𝑡𝑠 𝑤𝑖𝑡ℎ 𝑎 𝑔𝑖𝑣𝑒𝑛 𝑜𝑢𝑡𝑐𝑜𝑚𝑒) 𝑋 (#𝑜𝑓 ℎ𝑖𝑒𝑟𝑎𝑟𝑐ℎ𝑦 𝑙𝑒𝑣𝑒𝑙𝑠) 
 
At each level in the hierarch we will set a binary event threshold (i.e., events at or above and below 
a given level). For each threshold, we will fit a logistic regression model.  
 
 
Longitudinal maternal pregnancy weight, postpartum weight, and weight since randomization will 
be compared by arm with a time and arm interaction using generalized estimating equations. 
Analyses of weight will be compared for all pairwise comparisons and by comparing the EFV- 
containing arm to the DTG-containing arms. A sensitivity analyses will be conducted using inverse 
probability weighting on gestational age at delivery. A two-sided, two-sample test for the equality 
of the difference in proportions of women defined as being obese or overweight at postpartum 
week 50 will be applied for the by-treatment arm comparisons. 
 
Missing Data Methods for Secondary Analyses 
Missing data methods will be used there is a large amount of missing data (e.g. >10% missing) or if 
requested by the study team. This section lays out the planned methods to account for missing data. 
Missing data methods will only be used to investigate the robustness of the complete case analyses, 
as previously discussed. 
 
Multiple imputation, as described in the primary efficacy analysis section, will be used for the 
following outcome measures: 
 
 
HIV-1 RNA <200 copies/mL at delivery (up to 14 days postpartum) using real-time test 
results obtained at site laboratories 
 
HIV-1 RNA <50 copies/mL at delivery (up to 14 days postpartum) using batched test results 
obtained from central laboratory 
 
HIV-1 RNA <200 copies/mL at 50 weeks postpartum using real-time test results obtained 
from site laboratories 
 
Infant serum creatinine and creatinine clearance rate (Schwartz formula) 
 
The FDA snapshot algorithm accounts for missing data by including a categorization of missed visits 
and study discontinuations; therefore, no special missing data methods will be used for the 
following outcome measures: 
 
 
HIV-1 RNA <200 copies/mL at delivery using real-time test results obtained from site 
laboratories and FDA snapshot algorithm 
 
HIV-1 RNA <200 copies/mL at 50 weeks postpartum using real-time results obtained from 
site laboratories and FDA snapshot algorithm 
 
Women or infants, as appropriate, who discontinue study early before experiencing an outcome 
listed below will be counted as failures (as an additional component of the outcome) for the following 
outcomes: 
 
 
Composite outcome of spontaneous abortion (occurring at <20 weeks gestation), fetal death 
(occurring at ≥20 weeks gestation), preterm delivery (<37 completed weeks), or small for 
gestational age (<10th percentile) or major congenital anomaly 


 
 
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 
Ranked composite infant safety outcome through 50 weeks postpartum 
 
Infant HIV infection at delivery and through 50 weeks postpartum 
 
Infant death due to any cause through 50 weeks postpartum 
 
HIV-1 antiretroviral drug resistance mutations at the time of maternal virologic failure (and 
at study entry for mothers with resistance detected at the time of virologic failure to 
determine if the resistance was present at enrollment or occurred post-enrollment) using 
the Stanford algorithm 
 
HIV-1 antiretroviral drug resistance mutations at the time HIV diagnosis for HIV-infected 
infants 
 
Preterm delivery (<37 completed weeks) 
 
Small for gestational age (<10th percentile) 
 
In addition to counting mother-infant pairs as failures if they discontinue the study early before 
experiencing an outcome, a second sensitivity analysis will count missing data as failures for the 
primary adverse pregnancy outcome measure (composite outcome of experiencing spontaneous 
abortion, fetal death, preterm delivery, or small for gestational age). 
 
8. Other Outcome Measures 
DXA Scans 
The following other outcome measures (stated in protocol version 2.0 LoA #3) address secondary 
objectives of bone mineral toxicity: 
 
Maternal lumbar spine and hip BMD Z-scores based on DXA scan at 50 weeks postpartum  
 
Infant whole body and lumbar spine BMC values based on DXA scan at 26 weeks 
postpartum  
Differences between treatment arms in maternal BMD Z-scores (lumbar spine and hip) and infant 
BMC values (whole body and lumbar spine) will be analyzed using two sample t-tests assuming 
unequal variance. Infant whole body values will be analyzed with and without the head. For 
maternal DXAs a sensitivity analysis testing for the interaction of treatment arm and duration 
exposed to Medroxyprogesterone acetate will be included. Differences between pooled groups 
comparing DTG to EFV and TDF to TAF will also be summarized descriptively.  
 
Pregnancy Dating 
Accuracy of the estimated date of delivery (EDD) is important for clinical care and identifying adverse 
pregnancy outcomes. The ACOG algorithm is used to estimate the EDD on IMPAACT 2010 and 
determines the estimated rates of adverse pregnancy outcome measures such as preterm delivery 
and infants small for gestational age. The estimate of gestational age for this study uses a centrally 
calculated value based upon the ultrasound fetal parameters in conjunction with the ACOG 
algorithm. This strategy has not been used in other IMPAACT studies. This approach was taken to 
minimize two sources of variability: 1) site-level variability due to different ultrasound machines and 
formulas, and 2) individual level ultrasound and LMP uncertainty due to varying fetal growth 
patterns, timing of ovulation, and recall in memory. The first source of variability is accounted for by 
applying a single formula to the fetal parameters. The second source of variability is accounted for 
using the ACOG algorithm that redates the gestational age based on the LMP and ultrasound. It is 
unknown how much this strategy will reduce variability in the estimate of gestational age. To help 
plan for future studies we will compare the variability using ultrasound machine alone, LMP alone, 
the ACOG with the ultrasound machine estimate, and IMPAACT 2010 estimate. Rates of EDD 


 
 
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redating using the ACOG algorithm will also be described by gestational age at ultrasound. 
 
 
9. Summaries to Investigate the Impact of SARS-COV-2  
The SARS-COV-2 pandemic occurred during the IMPAACT 2010 follow-up. The majority of women 
and infants completed study follow-up before the SARS-COV-2 pandemic, however, there were a 
handful of women and infants who still needed to complete week 38 and week 50 study visits. On 
March 31st, 2020 the study team sent a clarification memo to the sites that widened the week 50 
window and clarified how to conduct at home visits (see SAP Section 11). Summaries that describe 
the impact of SARS-CoV-2 on IMPAACT 2010 will focus on the week 38 and 50 visits, and 
measurements of viral load, infant growth, and maternal weight. The pre-pandemic period will be 
defined as before March 31, 2020, and the post-pandemic period will be defined on and after 
March 31, 2020. 
 
Data Quality Summaries 
 
Frequency of COVID-related missingness in the post-pandemic period overall and over 
time 
 
Summaries comparing pre-pandemic period to post-pandemic period: 
o Frequency of the week 50 viral load, infant growth, and weight data availability  
o Per-person per-month rate of reported adverse events  
o Per-person per-month rate of virologic failures  
 
Retention 
 
Percentage of women and infants discontinue the study early comparing the pre-
pandemic versus the post-pandemic period 
 
 Visit Completion  
 
Percent of missed week 38 and week 50 visits overall and by site comparing the pre-
pandemic period to the post-pandemic period  
 
Percent of post-pandemic week 50 visits that were conducted within the pre-pandemic 
week 50 window (through week 56) compared to the extended visit window (week 74) 
 
Outcome 
 
Multiple imputation of the missing week 50 viral loads, maternal weight, and infant 
growth  
 
Multiple imputation of the week 50 viral loads, maternal weight, and infant growth 
considering participants who were missing these outcomes or with measurements outside 
of the pre-pandemic window treated as missing 
 
 
10. Outline of Report Contents 
The following summaries are planned content of the final analysis report: 
1. Accrual 
2. Eligibility Violations 
3. Selected Characteristics at Baseline 


 
 
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4. Study Status and Loss to Follow-up 
5. Study Treatment Status and Duration of Treatment 
6. Safety 
7. Pregnancy Outcomes 
8. Repeat Pregnancy Frequency and Outcomes 
9. Primary Outcome Measures 
10. Secondary Outcome Measures (those required to be submitted to ClinicalTrials.gov) 
 
 
11. Protocol History 
 
IMPAACT 2010 protocol version 1.0 was finalized in December 2016. Clarification Memoranda (CM) 
#1 and #2 were also finalized in July 2017 before study opening. Protocol version 2.0 was 
implemented on December 8, 2017 before study opening. Major changes to protocol version 2.0 
were primarily due to requests from the FDA and DSMB. 
 
CM #1, July 21, 2017: 
 
IMPAACT P1026s TAF PK results met the criteria for opening IMPAACT 2010 to accrual. 
 
CM #2, July 21, 2017: 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
(DAIDS AE Grading Table) used was updated to Version 2.1, dated March 2017. 
 
Fetal ultrasound scans performed during the current pregnancy prior to the study screening 
period may also be used. The earliest results should be used for estimating gestational age. 
 
Clarifications were added about recording requirements for maternal and infant physical 
examinations, concomitant medications, and ultrasound scans. 
 
At the suggestion of the DSMB and FDA, the following major changes were implemented to the 
protocol: 
 
Protocol Version 2.0, December 8, 2017: 
 
The primary objective testing whether treatment initiated during pregnancy with a DTG- 
containing regimen is superior to the EFV-containing regimen with regard to virologic 
efficacy at delivery was changed to a non-inferiority test. The secondary objective tests 
superiority. 
 
The total sample size increased from 549 mother-infant pairs to 639 mother-infant pairs to 
increase the power for the non-inferiority analysis. 
 
The accrual cap was lifted for more than 30 mother-infant pairs to enroll each month. 
 
Comparing the time to maternal HIV-1 RNA <200 copies/mL between a DTG-containing 
regimen to EFV/FTC/TDF was added as a secondary objective. 
 
Comparing adverse pregnancy outcomes, maternal adverse events, and infant adverse 
events between a DTG-containing regimen to EFV/FTC/TDF was added as a secondary 
objective. 
 
The allowable window for conducting a Delivery Visit was expanded to 27 days after the 
pregnancy outcome. The targeted window for Delivery Visits remains up to 14 days and the 
primary and secondary delivery outcome measures will only be used if measured within the 
targeted 14 day window. 
 
An exclusion criterion was added to exclude mothers with a history of antiretroviral drug 


 
 
IMPAACT 2010 Primary Statistical Analysis Plan version 5.0 
October 26, 2020 
Page 22 of 24 
 
resistance mutations that would impact selection of ART regimen. 
 
If study-supplied study drugs of DTG, FTC/TAF, FTC/TDF, or EFV/FTC/TDF are not available, 
non-study supplies of these ARVs were approved to be prescribed and dispensed through 
study site pharmacies, following review and approval by the CMC. Small for gestational age 
will be calculated from the INTERGROWTH-21st Project, which is a complement to WHO 
published international growth standards by developing international growth standards for 
fetuses and infants. 
 
EPDS, PSQI, and GAD-7 will also be administered at maternal early discontinuation visits. 
 
When visit windows overlap by a period of one day; the day of overlap was determined to 
be prioritized for the completion of the earlier of the two visits. Missed evaluations were 
also approved to be taken at the next scheduled visit. 
 
Exceptions to antiretroviral receipts within six months prior to study entry were contracted 
to TDF or FTC/TDF for pre-exposure prophylaxis instead of all ARVs. 
 
On July 27, 2018, LoA #1 for protocol version 2.0 was distributed to sites. LoA #1 was in response to 
results from an ongoing observational study in Botswana reporting the potential increased risk of 
neural tube defects (NTDs) associated with exposure to DTG at the time of conception. These 
findings were not of immediate concern for mother-infant pairs on IMPAACT 2010 because DTG is 
initiated at or after 14 weeks gestation. However, women may become pregnant on study prior to 
index pregnancy and might be exposed to DTG. Because of this, accrual was paused on May 18, 
2018 until LoA #1 could be implemented. The major changes implemented by LoA #1 for protocol 
version 2.0 were as follows: 
 
At study entry, mother reports that she does not wish to become pregnant again for at least 
50 weeks after her current pregnancy and that she is willing to use effective contraception 
during this period. 
 
Pregnancy testing is required at each scheduled postpartum study visit. 
 
Maternal fertility intentions , willingness to use effective contraceptive postpartum in 
relation to study requirements, and contraception history will be collected 
 
Glucose, hematocrit, and stored whole blood for folate and HbA1c will be collected for 
testing 
 
Contraception counseling and a documentation plan for initiating effective contraception 
postpartum will be provided 
 
EAE reporting categories for women are changed in Arm 3 from SUSARs to SAEs. EAE 
reporting across arms will be consistent. 
 
Women who conceive while taking DTG postpartum will be switched from DTG to an 
alternate ARV if still in the first trimester when the pregnancy is identified. 
 
Mothers who become pregnant on study should be offered an ultrasound scan between 14 
and 22 weeks gestation to confirm the dating of pregnancy and evaluate fetal anatomy. 
 
Exploratory outcomes were added to Section 9.2.3: 
o Maternal folate, glucose, and HbA1c 
o Infant folate and glucose 
 
Clarification Memorandum (CM) #1 for protocol Version 2.0 was distributed on September 25, 2018. 
This was due to a study team concern with the definition of grade 3 or 4 creatinine clearance: <60 
mL/min or mL/min/1.73m2 or ≥30% decrease from baseline (similarly, an increase of at least 1.5 x 
ULN creatinine above baseline). The team considered a percent decrease in creatinine clearance 
from baseline as unimportant for IMPAACT 2010 because large decreases in creatinine clearance are 
expected after delivery. This memo specified that grades should be based on absolute values of 


 
 
IMPAACT 2010 Primary Statistical Analysis Plan version 5.0 
October 26, 2020 
Page 23 of 24 
 
creatinine and creatinine clearance only, and not on grades that are based on changes from 
baseline. The CM also noted that primary maternal safety analysis would only include creatinine and 
creatinine clearance events based upon absolute values rather than changes in value from baseline. 
 
LoA # 2 for protocol Version 2.0 was finalized on August 23, 2019 for the following reasons: 
 
Allow plasma stored at the Screening Visit for HIV-1 RNA viral load testing to describe the 
virologic profiles of enrolled mothers in response to the higher than expected suppression 
rates among women at entry 
 
Clarify that the primary outcome measure of maternal grade 3 or 4 adverse events would only 
include creatinine or creatinine clearance adverse events that met the DAIDs grading table 
criteria for a grade 3 or higher event based on values alone and not change in levels. 
 
Clarify infant bone outcome measures should be based on absolute bone mineral content 
(BMC) values instead of Z-scores, because international normative BMC values have not 
been established for infants. 
 
Add a secondary study objective and outcome measures and statistical analyses to 
describe the effects of study drug regimens on changes in maternal weight 
 
LoA #3 for protocol Version 2.0 was finalized on June 10, 2020 to incorporate the contents of 
protocol Clarification Memorandum (CM) #2 (issued on March 31, 2020) that implemented 
safeguards for study participants against SARS-CoV-2. Sites were instructed to follow applicable 
government, health authority, and institutional policies with respect to conduct of study visits and 
procedures, with utmost importance placed on the health and well-being of study participants and 
study staff. Week 50 visits were broadened to include up to 12 weeks before and up to 24 weeks 
after the visit target date. Alternate laboratories using alternate assays were permitted if labs could 
not be performed within a site’s Protocol Analyst List. Sites with limited capacity to conduct in-
person study clinic visits were advised to prioritize maternal HIV-1 RNA viral load testing and infant 
diagnostic HIV nucleic acid testing. Subsequently, maternal serum creatinine, followed by other 
maternal chemistries and hematology were the next highest priority for data collection. The 
following were allowed to be administered or obtained remotely: medical and medication histories, 
adherence assessments, counseling, and support, contraception counseling, and questionnaires. 
DXA scans could be missed or skipped. Sites were instructed to document when missed, out-of-
window, off-site, remote contact, or impartial visits occurred, alternate laboratories or assays were 
used, or alternate study drugs were provided.  
 


 
 
IMPAACT 2010 Primary Statistical Analysis Plan version 5.0 
October 26, 2020 
Page 24 of 24 
 
12. Appendix 
SAP Version History 
 
Version 
Changes Made 
Effective Date 
1.0 
Original Version 
12/08/17 
2.0 
 
Added strategies to handle missing data in study design section 
 
Further defined baseline and study visit weeks 
 
Added missing data methods for secondary analyses 
 
Clarified definition for gestational age and added hierarchy of 
estimation methods to account for missing data 
 
Updated dates for version 2.0 of the protocol in Protocol 
History 
 
Added information on study randomization 
 
Added outline of report contents 
 
Added protocol history for LoA #1 for protocol version 2.0 
 
Based on DSMB recommendation, principle results will be 
released after all women have pregnancy outcome results, 
while follow-up to 50 weeks postpartum is continuing 
 
Defined gestational age strata in Section 6 
10/4/18 
3.0 
 
Added analysis of primary efficacy outcome measure by 
maternal suppression status at baseline 
 
Added inclusion criteria for creatinine and creatinine clearance 
events in the primary maternal safety analysis 
 
Added further analyses for creatinine clearance 
 
Added protocol history for CM #1 for protocol version 2.0 
 
Added signature page 
03/13/19 
4.0 
 
Describe final pregnancy analysis report and analyses included 
 
Updated formatting of outcome measures 
 
Provided further clarification for creatinine and creatinine 
clearance events for primary maternal adverse safety outcome 
measure 
 
Added secondary objective and outcome measure on maternal 
weight change 
 
Added analysis for maternal weight change 
 
Added analysis of pregnancy dating methods 
 
Added major changes that were included in LoA #2 for protocol 
version 2.0 
10/17/19 
5.0 
 
Added analysis of DXA scan results 
 
Added logistic regression and weighted ordinal logistic models to 
hierarchy analysis 
 
Added analyses that describe effect of SARS-CoV-2 on study 
10/26/2020 
 
 
 
 

Prot_003.pdf: 
Letter of Amendment #3 
Page 1 of 5 
10 June 2020 
IMPAACT 2010 Protocol Version 2.0 
Letter of Amendment #3 for: 
 
IMPAACT 2010 
Phase III Study of the Virologic Efficacy and Safety of 
Dolutegravir-Containing versus Efavirenz-Containing Antiretroviral Therapy 
Regimens in HIV-1-Infected Pregnant Women and their Infants 
 
Version 2.0, dated 8 December 2017 
 
DAIDS Study ID #30129 
IND #133,438 
 
Letter of Amendment Date: 10 June 2020 
 
 
Table of Contents 
 
Information/Instructions to Study Sites from the Division of AIDS ............................................................ 1 
Letter of Amendment Signature Page ........................................................................................................... 2 
Summary of Modifications, Rationale, and Implementation ........................................................................ 3 
 
 
Information/Instructions to Study Sites from the Division of AIDS 
 
The information contained in this Letter of Amendment (LoA) affects the IMPAACT 2010 study and 
must be submitted to site Institutional Review Boards and/or Ethics Committees (IRBs/ECs) as soon as 
possible for their review and approval. Approval must also be obtained from other site regulatory entities 
if applicable per the policies and procedures of the regulatory entities. All applicable IRB/EC and 
regulatory entity requirements must be followed. 
 
This LoA incorporates the contents of protocol Clarification Memorandum (CM) #2, which was issued on 
31 March 2020 to safeguard the health and well-being of IMPAACT 2010 study participants in the 
context of circulating SARS-CoV-2 and the associated COVID-19 pandemic. Per the study Sponsor, sites 
were instructed to implement the guidance provided in CM #2 immediately. 
 
Upon obtaining IRB/EC approvals and any other applicable regulatory entity approvals, sites are required 
to submit an LoA registration packet to the DAIDS Protocol Registration Office (DAIDS PRO) at the 
Regulatory Support Center. Sites will receive a registration notification for the LoA after the DAIDS PRO 
verifies that all required registration documents have been received and are complete. Sites should not 
await this notification before implementing this LoA.  
 
Please file this LoA, all associated IRB/EC and regulatory entity correspondence, and all correspondence 
with the DAIDS PRO in your essential document files for IMPAACT 2010. 
 


Letter of Amendment #3 
Page 2 of 5 
10 June 2020 
IMPAACT 2010 Protocol Version 2.0 
IMPAACT 2010 
Phase III Study of the Virologic Efficacy and Safety of 
Dolutegravir-Containing versus Efavirenz-Containing Antiretroviral Therapy 
Regimens in HIV-1-Infected Pregnant Women and their Infants 
 
DAIDS Study ID #30129 
 
 
Version 2.0, Letter of Amendment #3 
Letter of Amendment Signature Page 
 
 
I will conduct this study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with United States (US) Health and 
Human Service regulations (45 CFR 46); applicable US Food and Drug Administration regulations; 
standards of the International Council on Harmonization Guideline for Good Clinical Practice (E6); 
Institutional Review Board/Ethics Committee determinations; all applicable in-country, state, and local 
laws and regulations; and other applicable requirements (e.g., US National Institutes of Health, Division 
of AIDS) and institutional policies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator of Record 
  
 
Date 
 
 
 
 
 
 
 
 
 
 
Name of Investigator of Record  
 
(printed) 
 
 


Letter of Amendment #3 
Page 3 of 5 
10 June 2020 
IMPAACT 2010 Protocol Version 2.0 
Summary of Modifications, Rationale, and Implementation 
 
This LoA incorporates the contents of protocol Clarification Memorandum (CM) #2, which was issued on 
31 March 2020 to safeguard the health and well-being of study participants in the context of circulating 
SARS-CoV-2 and the associated COVID-19 pandemic. CM #2 provided operational flexibility for 
conducting study visits and procedures when needed to ensure ongoing access to maternal study drug and 
to prioritize the conduct of clinically and scientifically important maternal and infant evaluations when 
possible.    
 
Consistent with the instructions provided in CM #2, implementation of this LoA is expected to be time-
limited in relation to the COVID-19 pandemic. In consultation with IMPAACT Network leadership and 
the study Sponsor, the IMPAACT 2010 Protocol Team will determine when, in the future, the 
specifications of this LoA are no longer applicable. When such a determination is made, study sites will 
be formally notified and instructed to inform IRBs/ECs and other applicable regulatory entities. 
 
  
Operational Guidance from Protocol CM #2, dated 31 March 2020 
 
This CM provides operational guidance to study sites from the IMPAACT 2010 Protocol Team. The 
Protocol Team acknowledges that the extent to which site operations may be disrupted by the COVID-19 
pandemic may vary across sites and over time. All sites should follow applicable government, health 
authority, and institutional policies with respect to conduct of study visits and procedures, with 
utmost importance placed on the health and well-being of study participants and study staff. Site 
investigators should continue to follow current protocol specifications for communication with the 
Protocol Team and/or Clinical Management Committee and should contact the Clinical Management 
Committee (impaact.2010cmc@fstrf.org) with any questions or concerns regarding this CM or 
management of study participants.  
 
Visit Scheduling 
 
Sites that anticipate operational disruptions or closures in the near future are advised to conduct study 
visits early in the allowable visit window. Visits conducted prior to opening of the allowable window 
would also be preferred to completely missing a visit at a later date. 
 
Sites that are currently experiencing operational disruptions or closures are advised to conduct study 
visits late in the allowable visit window. Visits conducted after closing of the allowable window 
would also be preferred to completely missed visits.  
 
Effective with the issuance of this CM, the allowable window for conducting maternal and infant 
Week 50 Visits is broadened to include up to 12 weeks before and up to 24 weeks after the visit target 
date.  
 
Prioritization of Study Visit Procedures 
 
Sites with full capacity to conduct study visits in-person at the study clinic should continue to do so in 
full compliance with the protocol. 
 
Sites may also conduct study visits — in full or in part — off-site if permitted by applicable 
government, health authority, and institutional policies. Where this option is permitted, site staff 
should communicate with maternal participants to determine in advance where and when such visits 
will take place, with adequate protections for safety, privacy, and confidentiality. Off-site visit 
procedures should be conducted by site staff who are adequately qualified and trained to conduct the 
procedures, as determined by the site Investigator of Record (IoR), with attention paid to occupational 
health, biohazard containment, and specimen and data chain of custody. These staff should also be 
adequately qualified and trained to immediately assess and/or manage any adverse events or social 


Letter of Amendment #3 
Page 4 of 5 
10 June 2020 
IMPAACT 2010 Protocol Version 2.0 
impacts that may occur during the visits. If adverse events requiring further evaluation or 
management are identified during an off-site visit, staff conducting the visit should arrange for 
appropriate clinical management, in consultation with the IoR or designee as needed.  
 
Sites with limited capacity to conduct in-person study visits should prioritize maternal HIV-1 RNA 
(viral load) testing and infant diagnostic HIV nucleic acid testing (NAT). If these tests cannot be 
performed consistent with a site’s Protocol Analyte List, the tests may be performed in alternate 
laboratories using alternate assays (alternate laboratories must adhere to local regulations for clinical 
laboratory testing).  
­ Maternal serum creatinine testing is the next highest priority (following maternal HIV-1 RNA 
testing and infant NAT), followed by other maternal chemistries and hematology. Specimen 
collection for storage is of lowest priority. 
­ Medical and medication histories may be obtained remotely (e.g., by telephone) 
­ Adherence assessment, counseling, and support may be provided remotely.  
­ Contraception counseling may be provided remotely. Sites should discuss options for ongoing 
access to contraception throughout the duration of study participation. 
­ Questionnaires may be administered remotely. 
­ DXA scans may be skipped/missed. 
 
Study Drug Supply 
 Prior to the Week 50 visit, sites are advised to dispense maternal study drug supplies in quantities 
sufficient for the remainder of the study follow-up period, i.e., through the end of the Week 50 visit 
window.  
 At the Week 50 visit, where feasible, sites are encouraged to provide a supply of non-study ARVs or 
to implement other post-study access plans to facilitate successful maternal transition to non-study 
ART and care. 
 Where feasible, sites are encouraged to implement study drug delivery options involving outdoor pick-
up or drop-off. Where outdoor pick-up or drop-off is not feasible, the Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks permit shipment or courier of study drug from the site 
directly to participants. This method should only be used in the short-term and if permissible per local 
institutional and IRB/EC policies. Refer to the Guidelines for additional details on this method. 
 Sites are permitted to utilize rapid urine pregnancy test kits (either performed by study staff or given to 
and performed by mothers themselves) in the context of these study drug pick-up or drop-off options. 
If pregnancy testing cannot be performed for any reason, however, study drug supplies should still be 
provided. Dolutegravir will not be provided to any mother who reports that she is newly pregnant.  
 
Documentation 
 
Site-specific contingency plans, and the implementation thereof, should be documented in essential 
document files for IMPAACT 2010.  
 
Documentation should be entered in participant study charts in real-time should any of the following 
occur: 
­ Missed visits  
­ Out-of-window visits 
­ Off-site visits (document the location of the visit) 
­ Incomplete or partial visits (document which procedures were performed and which were not) 
­ Remote contacts performed in lieu of in-person visits (document method used to complete the 
contact and which procedures were performed) 
­ Any other participant contacts  
­ Use of alternate laboratories or alternate laboratory assays 
­ Alternate provision of study drug  


Letter of Amendment #3 
Page 5 of 5 
10 June 2020 
IMPAACT 2010 Protocol Version 2.0 
 
In consultation with the Division of AIDS, the IMPAACT Network is developing comprehensive 
guidance for documenting and/or reporting protocol deviations that may occur due to limited site 
capacity to conduct study visits or procedures during the COVID-19 pandemic. Similar guidance will 
be provided for documentation of use of alternate laboratories or alternate laboratory assays. Once 
this Network-level guidance is available, it will be provided in a separate communication to all sites.  

Prot_002.pdf: 
Letter of Amendment #2 
Page 1 of 10 
23 August 2019 
IMPAACT 2010 Protocol Version 2.0 
Letter of Amendment #2 for: 
 
IMPAACT 2010 
Phase III Study of the Virologic Efficacy and Safety of 
Dolutegravir-Containing versus Efavirenz-Containing Antiretroviral Therapy 
Regimens in HIV-1-Infected Pregnant Women and their Infants 
 
Version 2.0, dated 8 December 2017 
 
DAIDS Study ID #30129 
IND #133,438 
 
Letter of Amendment Date: 23 August 2019 
 
 
TABLE OF CONTENTS 
 
Information/Instructions to Study Sites from the Division of AIDS ............................................................ 1 
Letter of Amendment Signature Page ........................................................................................................... 2 
Summary of Modifications and Rationale .................................................................................................... 3 
Implementation ............................................................................................................................................. 4 
 
 
Information/Instructions to Study Sites from the Division of AIDS 
 
The information contained in this Letter of Amendment (LoA) affects the IMPAACT 2010 study and 
must be submitted to site Institutional Review Boards and/or Ethics Committees (IRBs/ECs) as soon as 
possible for their review and approval. Approval must also be obtained from other site regulatory entities 
if applicable per the policies and procedures of the regulatory entities. All applicable IRB/EC and 
regulatory entity requirements must be followed. 
 
Upon obtaining IRB/EC approval and any other applicable regulatory entity approvals, each site should 
immediately begin implementing this LoA. Because this LoA does not impact the IMPACT 2010 
informed consent forms, re-consenting of previously enrolled participants is not required, unless sites are 
instructed otherwise by their IRBs/ECs or other regulatory entities.  
 
Upon obtaining IRB/EC approvals and any other applicable regulatory entity approvals, sites are required 
to submit an LoA registration packet to the DAIDS Protocol Registration Office (DAIDS PRO) at the 
Regulatory Support Center. Sites will receive a registration notification for the LoA after the DAIDS PRO 
verifies that all required registration documents have been received and are complete. Sites should not 
await this notification before implementing this LoA.  
 
Please file this LoA, all associated IRB/EC and regulatory entity correspondence, and all correspondence 
with the DAIDS PRO in your essential documents files for IMPAACT 2010. If the IMPAACT 2010 
protocol is amended in the future, the contents of this LoA will be incorporated into the next version of 
the protocol. 
 


Letter of Amendment #2 
Page 2 of 10 
23 August 2019 
IMPAACT 2010 Protocol Version 2.0 
IMPAACT 2010 
Phase III Study of the Virologic Efficacy and Safety of 
Dolutegravir-Containing versus Efavirenz-Containing Antiretroviral Therapy 
Regimens in HIV-1-Infected Pregnant Women and their Infants 
 
DAIDS Study ID #30129 
 
 
Version 2.0, Letter of Amendment #2 
Letter of Amendment Signature Page 
 
 
I will conduct this study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with United States (US) Health and 
Human Service regulations (45 CFR 46); applicable US Food and Drug Administration regulations; 
standards of the International Conference on Harmonization Guideline for Good Clinical Practice (E6); 
Institutional Review Board/Ethics Committee determinations; all applicable in-country, state, and local 
laws and regulations; and other applicable requirements (e.g., US National Institutes of Health, Division 
of AIDS) and institutional policies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator of Record 
  
 
Date 
 
 
 
 
 
 
 
 
 
 
Name of Investigator of Record  
 
(printed) 
 
 


Letter of Amendment #2 
Page 3 of 10 
23 August 2019 
IMPAACT 2010 Protocol Version 2.0 
Summary of Modifications and Rationale 
 
The purpose of this LoA is to: 
 
 
Permit use of plasma stored at the Screening Visit for maternal HIV-1 RNA (viral load) testing. Such 
testing may be of interest to further characterize the virologic profiles of mothers enrolled in the study 
and to assist with interpretation of study outcomes for mothers who may have had a suppressed viral 
load at study entry. No additional blood will be collected for this testing. Testing will be performed at 
the same central laboratory designated to perform HIV-1 RNA testing for the secondary study 
objective evaluating virologic suppression to less than 50 copies/mL at delivery.  
 
 
Clarify that statistical analyses of maternal creatinine levels and creatinine clearance rates will be 
based on severity grades determined from the absolute values of these outcome measures. The 
Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, referenced 
in protocol Section 7.3.3, provides severity grading for these parameters based on both absolute value 
and change from baseline. Because mothers are pregnant at study entry, and experience physiologic 
changes during pregnancy that affect these parameters, changes in these parameters from baseline do 
not provide a valid measure of renal function over time (antepartum and postpartum). Therefore, 
analyses of these outcome measures will be based on absolute values.  
 
 
Clarify that statistical analyses of infant bone outcome measures will be based on absolute bone 
mineral content (BMC) values. Because international normative BMC values have not been 
established for infants, Z-scores will not be used for these analyses.  
 
 
Add a secondary study objective and associated outcome measures and statistical analyses related to 
the effects of study drug regimens on changes in maternal weight. Results of recent studies have 
suggested that regimens containing dolutegravir (DTG) may be associated with weight gain, as may 
regimens containing tenofovir alafenamide (TAF) (1, 2). The applicability of these results to pregnant 
and postpartum women is unclear; therefore, data on maternal weight collected in this study will be 
analyzed for these possible effects.  
 
References: 
1. Bourgi K, Rebeiro PF, Turner M, Castilho JL, Hulgan T, Raffanti SP, et al. Greater Weight Gain 
in Treatment Naive Persons Starting Dolutegravir-Based Antiretroviral Therapy. Clinical 
infectious diseases : an official publication of the Infectious Diseases Society of America. 2019. 
2. Gomez M, Seybold U, Roider J, Harter G, Bogner JR. A retrospective analysis of weight changes 
in HIV-positive patients switching from a tenofovir disoproxil fumarate (TDF)- to a tenofovir 
alafenamide fumarate (TAF)-containing treatment regimen in one German university hospital in 
2015-2017. Infection. 2019;47(1):95-102. 
 
 
Add as a new appendix to the protocol (Appendix VI) the listing of prohited and precautionary 
medications that was previously posted on the study-specific website. The posted listing is dated 
5 October 2018 and its content remains current as of the date of this LoA. The listing is being added 
as an appendix to the protocol at the request of DAIDS. 
 
 
Update links to websites where DAIDS resources for key aspects of study implementation can be 
accessed. 
 


Letter of Amendment #2 
Page 4 of 10 
23 August 2019 
IMPAACT 2010 Protocol Version 2.0 
Implementation 
 
Modifications of protocol text are provided below, generally in order of appearance in the protocol. 
Where applicable, modified text is shown using strikethrough for deletions and bold type for additions.  
 
1. Section 2.2, secondary objective 2.2.7, added:  
 
2.2.7 
Whether changes in maternal weight differ for any pairwise comparison or when 
comparing a DTG-containing regimen to EFV/FTC/TDF 
 
This addition is also incorporated into the protocol Schema (edits not shown). 
 
2. Section 5.9, second sentence: 
 
A list of prohibited medications will be is included in Appendix VI and posted on the study-specific 
website: http://impaactnetwork.org/studies/IMPAACT2010.asp. 
 
3. Section 5.10: 
 
A list of medications that should be used with caution while on study drug will be is included in 
Appendix VI and posted on the study-specific website: 
http://impaactnetwork.org/studies/IMPAACT2010. asp. 
 
4. Section 6.1, within the procedural table for Screening Visits, row for Laboratory, Blood, last bullet 
point: 
 
 
Stored plasma for antiretroviral resistance testing and possible HIV-1 RNA testing 
 
5. Section 7.3.1, first paragraph: 
 
Requirements, definitions, and methods for expedited reporting of adverse events are outlined in 
Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE 
Manual), which is available at https://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-
reporting-adverse-events-daids on the DAIDS RSC website at: 
http://rsc.techres.com/safetyandpharmacovigilance. 
 
6. Section 7.3.1, second paragraph, last sentence: 
 
This form is available at https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting on 
the DAIDS RSC website at: http://rsc.techres.com/safetyandpharmacovigilance. 
 
7. Section 7.3.3, first paragraph, second sentence: 
 
This table is available at https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-
grading-tables on the RSC website at http://rsc.tech-res.com/clinical-research-
sites/safetyreporting/daids-grading-tables. 
 


Letter of Amendment #2 
Page 5 of 10 
23 August 2019 
IMPAACT 2010 Protocol Version 2.0 
8. Section 9.2, table rows for 9.2.1.2 and 9.2.2.4, second bullet point in each row:  
 
 
Maternal grade 3 or higher adverse events, including events resulting in death due to any cause, 
through 50 weeks postpartum (refer to Section 7.3.3 for severity grading; for this outcome 
measure, grade 3 or higher creatinine levels and creatinine clearance rates will be defined 
based on absolute values (>1.8 x ULN for creatinine, <60 mL/min for creatinine clearance 
rate)) 
 
9. Section 9.2, table row for 9.2.2.7, added, corresponding to secondary objective 2.2.7:  
 
 
Change in maternal weight antepartum (from study entry to delivery) 
 
Change in maternal weight postpartum (from delivery to 50 weeks postpartum) 
 
Change in maternal weight overall (from study entry to 50 weeks postpartum) 
 
10. Section 9.2, table row for Other Outcome Measures, third bullet point:  
 
 
Infant whole body and lumbar spine BMC values Z-scores based on DXA scan at 26 weeks 
postpartum 
 
11. Section 9.6, last paragraph, added:  
 
The results of any HIV-1 RNA testing performed with plasma stored at the Screening Visit will 
be analyzed descriptively. For statistical analyses that evaluate virologic change from baseline, 
the HIV-1 RNA result from the study Entry Visit will be considered the baseline value.  
 
12. Section 9.6.2, last paragraph, added:  
 
Longitudinal maternal pregnancy weight, postpartum weight, and weight since randomization 
will be compared by arm with a time and arm interaction using generalized estimating 
equations. Analyses will compare each arm to the other arms (all pairwise comparisons) and 
compare the EFV-containing arm to the DTG-containing arms. 
 
13. Section 13.2, fourth paragraph: 
 
For additional information on the protocol registration process and specific documents required for 
initial and amendment registrations, refer to the current version of the DAIDS Protocol Registration 
Manual, which is available at https://www.niaid.nih.gov/research/daids-clinical-site-
implementation-operations 
on the RSC website at http://rsc.tech-res.com/clinicalresearch-sites/protocol-registration. 
 
14. Added Appendix VI, Prohibited and Precautionary Medications, as shown starting on the next page. 
 
 


Letter of Amendment #2 
Page 6 of 10 
23 August 2019 
IMPAACT 2010 Protocol Version 2.0 
Appendix VI 
Prohibited and Precautionary Medications 
 
The following information may not be all-inclusive. Our understanding of drug interactions continues to 
grow as new information becomes available. Please refer to the most up-to-date prescribing information 
(package inserts) and the following drug interaction websites when determining the significance of 
potential drug interactions; these websites are regularly updated as new information becomes available: 
 
HIV drug interaction: www.hiv-druginteractions.org 
 
inPractice: http://www.inPractice.com 
 
Any mother enrolled in IMPAACT 2010 who requires a prohibited medication must have the relevant 
study drug(s) held or permanently discontinued. Upon identification of the need for a prohibited 
medication, the site investigator should consult the IMPAACT 2010 Clinical Management Committee 
(CMC) for further guidance on study drug management. Consultation with the CMC is recommended but 
not required for precautionary medications. 
 
Per protocol Section 5.8.1, mothers who have not initiated cotrimoxazole or isoniazid prophylaxis prior to 
study entry should preferably defer initiation of these medications until at least two weeks after initiation 
of their study drug regimen, if eligible to initiate such prophylaxis per local standards of care. 
 
Refer to protocol Section 8.4 for additional information on management of mothers who require rifampin-
containing treatment for active tuberculosis (TB). 
 
The remainder of this document provides further information on medications considered prohibited or 
precautionary with concurrent use of each study drug agent.  
 
Note: With respect to IMPAACT 2010 exclusion criterion 4.2.4 (eighth bullet point), receipt of any 
antiretrovirals (ARVs) within the 14 days prior to study entry — as allowed per inclusion criterion 4.1.3 
and exclusion criterion 4.2.4 (seventh bullet) — should not be considered exclusionary when assessing 
eligibility for this study. Upon enrollment, mothers will discontinue any non-study-supplied ARVs and 
begin taking study-supplied ARVs consistent with their random assignment (i.e., ARVs that might 
otherwise be noted as prohibited in this document will not be co-administered with study-supplied 
ARVs).  
 
1 
Precautionary and Prohibited Medications for Dolutegravir (DTG) 
 
1.1 
Prohibited Medications for DTG 
 
DTG should NOT be coadministered with dofetalide. 
 
DTG is metabolized by UGT1A1 with some contribution from CYP3A. DTG is also a substrate 
of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs that induce these enzymes and 
transporters may decrease DTG plasma concentration and reduce the therapeutic effect of DTG. 
Coadministration of DTG and drugs that inhibit these enzymes may increase DTG plasma 
concentration. 
 


Letter of Amendment #2 
Page 7 of 10 
23 August 2019 
IMPAACT 2010 Protocol Version 2.0 
The following drugs should NOT be coadministered with DTG, either due to established or 
potential significant interactions or due to lack of data to guide DTG dosing: 
 
Nevirapine 
 
Oxcarbazepine 
 
Phenytoin 
 
Phenobarbital 
 
St. John’s wort 
 
1.2 
Precautionary Medications for DTG 
 
The following drugs should be used with caution: 
 
Cation-containing antacids or laxatives, sucralfate, oral supplements containing iron or 
calcium, or buffered medications (DTG should be taken two hours before or six hours after 
taking these medications; alternatively, DTG and supplements containing calcium or iron can 
be taken together with food) 
 
Etravirine (coadministration without atazanavir/ritonavir, darunavir/ritonavir, or 
lopinavir/ritonavir is not recommended) 
 
Efavirenz, fosamprenavir/ritonavir, and tipranavir/ritonavir (dose of DTG should be adjusted 
per the package insert) 
 
Carbamazepine (dose of DTG should be adjusted per the package insert) 
 
Rifampin (refer to protocol Section 8.4; the CMC should be informed of all TB diagnoses and 
consulted on study drug management, with the general expectation the dose of DTG will be 
adjusted per the package insert during the period of rifampin treatment) 
 
Metformin (dose of metformin should be limited or adjusted per the package insert) 
 
2 
Precautionary and Prohibited Medications for Tenofovir Alafenamide (TAF) 
 
2.1 
Prohibited Medications for TAF 
 
TAF should not be coadministered with tenofovir disoproxil fumarate (TDF) or other drugs 
containing TDF (e.g., EFV/FTC/TDF, FTC/RPV/TDF, EVG/COBI/FTC/TDF, or FTC/TDF). 
TAF also should not be coadministered with other TAF-containing products (e.g., 
FTC/RPV/TAF). 
 
Note: Receipt of TAF or TDF within the 14 days prior to study entry should not be considered 
exclusionary. 
 
TAF is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Drugs that strongly affect P-gp 
activity may lead to changes in TAF absorption. Drugs that induce P-gp activity are expected to 
decrease the absorption of TAF, resulting in decreased plasma concentration of TAF, which 
may lead to loss of therapeutic effect and development of resistance. 
 
Due to interactions that decrease TAF concentrations, the following drugs should NOT be 
coadministered with TAF: 
 
Tipranavir/ritonavir  


Letter of Amendment #2 
Page 8 of 10 
23 August 2019 
IMPAACT 2010 Protocol Version 2.0 
 
Rifabutin, rifampin, and rifapentine (refer to protocol Section 8.4; the CMC should be 
informed of all TB diagnoses and consulted on study drug management, with the general 
expectation that TAF will be replaced with TDF during the period of TB treatment with these 
drugs)  
 
St. John’s wort 
 
2.2 
Precautionary Medications for TAF 
 
Because tenofovir is primarily excreted by the kidneys by a combination of glomerular filtration 
and active tubular secretion, coadministration of TAF with drugs that reduce renal function or 
compete for active tubular secretion may increase concentrations of tenofovir and other renally 
eliminated drugs and this may increase the risk of adverse reactions. Because of this, the 
following drugs, if administered systemically (and not only topically), should be used with 
caution: 
 
Acyclovir, cidofovir, ganciclovir, valacyclovir, and valganciclovir 
 
Aminoglycosides (e.g., gentamicin) 
 
High-dose or multiple NSAIDs 
 
The following drugs should also be used with caution: 
 
Carbamazepine, oxcarbazepine, phenobarbital, and phenytoin (an alternative anticonvulsant 
should be considered) 
 
3 
Precautionary and Prohibited Medications for Tenofovir Disoproxil Fumarate (TDF) 
 
3.1 
Prohibited Medications for TDF 
 
TDF should NOT be coadministered with adefovir dipivoxil. 
 
TDF should not be coadministered with tenofovir alafenamide (TAF) or other drugs containing 
TAF (e.g., FTC/RPV/TAF). TDF also should not be coadministered with other TDF-containing 
products (e.g., EFV/FTC/TDF, FTC/RPV/TDF, EVG/COBI/FTC/TDF, or FTC/TDF). 
 
Note: Receipt of TDF or TAF within the 14 days prior to study entry should not be considered 
exclusionary. 
 
TDF also should NOT be coadministered with atazanavir without ritonavir. 
 
3.2 
Precautionary Medications for TDF 
 
Because tenofovir is primarily excreted by the kidneys by a combination of glomerular filtration 
and active tubular secretion, coadministration of TAF with drugs that reduce renal function or 
compete for active tubular secretion may increase concentrations of tenofovir and other renally 
eliminated drugs and this may increase the risk of adverse reactions. Because of this, the 
following drugs, if administered systemically (and not only topically), should be used with 
caution: 
 
Acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir 
 
Aminoglycosides (e.g., gentamicin) 
 
High-dose or multiple NSAIDs 
 


Letter of Amendment #2 
Page 9 of 10 
23 August 2019 
IMPAACT 2010 Protocol Version 2.0 
The following drugs should also be used with caution: 
 
Didanosine (coadministration increases didanosine concentrations; use with caution and 
monitor for didanosine-associated adverse reactions, including pancreatitis and neuropathy; 
dose of didanosine may be adjusted per the package insert) 
 
Lopinavir/ritonavir, atazanavir coadministered with ritonavir, and darunavir coadministered 
with ritonavir (coadministration increases tenofovir concentrations; use with caution and 
monitor for TDF-associated adverse reactions) 
 
Ledipasvir/sofosbuvir (coadministration increases tenofovir concentrations; use without a 
protease inhibitor with caution and monitor for TDF-associated adverse reactions; when a 
protease inhibitor is used, consider an alternative Hepatitis C or antiretroviral therapy) 
 
4 
Precautionary and Prohibited Medications for Emtricitabine (FTC) 
 
4.1 
Prohibited Medications for FTC 
 
FTC should not be coadministered with lamivudine (3TC) or other drugs containing 3TC. FTC 
also should not be coadministered with other emtricitabine-containing products (e.g., 
EFV/FTC/TDF, FTC/RPV/TDF, EVG/COBI/FTC/TDF, or FTC/TDF). 
 
Note: Receipt of FTC within the 14 days prior to study entry should not be considered 
exclusionary. 
 
4.2 
Precautionary Medications for FTC 
 
Because FTC is primarily excreted by the kidneys by a combination of glomerular filtration and 
active tubular secretion, coadministration of FTC with drugs that reduce renal function or 
compete for active tubular secretion may increase concentrations of FTC and other renally 
eliminated drugs and this may increase the risk of adverse reactions. Because of this, the 
following drugs, if administered systemically (and not only topically), should be used with 
caution: 
 
Acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir 
 
Aminoglycosides (e.g., gentamicin) 
 
High-dose or multiple NSAIDs 
 
5 
Prohibited and Precautionary Medications with Efavirenz (EFV) 
 
5.1 
Prohibited Medications for EFV 
 
EFV should NOT be coadministered with other NNRTIs. 
 
Note: Receipt of EFV within the 14 days prior to study entry should not be considered 
exclusionary. 
 
The following drugs should NOT be coadministered with EFV because of potential loss of 
therapeutic effect or because data are not available on drug-drug interactions: 
 
Unboosted fosamprenavir calcium 
 
Indinavir and saquinavir 
 
Boceprevir and simeprevir 
 
Carbamazepine (alternative anticonvulsant treatment should be used) 
 
Itraconazole, ketoconazole, and voriconizole (alternative antifungal treatment should be used) 


Letter of Amendment #2 
Page 10 of 10 
23 August 2019 
IMPAACT 2010 Protocol Version 2.0 
There is limited information available on the potential for a pharmacodynamics interaction 
between EFV and drugs that prolong the QTc interval. QTc prolongation has been observed with 
the use of EFV. Alternatives to EFV should be considered when coadministered with a drug with 
a known risk of Torsade de Pointes. Use of atovaquone/proguanil is not recommended with EFV. 
 
5.2 
Precautionary Medications for EFV 
 
EFV has been shown in vivo to induce CYP3A and CYP2B6. Other compounds that are 
substrates of CYP3A or CYP2B6 may have decreased plasma concentrations when 
coadministered with EFV. Drugs that induce CYP3A activity (e.g., phenobarbital, rifampin, 
rifabutin) would be expected to increase the clearance of EFV resulting in lowered plasma 
concentrations. 
 
The following drugs should be used with caution: 
 
Fosamprenavir/ritonavir, atazanavir, and lopinavir/ritonavir (refer to package inserts for dose 
adjustments for these drugs)  
 
Ritonavir (monitor for elevation of liver enzymes and for adverse clinical experiences) 
 
Maraviroc (refer to package insert for this drug) 
 
Warfarin (monitor INR and adjust warfarin dose if necessary) 
 
Phenytoin and phenobarbital (monitor for anticonvulsant plasma levels) 
 
Bupropion and sertraline (adjust dose of these drugs based on clinical response) 
 
Posaconazole (avoid use unless benefit outweighs risk) 
 
Rifabutin and rifampin (refer to protocol Section 8.4 and the package insert for EFV; the 
CMC should be informed of all TB diagnoses and consulted on study drug management 
during the period of rifampin treatment) 
 
Artemether/lumefantrine and macrolide antibiotics, including clarithromycin (alternative 
treatment should be considered as should the risk:benefit ratio of adding drugs that may have 
a risk of QTc prolongation) 
 
Diltiazem and other calcium channel blockers, e.g., felodipine, nicardipine, nifedipine, 
verapamil (refer to package inserts for dose adjustments for these drugs) 
 
HMG-CoA reductase inhibitors, including atorvastatin, pravastatin, and simvastatin (refer to 
package inserts for dose adjustments for these drugs) 
 
Hormonal contraceptives, including oral ethinyl estradiol/norgestimate and implant 
etonogestral (reliable barrier methods of contraception should be used in addition to 
hormonal contraceptives) 
 
Immunosuppressants, including cyclosporine, tacrolimus, sirolimus, and others metabolized 
by CYP3A (refer to package inserts for dose adjustments for these drugs) 
 
Methadone (monitor for signs of methadone withdrawal and increase dose if required to 
alleviate withdrawal symptoms) 

Prot_001.pdf: 
 
Letter of Amendment #1 
Page 1 of 27 
20 July 2018 
IMPAACT 2010 Protocol Version 2.0 
Letter of Amendment #1 for: 
 
IMPAACT 2010 
Phase III Study of the Virologic Efficacy and Safety of 
Dolutegravir-Containing versus Efavirenz-Containing Antiretroviral Therapy 
Regimens in HIV-1-Infected Pregnant Women and their Infants 
 
Version 2.0, dated 8 December 2017 
 
DAIDS Study ID #30129 
IND #133,438 
 
Letter of Amendment Date: 20 July 2018 
 
 
TABLE OF CONTENTS 
 
Information/Instructions to Study Sites from the Division of AIDS ............................................................ 2 
Letter of Amendment Signature Page ........................................................................................................... 3 
Summary of Modifications and Rationale .................................................................................................... 4 
Implementation ............................................................................................................................................. 4 
Updates of Abbreviations and Acronyms ................................................................................................. 4 
Updates of Protocol Team Roster ............................................................................................................. 4 
Updates of Section 1, Introduction ........................................................................................................... 5 
Updates of Section 2, Objectives .............................................................................................................. 6 
Updates of Section 4, Study Population .................................................................................................... 7 
Updates of Section 5, Study Drug Considerations .................................................................................... 8 
Updates of Section 6, Study Visits and Procedures .................................................................................. 8 
Updates of Section 7, Safety Assessment, Monitoring, and Reporting .................................................. 14 
Updates of Section 8, Participant Management ...................................................................................... 15 
Updates of Section 9, Statistical Considerations .................................................................................... 18 
Updates of Section 12, Human Subjects Protections .............................................................................. 18 
Updates of Section 15, References ......................................................................................................... 18 
Updates of Appendix I, Schedule of Evaluations ................................................................................... 19 
Updates of Appendix III, Sample Informed Consent Form .................................................................... 19 
Updates of Appendix V, Sample Informed Consent Form for Use of Study Drug during Subsequent 
Pregnancy ................................................................................................................................................ 22 
Appendix I Schedule of Evaluations ........................................................................................................... 24 
 
 
 
 


 
Letter of Amendment #1 
Page 2 of 27 
20 July 2018 
IMPAACT 2010 Protocol Version 2.0 
Information/Instructions to Study Sites from the Division of AIDS 
 
The information contained in this Letter of Amendment (LoA) affects the IMPAACT 2010 study, 
including the study informed consent forms (ICFs), and must be submitted to site Institutional Review 
Boards and/or Ethics Committees (IRBs/ECs) as soon as possible for their review and approval. Approval 
must also be obtained from other site regulatory entities if applicable per the policies and procedures of 
the regulatory entities. Study sites may request expedited review of this LoA and revised site-specific 
informed consent forms. However, each review body should determine the review procedure to be 
followed, according to its policies and procedures; all applicable IRB/EC and regulatory entity 
requirements must be followed. 
 
Before this LoA can be implemented at any site, an “Implementation Notice” for the LoA must be issued 
by the IMPAACT Operations Center confirming that all operational requirements for implementing the 
LoA at the network level have been completed. Sites should also follow the instructions below regarding 
site-specific timing of implementation of the LoA: 
 
For sites that were activated to initiate the study prior to issuance of this LoA: 
 
 
Upon obtaining all required IRB/EC and regulatory entity approvals, each site should immediately 
begin implementing this LoA. Sites are required to submit an LoA registration packet to the DAIDS 
Protocol Registration Office (DAIDS PRO) at the Regulatory Support Center (RSC). Sites will 
receive a registration notification for the LoA after the DAIDS PRO verifies that all required 
registration documents have been received and are complete. Sites should not await this notification 
before implementing this LoA. 
 
Participant accrual may be resumed upon receipt of all required IRB/EC and regulatory entity 
approvals of protocol Version 2.0 and this LoA, using revised site-specific ICFs corresponding to this 
LoA. 
 
For mother-infant pairs enrolled prior to implementation of this LoA, re-consent for study 
participation should be obtained at the next scheduled study visit, using the revised site-specific ICFs 
corresponding to this LoA.  
 
For sites that were not activated to initiate the study prior to issuance of this LoA: 
 
 
Upon obtaining all required IRB/EC and regulatory entity approvals, sites are required to submit an 
LoA registration packet to the DAIDS PRO at the RSC. Sites will receive a registration notification 
for the LoA after the DAIDS PRO verifies that all required registration documents have been received 
and are complete. 
 
Activation will occur following receipt of all required IRB/EC and regulatory entity approvals for 
protocol Version 2.0 and this LoA; receipt of a protocol registration notification for protocol Version 
2.0; receipt of the protocol registration notification for this LoA; completion of all other study 
activation requirements; and receipt of a site-specific study activation notice from the IMPAACT 
Operations Center.  
 
Please file this LoA, corresponding site-specific informed consent forms, all associated IRB/EC and 
regulatory entity correspondence, and all correspondence with the DAIDS PRO in your essential 
documents files for IMPAACT 2010. If the IMPAACT 2010 protocol is amended in the future, the 
contents of this LoA will be incorporated into the next version of the protocol. 
 


 
Letter of Amendment #1 
Page 3 of 27 
20 July 2018 
IMPAACT 2010 Protocol Version 2.0 
IMPAACT 2010 
Phase III Study of the Virologic Efficacy and Safety of 
Dolutegravir-Containing versus Efavirenz-Containing Antiretroviral Therapy 
Regimens in HIV-1-Infected Pregnant Women and their Infants 
 
DAIDS Study ID #30129 
 
 
Version 2.0, Letter of Amendment #1 
Letter of Amendment Signature Page 
 
 
I will conduct this study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with United States (US) Health and 
Human Service regulations (45 CFR 46); applicable US Food and Drug Administration regulations; 
standards of the International Conference on Harmonization Guideline for Good Clinical Practice (E6); 
Institutional Review Board/Ethics Committee determinations; all applicable in-country, state, and local 
laws and regulations; and other applicable requirements (e.g., US National Institutes of Health, Division 
of AIDS) and institutional policies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator of Record 
  
 
Date 
 
 
 
 
 
 
 
 
 
 
Name of Investigator of Record  
 
(printed) 
 
 


 
Letter of Amendment #1 
Page 4 of 27 
20 July 2018 
IMPAACT 2010 Protocol Version 2.0 
Summary of Modifications and Rationale 
 
The main purpose of this LoA is to update the IMPAACT 2010 protocol and sample informed consent 
forms in response to a recent report of a potential increased risk of neural tube defects (NTDs) associated 
with exposure to dolutegravir (DTG) at the time of conception. The recent report was based on a 
preliminary unplanned analysis of data from an observational surveillance study of birth outcomes 
conducted in Botswana. As explained in protocol text below, these findings are not of immediate concern 
for mother-infant pairs entering the IMPAACT 2010, as DTG is initiated in the study at or after 14 weeks 
gestation, well after neural tube formation has occurred. The findings are of potential concern, however, 
in the event of subsequent pregnancies that enrolled mothers may conceive while taking DTG. Protocol 
modifications are incorporated to inform site investigators and study participants and to mitigate against 
the potential increased risk of NTDs in subsequent pregnancies. Modifications are also incorporated to 
enable exploration of potential mechanisms of action that may lead to NTDs.  
 
This LoA also harmonizes expedited adverse event (EAE) reporting requirements for all study 
participants, regardless of random assignment or maternal antiretroviral treatment (ART) regimen, as 
recommended by the Data and Safety Monitoring Board that oversees the study, and incorporates minor 
corrections and clarifications of protocol text.  
 
 
Implementation 
 
Modifications of protocol text are presented below, generally in order of appearance in the protocol. 
where applicable, modified text is showing using strikethrough for deletions and bold type for additions. 
 
Updates of Abbreviations and Acronyms 
 
1. 
In the listing of abbreviations and acronyms, the following terms are added: 
 
IUD 
intrauterine device 
IUS 
intrauterine system 
NTD 
neural tube defect 
 
 
Updates of Protocol Team Roster  
 
2. 
In the protocol team roster, the following Protocol Investigator is added:  
 
Chelsea Morroni, MD 
Liverpool School of Tropical Medicine 
Botswana Harvard AIDS Institute Partnership 
Private Bag BO320 
Gaborone, Botswana 
Phone: +267-765-24112 
Email: chelsea.morroni@lstmed.ac.uk 
 
 


 
Letter of Amendment #1 
Page 5 of 27 
20 July 2018 
IMPAACT 2010 Protocol Version 2.0 
Updates of Section 1, Introduction 
 
3. 
In Section 1.1, Background, fourth paragraph:  
 
DTG, a once-daily integrase inhibitor, is highly efficacious and generally well tolerated. It appears 
to have a very high barrier to development of HIV drug resistance. In a head-to-head study 
comparing DTG combined with ABC and 3TC to EFV/FTC/TDF, the DTG combination had 
superior virologic activity at 48 weeks (described below) (12). A Cochrane review comparing 
DTG plus two nucleoside reverse transcriptase inhibitors (NRTIs) to EFV plus two NRTIs 
concluded that DTG-containing regimens were superior to EFV-containing regimens at 48 
and 96 weeks with regard to efficacy, and were associated with reductions in treatment 
discontinuation (12a). The authors recommended that DTG-based regimens should be 
considered in future WHO guidelines for initial HIV treatment, and the PEPFAR program 
has been supporting this recommendation. As of early 2018, more than two dozen countries 
had changed their guidelines to include DTG in their preferred initial treatment regimen, 
with 50 additional countries planning to make this change soon (12b, 12c). DTG is included in 
two of the preferred first-line regimens recommended for adults by the US DHHS (13) and is used 
with increasing frequency in well-resourced settings. DTG was also recently included in WHO 
guidelines as an alternative first-line agent in non-pregnant adults (3) and is being incorporated into 
new national program guidelines for first-line use in some resource-limited countries. In 2015, 
CHAI, UNAIDS, and UNITAID announced a new agreement under which generically-
manufactured DTG will be available for $44 /patient per year (a price that is comparable to that of 
EFV) (14). Hence, it is expected that DTG may soon become a cornerstone of preferred first-line 
ART treatment globally. However, further data regarding the safety of DTG in pregnancy, and 
the safety and efficacy of DTG with concomitant tuberculosis treatment, are awaited prior to 
recommendation for and adoption of use of DTG more widely. 
 
4. 
In Section 1.1, Background, seventh paragraph:  
 
In sum, it is very likely that both DTG and TAF will be used with increasing frequency in the 
future, potentially as components of first-line recommended ART globally. The WHO 2015 
guidelines update noted that neither DTG nor TAF had been studied in pregnancy (both were 
pregnancy Category B); however, as described in Sections 1.2.2 and 1.3.2, data from studies in 
pregnancy are emerging. If DTG and TAF are included in future WHO-recommended first-line 
regimens in resource-limited settings as anticipated, it will be important to have data regarding their 
efficacy and safety in pregnancy (given the because of both an ethical imperative to offer 
pregnant women optimal ART regimens when possible and a desire to use the same first-line 
ART regimens in pregnant and non-pregnant patients, for programmatic simplicity). These data will 
also be of relevance in the US and other well-resourced settings. 
 
5. 
In Section 1.2.2, Dolutegravir: Studies in Pregnancy, fifth (added), sixth (added), seventh (added), 
and eighth paragraphs: 
 
To date, the largest body of data related to birth outcomes following use of DTG in pregnancy 
is from the Tsepamo birth outcomes surveillance study conducted in Botswana. This study 
was designed to evaluate adverse birth outcomes by maternal HIV status and ART regimen, 
and to determine whether there is an increased risk of neural tube defects (NTDs) among 
infants exposed to EFV from conception. Botswana’s HIV program moved to universal ART 
with DTG+FTC/TDF provided as the first-line regimen for patients starting ART, including 
pregnant women, in May 2016 (women already on other regimens were not switched to a 
DTG-containing regimen). The previous first-line regimen was EFV/FTC/TDF. Almost all 


 
Letter of Amendment #1 
Page 6 of 27 
20 July 2018 
IMPAACT 2010 Protocol Version 2.0 
women on DTG-based and EFV-based ART took these drugs in combination with FTC/TDF. 
More than 95% of women in Botswana deliver in-hospital, and obstetric records are available 
for more than 99% of women. The Tsepamo study is conducted at eight of the largest public 
maternity wards across Botswana, representing approximately 45% of all births in the 
country. Research assistants abstract exposure data from maternity cards for all consecutive 
in-hospital deliveries. Trained nurse midwives perform systematic infant surface 
examinations of all newborns, whether stillborn or live born. Reports and photographs (when 
available) of major abnormalities are reviewed by an experienced medical geneticist who is 
blinded to exposure information. (27a-27c) 
 
A preliminary unscheduled analysis of Tsepamo study data collected between 15 August 2014 
and 1 May 2018 was recently performed at the request of colleagues who were preparing for a 
WHO meeting. This analysis identified four infants with NTDs born to 426 women who 
became pregnant while taking DTG (prevalence 0.94%, 95% CI 0.37%, 2.4%). In 
comparison, 14 infants with NTDs were born to 11,300 women who became pregnant while 
taking a non-DTG-containing three-drug ART regimen (prevalence 0.12%, 95% CI 0.07%, 
0.21%); approximately half of these women were taking an EFV-containing regimen). No 
NTDs were identified among infants born to 2,812 women who started DTG-containing ART 
during pregnancy (including 280 women who started DTG-containing ART during the first 
trimester). (27d) 
 
At this time, only a small amount of additional data exists regarding birth outcomes among 
women taking DTG from conception, from multiple sources of varying data quality and 
completeness; from these sources, only one NTD was reported among infants born to 
approximately 323 women taking DTG from conception (27e). Additional data will continue 
to be collected — in Botswana and ideally in other settings — to try to determine whether this 
signal for NTDs with DTG exposure from conception persists, and whether it is found in 
different populations. The mechanisms underlying this NTD finding (if confirmed) are 
unknown; lower maternal folate levels, maternal diabetes, and maternal obesity are among 
the known risk factors for NTDs (27f, 27g). 
 
An observational surveillance study of birth outcomes in women starting ART during pregnancy (in 
the context of the national HIV treatment program) The Tsepamo study had previously showed 
similar rates of other adverse pregnancy outcomes (stillbirth, neonatal death, preterm or very 
preterm birth, small for gestational age or very small for gestational age) among 845 women 
initiating DTG/TDF/FTC (at median 19 weeks gestation) compared with 4593 women initiating 
EFV/TDF/FTC (at median 21 weeks gestation) in pregnancy. Among 512 women initiating ART in 
the first trimester of pregnancy (116 DTG/TDF/FTC, 396 EFV/TDF/FTC), one major congenital 
abnormality was identified (skeletal dysplasia in an EFV-exposed infant). (28) 
 
 
Updates of Section 2, Objectives 
 
6. 
In Section 2.3, Exploratory Objectives: 
 
2.3.7 
Assess potential markers of NTDs and the association of these markers with maternal 
ART regimens 
 
This update is also incorporated into the protocol Schema (edits not shown). 
 
 


 
Letter of Amendment #1 
Page 7 of 27 
20 July 2018 
IMPAACT 2010 Protocol Version 2.0 
Updates of Section 4, Study Population 
 
7. 
In Section 4.1, Inclusion Criterion 4.1.2, last paragraph: 
 
At least one sample should be tested using a test that can distinguish HIV-1 from HIV-2. If 
both samples are tested using antibody tests, at least one of the samples must be tested in a 
laboratory setting that operates according to Good Clinical Laboratory Practice (GCLP) guidelines 
and participates in an appropriate external quality assurance program. If nucleic acid testing is used, 
at least one test must be performed in a CLIA-certified (for US sites) or VQA-certified (for non-US 
sites) laboratory. For tests performed in other settings, adequate source documentation including the 
date of specimen collection, date of testing, test performed, and test result must be available. FDA-
approved testing methods should be used when possible. 
 
8. 
In Section 4.1, Inclusion Criterion 4.1.8 (added): 
 
4.1.8 
At study entry, mother reports that she does not wish to become pregnant again for at 
least 50 weeks after her current pregnancy and that she is willing to use effective 
contraception during this period  
 
Effective contraception may include surgical sterilization (i.e., hysterectomy, bilateral 
oophorectomy, tubal ligation, or salpingectomy) or any of the following methods: 
 
 
Contraceptive intrauterine device (IUD) or intrauterine system (IUS) 
 
Subdermal contraceptive implant 
 
Progestogen injections  
 
Progestogen only oral contraceptive pills 
 
Combined estrogen and progestogen oral contraceptive pills 
 
Percutaneous contraceptive patches 
 
Contraceptive vaginal rings 
 
Note: IUDs, IUSs, implants, and injections are strongly recommended due to their lower 
failure rates with typical use. Male or female condom use is recommended with all 
contraceptive methods for dual protection against pregnancy and to avoid transmission 
of HIV and other sexually transmitted infections. 
 
9. 
In Section 4.2, Exclusion Criterion 4.2.4, ninth bullet point: 
 
 
Clinically significant acute illness requiring systemic treatment and/or hospitalization (i.e., 
major medical condition that is likely to lead to hospitalization and/or to an adverse 
pregnancy outcome) within 14 days prior to study entry 
 
10. 
In Section 4.2, Exclusion Criterion 4.2.4, note (added at end of criterion): 
 
Note: Testing to rule out HIV-2 infection is not required. 
 
 


 
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IMPAACT 2010 Protocol Version 2.0 
Updates of Section 5, Study Drug Considerations 
 
11. 
In Section 5.8.1, Maternal Concomitant Medications, IMPORTANT INTERACTIONS WITH 
HORMONAL CONTRACEPTIVES, added: 
 
IMPORTANT INTERACTIONS WITH HORMONAL CONTRACEPTIVES 
 
Participants will be counseled to use effective contraception postpartum (see Section 8.6). 
 
Higher contraceptive failure rates have been observed for combined oral contraceptives and 
for progestin-containing subdermal implants when is used in combination with EFV (122a). 
Mothers taking EFV should be advised to use alternative forms of contraception or to use 
condoms in combination with oral contraceptives and with progestin-subdermal implants. 
 
Data on interactions between DTG and hormonal contraceptives are limited. DTG does not 
lead to significant cytochrome P450 (CYP) inhibition or induction, which reduces the 
likelihood of significant interaction between DTG and ethinyl estradiol (which is metabolized 
by CYP enzymes). One study did not find any significant interaction between DTG and a 
norgestimate/ethinyl estradiol oral contraceptive (122b). Studies of interactions between DTG 
and progestogen-only contraceptives are underway, but data from these studies are not yet 
available. 
 
 
Updates of Section 6, Study Visits and Procedures 
 
12. 
In Section 6.1, Screening Visits, Procedural Table, Clinical Procedures, first and fourth (added) 
bullet points: 
 
 
Obtain available maternal medical records and maternal medical, and medications, and 
contraception history 
 
Assess maternal fertility intentions and willingness to use effective contraceptive 
postpartum in relation to study requirements 
 
13. 
In Section 6.1, Screening Visits, Procedural Table, Laboratory Procedures, third (added), fifth 
(added), and sixth (added) bullet points: 
 
 
Glucose 
 
Stored whole blood for folate testing 
 
Stored whole blood for HbA1c testing 
 
14. 
In Section 6.2, Entry Visit, Procedural Table, Clinical Procedures, first and second (added) bullet 
points: 
 
 
Update medical, and medications, and contraception history since the last visit* 
 
Confirm maternal fertility intentions and willingness to use effective contraceptive 
postpartum in relation to study requirements*  
 


 
Letter of Amendment #1 
Page 9 of 27 
20 July 2018 
IMPAACT 2010 Protocol Version 2.0 
15. 
In Section 6.3, Maternal Antepartum Follow-Up Visits, fourth paragraph (added): 
 
Contraception counseling should be provided at each antepartum follow-up visit (see Section 
8.6); plans for initiation of effective contraception postpartum should be documented 
beginning at Antepartum Follow-Up Week 4 and reviewed and updated (if applicable) at each 
subsequent visit. 
 
16. 
In Section 6.3.1, Antepartum Follow-Up Week 4 Visit, Procedural Table, Clinical Procedures, first 
and second (added) bullet points: 
 
 
Obtain interval medical, and medications, and contraception history 
 
Provide contraception counseling and document plan for initiating effective contraception 
postpartum 
 
17. 
In Sections 6.3.2, 6.3.3, and 6.3.4, Antepartum Follow-Up Week 8, Week 12, and Q4 Week Visits, 
Procedural Tables, first and second (added) bullet points: 
 
 
Obtain interval medical, and medications, and contraception history 
 
Provide contraception counseling and review and update (if applicable) plan for initiating 
effective contraception postpartum 
 
18. 
In Section 6.3.3, Antepartum Follow-Up Week 12 Visit, Procedural Table, Laboratory Procedures, 
second (added) and fourth (added) bullet points: 
 
 
Glucose  
 
Stored whole blood for HbA1c testing 
 
19. 
In Section 6.4, Maternal and Infant Delivery Visit, fourth paragraph (added), fifth paragraph 
(added), and note (added): 
 
Contraception counseling should be provided at the Delivery Visit (see Section 8.6) and 
previously-discussed plans for initiation of effective contraception should be finalized at this 
visit. Effective contraceptive methods are listed in inclusion criterion 4.1.8; IUDs, IUSs, and 
implantable and injectable hormonal methods are strongly recommended due to their lower 
failure rates with typical use. Condom use is recommended with all contraceptive methods 
and counseling should emphasize the importance of condom use during the early postpartum 
period prior to initiation of effective contraception. Study staff should actively facilitate access 
to contraceptive services and, to the extent possible, should provide these services on-site. 
 
Mothers choosing contraceptive methods that are clinically appropriate to initiate as of the 
date of the Delivery Visit should initiate their chosen method at the visit (if not already 
initiated). Other mothers may return for an additional visit for this purpose. All mothers 
should initiate effective contraception as soon as feasible and within 27 days after delivery. 
Because this time frame aligns with the allowable visit window for the Delivery Visit, conduct 
of a separate visit to initiate contraception within 27 days after delivery will be considered a 
split Maternal Delivery Visit. Refer to Section 8.6 for more information on management of 
mothers who do not wish to or are not able to use effective contraception; for any such 
mothers, DTG must be switched to an alternate ARV, in consultation with the CMC.  
 


 
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IMPAACT 2010 Protocol Version 2.0 
Note: For mothers who undergo documented surgical sterilization (i.e., hysterectomy, bilateral 
oophorectomy, tubal ligation, or salpingectomy) after delivery or other pregnancy outcome, 
contraception counseling and initiation of other contraceptive methods are not required 
thereafter. 
 
20. 
In Section 6.4, Maternal and Infant Delivery Visit, Maternal Procedural Table, Clinical Procedures, 
first, second (added), and third (added) bullet points, with footnote (added): 
 
 
Obtain interval medical, and medications, and contraception history 
 
Provide contraception counseling and finalize plan for initiating effective contraception  
 
Initiate effective contraception† 
 
†If the Maternal Delivery Visit is split, and the mother returns for an additional visit 
within the allowable visit window at which effective contraception is initiated, the 
following should additionally be performed on the day effective contraception is 
initiated: 
 
 
Obtain interval medical, medications, and contraception history  
 
Provide contraception counseling 
 
Following counseling and pregnancy testing, initiate effective contraception 
 
Identify/review/update adverse events 
 
Perform additional evaluations per Section 8 and/or if clinically indicated (consult CMC if 
indicated) 
 
21. 
In Section 6.4, Maternal and Infant Delivery Visit, Maternal Procedural Table, Laboratory 
Procedures, second (added), third (added), seventh (added), and eighth (added) bullet points: 
 
 
Glucose 
 
Hematocrit 
 
Stored whole blood for folate testing 
 
Stored whole blood for HbA1c testing 
 
22. 
In Section 6.4, Maternal and Infant Delivery Visit, Infant Procedural Table, Laboratory Procedures, 
third (added) and fifth (added) bullet points: 
 
 
Glucose 
 
Stored whole blood for folate testing 
 
23. 
In Section 6.5, Maternal and Infant Postpartum Follow-Up Visits: 
 
Following delivery, mothers and infants will complete scheduled follow-up visits at 6, 14, 26, 38, 
and 50 weeks postpartum. For both mothers and infants, the target dates for all postpartum visits are 
counted from the date of delivery (or other pregnancy outcome) as Day 0. The Week 6 Visit may be 
conducted within an allowable window of ± 2 weeks. For all other visits, the allowable window is 
± 6 weeks. There is no required sequencing of procedures at these visits.  
 
Contraception counseling should be provided at each visit (see Section 8.6); study staff should 
actively facilitate access to contraceptive services and, to the extent possible, should provide 
these services on-site. For any mother taking DTG postpartum who reports a desire to 


 
Letter of Amendment #1 
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20 July 2018 
IMPAACT 2010 Protocol Version 2.0 
become pregnant, or who does not wish to or is not able to use effective contraception, DTG 
must be switched to an alternate ARV, in consultation with the CMC.  
 
Note: For mothers who undergo a documented surgical sterilization procedure during 
postpartum follow-up, contraception counseling and continuation of contraception is not 
required thereafter. 
 
All infants will undergo HIV testing at Weeks 6, 14, and 50, regardless of feeding method. 
Breastfed infants will additionally undergo testing at Weeks 26 and 38 if they were exposed to 
breast milk since the date of their last test. In the event of any positive test, the infant should be 
recalled to the clinic as soon as possible for confirmatory testing. See also Section 6.8. 
 
Maternal creatinine and CrCl evaluations are required at Postpartum Follow-Up Weeks 14, 26, and 
50. As soon as the creatinine results from these visits are obtained, the estimated CrCl rate should 
be calculated using the Cockcroft-Gault formula, graded for severity, and assessed for clinical 
significance concurrent with all other laboratory test results. 
 
24. 
In all subsections of Section 6.5 and in Sections 6.6 and 6.9, Maternal Procedural Tables for all 
scheduled Postpartum Follow-Up Visits, Post ARV Switch Visits, and Early Discontinuation Visits, 
Clinical Procedures, first and second (added) bullet points: 
 
 Obtain interval medical, and medications, and contraception history 
 Provide contraception counseling; prescribe and dispense contraception as needed 
 
25. 
In Sections 6.5.1, 6.5.2, 6.5.3, 6.5.4, 6.6, 6.7, and 6.9, Maternal Procedural Tables for Postpartum 
Follow-Up Visits (Weeks 6, 14, 26, and 38), Post ARV Switch Visits, Confirmation of Virologic 
Failure Visits, and Early Discontinuation Visits, Laboratory Procedures, row added: 
 
Laboratory
Blood or
Urine 
Collect blood or urine for: 
 Pregnancy test 
 
26. 
In Section 6.5.3, Postpartum Follow-Up Week 26 Visit, Infant Procedural Table, Radiology 
Procedures: 
 
Radiology (at selected sites)
At DXA sites only, for selected participants, DXA scan of whole 
body and lumbar spine 
 
27. 
In Section 6.5.5, Postpartum Follow-Up Week 50 Visit, Maternal Procedural Table, Laboratory and 
Radiology Procedures: 
 
Laboratory 
Blood or 
Urine 
Collect blood or urine for: 
 Pregnancy test (test is required for all mothers; at DXA sites, for 
selected DXA participants, perform test on same day (preferably) 
or within 14 days prior to DXA scan) 
At DXA sites only, collect blood or urine for: 
 Pregnancy test on same day (preferably) or within 14 days prior to 
DXA scan
 
Radiology (at selected sites)
At DXA sites only, for selected participants, DXA scan of lumbar 
spine and hip 
 


 
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IMPAACT 2010 Protocol Version 2.0 
28. 
In Section 6.7, Additional Procedures for Confirmation of Maternal Virologic Failure, Procedural 
Table, Clinical Procedures, first and second (added) bullet points: 
 
 Obtain interval medical, and medications, and contraception history (targeted physical exam 
may be performed if clinically indicated) 
 Provide contraception counseling; prescribe and dispense contraception as needed 
 
29. 
In Section 6.11, Maternal Medical, Medications, and Contraception History, section title and first 
paragraph: 
 
Maternal Medical, and Medications, and Contraception History 
 
Collection of medical, and medications, and contraception history information is required at each 
scheduled maternal visit. A baseline history is established at Screening and Entry, and interval 
(since the last visit) histories are obtained at subsequent follow-up visits. With respect to 
contraception history:  
 
 
Future fertility intentions and willingness to use effective contraception following the 
current pregnancy will be assessed as part of eligibility determination at Screening and 
Entry. 
 
Contraception plans will be documented during antepartum follow-up and finalized at the 
Delivery Visit. 
 
Contraception use will be documented throughout postpartum follow-up.  
 
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. 
 
30. 
Within Section 6.11, Maternal Medical, Medications, and Contraception History, Table 3 title, 
second column heading, and third row under baseline history elements: 
 
Documentation Requirements for Maternal Medical, and Medications, and Contraception Histories 
Assess for and 
Source Document
Enter into 
eCRFs or SES
Reproductive and obstetrical history: 
 Dates and outcomes of all prior pregnancies 
 Date of last menstrual period prior to the current 
pregnancy 
 Medications taken at the time of conception 
and during the current pregnancy  
 Complications in the current pregnancy 
 Other targeted conditions potentially associated 
with adverse pregnancy outcomes in the current 
pregnancy 
 Future fertility intentions and willingness to 
use effective contraceptive postpartum 
(following the current pregnancy)   
Yes (all) 


 
Letter of Amendment #1 
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20 July 2018 
IMPAACT 2010 Protocol Version 2.0 
31. 
Within Section 6.11, Maternal Medical, Medications, and Contraception History, Table 3, fourth 
row, fifth row (added), and sixth row (added) under interval history elements: 
 
Assess for and 
Source Document 
Enter into 
eCRFs  
Use of any new medications since the last visit  
(see Section 5.8.1 for more information on concomitant 
medications) 
 All ARVs taken from time of 
enrollment through completion of 
follow-up (including timing of dosing 
at the Delivery and Week 6 
Postpartum Visits) 
 All medications taken during 
pregnancy 
 Postpartum, any new use of: 
– Folate 
– Cotrimoxazole 
– Isoniazid prophylaxis 
– Medications to treat active 
tuberculosis 
– Hormonal contraceptives 
 Postpartum, 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  
corticosteroids were taken for fetal lung 
maturity at any time during pregnancy.
Contraception plans and use of contraception 
 All contraceptive methods used 
through completion of follow-up 
Occurrence of subsequent pregnancy 
 Date of last menstrual period prior 
to pregnancy 
 All medications taken at time of 
conception and during pregnancy 
 All available fetal ultrasound 
findings 
 Pregnancy outcome 
 
32. 
In Section 6.18.2, Specimen Preparation, Testing, Storage, and Shipping, fourth paragraph: 
 
Most specimens collected and stored at site laboratories per the Schedule of Evaluations are 
expected to be requested for centralized testing after all participants have completed follow-up 
(through Week 50 postpartum). However, an interim shipment is planned when all enrolled mothers 
have delivered. At this time, all specimens stored for centralized HIV-1 RNA testing will be 
requested for shipment to the designated testing laboratory. These specimens will then be tested as 
needed to evaluate outcomes through the delivery time point. Interim shipments may also be 
required for urine samples stored for evaluation of markers of renal toxicity and whole blood 
samples stored for evaluation of folate and HgA1c. Alternative shipping arrangements may be 
specified by the Protocol Team as needed; detailed shipping instructions will be provided in the 
LPC. 
 


 
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IMPAACT 2010 Protocol Version 2.0 
Updates of Section 7, Safety Assessment, Monitoring, and Reporting 
 
33. 
In Section 7.2.1, Safety-Related Data Collection for Mothers, listing of adverse events required to 
be entered into eCRFs, last bullet point: 
 
 
All serious adverse events (SAEs) as defined in Version 2.0 of the DAIDS EAE Manual and 
all other events that meet criteria for expedited adverse event (EAE) reporting 
 
34. 
In Section 7.2.1, Safety-Related Data Collection for Mothers, listing of laboratory test results 
required to be entered into eCRFs, first (added), third (added), and fourth (added) bullet points: 
 
 
All pregnancy test results 
 
All glucose results 
 
All hematocrit results from the Screening and Delivery Visits (required for interpretation 
of folate test results) 
 
35. 
In Section 7.2.2, Safety-Related Data Collection for Infants, listing of laboratory test results 
required to be entered into eCRFs, second and third bullet points (added): 
 
 
All glucose results 
 
All hematocrit results from the Delivery Visit (required for interpretation of folate test 
results) 
 
36. 
In Section 7.3.2, EAE Reporting Requirements for this Study, is updated as shown below. 
 
As indicated in Table 5, below, both the SAE (serious adverse event) and SUSAR (suspected 
unexpected serious adverse reaction) reporting categories, as defined in Version 2.0 of the DAIDS 
EAE Manual, will be used for this study. The SUSAR category is used for participants in Arm 3, 
who will be exposed to an approved regimen at approved doses for an approved indication.  
Any changes of maternal ART regimen will not alter the EAE reporting categories shown in 
Table 5. 
Table 5  
Expedited Adverse Event Reporting Requirements for IMPAACT 2010 
 
Study Entry through
Week 14 Postpartum
After Week 14 Postpartum
through Study Exit
Study Drugs for which 
Expedited Reporting 
is Required 
 
Mothers 
Infants 
Mothers 
Infants 
Arm 1 
SAEs 
SAEs 
SAEs 
SUSARs 
DTG, FTC, TAF 
Arm 2 
SAEs 
SAEs 
SAEs 
SUSARs 
DTG, FTC, TDF 
Arm 3 
SUSARs 
SUSARs 
SUSARs 
SUSARs 
EFV, FTC, TDF 
Arm 3 
SAEs 
SAEs 
SAEs 
SUSARs 
EFV, FTC, TDF 
 
For mothers in Arm 1 or Arm 2, the EAE reporting categories listed above will be remain 
unchanged regardless of ART regimen changes. For mothers in Arm 3 who switch to a DTG-
containing or TAF-containing regimen, the EAE reporting category will also be switched to the 
SAE reporting category, from the date of the switch through study exit.  
 


 
Letter of Amendment #1 
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IMPAACT 2010 Protocol Version 2.0 
In addition to the above, the following must also be reported in an expedited manner (i.e., as EAEs) 
for mothers in Arm 1 or Arm 2 and for mothers in Arm 3 who switch to a DTG-containing or TAF-
containing regimen: 
 
 
Pregnancy complications that result in medically indicated and/or elective termination of the 
pregnancy 
 
Spontaneous abortions and fetal deaths 
 
In addition to the above, the following must also be reported in an expedited manner (i.e., as EAEs) 
for mothers in all arms: 
 
 
Pregnancy complications that result in medically indicated and/or elective termination of 
the pregnancy 
 
Spontaneous abortions and fetal deaths 
 
Hepatic toxicities that result in discontinuation of DTG or EFV 
 
Serious ABC hypersensitivity reactions in mothers switching from TDF or TAF to ABC 
 
 
Updates of Section 8, Participant Management 
 
37. 
In Section 8.6, Contraception and Management of Mothers who Become Pregnant on Study, is 
updated as shown below: 
 
8.6.1 Contraception Counseling and Provision 
 
The WHO advises that “At least two years between giving birth and the next pregnancy 
is healthy for both mother and child” (122c). Mothers enrolled in this study will be 
provided with contraception counseling throughout antepartum and postpartum follow-
up. Mothers will be informed of available contraceptive methods and counseled to 
initiate effective contraception as soon as appropriate after delivery. IUDs, IUSs, and 
implantable and injectable hormonal methods are strongly recommended due to their 
lower failure rates with typical use; mothers should be encouraged to use one of these 
methods. Male or female condom use will be recommended with all contraceptive 
methods for dual protection against pregnancy and to avoid transmission of HIV and 
other sexually transmitted infections; the importance of condom use will be emphasized 
during the early postpartum period prior to initiation of effective contraception. 
Mothers will be informed of the benefits of folate intake for a healthy pregnancy and 
advised to take folate supplements and/or eat folate-rich foods. 
 
Fertility intentions and willingness to use effective contraception postpartum will be 
documented at the Screening and Entry Visits as part of eligibility determination for the 
study. Contraception counseling will be provided to enrolled mothers at each 
antepartum follow-up visit; plans for initiating effective contraception postpartum will 
be documented beginning at the Antepartum Week 4 Visit; and these plans will be 
reviewed and updated (if applicable) at each subsequent antepartum visit. At the 
Delivery Visit, previously-discussed plans will be reviewed, further counseling will be 
provided, and plans for initiating effective contraception will be finalized. Mothers 
choosing contraceptive methods that are clinically appropriate to initiate as of the date 
of the Delivery Visit will ideally initiate their chosen method at the Delivery Visit (if not 
already initiated). Other mothers will complete an additional visit within 27 days after 


 
Letter of Amendment #1 
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20 July 2018 
IMPAACT 2010 Protocol Version 2.0 
delivery at which initiation should occur. Contraception counseling will then continue 
throughout postpartum follow-up, unless a mother undergoes a documented surgical 
sterilization procedure, after which counseling may be discontinued.  
 
Contraception counseling will be provided per site SOPs, which should reflect study-
specific requirements, locally available contraceptive methods, and site-specific plans 
for provision of contraceptive methods to study participants. The benefits of child 
spacing for maternal and child health will be emphasized to all mothers, and the 
importance of avoiding pregnancy while on DTG will be further emphasized to mothers 
taking DTG postpartum. While mothers in all study arms will be provided with 
contraception counseling and access to contraceptive services, use of effective 
contraception is most important for mothers taking DTG postpartum. 
 
Study staff should actively facilitate access to contraceptive services and, to the extent 
possible, should provide these services to study participants on-site. At sites where full 
service provision is not possible, study staff should actively refer participants to local 
service providers for methods that cannot be provided on site. Access to effective 
contraception should be provided or facilitated for all mothers, regardless of study arm 
and ART regimen. The benefits of long-acting reversible methods compared to other 
methods — including higher effectiveness with typical use — should be emphasized to 
all mothers. A long-acting reversible method (IUD, IUS, or implantable or injectable 
hormonal method) should be strongly recommended to mothers taking DTG whenever 
possible.  
 
Potential interactions with other medications, including but not limited to ARVs, should 
be considered when selecting a contraceptive method. For example, the efficacy of 
combined oral contraceptives and progestin-containing subdermal implants appears to 
be decreased when used in combination with EFV. For women who will be 
breastfeeding, IUDs, IUSs, and progestin-only implants and injections can be started 
shortly after delivery. 
 
Regardless of the contraception counseling and access to effective contraception 
provided or facilitated by study staff, some mothers may decline or stop use of effective 
contraception. This is acceptable; each mother’s choices should be accepted and will 
have no impact on her continued study participation. Mothers should be supported in 
open and honest reporting of their pregnancy intentions and adherence to contraceptive 
use, with active reminders that their continued participation in the study will not be 
affected by their choice of contraceptive method or their adherence to their chosen 
method. Mothers should also be reminded to inform study staff if they wish to become 
pregnant, miss a dose of contraception, or suspect they may be pregnant, again with no 
impact on their continued participation in the study. However, for any mother taking 
DTG postpartum who reports a desire to become pregnant or who does not wish to or is 
not able to use effective contraception (as listed in criterion 4.1.8), DTG must be 
switched to an alternate ARV, in consultation with the CMC.  
 
Mothers should be provided with contraception counseling as needed during their 
participation in the study. Counseling should be provided per site SOPs, which should reflect 
WHO guidelines for HIV-infected women as well as local standards of care. Counseling 
should begin during pregnancy and continue postpartum as needed for each mother, and 
should reflect the ARVs that mothers are currently taking and the potential interactions 
between these ARVs and available contraceptive methods. Study sites should ideally 


 
Letter of Amendment #1 
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20 July 2018 
IMPAACT 2010 Protocol Version 2.0 
integrate provision of contraceptive methods with other services offered to study participants 
and should provide referrals to non-study sources of methods that cannot be provided at the 
study site. 
 
8.6.2 Management of Mothers who Become Pregnant on Study 
 
Pregnancy testing is required at each scheduled postpartum study visit following the 
Delivery Visit and not required per the study Schedule of Evaluations. Nonetheless, testing 
may additionally be performed when clinically indicated at any time during postpartum 
maternal follow-up. Mothers should be instructed to contact study staff as soon as 
possible if they suspect they may be pregnant at any time during postpartum follow-up, 
so that an interim pregnancy test can be performed between scheduled visits if 
indicated. 
 
Mothers who become pregnant will be maintained in follow-up and may remain on their 
current ART regimen during the new pregnancy. When the new pregnancy is identified, 
mothers will be provided information and counseling on their current ART regimen and what 
is known about the safety of the ARVs that comprise the regimen during pregnancy. Mothers 
who conceive while taking DTG will be switched from DTG to an alternate ARV if still 
in the first trimester when the pregnancy is identified; if the pregnancy is identified 
after the first trimester, mothers taking DTG may choose to continue their current 
regimen wish to change regimens based on this counseling will be permitted to do so, and. 
Site clinicians should may consult with the CMC regarding any mothers who conceive while 
taking DTG and any other mothers for whom a regimen change may be clinically indicated 
or otherwise considered in the best interest of the mother or fetus. For any mother whose 
study drug regimen is modified such that DTG or EFV is replaced with another ARV, an 
additional study visit should be conducted approximately four weeks after the switch as 
described in Section 6.6. Mothers who choose to receive study drug during a subsequent 
pregnancy must provide separate informed consent to do so (refer to Section 12.3 and 
Appendix V).  
 
Mothers who become pregnant on study should be offered a referral for a fetal 
ultrasound scan between 14 and 22 weeks gestation. The scan should confirm the dating 
of the pregnancy and evaluate fetal anatomy; results should be entered into eCRFs. To 
provide optimal assessment of fetal anatomy, it is preferable for this scan to be 
performed between 18 and 22 weeks gestation; however, the scan can be performed as 
early as 14 weeks gestation if necessary. Mothers may choose to undergo or decline this 
scan, after discussion with study staff. 
 
All pregnancies and pregnancy outcomes should be ascertained and entered into eCRFs. For 
mothers who are pregnant at the time of study exit, additional post-study contacts should be 
completed to ascertain their pregnancy outcomes as well as any ART regimen changes after 
study exit (see Section 6.10). These data may be ascertained based on maternal report but 
medical records should be obtained whenever possible to supplement maternal reports. 
 
Study sites are strongly encouraged to prospectively register participants with subsequent 
pregnancies in the Antiretroviral Pregnancy Registry (APR) prior to pregnancy outcome by 
calling the following number in the US: +1-800-258-4263. Outside of the US, please see the 
APR website (www.apregistry.com) for additional toll-free numbers. 
 
 


 
Letter of Amendment #1 
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IMPAACT 2010 Protocol Version 2.0 
Updates of Section 9, Statistical Considerations 
 
38. 
In Section 9.2.3, table row added for Section 9.2.3.7: 
 
9.2.3.7  Maternal folate, glucose, and HbA1c 
 Infant folate and glucose 
 
39. 
In Section 9.6.3, Exploratory Outcome Analyses, second paragraph: 
 
The DTG-containing arms will be compared to the EFV-containing arm for the maternal 
postpartum depression score, folate, glucose, and HbA1c using a two-sample t-test to test the 
equality of means. Similarly, infant folate and glucose will be compared between the DTG-
containing arms and the EFV-containing arm using a two-sample t-test.  
 
40. 
In Section 9.6.3, Exploratory Outcome Analyses, fourth paragraph: 
 
Generalized linear models and Cox regression models will be used to investigate immunologic 
and hormonal predictors of adverse pregnancy outcomes and postpartum maternal health 
outcomes while adjusting for potential confounders. Maternal and infant folate and glucose and 
maternal HbA1c will be analyzed in a similar manner. 
 
 
Updates of Section 12, Human Subjects Protections 
 
41. 
In Section 12.5, Potential Risks, fourth paragraph: 
 
Please refer to Section 1.2-1.8 and the Package Inserts for the study drugs for a complete 
description of the potential risks associated with use of these drugs. DTG taken at the time of 
conception or very early pregnancy may be associated with NTDs in the fetus. There is no 
evidence that the risk of NTDs or other birth defects is increased when DTG is started after 
the early first trimester of pregnancy. Every effort will be made in this study to avoid the 
occurrence of new pregnancies among mothers taking DTG. 
 
 
Updates of Section 15, References 
 
42. 
The following references were added in Section 15: 
 
12a. Rutherford GW, Horvath H. Dolutegravir Plus Two Nucleoside Reverse Transcriptase 
Inhibitors versus Efavirenz Plus Two Nucleoside Reverse Transcriptase Inhibitors As 
Initial Antiretroviral Therapy for People with HIV: A Systematic Review. PLOS ONE. 
2016;11(10):e0162775. 
12b. Joint United Nations Programme on HIV/AIDS (UNAIDS). Global AIDS Monitoring 
2018: Indicators for monitoring the 2016 United Nations Political Declaration on 
Ending AIDS. Geneva: 2018 [cited 30 May 2018]. Available from: 
http://www.unaids.org/sites/default/files/media_asset/global-aids-monitoring_en.pdf. 
12c. HIV Treatment and Care: Treat All: Policy Adoption and Implementation Status in 
Countries [fact sheet]. Geneva: World Health Organization Department of HIV/AIDS. 
2017 [cited 30 May 2018]. Available from: 
http://apps.who.int/iris/bitstream/handle/10665/259532/WHO-HIV-2017.58-
eng.pdf?sequence=1. 


 
Letter of Amendment #1 
Page 19 of 27 
20 July 2018 
IMPAACT 2010 Protocol Version 2.0 
27a. Shapiro R. Birth Outcomes Surveillance in Botswana. RO1 from United States National 
Institutes of Health (Project Number 5R01HD080471-05). Available from: 
https://projectreporter.nih.gov/project_info_details.cfm?aid=9481292&icde=39703357 
27b. Zash R, Jacobson DL, Diseko M, Mayondi G, Mmalane M, Essex M, et al. Comparative 
Safety of Antiretroviral Treatment Regimens in Pregnancy. JAMA Pediatr. 
2017;171(10):e172222. 
27c. World Health Organization Statement on DTG: Potential safety issue affecting women 
living with HIV using dolutegravir at the time of conception [press release]. Geneva, 18 
May 2018 [cited 31 May 2018]. Available from: 
http://www.who.int/hiv/mediacentre/news/dtg-statement/en/. 
27d. Shapiro R, Zash R. Personal communication. May 2018. 
27e. Mofenson L. Personal communication. May 2018. 
27f. Padmanabhan R. Etiology, pathogenesis and prevention of neural tube defects. 
Congenital Anomalies. 2006;46(2):55-67. 
27g. Parnell AS, Correa A, Reece EA. Pre-pregnancy Obesity as a Modifier of Gestational 
Diabetes and Birth Defects Associations: A Systematic Review. Maternal and Child 
Health Journal. 2017;21(5):1105-20. 
122a. Nanda K, Stuart GS, Robinson J, Gray AL, Tepper NK, Gaffield ME. Drug interactions 
between hormonal contraceptives and antiretrovirals. AIDS. 2017;31(7):917-52. 
122b. Song IH, Borland J, Chen S, Wajima T, Peppercorn AF, Piscitelli SC. Dolutegravir has 
no effect on the pharmacokinetics of oral contraceptives with norgestimate and ethinyl 
estradiol. Annals of Pharmacotherapy. 2015;49(7):784-9. 
122c. World Health Organization Department of Reproductive Health and Research 
(WHO/RHR) and Johns Hopkins Bloomberg School of Public Health/Center for 
Communication Programs (CCP) Knowledge for Health Project. Family Planning: A 
Global Handbook for Providers (2018 update). Baltimore and Geneva: CCP and WHO, 
2018. Available from: http://www.who.int/reproductivehealth/publications/fp-global-
handbook/en/ 
 
 
Updates of Appendix I, Schedule of Evaluations 
 
43. 
Consistent with the updates in protocol Section 6, and for ease of reference and implementation, the 
Schedule of Evaluations is updated as shown (with revisions incorporated) on pages 24-27 of this 
LoA. 
 
 
Updates of Appendix III, Sample Informed Consent Form 
 
44. 
In Item 4, “We will ask you questions, examine you, and discuss the study requirements with you,” 
fourth bullet point: 
 
 
Talk with you about the study requirements and if you are able to meet the requirements. This 
will include talking about your plans for having more children in the future.  
 
45. 
In Item 7, “If you and your baby qualify, you will enter the study within 2 weeks of your first visit,” 
second bullet point (added): 
 
 
Ask about your plans for having more children in the future. 
 


 
Letter of Amendment #1 
Page 20 of 27 
20 July 2018 
IMPAACT 2010 Protocol Version 2.0 
46. 
In Item 9, “Mothers will have visits every 4 weeks while pregnant,” third bullet point (added): 
 
 
Talk with you about family planning and the methods of family planning you would like 
to use after your pregnancy. There are certain methods specified to be used in this study. 
Different methods may be required depending on the ARVs you are taking. We will tell 
you about the methods and help you choose the best method for you.  
 
47. 
In Item 10, “Mothers and babies will have a visit soon after delivery. Then they will have 5 more 
visits over 1 year,” first and second (added) paragraph: 
 
We will stay in contact with you as you get close to your delivery date. We will ask you to contact 
us when your labor begins. We will arrange for your first mother-baby visit as soon as possible 
after delivery. It is important for this visit to take place close to the baby’s birth. At the latest, the 
visit should must be within 14 days of the baby’s birth. This visit will take up to 4 hours. 
 
We will talk with you again about family planning and help you with starting your chosen 
method. We may ask you to return on another day to start your chosen method. Your chosen 
method should be started within the first month after delivery. If you do not use family 
planning, you may be required to change the ARVs you are taking. See also #13a (below).   
 
48. 
In Item 10, “Mothers and babies will have a visit soon after delivery. Then they will have 5 more 
visits over 1 year,” under “For mothers, we also will,” second (added) bullet point and added 
paragraph following bulleted list: 
 
 
Draw blood (1 mL or a few drops) or collect urine (5 mL or about 1 teaspoon) for a 
pregnancy test. 
 
[…] 
 
We will talk with you about family planning at each visit. We will ask you to tell us right away 
if you wish to become pregnant again or if you think you may be pregnant. We will give you 
family planning or tell you where you can go for family planning as needed. See also #13a 
(below). 
 
49. 
Item 12, “Mothers will have extra visits if their ARVs are changed or if their HIV is not 
controlled,” paragraph added following bulleted list: 
 
We will also talk with you about family planning. We will ask you to tell us right away if you 
wish to become pregnant again or if you think you may be pregnant. We will give you family 
planning or tell you where you can go for family planning as needed. See also #13a (below). 
 
50. 
Item 13a, “Mothers should not become pregnant again while taking DTG,” (added): 
 
13a. Mothers should not become pregnant again while taking DTG. 
 
We will talk with you about family planning at each visit. After delivery, if you wish to 
become pregnant again, or think you may be pregnant, please tell us right away. We will test 
your blood or urine to find out if you are pregnant. 
 


 
Letter of Amendment #1 
Page 21 of 27 
20 July 2018 
IMPAACT 2010 Protocol Version 2.0 
If you are taking DTG, you should not become pregnant again while taking DTG. This is 
because taking DTG at the time of becoming pregnant may increase the risk of serious birth 
defects of the brain or spine in the new baby. For this reason, you will be required to use 
family planning if you are taking DTG. We will tell you about the methods that must be used. 
If you wish to become pregnant again, or do not wish to use the required family planning 
methods, you will stop taking DTG. We will give you other ARVs to take instead of DTG. 
This will have no effect on your staying in the study. You and your baby will stay in the study 
as originally planned. 
 
51. 
For Item 14, “Mothers who become pregnant again may have extra procedures,” first paragraph 
(deleted): 
 
Mothers could become pregnant again while in the study. We will talk with you about family 
planning. If you wish to become pregnant again, or think you may be pregnant, please tell us right 
away. We will test your blood or urine to find out if you are pregnant.  
 
52. 
For Item 14, “Mothers who become pregnant again may have extra procedures,” third paragraph 
(added): 
 
The study can offer an ultrasound scan of your new baby when you are 14 to 22 weeks 
pregnant. It is your choice whether or not to have the scan. There will be no cost to you for 
transport or having the scan done. 
 
53. 
For Item 16, “We may change or stop your ARVs,” first paragraph: 
 
At all of your visits, we will check whether the ARVs you are taking may be causing bad effects. If 
so, the ARVs may be changed or stopped. The ARVs may be changed if you have certain illnesses 
or need to take other medicines that cannot be taken with ARVs. DTG may be changed if you do 
not use family planning, or if you become pregnant again while taking DTG. We will always 
discuss ARV changes with you. Please tell us about any problems you may have with taking your 
ARVs.  
 
54. 
For Item 24, “There are other possible risks from ARVs,” Possible effects on pregnancy, unborn 
babies, and breastfeeding babies, third paragraph: 
 
In this study, ARVs are given after the first 3 months of pregnancy. The ARVs are continued 
through pregnancy and after delivery. After delivery, mothers who become pregnant again may be 
taking ARVs during the first 3 months of their new pregnancy. If you become pregnant again, we 
will talk with you about your choices for taking ARVs during your new pregnancy (see also #14 
above). Early results from a large study in Botswana showed that DTG may increase the risk 
of serious birth defects of the brain or spine in the new baby. The increased risk was seen 
among babies whose mothers were taking DTG when they became pregnant. These birth 
defects happen during the first few weeks of pregnancy, before mothers may know they are 
pregnant. These birth defects have not been seen among babies whose mothers started taking 
DTG later in pregnancy.  
 


 
Letter of Amendment #1 
Page 22 of 27 
20 July 2018 
IMPAACT 2010 Protocol Version 2.0 
55. 
On the Signatures page:  
 
If you decide to join this study with your baby, sign or make your mark below. 
 
Before deciding whether to join this study with your baby, make sure you have read this form, or 
had it read to you, and that all of your questions have been answered. You should feel that you 
understand the study, its risks and benefits, and what is expected of you and your baby if you 
decide to join. 
 
Your signature or mark on this form means you understand the study and have decided to 
join with your baby. It also means you:  
 
 
Understand the potential risk of becoming pregnant again while taking DTG 
 
Understand the importance of using family planning after your baby is born  
We will tell you any new information from this study or other studies that may affect your 
willingness for you and your baby to stay in the study. You can ask questions or request more 
information at any time.  
 
You do not give up any rights by signing this form. 
 
 
Updates of Appendix V, Sample Informed Consent Form for Use of Study Drug during Subsequent 
Pregnancy 
 
56. 
In Item 3, “The risks and benefits of taking ARVs from the study in your new pregnancy are the 
same as in your previous pregnancy,” title and section: 
 
The risks and benefits of taking ARVs from the study in your new pregnancy may not be are the same as in 
your previous pregnancy. 
 
In your previous pregnancy (when you first joined the study), you started taking ARVs 3 or 
more months after you became pregnant. For this new pregnancy, you have been taking 
ARVs since you first became pregnant. Because of this, the risks and benefits of the ARVs 
may be different in your new pregnancy.  
 
The ARV called dolutegravir (DTG) may increase the risk of serious birth defects of the brain 
or spine in the new baby, if taken at the time of becoming pregnant or early in pregnancy. For 
this reason, if you learn of your new pregnancy within the first 3 months, you will stop taking 
DTG. If you learn of your new pregnancy later than that, you can keep taking DTG. This is 
because these defects happen in the first 4 weeks of pregnancy.  
 
If you are past the first three months in your new pregnancy, there is no change in the possible risks 
and benefits of taking ARVs from the study now compared to when you first joined the study. If 
you are in the first three months, it is possible that the risks and benefits could be different. We do 
not yet know much about this at this time. 
 
We will tell you review what is known about the risks and benefits of all the ARVs you are taking 
with you. If any new information about the risks and benefits becomes available later, we will give 
you that information and again discuss your choice of ARVs. You can ask questions or request 
more information at any time. We will help you choose the ARVs that are best for you.  
 


 
Letter of Amendment #1 
Page 23 of 27 
20 July 2018 
IMPAACT 2010 Protocol Version 2.0 
57. 
In Item 6, “The study cannot provide medical care for your new pregnancy,” first paragraph 
(added):  
 
The study can offer an ultrasound scan of your new baby when you are 14 to 22 weeks 
pregnant. It is your choice whether or not to have the scan. There will be no cost to you for 
transport or having the scan done.  
 
The study cannot provide medical care related to your new pregnancy or delivery of a new baby. If 
you have another baby, that baby will not be in the study. Therefore, it is important for you to 
receive medical care related to your pregnancy outside the study. We will tell you where you can go 
for this care. [Sites may modify or add to the preceding sentence to provide site-specific details on 
provision and/or referral for care. 
 


 
Letter of Amendment #1 
Page 24 of 27 
20 July 2018 
IMPAACT 2010 Protocol Version 2.0 
Appendix I Schedule of Evaluations 
Antepartum 
 
 
Weeks During Pregnancy 
Post
Study Visit 
Screen 
Entry 
Week 4 
Week 8 
Week 12 
Q4 Weeks1 
ARV 
Early 
Visit Window 
up to -14 d 
Day 0 
±2 wks 
±2 wks 
±2 wks 
±2 wks 
Switch2 
D/C3 
MATERNAL EVALUATIONS
 
 
Informed consent 
X 
 
 
 
 
 
 
Maternal medical, medications, and 
contraception history
X 
X 
X 
X 
X 
X 
X 
X 
ARV adherence questionnaire4 
 
 
X 
X 
X 
X 
X 
X 
Sleep and anxiety questionnaires 
 
X 
 
X 
 
 
X 
 
Depression questionnaire 
 
 
 
 
 
 
X 
 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
Fetal ultrasound 
prior to or 
within 14 days after entry 
 
 
 
 
 
Confirmatory pregnancy testing5 
X 
 
 
 
 
 
 
Confirmatory HIV testing  
0-6 mL 
 
 
 
 
 
 
 
Hepatitis B surface antigen 
 
3 mL 
 
 
 
 
 
 
AST, ALT, creatinine, CrCl 
4 mL 
 
4 mL 
 
4 mL 
4 mL Wk 24 
4 mL 
4 mL 
Glucose 
X* 
 
 
 
X* 
 
 
 
Complete blood count 
3 mL 
 
 
 
 
 
 
 
CD4+ cell count 
 
3 mL 
 
 
 
 
 
 
HIV-1 RNA (store residual plasma)6 
 
6 mL 
6 mL 
6 mL 
6 mL 
6 mL Wk 246 
6 mL 
6 mL 
Stored whole blood 
X* 
 
 
 
X* 
 
 
Stored plasma 
6 mL 
 
 
 
 
 
 
Stored plasma and cell pellets 
 
10 mL 
 
10 mL 
 
 
 
Stored urine  
 
15 mL 
 
 
 
 
15 mL 
Total blood volume 
13-20 mL 
22 mL 
10 mL 
16 mL 
10 mL 
0-10 mL 
10 mL
10 mL 
 
 
 


 
Letter of Amendment #1 
Page 25 of 27 
20 July 2018 
IMPAACT 2010 Protocol Version 2.0 
Appendix I Antepartum Footnotes: 
 
*For these evaluations, the required blood volume will be obtained from other collected specimens; refer to the LPC for detailed specimen 
collection and processing instructions.   
1Refer to Section 6.3.4. After antepartum study Week 12, mothers will complete scheduled follow-up visits every four weeks (Q4) prior to 
delivery. Depending on the date of delivery, these visits may take place at antepartum study Weeks 16, 20, 24, and 28.  
2Refer to Section 6.6.  
3Refer to Section 6.9. 
4Routine questionnaire at all indicated visits; barriers and facilitators questionnaires at Antepartum Week 8. 
5Refer to Section 6.1. If available medical records document a positive pregnancy test result, or if pregnancy is confirmed by ultrasound 
scan prior to entry, no pregnancy testing is required. Otherwise, a blood (1 mL) or urine (5 mL) pregnancy test should be performed, with 
results available for final eligibility determination prior to entry. The total blood volume shown in the Screen column above 
accommodates collection of 1 mL of blood if needed. 
6It is generally not expected that mothers will meet the criteria for confirmation of virologic failure (≥200 copies/mL at or after at least 24 
weeks on study) during antepartum follow-up; however, if these criteria are met prior to delivery, the Confirmation of Virologic Failure 
evaluations shown on the next page and further described in Section 6.7 should be performed.  
 


 
Letter of Amendment #1 
Page 26 of 27 
20 July 2018 
IMPAACT 2010 Protocol Version 2.0 
Appendix I Schedule of Evaluations 
Delivery and Postpartum 
Delivery 
Weeks Postpartum 
Post 
Confirmation 
 
Study Visit 
up to 14/27 d† 
6 
14 
26 
38 
50 
ARV 
of Virologic  
Early 
Visit Window 
New Day 0 
±2 wks 
±6 wks 
±6 wks 
±6 wks 
±6 wks 
Switch1 
Failure2 
D/C3 
MATERNAL EVALUATIONS
 
 
 
 
Maternal medical, medications, and contraception history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ARV adherence questionnaire4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sleep and anxiety questionnaires 
 
 
 
 
X 
 
X 
 
 
Depression questionnaire 
 
X
 
 
 
X 
X 
 
 
Physical examination 
X 
X
X 
X 
X 
X 
X 
[X] 
X 
Pregnancy test5 
[X] 
X 
X 
X 
X 
X 
X 
X 
X 
AST, ALT, creatinine, CrCl 
4 mL 
4 mL 
4 mL 
 
4 mL 
4 mL 
 
4 mL 
Glucose 
X* 
 
 
 
 
 
 
 
 
Complete blood count 
 
 
 
3 mL 
 
3 mL 
 
 
 
CD4+ cell count 
 
 
 
3 mL 
 
3 mL 
 
 
 
HIV-1 RNA (store residual plasma) 
6 mL 
 
6 mL 
6 mL 
6 mL 
6 mL 
6 mL 
6 mL 
6 mL 
ARV resistance testing (store residual plasma) 
 
 
 
 
 
 
 
6 mL 
 
Stored whole blood 
X* 
 
 
 
 
 
 
 
 
Stored plasma 
6 mL 
6 mL 
 
 
 
 
 
 
 
Stored plasma and cell pellets 
10 mL 
 
 
 
 
10 mL 
 
 
 
Stored serum6 
0-4 mL6 
 
 
 
 
 
 
 
Stored breast milk (if breastfeeding) 
 
20 mL
 
 
 
 
 
 
 
Stored urine  
 
 
 
 
15 mL 
 
 
15 mL 
Stored hair 
X 
 
 
 
 
 
 
 
DXA scan (at selected sites)7 
 
 
 
 
 
X7 
 
 
 
Total blood volume 
26-31 mL 
7 mL 
11 mL 
17 mL 
7 mL 
27 mL 
11 mL 
13 mL 
11 mL 


 
Letter of Amendment #1 
Page 27 of 27 
20 July 2018 
IMPAACT 2010 Protocol Version 2.0 
Appendix I Schedule of Evaluations 
Delivery and Postpartum 
Delivery 
Weeks Postpartum 
Post 
Confirmation 
 
Study Visit 
up to 14/27 d† 
6 
14 
26 
38 
50 
ARV 
of Virologic  
Early 
Visit Window 
New Day 0 
±2 wks 
±6 wks 
±6 wks 
±6 wks 
±6 wks 
Switch1 
Failure2 
D/C3 
INFANT EVALUATIONS
 
 
 
 
 
 
 
 
 
Infant medical and feeding history 
X 
X 
X 
X 
X 
X 
 
 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
 
 
X 
HIV NAT (store remnant samples)8,9 
3 mL 
4 mL9 
3 mL 
3 mL if BF 
3 mL if BF 
3 mL 
 
 
3 mL 
ALT and creatinine10 
1 mL 
 
 
1 mL if BF 
 
 
 
 
 
Glucose 
X* 
 
 
 
 
 
 
 
 
Complete blood count10 
1 mL 
 
 
1 mL if BF 
 
 
 
 
 
Stored whole blood 
X* 
 
 
 
 
 
 
 
 
Stored serum6 
0-1 mL6 
 
 
 
 
 
 
 
 
Stored hair 
X 
 
 
 
 
 
 
 
 
DXA scan (at selected sites) 
 
 
 
X 
 
 
 
 
 
Total blood volume 
5-6 mL 
4 mL 
3 mL 
0-5 mL 
0-3 mL 
3 mL 
 
 
3 mL 
 
†The Delivery Visit should be conducted as soon as possible after delivery and within a targeted window of 14 days after delivery. If the visit cannot be 
conducted within the targeted window, it may be conducted within an allowable window of 27 days after delivery. The timeliness of visit completion at each site 
will be closely monitored and corrective actions taken when needed, as described in Sections 6.4 and 9.5.1. 
*For these evaluations, the required blood volume will be obtained from other collected specimens; refer to the LPC for detailed specimen collection and 
processing instructions. 
1Refer to Section 6.6.  
2Refer to Sections 6.7 and 8.3. 
3Refer to Section 6.9. 
4Routine questionnaire at all indicated visits; barriers and facilitators questionnaires at Postpartum Week 38. 
5Refer to Section 6.4 for pregnancy testing requirements at the Delivery Visit (testing may be required if a split visit conducted). At visits following the Delivery 
Visit, a blood (1 mL) or urine (5 mL) pregnancy test must be performed at each scheduled visit. The total blood volume shown in each column accommodates 
collection of 1 mL of blood if needed. 
6At Delivery, collect maternal and infant blood for serum storage only if the mother is at risk for Zika virus infection (due to local transmission, travel, or other 
exposure) and maternal Zika virus infection during the current pregnancy is suspected.  
7Maternal DXA scan must be preceded by a pregnancy test, either on the day of the scan (preferably) or within 14 days prior to the scan.  
8For infants ever exposed to breast milk, perform HIV NAT at Delivery and Weeks 6, 14, 26, 38, and 50. For infants never exposed to breast milk, perform HIV 
NAT at Delivery and Weeks 6, 14, and 50. Also refer to Section 6.8. Any infant with an initial positive HIV NAT result should be recalled to the clinic as soon 
as possible for confirmatory testing.  
9At Week 6, 4 mL is required to provide sufficient plasma for HIV NAT and testing of ARV drug levels. 
10At Week 26, perform testing (ALT, creatinine, complete blood count) for infants ever exposed to breast milk.