Conditions: HIV Infections
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 780
Healthy volunteers: yes

Brief summary:
The purpose of this study was to evaluate the pharmacokinetics, feasibility, acceptability, and safety of a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) as oral daily pre-exposure prophylaxis (PrEP) to prevent HIV during pregnancy and postpartum in adolescents and young women and their infants.

Detailed description:
This study evaluated the pharmacokinetics, feasibility, acceptability, and safety of FTC/TDF as oral daily PrEP to prevent HIV during pregnancy and postpartum in adolescents and young women and their infants. The study was conducted in two consecutive components: 1) Pharmacokinetics (PK) Component and 2) PrEP Comparison Component.

In the PK Component, women enrolled in one of two groups. Group 1 included pregnant women at 14 to 24 weeks' gestation and Group 2 included postpartum women who delivered 6 to 12 weeks prior to enrollment. Both groups received a fixed-dose combination of FTC/TDF administered once daily by direct observation from Day 0 through Week 12.

Mothers in the PK Component had weekly study visits through Week 12. Infants in Group 1, whose mothers enrolled during pregnancy, had study visits at birth and six weeks of life; infants in Group 2, who were enrolled with their mothers 6-12 weeks after birth, had study visits at Week 6 and Week 12. Study visits for mothers and infants in the PK Component included evaluation of drug levels and monitoring for adverse effects.

In the PrEP Comparison Component, pregnant women enrolled in one of two cohorts. Mothers in Cohort 1 chose to initiate PrEP at study entry, and mothers in Cohort 2 declined PrEP at entry. Participants in both Cohorts received a standard of care package of HIV prevention services, a study-specific behavioral risk reduction intervention, and periodic one-way short message service (SMS) messages to promote maternal and child health from Day 0 through Week 26. Cohort 1 opted to also receive daily oral FTC/TDF as PrEP and enhanced adherence support, including weekly two-way SMS messaging and feedback of drug levels with tailored adherence counseling. Participants who changed their mind about using PrEP during study participation were able to subsequently stop PrEP (Cohort 1) or initiate PrEP (Cohort 2/Step 2).

Mothers in the PrEP Comparison Component had regular study visits through delivery and Week 26 (postpartum). Infants in the PrEP Comparison Component had four study visits from birth through week 26 of life. For mothers, study visits included physical examinations, blood and urine collection, vaginal and (optional) rectal swab collection, vaginal secretions collection, ultrasounds, and dual-energy x-ray absorptiometry (DXA) scans. For infants, study visits included physical examinations, rectal swab and blood collection, and DXA scans.

In the PrEP Comparison Component analysis, maternal and infant participants were classified based on their PrEP exposure. The PrEP-exposed group included participants from Cohort 1 (throughout the entire study follow-up) and from Cohort 2/Step 2 (from Step 2 entry to the end of follow-up). The PrEP-unexposed group comprised participants from Cohort 2/Step 1 who did not enroll in Cohort 2/Step 2 (throughout the entire study follow-up) or who enrolled in Cohort 2/Step 2 (from study entry until enrolling in Cohort 2/Step 2).

Arms:
arm 1: Mothers enrolled during singleton pregnancy at 14-24 weeks' gestation received PrEP once daily under direct observation from day 0 through week 12. arm 2: Mothers enrolled postpartum within 6-12 weeks after delivery received PrEP once daily under direct observation from day 0 through week 12. arm 3: Mothers who initiated PrEP at study entry received daily oral PrEP, a behavioral HIV risk reduction package and enhanced adherence support from day 0 through postpartum week 26. arm 4: Mothers who declined PrEP initiation at study entry received a behavioral HIV risk reduction package from day 0 through postpartum week 26. arm 5: Mothers from Cohort 2/Step 1 who subsequently chose to initiate PrEP during the study received daily oral PrEP and enhanced adherence support from Step 2 entry through postpartum week 26, along with the behavioral HIV risk reduction package. arm 6: Infants born to women in PK Component Group 1. Infants did not directly receive PrEP, but may have been exposed to PrEP through placental or breastmilk transfer. arm 7: Infants born to women in PK Component Group 2. Infants did not directly receive PrEP, but may have been exposed to PrEP through breastmilk transfer. arm 8: Infants born to women in PrEP Comparison Cohort 1. Infants did not directly receive PrEP, but may have been exposed to PrEP through placental or breastmilk transfer. arm 9: Infants born to women in PrEP Comparison Cohort 2/Step 1. Infants were not exposed to PrEP during the study. arm 10: Infants born to women in PrEP Comparison Cohort 2/Step 2. Infants did not directly receive PrEP, but may have been exposed to PrEP through placental or breastmilk transfer.

Interventions: intervention 1: Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) intervention 2: Behavioral HIV risk reduction package intervention 3: Enhanced adherence support
Intervention descriptions: intervention 1: 200 mg/300 mg of FTC/TDF administered orally as a fixed-dose combination tablet once daily intervention 2: Included cohort-appropriate SMS messages. intervention 3: Included two-way SMS messaging and tailored counseling with drug level feedback.

Protocol document:
Prot_ICF_002.pdf: 
IMPAACT 2009 
 
 
Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral Pre-
Exposure Prophylaxis for Primary HIV Prevention during Pregnancy 
and Postpartum in Adolescents and Young Women and their Infants 
 
 
 
A 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 
 
 
Pharmaceutical Support Provided by: 
Gilead Sciences, Inc. 
 
 
 
DAIDS ES # 30020 
IND #136,735 Held By DAIDS 
 
 
Protocol Co-Chairs: 
 
Benjamin Chi, MD, MSc 
Lynda Stranix-Chibanda, MBChB, MMED 
 
NIAID Medical Officer:  
Hans Spiegel, MD, DrMedSc 
 
NICHD Medical Officer: 
Nahida Chakhtoura, MD, MsGH 
 
Clinical Trials Specialists: 
Kathryn Lypen, MPH 
 
Emily Brown, MA 
 
 
 
 
 
FINAL Version 3.0 
19 November 2020
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 2 of 173 
 
  
   
 
19 November 2020 
IMPAACT 2009 
Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral Pre-Exposure 
Prophylaxis for Primary HIV Prevention during Pregnancy and Postpartum in 
Adolescents and Young Women and their Infants  
 
 
Protocol Signature Page ......................................................................................................... 5 
ABBREVIATIONS AND ACRONYMS ....................................................................................... 6 
PROTOCOL TEAM ROSTER .................................................................................................... 8 
SITE ROSTER ..........................................................................................................................11 
SCHEMA – Pharmacokinetics Component ...........................................................................13 
SCHEMA – PrEP Comparison Component ............................................................................14 
1 
INTRODUCTION ...........................................................................................................17 
1.1 
Background ..................................................................................................................................... 17 
1.2 
Prior Research................................................................................................................................. 17 
1.3 
Rationale ......................................................................................................................................... 27 
1.4 
Hypothesis for the PK Component .................................................................................................. 31 
1.5 
Hypotheses for the PrEP Comparison Component ......................................................................... 31 
2 
OBJECTIVES ................................................................................................................32 
2.1 
Primary Objective for PK Component .............................................................................................. 32 
2.2 
Secondary Objective for PK Component ......................................................................................... 32 
2.3 
Primary Objectives for PrEP Comparison Component .................................................................... 32 
2.4 
Other Objectives for PrEP Comparison Component ....................................................................... 32 
2.5 
Exploratory Objective for PrEP Comparison Component ................................................................ 33 
3 
STUDY DESIGN ...........................................................................................................33 
3.1 
PK Component Study Design .......................................................................................................... 33 
3.2 
PrEP Comparison Component Study Design .................................................................................. 34 
3.3 
Standard of Care ............................................................................................................................. 37 
4 
STUDY POPULATION ..................................................................................................38 
4.1 
PK Component (Groups 1 and 2) .................................................................................................... 38 
4.2 
PrEP Comparison Component (Cohorts 1 and 2) ........................................................................... 40 
4.3 
Infant Enrollment ............................................................................................................................. 42 
4.4 
Co-Enrollment Considerations ......................................................................................................... 42 
4.5 
Recruitment, Screening, and Enrollment Process ........................................................................... 42 
4.6 
Participant Retention ....................................................................................................................... 43 
4.7 
Participant Withdrawal or Termination from the Study .................................................................... 43 
5 
STUDY DRUG CONSIDERATIONS ..............................................................................44 
5.1 
Study Drug Regimen ....................................................................................................................... 44 
5.2 
Study Drug Formulation ................................................................................................................... 46 
5.3 
Behavioral Counseling and Adherence Support .............................................................................. 46 
5.4 
Concomitant Medications ................................................................................................................ 48 
5.5 
Prohibited Medications .................................................................................................................... 49 
6 
STUDY VISITS AND PROCEDURES ...........................................................................49 
6.1 
PK Component ................................................................................................................................ 49 
6.2 
PrEP Comparison Component ........................................................................................................ 55 
6.3 
Management of Participants with Suspected or Confirmed HIV Seroconversion (PK and PrEP 
Comparison Components) ............................................................................................................... 67 
6.4 
Early Discontinuation Visit ............................................................................................................... 70 
6.5 
PrEP Comparison Component – Interim Visit for Drug Level Feedback ......................................... 72 
6.6 
Management of Infants Whose Mother Dies ................................................................................... 72 
6.7 
Management of Women Whose Infant Dies or Experience Fetal Demise ....................................... 72 


 
IMPAACT 2009, FINAL Version 3.0 
Page 3 of 173 
 
  
   
 
19 November 2020 
6.8 
Maternal Medical and Medication History ........................................................................................ 72 
6.9 
Maternal Physical Examinations ...................................................................................................... 73 
6.10 
Maternal DXA Scans ....................................................................................................................... 74 
6.11 
Infant Medical and Medication History ............................................................................................. 74 
6.12 
Infant Feeding History ..................................................................................................................... 75 
6.13 
Infant Physical Examinations ........................................................................................................... 75 
6.14 
Infant DXA Scans ............................................................................................................................ 76 
6.15 
Fetal Ultrasound .............................................................................................................................. 76 
6.16 
Questionnaires and Computer-Assisted Self-Interview (CASI) ....................................................... 77 
6.17 
Additional Considerations for Laboratory Procedures ..................................................................... 78 
7 
SAFETY MONITORING, ASSESSMENT AND REPORTING .......................................79 
7.1 
Safety-Related Roles and Responsibilities ...................................................................................... 79 
7.2 
Safety-Related Data and Pre-Existing Conditions Data Collection .................................................. 80 
7.3 
Expedited Adverse Event (EAE) Reporting ..................................................................................... 82 
8 
PARTICIPANT MANAGEMENT ....................................................................................83 
8.1 
Maternal and Infant Adverse Events ............................................................................................... 83 
8.2 
Management of Participants Who Become Pregnant on Study ....................................................... 85 
8.3 
Criteria for Premature Discontinuation of Study Drug ...................................................................... 85 
9 
STATISTICAL CONSIDERATIONS ..............................................................................86 
9.1 
PK Component ................................................................................................................................ 86 
9.2 
PrEP Comparison Component ........................................................................................................ 89 
9.3 
Monitoring ........................................................................................................................................ 99 
10 
CLINICAL PHARMACOLOGY PLAN ......................................................................... 101 
10.1 
Pharmacology Overview and Objectives ....................................................................................... 101 
10.2 
Study Design, Modeling and Data Analysis ................................................................................... 101 
11 
DATA HANDLING AND RECORD KEEPING ............................................................. 102 
11.1 
Data Management Responsibilities ............................................................................................... 102 
11.2 
Essential and Source Documents and Access to Source Data ..................................................... 103 
11.3 
Quality Control and Quality Assurance .......................................................................................... 103 
12 
CLINICAL SITE MONITORING ................................................................................... 104 
13 
HUMAN SUBJECTS PROTECTIONS......................................................................... 104 
13.1 
Institutional Review Board/Ethics Committee Review and Approval ............................................. 104 
13.2 
Vulnerable Participants .................................................................................................................. 104 
13.3 
Informed Consent .......................................................................................................................... 105 
13.4 
Potential Benefits........................................................................................................................... 106 
13.5 
Potential Risks ............................................................................................................................... 106 
13.6 
Potential Social Impact .................................................................................................................. 108 
13.7 
Reimbursement/Compensation ..................................................................................................... 108 
13.8 
Privacy and Confidentiality ............................................................................................................ 108 
13.9 
Communicable Disease Reporting ................................................................................................ 109 
13.10 
Management of Incidental Findings ............................................................................................... 109 
13.11 
Management of New Information Pertinent to Study Participation ................................................ 109 
13.12 
Post-Trial Access to Study Drug .................................................................................................... 109 
14 
ADMINISTRATIVE PROCEDURES ............................................................................ 110 
14.1 
Regulatory Oversight ..................................................................................................................... 110 
14.2 
Protocol Registration ..................................................................................................................... 110 
14.3 
Study Implementation .................................................................................................................... 111 
14.4 
Protocol Deviation Reporting ......................................................................................................... 111 
14.5 
Critical Event Reporting ................................................................................................................. 111 
14.6 
ClinicalTrials.gov ........................................................................................................................... 111 
15 
PUBLICATIONS ......................................................................................................... 111 
16 
REFERENCES ............................................................................................................ 112 


 
IMPAACT 2009, FINAL Version 3.0 
Page 4 of 173 
 
  
   
 
19 November 2020 
Appendix IA (Schedules of Evaluation): Maternal PK Component Group 1 and Group 2122 
Appendix IB (Schedule of Evaluations): Infant PK Component Group 1 .......................... 123 
Appendix IC (Schedule of Evaluations): Infant PK Component Group 2 .......................... 123 
Appendix IIA (Schedule of Evaluations): Maternal PrEP Comparison Component: Cohort 
1, Cohort 2/Step 2 ...................................................................................................... 124 
Appendix IIB (Schedule of Evaluations): Maternal PrEP Comparison Component Cohort 2
 .................................................................................................................................... 125 
Appendix IIC (Schedule of Evaluations): Infant PrEP Comparison Component (both 
cohorts) ...................................................................................................................... 126 
Appendix IID (Schedule of Evaluations): Maternal Suspected or Confirmed HIV Infection
 .................................................................................................................................... 127 
Appendix IIE (Schedule of Evaluations): Infant HIV Exposure and Infection ................... 128 
Appendix III: Targeted Medications List .............................................................................. 129 
Appendix IV: General Management Guidelines for Maternal Toxicities ............................ 130 
Appendix V: General Management Guidelines for Maternal Increased Creatinine and 
Reduced Creatinine Clearance ................................................................................. 132 
Appendix VI: Sample Informed Consent Form for PK Component (Groups 1 & 2) .......... 133 
Appendix VII: Sample Informed Consent Form for PrEP Comparison Component ......... 146 
Appendix VIII: Sample Informed Consent Form for Specimen Storage and Future Use . 163 
Appendix IX: Sample In-depth Interview Informed Consent Form .................................... 167 
Appendix X: Guidance for Study Implementation at Sites Experiencing Operational 
Disruptions Due to COVID-19 ................................................................................... 172 
 
 
 
 
 
 
 
 
 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 5 of 173 
 
  
   
 
19 November 2020 
IMPAACT 2009 
Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral Pre-Exposure 
Prophylaxis for Primary HIV Prevention during Pregnancy and Postpartum in 
Adolescents and Young Women and their Infants  
 
DAIDS Study ID #30020 
 
 
Version 3.0 
19 November 2020 
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 (U.S.) Health and 
Human Service regulations (45 CFR 46); applicable U.S. 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., U.S. National Institutes of Health, Division 
of AIDS) and institutional policies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator of Record 
  
 
Date 
 
 
 
 
 
 
 
 
 
 
 
Name of Investigator of Record  
 
(printed) 
 
 
 
 
 
 
 
 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 6 of 173 
 
  
   
 
19 November 2020 
IMPAACT 2009 
Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral Pre-Exposure 
Prophylaxis for Primary HIV Prevention during Pregnancy and Postpartum in 
Adolescents and Young Women and their Infants  
 
ABBREVIATIONS AND ACRONYMS 
 
AIDS 
Acquired Immunodeficiency Syndrome 
ALT 
Alanine transaminase 
AP 
Antepartum 
AST 
Aspartate aminotransferase 
cART 
Combination anti-retroviral therapy 
CASI 
Computer-assisted self-interviewing 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CMC 
Clinical Monitoring Committee 
COVID-19 
Coronavirus disease 2019 
Css 
Steady state concentration 
DAIDS 
Division of AIDS  
DAERS 
DAIDS Adverse Experience Reporting System 
DBS 
Dried blood spot 
DMC 
Data Management Center  
DOT 
Directly observed therapy 
DXA 
Dual-energy x-ray absorptiometry 
EC 
Ethics committee 
eCRF 
Electronic Case Report Form 
EAE 
Expedited adverse event 
FDA 
Food and Drug Administration 
FTC/TDF 
emtricitabine/tenofovir disoproxil fumarate (Truvada®) 
GDPR 
General Data Protection Regulation 
HIV 
Human Immunodeficiency Virus 
IATA 
International Air Transport Association 
IDI 
In-depth interview 
IMPAACT 
International Maternal Pediatric Adolescent AIDS Clinical Trials Network 
iNSC 
Integrated Next Step Counseling 
IRB  
Institutional review board 
IND 
Investigational new drug 
IoR 
Investigator of Record  
IQR 
Interquartile range 
L&D 
Labor and Delivery 
LDMS 
Laboratory data management system 
LPC 
Laboratory processing chart 
MSM 
Men who have sex with men 
mHealth 
Mobile health 
MOP 
Manual of procedures 
NIAID 
National Institute of Allergy and Infectious Diseases 
NICHD 
National Institute of Child Health and Human Development 
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health 
OHRP 
Office for Human Research Protections 
PCR 
Polymerase chain reaction 


 
IMPAACT 2009, FINAL Version 3.0 
Page 7 of 173 
 
  
   
 
19 November 2020 
PID 
Participant identification number 
PK 
Pharmacokinetic  
PP 
Postpartum  
PrEP  
Pre-exposure prophylaxis   
RNA 
Ribonucleic acid 
SD 
Standard deviation 
SES 
Subject Enrollment System 
SMS 
Short message service 
SPDSMP 
Study Progress, Data, and Safety Monitoring Plan 
SOE 
Schedule of Evaluations  
SOP 
Standard operating procedure 
STI 
Sexually transmitted infection 
TDF 
Tenofovir disoproxil fumarate 
TFV-DP 
Tenofovir disoproxil fumarate-diphosphate 
U.S. 
United States 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 8 of 173 
 
  
   
 
19 November 2020 
IMPAACT 2009 
Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral Pre-Exposure 
Prophylaxis for Primary HIV Prevention during Pregnancy and Postpartum in 
Adolescents and Young Women and their Infants  
 
PROTOCOL TEAM ROSTER 
 
Protocol Co-Chairs 
Benjamin Chi, MD, MSc 
 
 
 
Department of Obstetrics and Gynecology 
University of North Carolina at Chapel Hill 
 
Chapel Hill, NC 27599 
Phone: (919) 445-4174 
Email: benjamin_chi@med.unc.edu 
 
Lynda Stranix-Chibanda, MBChB, MMED 
Department of Paediatrics and Child Health 
College of Health Sciences 
University of Zimbabwe, 
PO. Box A178, Avondale 
Harare, Zimbabwe 
Phone: +263 4 704890 
Email: lstranix@uzchs-ctu.org  
 
Protocol Vice-Chair  
K Rivet Amico, PhD 
Associate Professor 
University of Michigan 
Department of Health Behavior and Health 
Education 
3830 School of Public Health 
1415 Washington Heights 
Ann Arbor, Michigan 48109-2029 
Phone: (734) 763-0051 
Email: ramico@umich.edu 
 
NIAID Medical Officer 
Hans M.L. Spiegel, MD, DrMedSc, DTMH, 
FAAP, Contractor, Kelly Government Solutions 
Sr. Medical Officer, PMPRB/Prevention 
Sciences Program,  
DAIDS, NIAID, NIH 
5601 Fishers Lane, 8B51A  
Rockville, MD 20852Phone: (240) 292-4633 
Email: hans.spiegel@nih.gov 
 
NICHD Medical Officer 
Nahida Chakhtoura, MD, MSGH  
Eunice Kennedy Shriver National Institute of  
Child Health and Human Development  
National Institutes of Health 6710B Rockledge 
Drive, Rm. 2140, MSC 7002 
Bethesda, MD  20817 
Phone: (301) 435-6872  
Email: nahida.chakhtoura@nih.gov  
 
NIMH Medical Officer  
Susannah Allison, Ph.D. 
Scientific Program Officer 
Infant, Child, & Adolescent Research Programs 
NIMH Division of AIDS Research 
5601 Fishers Lane, 9G22, MSC 9830 
Rockville, MD 20852-9830 
Phone: (240) 627-3861 
Email: Susannah.Allison@nih.gov 
 
Clinical Trials Specialists 
Kathryn Lypen, MPH 
IMPAACT Operations Center  
FHI 360  
359 Blackwell Street, Suite 200 
Durham, NC 27701, USA 
Phone: (919) 544-7040, Ext. 11684 
Email: klypen@fhi360.org 
 
Emily Brown, MA 
IMPAACT Operations Center  
FHI 360  
359 Blackwell Street, Suite 200 
Durham, NC 27701, USA 
Phone: (919) 544-7040, Ext. 11123 
Email: embrown@fhi360.org 
 
Protocol Investigators 
Geri R. Donenberg, PhD 
Associate Dean of Research,  
School of Public Health 
Professor, Department of Medicine 
Director, Community Outreach Intervention 
Projects and Healthy Youth Program 
1603 W. Taylor Street, 845 SPHPI 
Chicago, IL 60612 
Phone: (312) 996-8602 
Email: gerid@uic.edu 


 
IMPAACT 2009, FINAL Version 3.0 
Page 9 of 173 
 
  
   
 
19 November 2020 
 
Lisa Hightow-Weidman, MD, MPH 
Associate Professor  
Institute for Global Health and Infectious 
Diseases 
University of North Carolina at Chapel Hill 
Phone: (919) 843-0033 
Email: lisa_hightow@med.unc.edu 
 
John Shepherd, PhD 
Population Sciences in the Pacific Program 
(Cancer Epidemiology) 
University of Hawaii Cancer Center 
701 Ilalo Street  
Suite 431 
Honolulu, HI  96813 
Phone: 808-440-5230 
Email: johnshep@hawaii.edu 
 
Nicole Tobin, MD 
David Geffen School of Medicine 
Division of Infectious Diseases 
University of California, Los Angeles 
10833 Le Conte Ave. 
Los Angeles, CA 90095 
Phone: 310-825-5235 
Email: NTobin@mednet.ucla.edu 
 
Savita Pahwa, MD 
University of Miami Miller School of Medicine 
1580 NW 10th Avenue 
BCRI 712, Miami, FL 33136 
Phone: (305)-243-7732 
Email: spahwa@med.miami.edu 
 
Petina Musara, BSW 
CTU Behavioral Sciences Coordinator 
University of Zimbabwe College of Health 
Sciences 
Clinical Trials Research Centre 
10 Routledge Street, Milton Park 
Harare, Zimbabwe 
Phone: +263-42-915-421  
Fax: + 263-4-704-897  
Email: pmusara@uzchs-ctrc.org 
 
Protocol Virologist  
Lisa Frenkel, MD 
Professor of Pediatrics, Laboratory Medicine  
Adjunct Professor, Global Health and Medicine 
University of Washington 
1900 - 9th Ave 
Box 359300/JMB-8 
Seattle, WA 98101 
Phone: (206) 987-5140 
Fax: (206) 884-7311 
Email: lfrenkel@uw.edu 
 
Protocol Pharmacologists 
Jennifer Kiser, PharmD 
University of Colorado Denver  
Skaggs School of Pharmacy and Pharmaceutical 
Sciences  
12850 E Montview Blvd, V20-C238 
Aurora, CO 80045 
Phone: (303) 724-6131 
Email: jennifer.kiser@ucdenver.edu  
 
Peter Anderson, PharmD 
University of Colorado Denver 
Skaggs School of Pharmacy and Pharmaceutical 
Sciences 
12850 E. Montview Blvd, V20-4101 
Aurora, CO 80045 
Phone: (303) 724-6128 
Fax: (303) 724-7266 
Email: Peter.Anderson@ucdenver.edu  
 
Gilead Sciences Representatives  
James Rooney, MD, PhD  
Vice President, Medical Affairs 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
Phone: (650) 522-5708 
Email: jrooney@gilead.com 
 
Protocol Pharmacist 
Kelly Parsons, PharmD, BCPS 
Pharmaceutical Affairs Branch 
NIH/NIAID/DAIDS/OCSO 
5601 Fishers Lane, 9E15 
Rockville, MD 20852 
Office: 240-669-5721 
Fax: 240-627-3112 
Email: kelly.parsons@nih.gov 
 
Protocol Epidemiologist 
Deborah Kacanek, ScD 
Senior Research Scientist  
Harvard School of Public Health 
Center for Biostatistics in AIDS Research 
Boston, MA 02115 
Phone: (617) 432-2833 


 
IMPAACT 2009, FINAL Version 3.0 
Page 10 of 173 
 
  
   
 
19 November 2020 
Email: dkacanek@sdac.harvard.edu 
 
Protocol Statistician 
Sharon Huang, MS 
Harvard School of Public Health 
Center for Biostatistics in AIDS Research 
651 Huntington Avenue 
Boston, MA 02115 
Phone: (617) 432-2873 
Email: sharon@sdac.harvard.edu  
 
Protocol Data Managers 
Benjamin Johnston, BS 
Frontier Science Foundation, Inc.  
4033 Maple Road  
Amherst, NY 14226-1056 
Phone: (716) 834-0900 x7407 
Email: johnston@fstrf.org 
 
Mattie Bartlett, MPH 
Frontier Science  
Foundation Inc.  
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: (716) 834-0900 x7270 
Email: bartlett@fstrf.org 
 
Protocol Laboratory Data Manager 
Frederic Bone 
Frontier Science Foundation, Inc.  
4033 Maple Road 
Amherst, NY 14226 
Phone: (716) 834-0900 Ext. 7306 
Email: bone@frontierscience.org  
 
Laboratory Center Representative 
Frances Whalen, MPH, MT(ASCP) 
Clinical Project Manager 
University of California Los Angeles 
11075 Santa Monica Blvd., Suite 200 
Los Angeles, CA 90025 
Phone: 704-422-4055 
Email: fwhalen@milabcentral.org 
 
Protocol Laboratory Technologists 
Cheryl Jennings 
Laboratory Project Manager  
Rush University Medical Center 
1750 W. Harrison Street, 1121 Jelke 
Chicago, IL  60612 
Phone: (312) 942-5954 
Email: cheryl_jennings@rush.edu 
 
Dean Kamangadazi Soko  
College of Medicine  
Johns Hopkins Research Project 
Queen Elizabeth Central Hospital 
Blantyre, Malawi 
Phone: 265 (0) 1 875 129 
Emails: dsoko@jhu.medcol.mw / 
sokodean@gmail.com 
 
Community Program Manager 
Marcus Bolton 
IMPAACT Operations Center 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701, USA 
Phone: (919) 544-7040 x11678 
Email: mbolton@fhi360.org 
 
Community Advisory Board Members 
Vincent Sserunjogi 
Site 30293, MU-JHU Research Collaboration 
Upper Mulago Hill Road 
P.O. Box 23491 Uganda 
Phone: +256 751674647 or +256 772 674647 
 
Scovia Aseru 
Baylor College of Medicine Children’s 
Foundation-Uganda 
Block 5 Mulago Hospital 
P.O. Box 72052, Kampala 
Phone: +256 714-119200/100 
Email: saseru@baylor-uganda.org 
 
 
 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 11 of 173 
 
  
   
 
19 November 2020 
SITE ROSTER 
 
Site 30301, JHU-Blantyre 
P.O. Box 1131 
Blantyre, Malawi 
 
Frank Taulo, MBBS, FCOG 
Investigator of Record 
Phone: +2651875129 
Email: ftaulo@yahoo.com 
 
Sharon Mambiya, MBBS 
Study Coordinator 
Phone: +2651875129 
Email: skunkanga@jhu.medcol.mw 
 
Linly Seyama 
Study Coordinator 
Phone: +2651875129 
Email: lseyama@jhu.medcol.mw 
 
Site 30303, Saint Mary’s 
15 Phillips Avenue 
Belgravia, Harare, Zimbabwe 
 
Tsungai Chipato, MBChB, FRCOG, MSE 
Investigator of Record 
Phone: +263 4 704890  
Email: tchipato@zol.co.zw 
 
Suzen Maonera 
Study Coordinator 
Phone: +263772288160 
Email: smaonera@uzchs-ctrc.org  
 
Site 30306, Seke North  
15 Phillips Avenue 
Belgravia, Harare, Zimbabwe 
 
Teacler Gamuchirai Nematadzira, MBChB, MSc 
Clin Epi 
Investigator of Record and Study Coordinator 
Phone: +263772288155 
Email: tnematadzira@uzchs-ctrc.org 
 
Site 31890, Harare Family Care Centre 
15 Phillips Avenue 
Belgravia, Harare, Zimbabwe 
 
Tichaona Vhembo MBChB, MPH 
Investigator of Record 
Phone: + 2634704890 
Email: tvhembo@uzchs-ctrc.org 
 
Sukunena J. Maturure, RN, DCN 
Study Coordinator 
Phone: +263 4 791946/ +263 712 437 682 
Email: smaturure@uzchs-ctrc.org 
 
Site 30293, Makerere University-Johns Hopkins 
University (MU-JHU) Research Collaboration 
MU‐JHU Care LTD 
Upper Mulago Hill Road 
P.O. BOX 23491 Uganda 
 
Clemensia Nakabiito, MBChB, MMed. Obs & 
Gyn 
Investigator of Record 
Phone: +256 414 540441/ +256 414 534 052/ 
+256 772 405332 
Email: cnakabiito@mujhu.org 
 
Brenda Gati, MBChB, MSc Epidemiology 
Co-Investigator 
Phone: +256 414 540441/ +256 772 881922 
Email: bgati@mujhu.org 
 
Phionah Kibalama, MBChB, MSc PH 
Study Coordinator 
Phone: 0414-541-044 
Email: pkibalama@mujhu.org 
 
Site 31798, Baylor Uganda 
Baylor College of Medicine  
Children's Foundation Uganda 
Block 5 Mulago Hospital 
P.O. Box 72052, Kampala Uganda  
 
Nicolette Nabukeera-Barungi, MBChB, MMed, 
PhD 
Investigator of Record 
Phone: +256 417-119200/100 
Email: nnabukeera@baylor-uganda.org 
 
Sarah Nanyunja, BSc Nursing 
Study Coordinator - Lead 
Phone: +256 417-119200/100 
Email: snanyunja@baylor‐uganda.org 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 12 of 173 
 
  
   
 
19 November 2020 
Site 8051, Shandukani, South Africa 
Wits Reproductive Health & HIV Research 
Institute (Wits RHI) 
Shandukani Research Centre 
Corner Esselen St. and Klein St. 
Hillbrow, Johannesburg, Gauteng, South Africa 
 
Maysseb (Masebole) Masenya, MD 
Investigator of Record 
Phone: +27 11 358 550 (ext. 5923)/ 
            +27 82 303 0054 
Email: MMasenya@wrhi.ac.za 
 
Hermien Gous, Pharm.D. 
CRS Coordinator 
Phone: +27-83-283-8360/  
            +27 11 358 5500 ext. 5502 
Email: hgous@wrhi.ac.za 
 
Hedwig Kowo, RN 
Study Coordinator 
Phone: +27-82-849-5350 
Email: hkowo@wrhi.ac.za 
 
 


IMPAACT 2009, FINAL Version 3.0 
Page 13 of 173 
19 November 2020 
IMPAACT 2009 
Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral Pre-Exposure 
Prophylaxis for Primary HIV Prevention during Pregnancy and Postpartum in 
Adolescents and Young Women and their Infants 
 
SCHEMA – Pharmacokinetics Component 
 
Purpose: 
To establish, among young HIV-uninfected women, the plasma drug 
concentrations associated with daily directly observed oral pre-exposure 
prophylaxis (PrEP) during pregnancy and postpartum. Findings from this 
component of the study will be used to guide the opening of the PrEP 
Comparison Component and interpretation of drug concentrations observed in 
that component. 
 
Design: 
Pharmacokinetic (PK) study with oral PrEP drug concentrations determined 
under adequate adherence conditions.  
 
Study Population: 
HIV-uninfected pregnant women 16-24 years of age and their infants  
 
Group 1: Enrolled during singleton pregnancy at 14-24 weeks’ gestation  
 
Group 2: Enrolled postpartum within 6-12 weeks after delivery 
 
 
 
Sample Size: 
Approximately 40 women (20 per group) to achieve at least 30 evaluable 
women (15 per group) and their infants. 
 
 
 
Study Intervention: 
Fixed dose combination of 200 mg emtricitabine (FTC) and 300 mg tenofovir 
disoproxil fumarate (TDF) administered once daily under direct observation for 
12 weeks. 
 
 
Study Duration: 
Approximately nine months total for this component. Analysis of PrEP drug 
levels will be completed within approximately three months after the last 
participant follow-up visit.  
Primary Objective  
 
• 
To determine the concentration of tenofovir diphosphate (TFV-DP) associated with adequate 
adherence to FTC/TDF among women observed ingesting daily oral PrEP during pregnancy and 
postpartum. 
 
Secondary Objective 
 
• 
To compare TFV-DP concentrations observed in pregnant and postpartum women. 
 
 
 
 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 14 of 173 
 
  
   
 
19 November 2020 
IMPAACT 2009 
Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral Pre-Exposure 
Prophylaxis for Primary HIV Prevention during Pregnancy and Postpartum in 
Adolescents and Young Women and their Infants 
 
SCHEMA – PrEP Comparison Component 
 
Purpose: 
To determine among young HIV-uninfected women and their infants, the 
feasibility, acceptability, and safety of oral pre-exposure prophylaxis (PrEP) 
during pregnancy and postpartum. 
 
Design: 
Parallel observational cohort study 
 
Study Population: 
Pregnant HIV-uninfected women,16-24 years of age, with a confirmed 
singleton pregnancy of 32 weeks’ gestation or less, and their infants. 
 
Cohort 1: Woman accepts PrEP initiation during pregnancy at study entry 
Cohort 2: Woman declines PrEP initiation during pregnancy at study entry 
 
Sample Size: 
Approximately 350 women to achieve at least 300 evaluable (200 in Cohort 1 
and 100 in Cohort 2) and their infants.  
 
Study Intervention: 
Both cohorts:  
1. Behavioral HIV risk reduction package, including cohort-appropriate SMS 
messages throughout follow-up. 
 
 
 
 
 Cohort 1 only:  
1. Daily oral PrEP (200 mg FTC/ 300 mg TDF) throughout follow-up. 
2. Enhanced adherence support, including SMS messaging and feedback of 
drug levels with tailored counseling.  
 
 
Study Duration: 
Approximately 24 months total for this component. Women will be accrued 
over a 12-month period (from the date of first enrollment) and followed 
through 26 weeks postpartum. For each woman, the duration of follow-up is 
expected to range from seven to 12 months depending on gestational age at 
entry. For each infant, the expected duration of follow-up is approximately six 
months.  
 
Primary Objectives  
 
• 
To characterize PrEP adherence among HIV-uninfected young women during pregnancy and for 
twenty-six weeks postpartum, when provided with enhanced adherence support through mobile 
technology and counseling based on observed drug levels.  
• 
To assess the safety of FTC/TDF for PrEP during pregnancy and postpartum by comparing 
pregnancy outcomes and maternal and infant safety outcomes between cohorts.  
 
 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 15 of 173 
 
  
   
 
19 November 2020 
Other Objectives  
 
• 
To identify individual, social, and structural barriers and facilitators to PrEP uptake during 
pregnancy and to adherence during pregnancy and postpartum. 
• 
To compare reported sexual risk behaviors and incidence of sexually transmitted infections, 
including HIV infection, among women who initiate PrEP during pregnancy versus women who 
decline PrEP. 
• 
To compare antiretroviral drug resistance among women and infants who acquire HIV with and 
without exposure to FTC/TDF for PrEP, including whether resistance was transmitted or acquired 
at time of transmission.  
• 
To compare bone density in women who initiated PrEP during pregnancy and women who 
decline PrEP. 
 
Exploratory Objective  
 
• 
To describe the composition of and changes in the maternal vaginal and gut microbiome and 
infant gut microbiome according to PrEP exposure. 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 16 of 173 
 
  
   
 
19 November 2020 
IMPAACT 2009 
Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral Pre-Exposure 
Prophylaxis for Primary HIV Prevention during Pregnancy and Postpartum in 
Adolescents and Young Women and their Infants  
 
Figure 1: OVERVIEW OF STUDY DESIGN 


 
IMPAACT 2009, FINAL Version 3.0 
Page 17 of 173 
 
  
   
 
19 November 2020 
1 
INTRODUCTION  
 
1.1 
Background  
 
Although oral PrEP with single- or dual-agent tenofovir-based regimens has been shown to be 
effective across a variety of settings, effectiveness is highly dependent on adherence to the 
regimen. For women, adherence may need to be near perfect because of lower cervical and 
vaginal drug concentrations as compared to the rectal mucosa. In randomized efficacy trials, 
disappointing findings among young women have traced back to poor adherence to the PrEP 
regimen. These findings have led to questions about the feasibility of PrEP as a public health 
intervention for young women. However, results from open label studies among women have 
demonstrated higher adherence levels (1). As such, PrEP  has become an increasingly important 
component of combination HIV prevention for this group (2). Nonetheless, more work is needed 
to optimize PrEP uptake and adherence in populations at substantial risk for HIV acquisition, 
including young pregnant women (3). Although considerable evidence has been gathered about 
the safety of antiretroviral drug use in HIV-infected pregnant women, evidence supporting the 
safety, feasibility, and acceptability of PrEP use during the antenatal and postpartum periods 
among HIV-uninfected women is needed.  
 
IMPAACT 2009 will evaluate the use of PrEP during pregnancy and postpartum among HIV-
uninfected adolescent and young adult women. Demographically speaking, young women in Sub-
Saharan Africa have the highest rate of new HIV infections globally (4, 5) and, because of a 
heightened risk for incident infection in pregnancy and postpartum (6), this population is in dire 
need of effective public health strategies for HIV prevention; however, it is unknown whether 
PrEP is feasible, acceptable, and safe among young women during pregnancy or in the early 
postpartum period. Women with HIV infection who become pregnant often display better health-
seeking behavior than their non-pregnant counterparts. For example, 90% of women with 
improved adherence during pregnancy in the WITS study cited their baby’s health as the primary 
reason for their adherence (7). A similar phenomenon has been observed among women without 
HIV, with adherence to daily medications such as multivitamins, ferrous sulfate, and folate being 
higher during pregnancy. The dual benefit of health interventions during pregnancy – for both 
mother and fetus – can be highly motivating and may represent a window in which PrEP, can be 
effectively introduced to young women without HIV infection.  
 
1.2 
Prior Research 
 
Evidence Supporting PrEP Efficacy for HIV Prevention 
 
Administration of antiretroviral agents to prevent sexual transmission of HIV has been studied in 
numerous settings. Single- and dual-agent tenofovir-based regimens have been shown to 
significantly reduce HIV acquisition among men who have sex with men (MSM), heterosexual 
men and women, injection drug users (8, 9) and HIV serodiscordant couples (9-13). The efficacy 
of oral daily PrEP has ranged from 0% to 86% in over ten clinical trials (1, 10-20). Interestingly, 
in at least two clinical trials of women, oral PrEP did not show a decreased risk of HIV 
transmission (14, 16); however, these results appeared to be related to poor adherence among 
study participants. In the FEMPrEP study, for example, only 12% of women had serum drug 
levels associated with good adherence throughout participation (16). In the Vaginal and Oral 
Interventions to Control the Epidemic (VOICE) study, less than 50% of women assigned to oral 
PrEP regimens had plasma tenofovir levels detected, despite participating in a rigorously 
conducted clinical trial (14).  


 
IMPAACT 2009, FINAL Version 3.0 
Page 18 of 173 
 
  
   
 
19 November 2020 
Given the growing body of evidence about its effectiveness, including encouraging “real world” 
demonstration projects (21), oral daily PrEP is now recommended for HIV prevention by the 
United States Centers for Disease Control and Prevention and the World Health Organization 
(WHO) (22, 23). As with many medical interventions, its effectiveness is highly dependent on 
adherence to prescribed drugs. This appears to be particularly true for women, who require near 
perfect adherence (i.e. six to seven doses per week) to reach the required preventive drug 
concentrations in the female genital tract (24). 
 
Understanding Adherence to PrEP among Pregnant and Postpartum Women 
 
Measuring medication adherence in clinical trials is vitally important because inadequate 
adherence negatively affects clinical response (25). Rates of adherence among adolescents and 
young adults with chronic illnesses, such as HIV, diabetes, and cancer are concerning and are 
often estimated to be about 50% overall (26, 27). Data on adherence to antiretroviral therapy 
(ART) during pregnancy among HIV-infected women are mixed. Several studies have 
demonstrated that pregnant women have greater adherence to ART than non-pregnant women (7, 
28-30); however, adherence during pregnancy, and even more so the postpartum period, can be 
improved. A meta-analysis conducted by Nachega and colleagues demonstrated adequate self-
reported adherence in only 76% of pregnant women with HIV, which dropped to 53% following 
delivery (31). Phillips and colleagues (2014) found that missed visits and disengagement from 
care occurred frequently among HIV-infected pregnant and postpartum women in South Africa 
(32).  
 
It is important to assess closely whether pregnant and postpartum women at risk for HIV 
infection would be willing and able to maintain consistent use of a daily medication regimen that 
is used solely for HIV prevention. Examination of the data on incident pregnancies during the 
Partners PrEP trial reveals that pill adherence was high overall and no differences were found 
between adherence among pregnant and non-pregnant women (33). Conversely, results from 
CAPRISA 004 showed that women who became pregnant during that trial were less likely to 
have adhered to pre-and post-coital study gel use (34). These discrepant results may be related to 
the lower median age of CAPRISA participants (22 years) compared to Partners PrEP 
participants (33 years), differences in oral versus vaginally applied products, differing perceived 
risk for acquiring HIV among study populations, and differences in eligibility criteria for 
enrollment. For example, Partners PrEP enrolled only couples with known discordancy in HIV 
status and used PrEP as a bridge until the infected partner had been on ART for six months, while 
CAPRISA 004 enrolled sexually active women.  
 
Adherence behaviors can also be extrapolated from studies of non-pregnant adolescent and young 
adult women. The FACTS 001 licensure trial for tenofovir gel that followed CAPRISA 004 
recently reported no effect on HIV acquisition among a large sample of young South African 
women, primarily because participants struggled to adhere to the prescribed regimen (15). 
Similarly, the VOICE trial (35) failed to show efficacy of either oral PrEP or daily vaginal gel, 
largely attributable to very low rates of adherence among a cohort of young women. Two recent 
randomized trials of the dapivirine vaginal ring showed modest efficacy overall, with an 
approximately 30% reduction in HIV incidence among those randomized to the intervention arm 
(36, 37). Interestingly, both studies demonstrated consistently low adherence among women 
under the age of 21, which attenuated the overall protective effect of the intervention.  
 
Follow-up studies have further investigated PrEP adherence. In the FEM-PrEP study, only 12% 
of participants had drug levels consistent with four to five doses per week throughout 
participation (38). Characteristics associated with adherence were limited and included site of 


 
IMPAACT 2009, FINAL Version 3.0 
Page 19 of 173 
 
  
   
 
19 November 2020 
recruitment (adjusted OR for the Bloemfontein site: 2.43, 95%CI: 1.32-4.48), liking the color of 
the pill (adjusted OR: 2.93, 05%CI: 1.18-7.27), and use of oral contraceptives at enrollment 
(adjusted OR: 0.37, 95%CI: 0.18-0.74) (38). In semi-structured interviews, five key facilitators 
for PrEP adherence emerged: a) participants supportive of research, b) HIV risk reduction 
counselling, c) adherence counseling, d) routine formation and use of reminder tools, and e) 
partner awareness and support (39). Interestingly, a significant proportion of women 
misrepresented their adherence behaviors during the study. In audio computer-assisted self-
interviews of 224 participants, 31% admitted to reporting adherence to the study intervention 
when in fact they had not taken the drug. The main reason (69%) was the belief that admission of 
non-adherence would result in their termination from the trial (40). Women expressed concerns 
about the investigational nature of the drug and its potential side effects; they also reported 
discouragement from partners, community members, and other participants (41). 
 
Similar adherence findings were observed in VOICE (MTN-003) (14), a randomized trial of oral 
and vaginal PrEP agents. Of particular relevance were the high levels of non-adherence 
determined by plasma drug levels (69%), a figure in stark contrast to the <10% non-adherence by 
participant self-report (42). A qualitative sub-study at the Johannesburg site (VOICE-C) revealed 
numerous potential barriers to study drug administration. These included perceptions that 
antiretroviral agents were associated with illness and concerns that they would be mistakenly 
identified as HIV-infected. The stigma associated with the PrEP agents occasionally led to 
relationship conflicts and early trial termination. While antiretroviral drugs were considered 
potent and beneficial for HIV-infected individuals, they were regarded as potentially harmful 
when taken by HIV-uninfected individuals (43). In a separate adherence disclosure study, where 
plasma drug level-based adherence assessments were provided to participants, women at all 
pharmacokinetic levels suggested that real-time drug monitoring and feedback could improve 
adherence to the PrEP agents (44). 
 
While adherence data from these prevention trials are sobering, all PrEP trials with negative 
results to date have been randomized, placebo-controlled trials in which participants were not 
only blinded to product versus placebo arm, but also counseled that the efficacy of the product 
itself was unknown. Additionally, the issues around adherence to a vaginal product or coitally 
dependent dosing may differ substantially from those of oral daily PrEP use. The current study 
differs from those trials in that participants will be provided with information on the known 
efficacy of the study product. This knowledge alone may significantly improve adherence to 
levels seen in recent open label studies of oral PrEP among MSM and heterosexual couples (21, 
45). Most encouraging are the recent results from the ADAPT trial (HPTN 067), which evaluated 
different oral PrEP dosing strategies in the context of open label use. At the Cape Town site, 
where half of the participants were women ≤25 years, adherence was highest in the daily dosing 
arm: 92.5% (week 10) and 79.3% (week 30) who had reported sex in the week prior had 
detectable serum tenofovir (1). In addition, semi-structured interviews and focus groups 
conducted in the ADAPT trial highlighted the ongoing importance of one’s overall trust in PrEP 
as being safe and effective, and the potential for community distrust to erode confidence in study-
provided information on these factors; however, this qualitative work also identified women who 
were strong advocates and champions for PrEP (46).  
 
Interim findings from the Plus Pills open-label study of high risk South African adolescents aged 
15-19 years (66% female) concluded that PrEP uptake and early adherence were reasonable (47). 
Good adherence to PrEP (>six pills/week) was reported by 72% of the sample with 76% having 
tenofovir plasma levels >40 ng/mL at 12 weeks. Ongoing evaluation, however, suggests that 
maintaining good adherence remains a challenge for these adolescents beyond the 12 week time 
point (48). The IMPAACT 2009 study specifically targets the distinctive period of pregnancy and 


 
IMPAACT 2009, FINAL Version 3.0 
Page 20 of 173 
 
  
   
 
19 November 2020 
breastfeeding because this is a time when young women may be motivated to initiate PrEP and 
maintain adherence at uniquely high rates, to protect both themselves and their infants from 
acquiring HIV infection. 
 
Among adopters of PrEP for HIV prevention, guidelines clearly promote the use of risk reduction 
and adherence counseling. Nonetheless, the exact kinds of support that will be most effective for 
youth and young adults is unknown. In the U.S., pilot projects have incorporated dried blood spot 
(DBS) monitoring with drug level feedback and integrated risk reduction counseling (49). DBS 
drug levels provide a vehicle for both monitoring as a proxy for adherence and an opportunity to 
target intervention efforts. Monitoring outcomes of preventative medications or behavioral 
strategies with biological measures is not uncommon (e.g., insulin monitoring for diabetics, 
oxygen saturation monitoring for asthmatics, and heart rate monitoring for relaxation training). 
Although the impact of drug level monitoring and feedback is unknown, early findings from 
several PrEP demonstration projects have been positive in terms of feasibility and acceptability 
(44, 50).  
 
Similarly, the use of mobile technology (i.e., “mHealth”) to support adherence has been shown to 
be effective across a broad range of settings (51, 52), and mobile phones are pervasive throughout 
Africa, especially among the youth population (53). Such technology-based strategies may have 
greater impact among adolescents and young adults, given their increased proficiency with such 
technologies even in resource-constrained settings (54-56), and SMS texting has been shown to 
be efficacious for encouraging HIV prevention, testing, care, and medication adherence (57, 58). 
Text messages developed by the Mobile Alliance for Maternal Action (MAMA) (59) have been 
shown to promote key outcomes such as prenatal care visit attendance and exclusive 
breastfeeding. MAMA has developed free, adaptable messages informed by experts in maternal, 
newborn and child health (Figure 2). 
 
Figure 2. MAMA: personalized, stage-based messages 
 
The PrEP adherence support package offered through the study is specifically designed to build 
on top of existing services at the study sites to accommodate the anticipated development of such 
capacity. Currently, public health maternity services make use of mobile technology in many 
countries across the region and cell phone penetration is already high. The major goal of the drug 
level analyses is scientific, to quantify PrEP uptake and use in this population. Nevertheless, there 
are efforts to develop low cost point of care assays for tenofovir testing, an ideal diagnostic 
modality for the study setting. This study will provide information on the acceptability and 
feasibility of drug-level guided adherence support in pregnant women. The intention is not to 
evaluate the efficacy of the adherence support package, although our work will offer important 


 
IMPAACT 2009, FINAL Version 3.0 
Page 21 of 173 
 
  
   
 
19 November 2020 
information about women’s experiences with it. A similar trial in non-pregnant adolescent and 
young women in sub-Saharan Africa has randomized participants to receive adherence 
counselling based on feedback from drug levels in addition to the standard of care support 
package (HPTN 082) and has assessed its effect on their motivation and ability to subsequently 
adhere to PrEP(60, 61). However, it remains vital for the experiences with drug level informed 
adherence support to be described in the context of pregnancy and breastfeeding, given that 
sexually active young women across the region targeted by PrEP implementation programs also 
have high rates of conception. The 2015 Zimbabwe Demographic Health Survey, for example, 
found that 17% of 15-19-year-old women have given birth and 27% have begun childbearing in 
rural areas (62). Findings are similar elsewhere in the region. 
 
Mixed methods studies typically involve collecting and analyzing data derived from both 
quantitative and qualitative data sources in order to gain greater insight into a research problem 
than would be gained by using only one of the two methods in isolation (63). By combining 
methods, the limitations and biases inherent in one single methodology can be lessened by using 
multiple forms of data collection. Qualitative studies nested within previous trials of biomedical 
prevention (e.g. VOICE, FEM PrEP, HPTN067/ADAPT) have significantly contributed to our 
understanding of women’s motivations to use PrEP (43, 64, 65) but it is not known yet how the 
context of pregnancy affects women’s perceptions and use of PrEP. As such, this study will 
include qualitative evaluations which will consist of in-depth interviews (IDI) with maternal 
participants. These interviews will explore the barriers and facilitators to PrEP initiation and 
adherence among young women during pregnancy as well as postpartum. The use of qualitative 
methods will give young women the opportunity to discuss PrEP in their own words, which will 
be critical to understanding women’s own perceptions of PrEP and adherence and to elucidating 
the mechanisms that underlie decisions about adherence among young women in the context of 
pregnancy. Refer to Section 3.2.1 for further detail.  
 
Choice of Study Agent 
 
Co-formulated TDF plus FTC was chosen for use in this study, based on efficacy data for both 
agents from pregnant animal studies, as well as the overall low rate of toxicity associated with 
their use in PrEP demonstration projects and implementation programs for women. At this time, 
FTC/TDF is the only PrEP product with sufficient safety and efficacy data during pregnancy to 
include in a clinical trial. Newer ARV agents are in development, with a gradual increase in 
available safety data from their use during pregnancy. For example, although tenofovir 
alafenamide (TAF) may appear promising, there are insufficient data about TAF use as treatment 
in HIV-infected pregnant women to consider its use for prophylaxis in uninfected pregnant 
women, where the risk-benefit ratio is quite different. Furthermore, there are no efficacy data yet 
available in humans on the efficacy of TAF as PrEP nor data to describe how TAF crosses the 
placenta in humans. While ongoing clinical trials plan to collect these data for TAF, the only 
PrEP agent available for use over the next several years is FTC/TDF. The primary aim of 
IMPAACT 2009 is to characterize adherence to and acceptability of oral PrEP, hence the study 
findings will apply to all forms of PrEP that utilize daily oral dosing. This protocol will fill 
critical gaps in knowledge related to the acceptability and feasibility of PrEP dosing during this 
time in a woman’s life.  


 
IMPAACT 2009, FINAL Version 3.0 
Page 22 of 173 
 
  
   
 
19 November 2020 
The Need for Safety Data for HIV-uninfected Pregnant and Postpartum Women  
 
The safety data for TDF and FTC/TDF are taken predominantly from clinical trials involving 
HIV-infected adults undergoing treatment for HIV and non-pregnant adults receiving PrEP for 
HIV prevention. While the pool of opportunistic safety data on PrEP use in pregnancy is growing, 
prior studies of PrEP in women tested frequently for incident pregnancy and stopped dosing upon 
confirmation of pregnancy. Studies in men and non-pregnant women may not translate directly 
into the pregnant and postpartum context. This is most obvious with regard to fetal and/or infant 
development, but the physiological changes associated with the pregnant state (specifically renal 
and hepatic) also may alter toxicity risk and pharmacokinetics of PrEP. A better understanding of 
obstetrical outcomes with PrEP is also urgently needed. Thus far, few have investigated this 
important question. While clinical guidelines from the Center for Disease Control (CDC) (22), 
and more recently the WHO (23) do not consider pregnancy to be a contraindication to PrEP, 
they call for further research to be done in concern with the scale up of PrEP delivery to women 
at substantial risk of HIV who become pregnant or are lactating (66). A systematic review in 
2016 concluded that there was no safety-related rationale to prohibit PrEP use in pregnant and 
breastfeeding women and that it should be continued in women who conceive on PrEP and 
remain at risk of acquiring HIV infection (67). Apart from characterizing important PrEP 
adherence patterns and drivers, the findings from our study will contribute to the body of 
evidence released to date by providing additional data collected under clinical trial conditions on 
safety outcomes experienced by HIV-uninfected women who take PrEP during pregnancy and 
lactation. 
 
Evaluating risk-benefit ratio 
 
Side effects associated with FTC/TDF (Truvada®) include diarrhea, nausea, fatigue, headache 
and rash which are seen in about 10% of participants during the initiation of therapy (68). While 
these early symptoms are generally well-tolerated and dissipate over a few weeks, such side 
effects may be less tolerable for pregnant or postpartum women. For HIV-infected pregnant and 
postpartum women, such risks – including the adverse bone and renal effects of TDF – are offset 
by the significant health benefits of taking the drug as part of ART. However, the risk of adverse 
drug effects in relation to the potential HIV prevention benefits for HIV-uninfected women at 
increased risk for infections requires further evaluation.  
 
Tenofovir is a highly-charged anion that does not readily permeate across epithelial barriers. The 
water soluble pro-drug administered by mouth, TDF, is well absorbed in the gut and is rapidly 
converted to the active form - tenofovir. While tenofovir is present in amniotic fluid and cord 
blood, there is low penetration of active drug from maternal blood into breastmilk and 
subsequently across the infant gut. Low blood-milk penetration and infant drug levels were 
recently confirmed in a prospective study of 50 HIV uninfected lactating women receiving 10 
days of directly observed oral dosing with FTC/TDF PrEP  (69). While more ready excretion of 
FTC into breastmilk was evident, infant plasma concentrations were 0.5% of levels expected 
from therapeutic dosing in infants. This suggests the risk of postnatal exposure to PrEP in 
breastfed infants is low. 
 
Renal damage 
  
TDF use has been associated with a small and asymptomatic decrease in glomerular filtration rate 
in HIV-infected individuals. Reports from completed PrEP clinical trials reveal no clinically 
significant elevations in serum creatinine (70) but transient decrease in estimated glomerular 
filtration rates and a return to baseline levels within four weeks of PrEP discontinuation (71). 


 
IMPAACT 2009, FINAL Version 3.0 
Page 23 of 173 
 
  
   
 
19 November 2020 
Glomerular filtration rates increase by up to 50% during pregnancy as part of normal physiologic 
changes. Reassuringly, in the women assigned to TDF-FTC-LPV/r (Arm C) in IMPAACT 
1077BF (PROMISE), creatinine elevations were uncommon overall with <1% of women 
(n=2/424) having a confirmed Grade 2 or higher renal chemistry event up to 14 days postpartum 
(72). A recent randomized trial of TDF use in pregnant women who were positive for hepatitis B 
virus e-antigen found similar maternal and infant safety profiles between the intervention and 
control arms. Although TDF was associated with higher creatinine kinase and alanine 
aminotransferase levels, these differences were modest and not thought to be clinically 
meaningful (73). 
 
Bone demineralization  
 
Consistent with data on reduced bone mineral density (BMD) among HIV-infected adults on 
ARVs, PrEP use has been associated with an approximate 1% reduction in BMD among trial 
participants (11, 74). The effect on BMD was shown to be reversible in young African women 
adherent to PrEP in the VOICE trial with a follow-up dual-energy x-ray absorptiometry (DXA) 
scan 48 weeks after stopping study drug (75). Of special note is that the women studied in these 
trials were not lactating. There are no data at this time to evaluate the additive effect of lactation 
on bone loss due to PrEP. The bone mineral resorption required for breastmilk production results 
in a 3-5% reduction in BMD over six months of lactation that is generally restored within six 
months of cessation of breastfeeding. Preliminary data from IMPAACT P1084s – a sub study of 
PROMISE conducted at eight African sites – revealed a decline in BMD at 74 weeks postpartum 
in HIV-infected women receiving TDF-based cART who breastfed for a mean of 61 weeks when 
compared to women not receiving cART (76). The mean difference at the lumbar spine was -
3.16% (95% CI -4.44, -1.87) and -2.33% (-3.23, -1.42) at the hip (both p-values<0.001). The 
IMPAACT 2009 study provides an important opportunity to study the effect of PrEP use and 
lactation on bone mass in young women who are yet to achieve peak bone mass. 
 
For U.S. infant populations, Siberry and colleagues reported reduced bone mineral content of 
uncertain clinical significance among newborns who had been exposed in utero to TDF taken by 
their HIV-infected mothers (77). However, more recent work from Cape Town, South Africa 
found that fetal exposure to TDF did not appear to alter fetal long bone growth (78). IMPAACT 
P1084s found that in utero exposure to TDF-containing cART was not associated with lower 
bone mineral content among HIV-exposed newborns, when compared to other cART regimens. 
However, the data suggested a substantial and significant bone mineral content reduction in 
newborns exposed to maternal triple cART when compared to maternal zidovudine monotherapy 
(79). The effect of exposure to in utero and postnatal ARVs on long term infant bone health, 
growth and development remains so far still uncertain. Six-month longitudinal outcomes are 
currently being analyzed for P1084s. 
 
DXA measurement of the hip and spine is the standard assessment to monitor BMD. BMD is 
expressed in absolute terms of grams of mineral per square centimeter scanned (g/cm2) and is 
compared to the expected BMD for the patient’s age and sex (Z-score) or to young adults of the 
same sex (T-score). There are no normative data for DXA scan assessment of BMD in infants. 
Undergoing a DXA scan involves exposure to less radiation than experienced during a chest x-
ray.  


 
IMPAACT 2009, FINAL Version 3.0 
Page 24 of 173 
 
  
   
 
19 November 2020 
Adverse pregnancy outcome 
 
A secondary analysis from the Partners PrEP study found no differences between women with 
incident pregnancies while taking PrEP in rates of preterm birth, congenital anomalies, or infant 
growth in the first year of life and women taking placebo; however, all women stopped the study 
medication at time of pregnancy detection, which occurred a median of 35 days (IQR: 29–45) 
after conception (69). In the ASPIRE trial (MTN 020) that evaluated the dapivirine ring for HIV 
prevention, 169 of 2551 women became pregnant and immediately stopped the study product 
upon diagnosis. The rates of adverse birth outcomes did not differ according to study arm (80). 
The Partners Demonstration Project, an open-label delivery study in Kenya and Uganda, HIV-
uninfected women in serodiscordant relationships were given the option of continuing PrEP even 
after pregnancy was diagnosed. Of the 34 who became pregnant, 30 elected to continue PrEP 
antenatally. When compared to 96 women who became pregnant in the Partners PrEP clinical 
trial, there were no differences in pregnancy loss, preterm delivery, or congenital anomalies, 
though sample sizes were small (81). Finally, use of TDF in the last trimester of pregnancy to 
reduce hepatitis B vertical transmission is increasingly common, with no reports of an effect on 
pregnancy outcome to date (73, 82). Encouragingly, an ongoing randomized study in Thailand of 
tenofovir use among HIV-uninfected, hepatitis B-positive pregnant women (ClinicalTrials 
#NCT01745822) has not raised any safety concerns at the interim DSMB review in July 2015 
(83, 84). 
 
These findings are in contrast to results from the PROMISE trial, which demonstrated higher 
proportions of severe adverse pregnancy outcome in healthy HIV-infected pregnant women who 
received TDF-FTC-LPV/r (9%) versus ZDV-3TC-LPV/r (4%) to prevent in utero HIV 
transmission (72). The risk of very preterm delivery before 34 weeks of gestation was also 
significantly higher in women who received TDF-FTC-LPV/r versus ZDV-3TC-LPV/r (6.0% 
versus 2.6%, p=0.036), as was the risk of infant death by Day 14 (4.4% versus 0.6%, p<0.001). 
Further work is underway to better understand this finding, including whether drug interactions 
related to concomitant lopinavir-ritonavir may have contributed to these health outcomes. The 
gestational age at delivery for IMPAACT 2009 will be confirmed using obstetrical ultrasound, 
thus addressing an important limitation of studies thus far. The improved precision of gestational 
age dating will be an important contribution to the medical literature around antiretroviral drug 
exposure and adverse birth outcomes, without the potential confounding from HIV infection.  
 
HIV drug resistance 
 
Because PrEP comprises only two agents, concerns about ARV resistance have been raised for 
PrEP users who acquire HIV infection. Early study results provide some reassurance in this 
regard. Antiretroviral resistance has been consistently rare across PrEP trials, limited only to 
those with unidentified acute HIV infection at the time of PrEP initiation and decreasing rapidly 
in the absence of continued PrEP exposure (9, 85). For those individuals who acquire HIV after 
enrollment, there were no cases of resistance (10). The lack of resistance among seroconverters 
on PrEP was attributed in part to the low adherence among these participants. Despite these 
findings, vigilance is still required. One case of multiclass drug resistant HIV transmission has 
been documented in an individual who was likely adherent to PrEP (86). With high levels of TDF 
resistance reported among individuals failing first-line TDF-based ART – up to 57% in sub-
Saharan Africa – (87) there are legitimate concerns about use of the same antiretroviral agent in 
both HIV prevention and treatment modalities. While early data remain encouraging, further 
investigation about adherence is needed in new populations such as pregnant and postpartum 
women. 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 25 of 173 
 
  
   
 
19 November 2020 
Behavioral disinhibition 
 
Alongside the potential for biological adverse events, there are behavioral risks that may be 
associated with the PrEP intervention as well. Risk compensation or risk homeostasis theory is 
based on the presumption that persons have an inherent set-point that determines their willingness 
to take risk (88, 89). According to this theory, any modification in the environment that reduces 
the external probability of risk could lead an individual to increase their risk-related behaviors 
(i.e., behavioral disinhibition) in order to maintain the homeostatic set point, thereby neutralizing 
the benefits of risk-reduction strategies. In this manner, risk compensation has the potential to 
threaten the benefits of emerging HIV prevention technologies. Despite considerable concerns for 
the potential for risk compensation (or safety offset), trials completed to date have not found 
supporting evidence for this. Rather, trials and projects consistently report “prevention synergies” 
where PrEP use has been associated with increased awareness of HIV prevention and 
commitment towards prevention (19, 90-94). In most trials to date, self-reported condom use 
increased, number of sexual partners decreased, and sexually transmitted infection diagnoses 
decreased in participants receiving PrEP (10, 13, 21, 95). While open label PrEP demonstration 
projects have shown high rates of STIs while on PrEP, these rates appear consistent with baseline 
diagnoses of STIs and thus aren’t rising in the context of PrEP (19, 90, 96). 
 
Other safety concerns 
 
Discontinuation of FTC/TDF in HIV-infected individuals with hepatitis B co-infection has been 
associated with subsequent liver injury. These “hepatic flares” have been documented in several 
settings when an agent with anti-hepatitis B activity (e.g., TDF, FTC, lamivudine [3TC]) is 
stopped (97-99). However, less is known about the incidence of such events in the absence of 
HIV co-infection. In the iPrEx study, HIV-uninfected participants with chronic hepatitis B 
infection on FTC/TDF did not encounter hepatic flares after PrEP was stopped, but the sample 
size was small (n=5) (100). Investigators reported similar findings in a multicenter study of TDF 
for PrEP in West Africa. Among 23 women with active hepatitis B in the intervention arm, none 
experienced acute exacerbation following discontinuation of the study agent (101). Nevertheless, 
participants will be screened for hepatitis B surface antigen prior to enrollment. Because of this 
potential risk of hepatitis B exacerbation and its potential impact during pregnancy, those with a 
positive result will be excluded from study participation.  
 
Potential changes in the microbiome with PrEP use in pregnancy 
 
Recent studies suggest that the vaginal microbiome in pregnancy could play an important role in 
maternal as well as neonatal health outcomes. It is well established that the vaginal bacterial 
community undergoes a shift in composition in pregnancy (102). Changes primarily involve 
dominance of Lactobacillus species that are believed to secrete antibacterial products and produce 
metabolites such as lactic acid. The resulting low pH represents an effort by the host to inhibit 
pathogen growth (103). Consequently, circumstances that lead to dysbiosis of the vaginal 
microbiome could result in complications of pregnancy including risk of preterm birth (104-106). 
 
Intravaginal practices are common in sub-Saharan African women, specifically vaginal drying, 
washing and insertion of herbs, which are associated with altered vaginal pH and bacterial 
vaginosis (107, 108). These practices continue during pregnancy and post-delivery (109), with 
specific cultural practices linked to preparing the vaginal tract for childbirth. It is known that the 
vaginal microbiome is more stable during pregnancy (110, 111); however, intravaginal practices 
that promote dysbiosis could affect wound healing, (112) which may be especially important 
following delivery in high HIV prevalence settings.  


 
IMPAACT 2009, FINAL Version 3.0 
Page 26 of 173 
 
  
   
 
19 November 2020 
Additionally, the microbiome appears to be important for local drug level concentrations and HIV 
acquisition risk. In a sub-study of a PrEP trial conducted by the Centre for the AIDS Programme 
of Research in South Africa (CAPRISA) of TFV vaginal gel to prevent HIV-infection in young 
South African women, efficacy varied by the composition of the vaginal microbiome. Among 
women whose microbiome contained >50% Lactobacilli, TFV vaginal PrEP use protected 61% 
of women from HIV acquisition. In contrast, only 18% of women whose microbiome was 
composed of <50% Lactobacilli were protected (113). In vitro studies demonstrated that TFV 
levels decreased by approximately half in the presence of Gardnerella vaginalis (114). 
Furthermore, in the FRESH study, women with bacterial communities dominated by Gardnerella 
vaginalis or diverse bacterial communities had up to a four-fold greater risk of acquiring HIV 
(115). These results are supported by more recent work by Hillier S. et al, showing that trough 
levels of TFV were lower in cervicovaginal fluid and plasma among women with higher levels of 
G. vaginalis, when intravaginal PrEP agents were used (116). This is in contrast to a secondary 
analysis from the Partners PrEP Study, which studied oral (vs. intravaginal) PrEP formulations. 
Heffron and colleagues found that bacterial vaginosis did not alter the efficacy of the oral PrEP 
intervention, though vaginal drug concentrations were not measured (117). Clearly, more work in 
this area is needed, particularly in the context of pregnancy.  
 
Most microbiome studies available assess the gut microbiome. While a healthy vaginal 
microbiome is often dominated by only a few bacteria, a healthy gut microbiome is characterized 
by greater diversity. While it is known that antibiotics and proton-pump inhibitors alter the gut 
microbiome, there are only a few studies about antiretroviral drugs which report a decrease of 
alpha diversity in treated individuals (118-120) . In the existing studies of the gut microbiome in 
HIV-infection, antiretroviral therapy does not restore the microbial dysbiosis of HIV-infection 
and HIV-associated dysbiosis correlates with immune activation and disease progression (121-
124). Furthermore, in a study of the HIV-associated microbiome in Uganda, the HIV-associated 
microbiome changes documented in previous studies were not seen in this East African cohort, 
likely due to differences in the baseline microbiota in the developed versus developing world 
(125). Given that as many as  20% of women report engaging in heterosexual anal intercourse in 
sub-Saharan Africa (126), the underlying changes to the maternal gut microbiome with oral PrEP 
may be an important factor in HIV acquisition  
 
Therefore, it is scientifically important to assess changes to both the vaginal and rectal microbiota 
of women on oral PrEP. Although the mechanisms of action appear different, changes in both the 
vaginal and rectal microbiome could affect the efficacy of PrEP interventions. At this time, 
however, data remains sparse, particularly among adolescent and young women who are 
pregnant. IMPAACT 2009 provides an ideal opportunity to characterise the microbiome in this 
sub-population and begin to study its relationship with FTC/TDF use. 
 
Maternal PrEP use and the infant gut flora 
 
The seeding of the neonatal gut by the maternal vaginal microbiome during birth and then by the 
microbiome present in breast milk constitute major mechanisms for protection of the infant from 
infections, atopy, and autoimmunity by influencing infant metabolism and immune system 
development (127). The host–microbial symbiosis that is established in early life contributes to 
host development and influences disease progression later in life. The immune system is 
intimately linked to the microbiome and dependent on the presence of commensal microbiota, 
particularly in the gastrointestinal tract and the infant immune system is modulated by the nature 
of colonizing bacterial species. In germ-free mice the immune system is altered, with deficits in 
both innate and adaptive immune components of the gut mucosa (128). Interestingly, emerging 
evidence indicates that the infant microbiota may be populated in utero, is seeded much earlier 


 
IMPAACT 2009, FINAL Version 3.0 
Page 27 of 173 
 
  
   
 
19 November 2020 
than was previously thought, and can be altered by gestational exposures (129). In pre-term and 
healthy term pregnancies, there is now evidence for maternal transmission of bacteria to the fetal 
gut during gestation, with bacteria associated with the placenta and amniotic fluid (130, 131), 
attributed to swallowing of amniotic fluid by the infant continuously from mid to late gestation. 
The evidence for transmission of microbes from the mother to the fetus during gestation is further 
corroborated by the observed similarity of the neonatal microbiota at the time of delivery with 
maternal skin and vaginal microbiota. 
 
A recent review by S Tamburini (132) discussed factors such as host genetics, prenatal 
environment and delivery mode that shape the newborn microbiome at birth. After birth, other 
factors such as antibiotic treatment, diet or environmental exposure further modulate the 
development of the infant’s microbiome and immune system, underscoring the relationship 
between composition of gut microbiome in infancy and risk for several diseases.  
 
In studies by Aldrovandi et al in Haiti (133), HIV infected women were found to manifest an 
altered microbiome with the result that the microbiome of their HIV exposed infants was 
disrupted. The studies of Madan JC et. al (132) have clearly demonstrated that the infant 
intestinal microbiome at approximately six weeks of age is significantly associated with both 
delivery mode and feeding method.  
 
The increasing evidence of the impact of the maternal microbiome on the infant gut microbiome 
highlights the importance of understanding the microbiome composition in mothers and infants. 
In the context of maternal oral FTC/TDF PrEP use, preliminary data generated in IMPAACT 
2009 will add to the pool of knowledge relating to the origin of the infant gut microbiome and 
explore the potential effect of maternal PrEP use on the infant microbiome. 
 
1.3 
Rationale 
 
1.3.1 
Feasibility and Acceptability of Pre-Exposure Prophylaxis during Pregnancy and 
Breastfeeding  
 
Adolescent and young adult women in sub-Saharan Africa have the highest HIV incidence rates 
globally (35). Three recent HIV prevention trials in this population (FEMPrEP, VOICE, and 
ASPIRE) reported HIV incidence rates of 5-6% despite monthly HIV testing, individualized risk-
reduction counseling, provision of condoms, and treatment of sexually transmitted infections (16, 
134, 135). In resource-limited settings with HIV incidence of this magnitude, pregnant and 
postpartum women are at high risk of acquiring HIV. In a meta-analysis and systematic review, 
Drake and colleagues found an overall incidence of 3.8 per 100 person-years, a figure that was 
comparable to (or even higher than) those observed in studies of “high risk” non-pregnant 
populations: female sex workers (2.7 per 100 person-years), HIV-discordant couples from South 
and East Africa (2.0–3.6 per 100 person-years), and men who have sex with men (MSM) in North 
and South America (6.1 per 100 person-years) (6). A more recent meta-analysis, conducted by 
Graybill and colleagues, found similarly high HIV incidence during pregnancy and breastfeeding 
(3.6 per 100 person years), even with numerous studies from the era of combination HIV 
prevention(136). A variety of biomedical and behavioral factors are thought to contribute towards 
this risk. First, observational data suggest that the hormonal changes women experience during 
pregnancy may increase HIV acquisition risk (137). As a result, HIV acquisition may be as much 
as four times higher among pregnant women than among non-pregnant women, with young, 
single women being at particularly high risk (6, 138-140). Second, reports from South Africa 
revealed that less than half (40%) of women who had been pregnant in the past year were aware 


 
IMPAACT 2009, FINAL Version 3.0 
Page 28 of 173 
 
  
   
 
19 November 2020 
of their sexual partner’s HIV status (141, 142). Third, cultural norms may increase a woman’s 
risk for HIV exposure, including decreased condom use during pregnancy or the sanctioning of 
external sexual partners for the husband while his wife or primary partner is pregnant or 
postpartum (70, 143). A recent cohort study of pregnant young women in Kenya (n=1304; 
median age 22 years), HIV incidence was 2.31/100 person years, condom use was reported by 
only 8% of participants, and none of the women who seroconverted identified that they had an 
HIV-infected partner (144).  
 
PrEP for HIV prevention has been shown to be highly efficacious among MSM, heterosexual 
men and women, serodiscordant couples and injection drug users (10-12, 45). While pregnant 
women have been excluded from enrollment into PrEP trials, very high rates of pregnancy (range 
3.9 to 52 per 100 person years) have occurred among participants in HIV prevention trials despite 
ready access to effective contraception (141, 145, 146). In the case of incident pregnancy, PrEP 
trial participants were instructed to stop study drug immediately, at an average gestational age of 
6 weeks (147). Data from these incident pregnancies as well as the registry data show that risk for 
toxicity appears to be low and neither pregnancy nor breastfeeding is considered a 
contraindication for PrEP initiation per the CDC and WHO clinical guidelines (148). Exposure to 
PrEP in early pregnancy, for example, was not associated with detectable differences in later 
pregnancy outcomes (147). The PrIYA PrEP implementation program in Kenya recorded no 
observed difference in pregnancy outcomes among women with prenatal PrEP use(149). In 
addition, the recommended regimen for PrEP, FTC/TDF, has been used safely for treatment of 
pregnant women with chronic hepatitis B infection as well as pregnant women with HIV for over 
a decade and forms the backbone of the first line treatment regimen recommended by the World 
Health Organization (WHO) (82, 150-153). 
 
Although there are numerous female-initiated antiretroviral prophylaxis strategies currently under 
study, daily oral PrEP is one of the few proven modalities supported by scientific evidence at this 
time. As PrEP trials move from efficacy to implementation, and licensing is being sought in low-
resource countries, several PrEP implementation projects are enrolling young women at high risk 
of acquiring HIV infection through unprotected sexual activity. Despite PrEP becoming available 
to young women in sub-Saharan Africa, critical scientific gaps remain concerning the safety and 
efficacy of PrEP use in young pregnant and postpartum women (10, 33, 154-156) and access 
remains restricted (157). While published reports suggest that young women may find the concept 
of oral PrEP acceptable during pregnancy and breastfeeding and are able to engage with PrEP, 
PrEP adherence may be particularly challenging during pregnancy(158-160). Importantly, the 
IMPAACT 2009 study will document context-specific barriers and facilitators of engaging with 
PrEP during pregnancy and postpartum, contributing much needed evidence to inform the PrEP 
implementation approach for adolescent and young women in high-burden settings(161). 
 
Pregnant and postpartum women are at increased high risk for HIV acquisition and acute 
infection during these periods is associated with higher risk of transmission to the fetus or infant. 
As highly efficacious ART regimens are implemented widely, including “Option B+” and Treat 
All strategies that do provide lifelong ART to all HIV-infected pregnant and postpartum women, 
primary prevention must also be implemented widely, delivering proven interventions to those at 
risk. Given the concentration of the HIV epidemic among young women in sub-Saharan Africa – 
and the lack of specific pregnancy and postpartum data from current PrEP studies – there is 
urgent need for targeted study in this critical area.  
 
IMPAACT 2009 will be conducted at sites in Sub-Saharan Africa, the region with the highest 
HIV incidence among adolescent and young adult women, including during pregnancy. It is in 
this population at substantial risk of acquiring HIV infection that the potential benefits of PrEP 


 
IMPAACT 2009, FINAL Version 3.0 
Page 29 of 173 
 
  
   
 
19 November 2020 
could outweigh risks and associated financial cost. Similarly, this population stands to benefit the 
most from participation in such a study.  
 
1.3.2 
Safety of Pre-Exposure Prophylaxis during Pregnancy and Breastfeeding 
 
Based on the existing evidence on safety and effectiveness, the World Health Organization does 
not list pregnancy as a contraindication to PrEP use. In settings of high HIV prevalence and 
serodiscordancy, the benefits of PrEP in pregnancy likely outweigh the associated potential risks 
(23). Despite reassuring data to date, in their comprehensive systematic review of TDF safety in 
pregnancy, Mofenson and colleagues acknowledged the limited number of studies examining 
safety among HIV-uninfected pregnant women (67). Most randomized studies of oral and vaginal 
PrEP, for example, discontinued study product once pregnancy was diagnosed (80, 147). 
Continued surveillance is needed to confirm the safety of PrEP during pregnancy and 
breastfeeding (67). Safety data from PrEP demonstration projects will contribute to this body of 
evidence. Early reports from the Partners Demonstration Project have been reassuring – with no 
increases in pregnancy loss, preterm birth, or congenital anomalies – but the sample of exposed 
pregnancies remain small (n=30) (81). There may be inherent limitations to this approach as well. 
PrEP adherence can be difficult to measure in clinical settings making it challenging to 
differentiate between a favorable safety profile vs. poor medication adherence to PrEP. A focus 
on sustainability has been a hallmark of many demonstration projects in sub-Saharan Africa; 
however, the integration of services into existing health systems can impose constraints on 
available health outcomes such as bone mineral density and vaginal microbiome. Further research 
is needed to enhance ongoing surveillance activities, to better understand the overall safety of 
PrEP during pregnancy and breastfeeding.  
 
Finally, the WHO recommends that PrEP be considered for HIV prevention during pregnancy 
and breastfeeding after carefully weighing the potential risks and benefits (23). To date, there 
have been no clinical studies directly evaluating safety among HIV-uninfected pregnant and 
breastfeeding women, a gap that – despite WHO guidance thus far – may limit implementation. 
Such a delay has already been observed in South Africa, where the Medicines Control Council 
(MCC) awaits additional safety data from this specific population before removing the current 
restriction on PrEP use for pregnant and breastfeeding women (personal communication, L-G 
Bekker). Without better information to support policy, the full implementation of PrEP in in 
pregnant and breastfeeding women appears unlikely. Given the high HIV incidence rates 
observed in this population, this could have important consequences for HIV prevention efforts 
globally. 
 
1.3.3 
Pharmacokinetic Thresholds of Adequate PrEP Adherence in Pregnancy and Breastfeeding   
 
Adherence to PrEP is crucial to overall effectiveness, but it has been traditionally difficult to 
quantify. Intracellular TFV-DP in red blood cells (measured with dried blood spots) is a relatively 
new modality that, given the agent’s long half-life of 17 days, can provide an objective measure 
for cumulative FTC/TDF PrEP adherence. The long half-life translates into drug accumulation 
such that increasing numbers of ingested doses produces higher TFV-DP that can be interpreted 
as cumulative adherence. Approximately 12 weeks of dosing (5 half-lives) is needed to achieve 
steady-state in red blood cells. For instance, the following TFV-DP concentration thresholds have 
been used in MSM studies to estimate average adherence: below the limit of quantitation (BLQ to 
<350 fmol/punch (< 2 doses per week), 350-699 fmol/punch (two to three doses per week), ≥700 
fmol/punch (≥4 doses per week). These interpretations were used in MSM in the iPrEx Open-
Label Extension and PrEP demonstration projects, and were correlated with PrEP efficacy (20, 


 
IMPAACT 2009, FINAL Version 3.0 
Page 30 of 173 
 
  
   
 
19 November 2020 
162). The relatively simple requirements for specimen collection and storage – using dried blood 
spots on filter paper – makes it adaptable to both programmatic and clinical settings. 
 
Among MSM, specific TFV-DP thresholds such as those above have been correlated with 
reduced HIV acquisition in the setting of FTC/TDF PrEP usage (20, 163). At present, however, 
there exists no analogous data among women in general including pregnant women. There are 
numerous physiologic changes associated with pregnancy (e.g., cardiovascular, hematologic, 
increased renal clearance of TDF (164), that may affect the drug levels observed with adequate 
adherence to FTC/TDF. For instance, pregnant women exhibited 39% higher renal clearance of 
tenofovir compared with non-pregnant women, which could translate to lower than expected 
TFV-DP in DBS during pregnancy (164). Additionally, pregnant women undergo plasma volume 
expansion and increased erythropoiesis during pregnancy, which could also translate into 
differences in expected TFV-DP in red blood cells (165). Generally, these changes are not 
marked in the first trimester of pregnancy but become more significant in the second and third 
trimesters. 
 
Given that adherence to PrEP is the primary outcome of this study, a Pharmacokinetic (PK) 
Component was included to establish expected TFV-DP thresholds in DBS for adequate 
adherence over time in this important population, when FTC/TDF is administered daily. Prior 
research in non-pregnant women has already established TFV-DP drug levels at various levels of 
adherence following initiation of daily oral PrEP (166); these levels are likely similar in the first 
trimester of pregnancy. The focus was instead on TFV-DP levels in the second and third 
trimesters of pregnancy in this study. Determination of these levels provides important general 
knowledge about PrEP in pregnancy. More importantly for this study, these results will directly 
inform the “biofeedback” counseling in the PrEP Comparison Component. 
 
1.3.3.1 
PK Component Results 
 
The PK Component evaluated PK characteristics of daily oral PrEP (FTC 200mg/TDF 300mg) 
among 20 pregnant (median gestational age: 18 weeks) and 20 postpartum (median time after 
delivery: 7 weeks) women at a median age of 20 years. Daily FTC/TDF was administered under 
direct observation for 12 weeks; of 3360 doses, 3352 [>99%] were directly observed). Weekly 
TFV-DP was measured from DBS using a validated liquid chromatography-tandem mass 
spectrometry assay. TFV-DP distributions were determined at 12 weeks and groups compared 
with the Wilcoxon test. Population PK models were fit to estimate half-life and steady state 
concentrations. 
 
TFV-DP accumulated with a half-life of 15.3 days (95%CI: 12.8,17.8) in pregnancy and 18.0 
days (95%CI: 15.3,20.7) postpartum, with steady state achieved by 8-10 weeks in both groups. 
Median TFV-DP was 965 fmol/punch (IQR: 691,1166) in pregnancy vs 1406 fmol/punch (IQR: 
1053,1859) postpartum (p=0.006). Predicted median TFV-DP was 890 fmol/punch (IQR: 
704,1143) in pregnancy vs 1418 fmol/punch (IQR: 1179,2139) postpartum. Under conditions of 
near perfect adherence, TFV-DP concentrations in DBS were approximately one-third lower in 
pregnancy compared to postpartum. TFV-DP levels in DBS observed in pregnancy also appeared 
lower than those reported in analogous studies of men and non-pregnant, non-lactating women in 
the US(167, 168). 
 
These results confirm previous findings (see Section 1.3.2) that suggested drug levels in pregnant 
women may be lower than in a non-pregnant population. The PK Component results do not, 
however, provide information about PrEP efficacy among pregnant women, and data about the 
adherence-efficacy relationship during pregnancy remain limited.  


 
IMPAACT 2009, FINAL Version 3.0 
Page 31 of 173 
 
  
   
 
19 November 2020 
1.3.4 
Microbiome composition among mothers and infants with PrEP exposure  
 
There is an emerging literature demonstrating the association between intravaginal PrEP 
formulations and the vaginal microbiome. Work from the CAPRISA 004 study has shown                  
decreased efficacious of intravaginal PrEP when vaginal dysbiosis is present (113); other studies 
have shown similar outcomes, either in elevated rates of HIV acquisition (115) or local decreases 
of drug concentrations (114, 116). To date, there has only been one analysis of oral PrEP and 
vaginal dysbiosis, which showed unchanged efficacy in the presence of bacterial vaginosis (117).  
 
While there are studies of the vaginal microbiome and HIV-risk, there are no published studies on 
the rectal microbiome and risk of HIV-acquisition. However, there is clear evidence that certain 
microbes are associated with gut inflammation (169) and inflammation and the presence of 
inflammatory cells are associated with elevated risk for HIV acquisition (115). If oral PrEP 
altered the rectal microbiome of pregnant women to a more inflammatory state, this could have 
important implications for HIV prevention measures. A recent meta-analysis found that as many 
as 20% of women reported heterosexual anal intercourse within the past three months (126). 
 
The scientific question remains as to whether use of oral FTC/TDF may alter microbial 
communities in the mother and infant, and how this might impact efficacy and/or downstream 
health outcomes. This is particularly important in the context of pregnancy and the early 
postpartum period, given the associated physiological changes that occur for both mother and 
newborn. In an exploratory aim, preliminary data on how FTC/TDF may alter the maternal 
(vaginal/gut) and infant gut microbiome will be obtained Repeat specimens will be collected over 
time to see how the bacterial communities change over time based on FTC/TDF exposure. 
Comparisons by PrEP allocation arm and investigation of associations with vaginal drug 
concentrations of TFV will be made. IMPAACT 2009 provides a unique platform to collect these 
important data and inform the ongoing scientific debate about how antiretroviral interventions 
may affect the local microbiome for both mother and infant. 
 
1.4 
Hypothesis for the PK Component 
 
In the context of monitored daily administration of PrEP, a TFV-DP threshold can be determined 
to track adequate adherence during pregnancy and breastfeeding. 
 
1.5 
Hypotheses for the PrEP Comparison Component 
 
• 
At least 75% of women who opt to initiate PrEP will achieve a high level of adherence 
throughout pregnancy, as measured by adequate TFV-DP concentrations in DBS specimens. 
 
• 
The rate of maternal and infant adverse events (including adverse pregnancy outcomes) will 
be higher among mother-infant pairs in which the mother initiates PrEP during pregnancy 
than in pairs in which the mother declines PrEP. 
 
• 
The mean bone mineral density for the lumbar spine and hip at baseline and at Week 26 
postpartum will be lower among women who initiated PrEP during pregnancy than among 
women who decline PrEP. 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 32 of 173 
 
  
   
 
19 November 2020 
2 
OBJECTIVES 
 
2.1 
Primary Objective for PK Component  
 
The primary objective of this component is: 
 
2.1.1 
To determine the concentration of tenofovir diphosphate (TFV-DP) associated with adequate 
adherence to FTC/TDF among women observed ingesting daily oral PrEP during pregnancy and 
postpartum. 
 
2.2 
Secondary Objective for PK Component 
 
The secondary objective of this component is: 
 
2.2.1 
To compare TFV-DP concentrations observed in pregnant and postpartum women. 
 
2.3 
Primary Objectives for PrEP Comparison Component  
 
The primary objectives of this component are:  
 
2.3.1 
To characterize PrEP adherence among HIV-uninfected young women during pregnancy and for 
twenty-six weeks postpartum, when provided with enhanced adherence support through mobile 
technology and counseling based on observed drug levels.  
 
2.3.2 
To assess the safety of FTC/TDF for PrEP during pregnancy and postpartum by comparing 
pregnancy outcomes and maternal and infant safety between cohorts.  
 
2.4 
Other Objectives for PrEP Comparison Component  
 
The other objectives of this component are:  
 
2.4.1 
To identify individual, social, and structural barriers and facilitators to PrEP uptake during 
pregnancy, and to adherence during pregnancy and postpartum. 
 
2.4.2 
To compare reported sexual risk behaviors and incidence of sexually transmitted infections, 
including HIV infection, among women who initiate PrEP during pregnancy versus women who 
decline PrEP. 
 
2.4.3 
To compare antiretroviral drug resistance among women and infants who acquire HIV with and 
without exposure to FTC/TDF for PrEP, including whether resistance was transmitted or acquired 
at time of transmission. 
 
2.4.4 
To compare bone density in women who initiated PrEP during pregnancy and women who 
decline PrEP. 
 
 
 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 33 of 173 
 
  
   
 
19 November 2020 
2.5 
Exploratory Objective for PrEP Comparison Component  
 
The exploratory objective for this protocol is: 
 
2.5.1 
To describe the composition of and changes in the maternal vaginal and gut microbiome and 
infant gut microbiome according to PrEP exposure. 
 
3 
STUDY DESIGN 
 
This study is comprised of two components: a) PK Component to establish the TFV-DP 
concentrations associated with adequate adherence to a daily FTC/TDF for PrEP regimen during 
pregnancy and postpartum period, and b) a PrEP Comparison Component to assess the feasibility, 
acceptability, and safety of PrEP provided to young women during pregnancy and postpartum. 
Refer to Figure 1 for an overview of the study design.  
 
3.1 
PK Component Study Design  
 
The PK Component will establish PK parameters for TFV-DP under adequate adherence during 
pregnancy and postpartum. This initial component is necessary because TFV-DP concentrations 
will be used in the PrEP Comparison Component both to measure adherence (as the primary 
outcome) and to guide counseling provided as part of the adherence support intervention. The PK 
Component will be open to all sites participating in the PrEP Comparison Component.  
 
Participants will be enrolled in two groups: pregnant women at 14-24 weeks’ gestation and 
postpartum women who delivered 6-12 weeks prior to enrollment. The rationale for combining 
participants in the 2nd and 3rd trimesters is that physiological changes such as plasma volume 
increase and RBC mass increase start early (Weeks 6-8) and peak late (~Week 32) (170). 
Similarly, renal drug clearances change gradually during pregnancy and are similar in trimesters 
two and three (171), removing the need to assess each trimester separately. These gradual 
changes, coupled with the 12 week TFV-DP buildup to steady-state, creates a challenge to study 
PK in isolated trimesters. Therefore, the PK component will combine the 2nd and 3rd trimesters to 
capture the “averaged” physiological changes over these two trimesters. In the postpartum period, 
enrollment will begin approximately six weeks following delivery, when most women first attend 
their routine postpartum visit. The enrollment window is extended to 12 weeks following 
delivery, to ensure that the follow-up period will occur in the first six months when most women 
continue to breastfeed. The PK Component is not powered to detect small differences in TFV-DP 
concentrations between the pregnancy and postpartum periods.  
 
Participants will be screened for HIV infection; only those who test negative will be eligible to 
initiate once-daily FTC/TDF for PrEP. Participants must be willing to initiate and adhere to PrEP 
and to be observed daily for adherence for 12-weeks. Refer to Section 4 for the study eligibility 
criteria.  
 
Immediately prior to PrEP initiation – and at weekly intervals during the PK Component – a 
maternal blood specimen will be collected via venipuncture. This specimen will be used to create 
a dried blood spot (DBS) specimen at the local designated laboratory, prior to storage and 
shipment to the reference pharmacology laboratory for testing. All maternal participants will have 
study drug administered under direct observation daily for a total of 12 weeks. Enrolled maternal 
participants who have not delivered by their Week 12 visit may elect to continue PrEP thereafter 
through their labor and delivery visit. This is offered to provide additional HIV prevention during 


 
IMPAACT 2009, FINAL Version 3.0 
Page 34 of 173 
 
  
   
 
19 November 2020 
the period of highest risk for vertical transmission of HIV and with the knowledge that 
unprotected intercourse, thus potential HIV exposure, may continue in the last trimester of 
pregnancy. 
 
At participating sites, pregnancy and postpartum periods are associated with elevated risk for HIV 
acquisition. As such, it would not be ethically possible to vary the dosing levels of PrEP during 
observation. Instead, the study aims to determine the drug levels associated with adequate 
adherence to the once-daily FTC/TDF regimen. Study staff will monitor and document maternal 
participants’ daily administration of FTC/TDF, as described in Section 5.1.1.1. Once the PK 
Component is complete, the distribution of TFV-DP concentrations measured in evaluable 
maternal participants will be analyzed. Refer to Section 9.1.1 for the definition of an evaluable 
participant.  
 
PrEP doses taken will be categorized into one of the following:  
 
1) Directly observed in-person by study staff  
2) Directly observed in real-time video (live streaming or time/date stamped recording) 
3) Self-reported, including still photos of dose ingestion 
4) Missed dose (missing data or reported as missed) 
 
Only doses directly observed in-person by study staff and doses observed in real-time video 
recording will be considered adequate documentation of the PrEP doses taken for the purposes of 
defining an evaluable participant, as described in Section 9.1.1.  
 
These data will be used to determine the drug thresholds to be used in the PrEP Comparison 
Component to categorize drug adherence. The drug threshold corresponding to adequate 
adherence will be defined from the distribution of steady-state TFV-DP concentrations at Week 
12 of the PK Component (refer to Section 9.1.6). The PK testing laboratory will provide sites 
with a drug level result and adherence status as it relates to the categorized level of adherence to 
use during adherence counselling sessions.  
 
Upon completion and analysis of the PK Component, the Clinical Management Committee 
(CMC) will make recommendations to the Study Monitoring Committee (SMC) to proceed to the 
PrEP Comparison Component with established TFV-DP thresholds. With approval from the 
SMC, the PrEP Comparison Component will commence with notification to sites being issued 
from the Protocol Team and operational guidance on managing the transition between protocol 
components. This notification will include the drug threshold established from review of the PK 
Component data. Refer to Section 9 for a complete description of statistical considerations, data 
monitoring, and data analysis plans. 
 
3.2 
PrEP Comparison Component Study Design 
 
The PrEP Comparison Component will assess feasibility, acceptability, adherence to, and safety 
of PrEP during pregnancy and postpartum in HIV-uninfected adolescents and young women. 
Women will be enrolled prior to 32 weeks’ gestation in two cohorts: those who agree to initiate 
PrEP (Cohort 1) and those who decline (Cohort 2). Infants will be enrolled in utero at the same 
time the woman is enrolled. A randomized trial in which one arm would not receive PrEP would 
be unethical at this time due to the overwhelming evidence supporting the efficacy of PrEP to 
prevent HIV infection (172). All women enrolled in the study will receive a standard of care 
package of HIV prevention services and a study-specific behavioral risk reduction intervention. 
Additionally, all women will receive support for antenatal, delivery and early infant care through 


 
IMPAACT 2009, FINAL Version 3.0 
Page 35 of 173 
 
  
   
 
19 November 2020 
one-way mHealth messaging services. Women who choose to initiate PrEP will be provided PrEP 
as well as a study-specific adherence support intervention.  
  
Regardless of cohort, all maternal participants will follow similar schedules of evaluations 
through the course of pregnancy and in the 26 weeks following delivery. Following Cohort 2 
provides an opportunity to document the process of decision-making around HIV prevention 
during this time of substantial risk; as these women may choose to initiate PrEP at any stage 
following study entry, triggers for change in PrEP perceptions and acceptability over time will be 
recorded to better understand women’s motivation to seek additional HIV prevention (see Section 
3.2.1) services. As Cohort 2 is not exposed to antiretroviral agents during pregnancy or 
postpartum, the study will also obtain preliminary safety data for TDF use in HIV-uninfected 
women during this period. Cohort 2 will serve as a comparison group for estimates of incidence 
and prevalence of maternal and infant safety outcomes including a) pregnancy outcomes, b) 
maternal adverse events, and c) infant growth and development between the two cohorts (see 
Section 9.2.2). The primary analysis will be based on original Cohort designation at baseline. 
Additional secondary analyses that consider the population of women who may initially decline 
PrEP and then later decide to initiate it will be considered, refer to Section 9. 
 
The primary objectives focus on women who initiate PrEP during pregnancy and continue 
through the first 26 weeks postpartum (Cohort 1). Adherence to PrEP will be assessed in this 
population by measuring TFV-DP drug levels in dried blood spots. Participants in this arm will 
receive an intervention designed to promote PrEP adherence, comprised of a) two-way SMS 
messaging related to PrEP adherence, and b) targeted adherence counseling guided by TFV-DP 
drug levels from past visits, refer to Section 6. Participants will be contacted and provided with 
their DBS TFV-DP concentration results, as described in Section 6.5. Less than adequate 
concentration results are defined during the PK Component by pharmacokinetic parameters 
established when drug adherence is measured using TFV-DP levels from dried blood spots. 
 
Maternal participants who change their intent regarding PrEP will be allowed to do so. 
Participants in Cohort 1 who choose to stop PrEP will continue in follow-up undergoing the same 
procedures. If these participants later elect to resume PrEP, HIV-infection status must be 
confirmed before resuming PrEP, refer to Sections 4.2.1 and 6.2.3. Maternal participants in 
Cohort 2 who subsequently choose to initiate PrEP will undergo a Step Change, during which 
eligibility for starting PrEP will be confirmed, refer to Sections 4.2.3 and 6.2.3. These participants 
are referred to as Cohort 2/Step 2 and will follow the procedures for Cohort 1. These switches 
onto or off PrEP will be considered in the feasibility/acceptability outcomes, refer to Section 9.2. 
While a formal step change will only be required when those originally declining PrEP later 
chose to initiate it, there is no upper limit set on the number of switches allowed. Switching will 
be closely monitored as part of feasibility and adherence outcomes. 
 
3.2.1 
Qualitative Evaluation Design 
 
Qualitative evaluations will complement the quantitative data collected through the measures of 
TFV-DP drug levels in dried blood spots allowing for a mixed methods approach to evaluating 
adherence. These evaluations will consist of in-depth interviews (IDI) with maternal participants 
who chose to take PrEP as well as those who decline. These data will contribute to secondary 
objective 2.4.1 in identifying individual, social, and structural barriers and facilitators to PrEP 
uptake during pregnancy, and adherence and continued use during pregnancy and postpartum, as 
well as factors influencing decisions not to initiate PrEP or to stop once started. Additionally, 
given the circumstances pertaining to the circulating SARS-CoV-2 and associated coronavirus 
disease 2019 (COVID-19), data may be collected related to the potential influence of the COVID-


 
IMPAACT 2009, FINAL Version 3.0 
Page 36 of 173 
 
  
   
 
19 November 2020 
19 pandemic on participants’ life and study participation, including study product adherence and 
acceptability.  
 
The sampling method will be designed to include a range of possible perspectives on the 
phenomenon under study, thus ideally qualitative samples are purposive in nature. A stratified 
purposive sample will be used, which will allow for consideration of the concepts of range, 
saturation/redundancy, and stratification in the sampling frame (173). The sample will be 
stratified based on PrEP initiation (Cohort 1 vs. Cohort 2) and PrEP adherence (Cohort 1 only). 
Stratification on these two factors will allow for a diverse purposive sample that will include a 
range of women who may have various experiences with PrEP use. Interviews will be conducted 
with three distinct groups of antepartum and postpartum adolescent and young women as shown 
in Table 1: Those a) who initiate and adhere to PrEP (Cohort 1), b) who initiate but do not adhere 
to PrEP, including early discontinuation (Cohort 1) and c) who decline PrEP at enrollment 
(Cohort 2). In addition, the site teams will aim to have equal representation in each group by 
pregnancy status (i.e., pregnant vs. postpartum). Interview groups may be enriched or expanded 
as needed given experiences gathered during the trial. 
 
Table 1: Expected number of interviews conducted with three distinct groups of  
antepartum and postpartum women 
Group 
Antepartum 
Postpartum 
Adherent PrEP maternal participants  
10 
10 
Non-adherent PrEP maternal 
participants 
10 
10 
Maternal Participants who decline PrEP 
10 
10 
 
Study staff members at each site will conduct IDIs with up to 60 young women. These interviews 
will be audio-recorded, transcribed and translated to English for analysis. With as many as ten 
respondents in each of the six strata, the protocol team expects saturation/redundancy to be 
reached. To monitor the sampling, each site will be allotted two to three slots per cell at a time, 
with additional slots opened as needed. If challenges arise with recruiting the targeted number of 
women from each site, adjustments may be made to the sampling frame by allowing other sites to 
enroll additional participants. Such adjustments will be done in a manner that allows for the 
overall target sample size to be reached within each stratum, and provides the desired 
representation or experiences across PrEP use and pregnancy status. 
 
All maternal participants enrolled in the PrEP Comparison Component of this study are eligible to 
complete the qualitative evaluations. However, determination of adherence will need to be 
assessed for maternal participants of Cohort 1 who are included. For enrollment purposes, 
adherence/non-adherence will be defined as either achieving or not achieving target TFV-DP 
levels measured by DBS (which will be defined following the PK phase): 
 
• 
Currently pregnant: At two consecutive antepartum visits 
• 
Postpartum: At both the Week 6 and Week 14 visits 
 
Maternal participants will be identified and solicited for participation by site study team members 
until each cell (Table 1) is complete. The interview will be conducted after written informed 
consent is provided.  
 
The interviews of participants identified for the “currently pregnant” strata will take place at or 
after the Week 12 visit and prior to Labor and Delivery (Cohorts 1 and 2). For the postpartum 
groups, because selection of Cohort 1 maternal participants will depend on the DBS results from 


 
IMPAACT 2009, FINAL Version 3.0 
Page 37 of 173 
 
  
   
 
19 November 2020 
the Week 14 visit, the interview may take place following the Week 14 visit through to and 
including the Week 26 visit. Women selected for the postpartum group from Cohort 2 may have 
their interviews anytime at or after the Week 14 visit through to and including the Week 26 visit. 
Interviews may be scheduled to take place at a regular study visit or an alternative date.  
 
The interviews will be conducted by study staff members at each site who will be trained in 
conducting the qualitative interview. Following the training, interviewers will practice conducting 
digitally recorded in-depth interviews with mock participants. Through the application of the 
interview guide, these interviews will identify the individual, social, and structural barriers and 
facilitators to PrEP uptake during pregnancy, and experiences with PrEP adherence (adequate and 
below adequate) during pregnancy and postpartum. The interview guide will be developed with 
input from the qualitative interviewers at the sites to ensure that the guide is both geographically 
and culturally appropriate. 
 
3.2.2 
Exploratory Objective for PrEP Comparison Design 
 
The microbiome exploratory objective will assess whether PrEP alters the maternal and 
subsequently the infant microbiome. The samples for this objective will be collected during the 
regularly scheduled study visits - Entry, late pregnancy, and Weeks 6 and 26 postpartum - during 
the PrEP Comparison Component and will include maternal vaginal and optional rectal swabs. 
The Entry sample will serve as a baseline microbiome for the maternal participant during 
pregnancy. The re-sampling at 12 weeks will determine if the microbiome has changed 
significantly on FTC/TDF PrEP; pregnant women who decline PrEP will serve as the control 
group. The six-week postpartum time point will allow assessment of the microbiome composition 
after childbirth in women receiving or not receiving FTC/TDF PrEP. Finally, the 26-week 
postpartum time point will determine if the microbiome changes once pregnancy is over. 
 
Infant rectal swabs or fresh stool will be collected at each timepoint to characterize the changes 
over time of the infant gut microbiome and potential changes resulting from exposure to maternal 
FTC/TDF PrEP. Changes in the microbiome will be assessed as described in Section 9. 
 
3.3 
Standard of Care 
 
Sites will ensure that all participants access a basic standard of care (SOC) package which will 
generally include: a) HIV testing and risk reduction counseling at all visits; b) counseling and 
provision of contraception options; c) STI testing at screening, and STI testing and presumptive 
syndromic STI treatment, as needed; d) information on proper use of male and female condoms, 
including condom demonstrations, and provision of condoms; e) pregnancy testing; and f) 
discussion of HIV testing and prevention for their sexual partner(s) and referrals to local testing 
options for their partners. Refer to Section 5.3.2 for additional details on counseling procedures.  
 
At all visits, participants presenting with physical signs or symptoms, consistent with an STI will 
be referred for or provided with treatment as indicated. Participants with a laboratory diagnosis 
consistent with an STI will be referred for or provided with treatment as indicated. Due to the 
timing of specific lab testing, this may occur as an interim visit. 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 38 of 173 
 
  
   
 
19 November 2020 
4 
STUDY POPULATION 
 
This study will be conducted among approximately 390 women and their infants (40 in the PK 
Component, and 350 in the PrEP Comparison Component) who will be selected for the study 
according to the criteria in Sections 4.1 - 4.4. The study-specific approach to recruitment, 
screening, and enrollment is described in Section 4.5. Considerations related to participant 
retention and withdrawal from the study are provided in Sections 4.6 and 4.7, respectively. 
 
4.1 
PK Component (Groups 1 and 2) 
 
4.1.1 
Inclusion Criteria 
 
Mothers must meet all the following criteria prior to study entry to be included in this component. 
 
4.1.1.1 
At study entry, mother is 16-24 years of age. 
 
• 
For mothers who are of legal age to provide independent informed consent as 
determined by site SOPs and consistent with site IRB/EC policies and 
procedures: The mother is willing and able to provide written informed consent 
for her and her infant’s study participation.  
 
• 
For mothers who are not of legal age to provide independent informed consent. 
The parent/guardian or other legally authorized representative of the mother and 
her infant is willing and able to provide written informed consent for the mother 
and her infant’s study participation; in addition, when applicable the mother is 
willing and able to provide written assent for her and her infant’s study 
participation.  
 
4.1.1.2 
At screening, evidence of a viable singleton pregnancy (Group 1 only) with 
sonographic confirmation* 
 
*Note: If adequate sonographic results are not available from medical records at 
screening, an ultrasound must be performed so that the result is available at study 
entry. 
 
4.1.1.3 
At study entry, pregnant or recently delivered, in one of the following two enrollment 
windows:  
 
• 
Group 1: Gestational age of 14 to 24 weeks, defined as greater than 13 weeks 
plus six days and less than 24 completed weeks of gestation with sonographic 
confirmation*, or 
• 
Group 2: 6 to 12 weeks postpartum, defined as between 42 and 84 days after the 
date of delivery. 
 
*Note: If adequate sonographic results are not available from medical records at 
screening, an ultrasound must be performed so that the result is available at study 
entry. 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 39 of 173 
 
  
   
 
19 November 2020 
4.1.1.4 
At study entry, willing to initiate once-daily oral PrEP and continue use for at least 12 
weeks under directly observed therapy and support for adherence. 
 
4.1.1.5 
Within 14 days prior to study entry, HIV negative by HIV RNA test.  
 
4.1.1.6 
At study entry, rapid test negative and absence of symptoms of acute HIV infection 
(i.e. acute viral illness).  
 
4.1.1.7 
At screening, Hepatitis B negative by Hepatitis B surface antigen test.  
 
4.1.1.8 
At screening, has the following laboratory test results: 
 
• 
Grade 1 or normal (<2.5 x ULN) ALT  
• 
Grade 1 or normal (≥9.5g/dL) hemoglobin   
• 
Grade 1 or normal (≥800cells/mm3) absolute neutrophil count (ANC)  
• 
Normal (≥90mL/min) estimated creatinine clearance (CrCl; Cockcroft-Gault 
formula) 
 
4.1.1.9 
At screening, mother has negative or trace proteinuria (less than Grade 1).  
 
4.1.1.10 
At screening, mother has normal dipstick urine for glucose (less than Grade 1). 
 
4.1.1.11 
At study entry, mother weighs > 35 kg.  
 
4.1.1.12 
Intention to stay within the study site’s catchment area for at least 12 weeks (or 
through delivery). 
 
4.1.2 
Exclusion Criteria (PK Component and PrEP Comparison Component)  
 
Mothers must be excluded from the study if any of the following are identified at any time prior 
to study entry:  
 
4.1.2.1 
Mother has any current significant uncontrolled, active or chronic disease process that, 
in the judgment of the site investigator, would make participation in the study 
inappropriate. 
 
4.1.2.2 
Mother has a known history of any of the following, as determined by the site 
investigator or designee based on maternal report and available medical records:  
 
• 
Sickle cell anemia (excluding sickle cell trait), chronic bleeding, blood 
transfusion within the past 120 days (excluding for chronic illness) or other 
blood dyscrasias 
• 
Bone fracture not explained by trauma  
• 
Allergy/sensitivity to FTC/TDF or its components  
 
4.1.2.3 
Fetus has a known or suspected major congenital anomaly, from chart review of prior 
data, defined as a structural malformation with surgical, medical, or cosmetic 
importance 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 40 of 173 
 
  
   
 
19 November 2020 
4.1.2.4 
Mother has confirmed renal insufficiency, a history of known renal parenchymal 
disease, or known single kidney at screening 
 
4.1.2.5 
Current use of prohibited medications listed in Section 5.5 
 
4.1.2.6 
Concurrent participation in a study of any biomedical HIV prevention intervention or 
investigational drug in an HIV vaccine study or microbicide study  
 
4.1.2.7 
Past participation in an HIV vaccine study 
 
4.1.2.8 
Currently taking a PrEP regimen from non-study sources 
 
4.1.2.9 
Any other condition or adverse social situation that, in the opinion of the site 
investigator, would preclude informed consent, make study participation unsafe, 
complicate interpretation of study outcome data, or otherwise interfere with achieving 
the study objectives 
4.1.2.10 
Past participation in IMPAACT 2009  
4.2 
PrEP Comparison Component (Cohorts 1 and 2) 
 
4.2.1 
Inclusion Criteria  
 
Mothers must meet all the following criteria prior to study entry to be included in this component. 
 
4.2.1.1 
At study entry, mother is 16-24 years of age. 
 
• For mothers who are of legal age to provide independent informed consent as 
determined by site SOPs and consistent with site IRB/EC policies and procedures: 
The mother is willing and able to provide written informed consent for her and her 
infant’s study participation.  
 
• For mothers who are not of legal age to provide independent informed consent. The 
parent/guardian or other legally authorized representative of the mother and her 
infant is willing and able to provide written informed consent for the mother and her 
infant’s study participation; in addition, when applicable the mother is willing and 
able to provide written assent for her and her infant’s study participation.  
                                                                      
4.2.1.2 
At screening, evidence of a viable singleton pregnancy with gestational age of 32 
weeks or less, defined as 224 days or less after the date of conception with 
sonographic confirmation *  
 
*Note: if adequate sonographic results are not available from medical records at 
screening, an ultrasound must be performed in the interim so that the result is 
available at study entry. 
 
4.2.1.3 
Within 14 days prior to study entry, negative by HIV RNA test.  
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 41 of 173 
 
  
   
 
19 November 2020 
4.2.1.4 
At study entry, HIV rapid test negative and absence of symptoms of acute HIV 
infection (i.e. acute viral illness).  
 
4.2.1.5 
At screening, Hepatitis B negative by Hepatitis B surface antigen test performed. 
 
4.2.1.6 
At screening, has the following laboratory test results:  
 
• 
Grade 1 or normal (<2.5 x ULN) ALT  
• 
Grade 1 or normal (≥9.5g/dL) HB  
• 
Grade 1 or normal (≥800cells/mm3) ANC  
• 
Normal (≥90mL/min) for estimated creatinine clearance (CrCl; Cockcroft-Gault 
formula) 
 
4.2.1.7 
At screening, mother has negative or trace proteinuria (less than Grade 1). 
 
4.2.1.8 
At screening, mother has normal dipstick urine for glucose (less than Grade 1). 
 
4.2.1.9 
Intention to stay within the study site’s catchment area through 26 weeks postpartum 
 
4.2.1.10 
Regular access to a cellular phone that is able to receive SMS messages, and for 
Cohort 1 only, is also able to send SMS messages. 
 
4.2.1.11 
Cohort 1 only: At study entry, expresses willingness to take PrEP from pregnancy up 
to 26 weeks postpartum  
 
Cohort 2 only: At study entry, expresses unwillingness to take PrEP from pregnancy 
up to 26 weeks postpartum 
 
4.2.1.12 
At study entry, mother weighs > 35 kg 
 
4.2.1.13 
Based on site investigator assessment at screening, mother is literate in one or more of 
the study languages 
 
4.2.2 
Exclusion Criteria 
 
Mothers who meet any of the criteria specified in Section 4.1.2 will be excluded from this 
component. 
 
4.2.3 
Step 2 Inclusion Criteria: Cohort 2 only 
 
Cohort 2 maternal participants who subsequently choose to initiate PrEP complete Step Change 
Visits 1 and 2, refer to Section 6.2.3.2 and Appendix IIB and must meet all of the following 
criteria in order to enter Cohort 2/Step 2 to initiate PrEP: 
 
4.2.3.1 
HIV negative by HIV RNA testing at Step Change Visit 1 and HIV rapid test negative 
and absence of symptoms of acute HIV infection (i.e. acute viral illness). at Step 
Change Visit 2.  
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 42 of 173 
 
  
   
 
19 November 2020 
4.2.3.2 
Prior to entering Step 2, Hepatitis B negative by Hepatitis B surface antigen test 
performed at Step Change Visit 1. 
 
4.2.3.3 
Normal (≥90mL/min) estimated creatinine clearance (CrCl; Cockcroft-Gault formula) 
at previous assessment and negative or trace proteinuria (less than Grade 1) at Step 
Change Visit 1.  
 
4.2.3.4 
Willing to take PrEP up to 26 weeks postpartum.  
 
4.2.3.5 
Regular access to a cellular phone that is able to receive and send SMS messages. 
 
4.3 
Infant Enrollment 
 
Infants enter the study at the same time their mother is enrolled. Infants in the PK Component - 
Group 1 and the PrEP Comparison Component enter the study, in utero, and infants in the PK 
Component - Group 2 enter the study six to 12 weeks after birth. There are no set inclusion or 
exclusion criteria for infants. If an infant is deemed too ill to undergo study procedures, the Site 
Investigator may opt to omit specific study procedures and prioritize those necessary for clinical 
management.  
4.4 
Co-Enrollment Considerations 
 
Maternal and infant participants should not take part in any concurrent research studies that use 
drugs or medical devices while in follow up. Co-enrollment in observational or other studies may 
be allowable with approval in advance by the Protocol Teams of both studies. Requests for such 
approval should be emailed to the CMC.  
 
 
4.5 
Recruitment, Screening, and Enrollment Process 
 
Sites will be responsible for developing appropriate recruitment processes that are geared toward 
their respective local communities. Recruitment materials should undergo approval, if applicable, 
per institutional review board (IRB)/Ethics Committee (EC) policies and procedures.  
 
Women at heightened risk of HIV acquisition will be recruited for the PK Component and PrEP 
Comparison Component from public health centers where standard of care HIV pre- and post-test 
counseling procedures include a standardized HIV risk assessment. Study staff will approach 
women who, based on this risk assessment, perceive themselves to be at heightened risk and 
express interest in learning more about methods to protect themselves. After introducing the 
study, study staff will invite women who express potential interest in the study to initiate the 
informed consent process; those who provide informed consent will then initiate the study 
screening process. Women who do not express potential interest in the study will be referred to 
standard of care HIV prevention services. 
 
All sites are eligible to participate in the PK Component; however, some may elect to opt out. It is 
also possible that not all sites will be needed to reach full accrual for this component. It is 
anticipated that all sites will participate in the PrEP Comparison Component.  
  
The IMPAACT Data Management Center (DMC) Subject Enrollment System (SES) will be used 
to assist with tracking the screening and enrollment process for both the PK Component and PrEP 


 
IMPAACT 2009, FINAL Version 3.0 
Page 43 of 173 
 
  
   
 
19 November 2020 
Comparison Component. When informed consent is obtained, participant identification numbers 
(PIDs) will be assigned to the mother and infant and a study-specific screening number will be 
obtained for the mother-infant pair through the SES. For pairs found to be eligible, enrollment 
will occur upon successful entry of required eligibility data into the SES. For pairs who are found 
to be ineligible for the study, or who do not enroll in the study for any reason, an eCRF will be 
entered to record the screening outcome. Refer to Section 9.3 for more information on monitoring 
participant accrual in this study. 
 
4.6 
Participant Retention 
 
Once a participant is enrolled in this study, the study staff will make every effort to retain them 
for the expected duration of follow-up in order to maximize statistical power and minimize 
potential bias associated with loss-to-follow-up. Study staff are responsible for developing and 
implementing local procedures to reach this goal. Refer to Section 9.3.1 for more information on 
monitoring participant retention in this study.  
 
4.7 
Participant Withdrawal or Termination from the Study 
 
Regardless of the participant retention methods used, maternal participants may voluntarily 
withdraw from the study for any reason at any time. The site IoR or designee also may withdraw 
participants from the study to protect their safety and/or if they are unwilling or unable to comply 
with required study procedures.  
 
Participants may also be withdrawn/discontinued from the study by the site investigator or 
designee under the following circumstances: 
 
• 
Participant re-locates away from access to any study site or is otherwise determined by 
the study staff to be lost-to-follow-up and unlikely to return to the study. 
• 
Participant judged by the investigator or designee that continued participation in the 
study would be unsafe or otherwise not in the best interest of the participant, after 
consultation with the Protocol Team.  
• 
Participant fails to comply with the study requirements so as to cause harm to 
him/herself or to seriously interfere with the validity of the study results. 
• 
At the discretion of the IMPAACT leadership, NIAID, NICHD, the Office for Human 
Research Protections (OHRP), the U.S. FDA, the pharmaceutical supplier(s), an in-
country national health or regulatory agency, or the IRB/EC. 
 
Every reasonable effort will be made to complete final evaluations for participants who terminate 
from the study prior to the last study assessment or visit; study staff will record the reason(s) for 
all withdrawals from the study in the participants’ study records. 
 
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 6.4. If the circumstances that led to a 
participant’s withdrawal change (e.g., she returns to the study site area after having re-located 
previously), the site investigator or designee should contact the Protocol Team to discuss options 
for resumption of follow-up. 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 44 of 173 
 
  
   
 
19 November 2020 
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 FTC/TDF 200 mg/300 mg (Truvada®). Truvada® is 
approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV-1 infection 
and for PrEP to reduce the risk of sexually acquired HIV in adults at substantial risk. Further 
information on Truvada is available in the current package insert available at: 
https://rsc.niaid.nih.gov/clinical-research-sites/pi-list 
 
Maternal participants in this study may be exposed to study drug through direct ingestion; infants 
may be exposed to study drug in utero and through breastfeeding.  
 
5.1 
Study Drug Regimen 
 
Maternal participants in Group 1 and Group 2 of the PK Component, in Cohort 1 of the PrEP 
Comparison Component, and Cohort 2/Step 2 of the PrEP Comparison Component will receive a 
fixed dose combination of FTC/TDF 200 mg/300 mg to be taken by mouth once daily for the 
duration specified in Section 5.1.2.  
 
5.1.1 
Study Drug Administration 
 
FTC/TDF will be administered orally as one fixed dose oral combination tablet (FTC 200 
mg/TDF 300 mg) once daily, with or without food. In the PK Component, administration will be 
directly observed. Instructions for maternal participants in the event of vomiting relevant for both 
components are below. Further guidelines for study drug administration in the PK Component 
and PrEP Comparison Component are specified in Sections 5.1.1.1 and 5.1.1.2, respectively.  
 
In the event of vomiting, maternal participants in both the PK and PrEP Comparison 
Components, will be instructed by study staff as follows:   
 
• 
If the maternal participant vomits within 15 minutes after taking a tablet, and suspects that the 
tablet has been thrown up (i.e., the tablet is visible in the vomit), she should wait 
approximately 30 minutes and then take another FTC/TDF tablet.  
 
Note: Participants in the PK Component should notify staff immediately upon vomiting and 
the same DOT procedures described below should be followed for the additional tablet.  
 
• 
If this maternal participant vomits again after taking the second tablet, she should not take 
any more tablets that day, but try again to take a tablet at her daily dose time the next day.  
 
• 
If the maternal participant is not able to determine that the tablet has been thrown up (i.e., the 
tablet is not visible in the vomit), she should not take any more tablets that day, but try again 
to take a tablet at her daily dose time the next day. 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 45 of 173 
 
  
   
 
19 November 2020 
5.1.1.1 PK Component 
 
In the PK Component, study staff must monitor maternal participants’ daily administration of 
FTC/TDF. Each study site must establish standard operating procedures (SOPs) describing how 
this will be done; depending on site-specific feasibility, options may include:  
 
• 
Directly observed therapy (DOT) at the study site 
• 
DOT at the participant’s home or other community-based location (see also Section 6.1.1) 
• 
Real-time video-based DOT (e.g., live streaming via FaceTime, Tango, Skype, or other 
similar method) 
 
The first two options listed above, which involve in-person direct observation by study staff, are 
preferred and should be used whenever possible. When use of these options is not possible, the 
third option of observation via live streaming video should be used. If live streaming is not 
possible, a video file may be saved by the participant and sent to study staff for non-live viewing, 
provided the file is dated and time-stamped.  
 
In the expected rare event that one of the three options listed above cannot be used, participants 
will be contacted to self-report their daily dose administration via telephone call or audio 
message, text message, and/or still photo. Whether directly observed or self-reported, all types of 
documented dose administrations will be adequately source documented and entered into 
electronic case report forms (eCRFs); however, dose administrations that are not directly 
observed will not be considered in primary analyses.  
 
5.1.1.2 PrEP Comparison Component 
 
In the PrEP Comparison Component, maternal participants will be encouraged to select a 
consistent daily “dose-time;” however, if a maternal participant forgets to take a dose at that time, 
the dose may be taken later in the day, as long as only one dose is taken on any calendar day.  
 
5.1.2 
Study Drug Duration 
 
5.1.2.1 PK Component 
 
Maternal participants in Group 1 and Group 2 of the PK Component will take FTC/TDF for 12 
weeks, beginning on the day of enrollment and continuing through the day of the Week 12 visit. 
Participants who have not delivered by their Week 12 visit may elect to continue PrEP thereafter 
through their labor and delivery visit.  
 
5.1.2.2 PrEP Comparison Component 
 
Maternal participants in Cohort 1 of the PrEP Comparison Component will take FTC/TDF 
through pregnancy and for 26 weeks postpartum, beginning on the day of enrollment and 
continuing through the day of the Week 26 postpartum visit. 
 
Maternal participants in Cohort 2 of the PrEP Comparison Component who declined PrEP 
initiation during pregnancy will not take FTC/TDF for the duration of the study unless they 
undergo a step change and enter Cohort 2/Step 2. 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 46 of 173 
 
  
   
 
19 November 2020 
Maternal participants in Cohort 2/Step 2 of the PrEP Comparison Component will take FTC/TDF 
for a variable duration, depending on timing of Step 2 entry. The duration will begin on the day of 
enrollment in Step 2 and continuing through the day of the Week 26 postpartum visit. 
 
5.2 
Study Drug Formulation  
 
FTC/TDF (supplied for this study as Truvada®) is a fixed dose combination tablet containing 200 
mg of emtricitabine (FTC) and 300 mg of tenofovir disoproxil fumarate (TDF) in each tablet. 
 
Tablets must be stored in their original containers at 25°C (77°F); with excursions permitted to 
15-30°C (59°-86°F) (see USP Controlled Room Temperature). Each container is packaged with a 
child-resistant screw cap and contains a silica gel to protect the product from humidity. The silica 
gel should not be removed from the container. 
 
5.2.1 
Study Drug Supply 
 
FTC/TDF will be supplied by Gilead Sciences, Inc. and made available to study sites through the 
National Institute of Allergy and Infectious Disease (NIAID) Clinical Research Products 
Management Center (CRPMC). Upon successful completion of protocol registration procedures, 
study drug may be obtained by the site pharmacist following instructions provided in the 
Pharmacy Guidelines and Instructions for DAIDS Clinical Trial Networks. 
 
5.2.2 
Study Drug Accountability 
 
Site pharmacists must maintain complete records of all study drugs received from the CRPMC 
and subsequently dispensed.  
 
The site pharmacist must follow the instructions in the Pharmacy Guidelines and Instructions for 
DAIDS Clinical Trials Networks for the destructions of unused study products.  
 
5.3 
Behavioral Counseling and Adherence Support 
 
5.3.1 
PK Component 
 
Adequate study drug adherence is required from maternal participants in the PK Component to 
accurately establish the target TFV-DP levels in DBS for use in the PrEP Comparison 
Component. To support near perfect dosing in the PK Component, study teams will have daily 
contact with maternal participants and directly observe each dose, providing counseling as 
directed by the circumstances. The mechanism for achieving this may differ by site and over 
time, being laid out in a standard operating procedures document. At in-clinic planned study 
visits, adherence and sexual health protection counseling will be offered as detailed below. 
 
Adherence and Sexual Health Protection Counseling:  
 
Integrated Next Step Counseling (iNSC, described in Section 5.3.2) will be adapted for context of 
PK Component. All maternal participants in both groups are provided education, support and 
problem solving at time of observed dose by the team member observing the dose (in person or 
virtually). Added efforts to engage participants failing to come-in, be present at home when a 
home visit has been scheduled, or call-in for observation of dose taking will include exploration 
of factors that could facilitate near-perfect/perfect coverage of observation. At study visits, 


 
IMPAACT 2009, FINAL Version 3.0 
Page 47 of 173 
 
  
   
 
19 November 2020 
women will be asked to engage in brief, discussions about their current strategies for sexual 
health protection and experiences with DOT. For women engaging well with DOT, support is 
provided to maintain this success. For women engaging intermittently or insufficiently with DOT, 
discussions will focus on problem solving and targeting increased DOT engagement and high 
adherence regardless of DOT. Thus, the iNSC approach will be used to promote non-PrEP related 
sexual health protection and support participants in their engagement with DOT and adherence.  
 
5.3.2 
PrEP Comparison Component 
 
Adherence and Sexual Health Protection Counseling:  
 
Integrated Next Step Counseling (iNSC). At study visits, all maternal participants in both cohorts 
receive iNSC, a participant-focused discussion of sexual health and well-being during the 
delivery of HIV-negative test results. iNSC includes exploration, problem solving and skills 
building around non-biomedical strategies to prevent HIV and other STIs and general well-being 
for all participants. For those receiving PrEP (Cohort 1 or Cohort 2/Step 2), counselors assess 
maternal participants’ desire to remain on PrEP. With confirmation of desire to continue with 
PrEP it subsequently focuses on a discussion of PrEP adherence. For those not on PrEP, the 
discussion ends with a discussion on whether she is interested in starting PrEP and providing 
appropriate follow-up, accordingly. For those who have been prescribed PrEP but have yet to 
start taking it, the discussion focuses on her decision to start PrEP andon regimen adherence 
education and planning. iNSC is participant-focused, relies on participant experiences rather than 
self-reported performance (e.g., does not ask participants to report numbers of missed doses or 
number of occurrences of condomless sex, but rather asks about experiences [positive and 
negative] with sexual health protection, areas where the participant would like to feel more 
confident, skilled or comfortable), uses Motivational Interviewing and problem solving strategies, 
and is based on a situated information, motivation and behavioral skills model of sexual health 
protection (which contextualizes individual behavior within its social-cultural and structural 
context). 
  
Drug level monitoring with feedback. DBS samples to measure TFV-DP levels will be obtained 
from participants in Cohort 1 and Cohort 2/Step 2 as per Appendix IIA. DBS levels strongly 
correlate with PrEP efficacy, so users and clinicians can interpret the drug level in the context of 
HIV prevention. TFV-DP levels in red blood cells (measured with DBS), by virtue of a 17-day 
half-life, represent cumulative adherence rather than only recent adherence. Monitoring outcomes 
of preventive medications with biological measurements is common in the management of 
chronic diseases. Per drug thresholds, established in the PK Component, specific ranges will be 
defined for a minimum three adherence categories, aligned with other similar studies and will be 
used to provide guidance for adherence counseling. (e.g. below adequate, adequate and above 
adequate). All participants in Cohort 1 and Cohort 2/Step 2 will receive iNSC with drug level 
feedback based on this categorization. 
 
Participants will be contacted when their DBS TFV-DP concentration results become available to 
site staff. Targeted iNSC, an adapted version of the standard PrEP check-in used at each visit 
(iNSC), will be used in delivering results of drug testing to participants. The approach allows 
staff to share results with participants in a systematic manner and differs based on result being 
delivered. Discussions around adherence and sexual health protection are offered (as an option for 
those with optimal levels) or requested as part of study procedures (for sub-optimal levels) to 
participants. Based on current evidence, any concentration below excellent will be considered 
below adequate. This threshold will be updated as needed should evidence emerge suggesting that 
women can achieve high protection with lower concentrations. Detailed steps for these 


 
IMPAACT 2009, FINAL Version 3.0 
Page 48 of 173 
 
  
   
 
19 November 2020 
procedures are provided in the study-specific iNSC manual/workbook and associated training 
material.  
 
During the PrEP Comparison Component, completion of iNSC sessions will be documented via 
eCRF. Counselors will complete a tracking form at the end of each session documenting the 
specific elements of iNSC included or deferred and related details. 
 
SMS Support:  
 
Beginning with enrollment and continuing through follow-up, all maternal participants, regardless 
of cohort, will receive periodic informational one-way messages about pregnancy and infant care. 
Message content and frequency, as well as standardized procedures for delivering messages via 
an automated computer system will be described in the study-specific MOP.  
 
Maternal participants in Cohort 1 and Cohort 2/Step 2 will also receive weekly two-way text 
messages that provide general adherence support. Beginning the week following enrollment 
(participants in Cohort 1), or the week following Step Change Visit 2 (participants in Cohort 
2/Step 2), and continuing through follow-up, each week, participants will receive a text message 
reminding them about the study support and inquiring how they are doing (e.g. ‘are you ok?’). 
Participants will be instructed to respond within 48 hours either that they are doing well or that 
they have a problem and request assistance. A study staff member will call to follow-up with any 
participant whose response indicates that there is a problem, and participants who fail to respond 
within two business days. Site staff will be expected to respond to text messages only during 
regular clinic hours, but are not restricted to do so. Participants will be instructed that all 
emergencies should be handled through their usual means such as contacting the nearest hospital 
emergency department. Message content and standardized procedures for delivering messages 
and tracking responses for two-way messaging via an automated computer system will be 
described in the study-specific MOP. 
 
Delivery of the SMS support package will be documented via usage statistics and automated 
system reporting of message delivery data. Telephone and in-person follow-up will be tracked 
manually and source documented.  
 
5.4 
Concomitant Medications  
 
The term concomitant medications is used in this study to refer to medications other than 
FTC/TDF.  
 
All concomitant medications received by maternal participants and their infants 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 6.8). This includes prescription and non-
prescription (over-the-counter) medications; vaccines and other preventive medications; 
contraceptives; antenatal vitamins, therapeutic foods, and other nutritional supplements; and 
alternative, complementary, and traditional medications and preparations.  
 
A listing of maternal and infant concomitant medications that must be entered into eCRFs is 
provided in Appendix III. 
 
eCRFs will also capture whether maternal participants received any traditional medications 
during follow-up. 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 49 of 173 
 
  
   
 
19 November 2020 
5.5 
Prohibited Medications  
 
Any mother who requires a medication considered prohibited while on study drug must have the 
study drug held. The CMC must be notified in advance (or as soon as possible thereafter) of any 
instances in which prohibited medications are administered. The following medications are 
prohibited during administration of FTC/TDF: 
• 
Investigational ARV agents, interferon or interleukin therapy 
• 
Agents with substantial nephrotoxic potential   
• 
Other agents that may inhibit or compete for elimination via active renal tubular secretion 
(e.g., probenecid), and/or other investigational agents   
 
6 
STUDY VISITS AND PROCEDURES 
 
The study visit and evaluation schedules for maternal participants and infants are provided in 
Appendices I - II; blood draw volumes for each visit are also detailed in these appendices. 
Presented in this section is additional information on visit-specific study procedures. Information 
related to scheduled visits is presented in Sections 6.1 – 6.4. Additional details related to study-
specific procedures, such as medical history, physical exams, ultrasound scans, DXA scans, and 
Computer-Assisted Self-Interview (CASI) evaluations are provided in Sections 6.8 – 6.16.  
 
All visits and procedures must be performed at the clinical research site or approved associated 
facilities except for certain visits in the PK component which may be done in the home, refer to 
Section 6.1.1. Unless otherwise specified, visits may be split, with required procedures performed 
on more than one day within the allowable visit window if necessary. Whenever possible, 
maternal and infant visits should be scheduled on the same date. All visits and procedures must 
be documented in accordance with the NIAID Division of AIDS (DAIDS) policies for source 
documentation; refer to Section 11 for more information on documentation requirements and 
completion of eCRFs. Refer to Section 7.3 for information on expedited adverse event (EAE) 
reporting, which may be required at any time during follow-up.  
 
For sites experiencing disruptions or limitations of usual operations due to COVID-19, 
operational guidance is provided in Appendix X. 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. 
 
In addition to the protocol-specified procedures listed in this section, study staff may complete 
other tasks consistent with site SOPs or local standard of care, including but not limited to 
collecting, reviewing, and updating demographic and locator information; reviewing elements of 
informed consent; 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 should inform maternal 
participants of clinically meaningful physical exam findings and laboratory test results when 
available. 
 
6.1 
PK Component 
 
6.1.1 
Maternal Screening, Enrollment and Follow-up (Group 1 and Group 2) 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 50 of 173 
 
  
   
 
19 November 2020 
Refer to Section 4.5 for a description of the study recruitment, screening, and enrollment process. 
For eligible women, enrollment must occur in time for study drug initiation within the following 
timeframes: 
 
• 
Group 1: 14 to 24 weeks gestation 
• 
Group 2: 6 to 12 weeks post delivery 
 
Generally, the visit requirements are the same regardless of whether the maternal participant is in 
Group 1 or Group 2: there will be a screening visit and an enrollment visit followed by 12 weekly 
visits. Other requirements at these visits that are specific to one group or the other are noted in the 
text and tables that follow. Participants in Group 1 will have a Labor & Delivery Visit (see 
Section 6.1.1.4). For participants who are still in weekly follow-up at the time of delivery, the 
Labor & Delivery visit may be combined with a weekly study visit. Participants who complete 
weekly follow-up prior to delivery will be permitted to continue the study drug through delivery 
with the labor and delivery visit considered their final visit.  
 
Further operational guidance for required procedures is as follows: 
 
• 
Maternal visits are described in Sections 6.1.1.1 – 6.1.1.4 
 
• 
Infant visits are described in Sections 6.1.2 –  6.1.3 
 
• 
Maternal creatinine testing is required in relation to the eligibility criteria in Section 4.1.2.4 
and to select follow up visits; as soon as the creatinine test result is obtained for a given visit, 
the estimated CrCl rate should be calculated using the Cockcroft-Gault formula, and all 
results should be graded for severity as specified in Section 7.2.1 and assessed for clinical 
significance concurrent with all other laboratory test results. 
 
• 
For Group 1, a fetal ultrasound report is required prior to entry to estimate gestational age and 
to assess for multiple gestation. Biometry from the ultrasound will be used to confirm (or 
change) the gestational age at study entry and gestational age at delivery. If ultrasound is 
performed during the screening period, results must be considered for purposes of eligibility 
determination. For example, if ultrasound indicates multiple gestation during the screening 
period, the woman (and her fetuses) should not be enrolled. Because ultrasound-based 
gestational dating is more accurate the earlier a woman is in her pregnancy, prior ultrasound 
results can be used to meet this requirement, if a report of biometric measurements is 
available as documentation. 
 
• 
Infants in Group 1 will have two study visits: at birth and at six weeks postpartum. Infants in 
Group 2 will have three study visits; at study entry and at six and 12 weeks after study entry.  
 
• 
Should a woman in Group 1 or Group 2 have any ongoing adverse events at the time of her 
last visit, the event will be followed as described in Section 8.1.  
 
• 
If allowed per local law and regulations and/or institutional policies, women in the PK 
Component may have study visits conducted in their home or in other off-site locations. 
Specifically, the visits scheduled at Weeks 1-3, 5-7 and 9-11 may be conducted off-site. At 
sites where off-site visits are permitted, study staff will discuss this option with participants in 
advance and agree on where and when such visits may take place, with adequate protections 
for participant privacy and confidentiality. Prior to each off-site visit, study staff will again 


 
IMPAACT 2009, FINAL Version 3.0 
Page 51 of 173 
 
  
   
 
19 November 2020 
confirm the date, location, and time of each visit with the participant. At off-site visits when 
specimen collection is required, the procedures specified in Section 6.17 must be followed. 
Off-site visits may only be conducted by designated study staff who are qualified to perform 
all protocol-specified procedures and have undergone study-specific and all other applicable 
training relevant to the procedures they will perform off site (e.g., HSP, GCP, IATA). These 
staff should also be adequately trained and qualified to immediately manage any adverse 
events and/or social impacts that may occur during off-site visits (e.g., fainting during 
phlebotomy, family dispute in the home). If adverse events requiring further evaluation or 
management are identified during an off-site visit, study staff conducting the visit will 
arrange for the participant to return to the study site as soon as possible. 
 
6.1.1.1 PK Component Maternal Screening (Group 1 and Group 2) 
 
Refer to Section 4.5 for a description of the study recruitment, screening, and enrollment process.  
 
Screening may be initiated after informed consent is obtained. All screening procedures except 
for sample collection for HIV RNA are expected to be performed within 30 days prior to study 
entry. Screening evaluations may be repeated during the 30-day period, with the latest outcomes 
used for eligibility determination. An HIV negative NAT test result, from a specimen collected 
within 14 days prior to enrollment, is required prior to entry. Multiple screening visits may be 
conducted within the 30-day time frame to complete all required procedures. If the 30-day 
screening period is exceeded, the screening process may be repeated. For potential participants 
who do not meet the eligibility criteria, screening may be discontinued once ineligibility is 
determined.  
 
PK Component Maternal Screening Visit Procedures  
Administrative 
and Regulatory 
• Obtain written informed consent  
• Assign participant identification number (PID) 
• Obtain screening number from SES 
Behavioral  
and Counseling 
• Integrated Next Step Counseling (iNSC) [see Section 5.3.1] 
Clinical 
• Obtain available medical records and medical/medication history  
• Perform complete maternal physical exam  
Laboratory 
Blood  
Collect blood for: 
• HIV RNA test (within 14 days prior to enrollment) 
• Rapid HIV test  
• Complete blood count (CBC) with differential and platelets 
• ALT, Creatinine, and CrCl  
• Hepatitis B surface antigen testing 
• Glucose (random) 
Urine 
Collect urine for: 
• Urinalysis (protein and glucose) 
Other 
Ultrasound 
For Group 1 only: Review medical records for results of any fetal ultrasound 
performed earlier in this pregnancy to confirm/determine gestational age. If 
no results are available, or if documented results are not adequate for study 
purposes, schedule ultrasound so that results are available prior to enrollment. 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 52 of 173 
 
  
   
 
19 November 2020 
6.1.1.2 PK Component Maternal Enrollment Visit (Group 1 and Group 2) 
 
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, HIV rapid test), should be performed first, prior to final eligibility determination 
and enrollment. If a participant is found to be ineligible on the day of enrollment, enrollment 
should not occur.  
 
Additional requirements for sequencing of procedures at the Entry Visit are as follows: 
 
• 
Rapid HIV test, and final eligibility determination and confirmation must precede enrollment 
• 
Blood collection for baseline TFV-DP level must precede ingestion of the first dose of study 
drug  
• 
Prescribing must precede dispensing and administering of study drug  
 
PK Component Maternal Enrollment Visit Procedures (Day 0) 
Administrative 
and Regulatory 
• Complete final eligibility determination and confirmation 
• Complete eligibility checklist1, enter checklist data into SES to enroll the 
participant, print and file a copy of the confirmation 
• Collect comprehensive locator information 
Behavioral  
and Counseling 
• iNSC [see Section 5.3.1] 
• Demographic/Behavioral Questionnaires [see Section 6.16] 
Clinical 
• Update medical and medication history since last visit   
• Perform complete maternal physical exam  
Laboratory 
 
Blood 
 
Prior to first dose of study drug, collect blood for: 
• HIV RNA test 
• Store plasma for HIV drug resistance testing 
• Rapid HIV test1 [see Section 6.3 in the event the test is (+)] 
• Baseline TFV-DP level (DBS)2  
Other 
• Collect vaginal swab for chlamydia and gonorrhea 
Other 
Ultrasound 
For Group 1 only: Review results of ultrasound performed prior to this visit 
and assign gestational age. 
Study Drug 
• Prescribe and dispense study drug 
• Conduct training on observed study dose administration based on site’s 
preferred method 
1 A negative test result must be available prior to enrollment. 
2 Baseline sample must be collected prior to ingestion of study drug. 
 
6.1.1.3 PK Component Maternal Follow Up (Group 1 and Group 2) 
 
Maternal participants will have once weekly follow-up visits for 12 weeks following the 
enrollment visit. Target dates for each visit are counted from the date of enrollment as Day 0, 
with an allowable visit window of ± 1 day. At all visits when study drug is dispensed (Weeks 4 
and 8), a negative rapid HIV test result must be available prior to prescribing PrEP. Weekly study 
visits scheduled at Weeks 4, 8 and 12 must be conducted in the study clinic. Weekly study visits 
at other time points (Weeks 1-3, 5-7 and 9-11) may be conducted in the study clinic or at an 
approved offsite location, for example the participant’s home, refer to Section 6.1.1. For off-site 
weekly study visits, a home visit plan will be developed with the participant prior to the visit to 
indicate her permission for this activity and record any special instructions for the study staff.  
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 53 of 173 
 
  
   
 
19 November 2020 
In addition, daily adherence will be assessed with directly observed dosing. The participant and 
study staff will develop an individualized plan for accomplishing this, determined by the maternal 
participant’s preferred method for observing doses as stated at study entry and reviewed during 
follow-up to accommodate any changes, refer to Section 5.1.1.1.  
 
For participants in Group 1 who deliver prior to completing all 12 weekly visits, the weekly 
follow-up schedule should be maintained to the extent possible after delivery The Labor and 
Delivery Visit may be combined with a weekly visit (refer to Section 6.1.1.4).  
 
PK Component Maternal Weekly Follow-up Procedures (every 7 days ± 1 day) x 12  
Behavioral  
and Counseling 
• iNSC [see Section 5.3.1] 
• Demographic/Behavioral Questionnaires [see Section 6.16] (Week 12 only) 
Clinical 
• Obtain interim medical/medications history 
• Weeks 4, 8, and 12 only: perform targeted physical exam    
• Identify/review/update adverse events  
• Perform additional evaluations per Section 8 and/or if clinically indicated 
(consult CMC as necessary) 
Laboratory 
 
Blood 
 
Collect blood for: 
• Week 12 only:  
• 
CBC with differential 
• 
Hepatitis B surface antigen testing 
• 
Pregnancy testing (Group 2 only): blood or urine test may be performed 
• Weeks 4 and 12, only:  
• 
ALT, Creatinine, and CrCl 
• Weeks 4, 8, and 12, only:  
• 
Rapid HIV test [see Section 6.3 in the event the test is (+)] 
• 
HIV RNA test 
• 
Store plasma for HIV drug resistance testing 
• All visits; Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12: 
• 
TFV-DP level (DBS) 
 
Urine 
• 
Pregnancy testing (Group 2, Week 12 only): blood or urine test may be 
performed 
Study Drug 
•  Weeks 4 and 8, only: Prescribe and dispense study drug  
• Week 12 only: collect all remaining study drug 
 
Note (Group 1 only): If a participant is still pregnant at Week 12, and wants to 
continue to receive study drug, study drug may be dispensed through delivery. 
No PK evaluations will be required. The final visit for maternal participants 
who choose to continue study drug will be at Labor & Delivery (L&D). 
 
 
6.1.1.4 PK Component Maternal Labor and Delivery (Group 1) 
 
 
Regardless of whether a maternal participant has completed the 12 weeks of PK follow up, a visit 
will be conducted within 14 days after delivery to document the pregnancy outcome and evaluate 
the infant (refer to Section 6.1.2 for details regarding the infant). If the participant is unable to 
return to the research clinic within the allowable visit window, follow-up and safety testing may 
be conducted at approved off-site facilities. If the Labor and Delivery Visit is within the window 
of one of the weekly visits, those visits may be combined. If the participant has completed the 12 
weeks of follow-up prior to labor and delivery, then this visit will be the final maternal study 
visit. If the participant had elected to remain on study drug beyond the 12 weeks of PK 
assessment, then study drug should be retrieved at the Labor and Delivery Visit.  


 
IMPAACT 2009, FINAL Version 3.0 
Page 54 of 173 
 
  
   
 
19 November 2020 
 
PK Component (Group 1): Maternal Labor and Delivery Visit Procedures (within +14 days after 
delivery) 
Administrative 
and Regulatory 
• Review locator information 
Behavioral  
and Counseling 
• iNSC [see Section 5.3.1] 
Clinical 
• Obtain interim medical/medications history and pregnancy outcome  
• Perform targeted physical exam  
• Identify/review/update adverse events  
Laboratory 
 
Blood 
Collect blood for: 
• HIV RNA test 
• Store plasma for HIV drug resistance testing  
• Rapid HIV test [see Section 6.3 in the event the test is (+)] 
• TFV-DP level (DBS) 
Study Drug 
• If the participant has completed the 12 weeks of follow-up prior to 
this visit: collect all remaining study drug  
• If the participant is still having weekly study visits for PK assessment: see 
Section 6.1.1.3 
 
6.1.2 
PK Component Infant Birth and PP Week 6 (Group 1) 
 
Infants in Group 1 will be evaluated for safety at birth and postpartum Week 6. Infant creatinine 
testing is required at all infant visits; the infant creatinine test result for a given visit will be 
recorded on the appropriate eCRF.  
 
6.1.2.1 PK Component Infant Birth (Group 1) 
 
The Group 1 infant birth visit will be conducted within 14 days after birth. Whenever possible, 
this visit should occur on the same day as the Labor & Delivery visit. 
 
PK Component (Group 1) Infant Birth Visit Procedures (within 14 days after birth) 
Clinical 
• Perform complete infant physical exam 
• Obtain birth history, interim medical and medications history since birth, 
and feeding history since birth 
Laboratory 
 
Blood 
Collect blood for: 
• Creatinine  
• TFV-DP level (DBS) 
 
6.1.2.2 PK Component Infant Postpartum Week 6 Visit (Group 1) 
 
This visit should be conducted six weeks (42 days) after infant birth (± 14 days). There is no 
corresponding maternal visit at this time. 
 
PK Component (Group 1) Infant Postpartum Week 6 Visit Procedures (Day 42 ± 14 days) 
Clinical 
• Obtain interim medical, medications, and feeding history  
•  Perform targeted physical exam  
Laboratory 
 
Blood 
Collect blood for: 
• Creatinine  


 
IMPAACT 2009, FINAL Version 3.0 
Page 55 of 173 
 
  
   
 
19 November 2020 
 
6.1.3 
PK Component Infant Entry, Week 6 and Week 12 after study entry (Group 2)  
 
Infants in Group 2 will be evaluated for safety at three time points: Entry, Week 6 and Week 12 
after study entry. These time points correspond to the maternal enrollment visit and two of the 
maternal follow up visits. Whenever possible, infant visits should be scheduled on the same date 
of the corresponding maternal visits. Because Group 2 maternal participants are enrolled at 6-12 
weeks’ post-partum, infants in this group enter the study at 6-12 weeks of age. Follow-up visit 
scheduling is then based on the date of enrollment and is unrelated to infant date of birth.  
 
6.1.3.1 PK Component Infant Entry (Group 2) 
 
PK Component (Group 2) Infant Entry Visit Procedures (Day 0 ± 14 days) 
Clinical 
• Obtain birth history, interim medical and medications history since birth, 
and feeding history since birth 
• Perform complete infant physical exam  
Laboratory 
 
Blood 
Collect blood for: 
• Creatinine  
• TFV-DP level (DBS) 
 
6.1.3.2 PK Component Infant Week 6 and 12 (Group 2) 
 
The Group 2 infant follow up visits will be conducted at Week 6 and 12 (± 14 days). Whenever 
possible, infant visits should be scheduled on the same date of the associated maternal visits. 
 
PK Component (Group 2) Infant Week 6 and 12 Visit Procedures (Days 42 and 84 ± 14 days) 
Clinical 
• Obtain interim medical, medications, and feeding history 
• Perform targeted infant physical exam  
Laboratory 
 
Blood 
Collect blood for: 
• Creatinine  
• TFV-DP level (DBS) (Week 6 visit only) 
 
6.2 
PrEP Comparison Component  
 
6.2.1 
PrEP Comparison Component Maternal Screening, Enrollment and Follow-up Visits 
 
Refer to Section 4.5 for a description of the study recruitment, screening, and enrollment process. 
Women will be evaluated for potential participation with a gestational age that will permit study 
enrollment before 32 completed weeks. Infants will enroll into the PrEP Comparison Component, 
in utero, at the time their mothers enter the study. Infants will have study visits at birth, and 6, 14 
and 26 weeks after birth.  
 
Screening may be initiated after informed consent is obtained. All screening procedures except 
for sample collection for HIV RNA are expected to be performed within 30 days prior to study 
entry. Screening evaluations may be repeated during the 30-day period, with the latest outcomes 
used for eligibility determination. A HIV negative NAT test result, from a specimen collected 
within 14 days prior to enrollment, is required prior to entry. Multiple screening visits may be 
conducted within the 30-day time frame to complete all required procedures. If the 30-day 
screening period is exceeded, the screening process may be repeated. For potential participants 
who do not meet the eligibility criteria, screening may be discontinued once ineligibility is 
determined.  


 
IMPAACT 2009, FINAL Version 3.0 
Page 56 of 173 
 
  
   
 
19 November 2020 
• 
Maternal creatinine testing is required in relation to the eligibility criteria in Section 
4.1.2.4 and to select follow up and step change visits; as soon as the creatinine test result 
is obtained for a given visit, the estimated CrCl rate should be calculated using the 
Cockcroft-Gault formula, and all results should be graded for severity as specified in 
Section 7.2.1. and assessed for clinical significance concurrent with all other laboratory 
test results. 
 
• 
Fetal ultrasound should be performed during the study screening period to estimate 
gestational age and to assess for multiple gestation. Specific biometric measurements 
(e.g., crown-rump length, femur length, biparietal diameter, head circumference, 
abdominal circumference) to ensure that gestational age estimate is consistent across sites 
will be documented. Biometry from the ultrasound will subsequently be used to confirm 
(or change) the gestational age at study entry and gestational age at delivery. If 
ultrasound is performed during the screening period, results must be considered for 
purposes of eligibility determination. For example, if ultrasound indicates multiple 
gestation during the screening period, the mother (and her fetuses) should not be enrolled. 
Because ultrasound-based gestational dating is more accurate the earlier a woman is in 
her pregnancy, the prior ultrasound results will be used to meet this requirement, 
provided that a report of biometric measurements is available as documentation.  
 
PrEP Comparison Component Maternal Screening Visit Procedures  
Administrative 
and Regulatory 
• Obtain written informed consent for PrEP Comparison Component 
Screening and Enrollment 
• Assign participant identification number (PID) 
• Obtain screening number from SES 
• Assess eligibility for screening 
Behavioral  
and Counseling 
• iNSC [see Section 5.3.2] 
 
Clinical 
• Obtain available medical records and medical/medication history  
• Perform complete maternal physical exam  
Laboratory 
Blood  
Collect blood for: 
• HIV RNA test  
• Rapid HIV test  
• CBC with differential  
• ALT, Creatinine, and CrCl 
• Hepatitis B surface antigen 
• Glucose (random) 
Urine 
Collect urine for: 
• Urinalysis (protein and glucose) 
Other 
Ultrasound 
Review medical records for results of any fetal ultrasound performed 
during this pregnancy to determine gestational age. If none are 
available, or if documented results are not adequate for study 
purposes, schedule ultrasound so that results are available prior to 
enrollment. 
Study Drug 
Not applicable 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 57 of 173 
 
  
   
 
19 November 2020 
6.2.1.1 PrEP Comparison Component Maternal Enrollment Visit 
 
For eligible women, enrollment must occur in time for study drug initiation prior to 32 completed 
weeks of gestation. The point of enrollment is taken to be the time when a participant has 
successfully been entered in the Subject Enrollment System (SES). 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., rapid HIV test, medical history, physical examination), 
should be performed first prior to final eligibility determination and assignment to a study cohort. 
If a participant is found to ineligible on the day of enrollment, enrollment should not occur.  
 
Additional requirements for sequencing of procedures at the Entry Visit are as follows: 
 
• 
Rapid HIV testing, and final eligibility determination and confirmation must precede 
enrollment. 
• 
For women in Cohort 1: 
o Enrollment must precede prescribing of study drug.  
o Study drug prescribing must precede dispensing.  
o Blood collection for baseline TFV-DP drug level evaluation must precede ingestion of 
study drug.  
 
PrEP Comparison Component Maternal Enrollment Visit Procedures (Day 0) 
Administrative 
and Regulatory 
• Complete final eligibility determination and confirmation 
• Complete eligibility checklist, enter checklist data into SES to enroll the 
participant, print and file a copy of the confirmation 
• Collect comprehensive locator information 
Behavioral  
and Counseling 
• iNSC [see Section 5.3.2 for specific counseling for each cohort] 
• CASI and COVID-19 questionnaire [see Section 6.16] 
Clinical 
• Update medication and medical history since last visit 
• Perform complete maternal physical exam  
Laboratory 
 
Blood 
 
Collect blood for: 
• HIV RNA test 
• Store plasma for HIV drug resistance testing 
• Rapid HIV test [see Section 6.3 in the event the test is (+)]1 
• Baseline TFV-DP level (DBS)2 
• Syphilis testing 
• HSV2 
Other 
Collect vaginal swab or urine for: 
• Chlamydia and gonorrhea 
Collect vaginal swab for: 
• Microbiome 
Collect rectal swab (if consented) for: 
• Microbiome 
Study Drug 
Cohort 1 only: 
• Prescribe and dispense study drug 
1 A negative test result must be available prior to enrollment.  
2 Baseline sample must be collected prior to ingestion of study drug for Cohort 1 participants; the sample 
for Cohort 2 participants can be collected at any time and is required to confirm the participant is not 
receiving PrEP as standard of care.  
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 58 of 173 
 
  
   
 
19 November 2020 
6.2.1.2 PrEP Comparison Component Maternal Antepartum Week 4, 8, 12 (during pregnancy) 
 
The Antepartum (AP) Week 4, 8 and 12 visits are targeted to take place on Study Days 28, 56 and 
84 respectively, counted from the date of study entry as Day 0, with an allowable window of ± 7 
days. A negative rapid HIV test result at each visit must be available, for participants in Cohort 1 
and Cohort 2/Step 2, prior to prescribing study drug.  
 
In addition to the standard of care HIV prevention package provided and routine safety 
evaluations for all study participants at these visits, adherence and acceptability assessments are 
performed in Cohort 1. 
 
Participants in Cohort 1 and Cohort 2 may deliver prior to completion of the AP Week 8 or Week 
12 visit. If so, evaluations indicated for the AP Week 8 and Week 12 visit should be conducted in 
addition to the evaluations required for the Maternal Labor and Delivery Visit (Week 0) (Section 
6.2.1.4). In those cases, the visit window of the L&D visit (+14 days) will apply. 
 
Note that women who are selected for and consent to participation in the Qualitative In-Depth 
Interview during pregnancy may be scheduled for their interview at or after the Week 12 visit. 
See Section 6.2.1.8 for details about this visit.  
 
PrEP Comparison Component Maternal AP Weeks 4, 8 and 12 (± 7 days) 
Behavioral  
and Counseling 
• CASI and COVID-19 questionnaire [see Section 6.16] 
Week 12: 
• Qualitative IDI Visit [see Section 6.2.1.8] 
Cohort 1 and Cohort 2/Step 2 only: 
• iNSC with drug level feedback [see Section 5.3.2] 
Cohort 2 only: 
• iNSC [see Section 5.3.2] 
• Assess for social harms [see Section 13.6] 
Clinical 
• Obtain interim medical/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) 
Laboratory 
 
Blood 
 
Collect blood for: 
• HIV RNA test 
• Store plasma for HIV drug resistance testing 
• Rapid HIV test [see Section 6.3 in the event the test is (+)] 
Weeks 4, 12:  
• ALT, Creatinine, and CrCl 
Cohort 1 and Cohort 2/Step 2 only: 
• TFV-DP level (DBS) 
Other 
Collect vaginal swab once at EGA 34-38/40 weeks for:  
• Microbiome 
Collect rectal swabs once at EGA 34-38/40 weeks (if consented) for: 
• Microbiome 
Cohort 1 and Cohort 2/Step 2 only; collect at one visit at EGA 34-38/40 
weeks:  
• Collect vaginal secretions for drug level 
Study Drug 
Cohort 1 and Cohort 2/Step 2 only: 
• Prescribe and dispense study drug 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 59 of 173 
 
  
   
 
19 November 2020 
6.2.1.3 PrEP Comparison Component Maternal Antepartum Week 24 and 36  
 
Participants in both Cohort 1 and Cohort 2 who enroll early in gestation (i.e., prior to 20 weeks’ 
gestation) may return for visits at AP Study Weeks 24 and 36. These visits are targeted to take 
place 168 and 252 days from the date of study entry (Day 0), respectively, with an allowable 
window of ± 14 days.  
 
In addition to the standard of care HIV prevention package provided and routine safety 
evaluations for all study participants at these visits, assessments are conducted in the PrEP study 
cohort of PrEP acceptability and adherence. 
 
Note that women who are selected for and consent to participation in the Qualitative In-Depth 
Interview during pregnancy may be scheduled for their interview at the time of their regular study 
visit at Week 24 or 36 or at an alternative date. See Section 6.2.1.8 for details about this visit.  
 
PrEP Comparison Component Maternal AP Week 24 and 36 Visit Procedures (± 14 days) 
Administrative 
and Regulatory 
• Review locator information 
Behavioral  
and Counseling 
• CASI and COVID-19 questionnaire [see Section 6.16] 
• Qualitative IDI Visit: [see Section 6.2.1.8] 
Cohort 1 and Cohort 2/Step 2 only: 
• iNSC with drug level feedback [see Section 5.3.2] 
Cohort 2 only: 
• iNSC [see Section 5.3.2] 
• Assess for social harms [see Section 13.6] 
Clinical 
• Obtain interim medical/medications history  
• Perform targeted physical exam  
• Identify/review/update adverse events  
• Perform additional evaluations per Section 8 and/or if clinically 
indicated (consult CMC team if indicated) 
Laboratory 
 
Blood 
 
Collect blood for: 
• HIV RNA test  
• Store plasma for HIV drug resistance testing  
• Rapid HIV test [see Section 6.3 in the event the test is (+)] 
• ALT, Creatinine, and CrCl  
Cohort 1 and Cohort 2/Step 2 only: 
• TFV-DP level (DBS) 
Other 
Collect vaginal swab once at EGA 34-38/40 weeks for: 
• Microbiome 
Collect rectal swabs once at EGA 34-38/40 weeks (if consented) for: 
• Microbiome 
Cohort 1 and Cohort 2/Step 2 only; collect once at EGA 34-38/40 weeks: 
• Collect vaginal secretions for drug level  
Study Product 
Cohort 1 and Cohort 2/Step 2 only: 
• Prescribe and dispense study drug 
 
 
 
 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 60 of 173 
 
  
   
 
19 November 2020 
6.2.1.4 PrEP Comparison Component Maternal Labor and Delivery Visit  
 
Note: The calendar will reset after delivery for postpartum visits, with the delivery date 
considered as Day 0, and subsequent visits calculated from this date.  
 
The maternal labor and delivery visit will be conducted within 14 days of delivery. If the delivery 
visit is conducted within 30 days of the last visit, procedures do not need to repeated except for 
the rapid HIV test, HIV RNA test and plasma storage for future resistance testing. If the mother 
does not deliver a live born infant the mother should still complete the Delivery Visit and all 
subsequent postpartum visits if she is willing to do so.  
 
PrEP Comparison Component Maternal Labor and Delivery Visit Procedures (L/D +14 days) 
Administrative 
and Regulatory 
• Review locator information 
Behavioral  
and Counseling 
• Qualitative Interview IDI Visit: to take place at the L/D visit or at an 
alternative date [see Section 6.2.1.8] 
Cohort 1 and Cohort 2/Step 2 only: 
• iNSC with drug level feedback [see Section 5.3.2] 
Cohort 2 only: 
• iNSC [see Section 5.3.2] 
• Assess for social harms [see Section 13.6] 
Clinical 
• Obtain interim medical/medications history, including pregnancy outcome 
• Perform targeted 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 RNA test 
• Store plasma for HIV drug resistance testing 
• Rapid HIV test [see Section 6.3 in the event the test is (+)] 
• TFV- DP level (DBS)1 
• ALT, Creatinine, and CrCl  
Other 
Radiology  
DXA scan of: 
• Hip 
• Lumbar Spine 
Study Product 
Cohort 1 and Cohort 2/Step 2 only: 
• Prescribe and dispense study drug 
1 DBS sampling is required for Cohort 1 and Cohort 2/Step 2 and Cohort 2; this requirement for Cohort 2 is 
to confirm and document the absence of PrEP exposure. 
 
6.2.1.5 PrEP Comparison Component Maternal Postpartum Week 6 
 
The PP Week 6 visit will be conducted six weeks (± 14 days) following the delivery date.  
PrEP Comparison Component Maternal PP Week 6 Visit Procedures (Week 6 ± 14 days) 
Behavioral  
and Counseling 
Cohort 1 and Cohort 2/Step 2 only: 
• iNSC with drug level feedback [see Section 5.3.2] 
Cohort 2 only: 
• iNSC [see Section 5.3.2] 
• Assess for social harms [see Section 13.6] 


 
IMPAACT 2009, FINAL Version 3.0 
Page 61 of 173 
 
  
   
 
19 November 2020 
PrEP Comparison Component Maternal PP Week 6 Visit Procedures (Week 6 ± 14 days) 
Clinical 
• Obtain interim medical/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) 
Laboratory 
 
Blood 
 
Collect blood for: 
• HIV RNA test 
• Store plasma for HIV drug resistance testing 
• Rapid HIV test [see Section 6.3 in the event the test is (+)] 
Cohort 1 and Cohort 2/Step 2 only: 
• TFV-DP level (DBS) 
 
Other 
Collect vaginal swab for: 
• Microbiome 
Collect rectal swabs (if consented) for: 
• Microbiome 
Cohort 1 and Cohort 2/Step 2 only:  
• Collect vaginal secretions for drug level 
Study Product 
Cohort 1 only and Cohort 2/Step 2 only: 
• Prescribe and dispense study drug 
 
6.2.1.6 PrEP Comparison Component Maternal Postpartum Week 14 
 
The PP Week 14 visit will be conducted 14 weeks (±14 days) following the date of delivery.  
 
Women in Cohort 2 who have been selected for and consented to participate in the Qualitative 
Evaluations postpartum may undergo their in-depth interview at this visit or any time up to and 
including the PP Week 26 visit.  
 
Because the DBS results from this visit will be used to evaluate adherence in Cohort 1, women 
from Cohort 1 may not be formally selected for participation in the Qualitative Evaluations until 
those results are available; however, if slots are still available study staff could approach potential 
participants to discuss the Qualitative Evaluations and to arrange for potential follow up for the 
in-depth interview, refer to Section 6.2.1.8.  
 
PrEP Comparison Component Maternal PP Week 14 Visit Procedures (± 14 days) 
Behavioral  
and Counseling 
• CASI and COVID-19 questionnaire [see Section 6.16] 
• Qualitative IDI Visit [see Section 6.2.1.8] 
Cohort 1 and Cohort 2/Step 2 only: 
• iNSC with drug level feedback [see Section 5.3.2] 
Cohort 2 only: 
• iNSC [see Section 5.3.2] 
• Assess for social harms [see Section 13.6] 
Clinical 
• Obtain interim medical/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) 


 
IMPAACT 2009, FINAL Version 3.0 
Page 62 of 173 
 
  
   
 
19 November 2020 
PrEP Comparison Component Maternal PP Week 14 Visit Procedures (± 14 days) 
Laboratory 
 
Blood 
 
Collect blood for: 
• HIV RNA test 
• Store plasma for HIV drug resistance testing 
• Rapid HIV test1[see Section 6.3 in the event the test is (+)] 
• ALT, Creatinine, and CrCl  
• CBC with differential 
• Pregnancy testing (blood or urine test may be performed) 
Cohort 1 and Cohort 2/Step 2 only: 
• TFV-DP level (DBS) 
 
Urine 
• Pregnancy testing (blood or urine test may be performed)  
Study Product 
Cohort 1 only and Cohort 2/Step 2 only: 
• Prescribe and dispense study drug 
 
6.2.1.7 PrEP Comparison Component Maternal Postpartum Week 26: Final Study Visit 
 
The PP Week 26 visit will be conducted 26 weeks (± 14 days) following the date of delivery.  
 
If slots are still available for the Qualitative In-Depth Interview and/or if a mother had previously 
consented to participate at the time of this visit, the in-depth interview may take place during this 
visit. It is acceptable for the interview to take place on a different date within the Week 26 visit 
window. 
 
PrEP Comparison Component Maternal PP Week 26 Visit Procedures (Week 26 ± 14 days) 
Behavioral  
and Counseling 
• iNSC [see Section 5.3.2] 
• CASI and COVID-19 questionnaire [see Section 6.16] 
• Qualitative IDI Visit [see Section 6.2.1.8] 
• Assess for social harms [see Section 13.6] 
Clinical 
• Obtain interim medical/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) 
Laboratory 
 
Blood 
 
Collect blood for: 
• HIV RNA test  
• Store plasma for HIV drug resistance testing 
• Rapid test [see Section 6.3 in the event the test is (+)] 
• ALT, Creatinine, and CrCl  
• Hepatitis B surface antigen 
• Syphilis testing 
• HSV2 
• Pregnancy testing (blood or urine test may be performed)  
Cohort 1 and Cohort 2/Step 2 only: 
• TFV-DP level (DBS) 


 
IMPAACT 2009, FINAL Version 3.0 
Page 63 of 173 
 
  
   
 
19 November 2020 
PrEP Comparison Component Maternal PP Week 26 Visit Procedures (Week 26 ± 14 days) 
Other 
Collect vaginal swab or urine for: 
• Chlamydia and gonorrhea 
Collect vaginal swab for: 
• Microbiome 
Collect rectal swabs (if consented) for: 
• Microbiome 
Cohort 1 and Cohort 2/Step 2 only:  
• Collect vaginal secretions for drug level 
 
Urine 
• Pregnancy testing (blood or urine test may be performed)  
Other 
Radiology 
DXA scan of:  
• Hip 
• Lumbar Spine 
Note: Pregnancy test required within 14 days prior to DXA scan.  
Study Drug 
Cohort 1 and Cohort 2/Step 2 only: 
• Collect study drug  
 
6.2.1.8 PrEP Comparison Component Maternal: Qualitative In-Depth Interview Visit 
 
A subset of women from both cohorts of the PrEP Component will be invited to participate in the 
Qualitative In-Depth Interviews. The primary activity for this evaluation will be a single in-depth 
interview which will be audio-recorded and transcribed. All women in this subset must provide 
written informed consent prior to participating. 
 
Up to 30 antepartum women and up to 30 postpartum women will be selected and interviewed. 
For Cohort 1, DBS results from two consecutive visits will be reviewed to categorize maternal 
participants as adherent or not prior to selection; up to ten antepartum women and up to ten 
postpartum women in each adherence category will be selected. Cohort 2 is comprised of women 
who declined PrEP. 
 
The timing of the interviews will differ according to pregnancy status and Cohort, as below: 
 
o For pregnant women in Cohort 1 (n=20) – after review of DBS results obtained between 
Week 12 and delivery. 
o For pregnant women in Cohort 2 (n=10) – at or after the Week 12 visit and prior to 
delivery. 
o For postpartum women in Cohort 1 (n=20) – after review of Week 14 DBS results and 
prior to study exit. 
o For postpartum women in Cohort 2 (n=10) – at or after Week 14 and prior to study exit. 
 
All interviews explore experiences around decision making around use of PrEP, which include 
PrEP start and experiences with taking PrEP over time (Cohort 1) and reasons PrEP was declined 
(Cohort 2). Experiences with PrEP from a socio-ecological perspective will be discussed and 
factors related to PrEP drug, self-perceptions of HIV exposure risk and need for PrEP, self-
administration/dosing, community influence, experiences at site and structural supports or 
challenges will be explored.  
 
Interview topics may include how women incorporated daily pill-taking into their daily routines, 
where they stored PrEP, and whether they disclosed their PrEP use with family members, peers, 
and their partner(s), and experiences with side-effects for Cohort 1. Women may also be asked 


 
IMPAACT 2009, FINAL Version 3.0 
Page 64 of 173 
 
  
   
 
19 November 2020 
questions regarding the impact of COVID-19 on their study participation, including PrEP 
adherence and acceptability.  
 
Among women who declined PrEP (Cohort 2), interview topics include factors that were 
associated with not initiating PrEP, including risk perception, personal and community beliefs 
about PrEP, and challenges related to COVID-19 that may have influenced PrEP decision 
making, and opinions about appropriateness of PrEP for other expecting or nursing women in the 
community.  
 
Interview guides used during the interviews will be developed using reviews of local literature 
and community advisory board (CAB) feedback. Local researchers/ethnographers will conduct all 
qualitative interviews with oversight from the study staff. All interviews will be audio-recorded 
and transcribed and translated into English by trained study staff. Coding will identify main 
themes emerging from each of the areas explored in the interview. 
 
6.2.2 
PrEP Comparison Component Infant Birth and PP Week 6, 14 and 26 Visit 
 
Infants born to women in the PrEP Comparison Component (both cohorts) will be evaluated for 
safety at four time points: birth and Weeks 6, 14 and 26 after birth. The date of birth is considered 
Day 0 and subsequent visits will be calculated from this date. These time points correspond to the 
maternal labor and delivery visit and maternal postpartum follow up visits at Weeks 6, 14 and 26. 
Whenever possible, infant visits should be scheduled on the same date of the associated maternal 
visits.  
 
6.2.2.1 PrEP Comparison Component Infant Birth Visit 
 
The allowable window for all evaluations expected at birth is within 14 days after birth; however, 
it is understood that sites may not be able to conduct the DXA scan on the same date as the other 
evaluations and may not be able to arrange a scan within that window. Sites should make every 
effort to schedule the DXA scan to take place within the 14-day window, but up to 21 days is 
allowed. See Section 6.14 for further details. 
 
PrEP Comparison Component Infant Birth Visit Procedures (Birth +14 days) 
Clinical 
• Obtain birth history, interim medical and medications history since 
birth, and feeding history since birth 
• Perform complete infant physical exam 
Laboratory 
 
Blood 
Collect blood for: 
• Creatinine  
• TFV-DP level (DBS) (for storage) 
Other 
• Rectal swabs or fresh stool for microbiome  
Other 
Radiology 
DXA scan of:  
• Whole body 
• Lumbar Spine 
 
6.2.2.2 PrEP Comparison Component Infant PP Week 6 and PP Week 14 Visits 
 
Study visits will be conducted six and fourteen weeks following birth for the infant (± 14 days). 
Whenever possible, infant visits should be scheduled on the same date of their associated 
maternal visits. 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 65 of 173 
 
  
   
 
19 November 2020 
PrEP Comparison Component Infant PP Week 6 and PP Week 14 Visit Procedures (± 14 days) 
Clinical 
• Perform targeted physical exam  
• Obtain interim medical/medications history and feeding history  
Laboratory  
• Rectal swabs or fresh stool for microbiome  
 
6.2.2.3 PrEP Comparison Component Infant PP Week 26 
 
The final study visit will be conducted 26 weeks following birth for the infant (± 14 days). 
Whenever possible, infant visits should be scheduled on the same date of their associated 
maternal visits. 
 
PrEP Comparison Component Infant PP Week 26 Visit Procedures (Week 14 ± 14 days) 
Clinical 
• Perform complete infant physical exam 
• Obtain interim medical/medications history including feeding history 
Laboratory 
 
Blood 
Collect blood for: 
• Creatinine  
Other 
• Rectal swabs or fresh stool for microbiome 
Other 
Radiology 
DXA scan of  
•  Lumbar spine 
 
6.2.3 
Management of Maternal Participants Who Subsequently Switch from Choice Made at 
Enrollment During the PrEP Comparison Component  
 
All participants enter the study on Step 1; however, the study will accommodate maternal 
participants who change their minds after enrollment about whether to receive PrEP. 
Management of these participants will be different depending on the cohort to which they were 
originally enrolled. 
 
6.2.3.1 Maternal Participants in Cohort 1 Who Subsequently Stop PrEP  
 
To the extent possible, staff should try to identify the reasons for maternal participants choosing 
to stop PrEP. Once the maternal participant has stated that she is not willing to continue PrEP and 
the decision to stop PrEP will be entered into an eCRF. If not already required for the study visit 
at which this decision is made, the following additional study procedures should be conducted: 
 
• 
iNSC 
• 
TFV-DP level (DBS) 
• 
HIV RNA test 
 
This will not constitute a change from Cohort 1 to 2; the maternal participant will continue to be 
followed as per her original assignment per Appendix IIA with the exception of the following 
evaluations: 
 
• 
iNSC with drug level feedback 
 
6.2.3.2 Maternal Participants in Cohort 2 Who Elect to Begin PrEP during Follow-up (Cohort 
2/Step2) 
 
Maternal participants who initially declined PrEP may subsequently inform study staff of an 
interest in starting PrEP. In preparation of PrEP initiation, evaluations should be performed as per 


 
IMPAACT 2009, FINAL Version 3.0 
Page 66 of 173 
 
  
   
 
19 November 2020 
the Step Change column in Appendix IIB. The Step Change will occur across two visits, Visit 1 
and Visit 2. Note that the Step Change Visit 1 may be combined with a regular study visit and 
procedures combined. The participant may not initiate PrEP until she has been determined to be 
HIV-uninfected via a rapid test, and has otherwise satisfied the eligibility criteria for a Step 
Change per Section 4.2.3. Blood collection for baseline TFV-DP drug level evaluation must 
precede ingestion of the first dose of study drug for Cohort 2/Step 2.  
 
PrEP Comparison Component Step Change from non-PrEP to PrEP Visit 1 
Administrative 
and Regulatory 
• Review PrEP Comparison Component follow up and risks 
Behavioral  
and Counseling 
• CASI and COVID-19 questionnaire 
• iNSC [see Section 5.3.2] 
• Assess for social harms [see Section 13.6] 
Clinical 
• Obtain interim medical records and medical/medication history 
• Perform targeted physical exam  
Laboratory 
Blood 
Collect blood for: 
• HIV RNA test 
• Store plasma for HIV drug resistance testing 
• CBC with differential 
• ALT, creatinine, and CrCl 
• Hepatitis B surface antigen 
• Glucose (random) 
Urine 
Collect urine for: 
• Urinalysis (protein and glucose) 
 
PrEP Comparison Component Step Change from non-PrEP to PrEP Visit 2 
Administrative 
and Regulatory 
• Complete final eligibility determination and confirmation1 
• Complete eligibility checklist1, enter checklist data into SES to enter the 
maternal participant into Step 2, print and file a copy of the confirmation 
Behavioral  
and Counseling 
• CASI and COVID-19 questionnaire 
• iNSC [see Section 5.3.2] 
• Assess for social harms [see Section 13.6] 
Clinical 
• Obtain interim medical records and medical/medication history 
• Perform targeted physical exam  
Laboratory 
 
Blood 
Collect blood for: 
• Rapid HIV test2 [see Section 6.3 in the event the test is (+)] 
• Baseline TFV-DP level (DBS)3 
Other 
Collect vaginal swab for: 
• Microbiome 
Collect rectal swabs (if consented) for: 
• Microbiome 
Study Drug 
• Prescribe and dispense study drug 
1 Perform prior to step change (entering Step 2) 
2 Review results prior to prescribing study drug.  
3 Baseline sample must be collected prior to ingestion of study drug.  
 
The maternal participant should continue with her regular follow up appointments. However, at 
subsequent visits, the study procedures applicable to Cohort 1 throughout this section and as per 
Appendix IIA will be conducted through study exit, and participants will be referred to as Cohort 
2/Step 2. 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 67 of 173 
 
  
   
 
19 November 2020 
6.3 
Management of Participants with Suspected or Confirmed HIV Seroconversion (PK and 
PrEP Comparison Components) 
 
It is imperative that pregnant and breastfeeding women newly diagnosed with HIV begin ART in 
a timely manner. To ensure that study participants who acquire HIV infection during follow-up 
initiate ART as soon as possible, each site will develop a site-specific SOP to outline their 
operational plan for ensuring prompt linkage to care and treatment. This will include details for 
rapid referral to local ART providers and mechanisms for frequent follow-up to ensure that 
women are initiated on ART within days of being diagnosed. Sites will also be required to 
include information about prophylaxis, screening, and possible treatment options for the infant. 
Women with newly diagnosed HIV infection (and their infants) may also co-enroll in other 
protocols focused on acute HIV, with prior agreement from both Protocol Teams. 
 
6.3.1 
Maternal Participants Who Test HIV-Positive (Confirmatory Visit) 
 
Appendices IIA and IIB specify frequent HIV testing for maternal participants by using both 
rapid HIV tests and an HIV RNA tests. In addition to the testing specified in these appendices, 
testing will also be performed if a participant has signs or symptoms consistent with acute HIV 
infection, or expresses a concern about recent HIV acquisition.  
 
Rapid test results are expected to be available at the visit when blood is collected; HIV RNA 
results are expected to be available within one to two weeks after blood collection. For any 
participant with a test result indicative of HIV infection, PrEP will be immediately stopped and 
additional Confirmatory Visit procedures will be performed as indicated in the table below and in 
Appendix IID. Confirmatory HIV testing should be performed according to the site’s HIV testing 
algorithm, which will be reviewed and approved by the IMPAACT Laboratory Center prior to 
study initiation. The CMC should be notified of initial positive test results, as well as 
confirmatory test results. PrEP should continue to be held for participants with discordant test 
results or not confirmed as infected, pending consultation with the CMC. PrEP can only be 
resumed with approval from the CMC.  
 
In general, the guidelines below should be followed for confirmatory testing.  
 
• 
If the initial test indicating infection is a rapid HIV test, additional Confirmatory Visit 
procedures should be performed on the same day as the initial test.  
 
• 
If the initial test indicating infection is an HIV-1 RNA test, the participant should be 
contacted immediately upon receipt of the test result to advise her to stop PrEP and 
request that she return to the clinic for confirmatory HIV testing and other required 
Confirmatory Visit procedures as soon as possible (within two business days).  
 
The Confirmatory Visit can be combined with other scheduled study visits if the visits are 
conducted within the allowable window of another scheduled visit. For maternal participants who 
have given birth when HIV infection is first indicated, infant HIV testing should also be 
performed at the Confirmatory Visit, as specified in Section 6.3.2.  
 
In all cases, maternal HIV-1-infection will be based on documented positive test results from two 
separate blood samples collected at different time points and following the site-specific approved 
HIV testing algorithm.  
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 68 of 173 
 
  
   
 
19 November 2020 
Sample collection and processing must follow procedures as indicated in Section 6.17.2.  
Participants with confirmed HIV infection will be immediately referred to non-study sources of 
appropriate HIV care and treatment, consistent with local standards of care, and scheduled for 
additional study follow-up four weeks from the date of specimen collection for the initial test 
result indicating HIV infection (see Section 6.3.2 for more information about this visit).  
 
Results from HIV drug resistance testing performed after transmission has been confirmed will be 
provided to participants and their HIV care providers when these results become available.  
 
Confirmatory Visit Procedures (PK Component and PrEP Comparison Component) 
Behavioral  
and Counseling 
• iNSC [see Section 5.3.2] 
Clinical 
• Refer to HIV care and treatment  
Laboratory 
 
Blood 
 
Collect blood for: 
• Confirmatory HIV (specimen collection for this testing must occur at a different 
timepoint from the initial positive test result)  
• CD4 count  
• Plasma and non-viable PBMC storage for HIV drug resistance testing 
Study Drug 
• Collect any remaining study drug (if applicable) 
Follow-up 
• Schedule visit four weeks from date of the initial HIV positive blood draw; this 
may be combined with scheduled study visit if windows overlap. 
 
6.3.2 
Maternal HIV Seroconversion: Management of Maternal Participants Four Weeks Post Date 
of Initial Positive HIV Test  
 
Maternal participants in the PK and PrEP Comparison Components should be scheduled for a 
visit four weeks after the date of the blood draw for the initial positive HIV test, per the table 
below and Appendix IID. This visit is in addition to scheduled visits and can be combined with a 
scheduled visit if conducted within the allowable window of the scheduled visit. At this visit, it 
will be important to confirm that the mother has received appropriate HIV care and treatment and 
– if still pregnant or breastfeeding – appropriate PMTCT interventions. Study staff should review 
any available laboratory results from the prior visit. This will be the final study visit for the 
women participating in the PK Component. Participants in the Prep Comparison Component will 
continue in the study, refer to Section 0.  
 
Maternal Procedures 4 Weeks (± 7 days) Following Diagnosis of HIV 
Clinical 
• Obtain interim history, and confirm receipt of appropriate HIV care and ARV 
medications started as treatment (and PMTCT, if still pregnant or breastfeeding) 
Laboratory 
 
Blood 
 
Collect blood for: 
• Plasma and non-viable PBMC storage for HIV drug resistance testing  
• CD4 count 
Follow-up 
PK Component 
• None. This will be the final study visit 
PrEP Component 
• Confirm time/date of next scheduled visit 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 69 of 173 
 
  
   
 
19 November 2020 
6.3.3 
Maternal HIV Seroconversion: Management of Maternal Participants at Every Visit (PrEP 
Comparison Cohort only) 
 
Maternal participants in the PrEP Comparison Component with confirmed HIV infection will 
remain on-study and continue to be followed through scheduled study exit per the applicable SoE 
(Appendix IIA or IIB). However, because they will no longer be on PrEP, the following 
procedures will no longer be performed among these participants:  
 
 
- 
Rapid HIV test  
- 
Study drug dispensing 
- 
iNSC with drug level feedback 
- 
Two-way SMS support (one-way SMS support should continue) 
- 
PrEP acceptability assessment 
- 
TFV-DP (DBS) level  
 
In addition, ALT, creatinine, CrCl and HIV RNA testing will be performed at a decreased 
frequency ̶ approximately every six months during scheduled study visits ̶ to monitor chemistries 
and HIV viral load among these participants.  
 
6.3.4 
Maternal HIV Seroconversion: Management of Infants 
 
Regardless of whether the mother is diagnosed as HIV-infected during participation in the PK or 
PrEP Comparison Component, her infant should remain on study through his or her scheduled 
study exit for safety monitoring.  
 
Infants of women diagnosed as HIV-infected during pregnancy should undergo HIV nucleic acid 
testing (NAT) as soon as possible after birth. Infants of women diagnosed after delivery should 
undergo HIV NAT on the day that the mother undergoes confirmatory HIV testing. If uninfected, 
the infant should be tested for HIV at each subsequent visit through study exit (see Appendix 
IIE). For all infants or infected mothers, site staff should provide referrals and otherwise facilitate 
to non-study standard of care services to prevent vertical HIV transmission.  
  
If an infant’s HIV NAT result is positive, the mother should be contacted immediately to return to 
the clinic with the infant, as soon as possible, to receive the results and undergo confirmatory 
testing. The CMC should be notified upon site awareness of a positive infant HIV result. Infant 
blood should be collected for confirmatory HIV testing, according to the site’s HIV testing 
algorithm reviewed and approved by the IMPAACT Laboratory prior to study initiation, and for 
HIV drug resistance testing per Appendix IIE. The CMC should be updated of the confirmatory 
test result.  
 
A confirmed diagnosis of infant HIV infection will be based on positive test results from two 
separate blood samples collected on different days following the site-specific approved infant 
HIV testing algorithm, which may include the following assays:  
 
• 
HIV DNA PCR 
• 
Plasma HIV RNA (quantitative or qualitative)  
• 
HIV total nucleic acid tests 
 
Sample collection and processing must follow procedures as indicated in Section 6.17.2.  
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 70 of 173 
 
  
   
 
19 November 2020 
Infants with confirmed HIV infection will remain on study through their scheduled study exit per 
the applicable SoE (Appendix IB, IC or IIC) and have additional procedures related to their HIV 
infection as per Appendix IIE. Site staff are responsible for ensuring that infants with confirmed 
HIV infection have access to non-study sources of appropriate HIV care and treatment, consistent 
with local standards of care.  
 
6.4 
Early Discontinuation Visit 
 
Refer to Section 4.7 for criteria for withdrawal from the study. Study staff will record the 
reason(s) for all withdrawals in participants’ study records. For any maternal or infant participant 
who is withdrawn or terminated from the study prior to scheduled completion of follow-up, every 
effort should be made to perform a final series of study evaluations possible, per the “early D/C” 
column of the Schedule of Evaluations; however, any evaluations for maternal and infant 
participants completed within 30 days prior to Early Discontinuation Visit need not be repeated at 
the visit except for HIV rapid testing which should be completed at the early discontinuation visit.  
 
6.4.1 
Early Discontinuation Visit During the PK Component 
 
6.4.1.1 Maternal Procedures at Early Study Discontinuation 
 
PK Component Maternal Early Study Discontinuation Procedures  
Behavioral  
and Counseling 
• iNSC [see Section 5.3.2] 
Clinical 
• Obtain interim medical/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) 
Laboratory 
 
Blood 
 
Collect blood for: 
• HIV RNA test 
•  Plasma storage for HIV resistance testing  
• Rapid HIV test [see Section 6.3 in the event the test is (+)] 
• TFV-DP level (DBS) 
• CBC with differential 
• ALT, creatinine and CrCl 
• Hepatitis B surface antigen 
Study Drug 
• Collect study drug 
 
6.4.1.2 Infant Procedures at Early Study Discontinuation  
 
If early discontinuation occurs after delivery, study procedures should be conducted for the infant 
where possible. 
 
PK Component Infant Early Study Discontinuation Procedures 
Clinical 
• Perform complete infant physical exam 
• Obtain interim medical/medications history including feeding history  
Laboratory 
 
Blood 
Collect blood for: 
• Creatinine  
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 71 of 173 
 
  
   
 
19 November 2020 
6.4.2 
Early Study Discontinuation During the PrEP Comparison Component 
 
6.4.2.1 Maternal Procedures at Early Study Discontinuation 
 
PrEP Comparison Component Maternal Early Study Discontinuation Procedures  
Behavioral  
and Counseling 
• iNSC [see Section 5.3.2] 
• Assess for social harms [see Section 13.6] 
Clinical 
• Obtain interim medical/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) 
Laboratory 
 
Blood 
 
Collect blood for: 
• HIV RNA test 
• Plasma storage for resistance testing  
• ALT, creatinine, and CrCl 
• Rapid HIV test [see Section 6.3 in the event the test is (+)] 
• Hepatitis B surface antigen 
• Syphilis testing 
• HSV2 
• Pregnancy testing, as needed (blood or urine test may be performed)  
Cohort 1 and Cohort 2/Step 2 only: 
• TFV-DP level (DBS) 
•  
Other 
Collect vaginal swab or urine for: 
• Chlamydia and gonorrhea 
Collect vaginal swab for: 
• Microbiome 
Collect rectal swabs (if consented) for: 
• Microbiome 
Cohort 1 and Cohort 2/Step 2 only:  
• Collect vaginal secretions for drug level 
 
Urine 
• Pregnancy testing, as needed (blood or urine test may be performed)  
Other 
Radiology 
DXA scan of:  
• Hip 
• Lumbar Spine 
• Note: Pregnancy test required within 14 days prior to DXA scan. 
Study Drug 
Cohort 1 or Cohort 2/Step 2 only: 
• Collect study drug 
 
6.4.2.2 Infant Procedures at Early Study Discontinuation  
 
PrEP Comparison Component Infant Early Study Discontinuation Procedures 
Clinical 
• Perform complete infant physical exam 
• Obtain interim medical/medications history including feeding history  
Laboratory 
 
Blood 
Collect blood for: 
• Creatinine  
Other 
• Rectal swabs or fresh stool for microbiome  
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 72 of 173 
 
  
   
 
19 November 2020 
6.5 
PrEP Comparison Component – Interim Visit for Drug Level Feedback 
 
Study staff will contact maternal participants within three business days of site receipt of their 
DBS TFV-DP concentration results. Delivery of test results will follow the approach detailed in 
Section 5.3.2 and the study-specific iNSC manual/workbook and associated training material. 
Drug level feedback should be scheduled to take place as soon as possible after receipt of the PK 
result. If an interim visit cannot be scheduled in-person, the visit may take place over the phone.  
 
6.6 
Management of Infants Whose Mother Dies  
 
For infants of maternal participants who die during the PK or PrEP Comparison Component, the 
infant will remain enrolled through scheduled exit to complete safety evaluations, although study 
procedures will be held until informed consent for the infant’s continued participation is obtained 
from the surviving parent or legal guardian.  
 
6.7 
Management of Women Whose Infant Dies or Experience Fetal Demise 
 
For maternal participants whose infants die or who experience fetal demise during the PK or 
PrEP Comparison Component, maternal study procedures will not change, with the following 
exception:  
 
• 
One-way SMS support messages should be discontinued upon site awareness of infant death 
or fetal demise. For maternal participants in Cohort 1 or Cohort 2/Step 2, two-way SMS 
support messages should continue. 
 
6.8 
Maternal Medical and Medication History  
 
Collection of medical and medication history is required at each scheduled maternal visit during 
the PK and PrEP Comparison Components. A baseline history is established at the screening and 
enrollment visits, and interim (since the last visit) histories are obtained at subsequent follow-up 
visits. All history may be 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 5.4 for more information on concomitant medications.  
 
The following should be source documented as part of the baseline medical and medication 
history: 
 
• 
Date of birth 
• 
Reproductive and obstetrical history (including date of last menstrual period prior to the 
current pregnancy and dates and outcomes of all prior pregnancies) 
• 
History of allergy and/or hypersensitivity  
• 
History of bone fracture (traumatic and non-traumatic) 
• 
History of substance use (e.g. tobacco smoking and/or alcohol use) 
• 
History of STI 
• 
Medical conditions (signs, symptoms, illnesses, and other diagnoses) occurring during the 30 
days prior to enrollment and/or ongoing at the time of enrollment 


 
IMPAACT 2009, FINAL Version 3.0 
Page 73 of 173 
 
  
   
 
19 November 2020 
• 
Medications, including alternative therapies, taken within the 30 days prior to enrollment 
and/or ongoing at the time of enrollment 
• 
Any other information needed to determine eligibility for the study 
 
The following should be source documented as part of interval medical and medication histories: 
 
• 
Current status of conditions that were ongoing at the previous visit 
• 
Current status of medications that were ongoing at the previous visit 
• 
Occurrence of any new conditions (signs, symptoms, illnesses, and other diagnoses) since the 
last visit (specifically including incident HIV and other STIs) 
• 
Use of any new medications, including alternative therapies, since the last visit 
 
In addition, at the Delivery Visit, all delivery-related history, including pregnancy outcome, 
should be documented.  
 
Refer to Sections 7.2 and 5.4, respectively, for information on entering medical and medications 
history information into eCRFs. 
 
6.9 
Maternal Physical Examinations  
 
A physical examination is required at each scheduled maternal visit during the PrEP Comparison 
Components. Complete exams are required at the Screening and Entry Visits; targeted exams are 
required at all other visits. For maternal participants in the PK Component, complete 
examinations are required at the screening and entry visits, and targeted examinations are 
required at Weeks 4, 8, 12, and at the Labor and Delivery visit (Group 1 only). 
 
Complete exams should include the following: 
 
• 
Height measurement (at screening only) 
• 
Weight measurement 
• 
Blood pressure measurement 
• 
Obstetric exam at AP visits (including fundal height measurement and assessment of fetal 
heart rate)  
• 
Auscultation of chest (heart and lung exam) 
• 
Examination of:  
o 
Skin 
o 
Head 
o 
Mouth 
o 
Neck 
o 
Abdomen 
o 
Extremities 
o 
Visual inspection of the genitalia 
 
Targeted exams should include the following: 
 
• 
Weight measurement 
• 
Blood pressure measurement  
• 
Obstetric exam at AP visits (including fundal height measurement and assessment of fetal 
heart rate)  


 
IMPAACT 2009, FINAL Version 3.0 
Page 74 of 173 
 
  
   
 
19 November 2020 
• 
Examination of body systems driven by prior and new signs, symptoms, and diagnoses 
including incident HIV and other STIs 
• 
Routine pelvic examination is not required unless clinically indicated or unless specimen 
collection required 
 
At all visits, additional assessments may be performed at the discretion of the examining 
clinician. For complaints of gynecologic symptoms, this may include a pelvic examination, with 
speculum if appropriate and available. Documentation of exam and medical management should 
be in line with the site guidelines for management of sexually transmitted infections.  
 
All exam findings should be source documented in participant study records, and weight and 
height (at Entry only) should be entered into eCRFs. Temperature and blood pressure should be 
entered into eCRFs if abnormal; other abnormal findings may also be entered into eCRFs if 
required as specified in Section 7.2. 
 
6.10 
Maternal DXA Scans  
 
Maternal participants in the PrEP Comparison Component will undergo DXA scans of the hip 
and lumbar spine at their Labor & Delivery Visit and Week 26 postpartum as well as early 
discontinuation visits, if applicable. 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 Data Management Center (DMC); however, if a maternal participant experiences a bone 
fracture subsequent to her scan, the result of her scan will be provided to the site as soon as 
available.  
 
6.11 
Infant Medical and Medication History  
 
Collection of medical and medication history is required at each scheduled infant visit during the 
PK and PrEP Comparison Components.  
 
Medical and medication history at birth will consist of information recorded on medical records at 
birth as well as information obtained at the Birth Visit. The Birth Visit should take place as soon 
as possible after birth, but may take place up to 14 days after birth; as such, information recorded 
at birth may differ from information obtained at the Birth Visit. 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 following should be source documented as part of medical and medications history at the 
Birth Visit: 
 
• 
Date and time of birth 
• 
Sex at birth  
• 
Length, weight, and head circumference at birth (obtain from medical records; these 
measurements will also be performed by study staff at the infant Birth Visit) 
• 
Apgar scores at one and five minutes (obtain from medical records) 
• 
Medications taken since birth 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 75 of 173 
 
  
   
 
19 November 2020 
The following should be source documented as part of interval medical and medication histories: 
 
• 
Current status of conditions that were ongoing at the previous visit 
• 
Current status of medications that were ongoing at the previous visit 
• 
Occurrence of any new conditions (signs, symptoms, illnesses, and other diagnoses) since the 
last visit 
• 
Use of any new medications since the last visit 
 
Refer to Sections 7.2 and 6.8, respectively, for information on entering medical and medications 
history information into eCRFs. 
 
6.12 
Infant Feeding History  
 
An infant feeding history is required at each scheduled visit during the PK and PrEP Comparison 
Components. At the Birth Visit, feeding history (since birth, to include the 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 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 5.4).  
 
6.13 
Infant Physical Examinations  
 
A physical examination is required at each scheduled infant visit during the PK and PrEP 
Comparison Components. In the PK Component, for Group 1 infants a complete exam is required 
at the Birth Visit and a targeted exam is required at the Postpartum Week 6 Visit; for Group 2 
infants a complete exam is required at the Entry Visit and targeted exams are required at the 
Week 6 and Week 12 Visits. In the PrEP Comparison Component, complete exams are required 
at the Birth and PP Week 26 Visits; targeted exams are required at the PP Week 6 and PP Week 
14 Visits. Complete exams are required at the Early Study Discontinuation Visit for all infants in 
both Components. 
 
Complete exams should include the following: 
 
• 
Length measurement 
• 
Weight measurement 
• 
Head circumference measurement 
• 
Assessment of anterior fontanel closure  
• 
Auscultation of chest (heart and lungs) 
• 
Examination of skin, head, mouth, neck, abdomen, extremities 
• 
Neurologic assessment 
 
Targeted exams should include the following: 
 
• 
Length measurement 
• 
Weight measurement 
• 
Head circumference measurement 
• 
Assessment of anterior fontanel closure 
• 
Auscultation of chest (heart and lungs) 
• 
Examination of body systems driven by prior and new signs, symptoms, and diagnoses 


 
IMPAACT 2009, FINAL Version 3.0 
Page 76 of 173 
 
  
   
 
19 November 2020 
 
At all visits, additional assessments may be performed at the discretion of the examining 
clinician. Also at all visits, the anthropometric growth measurements listed above should be 
charted on standard infant growth charts and weight-for-length should be assessed in relation to 
WHO growth standards.  
 
All exam findings should be source documented in participant study records. Weight, length, and 
head circumference should be entered into eCRFs. Temperature should be entered into eCRFs if 
abnormal; other abnormal findings may also be entered into eCRFs if required as specified in 
Section 7.2. 
 
6.14 
Infant DXA Scans  
 
Infants in the PrEP Comparison Component will undergo DXA scans of the whole body and 
lumbar spine at their Birth Visit and of the lumbar spine 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 Data Management Center (DMC). The centralized 
readings of all scans will be made available to the study sites after the last scan has been read 
centrally. However, if 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.  
 
6.15 
Fetal Ultrasound 
 
If sonographic results from the current pregnancy are not available from medical records at the 
time of screening during the PK and PrEP Comparison Components, a fetal ultrasound scan will 
be performed to confirm (or used to re-calculate) gestational age at entry into the study. Scans 
should be performed during the 30-day study screening period, and results must be available at 
the time of enrollment.  
 
Ultrasound scans may be performed at the study site or at off-site facilities. A result report that 
minimally documents the following must be obtained for filing in participant study charts and 
entry into eCRFs: 
 
• 
Date of scan 
• 
Number of fetuses 
• 
Biometry measures for 
- If ≤ 14 weeks gestation: 
• Crown-rump length  
- If > 14 weeks gestation: 
• Femur length, abdominal circumference, and either or both head circumference and 
biparietal diameter  
• 
Calculated gestational age on the date of the scan or estimated date of delivery  
 
 
 
 
 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 77 of 173 
 
  
   
 
19 November 2020 
6.16 
Questionnaires and Computer-Assisted Self-Interview (CASI) 
 
6.16.1 PK Component 
 
During enrollment and at Study Exit of the PK Component, maternal participants will be queried 
on demographic and behavioral HIV risk characteristics; this information will be recorded on an 
eCRF. Items from the following domains will be included: 
 
• 
Sociodemographic characteristics 
o Current living situation 
o Household composition 
• 
HIV risk perception for mother and infant  
• 
Sexual behaviors 
6.16.2 PrEP Comparison Component   
 
6.16.2.1 COVID-19 
 
Throughout follow-up of the PrEP Comparison Component, a COVID-19 questionnanire will be 
administered to maternal participants at select study visits (see Appendices IIA and IIB and 
Section 6.2). This questionnaire will cover topics such as the potential impact of COVID-19 on 
participants’ life and study participation; this information will be recorded on an eCRF. 
 
6.16.2.2 CASI 
 
During enrollment and follow-up of the PrEP Comparison Component, maternal participants will 
be queried on the contextual factors, that have been shown to impact differential uptake and 
sustained use of PrEP in prior trials. Items from the following domains will be programmed into 
the CASI:  
 
• 
Sociodemographic characteristics 
o Current living situation 
o Household composition 
o Private space for product storage 
• 
HIV risk perception for mother and infant  
• 
HIV stigma 
• 
PrEP stigma 
• 
Sexual behaviors 
• 
Substance use 
• 
PrEP beliefs and PrEP readiness 
• 
Future orientation and aspirations; self-efficacy  
• 
Mental health and post-traumatic stress symptoms 
• 
Disclosure to peers, family members, and partner(s) about PrEP use and participation in the 
study  
• 
Gender-based violence (GBV) 
• 
Partnership characteristics: partner’s HIV status 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 78 of 173 
 
  
   
 
19 November 2020 
6.17 
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-laboratory-specimens-management  
 
6.17.1 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 available on 
the IMPAACT web site: www.impaactnetwork.org.  
 
In accordance with U.S. National Institutes of Health (NIH) recommendations, adult blood 
collection will not exceed 10.5 mL/kg or 550 mL, whichever is smaller, over any eight-week 
period. 
 
In accordance with U.S. National Institutes of Health (NIH) recommendations, pediatric 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 blood collection must be limited, available specimens should be prioritized for 
use in the following order: (1) HIV testing, (2) Creatinine, (3) Drug levels, (4) stored plasma.  
 
6.17.2 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 6.17.1, 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.  
 
Safety tests will be conducted in real time at the site laboratories.  
 
Dried blood spot samples will be shipped to regional laboratories for TVF-DP drug levels. 
Samples will be shipped at a frequency which permits a site to receive results by the next study 
visit for the PrEP Comparison participants.  
 
Infant specimens for HIV nucleic acid testing for infant HIV diagnosis and maternal specimens 
for HIV testing must be tested in a VQA-certified laboratory. HIV antibody tests must be 
performed according to GCLP guidelines and the laboratory must participate in an appropriate 
external QA program.  
 
Maternal and infant sample swabs for microbiome analyses will be stored and batch shipped for 
analysis. No data from these samples will be available to the sites during the study. 
 
Maternal vaginal secretions samples for drug level may be obtained with a soft plastic aspirator 
without speculum placement or by another appropriate technique and can be collected by the 
participant or by a clinician. Samples will be stored and batch shipped for testing. Since target 
drug concentrations for vaginal samples have not been determined, real time testing and reporting 
of vaginal specimen results to the sites will not be done. No vaginal specimens will be collected if 


 
IMPAACT 2009, FINAL Version 3.0 
Page 79 of 173 
 
  
   
 
19 November 2020 
contraindicated by a pregnancy complication such as placenta previa or premature rupture of 
membranes. 
 
After all protocol-specified laboratory testing has been performed, residual maternal and infant 
specimens may be of interest for future research use. Maternal participants (or other authorized 
guardians if applicable) 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. 
Participants may choose to provide or to decline informed consent for future research use of 
residual specimens with no impact on other aspects of participation in the study. With permission, 
human genetic tests may be performed on these samples. The genetic testing may be used to help 
understand variability in enzymes responsible for tenofovir and emtricitabine disposition and 
drug response including, drug transporters, kinases, phosphotransferases, or enzymes involved in 
drug response.  
 
6.17.3 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 U.S. 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 MONITORING, ASSESSMENT AND REPORTING 
 
7.1 
Safety-Related Roles and Responsibilities 
 
Participant safety will be carefully assessed, monitored, and reported at multiple levels 
throughout this study. Sections 7.1, 7.2, and 7.3 describe safety-related roles, responsibilities, and 
procedures for site investigators. The safety monitoring roles of the Clinical Management 
Committee (CMC) and the IMPAACT Study Monitoring Committee (SMC) are briefly 
referenced in Section 7.1 and described in greater detail in Section 9.3. 
 
7.1.1 
Site Investigators 
 
Site investigators are responsible for continuous monitoring of all study participants and for 
alerting the CMC if unexpected concerns arise. Site investigators will record safety-related data 
on 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 Chair and Vice Chairs, 
Medical Officers, Pharmacologists, Statisticians, Epidemiologist, Data Managers, Laboratory 
Data Managers, Clinical Trial Specialists, at least one international Protocol Investigator, or their 


 
IMPAACT 2009, FINAL Version 3.0 
Page 80 of 173 
 
  
   
 
19 November 2020 
designees. 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 and 
management of adverse events, study drug administration, and other concomitant medications. 
Refer to Section 8 for more information on participant management. 
 
On behalf of the full Protocol Team, the CMC will monitor participant safety through routine 
review of study data reports as described in Section 9.3. 
 
7.1.3 
Study Monitoring Committee (SMC)  
 
An independent IMPAACT Study Monitoring Committee (SMC) will monitor participant safety 
through routine and as needed reviews of study data. Refer to Section 9.3.3 for more information 
on the composition and role of the SMC in monitoring of this study.  
 
7.2 
Safety-Related Data and Pre-Existing Conditions Data Collection   
 
Note: This section describes eCRF data recording 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 maternal and infant participants, in both the PK Component and in 
the PrEP Comparison Component, 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 maternal participants) and 7.2.2 (for infants). Additionally, in the PrEP Comparison 
Component all reported social harms will likewise be documented on eCRFs as specified in 
Section 13.6.   
 
7.2.1 
Safety-Related Data Collection for Maternal Participants   
 
Pre-Existing Conditions 
 
All pre-existing conditions identified among maternal participants during the 30 days prior to 
study entry will be recorded on maternal medical history eCRFs.  
 
Adverse Events 
 
The following adverse events— inclusive of abnormal laboratory test results and clinical signs, 
symptoms, and diagnoses — will be entered into maternal adverse events eCRFs: 
 
For the PK Component: 
• 
All Grade 3 or higher adverse events 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 81 of 173 
 
  
   
 
19 November 2020 
For the PrEP Comparison Component: 
• 
All Grade 2 or higher adverse events 
 
For both the PK Component and PrEP Comparison Component: 
• 
All adverse events that lead to a change of study drug 
• 
All complications and sequela of adverse pregnancy outcomes. 
• 
All serious adverse events (SAEs) as defined in Version 2.0 of the Manual for Expedited 
Reporting of Adverse Events to DAIDS (DAIDS EAE Manual)  
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: 
 
For the PK Component: 
• 
All Grade 3 or higher hemoglobin, white blood cell count, absolute neutrophil count, and 
platelet count results 
 
For the PrEP Comparison Component: 
• 
All Grade 2 or higher hemoglobin, white blood cell count, absolute neutrophil count, and 
platelet count results 
 
For both the PK Component and PrEP Comparison Component: 
• 
All HIV test results 
• 
All creatinine and creatinine clearance results regardless of severity grade 
• 
All Grade 2 or higher ALT results 
• 
All results that lead to a discontinuation of study drug 
• 
All results that are serious as defined in Version 2.0 of the DAIDS EAE Manual 
 
7.2.2 
Safety-Related Data Collection for Infants 
 
Pre-Existing Conditions 
 
Given that infants in Group 1 of the PK Component, Cohort 1 and Cohort 2/Step 2 (specifically, 
infants of mothers who undergo the step change while pregnant) of the PrEP Comparison 
Component 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 — will be entered into infant adverse events eCRFs: 
 
For the PK Component:  
• 
All Grade 3 or higher clinical signs, symptoms and diagnosis 
 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 82 of 173 
 
  
   
 
19 November 2020 
For the PrEP Comparison Component:  
• 
All Grade 2 or higher clinical signs, symptoms and diagnosis 
 
For both the PK Component and PrEP Comparison Component:  
• 
Suspected congenital anomalies 
• 
All SAEs as defined in Version 2.0 of the DAIDS EAE Manual  
 
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 HIV test results 
• 
All creatinine results regardless of severity grade 
• 
All results that are serious as defined in Version 2.0 of the DAIDS EAE Manual 
 
7.3 
Expedited Adverse Event (EAE) Reporting 
 
EAEs will be reported only for participants in this study who are exposed to study drug.  
 
7.3.1 
Adverse Event Reporting to DAIDS 
 
Requirements, definitions, and methods for expedited reporting of adverse events (AEs) are 
outlined in Version 2.0 of the DAIDS EAE Manual, which is available on the RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-reporting-adverse-events-daids. 
 
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 via the DAIDS EAE Form. This form is available on the 
DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting 
 
For questions about DAERS, please contact NIAID Clinical Research Management System 
Support via email at CRMSsupport@niaid.nih.gov. Site queries may also be sent from within the 
DAERS application itself.  
 
For questions about expedited reporting, please contact DAIDS RSC Safety Office via email at 
DAIDSRSCSafetyOffice@tech-res.com. 
 
7.3.2 
EAE Reporting Requirements for this Study 
 
• 
EAEs will be reported only for maternal and infant participants in this study who are exposed 
to study drug. 
 
• 
The serious adverse event (SAE) reporting category, as defined in Version 2.0 of the DAIDS 
EAE Manual, will be used for this study. 
 
• 
The study agent for which expedited reporting is required is FTC/TDF.  
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 83 of 173 
 
  
   
 
19 November 2020 
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: https://rsc.niaid.nih.gov/clinical-research-
sites/daids-adverse-event-grading-tables. For maternal participants in the PrEP Comparison 
Component, grading of creatinine and CrCl should be based on absolute value only, not on 
percentage change from baseline. 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 
 
For maternal and infant participants exposed the study drug, the EAE reporting period begins at 
first exposure to study drug and ends on the date of last exposure to study drug.  
 
For mothers, exposure to study drug is based on ingestion of FTC/TDF. The EAE reporting 
period begins on the day of first FTC/TDF tablet ingestion and ends on the last day of FTC/TDF 
tablet ingestion.  
 
For infants, exposure to study drug may occur in utero and/or through breast milk while the 
mother is taking FTC/TDF. The EAE reporting period begins on the day of the first exposure in 
utero or through breast milk and ends after the day of last exposure in utero or through breast 
milk. For example, for an infant whose mother takes FTC/TDF during pregnancy but not 
postpartum, the infant’s EAE reporting period would begin on the day of the mother’s first 
FTC/TDF tablet ingestion during pregnancy and ends after delivery. For an infant, whose mother 
takes FTC/TDF during pregnancy and postpartum, and breastfeeds the infant, the infant’s EAE 
reporting period would begin on the day of the mother’s first FTC/TDF tablet ingestion during 
pregnancy and end after the mother’s date of last FTC/TDF tablet ingestion. 
 
After the above-specified period, only suspected, unexpected, serious adverse reactions 
(SUSARs), as defined in Version 2.0 of the DAIDS EAE Manual, will be reported to DAIDS if 
the study staff become aware of such events on a passive basis (e.g., from publicly available 
information). 
 
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 11. 
Among other details, source documentation will include the severity of each event (graded as 


 
IMPAACT 2009, FINAL Version 3.0 
Page 84 of 173 
 
  
   
 
19 November 2020 
described in Section 7.3.3) and its relationship to study drug assessed by the site clinician 
according to the following categories and definitions: 
 
Related:  
There is a reasonable possibility that the AE may be related to FTC/TDF 
 
Not related:  
There is not a reasonable possibility that the AE is related to FTC/TDF  
 
Maternal participants who choose to take PrEP are considered exposed to study drug immediately 
after initiation of dosing through ingestion of the last dose of study drug. Infant participants are 
considered exposed to study drug in utero and through breast milk, if their mothers choose to take 
PrEP and to breastfeed. Infant exposure begins immediately after initiation of maternal dosing 
and ceases following ingestion of the last maternal dose of study drug or breast milk feed (or after 
birth, if not breastfed).  
 
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. Additional 
evaluations beyond those listed in the Schedule of Evaluations may be performed at the discretion 
of the site investigator to determine the etiology of a given event and/or further assess its severity 
or relationship to study drug. Clinical management of all adverse events should be provided 
consistent with the best medical judgment of the site investigator and local clinical practice 
standards. 
 
8.1.1 
Management of Maternal Adverse Events 
 
Maternal adverse events will be managed based on their severity and assessed relationship to 
study drug. Refer to management table in Appendix V for detailed guidance on management of 
reduced creatinine clearance. All other adverse events should be managed as shown in Appendix 
IV for general toxicities. Site investigators will consult with the CMC as directed in the Maternal 
Toxicity Management Tables in Appendices IV and V and otherwise at their discretion as needed. 
The protocol Clinical Management Committee (CMC) will be notified of all events resulting in a 
change in the administration of the study drug. Clinical or laboratory AEs that are not related to 
FTC/TDF need not result in study drug interruption, unless the site investigator deems 
interruption necessary due to the specific circumstances. All maternal participants will remain on 
study and complete all follow-up visits, even if FTC/TDF is discontinued early due to toxicity or 
other reasons. Maternal participants with an ongoing AE at the time of the End of Study visit of 
Grade 3 or higher will continue to be followed until resolution or stabilization of the event. The 
CMC may request additional follow-up of selected AEs of lower grade based on the clinical 
context.  
 
For maternal participants with other ongoing adverse events at End of Study visit, sites will 
continue to manage these conditions per local guidelines until the participant has been 
transitioned to a non-study primary care provider for continued monitoring, care and treatment. 
For adverse events of any severity assessed to be related to study-supplied study drug FTC/TDF 
that are ongoing at week 26 postpartum, sites will inform the CMC of their plan for continued 
clinical management  
 
8.1.2 
Compromised Renal Function  
 
Further action is required if reduced creatinine clearance is recorded at any time during follow-up 
to evaluate potential compromise of a maternal participant’s renal function. Appendix V provides 
general guidance for management of the FTC/TDF in response to reduced creatinine clearance. 


 
IMPAACT 2009, FINAL Version 3.0 
Page 85 of 173 
 
  
   
 
19 November 2020 
8.1.3 
Maternal Bone Mineral Density Concerns 
 
There is no clarity on which bone density normative ranges should apply to women in Sub-
Saharan Africa, given that available data suggests American Caucasian reference ranges are not 
appropriate and there are no accepted normative ranges for the region. Additionally, the degree of 
bone lost during periods of lactation is highly variable and maternal participants are likely to 
continue lactating for several months’ post study exit. Thus, bone density scans conducted in this 
setting after delivery and prior to breastfeeding cessation are difficult to interpret clinically for the 
individual woman. Hence, maternal DXA scan data obtained in this study will only be of use for 
research purposes alone. The site investigator may specifically request these data for an 
individual participant at their discretion. 
 
8.1.4 
Infant Bone Mineral Density Concerns 
 
There are no normal ranges for infant bone mineral content in current use. Infant DXA scan data 
obtained for this study are for research purposes alone and are not readily interpreted for clinical 
use. If normal values for infants become established while implementing this protocol, the DXA 
results will be communicated to the site investigator who will use his or her clinical judgment 
regarding medical consultation and referral.  
 
8.2 
Management of Participants Who Become Pregnant on Study  
 
Pregnancy testing will be performed according to the relevant Schedule of Evaluations and when 
clinically indicated at any time during maternal follow-up and participants will be provided with 
contraception counseling per local standards of care, see Section 3.3. 
 
Participants enrolled in Group 2 of the PK Component or in the PrEP Comparison Component 
who become pregnant during the study will be maintained in follow-up through scheduled study 
exit with no change to their study drug regimen. When the new pregnancy is identified, 
participants in Cohort 2 of the PrEP Comparison Component will be offered PrEP; if they choose 
to start PrEP, they will enter Cohort 2/Step 2 (see Section 5.1). Given that these participants will 
exit the study prior to delivery, those receiving PrEP will be referred to standard of care maternity 
services and efforts will be made to transition participants to locally available sources of PrEP to 
avoid gaps in PrEP coverage.  
 
Participants who are pregnant at the time of study exit, will be contacted by study staff to 
ascertain their pregnancy outcomes (completion/termination of the pregnancy) and this 
information will be entered onto eCRFs. Outcomes may be ascertained based on participant 
report but medical records should be obtained whenever possible to supplement these reports. 
 
8.3 
Criteria for Premature Discontinuation of Study Drug  
 
Study drug will be permanently discontinued before study exit in the following scenarios: 
• 
Confirmed maternal HIV infection 
• 
Confirmed maternal Grade 4 laboratory abnormality related to study drug  
• 
Confirmed maternal Grade 3 laboratory abnormality related to study drug that does not 
resolve to Grade 2 or lower within 14 days of study drug hold  
• 
Confirmed maternal Grade 3 or higher laboratory abnormality or clinical AE that recurs 
during re-challenge with the study drug after a hold  
• 
Confirmed maternal creatinine clearance <50mL/minute 


 
IMPAACT 2009, FINAL Version 3.0 
Page 86 of 173 
 
  
   
 
19 November 2020 
9 
STATISTICAL CONSIDERATIONS 
 
9.1 
PK Component 
 
9.1.1 
General Design Issues-PK Component 
 
The IMPAACT 2009 PK Component aims to establish drug thresholds for adequate adherence in 
pregnancy and postpartum when FTC/TDF is administered daily during pregnancy and in the 
postpartum period under directly observed conditions. All maternal participants will be 
administered once daily FTC/TDF. All doses will be directly observed for the 12-week duration. 
DBS specimens will be collected at weekly intervals for analysis. Approximately 40 maternal 
participants will be recruited to obtain at least 30 evaluable maternal participants with 20 
participants who are recruited in the antepartum group (14-24 weeks of gestation), and 20 who 
are recruited in the postpartum group (6-12 weeks postpartum). A maternal participant is 
considered evaluable if she fulfils the following criteria; a) completes PK Component follow-up, 
b) has adequate documentation that PrEP doses were directly observed, c) has demonstrated 
adequate adherence to PrEP, defined as no more than 12 total directly observed doses missed over 
12 weeks (maternal participants with more than three consecutively missed doses will be 
reviewed by the CMC to determine evaluability), and (d) had adequate DBS samples shipped to 
the PK testing laboratory, defined as no more than one missed specimen in any given two-week 
interval over 12 weeks with a minimum of  seven samples correctly collected, processed, handled 
and shipped. The rationale for this design is to collect as many weekly measurements as feasible 
to enable the most robust estimates, but also to allow flexibility for occasional missed visits and 
doses to enable practicability for participants and sites.  
 
9.1.2 
Outcome Measures-PK Component 
 
9.1.2.1 Primary Outcome Measure 
 
• 
 Steady state TFV-DP concentrations at Week 12. 
 
9.1.2.2 Secondary Outcome Measures 
 
• 
Steady state TFV-DP concentrations at Week 12. 
 
9.1.3 
Randomization and Stratification-PK Component  
 
There is no randomization in this study. The enrollment will be stratified by: 
 
• 
Group 1 (Antepartum women 14-24 weeks’ gestation) vs. Group 2 (Postpartum women who 
delivered 6-12 weeks prior to enrollment) 
 
9.1.4 
Sample Size and Accrual-PK Component 
 
An important objective of the PK Component is to determine the TFV-DP concentration 
corresponding to optimal adherence. We will estimate the 25th percentile of the TFV-DP 
distribution in each of the two groups. Table 2 shows estimated 95% CIs around the 25th 
percentile based on the normal distribution assumption at various sample sizes. With a sample 
size of 15 per group, the bounds of the 95% confidence interval are the 12th and 43rd percentile. 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 87 of 173 
 
  
   
 
19 November 2020 
Table 2: 95% Confidence Intervals of Estimated 25th percentile of TFV-DP Steady State Concentration (Css) 
Sample Size per Group 
95% Confidence Interval (percentile) 
15 
(12th, 43th) 
20 
(13th, 41th) 
30 
(15th, 38th) 
50 
(17th, 35th) 
80 
(18.5th, 33th) 
100 
(19th, 32th) 
 
Table 3 shows the precision of the estimate of minimum detectable difference in means for 
comparisons of mean TFV-DP steady state concentrations in DBS between the antepartum and 
postpartum group, given different sample sizes per group, alpha 0.05 using a two sample t-test. 
For example, with a sample size of 15 per group the half width of the 95% confidence interval 
around the difference in means is .75 of the standard deviation. 
 
Table 3: Precision of Estimated Differences in Mean Css in DBS: PK Component 
Sample Size per Group 
Precision of estimated difference in mean Css  
(between AP and PP group) 
20 
271 (64% of SD*) 
18 
287 (68% of SD) 
15   
(protocol targeted) 
316 (75% of SD) 
12 
358 (85% of SD) 
10 
397 (94% of SD) 
*SD=423 (DOT-DBS Study, CROI 2017)  
 
9.1.5 
Monitoring-PK Component 
 
Reports summarizing data on accrual, missed weekly visits, missed PrEP doses, doses with 
inadequate source documentation of direct observation, number and adequacy of DBS specimens 
reaching the testing laboratory, mode of delivery, and safety and tolerability of FTC/TDF will be 
compiled by the Data Management Center (DMC) and reviewed and discussed by the CMC. 
Reports will be sent at least monthly. Adverse events will be monitored throughout the follow-up 
period. If the CMC identifies any potentially treatment-related toxicities, which may compromise 
participant safety, it will determine whether the study needs to be suspended or modified. Refer to 
Section 9.3 for details on monitoring by the CMC and Safety Monitoring Committee (SMC).  
 
9.1.6 
Analysis-PK Component 
 
Prior to conducting analyses for the PK Component, the CMC (to include a minimum of the 
Protocol Epidemiologist and/or Statistician and the Pharmacologist), will review the pattern of 
completeness of each maternal participant’s TFV-DP concentration data to determine suitability 
for inclusion in the analysis. Weekly TFV-DP concentration levels in DBS will be plotted for 
each maternal participant. In each of the two groups (antepartum and postpartum groups), the 
distributions of steady state concentration (Css) defined as the TFV-DP concentration observed at 
Week 12 corresponding to 6-7 day/week adherence (“excellent adherence”), will be summarized. 
Estimates of median, IQR, mean, standard deviation, and 95% confidence intervals will be 
calculated for each of the two groups. Differences in mean Css between the antepartum and 
postpartum groups will be evaluated using two sample t tests.  
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 88 of 173 
 
  
   
 
19 November 2020 
Estimated concentrations corresponding to numbers of doses/week (or percentages of doses 
taken) in the antepartum and postpartum periods will be derived from the two measures above 
(antepartum Css and postpartum Css after 12 weeks of daily dosing), assuming dose 
proportionality (in cases that doses were missed). The drug threshold corresponding to “excellent 
adherence” will be defined as TFV-DP levels meeting or exceeding the 25th percentile of the 
distribution of TFV-DP concentrations at Week 12 of the PK Component. “Excellent adherence” 
is defined as the TFV-DP concentration corresponding to 6/7 doses per week on average, based 
on Cottrell et al who modeled that at least 6/7 doses per week is needed for adequate drug 
concentrations in women. The PK testing laboratory will provide sites with a drug level result and 
reference ranges as it relates to the categorized level of adherence to use during adherence 
counselling sessions (24). The reference ranges will include approximately three adherence 
categories, aligned with other similar studies in the field. For example, excellent adherence 
(equivalent to six to seven doses per week), good adherence with room for improvement (four to 
five doses per week), poor adherence (one to three doses per week), and not taking any doses 
(undetected TFV-DP levels). 
 
If in the PK Component, TFV-DP variability at Week 12 appears high, this will be discussed 
among the CMC. For example, the team will decide if the threshold corresponding to adequate 
adherence should be set at the median or a different percentile instead of the 25th percentile.  
 
In addition, antepartum and postpartum TFV-DP concentration thresholds corresponding to 
“excellent adherence” and the adherence categories for Weeks 4, 8 of the PrEP Comparison 
Component will be derived using the methods described above but from the distributions 
observed at Weeks 4 and 8 of the PK Component. For additional details on PK data analysis 
please refer to Section 10.2. 
 
9.1.7 
Decision to open PrEP Comparison Component 
 
The CMC will use the PK data (see Section 9.1.6) and monitoring reports (see Section 9.1.5) to 
come to a decision regarding whether PK Component data are sufficient to recommend opening 
the PrEP Comparison Component. The CMC will then convene to review the matrix and present 
the decision to the SMC whether or not to open enrollment to the PrEP Comparison Component 
according to Table 4. The decision will be communicated to study staff by way of a notification 
which will include detail of the adherence target identified in the PK Component. 
 
Table 4: Criteria to open enrollment to the PrEP Comparison Component 
 
Acceptable 
Requires CMC review group 
discussion 
Evaluable Maternal 
Participants 
15 or more in each Group in the PK 
Component who meet the evaluability 
criteria set out in Section 9.1.1 
14 or less in any Group in the PK 
Component who meet the evaluability 
criteria set out in Section 9.1.1 
PK Assay 
15 or more maternal participants in 
each Group in the PK Component with 
valid and complete TVF-DP 
concentration data 
 
Css 
Distribution of steady state 
concentration data available 
 
Target Threshold 
Defined for both Groups in the PK 
Component  
Not defined or defined for only one 
Group in the PK Component 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 89 of 173 
 
  
   
 
19 November 2020 
9.2 
PrEP Comparison Component 
 
Primary outcome measures listed 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 manuscript and results reporting to ClinicalTrials.gov. 
Outcomes of interest for additional objectives intended for subsequent publications are listed 
under “Other” and “Exploratory” Outcome Measures.  
 
9.2.1 
General Design Issues: PrEP Comparison Component 
 
The IMPAACT 2009 PrEP Comparison Component is a prospective non-randomized open label 
study. The objectives are to 1) estimate and describe PrEP adherence during pregnancy and post-
partum among HIV-uninfected adolescent and young adult women (aged 16-24 years) who 
initiate once-daily FTC/TDF in pregnancy and are followed through 26 weeks postpartum when 
offered adherence support through mobile technology and drug level-directed counseling 2) 
compare maternal and infant adverse events (including pregnancy outcomes) at delivery and 
Week 26 postpartum between women who initiate PrEP and women who decline PrEP over the 
observation period but receive HIV risk reduction and SMS interventions.  
 
Two important design issues regarding the PrEP Comparison Component are as follows: 1) 
Assignment to each of the two cohorts is determined by maternal participant choice rather than by 
randomization. The team agreed that it would be unethical to deny women at high risk of 
acquiring HIV infection the opportunity to use PrEP, given the mounting evidence that PrEP use 
is an HIV prevention strategy with proven effectiveness. Due to the non-randomized design, 
potential confounders of the association between PrEP use and adverse pregnancy or safety 
outcomes may be distributed differently in the two groups, introducing bias. For example, HIV-
uninfected women in serodiscordant relationships may be more willing to initiate PrEP and may 
also be at higher risk of adverse pregnancy outcomes than women with partners of known HIV-
uninfected status. To address the first challenge, potential confounders at entry and follow up will 
be measured and adjusted for in multivariable models. An important limitation is that particularly 
for endpoints with low event rates, the small sample size will limit the number of confounders 
that can be included in multivariable models. 2) A second important design issue is that statistical 
power is limited for making conclusions regarding the safety of PrEP in pregnancy or postpartum. 
This study will yield estimates of the incidence and prevalence of selected safety outcomes in 
each of the two groups, with 95% confidence intervals for descriptive purposes. The study allows 
adequate power to detect large cohort differences, depending on the true background rate of the 
event. 
 
9.2.2 
Outcome Measures: PrEP Comparison Component 
 
9.2.2.1 Primary Outcome Measures 
 
Table 5 summarizes the primary outcome measures for each study objective of the PrEP 
Comparison Component: 
 
 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 90 of 173 
 
  
   
 
19 November 2020 
Table 5: Primary Outcome Measures – PrEP Comparison Component 
Primary Outcome Measures – PrEP Comparison Component 
Objective 
Outcome Measures 
2.3.1 
PrEP adherence: TFV-DP drug concentration level in Dried Blood Spots (DBS)  
2.3.2 
Maternal Adverse Events:  
• 
Maternal Grade 3 or higher adverse events (signs, symptoms, labs, and diagnoses) 
• 
Maternal Grade 2 or higher chemistry abnormalities  
2.3.2 
Adverse Pregnancy Outcomes:  
Composite outcome of  
• 
Spontaneous abortion (occurring at <20 weeks gestation) 
• 
Stillbirth (occurring at ≥20 weeks gestation) 
• 
Preterm delivery (<37 completed weeks’ gestation) 
• 
Small for gestational age (<10th percentile using INTERGROWTH-21st norms and 
ultrasound derived gestational age at delivery) 
Infant Safety: 
• 
Infant death within the first 26 weeks of life 
• 
Infant Grade 3 or higher adverse events (signs, symptoms, labs, diagnoses) reported 
between birth and exit 
• 
Infant bone mineral content based on DXA scan of the whole body (WB-BMC) at birth and 
lumbar spine (LS-BMC) at birth and 26 weeks postpartum  
• 
Infant creatinine and CrCl rate at birth and 26 weeks postpartum 
• 
Infant length for age z-score at birth and exit 
 
9.2.2.2 Other Outcome Measures 
 
Table 6 summarizes the other outcome measures for each study objective of the PrEP 
Comparison Component: 
 
Table 6: Other Outcome Measures – PrEP Comparison Component  
Other Measures – PrEP Comparison Component 
Objective 
Outcome Measure 
2.4.1 
PrEP adherence: TFV-DP drug concentration level in DBS 
2.4.2 
Sexual risk behavior  
• 
Any condomless vaginal or anal sex  
• 
Incident sexually transmitted infection defined as any new HSV, syphilis, chlamydia or 
gonorrhea infections during follow-up 
• 
Incident HIV infection 
2.4.3 
• 
Antiretroviral drug resistance: presence of virus resistant to TDF at time of HIV diagnosis 
2.4.4 
Bone mineral density – Mean maternal bone mineral density (g/m2) based on DXA scan of the 
lumbar spine (LS-BMD) and hip (H-BMD) at delivery and 26 weeks postpartum 
 
 
 
 
 
 
 
 
 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 91 of 173 
 
  
   
 
19 November 2020 
9.2.2.3 Exploratory Outcome Measures 
 
Table 7 summarizes the exploratory outcome measures for each study objective of the PrEP 
Comparison Component: 
 
Table 7: Exploratory Outcome Measures – PrEP Comparison Component 
Exploratory Outcome Measures – PrEP Comparison Component 
Objective 
Outcome Measures 
2.5.1 
Microbiome – PrEP or no PrEP exposure 
• 
Compare the maternal vaginal/rectal microbiome, differences in diversity (continuous), 
bacterial composition (continuous) and relationship to blood and cervicovaginal drug levels 
(continuous) longitudinally at study entry, late pregnancy, six weeks post-partum and 26 weeks 
post-partum 
• 
Compare the infant microbiome differences in diversity and bacterial composition initially at six 
weeks post-partum and 26 weeks post-partum 
 
9.2.3 
Randomization and Stratification 
 
There will be no randomization for this study. To monitor the balance of the maternal participants 
enrolled among various groups, the enrollment will be stratified by: 
 
• 
Cohort: PrEP vs. No PrEP at enrollment 
• 
Trimester of enrollment during pregnancy: 2nd trimester vs. 3rd trimester 
• 
Country 
• 
Age at enrollment: 16-17 years vs. 18 years of age and older 
 
Stratifying by the above factors in this non-randomized study is for the purpose of monitoring 
the accrual to ensure that there are not large differences between the two cohorts (PrEP and No 
PrEP) in the proportion of women who are 16-17 years old, who are from a specific country, or 
who enroll in the 2nd (vs. 3rd) trimester of pregnancy, and to ensure a proportion of enrolled 
women are in the 16-17 year old age group. 
 
9.2.4 
Sample Size and Accrual 
 
The PrEP Comparison Component will enroll a total of 350 (233 in Cohort 1 and 117 in Cohort 
2) women over a 12-month period. Women will be followed through 26 weeks postpartum. 
Expected duration of follow-up for a given maternal participant is between 7 and 12 months 
depending on the gestational age of the pregnancy at enrollment. The following sample size and 
power calculations assume a final analysis sample of 300 women (200 in Cohort 1 and 100 in 
Cohort 2). The primary reason for the 2:1 enrollment into the two cohorts was to balance the need 
for a “No PrEP” comparison group (to provide the background rates for safety outcome 
measures) with the need for a large enough PrEP group to examine outcomes that would be 
restricted to women in that group (Adherence). To achieve this sample size at the analysis phase, 
this study will enroll ~350 women to accommodate a decrease of ~15% due to maternal attrition. 
 
Table 8 shows the expected precision of a range of PrEP adherence estimates across different 
sample sizes in Cohort 1. For example, with a sample size of 200 women in Cohort 1, the width 
of the 95% confidence interval for an estimated adherence rate of 75% is 13%.  
 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 92 of 173 
 
  
   
 
19 November 2020 
Table 8: Precision (shown as 2-sided 95% confidence intervals) of different estimates of the 
proportion with good adherence (for illustration, defined as meeting or exceeding the threshold 
corresponding to protective drug levels of TFV-DP) at different sample sizes for Cohort 1. 
Sample Size in Cohort 1  
% Adherent  
150 
200 
250 
300 
50 
42-58% 
43-57% 
44-56% 
44-56% 
60 
52-68% 
53-67% 
54-66% 
54-66% 
65 
57-73% 
58-72% 
59-71% 
59-70% 
70 
62-77% 
63-76% 
64-76% 
65-75% 
75 
67-82% 
68-81% 
69-80% 
70-80% 
80 
73-82% 
74-85% 
75-85% 
75-84% 
 
Table 9 below shows the precision of estimates of safety outcomes (e.g. preterm birth) expected 
with a range of event rates and a sample size of 200 women in Cohort 1 and 100 women in 
Cohort 2. It is expected that the rates of these outcomes will be low particularly since this is a 
young group of healthy HIV uninfected women. To that end, a range of AE rates with 
corresponding confidence intervals is included in the protocol. 
 
Table 9: 95% Confidence Intervals for different possible event rates of safety outcomes in Cohort 1 (n=200) 
and Cohort 2 (n=100) 
Event Rate 
95% Confidence Interval 
Cohort 1 (n=200) 
95% Confidence Interval 
Cohort 2 (n=100) 
0.5% 
(0, 2.8) 
(0, 3.6) 
2.0% 
(0.5, 5.0) 
(0.2, 7.0) 
4.0% 
(1.7, 7.7) 
(1.1, 9.9) 
10.0% 
(6.2, 15.0) 
(4.9, 17.6) 
15.0% 
(10.4, 20.7) 
(8.6, 23.5) 
20.0% 
(14.7, 26.2) 
(12.7, 29.2) 
30.0% 
(23.7, 36.9) 
(21.2, 40.0) 
 
The study allows adequate power to detect moderate cohort differences from 8.5% to 16%, 
depending on the true background rate of the event, as summarized below in Table 10. The table 
shows minimum detectable differences in safety outcomes between Cohort 1 and Cohort 2 which 
could be achieved with 80% power and alpha=0.05. For example, based on a sample size of 200 
in Cohort 1, and assuming a 2:1 enrollment among women agreeing to and declining PrEP, 
differences of at least 13% will be detectable between the two cohorts in the proportion of 
maternal adverse events for events with a 10% background rate (10% in Cohort 2, 23% in Cohort 
1).  
 
Table 10: Minimum detectable differences in safety outcomes based on evaluable sample size of 300 for 
Cohort 1(n=200) and Cohort 2 (n=100), 80% power, alpha=0.05 
% with event in Cohort 2 (N=100) 
% with event in Cohort 1 (N=200) 
Odds Ratio 
2% 
10.5% 
5.8 
5% 
15.6% 
3.5 
10% 
23% 
2.67 
15% 
29% 
2.36 
20% 
35% 
2.19 
25% 
41% 
2.10 
 
 
To address primary objective 2.3.2, the mean bone mineral content of infants at birth and at age 
26 weeks will be estimated and differences in mean bone mineral content between infants in 
Cohort 1 and Cohort 2 will be evaluated using two sample t tests. Table 11 shows the statistical 


 
IMPAACT 2009, FINAL Version 3.0 
Page 93 of 173 
 
  
   
 
19 November 2020 
power the study would have to detect a range of estimated differences in means. For example, 
with a sample size of 200 in Cohort 1 and 100 in Cohort 2 this study will be able to detect 
differences in mean bone mineral content of at least 0.35 SD with 80% power. Based on the 
SMARTT study in the U.S., assuming a standard deviation of 16.6 (77) this would be equivalent 
to a difference in means of 5.81g. Assuming a standard deviation of 14.9 found in the P1084s 
study (79) this would be equivalent to a difference in means of 5.22 g. 
 
Table 11: Estimated Power to Detect the Mean Differences in Infant Growth Outcomes 
Infant DXA, Whole Body Bone Mineral Content (BMC) (g) at Birth (Mean=63.8, SD=16.6)** 
Difference to be Detected 
Effect Size (SD) 
Power (based on sample sizes*) 
N1=200 
N2=100 
N1=180 N2=90 
N1=160 N2=80 
4% (of 63.8) 
2.55 (16.6) 
24% 
22% 
20% 
5% 
3.19 
35% 
32% 
29% 
6% 
3.83 
47% 
43% 
39% 
7% 
4.47 
59% 
55% 
50% 
8% 
5.10 
71% 
66% 
61% 
9% 
5.74 
80% 
76% 
71% 
10% 
6.38 
88% 
84% 
80% 
0.25*SD 
4.15 
53% 
49% 
44% 
0.30*SD 
4.98 
68% 
64% 
59% 
0.35*SD 
5.81 
81% 
77% 
72% 
0.40*SD 
6.64 
90% 
87% 
83% 
0.45*SD 
7.47 
96% 
94% 
91% 
0.50*SD 
8.30 
98% 
97% 
95% 
0.75*SD 
12.45 
> 99% 
> 99% 
> 99% 
*Sample Sizes:  N1 -- Cohort 1 (PrEP), N2 – Cohort 2 (no PrEP)  
**Data were from PHACS SMARTT Study (Siberry, 2015) 
 
To address other objective 2.4.4, the mean bone mineral density of the lumbar spine and of the 
hip of women at delivery and at 26 weeks post-delivery will be estimated and differences in mean 
bone mineral density between women in Cohort 1 and Cohort 2 will be evaluated using two 
sample t tests. Table 12 shows estimated statistical power to detect a range in differences in mean 
maternal bone mineral density that the study could detect given different sample sizes. For 
example, with a sample size of 300 (200 PrEP and 100 no PrEP) the study would have at least 
80% power to detect a minimum 4% difference in mean BMD and .35 SD difference in means 
between groups at delivery and 26 weeks postpartum. 
 
 
 
 
 
 
 
 
 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 94 of 173 
 
  
   
 
19 November 2020 
Table 12: Estimated Power to Detect the Mean Differences in Maternal Growth Outcomes 
Maternal DXA, Whole Body Bone Mineral Content (BMC) (g)  
(Mean=0.979, SD=0.111)** 
BMD 
Difference to be 
Detected 
Effect Size (SD*) 
Power (based on sample sizes**) 
N1=200 
N2=100 
N1=180 
N2=90 
N1=160 N2=80 
Lumbar 
Spine 
1% (of 0.979*) 
0.0098 (0.111*) 
11% 
10% 
10% 
2% 
0.0196 
30% 
28% 
25% 
3% 
0.0294 
58% 
53% 
49% 
4% 
0.0392 
82% 
78% 
73% 
5% 
0.0490 
95% 
93% 
89% 
6% 
0.0587 
99% 
98% 
97% 
0.10*SD 
0.0111 
13% 
12% 
11% 
0.15*SD 
0.0167 
23% 
21% 
19% 
0.20*SD 
0.0222 
37% 
34% 
31% 
0.25*SD 
0.0278 
53% 
49% 
44% 
0.30*SD 
0.0333 
69% 
64% 
59% 
0.35*SD 
0.0389 
81% 
77% 
72% 
0.40*SD 
0.0444 
90% 
87% 
83% 
Total Hip 
1% (of 0.968*) 
0.0097 (0.119*) 
10% 
10% 
9% 
2% 
0.0194 
26% 
24% 
22% 
3% 
0.0290 
51% 
47% 
43% 
4% 
0.0387 
75% 
71% 
66% 
5% 
0.0484 
91% 
88% 
84% 
6% 
0.0581 
98% 
97% 
94% 
0.10*SD 
0.0119 
13% 
12% 
11% 
0.15*SD 
0.0179 
23% 
21% 
19% 
0.20*SD 
0.0238 
37% 
34% 
31% 
0.25*SD 
0.0298 
53% 
49% 
44% 
0.30*SD 
0.0357 
68% 
64% 
59% 
0.35*SD 
0.0417 
81% 
77% 
72% 
0.40*SD 
0.0476 
90% 
87% 
83% 
*Data were from JAIDS (Mirembe, 2015): mean (SD) =0.979 (0.111) for lumbar spine; mean (SD) = 0.968 (0.119) for 
total hip. 
**Sample Sizes: N1 -- PrEP Arm, N2 -- non-PrEP Arm 
 
 
 
9.2.5 
Monitoring – PrEP Comparison Component 
 
Since this study is not randomized, some potential concerns are differential enrollment into the 
two cohorts, either by country, gestational period of enrollment, or in the proportion of women in 
the youngest age group (16-17 years old). Large differences in cohort enrollment – by country, 
age or by gestational period of enrollment could introduce bias or make some analyses no longer 
feasible. To manage those potential risks, the balance between Cohorts 1 and 2 during enrollment 
at each site will be monitored by the CMC and active measures undertaken to minimize such 
biases. The accruals and updated status of women in Cohort 1 and Cohort 2 will be closely 
monitored and reported regularly to participating sites for each site and across all sites to guide 


 
IMPAACT 2009, FINAL Version 3.0 
Page 95 of 173 
 
  
   
 
19 November 2020 
the recruitment strategies. If the CMC observes significant divergence between cohorts in these 
enrollment characteristics then the team will discuss and agree on plans for notifying sites to 
adopt remedial measures, which may include curtailing enrollment to the Cohort more commonly 
chosen while enrollment into the other Cohort proceeds.  
 
9.2.6 
Analyses-PrEP Comparison Component 
 
The primary analyses to address the objectives of the PrEP Comparison Component are outlined 
below. For a more detailed description of the analyses to be conducted, please refer to the 
Statistical Analysis Plan. 
 
Descriptive summaries: 
 
Entry demographic, pregnancy, pregnancy history, psychosocial, sexual behavior and partner 
characteristics of women in Cohort 1 and women in Cohort 2 will be summarized and compared 
using chi square tests (or Fishers exact test as appropriate) for discrete variables and t tests or 
Wilcoxon rank sum tests for continuous variables. Logistic regression models will be fit to 
identify predictors of PrEP initiation. 
 
Primary Objective 2.3.1: 
 
• 
Women in Cohort 1 will comprise the analysis sample. A binary indicator, “optimal 
adherence” will be created, as defined above as TFV-DP levels in DBS meeting or exceeding 
the threshold determined in the PK Component as corresponding to protective levels of PrEP 
(24). At each visit that TFV-DP levels are obtained (see Appendix IIA), the proportion of 
women with optimal adherence will be calculated based on their TFV-DP levels at each visit. 
The proportion of visits with optimal adherence in the pregnancy vs. postpartum periods will 
be calculated and compared.  
 
• 
Exploratory analyses identifying baseline and time-varying predictors of optimal adherence 
will be conducted with multivariable regression models using generalized estimating 
equations with a logistic link (to account for repeated measures across time for each 
participant).  
 
• 
Adherence (as measured in TFV-DP levels) will also be summarized as a continuous outcome 
(median, IQR and mean [SD]) at each time point noted above when drug levels are measured, 
and “average” adherence across pregnancy and postpartum periods, will be calculated, using 
generalized estimating equations. We will focus on periods during which the participant has 
fomally elected to be on PrEP. If a woman elects to formally stop PrEP (by notifying study 
personnel), periods of being formally off study drug will not be considered in adherence 
calculations. 
 
• 
Other approaches to summarizing the adherence outcome will be considered. This includes an 
ordinal variable with categories corresponding to different dosing levels. For this type of 
outcome, at each visit that drug levels are measured in DBS, descriptive analyses will 
summarize the proportion of women in each adherence category, refer to categories discussed 
in Section 9.1.6.  
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 96 of 173 
 
  
   
 
19 November 2020 
• 
Baseline characteristics, and patterns of adherence and duration on PrEP will be summarized 
separately for women in Cohort 2 who later decide to initiate PrEP using the approaches 
outlined above. 
 
• 
The following additional descriptive statistics will be calculated: The proportion of women a) 
with at least one visit with TFV-DP levels corresponding to optimal adherence, b) who had 
TFV-DP levels corresponding to optimal adherence at all visits, c) who had no detectable 
TFV-DP levels at any visit.  
 
Primary Objective 2.3.2: 
 
Analyses of adverse pregnancy outcomes: The proportion of women in Cohort 1 and Cohort 2 
with adverse pregnancy outcomes (a composite indicator defined as at least one of the following: 
spontaneous abortion (occurring at <20 weeks gestation), stillbirth (occurring at ≥20 weeks 
gestation), preterm delivery (<37 completed weeks gestation), or small for gestational age (<10th 
percentile using INTERGROWTH-21st norms and ultrasound (US)- derived gestational age at 
delivery) will be estimated and compared. Univariable and multivariable logistic regression 
methods will be used to evaluate associations of PrEP use and the composite outcome indicating 
presence vs. absence of any adverse pregnancy outcomes, controlling for potential confounders. 
The same analyses will be conducted for each of the pregnancy outcomes which comprise the 
composite outcome separately. 
 
Analyses of maternal adverse events and infant adverse events: Cumulative rates of maternal 
adverse events and infant adverse events will be compared, respectively, in Cohort 1 and Cohort 
2. Where appropriate, there will be stratification according to time period (i.e., antepartum (AP) 
and postpartum (PP), and within AP by gestational age category of enrollment). Maternal adverse 
events will be considered separately from infant adverse events. Cox proportional hazards 
regression will be used to evaluate differences in the rate of adverse events in the two cohorts. For 
the maternal adverse events, among women in Cohort 1, person time will begin accruing when 
PrEP is initiated and for women in Cohort 2 it will begin accruing after study entry. Rates of 
maternal and infant adverse events in AP and PP periods will also be calculated and compared 
across levels of PrEP adherence (based on TFV-DP levels in DBS). Models will be fit adjusting 
for potential confounders. 
 
Analyses of infant safety outcomes re: bone health and creatinine clearance: To address Primary 
Objective 2.3.2, to evaluate infant safety outcomes, (CrCl measured by Schwartz equation at birth 
and 26 weeks anthropometric growth measures at birth and 26 weeks, bone mineral content 
measured by dual energy X-ray absorptiometry (DXA) at birth and 26 weeks), mean length-for-
age z-scores for the growth parameters and mean grams for BMC will be calculated, and means 
will be compared between infants in Cohort 1 and infants in Cohort 2 using two sample t-tests at 
each time point of evaluation. If normality assumptions are not met the Wilcoxon Rank Sum test 
will be used to evaluate differences in these endpoints by Cohort. 
 
Other Objective 2.4.1: 
 
Exploratory analyses will be conducted to identify individual, social, and structural barriers and 
facilitators to PrEP uptake during pregnancy, and to adherence and continued use during 
pregnancy and breastfeeding. Women in both cohorts (Cohort 1 and Cohort 2) will be included in 
analyses of predictors of PrEP uptake at enrollment. Logistic regression methods will be used to 
evaluate univariate and multivariate associations of baseline demographic, psychosocial, sexual 
behavior and partner characteristics noted below with PrEP uptake and adherence. 


 
IMPAACT 2009, FINAL Version 3.0 
Page 97 of 173 
 
  
   
 
19 November 2020 
Primary Covariates and Potential Confounders: 
 
Behavioral and Contextual Factors (both cohorts) 
demographic, psychosocial, sexual behavior and partner characteristics  
 
• 
Sociodemographic characteristics 
o Current living situation 
o Household composition 
o Private space for product storage 
• 
HIV risk perception for mother and infant 
• 
HIV stigma  
• 
PrEP stigma 
• 
Sexual behaviors 
• 
Substance use 
• 
Mental health and post-traumatic stress symptoms 
• 
Disclosure to peers, family members, teachers, and partner(s) about PrEP use and 
participation in the study  
• 
Gender-based violence (GBV) 
• 
Partnership characteristics: partner’s HIV status  
 
To evaluate factors associated with PrEP use, a similar approach will be used, but analyses will 
be restricted to Cohort 1 with the binary indicator of “optimal adherence” (based on TFV-DP 
levels) as the outcome. 
 
To complement both exploratory analyses described above, key themes will be summarized from 
the qualitative data regarding how aspects of PrEP, women’s perception of risk, the context of 
pregnancy, and interpersonal and structural influences contribute to PrEP uptake, use, and 
discontinuation. Additional details regarding the qualitative data analysis are at the end of this 
analysis section. 
 
Other Objective 2.4.2: 
 
Analyses to address this objective will include women in Cohort 1 and women in Cohort 2 in the 
analysis sample. Estimates of the proportion of women (at each visit) reporting condomless 
vaginal or anal sex at each visit that it is measured, and the proportion of visits with condomless 
vaginal or anal sex during pregnancy and during the postpartum period will be compared between 
Cohort 1 and Cohort 2 using chi square tests. To evaluate the association of Cohort (Cohort 1 vs. 
Cohort 2) with sexual risk behavior, GEE models will be fit, including adjustment for 
sociodemographic and behavioral factors that could confound the association of Cohort with risky 
sexual behavior. Cox regression methods will be used to estimate and compare the incidence rates 
of STIs in the antepartum period, the postpartum period, and throughout the study, among women 
with no STIs at enrollment in Cohort 1 and Cohort 2, adjusting for baseline confounders. 
Cox regression methods will be used to estimate and compare HIV incidence rates in pregnant 
and breastfeeding women who have initiated PrEP, in comparison to women who decline PrEP 
during the antenatal period. 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 98 of 173 
 
  
   
 
19 November 2020 
Other Objective 2.4.3: 
 
Among women and infants who acquire HIV infection, the proportion with antiretroviral drug 
resistance to FTC/TDF-at the time of HIV diagnosis will be calculated. In addition, testing of 
entry specimens will be performed to see if resistance was transmitted or selected by the study 
drugs. 
 
Other Objective 2.4.4: 
 
Student t tests will be used to compare the mean maternal bone mineral density of the lumbar 
spine and of the hip for Cohort 1 and Cohort 2 at delivery and week 26 post-delivery. 
 
Exploratory Objective 2.5.1: 
 
The distribution of maternal microbiome parameters in the PrEP and no PrEP groups will be 
described at the maternal (vaginal, gut) and infant (gut) sites. The changes in these parameters 
from entry to delivery will be evaluated according to PrEP use, and the relationship between 
vaginal microbiota and drug (PrEP) levels via univariate and multivariate regression models will 
be assessed. The potential effect of other factors, including recent antibiotic use, contraception 
use (including methods), and mode of delivery (i.e., vaginal vs. Caesarean delivery) will also be 
assessed. 
 
Qualitative Analysis 
 
All interviews will be audio-recorded and transcribed and translated into English by trained staff 
at each respective study site. Qualitative interviewers will also complete a debriefing summary 
report to facilitate more rapid “real-time” summary and analysis of qualitative data prior to formal 
analysis of interview transcripts. Quality assurance of each transcript will be conducted at the site 
level and centrally (across sites), by listening to the digital recordings, comparing the content to 
that in the transcriptions, noting the tone of the maternal participant when appropriate, and 
making appropriate corrections. Sites will also be responsible for ensuring that transcriptions are 
appropriately stripped of identifying information before they are transmitted to the DMC. 
 
A team composed of study staff and Protocol Team members with expertise in qualitative 
research will code and analyze the qualitative data using Atlas-ti or a comparable analysis 
software package. Since this study seeks to learn about the range of factors that impact young 
women’s uptake of and adherence to PrEP, the qualitative analysis will utilize a psychological 
phenomenological framework. Phenomenology is specifically focused on describing what a given 
group of people have in common as they experience a particular phenomenon, and it is an 
inductive analytic approach that allows the patterns, themes, and categories of analysis to emerge 
from the data (63, 174). Given that influences on PrEP uptake may be different from influences 
on PrEP adherence, PrEP uptake and adherence among pregnant and post-partum women as 
separate (but related) phenomena will be investigated. 
 
Data coding and analysis will be both iterative and interactive processes. The analysis team will 
first read all interview transcripts to increase familiarity with the data. Next, the team will assign 
a priori codes and create emergent codes. Transcripts will then be re-read to create pattern codes 
that connect subsequent concepts under larger headings. Consistent patterns in meaning, 
concepts, and themes across all interviews will be identified, and data matrices will be created as 
visual representations of the findings. Comparative analyses will be conducted to clarify 
differences that may exist for any subgroups of young women. Coding and analytic activities will 


 
IMPAACT 2009, FINAL Version 3.0 
Page 99 of 173 
 
  
   
 
19 November 2020 
be discussed during qualitative data analysis meetings, and discrepancies in coding and 
interpretation will be resolved through consensus.  
 
9.3 
Monitoring 
 
Implementation of this study will be monitored at multiple levels, consistent with standard 
IMPAACT procedures. A Study Progress, Safety, and Data Monitoring Plan (SPDSMP) that 
details monitoring roles and responsibilities and data to be reviewed at each level will be prepared 
before the study opens to accrual. Please refer to Sections 11 and 12 for 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 across sites is provided below. 
 
9.3.1 
Monitoring by the Protocol Team 
 
The Protocol Team is responsible for continuous monitoring of study progress, including timely 
achievement of key milestones, and the quality of study conduct. As indicated in Sections 4.4 and 
4.5, the Protocol Team will closely monitor participant accrual and retention based on reports that 
will be generated at least monthly by the SDMC. If accrual or retention rates fall below target, 
team members will work with study sites to identify operational issues or problems and to take 
appropriate action to address below-target rates.  
 
Team members will similarly review other key indicators of the quality of study conduct (e.g., 
endpoint evaluability, data quality and completeness) based on reports generated by the SDMC 
and take action with study sites as needed to ensure high quality study conduct throughout the 
period of study implementation. As indicated in Section 5.1.1.1 the site staff will actively monitor 
the documentation of doses taken throughout the data collection period for the PK Component 
only. If the site staff identifies a participant having missed more than three consecutive doses, the 
Protocol Team will review the participant’s data to determine if the participant may be considered 
evaluable. 
 
9.3.2 
Participant Safety 
 
On behalf of the Protocol Team, the CMC will closely monitor participant safety through routine 
review of safety data reports generated by the SDMC. These reports will provide tabulations of 
adverse events (defined in Section 8.1) and social harms (refer to Sections 7.2 and 13.6) identified 
in enrolled participants, including abnormal laboratory test results, signs, symptoms, and 
diagnoses, pooled across arms. Further detail will be provided in the SPDSMP. The CMC will 
review these reports via conference call or other meeting at least monthly. Prior to each call, the 
DAIDS Medical Officer will review any AEs ≥Grade 3 and EAEs (defined in Section 7.3) 
reported to the DAIDS Safety Office that are not yet reflected in the data reports. The CMC will 
continually evaluate the pattern and frequency of reported events and assess for any individual 
occurrences or trends of concern. 
 
9.3.3 
Monitoring by the SMC 
 
An independent IMPAACT Study Monitoring Committee (SMC) will review this study regularly, 
following policies described in the IMPAACT Manual of Procedures. The composition of the 
SMC will include the SMC Chair; IMPAACT Chair or Vice-Chair; IMPAACT Prevention 
Scientific representative; representatives of the IMPAACT Operations Center and Statistical and 
Data Management Center; and representatives of NIAID and NICHD.  


 
IMPAACT 2009, FINAL Version 3.0 
Page 100 of 173 
 
  
   
 
19 November 2020 
 
SMC reviews will occur at least annually and on a more frequent or ad hoc basis if any safety 
issues or concerns arise. Ad hoc reviews may also be triggered per the safety monitoring 
guidelines specified below. Based on any of its reviews, the SMC may recommend that the study 
proceed as currently designed, proceed with design modifications, or be discontinued. The SMC 
may also provide operational recommendations to help address any study implementation 
challenges that may be identified during their reviews.  
 
The SMC will monitor study progress, quality of study conduct, and participant safety. The SMC 
will generally review the same types of data reports as the Protocol Team and CMC. For ad hoc 
or triggered safety reviews, more limited data may be reviewed, focusing on the events that 
triggered the reviews.  
 
Adverse events in both groups and proportion of women with Week 12 TFV-DP drug levels 
below the limit of quantification in Cohort 1 (as well as decisions to initiate PrEP later in the 
study among women in Cohort 2) will be monitored and summaries prepared at regular intervals 
for review by the SMC. 
 
The following events will trigger a SMC review. These events and further details will be 
described in the SPDSMP. 
 
Transition from PK Component to PrEP Comparison Component: Following completion of the 
PK Component, the CMC reviewed data from the PK Component (see Section 1.3.4), determined 
that the criteria outlined in protocol Section 9.1.7 had been met, and provided a recommendation 
to proceed to the PrEP Comparison Component to the SMC. The SMC reviewed the 
recommendation, which included the recommended TFV-DP threshold for adherence monitoring, 
and after consulting with the IMPAACT Scientific Leadership Group and convening reviews of 
the PK Component data by an independent PK Panel and independent Ethics review panel, 
determined that the protocol may begin enrollment into the PrEP Comparison Component. 
 
PrEP Comparison Component:  
 
• 
Monitoring the proportion of women in Cohort 1 without quantifiable levels of TFV-DP 
at Week 12 (excluding women who have decided to stop PrEP): 
o At any site, if this proportion at Week 12 is greater than 40% after 15 maternal 
participants in Cohort 1 have completed that study visit, the CMC will review the 
data and consult with site investigators, and make a recommendation to the SMC 
regarding the need for remedial actions or discontinuation of enrollment at the 
site. The SMC will convene to consider the CMC’s recommendation.  
• 
Monitoring participant safety outcomes (for women or infants in Cohort 1 and Cohort 2, 
Step 2). Ad hoc SMC reviews will be convened:   
o If the proportion of women experiencing Grade 3 or higher adverse events is 
greater than 15%, after 50 women have been enrolled  
o If the rate of adverse pregnancy outcomes is greater than 20%, after 25% of 
pregnancies have been completed.  
o If the proportion of livebirth infants experiencing Grade 3 or higher adverse 
events is greater than 15%, after 50 completed pregnancies resulting in live 
births. 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 101 of 173 
 
  
   
 
19 November 2020 
Please refer to the SPDSMP for further details regarding the above conditions that would meet 
criteria for triggering an additional SMC review. The SMC will convene as part of its standard 
regularly scheduled review to review data from the PrEP Comparison Component. 
 
10 
CLINICAL PHARMACOLOGY PLAN 
 
10.1 
Pharmacology Overview and Objectives 
 
PK Component: The primary objective is to determine TFV-DP thresholds associated with 
optimal adherence to FTC/TDF among women who initiate PrEP during pregnancy and 
postpartum. 
 
PrEP Comparison Component: The primary objective is to determine TFV-DP to assess 
adherence to FTC/TDF among women who initiate PrEP. 
 
10.2 
Study Design, Modeling and Data Analysis  
 
PK Component:  
 
All maternal participants will be administered once daily FTC/TDF. All doses will be DOT for 
the 12-week duration. DBS specimens will be collected at weekly intervals for analysis. 
 
The goal is to quantify steady state TFV-DP in DBS. Css (drug concentration at steady state) will 
be determined by visual inspection of the plateauing of concentrations on the concentration time 
curve. Additionally, the following expression will be fit to the concentration time data, 
Ct=Css*(1-e-K*t), where Ct is the drug concentration at time t, Css is the fitted steady state drug 
concentration, K is the fitted first-order elimination rate constant. Half-life will be determined as 
ln(2)/K. This model assumes first-order pharmacokinetics, which appears to be followed by TFV-
DP in DBS (175). In addition, all available drug concentration samples will be utilized in a 
population pharmacokinetic model, thereby accounting for possible non-linearity and missed 
doses due to protocol deviations. Predicted Css from modeling will be subjected to the same 
analyses as above. 
 
PrEP Comparison Component:  
 
All maternal participants will be prescribed once daily FTC/TDF. Visits will occur at Weeks 4, 8, 
12 and then every 12 weeks (while pregnant) as well as the time of delivery, and 6, 14, and 26 
weeks post-delivery. At each of these visits DBS specimens will be collected for analysis. 
 
The goal for the PrEP Comparison Component is to use the expected TFV-DP levels in DBS 
from PK Component to define a threshold for optimal adherence. This threshold will be 
incorporated into the study-specific MOP for the PrEP Comparison Component. This threshold 
may be the 25th percentile of six or more doses per week on average, which would be 6/7ths of 
expected level determined in the PK Component. The percentile used (i.e. 25th percentile versus 
median, etc.) will be determined by the CMC team (described above) and will be based upon the 
variability in the TFV-DP concentrations in the PK component.  
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 102 of 173 
 
  
   
 
19 November 2020 
10.2.1 Number of Participants  
 
PK Component:  
 
Approximately 40 women will be enrolled to obtain at least 30 evaluable with 20 who are in 
Group 1, the antepartum period (14-24 weeks of gestation), and 20 in Group 2, the postpartum 
period (6-12 weeks postpartum). 
 
PrEP Comparison Component:  
 
Approximately 350 women will be enrolled to obtain at least 300 evaluable (200 Cohort 1 and 
100 in Cohort 2). 
 
10.2.2 Phlebotomy and PK Sampling 
 
DBS will be collected by spotting EDTA blood from venipuncture (refer to the LPC for 
procedure).  
 
10.2.3  Processing, Handling, and Storage of PK Specimens 
 
Details regarding collection, processing, handling and storage of PK samples will be provided in 
the study-specific LPC.  
 
10.2.4 Laboratory Performing the Assays 
 
It is expected that the University of Cape Town Laboratory will test samples from both the PK 
Component and the PrEP Comparison Component to provide testing consistency between study 
components. In addition, the University of Colorado Antiviral Pharmacology Laboratory will co-
assay approximately 50 samples from the PK Component to provide a quality assurance 
assessment.  
 
11 
DATA HANDLING AND RECORD KEEPING 
 
11.1 
Data Management Responsibilities 
 
As described in Section 4.4, data on screening and enrollment in this study will be collected using 
the DMC Subject Enrollment System.  
 
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 web site referenced in Section 11.2). All DAIDS policies referenced in this 
section are available at:  
https://www.niaid.nih.gov/research/daids-clinical-research-policies-standard-procedures 
 
eCRFs and an eCRF completion guide will be made available to study sites by the DMC. Study 
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 the timeframes specified 


 
IMPAACT 2009, FINAL Version 3.0 
Page 103 of 173 
 
  
   
 
19 November 2020 
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 
www.fstrf.org.  
 
11.2 
Essential and Source Documents and Access to Source Data 
 
All DAIDS policies referenced in this section are available at: 
https://www.niaid.nih.gov/sites/default/files/daids-sourcedocpolicy.pdf. 
 
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.  
 
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 the study drug 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, the FDA, site drug regulatory authorities, site IRBs/ECs, 
OHRP, and other U.S., 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. No study records may be removed to an off-site location or destroyed prior 
to receiving approval from NIAID.  
 
11.3 
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-site-implementation-operations 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 104 of 173 
 
  
   
 
19 November 2020 
12 
CLINICAL SITE MONITORING 
 
Site monitors under contract to NIAID will visit study sites to inspect study facilities and review 
participant study records including consent forms, 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.  
 
13 
HUMAN SUBJECTS PROTECTIONS 
 
13.1 
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 CRF 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. 
 
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 14.2). 
 
13.2 
Vulnerable Participants 
 
The NIH is mandated by law to ensure that pregnant women and children be included in clinical 
research when appropriate (176, 177). This study responds to that mandate and will provide 
clinical research data to inform PrEP guidelines for pregnant and lactating women. Nonetheless, 
the pregnant women, fetuses, and children who take part in this study are considered vulnerable 
participants per the U.S. 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 14.2, 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 


 
IMPAACT 2009, FINAL Version 3.0 
Page 105 of 173 
 
  
   
 
19 November 2020 
site-specific ICFs as needed to accommodate the parental consent requirements associated with 
the IRB/EC determination. 
 
Study sites must comply with the requirements of the DAIDS policy on Enrolling Children 
(including Adolescents) in Clinical Research, which is available at:  
https://www.niaid.nih.gov/sites/default/files/enrollingchildrenrequirements.pdf 
 
13.3 
Informed Consent 
 
Refer to Section 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. 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. 
Maternal participants will be extensively counseled on the importance of obstetrical and newborn 
care, as well as HIV prevention strategies while pregnant and postpartum. 
 
Maternal participants who have reached the legal age of independent informed consent for 
research (typically 18 years of age) are expected to provide written informed consent for their 
own and their infant’s study participation. For maternal participants who have not reached the 
legal age of independent consent, two options may be considered: 
 
• 
Parental consent with participant assent: In this case, (i) the parent or legal guardian of the 
minor maternal participant must provide informed consent for the maternal participant’s and 
her infant’s study participation and (ii) the minor maternal participant must provide written 
assent for her and her infant’s study participation.  
 
• 
Waiver of parental consent: In this case, if site ethical review bodies (IRBs/ECS) provide a 
waiver of parental consent, the minor maternal participant may provide written informed 
consent for her and their infant’s study participation. For this study, IRBs/ECs may find that a 
waiver of parental consent is ethically justified for 16-17 year-old participants, given the 
perceived favorable risk-benefit profile of study participation. If such a waiver is obtained, 
then minors will provide consent and parental or legal guardian consent will not be sought. If 
this were to occur at any site, specific requirements would be developed in collaboration with 
local regulatory authorities and be reflected in the site-specific consent forms. 
 
All sites must establish the SOPs that document the locally-applicable legal age of independent 
informed consent for research, noting whether this age differs for young women who are 
pregnant. Site SOPs must also specify procedures to be followed when obtaining informed 
consent and assent for this study, reflecting all applicable IRB/EC determinations and all other 
IRB/EC requirements. 
 
Sites will adapt the consent forms to clarify for minor participants what information will and will 
not be shared with parents/guardians based on local regulations. Even under a consent/assent 
requirement, minors can consent independently to some procedures in the study depending on 
local laws; for example, minors may be allowed to consent independently to:  
 
• 
Medical treatment, including STI and HIV treatment 


 
IMPAACT 2009, FINAL Version 3.0 
Page 106 of 173 
 
  
   
 
19 November 2020 
• 
Contraceptives access and contraceptive advice and information, including emergency 
contraceptives 
• 
Pregnancy testing and counseling. 
 
In accordance with the DAIDS policy on Enrolling Children (including Adolescents) in Clinical 
Research (available at the website referenced in Section 13.2), all study 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.  
 
13.4 
Potential Benefits 
 
For all participants, the services provided to support antenatal and early newborn care may result 
in improved health-seeking behaviors. Those who initiate and adhere to daily oral PrEP could 
have the benefit of reduced HIV acquisition. From a broader perspective, however, the 
information learned from this study will help program managers and policymakers understand the 
feasibility of this intervention among pregnant, HIV-uninfected women in sub-Saharan Africa.  
 
13.5 
Potential Risks  
 
13.5.1 Venipuncture 
 
Venipuncture is sometimes associated with discomfort. Venipuncture may lead to discomfort, 
dizziness, bruising, swelling, and rarely, an infection at the venipuncture site.  
 
13.5.2 HIV and STI Testing 
 
Site will collect from women vaginal swabs or urine (PrEP Comparison Component only) for 
chlamydia and gonorrhea testing. Maternal participants may become embarrassed, worried, or 
anxious when completing their STI testing, HIV risk assessment and/or receiving HIV 
counseling. They also may become worried or anxious while waiting for their HIV and additional 
STI test results. Individuals who learn that they have an HIV infection or other STI may 
experience anxiety or depression related to their test results. Staff members will be trained to 
provide counseling following these tests, to provide the necessary information for future 
prevention (if negative) or for care and treatment (if positive).  
 
13.5.3 Dual-Energy X-ray Absorptiometry Scan 
 
Bone mineral density is measured by dual-energy x-ray absorptiometry (DXA) which involves 
exposure to radiation. For this protocol, a maternal DXA scan will be conducted for both Cohorts 
in the PrEP Comparison Component per Appendices IIA and IIB for a total radiation exposure of 
up to 1.36 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 two to 
three-day period at sea level (approximately 0.8 mrem per day).  
 
For infant participants in both Cohorts of the PrEP Comparison Component, a DXA scan of the 
whole body is conducted at birth and a DXA scan of the lumbar spine is done at birth and study 
exit. Assuming that up to three attempts may be required to complete scans of the whole body and 
lumbar spine in infants who undergo DXA scans, the total radiation exposure will be a maximum 


 
IMPAACT 2009, FINAL Version 3.0 
Page 107 of 173 
 
  
   
 
19 November 2020 
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 five-
day period at sea level. For both maternal and infant participants, 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). 
 
13.5.4 PrEP (FTC/TDF)  
 
FTC/TDF may have side effects, some of which are listed below. This list includes the more 
serious or common side effects with known or possible relationship. Maternal participants taking 
FTC/TDF will be monitored closely for any side effects, and are asked to report all side effects to 
the study site clinician. Refer to Section 1.3.2 for information of the safety of PrEP during 
pregnancy and breastfeeding.  
 
The following side effects have been commonly associated with the use of FTC/ TDF as 
treatment in HIV-infected adults: 
 
• 
Gastrointestinal intolerance (such as nausea, abdominal pain, diarrhea, or vomiting), most 
commonly in the first month and typically resolves without treatment 
• 
Flatulence (gas), most commonly in the first month and typically resolves without 
treatment 
• 
Headache, dizziness, tiredness, or inability to sleep 
 
Rare, but serious side effects include: 
• 
Rash 
• 
Worsening or new kidney damage 
• 
Bone pain and bone changes such as thinning and softening 
• 
Allergic reaction 
• 
Lactic acidosis (buildup of too much acid in the body). Lactic acidosis can cause shortness 
of breath, nausea and liver failure. 
• 
Depression and unusual dreams have been reported in HIV infected persons taking Truvada 
 
13.5.5 HIV Resistance 
 
It is possible that a maternal participant who is taking PrEP and becomes infected with HIV during 
this study may develop resistance to FTC/TDF. Multiple steps will be taken to minimize the risk 
of drug resistance. HIV testing will be performed frequently throughout follow-up for all maternal 
participants. If acute HIV infection is suspected after enrollment for any participant accepting 
PrEP, the participant will undergo evaluation using tests described in Appendix IID. These steps 
should minimize the risk of drug resistance occurrence by identifying HIV infection in its early 
stages and stopping study drug. If a participant becomes infected during the study, real-time 
resistance testing will be conducted for clinical management (see Section 6.3). 
 
13.5.6 Sensitive Questions 
 
Maternal participants will be asked questions about their sexual behavior that may make them 
feel uneasy. Maternal participants do not have to answer any question that they do not want to 
and can stop answering the questions at any time. 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 108 of 173 
 
  
   
 
19 November 2020 
13.5.7 Mobile Phones 
 
As described in Section 3.2, all maternal participants enrolled in the PrEP Comparison 
Component will receive SMS texts on antenatal, delivery, and early infant care, and maternal 
participants in Cohort 1 will also participate in SMS messaging to promote PrEP adherence. It is 
possible that timing or volume of text messages will be inconvenient to maternal participants. 
Because the costs for text messaging will be covered by the project, it should not incur additional 
expense for the maternal participant.  
 
Information entered by maternal participants into mobile phone programs will be maintained on a 
21CFR Part 11 compliant secure server via a secure, password-protected log-in. However, it is 
possible that someone who has access to the maternal participant’s phone may see this 
information, revealing participation in the study. It will not be possible for the study team to 
access any private information on maternal participants’ mobile phones. Lost or stolen phones are 
a practical reality. Maternal participants will be trained to secure their phones with a password or 
PIN and to delete old messages. Messages will not disclose individual level information so that if 
accessed will not compromise confidentiality around health status or medication use. 
 
13.6 
Potential Social Impact 
 
Participation in clinical research includes the risk of loss of confidentiality. Although study sites 
make every effort to protect participant privacy and confidentiality, it is possible that participants' 
involvement in the study could become known to others, and that social harms – non-medical 
adverse consequences –  may result (e.g., because participants could be perceived as being HIV-
infected or at "high risk" for HIV infection, or because a participant’s choice to participate or use 
PrEP is not supported). For example, participants could be treated unfairly, or could have 
problems being accepted by their families and/or communities or could experience problems in 
their relationships with their partner(s). The Protocol Team believes this risk is small, given that 
the target population is HIV-uninfected women; however, study staff will work to minimize such 
potential risks both at the clinic and community levels. 
 
At every follow-up visit in the PrEP Comparison Component, sites will assess for social harms 
experienced since the last visit. All reported social harms will be source documented and entered 
into eCRFs for maternal participants. As part of routine study monitoring, social harms will be 
tabulated and reviewed as described in Sections 7.2 and 9.3.2. In the event that a participant 
reports a social harm, every effort will be made by study staff to provide appropriate follow-up 
support and counseling to the participant as necessary; referrals to appropriate non-study 
resources may also be provided. Each site will provide such support in accordance with local 
standards of care and site SOPs. 
 
13.7 
Reimbursement/Compensation 
 
Pending IRB/EC approval, maternal 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 IRB/EC policies and procedures.  
 
13.8 
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 


 
IMPAACT 2009, FINAL Version 3.0 
Page 109 of 173 
 
  
   
 
19 November 2020 
released without written permission to do so except as necessary for review, monitoring, and/or 
auditing as described in Section 11.2. 
 
All study-related information will be stored securely. Participant research records will be stored 
in locked areas with access limited to study staff. Participant information necessary for 
implementation of the mHealth component (SMS messages), such as names and phone numbers, 
will be maintained on a General Data Protection Regulation (GDPR) compliant cloud server. All 
laboratory specimens, eCRFs, and other documents that may be transmitted off-site (e.g., EAE 
report forms, photographs of observed reactions, SMS message logs) 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.  
 
13.9 
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. 
 
13.10 Management of Incidental Findings 
 
Site clinicians will inform maternal participants (or other authorized guardians if applicable) of 
all clinically meaningful physical exam findings and laboratory test results, including results of 
HIV tests and hematology and chemistry tests. When applicable, site clinicians will provide 
referrals to non-study sources of medical care for further evaluation and/or treatment of these 
findings.  
 
The results of protocol-specified DXA scans for infants are not planned to be provided to 
maternal participants, as there are no normal values for this test in infants and it is not expected to 
be relevant to clinical care and management. If, however, new information becomes available 
during the course of the study indicating that the results of the DXA scan are of clinical 
relevance, the results of this test will be provided prior to study exit. 
 
13.11 Management of New Information Pertinent to Study Participation 
 
Maternal participants will be provided any new information learned over the course of the study 
that may affect their willingness to continue receiving study drug, their decision to take up PrEP 
and/or remain in follow-up in the study.  
 
13.12 Post-Trial Access to Study Drug 
 
Maternal participants who choose to continue PrEP after exiting the study will be referred to 
appropriate non-study PrEP programs, if available, for continued services. If a PrEP program is 
not in place, maternal participants will be required to stop PrEP at the end of the study period. 
Participants will be counseled and referred to all HIV prevention methods available, outside of 


 
IMPAACT 2009, FINAL Version 3.0 
Page 110 of 173 
 
  
   
 
19 November 2020 
the study, consistent with local standards of care. Each site will be required to engage applicable 
stakeholders and outline locally relevant procedures.  
  
14 
ADMINISTRATIVE PROCEDURES 
 
14.1 
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). Study drug FTC/TDF is provided by Gilead Sciences, Inc.; however, 
this organization is not involved in sponsorship or regulatory oversight of this study.  
 
The Division of AIDS (DAIDS) within the NIAID is responsible for regulatory oversight of this 
study. DAIDS will distribute safety-related information pertaining to the study drug prior to and 
during the conduct of the study, in accordance with its sponsor obligations.  
 
NIAID provides funding to the clinical research sites at which this study will be conducted and 
contracts with independent clinical site monitors who will perform monitoring visits as described 
in Section 12. As part of these visits, monitors will inspect study-related documentation to ensure 
compliance with all applicable U.S. and local regulatory requirements. 
 
14.2 
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 IRB/EC, 
local IBC, 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 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. 
 
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 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 111 of 173 
 
  
   
 
19 November 2020 
14.3 
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 MOP, study-specific MOP, LPC, and other study implementation materials, 
which will be available on the IMPAACT web site: www.impaactnetwork.org. 
 
Study implementation at each site will also be guided by site-specific SOPs. The DAIDS policy 
on Requirements for Manual of Operations 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 11.2). These SOPs should be updated and/or supplemented as 
needed to describe roles, responsibilities, and procedures for this study. 
 
14.4 
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 11.2), 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.  
 
All DAIDS policies referenced in this section are available at: 
https://www.niaid.nih.gov/research/daids-clinical-research-policies-standard-procedures 
 
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. 
 
14.5 
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/research/daids-clinical-research-
event-reporting-safety-monitoring 
 
14.6 
ClinicalTrials.gov 
 
This protocol is subject to the United States Food and Drug Administration Amendments Act of 
2007 (FDAAA), including registration in ClinicalTrials.gov. 
 
15 
PUBLICATIONS 
 
All presentations and publications of data collected in this study are governed by NIH public 
access policy and IMPAACT policies, which are available in the IMPAACT Manual of 
Procedures.  
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 112 of 173 
 
  
   
 
19 November 2020 
16 
REFERENCES 
 
1. 
Bekker LG GR, Hughes J, Amico R, Roux S, Hendrix C, Anderson P, Dye B, Elharrar V, Stirratt 
M. HPTN 067/ADAPT Cape Town: a comparison of daily and nondaily dosing in African 
women [Abstract 978LB]. Paper presented at: Conference on Retroviruses and Opportunistic 
Infections 2015; Seattle, WA. 2015. 
2. 
PEPFAR. DREAMS Innovation Challenge Fact Sheet. In: DREAMS, editor. 2016. 
3. 
Venter WD, Cowan F, Black V, Rebe K, Bekker LG. Pre-exposure prophylaxis in Southern 
Africa: feasible or not? J Int AIDS Soc. 2015;18(4 Suppl 3):19979. 
4. 
Shisana O, Rehle T, Simbayi LC, Zuma K, Jooste S, Zungu N. South African National HIV 
Prevalence, Incidence and Behaviour Survey. South Africa: HSRC Press; 2014. 
5. 
UNAIDS. Global AIDS Update. Switzerland; 2016. 
6. 
Drake AL, Wagner A, Richardson B, John-Stewart G. Incident HIV during pregnancy and 
postpartum and risk of mother-to-child HIV transmission: a systematic review and meta-analysis. 
PLoS Med. 2014;11(2):e1001608. 
7. 
Mellins CA, Chu C, Malee K, Allison S, Smith R, Harris L, et al. Adherence to antiretroviral 
treatment among pregnant and postpartum HIV-infected women. AIDS Care. 2008;20(8):958-68. 
8. 
Parekh BS, Hu DJ, Vanichseni S, Satten GA, Candal D, Young NL, et al. Evaluation of a 
sensitive/less-sensitive testing algorithm using the 3A11-LS assay for detecting recent HIV 
seroconversion among individuals with HIV-1 subtype B or E infection in Thailand. AIDS 
ResHumRetroviruses. 2001;17(5):453-8. 
9. 
Fonner VA, Dalglish SL, Kennedy CE, Baggaley R, O'Reilly K R, Koechlin FM, et al. 
Effectiveness and safety of oral HIV pre-exposure prophylaxis (PrEP) for all populations: A 
systematic review and meta-analysis. AIDS. 2016. 
10. 
Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, et al. Antiretroviral 
Prophylaxis for HIV Prevention in Heterosexual Men and Women. N Engl J Med. 
2012;367(5):399-410. 
11. 
Thigpen MC, Kebaabetswe PM, Paxton LA, Smith DK, Rose CE, Segolodi TM, et al. 
Antiretroviral Preexposure Prophylaxis for Heterosexual HIV Transmission in Botswana. N Engl 
J Med. 2012;367(5):423-34. 
12. 
Choopanya K, Martin M, Suntharasamai P, Sangkum U, Mock PA, Leethochawalit M, et al. 
Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the 
Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial. The 
Lancet. 2013;381(9883):2083-90. 
13. 
Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. Preexposure 
Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men. N Engl J Med. 
2010;363(27):2587-99. 
14. 
Marrazzo JM, Ramjee G, Richardson BA, Gomez K, Mgodi N, Nair G, et al. Tenofovir-Based 
Preexposure Prophylaxis for HIV Infection among African Women. N Engl J Med. 
2015;372(6):509-18. 
15. 
Rees H D-MS, Lombard C, Baron D, Panchia R, Myer L, Schwartz J, Doncel G, Gray G. FACTS 
001 Phase III trial of pericoital tenofovir 1% gel for HIV prevention in women [Abstract 26LB]. 
Paper presented at: Conference on Retroviruses and Opportunistic Infections 2015; Seattle, WA. 
2015. 
16. 
Van Damme L, Corneli A, Ahmed K, Agot K, Lombaard J, Kapiga S, et al. Preexposure 
Prophylaxis for HIV Infection among African Women. N Engl J Med. 2012;367:411-22. 
17. 
Abdool Karim Q, Abdool Karim SS, Frohlich JA, Grobler AC, Baxter C, Mansoor LE, et al. 
Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV 
infection in women. Science. 2010;329(5996):1168-74. 
18. 
Molina J-M, Capitant C, Spire B, Pialoux G, Cotte L, Charreau I, et al. On-Demand Preexposure 
Prophylaxis in Men at High Risk for HIV-1 Infection. N Engl J Med. 2015;373(23):2237-46. 


 
IMPAACT 2009, FINAL Version 3.0 
Page 113 of 173 
 
  
   
 
19 November 2020 
19. 
McCormack S, Dunn DT, Desai M, Dolling DI, Gafos M, Gilson R, et al. Pre-exposure 
prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from 
the pilot phase of a pragmatic open-label randomised trial. The Lancet.387(10013):53-60. 
20. 
Grant RM, Anderson PL, McMahan V, Liu A, Amico KR, Mehrotra M, et al. Uptake of pre-
exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who 
have sex with men: a cohort study. The Lancet Infectious Diseases. 2014;14(9):820-9. 
21. 
McCormack S DD. Pragmatic open-label randomised trial of preexposure prophylaxis: the 
PROUD study [Abstract 22LB]. Paper presented at: Conference on Retroviruses and 
Opportunistic Infections 2015; Seattle, WA. 2015. 
22. 
Preexposure prophylaxis for the prevention of HIV infection in the United States - 2014 clinical 
practice guideline. In: CDC, editor. 2014. p. 1-67. 
23. 
World Health Organization. Guideline on when to start Antiretroviral Therapy and on Pre-
Exposure Prophylaxis for HIV. 2015. 
24. 
Cottrell ML, Yang KH, Prince HM, Sykes C, White N, Malone S, et al. A Translational 
Pharmacology Approach to Predicting HIV Pre-Exposure Prophylaxis Outcomes in Men and 
Women Using Tenofovir Disoproxil Fumarate+/-Emtricitabine. J Infect Dis. 2016. 
25. 
Miller LG, Hays RD. Measuring adherence to antiretroviral medications in clinical trials. HIV 
Clin Trials. 2000;1(1):36-46. 
26. 
Murphy DA, Wilson CM, Durako SJ, Muenz LR, Belzer M. Antiretroviral medication adherence 
among the REACH HIV-infected adolescent cohort in the USA. AIDS Care. 2001;13(1):27-40. 
27. 
La Greca AM, Auslander WF, Greco P, Spetter D, Fisher EB, Jr., Santiago JV. I get by with a 
little help from my family and friends: adolescents' support for diabetes care. J Pediatr Psychol. 
1995;20(4):449-76. 
28. 
Vaz MJ, Barros SM, Palacios R, Senise JF, Lunardi L, Amed AM, et al. HIV-infected pregnant 
women have greater adherence with antiretroviral drugs than non-pregnant women. Int J STD 
AIDS. 2007;18(1):28-32. 
29. 
Henegar CE, Westreich DJ, Maskew M, Miller WC, Brookhart MA, Van Rie A. Effect of 
pregnancy and the postpartum period on adherence to antiretroviral therapy among HIV-infected 
women established on treatment. J Acquir Immune Defic Syndr. 2015;68(4):477-80. 
30. 
Bardeguez AD, Lindsey JC, Shannon M, Tuomala RE, Cohn SE, Smith E, et al. Adherence to 
antiretrovirals among US women during and after pregnancy. J AcquirImmuneDeficSyndr. 
2008;48(4):408-17. 
31. 
Nachega JB, Uthman OA, Anderson J, Peltzer K, Wampold S, Cotton MF, et al. Adherence to 
antiretroviral therapy during and after pregnancy in low-income, middle-income, and high-
income countries: a systematic review and meta-analysis. AIDS. 2012;26(16):2039-52. 
32. 
Phillips T, Thebus E, Bekker LG, McIntyre J, Abrams EJ, Myer L. Disengagement of HIV-
positive pregnant and postpartum women from antiretroviral therapy services: a cohort study. J 
Int AIDS Soc. 2014;17:19242. 
33. 
Matthews LT, Heffron R, Mugo NR, Cohen CR, Hendrix CW, Celum C, et al. High medication 
adherence during periconception periods among HIV-1-uninfected women participating in a 
clinical trial of antiretroviral pre-exposure prophylaxis. J Acquir Immune Defic Syndr. 
2014;67(1):91-7. 
34. 
Matthews LT SS, Mansoor LE, Yende-Zuma N, Bangsberg DR, Karim QA. Women with 
pregnancies had lower adherence to 1% tenofovir vaginal gel as HIV preexposure prophylaxis in 
CAPRISA 004, a phase IIB randomized-controlled trial. PLoS One. 2013(8(3):e56400). 
35. 
Joint United Nations Programme on HIV/AIDS (UNAIDS). The Gap Report [Report]. Geneva, 
Switzerland: UNAIDS; 2014 [Available from: 
http://www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/2014/UNAID
S_Gap_report_en.pdf. 


 
IMPAACT 2009, FINAL Version 3.0 
Page 114 of 173 
 
  
   
 
19 November 2020 
36. 
Baeten JM, Palanee-Phillips T, Brown ER, Schwartz K, Soto-Torres LE, Nel A, et al. A phase III 
trial of the dapivirine vaginal ring for HIV-1 prevention in women.  Conference on Retroviruses 
and Opportunistic Infections; Boston, MA2016. 
37. 
Kapiga S, Bekker LG, Borremans M, Rosenberg Z, editors. Safety and efficacy of dapivirine 
vaginal ring for HIV-1 prevention in African women. Conference on Retroviruses and 
Opportunistic Infections 2016; Boston, MA. 
38. 
Corneli AL, Deese J, Wang M, Taylor D, Ahmed K, Agot K, et al. FEM-PrEP: Adherence 
Patterns and Factors Associated With Adherence to a Daily Oral Study Product for Pre-exposure 
Prophylaxis. Journal of Acquired Immune Deficiency Syndromes (1999). 2014;66(3):324-31. 
39. 
Corneli A, Perry B, Agot K, Ahmed K, Malamatsho F, Van Damme L. Facilitators of adherence 
to the study pill in the FEM-PrEP clinical trial. PLoS One. 2015;10(4):e0125458. 
40. 
Corneli AL, McKenna K, Perry B, Ahmed K, Agot K, Malamatsho F, et al. The science of being 
a study participant: FEM-PrEP participants' explanations for overreporting adherence to the study 
pills and for the whereabouts of unused pills. J Acquir Immune Defic Syndr. 2015;68(5):578-84. 
41. 
Corneli A, Perry B, McKenna K, Agot K, Ahmed K, Taylor J, et al. Participants' Explanations for 
Nonadherence in the FEM-PrEP Clinical Trial. J Acquir Immune Defic Syndr. 2016;71(4):452-
61. 
42. 
van der Straten A, Brown ER, Marrazzo JM, Chirenje MZ, Liu K, Gomez K, et al. Divergent 
adherence estimates with pharmacokinetic and behavioural measures in the MTN-003 (VOICE) 
study. J Int AIDS Soc. 2016;19(1):20642. 
43. 
van der Straten A, Stadler J, Luecke E, Laborde N, Hartmann M, Montgomery ET. Perspectives 
on use of oral and vaginal antiretrovirals for HIV prevention: the VOICE-C qualitative study in 
Johannesburg, South Africa. J Int AIDS Soc. 2014;17(3 Suppl 2):19146. 
44. 
van der Straten A, Montgomery ET, Musara P, Etima J, Naidoo S, Laborde N, et al. Disclosure of 
pharmacokinetic drug results to understand nonadherence. AIDS. 2015;29(16):2161-71. 
45. 
Baeten J HR, Kidoguchi L, et al. Near elimination of HIV transmission in a demonstration project 
of PrEP and ART [Abstract 24]. Paper presented at: Conference on Retroviruses and 
Opportunistic Infections 2015; Seattle, WA. 2015. 
46. 
Amico KR, editor HPTN 067 ADAPT: ‘PrEP Ubuntu’ and Experiences with open-label PrEP 
Among South African Women. 8th IAS Conference on HIV Pathogenesis, Treatment & 
Prevention; 2015 19-22 July 2015; Vancouver, Canada. 
47. 
K. Gill, R. Marcus, J. Dietrich, T. Bennie, S. Hosek, G. Gray, et al., editors. An analysis of 
baseline and early data from the Plus Pills study: an open-label trial of pre-exposure prophylaxis 
for South African adolescents. 21st International AIDS Conference; 2016; Durban. 
48. 
Bekker L-G. PlusPills principal investigator In: Hosek S, editor. 2017. 
49. 
Amico KR MV, Marcus J, Goicochea P, Vargas L, Grant R, Liu A. Integrated Next Step 
Counseling (iNSC): A discussion based sexual health promotion conversation to support men 
who have sex with men using PrEP in the iPrEx open label extension [80467]. Oral presentation 
at the 7th Annual HIV Treatment and Prevention Adherence Conference of the International 
Association of Providers in AIDS Care, Miami, FL. 2012. 
50. 
Kofron R. Real time plasma TFV levels to support adherence in a pre-exposure prophylaxis 
demonstration project. 9th International Conference on HIV Treatment and Prevention Adherence 
IAPAC, Miami, FL. 2014. 
51. 
Amico KR. Evidence for Technology Interventions to Promote ART Adherence in Adult 
Populations: a Review of the Literature 2012-2015. Curr HIV/AIDS Rep. 2015;12(4):441-50. 
52. 
Muessig KE, Nekkanti M, Bauermeister J, Bull S, Hightow-Weidman LB. A systematic review of 
recent smartphone, Internet and Web 2.0 interventions to address the HIV continuum of care. 
Curr HIV/AIDS Rep. 2015;12(1):173-90. 
53. 
Poushter J, Oates R. Cell Phones in Africa: Communication Lifeline: Texting Most Common 
Activity, but Mobile Money Popular in Several Countries. Pew Research Center; 2015. 


 
IMPAACT 2009, FINAL Version 3.0 
Page 115 of 173 
 
  
   
 
19 November 2020 
54. 
Hightow-Weidman LB, Muessig KE, Bauermeister J, Zhang C, LeGrand S. Youth, Technology, 
and HIV: Recent Advances and Future Directions. Curr HIV/AIDS Rep. 2015;12(4):500-15. 
55. 
Swahn MH, Braunstein S, Kasirye R. Demographic and psychosocial characteristics of mobile 
phone ownership and usage among youth living in the slums of Kampala, Uganda. West J Emerg 
Med. 2014;15(5):600-3. 
56. 
Ybarra ML, Mwaba K, Prescott TL, Roman NV, Rooi B, Bull S. Opportunities for technology-
based HIV prevention programming among high school students in Cape Town, South Africa. 
AIDS Care. 2014;26(12):1562-7. 
57. 
Lim MS, Hocking JS, Aitken CK, Fairley CK, Jordan L, Lewis JA, et al. Impact of text and email 
messaging on the sexual health of young people: a randomised controlled trial. J Epidemiol 
Community Health. 2012;66(1):69-74. 
58. 
van Velthoven MH, Brusamento S, Majeed A, Car J. Scope and effectiveness of mobile phone 
messaging for HIV/AIDS care: a systematic review. Psychol Health Med. 2013;18(2):182-202. 
59. 
Mobile Alliance for Maternal Action. The power of health in every mama’s hand  [Available 
from: http://www.mobilemamaalliance.org/mobile-messages. 
60. 
Celum C, Mgodi N, Bekker L-G, Hosek S, Donnell D, Anderson PL, et al. PrEP adherence and 
effect of drug level feedback among young African women in HPTN 082.  International AIDS 
Conference; 2019 July 21-24; Mexico City, Mexico2019. 
61. 
Scorgie F, Khoza N, Delany-Moretlwe S, Mangxilana N, Atujuna M, Musara P, et al. Measuring 
perceptions of sexual risk among adolescent girls and young women taking PrEP: A new 
qualitative method using visual timelines in HPTN 082.  International AIDS Conference; 2019 
July 21-24; Mexico City, Mexico2019. 
62. 
Zimbabwe: Standard DHS, 2015  [Available from: http://dhsprogram.com/what-we-
do/survey/survey-display-475.cfm. 
63. 
Creswell JW. Qualitative inquiry and research design: Choosing among five approaches. 
Research Design. . Thousand Oaks, CA: Sage Publications 2012. 
64. 
Stadler J, Scorgie F, van der Straten A, Saethre E. Adherence and the Lie in a HIV Prevention 
Clinical Trial. Med Anthropol. 2015:1-14. 
65. 
Corneli A, Perry B, McKenna K, Agot K, Ahmed K, Taylor J, et al. Participants' explanations for 
non-adherence in the FEM-PrEP clinical trial. Journal of acquired immune deficiency syndromes 
(1999). 2015. 
66. 
Mofenson LM. Tenofovir Pre-exposure Prophylaxis for Pregnant and Breastfeeding Women at 
Risk of HIV Infection: The Time is Now. PLoS Med. 2016;13(9):e1002133. 
67. 
Mofenson LM, Baggaley RC, Mameletzis I. Tenofovir Disoproxil Fumarate Safety for Women 
and their Infants during Pregnancy and Breastfeeding: Systematic Review. AIDS. 2016. 
68. 
Plosker GL. Emtricitabine/tenofovir disoproxil fumarate: a review of its use in HIV-1 pre-
exposure prophylaxis. Drugs. 2013;73(3):279-91. 
69. 
Mugwanya KK, Hendrix CW, Mugo NR, Marzinke M, Katabira ET, Ngure K, et al. Pre-exposure 
prophylaxis use by breastfeeding HIV-uninfected women: a prospective short-term study of 
antiretroviral excretion in breast milk and infant absorption. PLoS Med. 2016;13(9):e1002132. 
70. 
Smith DJ. Modern Marriage, Men’s Extramarital Sex, and HIV Risk in Southeastern Nigeria. Am 
J Public Health. 2007;97(6):997-1005. 
71. 
Mugwanya K CC, Baeten J, et al. Reversibility of kidney function decline in HIV-1 uninfected 
men and women using pre-exposure prophylaxis [Abstract 981]. Paper presented at: Conference 
on Retroviruses and Opportunistic Infections 2015; Seattle, WA. 2015. 
72. 
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. 
73. 
Pan CQ, Duan Z, Dai E, Zhang S, Han G, Wang Y, et al. Tenofovir to Prevent Hepatitis B 
Transmission in Mothers with High Viral Load. N Engl J Med. 2016;374(24):2324-34. 


 
IMPAACT 2009, FINAL Version 3.0 
Page 116 of 173 
 
  
   
 
19 November 2020 
74. 
Liu AY, Vittinghoff E, Sellmeyer DE, Irvin R, Mulligan K, Mayer K, et al. Bone mineral density 
in HIV-negative men participating in a tenofovir pre-exposure prophylaxis randomized clinical 
trial in San Francisco. PLoS One. 2011;6(8):e23688. 
75. 
Mirembe BG, Kelly CW, Mgodi N, Greenspan S, Dai JY, Mayo A, et al. Bone Mineral Density 
Changes Among Young, Healthy African Women Receiving Oral Tenofovir for HIV Preexposure 
Prophylaxis. Journal of acquired immune deficiency syndromes (1999). 2016;71(3):287. 
76. 
Stranix-Chibanda L, Tierney C, Marr C, George K, Sebikari D, Dadabhai S, et al. Impact of 
tenofovir-containing triple antiretroviral therapy (ART) on bone mineral density in HIV-infected 
breastfeeding women in sub-Saharan Africa.  International Workshop on HIV Pediatrics; 2016 
Jul 15-16; Durban, South Africa2016. 
77. 
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. Clin Infect Dis. 2015;61(6):996-1003. 
78. 
Jao J ML, Phillips T, Petro G, Zerbe A, Abrams EJ. In utero tenofovir exposure is not associated 
with fetal long bone growth. Paper presented at: 8th IAS Conference on HIV Pathogenesis, 
Treatment, and Prevention 2015; Vancouver, Canada 2015. 
79. 
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; 2016 Feb 22-25; Boston, MA2016. 
80. 
Makanani B, Balkus J, Palanee-Phillips T, Mbilizi Y, Piper J, Kintu K, et al., editors. Pregnancy 
incidence and outcomes among women using the dapivirine vaginal ring. Conference on 
Retroviruses and Opportunistic Infections (CROI); 2017 February 13–16, 2017; Seattle, 
Washington. 
81. 
Heffron R, Mugo NR, Hong T, Bukusi EA, Katabira E, Asiimwe S, et al., editors. PrEP used in 
pregnancy does not increase poor birth outcomes. Conference on Retroviruses and Opportunistic 
Infections (CROI); 2017; Seattle, Washington. 
82. 
Brown RS, Jr., McMahon BJ, Lok AS, Wong JB, Ahmed AT, Mouchli MA, et al. Antiviral 
therapy in chronic hepatitis B viral infection during pregnancy: A systematic review and meta-
analysis. Hepatology. 2016;63(1):319-33. 
83. 
Jourdain G, Ngo-Giang-Huong N, Cressey TR, Hua L, Harrison L, Tierney C, et al. Prevention of 
mother-to-child transmission of hepatitis B virus: a phase III, placebo-controlled, double-blind, 
randomized clinical trial to assess the efficacy and safety of a short course of tenofovir disoproxil 
fumarate in women with hepatitis B virus e-antigen. BMC Infect Dis. 2016;16:393. 
84. 
Jourdain G. personal communication. 2016. 
85. 
Weis J MC, Matsen F, et al. PrEP-selected drug resistance fades by six months following drug 
cessation [Abstract 983]. Paper presented at: Conference on Retroviruses and Opportunistic 
Infections 2015; Seattle, WA. 2015. 
86. 
Larmarange JI, Collins; Orne-Gliemann, Joanna; McGrath, Nuala; Plazy, Mélanie; Baisley, 
Kathy; Bärnighausen,Till; Dabis, Francois; Pillay, Deenan Measuring the Impact of Test & Treat 
on the HIV Cascade: The Challenge of Mobility. Conference on Retroviruses and Opportunistic 
Infections. 2016. 
87. 
Global epidemiology of drug resistance after failure of WHO recommended first-line regimens 
for adult HIV-1 infection: a multicentre retrospective cohort study. Lancet Infect Dis. 2016. 
88. 
Wilde GJS. The Theory of Risk Homeostasis: Implications for Safety and Health. Risk Anal. 
1982;2(4):209-25. 
89. 
Wilde G. Risk homeostasis theory: an overview. Inj Prev. 1998;4(2):89-91. 
90. 
Hosek S RB, Landovitz R, Kapogiannis B, Siberry G, Liu N, Rutledge B, Brothers J, Rooney J, 
Wilson CM. An HIV pre-exposure prophylaxis demonstration project and safety study for young 
men who have sex with men in the United States (ATN 110). J Int AIDS Soc. 2015;18. 
91. 
Amico KR, Stirratt MJ. Adherence to preexposure prophylaxis: current, emerging, and 
anticipated bases of evidence. Clin Infect Dis. 2014;59 Suppl 1:S55-60.  


 
IMPAACT 2009, FINAL Version 3.0 
Page 117 of 173 
 
  
   
 
19 November 2020 
92. 
Liu AY, Vittinghoff E, Chillag K, Mayer K, Thompson M, Grohskopf L, et al. Sexual risk 
behavior among HIV-uninfected men who have sex with men participating in a tenofovir 
preexposure prophylaxis randomized trial in the United States. J Acquir Immune Defic Syndr. 
2013;64(1):87-94. 
93. 
Marcus JL, Glidden DV, Mayer KH, Liu AY, Buchbinder SP, Amico KR, et al. No evidence of 
sexual risk compensation in the iPrEx trial of daily oral HIV preexposure prophylaxis. PLoS One. 
2013;8(12):e81997. 
94. 
Kimberly Koester RA, Albert Liu, Vanessa McMahon, Sybil Hosek, Kenneth Mayer, Robert 
Grant. Qualitative findings from the iPrEx Open Label Extension (OLE) in the US.  International 
AIDS Conference,; Melbourne, Australia 2014. 
95. 
Hosek SG, Siberry G, Bell M, Lally M, Kapogiannis B, Green K, et al. The acceptability and 
feasibility of an HIV preexposure prophylaxis (PrEP) trial with young men who have sex with 
men. J Acquir Immune Defic Syndr. 2013;62(4):447-56. 
96. 
McCormack S. Sexually Transmitted Infection Control in the Era of PrEP.  Conference on 
Retroviruses and Opportunistic Infections; Boston, Massachusetts2016. 
97. 
Bessesen M, Ives D, Condreay L, Lawrence S, Sherman KE. Chronic active hepatitis B 
exacerbations in human immunodeficiency virus-infected patients following development of 
resistance to or withdrawal of lamivudine. Clin Infect Dis. 1999;28(5):1032-5. 
98. 
Mondou E, Sorbel J, Anderson J, Mommeja-Marin H, Rigney A, Rousseau F. Posttreatment 
exacerbation of hepatitis B virus (HBV) infection in long-term HBV trials of emtricitabine. Clin 
Infect Dis. 2005;41(5):e45-7. 
99. 
Bellini C, Keiser O, Chave JP, Evison J, Fehr J, Kaiser L, et al. Liver enzyme elevation after 
lamivudine withdrawal in HIV-hepatitis B virus co-infected patients: the Swiss HIV Cohort 
Study. HIV Med. 2009;10(1):12-8. 
100. 
Solomon MM, Schechter M, Liu AY, McManhan VM, Guanira JV, Hance RJ, et al. The Safety 
of Tenofovir-Emtricitabine for HIV Pre-Exposure Prophylaxis (PrEP) in Individuals With Active 
Hepatitis B. J Acquir Immune Defic Syndr. 2016;71(3):281-6. 
101. 
Peterson L, Taylor D, Roddy R, Belai G, Phillips P, Nanda K, et al. Tenofovir disoproxil 
fumarate for prevention of HIV infection in women: a phase 2, double-blind, randomized, 
placebo-controlled trial. PLoS Clin Trials. 2007;2(5):e27. 
102. 
Nuriel-Ohayon M, Neuman H, Koren O. Microbial Changes during Pregnancy, Birth, and 
Infancy. Front Microbiol. 2016;7:1031. 
103. 
O'Hanlon DE, Moench TR, Cone RA. Vaginal pH and microbicidal lactic acid when lactobacilli 
dominate the microbiota. PLoS One. 2013;8(11):e80074. 
104. 
Hyman RW, Fukushima M, Jiang H, Fung E, Rand L, Johnson B, et al. Diversity of the vaginal 
microbiome correlates with preterm birth. Reprod Sci. 2014;21(1):32-40. 
105. 
Shiozaki A, Yoneda S, Yoneda N, Yonezawa R, Matsubayashi T, Seo G, et al. Intestinal 
microbiota is different in women with preterm birth: results from terminal restriction fragment 
length polymorphism analysis. PLoS One. 2014;9(11):e111374. 
106. 
Vinturache AE, Gyamfi-Bannerman C, Hwang J, Mysorekar IU, Jacobsson B. Maternal 
microbiome - A pathway to preterm birth. Semin Fetal Neonatal Med. 2016;21(2):94-9. 
107. 
Turner AN, Morrison CS, Munjoma MW, Moyo P, Chipato T, van de Wijgert JH. Vaginal 
practices of HIV-negative Zimbabwean women. Infect Dis Obstet Gynecol. 2010;2010. 
108. 
Alcaide ML, Chisembele M, Malupande E, Arheart K, Fischl M, Jones DL. A cross-sectional 
study of bacterial vaginosis, intravaginal practices and HIV genital shedding; implications for 
HIV transmission and women's health. BMJ Open. 2015;5(11):e009036. 
109. 
Kinuthia J, Richardson BA, Drake AL, Matemo D, Unger JA, McClelland RS, et al. Sexual 
Behavior and Vaginal Practices During Pregnancy and Postpartum: Implications for HIV 
Prevention Strategies. J Acquir Immune Defic Syndr. 2017;74(2):142-9. 


 
IMPAACT 2009, FINAL Version 3.0 
Page 118 of 173 
 
  
   
 
19 November 2020 
110. 
Romero R, Hassan SS, Gajer P, Tarca AL, Fadrosh DW, Nikita L, et al. The composition and 
stability of the vaginal microbiota of normal pregnant women is different from that of non-
pregnant women. Microbiome. 2014;2(1):4. 
111. 
Huang YE, Wang Y, He Y, Ji Y, Wang LP, Sheng HF, et al. Homogeneity of the vaginal 
microbiome at the cervix, posterior fornix, and vaginal canal in pregnant Chinese women. Microb 
Ecol. 2015;69(2):407-14. 
112. 
Zevin AS, Xie IY, Birse K, Arnold K, Romas L, Westmacott G, et al. Microbiome Composition 
and Function Drives Wound-Healing Impairment in the Female Genital Tract. PLoS Pathog. 
2016;12(9):e1005889. 
113. 
Zevin AS, McKinnon L, Burgener A, Klatt NR. Microbial translocation and microbiome 
dysbiosis in HIV-associated immune activation. Curr Opin HIV AIDS. 2016;11(2):182-90. 
114. 
Cohen J. INFECTIOUS DISEASE. Vaginal microbiome affects HIV risk. Science. 
2016;353(6297):331. 
115. 
Gosmann C, Anahtar MN, Handley SA, Farcasanu M, Abu-Ali G, Bowman BA, et al. 
Lactobacillus-Deficient Cervicovaginal Bacterial Communities Are Associated with Increased 
HIV Acquisition in Young South African Women. Immunity. 2017;46(1):29-37. 
116. 
Hillier S, Meyn LA, Bunge K, Austin M, Moncla BJ, Dezzutti CS, et al., editors. Impact of 
vaginal microbiota on genital tissue and plasma concentrations of tenofovir. Conference on 
Retroviruses and Opportunistic Infections (CROI); 2017; Seattle, Washington. 
117. 
Heffron R, McClelland RS, Balkus J, Celum C, Cohen CR, Mugo NR, et al., editors. Daily oral 
PrEP is effective among women with abnormal vaginal microbiota. Conference on Retroviruses 
and Opportunistic Infections (CROI); 2017; Seattle, Washington. 
118. 
Lozupone CA, Rhodes ME, Neff CP, Fontenot AP, Campbell TB, Palmer BE. HIV-induced 
alteration in gut microbiota. Gut Microbes. 2014;5(4):562-70. 
119. 
Noguera-Julian M, Rocafort M, Guillen Y, Rivera J, Casadella M, Nowak P, et al. Gut 
Microbiota Linked to Sexual Preference and HIV Infection. EBioMedicine. 2016;5:135-46. 
120. 
Nowak P, Troseid M, Avershina E, Barqasho B, Neogi U, Holm K, et al. Gut microbiota diversity 
predicts immune status in HIV-1 infection. AIDS. 2015;29(18):2409-18. 
121. 
Vujkovic-Cvijin I, Dunham RM, Iwai S, Maher MC, Albright RG, Broadhurst MJ, et al. 
Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan 
catabolism. Sci Transl Med. 2013;5(193):193ra91. 
122. 
Lozupone CA, Li M, Campbell TB, Flores SC, Linderman D, Gebert MJ, et al. Alterations in the 
gut microbiota associated with HIV-1 infection. Cell Host Microbe. 2013;14(3):329-39. 
123. 
McHardy IH, Li X, Tong M, Ruegger P, Jacobs J, Borneman J, et al. HIV Infection is associated 
with compositional and functional shifts in the rectal mucosal microbiota. Microbiome. 
2013;1(1):26. 
124. 
Lozupone CA, Rhodes ME, Neff CP, Fontenot AP, Campbell TB, Palmer BE. HIV-induced 
alteration in gut microbiota: driving factors, consequences, and effects of antiretroviral therapy. 
Gut Microbes. 2014;5(4):562-70. 
125. 
Monaco CL, Gootenberg DB, Zhao G, Handley SA, Ghebremichael MS, Lim ES, et al. Altered 
Virome and Bacterial Microbiome in Human Immunodeficiency Virus-Associated Acquired 
Immunodeficiency Syndrome. Cell Host Microbe. 2016;19(3):311-22. 
126. 
Owen BN, Elmes J, Silhol R, Dang Q, McGowan I, Shacklett B, et al. How common and frequent 
is heterosexual anal intercourse among South Africans? A systematic review and meta-
analysis2017. 
127. 
Nguyen QN, Himes JE, Martinez DR, Permar SR. The Impact of the Gut Microbiota on Humoral 
Immunity to Pathogens and Vaccination in Early Infancy. PLoS Pathog. 2016;12(12):e1005997. 
128. 
Gordon HA, Pesti L. The gnotobiotic animal as a tool in the study of host microbial relationships. 
Bacteriol Rev. 1971;35(4):390-429. 
129. 
Hu J, Nomura Y, Bashir A, Fernandez-Hernandez H, Itzkowitz S, Pei Z, et al. Diversified 
microbiota of meconium is affected by maternal diabetes status. PLoS One. 2013;8(11):e78257. 


 
IMPAACT 2009, FINAL Version 3.0 
Page 119 of 173 
 
  
   
 
19 November 2020 
130. 
Collado MC, Rautava S, Aakko J, Isolauri E, Salminen S. Human gut colonisation may be 
initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Sci Rep. 
2016;6:23129. 
131. 
Hansen R, Scott KP, Khan S, Martin JC, Berry SH, Stevenson M, et al. First-Pass Meconium 
Samples from Healthy Term Vaginally-Delivered Neonates: An Analysis of the Microbiota. 
PLoS One. 2015;10(7):e0133320. 
132. 
Tamburini S, Shen N, Wu HC, Clemente JC. The microbiome in early life: implications for 
health outcomes. Nat Med. 2016;22(7):713-22. 
133. 
Bender JM, Li F, Martelly S, Byrt E, Rouzier V, Leo M, et al. Maternal HIV infection influences 
the microbiome of HIV-uninfected infants. Sci Transl Med. 2016;8(349):349ra100. 
134. 
Marrazzo J RG, Nair G, et al. Pre-exposure prophylaxis for HIV in women: daily oral tenofovir, 
oral tenofovir/emtricitabine, or vaginal tenofovir gel in the VOICE study (MTN 003) [Abstract 
26LB]. Paper presented at: 20th Conference on Retroviruses and Opportunistic Infections 2013; 
Atlanta, GA. 2013. 
135. 
Baeten JM, Palanee-Phillips T, Brown ER, Schwartz K, Soto-Torres LE, Govender V, et al. Use 
of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention in Women. N Engl J 
Med.0(0):null. 
136. 
Graybill LA, Kasaro M, Freeborn K, Walker JS, Poole C, Powers KA, et al. Incident HIV among 
pregnant and breast-feeding women in sub-Saharan Africa: a systematic review and meta-
analysis. AIDS. 2020;34(5):761-76. 
137. 
Gray RH, Li X, Kigozi G, Serwadda D, Brahmbhatt H, Wabwire-Mangen F, et al. Increased risk 
of incident HIV during pregnancy in Rakai, Uganda: a prospective study. Lancet. 
2005;366(9492):1182-8. 
138. 
Mugo NR, Heffron R, Donnell D, Wald A, Were EO, Rees H, et al. Increased risk of HIV-1 
transmission in pregnancy: a prospective study among African HIV-1-serodiscordant couples. 
AIDS. 2011;25(15):1887-95. 
139. 
Moodley D, Esterhuizen TM, Pather T, Chetty V, Ngaleka L. High HIV incidence during 
pregnancy: compelling reason for repeat HIV testing. AIDS. 2009;23(10):1255-9. 
140. 
Keating MA, Hamela G, Miller WC, Moses A, Hoffman IF, Hosseinipour MC. High HIV 
incidence and sexual behavior change among pregnant women in Lilongwe, Malawi: implications 
for the risk of HIV acquisition. PLoS One. 2012;7(6):e39109. 
141. 
Matthews L, Moore L, Crankshaw T, Milford C, Mosery F, Greener R, et al. South Africans with 
recent pregnancy rarely know partner's HIV serostatus: implications for serodiscordant couples 
interventions. BMC Public Health. 2014;14(1):843. 
142. 
Schwartz SR, Bassett J, Sanne I, Phofa R, Yende N, Van Rie A. Implementation of a safer 
conception service for HIV-affected couples in South Africa. AIDS. 2014;28 Suppl 3:S277-85. 
143. 
Mutambirwa J. Pregnancy, childbirth, mother and child care among the indigenous people of 
Zimbabwe. Int J Gynaecol Obstet. 1985;23(4):275-85. 
144. 
Kinuthia J, Drake AL, Matemo D, Richardson BA, Zeh C, Osborn L, et al. HIV acquisition 
during pregnancy and postpartum is associated with genital infections and partnership 
characteristics. AIDS. 2015;29(15):2025-33. 
145. 
Ngure K, Heffron R, Mugo NR, Celum C, Cohen CR, Odoyo J, et al. Contraceptive method and 
pregnancy incidence among women in HIV-1-serodiscordant partnerships. AIDS. 
2012;26(4):513-8. 
146. 
Odutola A, Baisley K, Hayes RJ, Rusizoka M, Tanton C, Weiss HA, et al. Pregnancy and 
contraceptive use among women participating in an HIV prevention trial in Tanzania. Sex 
Transm Infect. 2012;88(6):436-43. 
147. 
Mugo NR, Hong T, Celum C, Donnell D, Bukusi EA, John-Stewart G, et al. Pregnancy incidence 
and outcomes among women receiving preexposure prophylaxis for HIV prevention: a 
randomized clinical trial. JAMA. 2014;312(4):362-71. 


 
IMPAACT 2009, FINAL Version 3.0 
Page 120 of 173 
 
  
   
 
19 November 2020 
148. 
Prevention CfDCa. Pre-exposure prophylaxis for the prevention of HIV infection in the United 
States. 2014. 
149. 
Dettinger JC, Kinuthia J, Pintye J, Abuna F, Begnel E, Mugwanya K, et al. Perinatal outcomes 
following maternal pre-exposure prophylaxis (PrEP) use during pregnancy: results from a large 
PrEP implementation program in Kenya. J Int AIDS Soc. 2019;22(9):e25378. 
150. 
Gibb DM, Kizito H, Russell EC, Chidziva E, Zalwango E, Nalumenya R, et al. Pregnancy and 
Infant Outcomes among HIV-Infected Women Taking Long-Term ART with and without 
Tenofovir in the DART Trial. PLoS Med. 2012;9(5):e1001217. 
151. 
Organization WH. Consolidated guidelines on the use of antiretroviral drugs for treating and 
preventing HIV infection: recommendations for a public health approach. 2013. 
152. 
Greenup AJ, Tan PK, Nguyen V, Glass A, Davison S, Chatterjee U, et al. Efficacy and safety of 
tenofovir disoproxil fumarate in pregnancy to prevent perinatal transmission of hepatitis B virus. 
J Hepatol. 2014;61(3):502-7. 
153. 
Hu YH, Liu M, Yi W, Cao YJ, Cai HD. Tenofovir rescue therapy in pregnant females with 
chronic hepatitis B. World J Gastroenterol. 2015;21(8):2504-9. 
154. 
Joseph Davey DL, Pintye J, Baeten JM, Aldrovandi G, Baggaley R, Bekker LG, et al. Emerging 
evidence from a systematic review of safety of pre-exposure prophylaxis for pregnant and 
postpartum women: where are we now and where are we heading? J Int AIDS Soc. 
2020;23(1):e25426. 
155. 
Baeten JM, Haberer JE, Liu AY, Sista N. Preexposure prophylaxis for HIV prevention: where 
have we been and where are we going? J Acquir Immune Defic Syndr. 2013;63 Suppl 2:S122-9. 
156. 
Heffron R, Pintye J, Matthews LT, Weber S, Mugo N. PrEP as Peri-conception HIV Prevention 
for Women and Men. Curr HIV/AIDS Rep. 2016;13(3):131-9. 
157. 
Hodges-Mameletzis I, Fonner VA, Dalal S, Mugo N, Msimanga-Radebe B, Baggaley R. Pre-
Exposure Prophylaxis for HIV Prevention in Women: Current Status and Future Directions. 
Drugs. 2019;79(12):1263-76. 
158. 
van der Straten A, Ryan JH, Reddy K, Etima J, Taulo F, Mutero P, et al. Influences on 
willingness to use vaginal or oral HIV PrEP during pregnancy and breastfeeding in Africa: the 
multisite MAMMA study. J Int AIDS Soc. 2020;23(6):e25536. 
159. 
Dettinger JC, Kinuthia J, Pintye J, Mwongeli N, Gómez L, Richardson BA, et al. PrEP 
Implementation for Mothers in Antenatal Care (PrIMA): study protocol of a cluster randomised 
trial. BMJ Open. 2019;9(3):e025122. 
160. 
Pintye J, Kinuthia J, Abuna F, Mugwanya K, Lagat H, Dettinger JC, et al. Frequency and 
predictors of tenofovir-diphosphate detection among young Kenyan women in a real-world pre-
exposure prophylaxis implementation program. Clin Infect Dis. 2020. 
161. 
Pintye J, Davey DLJ, Wagner AD, John-Stewart G, Baggaley R, Bekker LG, et al. Defining gaps 
in pre-exposure prophylaxis delivery for pregnant and post-partum women in high-burden 
settings using an implementation science framework. Lancet HIV. 2020;7(8):e582-e92. 
162. 
Liu AY, Cohen SE, Vittinghoff E, Anderson PL, Doblecki-Lewis S, Bacon O, et al. Preexposure 
Prophylaxis for HIV Infection Integrated With Municipal- and Community-Based Sexual Health 
Services. JAMA Intern Med. 2016;176(1):75-84. 
163. 
Anderson PL, Glidden DV, Liu A, Buchbinder S, Lama JR, Guanira JV, et al. Emtricitabine-
tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men. 
Sci Transl Med. 2012;4(151):151ra25. 
164. 
Benaboud S, Hirt D, Launay O, Pannier E, Firtion G, Rey E, et al. Pregnancy-Related Effects on 
Tenofovir Pharmacokinetics: a Population Study with 186 Women. Antimicrob Agents 
Chemother. 2012;56(2):857-62. 
165. 
Lurie S, Mamet Y. Red blood cell survival and kinetics during pregnancy. Eur J Obstet Gynecol 
Reprod Biol. 2000;93(2):185-92. 


 
IMPAACT 2009, FINAL Version 3.0 
Page 121 of 173 
 
  
   
 
19 November 2020 
166. 
Anderson P, Liu AY, Castillo-Mancilla J, Seifert S, McHugh C, Wagner T, et al., editors. TFV-
DP in dried blood spots (DBS) following directly observed therapy: DOT-DBS Study. 
Conference on Retroviruses and Opportunistic Infections (CROI); 2017; Seattle, Washington. 
167. 
Anderson PL, Stranix-Chibanda L, Huang S, Hosek S, Kacanek D, Nematadzira T, et al. TFV-DP 
in DBS for pregnant/postpartum adolescent and young women on PrEP in Africa.  Conference on 
Retroviruses and Opportunistic Infections; Boston, MA2020. 
168. 
Anderson PL, Liu AY, Castillo-Mancilla JR, Gardner EM, Seifert SM, McHugh C, et al. 
Intracellular Tenofovir-Diphosphate and Emtricitabine-Triphosphate in Dried Blood Spots 
following Directly Observed Therapy. Antimicrob Agents Chemother. 2018;62(1). 
169. 
Arpaia N, Rudensky AY. Microbial metabolites control gut inflammatory responses. Proc Natl 
Acad Sci U S A. 2014;111(6):2058-9. 
170. 
Costantine MM. Physiologic and pharmacokinetic changes in pregnancy. Front Pharmacol. 
2014;5:65. 
171. 
De Sousa Mendes M, Hirt D, Urien S, Valade E, Bouazza N, Foissac F, et al. Physiologically-
based pharmacokinetic modeling of renally excreted antiretroviral drugs in pregnant women. Br J 
Clin Pharmacol. 2015;80(5):1031-41. 
172. 
Bekker L-G RK, Venter F. Southern African guidelines on the safe use of pre-exposure 
prophylaxis in persons at risk of acquiring HIV-1 infection. S Afr J HIV Med. 2016;17(1). 
173. 
Office of Behavioral and Social Sciences Research NIoH. Qualititative methods in health 
research: opportunities and considerations in application and review. 
174. 
Patton MQ. Qualitative Research and Evaluation Methods. 3rd ed. Thousand Oaks, CA: Sage 
Publications 2002. 
175. 
Castillo-Mancilla JR, Zheng JH, Rower JE, Meditz A, Gardner EM, Predhomme J, et al. 
Tenofovir, emtricitabine, and tenofovir diphosphate in dried blood spots for determining recent 
and cumulative drug exposure. AIDS Res Hum Retroviruses. 2013;29(2):384-90. 
176. 
National Institutes of Health. Guidelines for the Inclusion of Women and Minorities as Subjects 
in Clinical Research. Federal Register.; 1994 March 18. 
177. 
National Institutes of Health. NIH Policy and Guidelines on the Inclusion of Children as 
Participants in Research Involving Human Subjects. 1998 March 6. 


IMPAACT 2009, FINAL Version 3.0 
Page 122 of 173                                                                       19 November 2020 
 
Appendix IA (Schedules of Evaluation): Maternal PK Component Group 1 and Group 2 
 
 
MATERNAL PROCEDURES 
 
SCR 
Entry 
(Day 0) 
Week (± 1 day) 
 
Group 1 
only 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12/ 
Exit 
and 
Early 
D/C1  
L&D2  
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and Drug History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Study drug dispensing 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
iNSC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Outcome 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Demographic/Behavioral Questionnaires 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X3 
 
HIV RNA4; store plasma for HIV drug 
resistance testing5  
4mL 
6mL 
 
 
 
6mL 
 
 
 
6mL 
 
 
 
6mL 
6mL 
Rapid HIV4,6  
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
TFV-DP level (DBS) 
 
4mL 
4 mL 
4mL 
4mL 
4mL 
4mL 
4mL 
4mL 
4mL 
4mL 
4mL 
4mL 
4mL 
4mL 
Complete Blood Count 
3mL 
 
 
 
 
 
 
 
 
 
 
 
 
3mL 
 
ALT, creatinine, CrCl 
4mL 
 
 
 
 
4mL 
 
 
 
 
 
 
 
4mL 
 
Hepatitis B surface antigen 
3mL 
 
 
 
 
 
 
 
 
 
 
 
 
3mL 
 
Glucose (random) 
1mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chlamydia/gonorrhea (swab) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis (protein and glucose) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ultrasound (Group 1 only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test (Group 2 only)7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 X 
 
Total maximum blood volume 
15mL 
10mL 
4mL 
4mL 
4mL 
14mL 
4mL 
4mL 
4mL 
10mL 
4mL 
4mL 
4mL 
21mL 
10mL 
1 If the participant has not delivered at 12 weeks of follow-up, participants may choose to continue in follow-up until delivery, refer to Section 5.1.2.1 
2 If within the window of one of the weekly visits, visits may be combined.  
3 Questionnaire is done at Week 12 visit only; questionnaire is not required at early D/C. 
4 If positive refer to Section 6.3 and Appendix IID for additional procedures. 
5 Store plasma for HIV drug resistance testing at all visits indicated EXCEPT Screening.  
6 Blood collected for other tests will be used for the rapid HIV test. Collection of additional blood is not required. 
7 Urine (5mL) or blood (1mL) tests are acceptable. The total blood volume shown above accommodates collection of 1mL of blood, if needed. 
 
 
 


IMPAACT 2009, FINAL Version 3.0 
Page 123 of 173                                                                       19 November 2020 
 
Appendix IB (Schedule of Evaluations): Infant PK Component Group 1 
 
 
 
 
 
 
 
 
 
 
 
Appendix IC (Schedule of Evaluations): Infant PK Component Group 2 
 
  
 
 
 
INFANT PROCEDURES: Group 1 
 
Birth 
 
PP Wk 6 
 
Early D/C 
 
Medical and Medications History  
X 
X 
X 
Physical Examination 
X 
X 
X 
Infant Feeding History 
X 
X 
 
X 
LABORATORY EVLUATIONS 
 
 
 
Creatinine  
1mL 
1mL 
1mL 
TFV-DP level (DBS) 
0.5mL 
 
 
Total maximum blood volume 
1.5mL 
1mL 
1mL 
INFANT PROCEDURES: Group 2 
Entry (Day 0) 
 
Wk 6 
 
Wk 12  
and  
Early D/C 
 
 
Medical and Medications History  
X 
X 
X 
Physical Examination  
X 
X 
X 
Infant Feeding History  
X 
X 
X 
 LABORATORY EVLUATIONS 
 
 
 
 Creatinine  
1mL 
1mL 
1mL 
 TFV-DP level (DBS) 
0.5mL 
0.5mL 
 
Total maximum blood volume 
1.5mL 
1.5mL 
1mL 


IMPAACT 2009, FINAL Version 3.0 
Page 124 of 173                                                                       19 November 2020 
 
Appendix IIA (Schedule of Evaluations): Maternal PrEP Comparison Component: Cohort 1, Cohort 2/Step 2  
 
MATERNAL PROCEDURES:  
SCR 
Entry 
Wk 4 
Wk 8 
Wk 12 
Wk 24 
Wk 36 
L&D 
PP 
Wk 6 
PP 
Wk 14 
PP 
Wk 26 / Exit 
and Early 
D/C 
Interim  
Visit 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
As per Section 
6.5 
Medical and Drug History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensing 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assess for social harms 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
iNSC 
X 
X 
 
 
 
 
 
 
 
 
X 
iNSC with drug level feedback 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
CASI evaluations and COVID-19 questionnaire 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X1 
Qualitative IDI 
 
 
 
 
X 
 
X 
HIV RNA2; store plasma for HIV drug resistance testing3 
4mL 
6mL 
6mL 
6mL 
6mL 
6mL 
6mL 
6mL 
6mL 
6mL 
6mL 
Rapid HIV2, 4  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TFV-DP level (DBS)  
 
4mL 
4mL 
4mL 
4mL 
4mL 
4mL 
4mL 
4mL 
4mL 
4mL 
Complete Blood Count 
3mL 
 
 
 
 
 
 
 
 
3mL 
 
ALT, creatinine, CrCl 
4mL 
 
4mL 
 
4mL 
4mL 
4mL 
4mL 
 
4mL 
4mL 
Hepatitis B surface antigen 
3mL 
 
 
 
 
 
 
 
 
 
3mL 
Syphilis 
 
1mL 
 
 
 
 
 
 
 
 
1mL 
HSV2 
 
1mL 
 
 
 
 
 
 
 
 
1mL 
Glucose (random) 
1mL 
 
 
 
 
 
 
 
 
 
 
Chlamydia/gonorrhea (vaginal swab or urine) 
 
X 
 
 
 
 
 
 
 
 
X 
Microbiome (rectal swabs); if consent provided 
 
X 
X5 (EGA 34-38/40 weeks)  
 
X 
 
X 
Microbiome (vaginal swab)  
 
X 
X5 (EGA 34-38/40 weeks)  
 
X 
 
X 
Vaginal secretion sampling for drug level 
 
 
X5(EGA 34 -38/40 weeks) 
 
X 
 
X 
Urinalysis (protein and glucose) 
X 
 
 
 
 
 
 
 
 
 
 
Ultrasound  
X 
 
 
 
 
 
 
 
 
 
 
 
DXA scan (Hip, Lumbar Spine)6 
 
 
 
 
 
 
 
X 
 
 
X 
Pregnancy Test7 
 
 
 
 
 
 
 
 
 
X 
X 
Total maximum blood volume  
15mL 
12mL 
14 mL 
10mL 
14mL 
14mL 
14mL 
14mL 
10mL 
18mL7 
20mL7 
 
1 CASI is done at Week 26 visit only; CASI is not required at early D/C.  
2 If positive refer to Section 6.3.1 and Appendix IID for additional procedures. 
3 Store plasma for HIV drug resistance testing at all visits indicated EXCEPT Screening. 
4 Blood collected for other tests will be used for the rapid HIV test; collection of additional blood is not required.  
5 Collect sample at any visit which occurs at an estimated 34 – 38/40 weeks’ gestation. 
6 DXA scan at Wk 26/Exit and early D/C (as applicable) must be preceded by a pregnancy test.  
7 Urine (5mL) or blood (1mL) tests are acceptable. The total blood volume shown above accommodates collection of 1mL of blood, if needed. Note: Pregnancy testing may be 
done prior to the DXA scan at Wk 26/Exit and Early D/C and does not need to be repeated. 


IMPAACT 2009, FINAL Version 3.0 
Page 125 of 173                                                                       19 November 2020 
 
Appendix IIB (Schedule of Evaluations): Maternal PrEP Comparison Component Cohort 2  
 
MATERNAL PROCEDURES:  
 
SCR 
Entry 
Wk 4 
Wk 8 
Wk 12 
Wk 24 
Wk 36 
L&D 
PP 
Wk 6 
PP 
Wk 14 
PP  
Wk 26 / Exit 
and 
Early D/C 
Step Change 
Visit 1 
Visit 2  
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and Drug History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensing 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Assess for social harms 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
iNSC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CASI evaluations and COVID-19 questionannire  
 
X 
X 
X 
X 
X 
X 
 
 
X 
X1 
X 
X 
Qualitative IDI 
 
 
 
 
X 
 
X 
 
 
HIV RNA2; store plasma for HIV drug resistance testing3  
4mL 
6mL 
6mL 
6mL 
6mL 
6mL 
6mL 
6mL 
6mL 
6mL 
6mL 
6mL 
 
Rapid HIV2,4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
TFV-DP level (DBS) 
 
4mL 
 
 
 
 
 
4mL 
 
 
 
 
4mL 
Complete Blood Count 
3mL 
 
 
 
 
 
 
 
 
3mL 
 
3mL 
 
ALT, creatinine, and CrCl 
4mL 
 
4mL 
 
4mL 
4mL 
4mL 
4mL 
 
4mL 
4mL 
4mL 
 
Hepatitis B surface antigen 
3mL 
 
 
 
 
 
 
 
 
 
3mL 
3mL 
 
Syphilis 
 
1mL 
 
 
 
 
 
 
 
 
1mL 
 
 
HSV2 
 
1mL 
 
 
 
 
 
 
 
 
1mL  
 
 
Glucose (random) 
1mL 
 
 
 
 
 
 
 
 
 
 
1mL 
 
Chlamydia/gonorrhea (vaginal swab or urine) 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Microbiome (rectal swabs); if consent provided 
 
X 
X5(EGA 34-38/40 weeks) 
 
X 
 
X 
 
X 
Microbiome (vaginal swab) 
 
X 
X5(EGA 34-38/40 weeks) 
 
X 
 
X 
 
 
X 
Urinalysis (protein and glucose) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Ultrasound  
X 
 
 
 
 
 
 
 
 
 
 
 
 
DXA scan (Hip, Lumbar Spine)6 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Pregnancy Test7 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Total maximum blood volume 
15mL 
12mL 
10mL 
6mL 
10mL 
10mL 
10mL 
14mL 
6mL 
14mL7 
16mL7 
17mL 
4mL 
1CASI is done at Week 26 visit only; CASI is not required at early D/C. 
2 If positive refer to Section 6.3.1 and Appendix IID for additional procedures. 
3Store plasma for HIV drug resistance testing at all visits indicated EXCEPT Screening. 
4Blood collected for other tests will be used for the rapid HIV test; collection of additional blood is not required. 
5Collect sample at any visit which occurs at an estimated 34 – 38/40 weeks’ gestation. 
6DXA scan at Wk 26/Exit and Early D/C (as applicable) must be preceded by a pregnancy test. 
7Urine (5mL) or blood (1mL) tests are acceptable. The total blood volume shown above accommodates collection of 1mL of blood, if needed. Note: Pregnancy testing may be 
done prior to the DXA scan at Wk 26/and Early D/C and does not need to be repeated. 


IMPAACT 2009, FINAL Version 3.0 
Page 126 of 173                                                                       19 November 2020 
 
Appendix IIC (Schedule of Evaluations): Infant PrEP Comparison Component (both cohorts) 
 
 
 
INFANT PROCEDURES 
Birth 
PP Wk 6 
PP Wk 14 
PP Wk 26 
Early D/C 
CLINICAL EVALUATIONS 
 
Medical and Medications History 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
Infant Feeding History 
X 
X 
X 
X 
X 
OTHER EVALUATIONS 
 
 
 
 
 
DXA scan:  
        Whole Body  
        Lumbar spine 
X 
 
 
 
 
X 
 
 
X 
 
LABORATORY EVALUATIONS 
 
 
 
 
 
Creatinine  
1mL 
 
 
1mL 
1mL 
TFV- DP level (DBS) 
0.5mL 
 
 
 
 
Microbiome (rectal swab or fresh 
stool) 
X 
X 
X 
X 
X 
Total maximum blood volume  
1.5mL 
 
 
1mL 
1mL 


IMPAACT 2009, FINAL Version 3.0 
Page 127 of 173                                                                       19 November 2020 
 
Appendix IID (Schedule of Evaluations): Maternal Suspected or Confirmed HIV Infection 
 
Note: Maternal participants continue to follow the relevant Schedule of Evaluations in Appendices IA, IIA, and IIB. These procedures are 
considered additional procedures and visits can be combined.  
 
Both PK and PrEP Comparison Components 
 
MATERNAL PROCEDURES 
Confirmatory Visit 
 
Confirmed Infected 
4 weeks after date of initial HIV positive 
blood draw  
CLINICAL EVALUATIONS 
Referral for HIV care and treatment (and PMTCT if 
pregnant or breastfeeding) 
X 
X 
Interim medical and medication history 
 
X 
iNSC 
X 
 
LABORATORY EVALUATIONS  
Confirmatory HIV Test1  
 
[Up to 10mL] 
 
 
Store plasma and non-viable PBMCs for HIV drug 
resistance testing  
12mL 
12mL 
CD4 Count  
3mL 
 
3mL 
Total maximum blood volume 
25mL 
15mL 
1.  HIV confirmatory testing will follow the site-specific approved HIV testing algorithm and Section 6.3.1.  
 
 
 
 
 
 
 
 
 


IMPAACT 2009, FINAL Version 3.0 
Page 128 of 173                                                                       19 November 2020 
 
Appendix IIE (Schedule of Evaluations): Infant HIV Exposure and Infection 
 
Note: Infant participants continue to follow the relevant Schedule of Evaluations in Appendices IB, IC or IIC. These procedures are considered 
additional procedures and visits can be combined. 
 
 
HIV Exposed 
HIV Infected 
INFANT PROCEDURES 
At Maternal 
Confirmatory Visit  
(at delivery if positive 
test was during 
pregnancy)  
At every study 
visit thereafter 
 
Confirmatory  
Testing 
(obtain as soon as 
possible after initial 
positive result) 
At every 
study visit 
thereafter 
 
 
CLINICAL EVALUATIONS 
Referral to primary care provider 
X 
 
 
 
Referral to HIV care and treatment 
 
 
X 
 
LABORATORY EVALUATIONS  
HIV nucleic acids testing (NAT)  
3mL 
3mL 
3mL 
 
Complete Blood Count  
 
 
 
0.5mL 
Lymphocyte subsets  
 
 
 
1mL 
Stored plasma and non-viable PBMCs 
for resistance testing 
 
 
2mL 
2mL 
Total maximum blood volume  
3mL 
3mL 
5mL 
3.5mL 
 
 
 
 
 
 
 
 
 
 


IMPAACT 2009, FINAL Version 3.0 
Page 129 of 173 
  19 November 2020 
Appendix III: Targeted Medications List 
 
All medications specified below must be entered into eCRFs.  
 
• 
Antimicrobial agents when administered by 
the following routes: 
o Oral 
o Vaginal 
o Intramuscular 
o Intravenous 
 
• 
Drugs that may Interfere with Tenofovir 
Excretion 
o Adefovir  
o Antineoplastics 
o Cidofovir 
o Cyclosporin A  
o Indomethacin  
o Penicillins 
o Probenecid  
o Rifampin  
o Sirolimus  
o Ursodiol  
o (Val)ganciclovir hydrochloride  
 
• 
Hormonal Contraceptives (Including 
hormones used for feminization) 
 
• 
Other Hormonal Therapy 
o Thyroid replacement  
o Anabolic agents 
 
• 
Inhaled Steroids  
 
• 
Systemic Glucocorticoids 
 
• 
Antiepileptics 
 
• 
Antidepressants  
o Serotonin release inhibitors 
o NRI 
 
• 
Lipid Lowering Agents 
• 
Appetite Stimulants 
 
• 
Herbal Medicine 
o St. John’s Wort 
o Garlic supplements 
o Echinacea 
 
• 
Over the Counter Agents (sold under a 
variety of trade names) 
o Androstenedione 
o Dihydroepiandrosterone, DHEA 
o Fish oil (n-3 fatty acids) 
o GH-releasers (arginine, ornithine, 
lysine) 
o β-hydroxy-β-methylbutyrate 
(betaHMB)  
 
 
 
 


IMPAACT 2009, FINAL Version 3.0 
Page 130 of 173 
19 November 2020 
Appendix IV: General Management Guidelines for Maternal Toxicities 
 
General Toxicities 
SEVERITY 
STUDY DRUG USE 
FOLLOW-UP AND MANAGEMENT 
 
Grade 1 and Grade 2 
 
Clinical and laboratory adverse events regardless 
of relatedness 
 
 
 
Study drug may be continued 
at the discretion of the site 
clinician 
Monitor consistent with the SoE (no additional 
evaluations are required). Consultation with the CMC is 
available but not required.  
Grade 3 and Grade 4  
 
Clinical adverse events  
assessed as not related to study drug  
 
 
 
Continue study drug   
 
 
Inform the CMC. Monitor every 7-10 days for 
improvement to Grade 2 or lower, unless instructed 
otherwise by the CMC. If severity worsens, or does not 
improve to Grade 2 or lower within 14 days, inform and 
request guidance from the CMC. 
Grade 3 and Grade 4  
 
Clinical adverse events  
assessed as related to study drug  
 
 
Hold study drug 
Consult the CMC for further guidance on study drug 
management. Monitor every 7-10 days for improvement to 
Grade 2 or lower, unless instructed otherwise by the 
CMC. 
 
 
 
 
 
 
 
 
 
 
 
 
 


IMPAACT 2009, FINAL Version 3.0 
Page 131 of 173                                                                       19 November 2020 
 
General Toxicities 
SEVERITY 
STUDY DRUG USE 
FOLLOW-UP AND MANAGEMENT 
Grade 3 laboratory adverse event 
Study drug may be continued 
at the discretion of the site 
clinician pending receipt of 
confirmatory test results. 
• Repeat the laboratory test within 7-10 days.  
• If the repeat test result is Grade 2 or lower, manage per the grade of 
the repeat test.  
• If the repeat test is Grade 3, inform the CMC and continue to 
monitor every 7-10 days until improvement to Grade 2 or lower, 
unless instructed otherwise by the CMC.  
– If the confirmed Grade 3 event is assessed as not related to study 
drug, study drug may be continued. 
If severity worsens, or does not improve to Grade 2 or lower 
within 14 days, inform and request guidance from the CMC. 
If the confirmed Grade 3 event is assessed as related to study drug, hold 
study drug until improvement to Grade 2 or lower, at which time re-
challenge with study drug may be considered in consultation with the 
CMC. Following re-challenge (if applicable), if the Grade 3 event 
recurs, permanently discontinue study drug. If severity worsens, or does 
not improve to Grade 2 or lower within 14 days, inform CMC and 
permanently discontinue study drug. 
Grade 4 laboratory adverse event 
Hold study drug pending 
receipt of confirmatory test 
results. 
 
• Repeat the laboratory test within 3 business days.  
• If the repeat test result is Grade 3 or lower, manage per the grade of 
the repeat test.  
• If the repeat test is Grade 4, continue to hold study drug. Inform the 
CMC and continue to monitor every 7-10 days until improvement to 
Grade 2 or lower, unless instructed otherwise by the CMC.  
• If severity does not improve to Grade 2 or lower within 14 days, 
inform the CMC and permanently discontinue study drug.  
• If severity improves to Grade 2 or lower, re-challenge may be 
considered in consultation with the CMC. Following re-challenge (if 
applicable), if the event recurs at Grade 3 or higher, permanently 
discontinue study drug. 
 
 
 
 


IMPAACT 2009, FINAL Version 3.0 
Page 132 of 173                                                                       19 November 2020 
 
 
Appendix V: General Management Guidelines for Maternal Increased Creatinine and Reduced Creatinine 
Clearance    
 
Maternal Increased Creatinine and Reduced Creatinine Clearance 
CONDITION AND SEVERITY 
STUDY DRUG USE 
FOLLOW-UP AND MANAGEMENT 
All grades 
 
• 
Assess participant for other potential causes of decreased renal 
function per site standard of care.  
• 
Management action should be taken based on the absolute value 
of each participant’s creatinine value and estimated CrCl (not 
change from study baseline). 
• 
Management should be based on the most severe result 
(creatinine or creatinine clearance). 
Grade 1 increased creatinine  
Continue study drug 
Follow-up per SOE 
Grade 2 increased creatinine OR reduced 
creatinine clearance (estimated CrCl <90 to 
≥60 mL/min) 
Continue study drug 
Repeat the test and perform urinalysis within 1 week of site 
awareness. 
• If the repeat test does not confirm Grade 2 severity, follow the 
management guidance for that severity grade. 
• If the repeat test confirms Grade 2 severity: 
o Inform the CMC, and  
o Monitor creatinine and CrCl every 2 weeks until creatinine 
and CrCl are stable or improving, and 
o Update the CMC with each new result 
Grade 3 or Grade 4 increased creatinine OR 
reduced creatinine clearance (estimated CrCl 
<60mL/min) 
 
Hold study drug while awaiting 
confirmatory test result.  
Repeat the test and perform urinalysis within 3 business days of site 
awareness.  
• If the repeat test does not confirm Grade 3 or Grade 4 severity: 
o Resume study drug at the site clinician’s discretion, and  
o Follow the management guidance for that severity grade 
• If the repeat test confirms Grade 3 or Grade 4 severity: 
o Inform the CMC, and 
o Permanently discontinue study drug, and 
o Monitor creatinine and CrCl at the frequency set by the 
CMC, and 
o Update the CMC with each new result 


 
IMPAACT 2009, FINAL Version 3.0 
Page 133 of 173 
19 November 2020 
 
Appendix VI: Sample Informed Consent Form for PK Component (Groups 1 & 2) 
 
IMPAACT 2009 
Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral Pre-Exposure Prophylaxis for 
Primary HIV Prevention during Pregnancy and Postpartum in Adolescents and Young Women and 
their Infants 
 
Version 3.0, dated 19 November 2020 
 
Introduction 
 
We invite you to take part in a research study with your baby named IMPAACT 2009. There are two 
parts to this study, and this form is for the first part – the “PK Component.”  
 
This form gives information about both parts of the study. Please read it, or have it read to you, and ask 
any questions you may have. You can take as much time as you need 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 will participate with your baby, we will ask you 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 learn more about a medication called “PrEP.” PrEP stands for “pre-
exposure prophylaxis.” For people who are not infected with HIV, but may be at risk of becoming 
infected with the HIV virus, taking medication called PrEP can help protect them. Other studies have 
shown that PrEP works very well in preventing HIV infection. We also know that the level of protection 
PrEP provides depends on whether someone takes PrEP every day. So far, not many women have taken 
PrEP while they are pregnant and just after delivery, even though women may be at heightened risk of 
becoming infected with HIV during this period. 
 
The purpose of the IMPAACT 2009 study is to find out whether young women in sub-Saharan Africa at 
heightened risk of becoming infected with HIV are interested and would be willing to take a PrEP pill 
once a day while they are pregnant and breastfeeding. The purpose of the first part of the study (PK 
Component) is to find out how much PrEP medication can be measured in the blood of women who take 
PrEP every day without missing any doses while they are pregnant and after delivery.  
 
We invite you to join the PK Component of this study because you are not infected with HIV and are 
pregnant or have just delivered. The PK Component of this study will include up to 40 mothers from 
clinical sites in Sub-Saharan Africa. Mothers who join the study after delivery will be in the study with 
their babies for twelve weeks. Mothers who join the study while pregnant will be in the study for at least 
twelve weeks, through labor and delivery. Their baby will also be seen when they are six weeks old.  
 
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. 
 
 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 134 of 173 
19 November 2020 
 
1. There are two parts to this study. You and your baby are being asked to join the first part – the PK 
Component. 
 
The two parts of the study are called the “PK Component” and the “PrEP Comparison Component.”  The 
PK Component will be done first. This part will include up to 40 mothers with their babies; half will join 
when they are pregnant (Group 1) and the others will join in the period after their delivery (Group 2).  
 
If you join the PK Component, you will take pills every day and have a study check-up every week for 12 
weeks.  
 
When the PK Component has been completed, the PrEP Comparison Component will be done and this 
part will include about 350 mothers and their babies. If you participate in the PK Component, you will not 
be able to participate in the PrEP Comparison Component. 
 
2. The study will assess PrEP use in women who are pregnant and just after delivery and their babies. 
 
The medicine being used for PrEP in this study is called Truvada®. Truvada® is a pill that contains two 
medications called “emtricitabine” and “tenofovir” that are commonly used to treat HIV infection and 
sometimes to treat Hepatitis. We know that Truvada® is safe and effective in reducing the risk of HIV 
infection when taken by people who are HIV uninfected. But, not many studies about PrEP have involved 
HIV uninfected women while they are pregnant and after delivery, so we need more information during 
this period. 
 
Truvada® is approved for PrEP in many countries around the world. In [insert site country], PrEP is 
approved for [insert details as relevant, e.g. of population in which PrEP is approved and if PrEP is 
national policy].  
 
3. The PK Component part will assess how much PrEP medication can be measured if a woman takes it 
daily. 
 
The PK Component will be done to look at how much of the PrEP drug is in your blood when you take 
PrEP every day for 12 weeks, during pregnancy (Group 1) or after delivery (Group 2). We will also 
measure how much PrEP is passed on to your baby.  
 
We need to do these measurements because the body changes during pregnancy, so the amount of PrEP 
drug found in the blood of pregnant women may be different from non-pregnant women. The information 
we gather from this part of the study will be used later to help us counsel women about how well they are 
taking PrEP and how well they are protected from HIV.  
 
4. Only mothers who qualify can participate in the study. 
 
If you decide to join the study with your baby, we will first do some tests to see if you qualify. More 
information about the tests is given in #5 (see below). If you qualify, you and your baby will enter the 
study. If you do not qualify, you and your baby cannot enter the study.  
 
If you qualify, you can choose if you want to join the study or not. You are free to join or not join. If you 
join, you can change your mind later and leave the study. Your decision will have no effect on the 
medical care that you and your baby would normally receive from your usual clinic. Your access to 
services, and the benefits and rights you normally have, will not be affected. 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 135 of 173 
19 November 2020 
 
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. 
 
Finding out if You and Your Baby Qualify – Visit 1 
 
5. 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 any medicines you or your baby take 
• 
Talk with you about the study requirements and if you meet them 
• 
Have you talk with a counselor about your health behaviors 
• 
Give you a physical examination (and your baby, if already delivered) 
• 
Collect urine to check how well your kidneys are working and if there is sugar is in your urine  
• 
Collect your blood (up to 15 mL or about 3 teaspoons) for tests. The tests will:  
– Check your blood cells 
– Check if you have Hepatitis B (a disease of the liver) 
– Check how well your liver and kidneys are working 
– Check your blood to confirm that you are not infected with HIV.  
– Check your blood sugar levels 
 
These procedures will take about 2 hours [here and throughout this form, sites may modify the expected 
visit duration as needed].  
 
6. If you are pregnant, we will also do an ultrasound scan. 
 
We need to know how long you have been pregnant when you enter the study and whether you may be 
pregnant with more than one baby. To do this, you will have an ultrasound scan and we will ask you the 
date of your last menstrual period [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.  
 
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 and measure the size.  
 
[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 
before entering the study. There is no cost for having the scan done.  
 
If you have already had an ultrasound and have the report, this may not be needed. 
 
7. We will tell you if you and your baby qualify. 
 
We will give you the results of all procedures and explain them to you.  
 
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 do qualify for the study and you agree to join with your baby, you will enter the study.  


 
IMPAACT 2009, FINAL Version 3.0 
Page 136 of 173 
19 November 2020 
 
Entering the Study – Visit 2 
 
8. If you and your baby qualify, you will enter the study within a couple of weeks.  
 
When you enter the study, we will: 
 
• 
Ask about your health and the medicines you take.  
• 
Have you talk with a counselor about your health behaviors and how to take PrEP. 
• 
Ask you questions about your health behaviors. 
• 
Give you a physical exam. 
• 
Collect a vaginal swab to check if you have sexually transmitted infections such as chlamydia or 
gonorrhea. For this specimen, a small swab is inserted into the vagina to collect some mucus.  
• 
Collect your blood (10 mL or about 2 teaspoons) for tests. These tests will: 
– Confirm you are not infected with HIV. 
– Check if any PrEP is in your blood. 
• 
Give you a supply of PrEP pills.  
• 
Save some of the blood in case you become infected with the HIV-virus during the study for extra 
HIV tests. 
 
It is very important that you take the PrEP pill once a day, every day for 12 weeks. 
 
Being in the Study 
 
9. You will take PrEP under Directly Observed Therapy (DOT) 
 
This is the most important part about being in the PK Component. We need to check that you swallow 
the PrEP pill every day to understand the levels of PrEP medication we measure in your blood. To do this, 
study staff will contact you every day during the 12 weeks you take PrEP; we call this directly observed 
therapy or DOT. Some women may prefer to take their pill in front of a study staff member at the clinic or 
at home each day. Other women may choose to video record themselves taking their pill or take their pill 
while on a video call with study staff using a smartphone, tablet or computer to confirm that they have 
taken their pill. We will talk with you to work out a suitable DOT plan if you decide to join the study. 
 
If you complete all your visits before delivering your baby, you may choose to continue taking PrEP until 
labor and delivery.  
 
 
If you don’t want us to contact you every day for 12 weeks, then you should not join the PK 
Component of the study. 
 
 
 
 
 
 
 
 
 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 137 of 173 
19 November 2020 
 
10. You will have a visit every week for 12 weeks. 
 
Each visit will take about 1-2 hours. You will need to return to the clinic for visits at Weeks 4, 8 and 12. 
For the other visits, you can either return to the clinic or the study staff can visit you at an off-site location 
which can include your home. The study staff will discuss the location and best time to visit you so that 
the visit is at a convenient time and the visit is done at a place you feel comfortable and confidentiality 
can be maintained. If you have already delivered when you enter the PK Component (Group 2), you will 
come with your baby.  
 
At these visits for all women we will:  
• 
Review your medical records 
• 
Ask about your health and the medicines you take 
• 
Give you a physical exam (at Weeks 4, 8 and 12 only) 
• 
Collect your blood (up to 4-21 mL or about 1-4 teaspoons) for tests. At different visits, the tests will:  
– Check your blood cells 
– Check if you have Hepatitis B 
– Check how well your liver and kidneys are working 
– Confirm you remain HIV uninfected 
– Check how much of the PrEP drugs are in your blood 
• 
Have you talk with a counselor about your health behaviors  
• 
Ask questions about how easy it is to take your PrEP every day and about your health behavior (at 
Week 12 only) 
• 
Give you a supply of PrEP pills 
• 
Save some of the blood in case you become infected with the HIV-virus during the study for extra 
HIV tests 
 
11. Your baby will also have study visits 
 
If you are pregnant when you join the study (Group 1), you and your baby will also have a study visit soon 
after delivery and at 6 weeks.  
 
You should contact us when your labor begins to arrange for a study visit as soon as possible after 
delivery. It is important for this visit to take place close to the baby’s birth. This visit will take up to 4 
hours.  
 
When you come to the clinic with your baby for the visit soon after delivery we will: 
• 
Review your and your baby’s medical records 
• 
Have you talk with a counselor about your health behaviors  
• 
Ask about your and your baby’s health and the medicines you take 
• 
Ask about how you are feeding your baby 
• 
Give you and your baby a physical exam 
• 
Collect blood from you (up to 10 mL or about 2 teaspoons) for tests: 
– To check how much PrEP is in your blood  
– To confirm you remain HIV uninfected 
• 
Save some of the blood in case you become infected with the HIV-virus during the study for extra 
HIV tests 
• 
Collect blood from your baby (up to 1.5 mL or less than ½ teaspoon) 
– To check how much PrEP is in your baby’s blood  
– To confirm your baby’s kidneys are working well (at the first visit only) 


 
IMPAACT 2009, FINAL Version 3.0 
Page 138 of 173 
19 November 2020 
 
Your next study visit for your baby only will be when your baby is about 6 weeks of age. This visit will 
take about 2 hours and will be a repeat of most of the procedures which took place soon after delivery. 
 
If you join the study after delivery (Group 2) your baby will have a study visit on the day you enter the study, 
after 6 weeks and after 12 weeks.  
 
When you come to the clinic with your baby for these visits we will: 
• 
Review your baby’s medical records 
• 
Ask about your baby’s health and medicines 
• 
Ask about how you are feeding your baby 
• 
Give your baby a physical exam 
• 
Collect blood from your baby (up to 1.5 mL or less than ½ teaspoon) 
– To check how much PrEP is in your baby’s blood  
– To confirm your baby’s kidneys are working well (at the first, sixth and twelfth visit 
only) 
 
While you are in the study, we will give you the results of the tests for you and your baby. We may need 
to repeat a blood test for you or your baby. If you become infected with HIV during the study, we still 
want you and your baby to complete all your study visits, but it is your choice. We will discuss with you 
how to get care and treatment for HIV outside the study and arrange it with the staff there [site to revise 
as needed]. 
 
12. If you become infected with HIV during the study, you and your baby will have extra visits.  
 
We will test you for HIV throughout the study using a rapid test in the clinic and another type of HIV test 
in the laboratory (RNA PCR) test. If your HIV test results are positive, we will take more blood to 
confirm the HIV infection and measure the HIV viral load (how much HIV is in the blood). It usually 
takes about a week for these results to come back. 
 
These extra visits will take about 1 hour. At these visits, we will: 
• 
Have you talk with a counselor about your health behaviors  
• 
Refer you for HIV care and treatment. 
• 
Collect your blood (15-25 mL or about 3.5 to 5 teaspoons) for tests.  
 
The tests will: 
– Confirm your HIV viral load 
– Check your cells 
– Check if the HIV in the blood is resistant to the medications in the PrEP pill 
• 
Save some of the blood for additional tests about the HIV virus 
• 
Collect any remaining PrEP pills from you 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 139 of 173 
19 November 2020 
 
13. Tests will be done at our laboratory. 
 
We will do tests of you and your baby’s specimens at our laboratory. Most of the tests will be done right 
away at a local facility. We will give you the results of these tests and explain the results to you. 
However, some specimens will be kept and tested together at the end of the study. 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. Some tests, such as the PrEP drug levels, are special and must be sent 
to specialized laboratories outside the country. If there are any specimens left-over after all the tests for 
this study have been done for you and your baby, we would like to keep those specimens because they 
may be useful for studies in the future. We will talk to you about what you want to happen to these left-
over specimens in another informed consent form. 
 
14. We may stop your PrEP. 
 
The examinations and laboratory tests we do during the study will help us to tell if the PrEP you are 
taking is causing any bad effects. If so, the PrEP may be stopped. PrEP may be stopped if you have 
certain illnesses or need to take other medicines that cannot be taken with PrEP. We will always discuss 
stopping PrEP with you. Please tell us about any problems you may have with taking PrEP.  
 
We may stop the PrEP you are receiving from the study if: 
 
• 
You are not able to come to study visits 
• 
You are not able to take PrEP every day 
• 
Taking PrEP may be harmful to you 
• 
You ask to stop taking PrEP 
 
15. We may take you and your baby off the study early. 
 
We expect you to stay in the study until you and your baby have completed all the study visits; Group 1 – 
until the baby is six weeks old; Group 2 – until the baby is about 3 months old. However, we may take 
you and your baby off the study early 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 
 
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 we do at the weekly study visits (see #10 and #11). We will answer any questions you 
may have and tell you how to contact us in the future, if you wish. 
 
16. 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 – you just need to tell us. 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 we do at the weekly study visits (see #10 and #11 above). We will 
answer any questions you may have and tell you how to contact us in the future, if you wish. 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 140 of 173 
19 November 2020 
 
17. How to stay uninfected after leaving the study.  
 
We cannot give you PrEP after you finish your study visits. Before you leave the study, we will talk again 
about how to protect yourself against HIV infection and give you information about other clinics that 
offer PrEP to women. If you want to continue taking PrEP, we will refer you there. [Sites to modify as 
necessary and insert information about referral letters and sharing study laboratory results with the non-
study PrEP provider, as appropriate]  
 
18. If you joined the study after delivery, we will test for pregnancy during the study.  
 
If you were not pregnant when you entered the study, we will test for pregnancy during the study. If you 
become pregnant, you will continue in the study and may continue to take PrEP during the study. If you 
choose to continue taking PrEP after you leave the study, we will refer you to clinics that offer PrEP to 
women. We will contact you after your last study visit to find out the outcome of your pregnancy.  
 
Risks of the Study 
 
19. There may be risks from the study procedures. 
 
 
Most procedures done in this study are routine medical procedures, with little risk to you and your baby.  
 
Blood Collection: Collecting blood can cause pain, swelling, bruising, or bleeding where the needle is 
inserted. Rarely, drawing blood can cause fainting or infection where the needle enters the skin.  
 
Urine Collection: There is no risk from collecting your urine 
 
Ultrasound scan: There is no risk from ultrasound 
 
Vaginal swab collection: You may feel a little discomfort when the swab is inserted into the vagina. The 
study staff will show you the swab and you can ask any questions about this procedure before it is done. 
 
HIV Testing: We will perform an HIV test at about five visits, which is done to make sure that you are 
HIV uninfected before starting or continuing PrEP. You will be counseled before and after the test is 
done. [Sites to insert reporting responsibilities in the country the site is located in. Also include whether if 
a participant tests positive, the results will become part of public health records, or any other record 
(medical file, etc.)] You can come to the clinic and ask for an HIV test anytime you are worried. 
 
STI Testing: You will be tested for STIs. [Insert here any reporting responsibilities for your state or local 
jurisdictions or reporting of these infections to public health authorities]. If you have any of these 
infections, we will provide you with treatment. 
 
Acquiring HIV Infection and Drug Resistance: You must understand this information about what PrEP 
can and can’t do: 
• 
PrEP cannot give you HIV infection 
• 
Taking PrEP prevents HIV in most people who take it every day, but 
• 
You still may become infected with HIV while you are taking PrEP 
• 
PrEP does not prevent pregnancy or STIs 
• 
You still need to use other methods to avoid HIV infection and other STIs while you are taking PrEP, 
like using condoms every time you have sex and keeping your number of sexual partners low. Study 
staff will discuss all the different ways you can keep yourself from getting these infections.  


 
IMPAACT 2009, FINAL Version 3.0 
Page 141 of 173 
19 November 2020 
 
If you become infected with HIV while you are taking PrEP, the strain of the HIV virus in your blood 
might be “resistant” to Truvada® and some other medications used for HIV treatment (ART). 
“Resistance” means the virus can’t be killed by that medication, which makes treating the HIV more 
difficult. If you become infected with HIV, we will test for HIV drug resistance. You will be able to 
discuss ART and resistance with the study staff.  
 
If you have any questions about anything we have said here, please talk to us. 
 
Other Risks: Also, there may be uncommon risks or risks we don’t know about yet that might occur. You 
should report any problems to the study staff immediately. There may also be some social risks to 
participating in this study. You may feel embarrassed or uncomfortable with some of the questions we 
will ask you, some of the procedures that will be done, or some of the test results that you will receive. 
You may also experience stigma as a result of being involved in a study about HIV because people may 
assume that you are HIV-infected. If you have HIV or other infections, knowing this could make you 
worried. Study staff are trained to help you deal with any feelings or questions you have. 
 
20. There are risks from PrEP(Truvada®) 
 
You or your baby may feel sick while participating in the study. These problems may be due to taking 
PrEP or due to an illness that has no relation to the study, like a cold or flu. You should tell us about any 
symptoms that you feel while you are participating in the study. You will be given a telephone number to 
contact the clinic.  
 
You should contact us if you experience any symptoms at any time. 
 
In PrEP research studies, nausea and diarrhea were the most common side effects, but happened in only 
about 10% or one in ten people. Nausea and diarrhea mainly happened in the first month and then went 
away. A small number (<1% or one in one hundred people) in PrEP studies showed a small decrease in 
how their kidneys work, but this stopped when the people stopped taking the drug.  
 
Other side effects, such as changes in bone mineral density (how much calcium and other minerals are in 
your bone which keeps them strong) were very rare in people taking the drug who did not have HIV and 
have always gotten better when the drug was stopped.  
 
You could have these side effects or other side effects that we do not know about. Please tell the staff here 
if you have any side effect that bothers you or does not go away.  
 
Other Medications: Some medications should not be taken while you are taking Truvada®. When you 
visit the study clinic, we will ask you about other medications that you are taking.  
 
Risks to your baby: The medicines in PrEP (Truvada®) are often used to treat women with HIV infection. 
Many HIV-infected women have taken these medicines while pregnant and breastfeeding. We know that 
these medicines pass through to the baby in the womb and are found in breastmilk in small amounts. The 
information we have so far suggests that these medicines do not cause serious problems in the baby. 
However, it is still possible that taking PrEP may cause some problems in the baby soon after birth or 
when they are older. The study staff will check for side effects in babies during study visits and tell you 
what to do if your baby has any side effects. You should contact the study staff at any time if you are 
worried about the baby’s health. 
 
Truvada® may have side effects that no one knows about yet. We will let you know if we learn anything 
that might make you change your mind about continuing to participate in the study. 


 
IMPAACT 2009, FINAL Version 3.0 
Page 142 of 173 
19 November 2020 
 
21. There could be risks of disclosure of your or your baby’s information. 
 
We will make every effort to keep you 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, you and your baby’s names will be written on some records that are 
kept in the clinic. Despite our best efforts to keep this 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.  
 
While you are in the PK Component, you will be contacted every day for 12 weeks by the study staff. 
Because of this, the people you live with may realize that you are involved in a study and could ask you 
questions about it. You can talk to study staff about how to handle this situation before you decide to join. 
 
Benefits of the Study 
 
22. There may be no benefit from being in the study. 
 
We will test you for HIV and other STIs throughout this study. If you take your Truvada® every day, it 
will help you to avoid HIV. Participating in this study may give you knowledge and skills that may help 
you to avoid HIV and other STIs. What we learn about PrEP use in young women may help women in the 
future decide if they want to take PrEP while they are pregnant and breastfeeding. 
 
Other information about the study 
 
23. There are no costs to you for being in the study. 
 
There are no costs to you or your baby for study visits or procedures or the PrEP that is given by the 
study, and you will not receive payment for participating in 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).] 
 
24. 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 (FDA) 
• 
The Office for Human Research Protections (OHRP) 
• 
Other U.S., local, and international regulatory entities 
• 
The IMPAACT Network that is coordinating the study 
• 
Gilead Sciences (the company that makes Truvada®) 
 
The study staff and these groups are required to make every effort to keep study records private and 
confidential. 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 143 of 173 
19 November 2020 
 
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 a website called www.ClinicalTrials.gov.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.  
 
25. 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 
 
26. 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] 
 
 
 
 
 
 
 
 
 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 144 of 173 
19 November 2020 
 
Signature Page for Maternal Participants 
 
Screening and Enrollment Consent for Maternal Participants of Legal Age to Provide Independent Consent 
 
IMPAACT 2009 
Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral Pre-Exposure Prophylaxis for 
Primary HIV Prevention during Pregnancy and Postpartum in Adolescents and Young Women and 
their Infants 
 
Version 3.0, dated 19 November 2020  
 
 
If you decide to join the PK Component of 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 Participant (print) 
 
Signature of Participant   
 
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) 
 
 
 
 
 
 
 
 
 
 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 145 of 173 
19 November 2020 
 
Signature Page for Maternal Participants 
Assent for Maternal Participants Not of Legal Age to Provide Independent Consent 
 
IMPAACT 2009 
Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral Pre-Exposure Prophylaxis for 
Primary HIV Prevention during Pregnancy and Postpartum in Adolescents and Young Women and 
their Infants 
 
Version 3.0, dated 19 November 2020  
 
 
If you decide to join the PK Component of 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 Participant (print) 
 
Signature of Participant   
 
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) 
 
 
 
 
 
 
 
 
 
 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 146 of 173 
19 November 2020 
 
Appendix VII: Sample Informed Consent Form for PrEP Comparison Component 
 
IMPAACT 2009 
Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral Pre-Exposure Prophylaxis for 
Primary HIV Prevention during Pregnancy and Postpartum in Adolescents and Young Women and 
their Infants 
 
Version 3.0, dated 19 November 2020  
 
Introduction 
 
We invite you to take part in a research study with your baby named IMPAACT 2009. There are two 
parts to this study, the first part was completed in 2019.This form is for the second part, called the “PrEP 
Comparison Component.”  
 
This form gives information about both parts of the study. Please read it, or have it read to you, and ask 
any questions you may have. You can take as much time as you need to fully understand the study. We 
will ask you questions to see if we have explained the study clearly. 
 
Here is a summary of important information about the study:  
 
• 
The study is testing a medicine called Truvada®, or pre-exposure prophylaxis (PrEP) used to prevent 
HIV among young women who are pregnant and not infected with HIV.  
• 
Truvada® is a pill that contains 2 anti-HIV medicines (ARVs), called emtricitabine and tenofovir. 
These medicines are often used to treat HIV infection, but they can also be safe and effective in 
reducing the chance of becoming infected with HIV when taken by people who are not infected with 
HIV. 
• 
PrEP is approved in many countries around the world, but not many studies have involved HIV 
uninfected women while they are pregnant and just after delivery. 
• 
The first part of this study found that the amount of PrEP drug found in the blood was lower when 
pregnant women took the medication compared to those who had recently given birth. At this time, it 
is not known whether this means PrEP works less well during pregnancy. The World Health 
Organization still recommends Truvada® for pregnant and breastfeeding women at risk for HIV.  
• 
Women will enter the study when they are pregnant and will be in the study for 26 weeks after their 
baby is born. 
• 
To be in the study, women can choose to take PrEP or not take PrEP. Those who choose to take PrEP 
will take one pill consistently at about the same time every day.  
• 
While in the study, women and their babies will have clinic visits including physical examinations, 
blood draws for laboratory tests and special x-rays that measure bone strength. Women will answer 
questions about themselves, their health, and their health behaviors and will receive weekly SMS 
messages. 
• 
Visits will be scheduled to take place at the clinical research site; however, if it is not possible to 
conduct study visits in-person at the study site, then visit procedures may be done off-site or remotely 
(such as by phone). 
• 
There are some possible risks for women and babies in the study. One possible risk for women who 
choose to take PrEP is that the medicine could cause side effects.  Regardless of whether they chose 
to take or not take PrEP, women may experience stigma from being in a study about HIV because 
people might think that they have HIV. 


 
IMPAACT 2009, FINAL Version 3.0 
Page 147 of 173 
19 November 2020 
 
• 
There are some possible benefits for women in the study. One possible benefit is that women could 
gain knowledge and skills that may help minimize the risk of getting HIV or other STIs in the future.  
• 
Your decision on your participation in the study will have no effect on the medical care you and your 
baby would normally receive. Your access to services, and the benefits and rights you normally have, 
will not be affected.  
 
More information is given in this form about the study, its risks and benefits. You should feel that you 
understand the study before deciding whether you will participate with your baby. If you decide to 
participate, we will ask you 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 learn more about a medication called “PrEP.” For people who are not 
infected with HIV, but may be at risk of becoming infected with the HIV virus, taking medication called 
PrEP can help protect them. Other studies in men and non-pregnant women have shown that PrEP works 
very well in preventing HIV infection. We also know that the level of protection PrEP provides depends 
on whether someone takes PrEP every day. So far, not many women have taken PrEP while they are 
pregnant and after delivery, even though women may be at heightened risk of becoming infected with 
HIV during this period. 
 
The purpose of the IMPAACT 2009 study is to find out whether young women in sub-Saharan Africa at 
heightened risk of becoming infected with HIV are interested and would be willing to take a PrEP pill 
once a day while they are pregnant and breastfeeding. The purpose of the second part of the study (PrEP 
Comparison Component) is to find out how likely and safe it is for young women to take PrEP during 
pregnancy and just after delivery.  
 
We invite you to join the PrEP Comparison Component of this study with your baby because you are 
pregnant and not infected with HIV. The PrEP Comparison Component of this study will include up to 
350 mothers from clinical sites in Sub-Saharan Africa. Each mother and baby will be in this part of the 
study during pregnancy and up to 26 weeks (about six months) 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. There are two parts to this study. You and your baby are being asked to join the second part, called the 
PrEP Comparison Component.  
 
The two parts of the study are called the “PK Component” and the “PrEP Comparison Component.” The 
PK Component was done first. That part included 40 mothers with their babies to see how much PrEP 
medication can be measured in her blood if a woman takes it once a day. While none of the women in the 
PK Component got HIV during the study, the results did show some differences in the amount of PrEP 
medicine in women’s blood during pregnancy and after birth. Women who were pregnant had drug levels 
about one third (33%) lower than women who recently had their baby. These results are similar to what 
has been found in other studies of the same medicine; however, at this time, it is not known whether this 
means PrEP works less well during pregnancy. We discussed these results with several expert groups, 
including representatives from the World Health Organization (WHO) and the U.S. Food and Drug 
Administration (FDA) and received approval from the IMPAACT Network to move to the second part of 
the study.   
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 148 of 173 
19 November 2020 
 
The PrEP Comparison Component will include about 350 mothers and their babies. If you join the PrEP 
Comparison Component, you will have a choice to begin taking a pill for PrEP once a day while you are 
pregnant and until your baby is about 26 weeks old. If you participated in the PK Component, you cannot 
participate in the PrEP Comparison Component. 
 
2. The study will assess PrEP use in women who are pregnant and just after delivery and their babies. 
 
The medicine being used for PrEP in this study is called Truvada®. Truvada® is a pill that contains two 
medications called “emtricitabine” and “tenofovir” that are commonly used to treat HIV infection and 
sometimes to treat Hepatitis. We know that Truvada® is safe and effective in reducing the risk of HIV 
infection when taken by men and non-pregnant women who are not infected with HIV, but more 
information is needed to learn about how well PrEP can prevent HIV among women while they are 
pregnant and just after delivery.   
 
Truvada® is approved for PrEP in many countries around the world. In [insert site country], PrEP is 
approved for [insert details as relevant, e.g. of population in which PrEP is approved].  
 
3. The PrEP Comparison Component will assess what woman like and do not like about taking PrEP and 
how safe it is during pregnancy and breastfeeding. 
 
The PrEP Comparison Component will be done to help understand why women may choose to take PrEP 
if it is offered to them, and what they like and do not like about taking PrEP. The PrEP Comparison 
Component will also assess whether women who choose to take PrEP take the medicine every day, as 
directed. We also want to learn how safe it is for women to take PrEP while pregnant and just after 
delivery. It is important to understand this because the body changes during pregnancy, so the amount of 
PrEP drugs found in the blood of pregnant women may be different from non-pregnant women, as we 
found during the first part of the study. Finally, the PrEP Comparison Component will help us learn more 
about how well protected women who take PrEP are from becoming infected with HIV, especially during 
pregnancy when the amount of PrEP in the body could be lower than the level we know protects against 
HIV infection.  
 
4. Only mothers who qualify can participate in the study. 
 
If you decide to join the study with your baby, we will first do some tests to see if you qualify. More 
information about the tests is given in #5 (see below). If you qualify, you and your baby will enter the 
study. If you do not qualify, you and your baby cannot enter the study.  
 
You can choose if you want to join the study or not. You are free to join or not join. If you join, you can 
change your mind later and leave the study. Your decisions will have no effect on the medical care that 
you and your baby would normally receive from your usual clinic. 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. 


 
IMPAACT 2009, FINAL Version 3.0 
Page 149 of 173 
19 November 2020 
 
Finding out if You and Your Baby Qualify—Visit 1  
 
5. 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 any medicines you or your baby take 
• 
Talk with you about the study requirements and if you meet them 
• 
Give you a physical examination  
• 
Have you talk with a counselor about your health behaviors 
• 
Collect urine to check how well your kidneys are working and if there is sugar is in your urine  
• 
Collect your blood (up to 15 mL or about 3 teaspoons) for tests. The tests will:  
– Check your blood cells 
– Check if you have Hepatitis B (a disease of the liver) 
– Check how well your liver and kidneys are working 
– Check your blood sugar levels 
– Check your blood to confirm that you are not infected with HIV 
 
These procedures will take about 2 hours [here and throughout this form, sites may modify the expected 
visit duration as needed].  
 
 
6. You will receive SMS messages as part of this study.  
 
As part of finding out if you qualify for this study, we will confirm that you have access to a mobile 
phone that is able to receive SMS messages, and confirm that you agree to receive SMS messages. For 
mothers who decide to take PrEP, we will also ask whether you are able to send SMS messages. 
 
Whether you decide to take PrEP or not, all mothers will receive routine SMS messages, starting the week 
you enter the study. These messages will give you information about pregnancy and infant care. 
 
Mothers who take PrEP will also receive weekly messages. The weekly message will ask how you are 
doing; these messages will not ask specifically about HIV or PrEP. You will be asked to respond to each 
weekly message within 48 hours and if you do not respond you may receive an additional text message or 
someone from the study team may try to call you. Someone from the study team may also call you if you 
respond to the message and ask for help.  
 
7. We will also do an ultrasound scan. 
 
We need to know how long you have been pregnant when you enter the study and whether you may be 
pregnant with more than one baby. To do this, you will have an ultrasound scan and we will ask you the 
date of your last menstrual period [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.  
 
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 and measure the size.  
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 150 of 173 
19 November 2020 
 
[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 
before entering the study. There is no cost for having the scan done.  
 
If you have already had an ultrasound and have the report, this may not be needed. 
 
8. We will tell you if and your baby qualify. 
 
We will give you the results of all procedures and explain them to you.  
 
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 do qualify for the study and you agree to join with your baby, you will enter the study.  
 
Choosing to be in the Study 
 
9. You can decide to take PrEP or not to take PrEP. 
 
If you qualify to join the study, you have a choice. You can choose to begin taking PrEP or you can 
choose to not take PrEP at all. You can still be in the study if you choose not to take PrEP. If you choose 
to start PrEP, you will take one pill every day up to 26 weeks after your baby is born. We found in the 
first part of the study that women who were pregnant had less PrEP drug in their body compared to 
women who had recently given birth, even when they took the same amount of PrEP. Therefore, it is 
especially important that women who are pregnant take their PrEP once a day every day. 
 
You can change your mind about PrEP while you are in the study. Those who start off taking it can stop; 
those who initially decided not to take it, may start if they so wish. Even if you change your mind, we 
would continue to follow you until 26 weeks after the birth of your child. 
 
To test PrEP, the mothers and babies in each group will be compared to the mothers and babies in the 
other group. 
 
Being in the Study   
 
10. If you and your baby qualify, you will enter the study. 
 
Different procedures will be done at your first visit depending on if you chose to take PrEP. Some 
procedures will be done for both groups of mothers. Other procedures will be done for only the group of 
mothers taking PrEP. 
 
This visit will take about 4 hours.  
 
For all mothers, on the day you enter the study, we will: 
 
• 
Ask about your health and the medicines you take 
• 
Give you a physical exam 
• 
Have you talk with a counselor about your health behaviors 
• 
Have you complete a survey on the computer, where you will answer questions about yourself, your 
health, and your health behaviors  


 
IMPAACT 2009, FINAL Version 3.0 
Page 151 of 173 
19 November 2020 
 
• 
Ask about how COVID-19 may be affecting you 
• 
Collect your blood (12 mL or about 2.5 teaspoons) for tests.  
These tests will: 
– Confirm you are HIV-uninfected 
– Check if you have syphilis or herpes 
– Check if any PrEP drug is in your blood 
• 
Save some of the blood in case you become infected with the HIV-virus during the study for extra 
HIV tests. 
• 
Collect vaginal swabs or urine to check if you have sexually transmitted infections such as chlamydia 
or gonorrhea and to check the type of bacteria present that are normally found in the vagina. For these 
specimens, a small swab is inserted into the vagina to collect some mucus.  
• 
Collect rectal swabs, by inserting a small swab into the rectum to get some of the fluid. If you prefer, 
the study staff can give you instructions so that you can collect this specimen yourself. You do not 
have to agree to this collection. We will ask you later if you agree to have rectal swabs collected. This 
testing will be done later in the study, so you and your doctor won’t get the results of these tests. 
 
For mothers taking PrEP, we also will: 
 
 
• 
Give you a supply of PrEP  
• 
Teach you about using PrEP and talk to you about your plans for taking your pills. It is very 
important that you take the PrEP pill once a day, every day. We will take as much time as needed 
for you to understand the instructions and will answer any questions you have about taking PrEP. 
 
11. You will return to the study clinic for 3 or more visits while you are pregnant. 
 
You will have visits when you have been in the study for about 4 weeks, 8 weeks, and 12 weeks. After 
that, you will have visits once every 12 weeks until delivery. The number of visits to the clinic you will 
have during pregnancy will depend on when you enter the study and when your baby is born. Most 
mothers will have about 3 visits while pregnant. Some may have up to 7 visits.  
 
Different procedures will be done at your visits depending on if you chose to take PrEP. Some procedures 
will be done for both groups of mothers. Other procedures will be done for only the group of mothers 
taking PrEP. 
 
Each visit will take about 1-2 hours.  
 
For all mothers, at these visits we will: 
  
• 
Review your medical records 
• 
Ask about your health and the medicines you take, and your relationships 
• 
Give you a physical exam 
• 
Have you talk with a counselor about your health behaviors 
• 
Have you complete a survey on the computer, where you will answer questions about yourself, your 
health, and your health behaviors  
• 
Ask about how COVID-19 may be affecting you 
• 
Collect your blood (up to 14 mL or about 3 teaspoons) for tests. At different visits, the tests will:  
– Check how well your liver and kidneys are working 
– Confirm that you are HIV-uninfected 
• 
Save some of the blood in case you become infected with the HIV-virus during the study for extra 
HIV tests 


 
IMPAACT 2009, FINAL Version 3.0 
Page 152 of 173 
19 November 2020 
 
At three visits, we will: 
• 
Collect two vaginal swabs to check the type of bacteria present. 
• 
Collect a rectal swab to check the type of bacteria present. If you agreed to have this specimen 
collected.  
 
For mothers taking PrEP, we also will: 
 
• 
Give you supplies of PrEP  
• 
Answer questions you have about taking your PrEP and talk to you about what makes it easier and 
harder to take your PrEP pills every day. 
• 
Provide counseling based on how much PrEP is found in your blood. We will use the test results from 
your past visit to talk to you about how well protected you are from becoming infected with HIV. 
• 
Have you complete a survey on the computer, where you will answer questions about taking PrEP. 
• 
Use blood already collected for additional tests. The tests will:  
– Confirm how much of the PrEP drugs are in your blood. We will let you know once the results 
are available. We may invite you for an extra visit.  
• 
At three visits, collect a small amount of fluid from your vagina to check the levels of PrEP drugs in 
your genital tract. This specimen can be collected by you or the clinic staff. This testing will be done 
later in the study, so you and your doctor won’t get the results of these tests. 
 
12. You and your baby will have a visit soon after delivery. Then you will have 3 more visits over 26 weeks.  
 
You should contact us when your labor begins to arrange for a study visit as soon as possible after 
delivery. It is important for this visit to take place close to the baby’s birth. This visit will take up to 4 
hours. 
 
Your next study visits for you and your baby will be when your baby is about 6, 14 and 26 weeks of age.  
 
Each visit will take about 2 hours.  
 
When you come to the clinic with your baby for the visit soon after delivery and when your baby is 6, 14, 
and 26 weeks of age we will: 
 
• 
Review your and your baby’s medical records 
• 
Ask about your and your baby’s health and the medicines you take, and your relationships 
• 
Ask about how you are feeding your baby  
• 
Give you and your baby a physical exam 
• 
Have you talk with a counselor about your health behaviors 
• 
Have you complete a survey on the computer, where you will answer questions about yourself, your 
health, and your health behaviors 
• 
Ask about how COVID-19 may be affecting you 
• 
Collect a vaginal swab or urine at your final visit to check for infections such as chlamydia or 
gonorrhea (at the Week 26 Postpartum visit only) 
• 
Collect vaginal swabs to check the type of bacteria present (at the Week 6 and Week 26 Postpartum 
visits only) 
• 
Collect rectal swabs to check the type of bacteria present (at the Week 6 and Week 26 Postpartum 
visits only)  
• 
Take blood from you (up to 20 mL or 4 teaspoons) for tests that will: 
– Check your cells 
– Check how well your liver and kidneys are working 


 
IMPAACT 2009, FINAL Version 3.0 
Page 153 of 173 
19 November 2020 
 
– Check if you have Hepatitis B (a disease of the liver) - at the Week 26 Postpartum visit only 
– Check if you have syphilis or herpes - at the Week 26 Postpartum visit only 
– Confirm you remain HIV uninfected  
• 
Save some of the blood in case you become infected with the HIV-virus during the study for extra 
HIV tests 
• 
Take blood from your baby (up to 1.5 mL or about ½ teaspoon) for tests that will: 
– Confirm your baby’s kidneys are working well (at the first and final visit only) 
• 
Collect rectal swabs or stool from your baby to check the type of bacteria present 
• 
You and your baby will also have DXA scans. 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, you 
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. Scans will be done for you and your baby shortly after delivery and 26 
weeks after birth or delivery. For safety reasons, you must have a pregnancy test before the scan done 
26 weeks after delivery to confirm you are not pregnant before having the scan. The results of the 
scans will not be available while the study is ongoing.  
 
For mothers taking PrEP, we also will: 
 
• 
Give you supplies of PrEP. At your final visit, we will collect any remaining PrEP from you. 
• 
Provide counseling based on how much PrEP drug is found in your blood. We will use the test results 
from your past visit to talk to you about how well protected you are from becoming infected with 
HIV. 
• 
Have you complete a survey on the computer, where you will answer questions about taking PrEP. 
• 
Use blood already collected for tests to confirm how much PrEP drug is in your blood. We will let 
you know once the results are available. We may invite you for an extra visit.  
• 
Collect a small amount of fluid from your vagina to check the levels of PrEP drugs in your genital 
tract. 
 
While you are in the study, we will give you the results of the tests for you and your baby. We may need 
to repeat a blood test for you or your baby. If you become infected with HIV during the study, we still 
want you and your baby to complete all your study visits, but it is your choice. We will discuss with you 
how to get care and treatment for HIV outside the study and arrange it with the staff there [site to revise 
as needed]. 
 
13. You will have extra visits if you choose to change from not taking PrEP to taking PrEP.  
 
If you choose to not take PrEP at the start of the study, you may change your mind during the study and 
choose to start taking PrEP. If you choose to start taking PrEP, you will be required to have two extra 
visits. These extra visits will take about 1 hour and Visit 1 may be combined with a regularly scheduled 
study visit.  
 
At Visit 1 we will: 
 
• 
Review your medical records 
• 
Ask about your health and the medicines you take, and your relationships  
• 
Give you a physical exam 
• 
Teach you about using PrEP and talk to you about your plans for taking your pills 
• 
Have you complete a survey on the computer, where you will answer questions about yourself, your 
health, and your health behaviors  


 
IMPAACT 2009, FINAL Version 3.0 
Page 154 of 173 
19 November 2020 
 
• 
Ask about how COVID-19 may be affecting you 
• 
Have you talk with a counselor about your health behaviors 
• 
Collect urine to check how well your kidneys are working and if there is sugar is in your urine  
• 
Collect your blood (17 mL or about 3.5 teaspoons) for tests. The tests will:  
– Check your cells 
– Check how well your liver and kidneys are working 
– Check if you have Hepatitis B 
– Check your blood sugar levels 
– Confirm you are HIV-uninfected 
• 
Save some of the blood in case you become infected with the HIV-virus during the study for extra 
HIV tests 
 
At Visit 2 we will: 
 
• 
Give you a supply of PrEP 
• 
Teach you about using PrEP and talk to you about your plans for taking your pills 
• 
Ask about your relationships 
• 
Have you complete a survey on the computer, where you will answer questions about yourself, your 
health, and your health behaviors  
• 
Ask about how COVID-19 may be affecting you 
• 
Have you talk with a counselor about your health behaviors  
• 
Collect your blood (4 mL or about 1 teaspoon) for tests. The tests will:  
– Confirm you are HIV-uninfected 
– Check if PrEP drug is in your blood 
• 
Collect vaginal swabs to check the type of bacteria present 
• 
Collect rectal swabs to check the type of bacteria present 
 
14. If you become infected with HIV during the study, you will have extra visits.  
 
We will test you for HIV throughout the study using a rapid test in the clinic and another type of HIV test 
in the laboratory (RNA PCR). If your HIV test results are positive, we will take more blood to confirm 
the HIV infection and measure the HIV viral load (how much HIV is in the blood). It usually takes about 
a week for these results to come back. 
 
These extra visits will take about 1 hour. At these visits we will: 
 
• 
Refer you for HIV care and treatment 
• 
Talk with a counselor about your health behaviors 
• 
Collect any remaining PrEP from you  
• 
Take your blood (15-25 mL or about 3.5 to 5 teaspoons) for tests.  
 
The tests will:  
– Confirm your HIV viral load  
– Check your cells  
– If you are found to be HIV-infected, check if the HIV in the blood is resistant to the medications 
in the PrEP pill 
• 
Save some of the blood for future HIV testing 
 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 155 of 173 
19 November 2020 
 
For babies, we also will: 
 
• 
Take blood (up to 6 mL or about 1 teaspoon) for tests. The tests will:  
– Check if your baby is HIV-infected. If the test is positive, a second test will be done to confirm if 
your baby is HIV-infected. 
– If the HIV infection is confirmed, check if the HIV in your baby’s blood is resistant to the 
medications in the PrEP pill. 
 
15. Tests will be done at different laboratories. 
 
We will do tests of you and your baby’s specimens at our laboratory. Most of the tests will be done right 
away at a local facility. We will give you the results of these tests and explain the results to you. 
However, some specimens will be kept and tested together at the end of the study. 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. Some tests are special and must be sent to specialized laboratories 
outside the country, including the United States. This includes: 
 
• 
Some tests for HIV viral load 
• 
Tests for resistance to PrEP 
• 
Tests of the amount of PrEP that can be found in blood 
• 
Test to determine the levels of normal bacteria in your vagina and gut and your baby’s gut 
 
The results of most of these tests are not expected to 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.  
 
If there are any specimens left-over after all the tests for this study have been done for you and your baby, 
we would like to keep those specimens because they may be useful for studies in the future. We will talk 
to you about what you want to happen to these left-over specimens in another informed consent form. 
 
16. We may take you and your baby off the study early. 
 
We expect you to stay in the study until you and your baby have completed all the study visits; until the 
baby is about 26 weeks of age. However, we may take you and your baby off the study early 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. 
 
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 we do at the weekly study visits (see #10 and #11), we may also give you a 
pregnancy test (see #18). We will answer any questions you may have and tell you how to contact us in 
the future, if you wish. 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 156 of 173 
19 November 2020 
 
17. 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 – you just need to tell us. 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 we do at the weekly study visits (see #10 and #11 above), we may also 
give you a pregnancy test (see #18). We will answer any questions you may have and tell you how to 
contact us in the future, if you wish. 
 
18. How to stay HIV uninfected after leaving the study. 
 
We can’t give you PrEP after you finish your study visits. Before you leave the study, we will talk again 
about how to protect yourself against HIV infection and give you information about other clinics that 
offer PrEP to women. If you want to continue taking PrEP, we will refer you there. [Sites to modify as 
necessary and insert information about referral letters and sharing study laboratory results with the non-
study PrEP provider, as appropriate] 
 
19. After delivery, we will test for pregnancy again during the study.  
 
We will test for pregnancy again during the study. If you become pregnant, you will continue in the study. 
When the new pregnancy is identified, if you were taking PrEP, you may continue to do so, and if you 
chose not to take PrEP you will be offered to start PrEP. If you choose to continue taking PrEP after you 
leave the study, we will refer you to clinics that offer PrEP. We will contact you after your last study visit 
to find out the outcome of your pregnancy.  
 
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.  
 
Blood Collection: Collecting blood can cause pain, swelling, bruising, or bleeding where the needle is 
inserted. Rarely, collecting blood can cause fainting or infection. 
 
Urine collection: There is no risk from collecting your urine. 
 
Vaginal and rectal swab collection: You may feel a little discomfort when the swabs are inserted into the 
vagina or the rectum. The study staff will show you the swab and you can ask any questions about this 
procedure before it is done. 
 
Vaginal fluid collection: You may feel a little discomfort when the sponge in inserted into the vagina. The 
study staff will show you the sponge and you can ask any questions about this procedure before it is done. 
 
Ultrasound scan: There is no risk from ultrasound. 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 157 of 173 
19 November 2020 
 
DXA Scans: 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.  
 
HIV Testing: We will perform an HIV test at every visit, which is routinely done to make sure that you 
are/your child is HIV uninfected before starting or continuing PrEP. You will be counseled before and 
after test is done. [Sites to insert reporting responsibilities in the state the site is located in. Also include 
whether if a participant tests positive, the results will become part of public health records, or any other 
record (medical file, etc.)] You can come to the clinic and ask for an HIV test anytime you are worried. 
 
Acquiring HIV Infection and Drug Resistance: You must understand this information about what PrEP 
can and can’t do: 
• 
PrEP cannot give you HIV. 
• 
PrEP is most effective when taken once a day, every day. 
• 
Taking PrEP prevents HIV in most people who take it every day, but 
• 
You still may become infected with HIV while you are taking PrEP. 
• 
It is possible that PrEP may not protect a woman against HIV infection as much during pregnancy as 
it does at other times because of the lower amount of PrEP drug measured in the body during 
pregnancy.  
• 
PrEP does not prevent pregnancy or STIs. 
• 
You still need use other methods to avoid HIV infection and other STIs while you are taking PrEP, 
like using condoms every time you have sex and keeping your number of sexual partners low. Study 
staff will discuss all the different ways you can keep yourself from getting these infections. 
 
If you become infected with HIV while you are taking PrEP, the strain of the HIV virus in your blood 
might become “resistant” to Truvada® and some other medications used for HIV treatment (ART). 
“Resistance” means the virus can’t be killed by that medication, which makes treating the HIV more 
difficult. If you become infected with HIV, we will test for HIV drug resistance. You will be able to 
discuss ART and resistance with the study staff.  
 
If you have any questions about anything we have said here, please talk to us. 
 
Sensitive Questions: The questions we will ask you about your sexual behavior, drug and alcohol use may 
make you feel uneasy. However, you do not have to answer any question that you do not want to and you 
can stop answering the questions at any time. 
 
Mobile Phones: Information that you send us from your mobile phone programs will be kept confidential. 
We will not be able to access any private information on your mobile phone. However, it may be possible 
for your information to be viewed by others who have access to your phone. We will do everything 
possible to make sure that your information is protected. [Sites to modify as needed: We will not mention 
the research study when texting you, but only text reminders about keeping up your health.] 
 
STI Testing: You will be tested for STIs. [Insert here any reporting responsibilities for your state or local 
jurisdictions or reporting of these infections to public health authorities]. If you have any of these 
infections, we will provide you with treatment. 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 158 of 173 
19 November 2020 
 
Other Risks: Also, there may be uncommon or previously unknown risks that might occur. You should 
report any problems to the study staff immediately. There may also be some social risks to participating in 
this study. You may feel embarrassed or uncomfortable with some of the questions we will ask you, some 
of the procedures that will be done, or some of the test results that you will receive. You may also 
experience stigma as a result of being involved in a study about HIV because people may assume that you 
have HIV. This could mean that you are treated badly in the community or by your family and friends. 
Being in the study could cause problems with your relationships with your partner if they do not support 
your choice to participate or use PrEP. Please talk to study staff if this happens. If you have HIV or other 
infections, knowing this could make you worried. Study staff are trained to help you deal with any 
feelings or questions you have. 
 
21. There are risks from PrEP.  
 
You or your baby may feel sick while participating in the study. These problems may be due to taking 
PrEP or due to an illness that has no relation to the study, like a cold or flu. You should tell us about any 
symptoms that you feel while you are participating in the study. You will be given a telephone number to 
contact the clinic.  
 
You should contact us if you experience any symptoms at any time. 
 
In PrEP research studies, nausea and diarrhea were the most common side effects, but happened in only 
about 10% or one in ten people. Nausea and diarrhea mainly happened in the first month and then went 
away. A small number (<1% or one in one hundred people) in PrEP studies showed a small decrease in 
how their kidneys work, but this stopped when the people stopped taking the drug.  
 
Other side effects, such as changes in bone mineral density (how much calcium and other minerals are in 
your bone which keeps them strong) were very rare in people taking the drug who did not have HIV and 
have always gotten better when the drug was stopped.  
 
You could have these side effects or other side effects that we do not know about. Please tell the staff here 
if you have any side effect that bothers you or does not go away.  
 
Other Medications: Some medications should not be taken while you are taking Truvada®. When you 
visit the study clinic, we will ask you about other medications that you are taking. 
 
Truvada ® may have side effects that no one knows about yet. We will let you know if we learn anything 
that might make you change your mind about continuing to participate in the study. 
 
Risks to your baby: The medicines in Truvada® are often used to treat women with HIV infection. Many 
HIV-infected women have taken these medicines while pregnant and breastfeeding. We know that these 
medicines pass through to the baby in the womb and are found in breastmilk in small amounts. The 
information we have so far suggests that these medicines do not cause serious problems in the baby. 
However, it is still possible that taking PrEP may cause some problems in the baby soon after birth or 
when they are older. The study staff will check for side effects in babies during study visits and tell you 
what to do if your baby has any side effects. You should contact the study staff at any time if you are 
worried about the baby’s health. 
 
22. There could be risks of disclosure of your or your baby’s information. 
 
We will make every effort to keep you 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 


 
IMPAACT 2009, FINAL Version 3.0 
Page 159 of 173 
19 November 2020 
 
only with a code number. However, you and your baby’s names will be written on some records that are 
kept in the clinic. Your name and telephone number will also be stored in the computer system used to 
send and track SMS messages. Despite our best efforts to keep this 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. You should contact the 
study staff at any time if you are worried about your and your baby’s privacy. 
 
Information collected for this study may be used for other research in the future. For example, researchers 
may use information from this study to try to answer different questions about using PrEP during 
pregnancy. Any future research done with the information from this study must be approved by the 
IMPAACT Network. If any future research is done, information about you or your baby may be used; this 
information will be labeled with a code number, and the only link between the code number and your or 
your baby’s name will be kept here at [site name]. Your or your baby’s name will not be given to other 
researchers. 
 
Benefits of the Study 
 
23. There may be no benefit from being in the study. 
 
We will test you for HIV and other STIs throughout this study. If you choose to take Truvada®, and you 
take it every day, it may help you to avoid HIV. Participating in this study may give you knowledge and 
skills that may help you to avoid HIV and other STIs. The SMS messages you receive may help ensure 
that you keep up with routine medical care for you and your baby. What we learn about PrEP use in 
young women may help women in the future decide whether to take PrEP while they are pregnant and 
breastfeeding. 
 
Other information about the study 
 
24. There are no costs to you for being in the study. 
 
There are no costs to you for study visits or procedures or the PrEP that is given by the study, and you 
will not receive payment for participating in 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).] 
 
25. 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 (FDA) 
• 
The Office for Human Research Protections (OHRP)  
• 
Other U.S., local, and international regulatory entities 
• 
The IMPAACT Network that is coordinating the study 
• 
Gilead Sciences (the company that makes Truvada®) 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 160 of 173 
19 November 2020 
 
The study staff and these groups are required to make every effort 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. 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.  
 
26. 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 
 
27. 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] 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 161 of 173 
19 November 2020 
 
Signature Page for Maternal Participants 
 
Screening and Enrollment Consent for Maternal Participants of Legal Age to Provide Independent 
Consent 
 
IMPAACT 2009 
Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral Pre-Exposure Prophylaxis for 
Primary HIV Prevention during Pregnancy and Postpartum in Adolescents and Young Women and 
their Infants 
 
Version 3.0, dated 19 November 2020  
 
 
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. 
 
For the optional rectal swab collection in mothers, write a ‘X’ to indicate your decision. 
 
 
________ 
Yes, I agree to provide rectal swab samples 
 
_________ 
No, I don’t want to provide rectal swab samples 
 
 
 
[Insert signature blocks as required by site IRB/EC policies.] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Participant (print) 
 
Signature of Participant   
 
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) 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 162 of 173 
19 November 2020 
 
Signature Page for Maternal Participants 
 
Assent for Maternal Participants of Not of Legal Age to Provide Independent Consent 
 
IMPAACT 2009 
Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral Pre-Exposure Prophylaxis for 
Primary HIV Prevention during Pregnancy and Postpartum in Adolescents and Young Women and 
their Infants  
 
Version 3.0, dated 19 November 2020 
 
 
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. 
 
 
For the optional rectal swab collection in mothers, write a ‘X’ to indicate your decision. 
 
 
________ 
Yes, I agree to provide rectal swab samples 
 
_________ 
No, I don’t want to provide rectal swab samples 
 
 
[Insert signature blocks as required by site IRB/EC policies.] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Participant (print) 
 
Signature of Participant   
 
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) 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 163 of 173 
19 November 2020 
 
Appendix VIII: 
Sample Informed Consent Form for Specimen Storage and Future Use 
 
IMPAACT 2009 
Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral Pre-Exposure Prophylaxis for 
Primary HIV Prevention during Pregnancy and Postpartum in Adolescents and Young Women and 
their Infants 
 
Version 3.0, dated 19 November 2020  
 
You have decided to join the study named above with your baby. As part of the study, you will have 
blood and urine collected, in addition to vaginal and rectal swabs and vaginal fluid collection. Your baby 
will have blood collected in addition to rectal swabs or stool samples. After these samples are tested for 
the study, some samples may be left-over. The IMPAACT Network would like to keep these left-over 
samples and use them for other research in the future. 
 
This form gives information about use of left-over 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 left-over samples at the end of the form.  
 
1. It is your decision whether or not to allow the left-over 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 left-over samples will be destroyed.  
 
2. If you agree, your and your baby’s left-over 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 left-over 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 left-over 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. Left-over samples could be used for different types of research.  
 
Left-over samples may be used for research on pregnancy, the immune system, and other diseases. The 
research may be done in the United States or in other locations.  
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 164 of 173 
19 November 2020 
 
If you agree, the left-over 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 how the body responds to 
PrEP, pregnancy, and the immune system. Testing all of your and/or your child’s genes, which is 
sometimes called whole genome sequencing, will not be done 
 
Any research done with the left-over 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 left-over 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 left-over 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. The only link between the code number and your 
and your baby’s name is kept here at [site name]. Your or your baby’s name will not be given to other 
researchers. 
 
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 left-over samples to be used for research, you and your baby will be part of the search 
for new information that may benefit people in the future. However, the research done with the left-over 
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 left-over 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 left-over 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  


 
IMPAACT 2009, FINAL Version 3.0 
Page 165 of 173 
19 November 2020 
 
• 
Other U.S., local, and international regulatory entities 
 
The people who do research with the left-over samples and the groups listed above are required to make 
efforts to keep information private and confidential. 
 
The results of research done with the left-over 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 left-over 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 left-over 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].  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 166 of 173 
19 November 2020 
 
Signatures 
 
Before deciding whether to allow your and your baby’s left-over 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 left-over samples, write your initials or make your mark next to your choice. 
 
__________ 
I allow my left-over samples to be used for research on pregnancy, the immune system, 
and other diseases. I also allow my samples to be used for tests of my genes.  
 
__________ 
I allow my left-over samples to be used for research on pregnancy, the immune system, 
and other diseases. I do not allow my samples to be used for tests of my genes.  
 
__________ 
I do not allow my left-over samples to be used for any research.  
 
For YOUR BABY’s left-over samples, write your initials or make your mark next to your choice. 
 
__________ 
I allow my baby’s left-over samples to be used for research on PrEP, pregnancy, the 
immune system, 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 left-over samples to be used for research on PrEP, pregnancy, the 
immune system, 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 left-over 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) 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 167 of 173 
19 November 2020 
 
Appendix IX: Sample In-depth Interview Informed Consent Form 
 
IMPAACT 2009 
Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral Pre-Exposure Prophylaxis for 
Primary HIV Prevention during Pregnancy and Postpartum in Adolescents and Young Women and 
their Infants 
 
Version 3.0, dated 19 November 2020  
 
Introduction 
 
You are being asked to take part in a qualitative evaluation of the IMPAACT 2009 research study. By 
joining this evaluation, you will participate in one in-depth interview with study staff. Participation is 
voluntary. You may refuse to join, or you may withdraw your consent to participate in this interview for 
any reason. The qualitative evaluations are for young women who are participating in the PrEP 
Comparison Component of IMPAACT 2009.  
 
Before you decide whether to participate, we would like to explain the purpose of the qualitative 
evaluations, the risks and benefits to you and what is expected of you.  
  
Participation is voluntary 
 
This consent form gives information about the qualitative evaluations that will be discussed with you. We 
will help you to understand the form and answer your questions before you sign this form. Once you 
understand this evaluation, and if you agree to take part, you will be asked to sign your name or make 
your mark on this form. You will be offered a copy of this form to keep.  
 
Before you learn about the qualitative evaluations, it is important that you know the following: 
• 
Your participation is voluntary. You do not have to take part if you do not want to. 
• 
You may decide not to take part or you may decide to leave at any time without losing your 
regular medical care. 
• 
You are not not required to participate in these interviews in order to remain in the rest of the 
study (IMPAACT 2009). 
 
About the qualitative evaluation  
 
The purpose of the IMPAACT 2009 study is to find out whether young women in sub-Saharan Africa at 
risk of becoming infected with HIV are interested and would be willing to take a PrEP pill once a day 
while they are pregnant and breastfeeding. The in-depth interview will ask young women what they like 
and do not like about taking PrEP. We will also ask questions to find out what makes some young women 
more or less interested in starting PrEP. Finally, if you are taking PrEP we will ask about difficulties you 
had taking PrEP and things that made taking PrEP easier. 
 
Entering the qualitative evaluation  
 
To understand better what makes it easier or harder for young women in this study to take their PrEP pills 
every day, we will be doing interviews with up to 60 young women at participating sites. You have been 


 
IMPAACT 2009, FINAL Version 3.0 
Page 168 of 173 
19 November 2020 
 
selected to take part in one interview sometime after your Week 12 study visit.  
These interviews will ask you questions about:  
 
• 
How and when you decided to take PrEP,  
• 
Whether you feel that you personally are at risk of HIV,  
• 
If you decided not to take PrEP, some of the reasons why you made that decision,  
• 
How you made daily pill-taking part of your/her routine if you decided to take PrEP,  
• 
Where you kept your PrEP pills if you decided to take PrEP,  
• 
Whether you talked to your family members, peers, and partner(s) about being in this study or 
taking PrEP pills,  
• 
If you decided to take PrEP, if you had any symptoms or side effects from the pills, and how this 
might have influenced your decision to take the pills, and  
• 
Other related topics will include, for example, whether the COVID-19 pandemic has impacted 
your study participation, including your decision whether or not to take PrEP, and your adherence 
to PrEP if you chose to take it. 
 
1. Procedure 
 
The interview will be led by a member of the research team that you do not work with during the study. If 
any of the questions make you upset, either you or the interviewer may stop the interview at any time. 
You will also be provided with contact and referral information if any of the questions raise issues that 
you would like to talk about later.  
 
[To be modified to reflect site practices: The interview will take place in a location that the study staff 
have determined will provide you with privacy and confidentiality such as the clinic, or another 
appropriate place. The study team will talk with you about this so you know where to go for the 
interview].  
 
The interview may be conducted remotely; for example, by cell phone or video chat, if we are not able to 
conduct a face-to-face study visit at the clinic or at an earlier agreed location due to COVID-19-related 
restrictions.  
 
The interview should take about 1 hour. There will be no cost to you for participation. You will receive 
[insert local amount] for your time and effort. 
 
Benefits of the qualitative evaluations 
 
2. There may be no benefit from being in the qualitative evaluation 
 
You may not receive any other direct benefit from being in this part of the qualitative evaluations; 
however, you or others in your community may benefit from this study later.  
 
Risk of the qualitative evaluation  
 
3. There is little risk from the qualitative evaluation procedures 
 
To minimize any discomfort and to protect your privacy the interview will be conducted in a private area 
that will allow you to speak comfortably without being overheard. Although we hope that you will be 
comfortable answering all of the questions openly and honestly, please keep in mind that you may refuse 
to answer any of the questions, or stop the interview completely, at any time. The greatest risk may 


 
IMPAACT 2009, FINAL Version 3.0 
Page 169 of 173 
19 November 2020 
 
involve your privacy and confidentiality. The steps that the study team have taken to protect your privacy 
are described below.  
 
 Other information about the qualitative evaluation  
 
4. Privacy 
 
Every effort will be made to keep your personal information confidential. Your personal information 
(name, address, phone number) will be protected by the research clinic. Your name, or anything else that 
might identify you personally, will not be used in any publication of information about this study.  
 
To help assure that we get the best understanding possible from your answers during the interview, the 
entire interview will be audio-recorded. After the interview is finished, the recording will be typed (called 
a transcript) by people who know how to do this. All identifying information will be removed from the 
transcript. Your name will not be included on the transcript. These recordings will be destroyed after all 
analysis is completed. 
 
Your records may be reviewed by the sponsor of the study (U.S. National Institutes of Health (NIH), U.S. 
NIMH) and their representatives, U.S. FDA, The Office for Human Research Protections (OHRP), other 
U.S., local, and international regulatory entities, [insert name of site] IRB/EC, study staff, study monitors 
and [insert applicable local regulatory authorities].  
 
People who may review your records include: [insert name of site] IRB, National Institutes of Health 
(NIH), study staff, study monitors, and the drug company (Gilead) supporting this study.  
  
If the study staff learns of possible child abuse and/or neglect or a risk of harm to you/your child or 
others, we will tell the proper authorities as we are required to do by the law. 
 
5. New Information 
 
You will be told any new information learned during the qualitative evaluation that might affect your 
willingness to stay in the study. You will also be told when the results of the qualitative evaluation may 
be available, and how to learn about them.  
 
6. Why you may be withdrawn from the qualitative evaluation without your consent 
 
You may be withdrawn from the qualitative evaluations without your/her consent if any of the following 
occur:  
• 
The study is stopped or canceled. 
• 
The study staff feels that staying in the study would be harmful to you. 
• 
Other reasons, as decided by the study staff.  
 
7. There are no costs to you for being in the qualitative evaluation   
 
There will be no cost to you for participating in these in-depth interviews, and you will not receive 
payment for participating in the in-depth interviews. 
 
[Insert information about compensation/reimbursement here, e.g., You will be reimbursed for the cost of 
transport to the clinic for these interviews. You will be given (specify amount).] 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 170 of 173 
19 November 2020 
 
8. Who to contact 
 
If you have questions, concerns, or problems at any time, use these contacts. 
 
• 
If you have questions about the qualitative evaluation:  
[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 qualitative evaluation:  
[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 qualitative evaluation 
participation:  
[insert name and telephone number of investigator or other study staff] 
 
• 
If you want to leave the qualitative evaluation:  
[insert name and telephone number of investigator or other study staff] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 171 of 173 
19 November 2020 
 
Signature page for Maternal Participants 
 
In-depth Interview Informed Consent Form for Maternal Participants of Legal Age to Provide Independent 
Informed Consent  
IMPAACT 2009 
Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral Pre-Exposure Prophylaxis for 
Primary HIV Prevention during Pregnancy and Postpartum in Adolescents and Young Women and 
their Infants 
 
Version 3.0, dated 19 November 2020  
 
If you decide to join the qualitative evaluation with your baby, sign or make your mark below. 
 
Before deciding whether to join the qualitative evaluation 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 the qualitative evaluations or other studies that may affect 
your willingness for you and your baby to stay in the qualitative evaluations. 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 Participant (print) 
 
Signature of Participant   
 
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) 
 
 


 
IMPAACT 2009, FINAL Version 3.0 
Page 172 of 173 
19 November 2020 
 
Appendix X: Guidance for Study Implementation at Sites Experiencing 
Operational Disruptions Due to COVID-19 
 
To safeguard the health and well-being of study participants in the context of circulating SARS-CoV-2 
and the associated coronavirus disease 2019 (COVID-19), the guidance provided in this appendix may be 
implemented at sites experiencing operational disruptions due to COVID-19.  
 
The extent to which site operations may be disrupted by COVID-19 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. All sites must also comply with any directives 
received from the study sponsor, the IMPAACT Network, and/or the IMPAACT 2009 Protocol Team. 
Should a determination be made in the future that the guidance provided in this appendix is no longer 
applicable, sites will be formally notified and instructed to inform their IRBs/ECs and other applicable 
regulatory entities. 
 
Visit Scheduling and Procedural Considerations 
• 
The allowable visit windows for all maternal and infant follow-up visits are extended by ±7 days, as 
follows:  
o Maternal antepartum visits at Weeks 4, 8, and 12: allowable visit window is expanded to ±14 
days. 
o Maternal antepartum visits at Weeks 24 and 36: allowable window is expanded to ±21 days.  
o Maternal Labor and Delivery Visit and Infant Birth Visit: allowable window is expanded to up to 
21 days after delivery/birth.  
o Maternal and Infant PP Weeks 6, 14, and 26: allowable visit window is expanded to ±21 days. 
• 
DXA scans are required at the Maternal Labor and Delivery Visit, Infant Birth Visit, and Maternal 
and Infant Week 26 visits. It is understood that sites may not be able to conduct the maternal and/or 
infant DXA scans on the same date as the other evaluations for these visits, and may not be able to 
arrange a scan within the corresponding visit windows. Sites should make every effort to schedule the 
DXA scan to take place within these windows, but up to 28 days is allowed.  
• 
Sites may make use of these expanded allowable visit windows as needed, however, the visit 
windows specified in protocol Section 6 remain the target and sites are encouraged to continue 
scheduling within these target windows whenever possible. Sites should consider current or 
anticipated operational disruptions or closures when scheduling visits and should schedule visits early 
or late in the allowable window, as appropriate. Visits conducted outside of allowable windows are 
also preferred to missed visits 
• 
If it is not possible to conduct study visits in-person at the study site, visit procedures may be 
performed off-site or remotely (e.g., by telephone) as described below. Site investigators must ensure 
that standard operating procedures (SOPs) are in place for off-site and remote procedures.  
• 
Sites may 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 participant families 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, 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 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 site investigator as needed.  


 
IMPAACT 2009, FINAL Version 3.0 
Page 173 of 173 
19 November 2020 
 
 
Study Drug Supply 
• Sites are encouraged to consider current or anticipated operational disruptions or closures, and to 
dispense study drug in sufficient quantities to avoid gaps in study drug supply.   
• Sites are encouraged to implement study drug dispensing and delivery options involving outdoor pick-
up or drop-off. Sites are also advised that, when other options are 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. 
 
Documentation 
• 
Site-specific contingency plans, and the implementation thereof, should be documented in essential 
document files for IMPAACT 2009.  
• 
Documentation should be entered in participant study charts in real-time (or close to real-time) if 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  
• 
In consultation with the Division of AIDS, the IMPAACT Network has developed and disseminated 
guidance for documenting and/or reporting protocol deviations that may occur due to limited site 
capacity to conduct study visits or procedures due to COVID-19. Please contact the IMPAACT 
Operations Center Clinical Trials Specialists with any questions related to documentation and 
reporting requirements.  
 
 
 

SAP_001.pdf: 
IMPAACT 2009 Version 3.0  
Primary Statistical Analysis Plan v2.0 
 
22 October 2024 
 
 
IMPAACT 2009 
Primary Statistical Analysis Plan  
 
Version 2.0 
 
 22 October 2024 
 
Pharmacokinetics, Feasibility, Acceptability, and Safety of Oral 
Pre-Exposure Prophylaxis for Primary HIV Prevention during 
Pregnancy and Postpartum in Adolescents and Young Women 
and their Infants 
 
DAIDS ES # 30020 
IND #136,735 Held by DAIDS 
NCT03386578 
 
 
Protocol Version 3.0  
 
 
Created by: 
 
Statistical and Data Analysis Center 
Harvard T.H. Chan School of Public Health
 


IMPAACT 2009 Version 3.0  
Primary Statistical Analysis Plan v2.0 
 
22 October 2024 
 
Page 1 of 22 
 
Table of Contents 
 
TABLE OF CONTENTS ................................................................................................................... 1 
VERSION HISTORY ........................................................................................................................ 3 
1 
INTRODUCTION ........................................................................................................................ 4 
1.1 
Purpose ............................................................................................................................ 4 
1.2 
Version History ............................................................................................................... 4 
2 
STUDY OVERVIEW ................................................................................................................... 4 
2.1 
Overview of Study Design .............................................................................................. 4 
2.1.1 
PK Component Study Design .............................................................................. 4 
2.1.2 
PrEP Comparison Component Study Design ...................................................... 5 
2.2 
Hypotheses ...................................................................................................................... 6 
2.2.1 
Hypothesis for the PK Component ....................................................................... 6 
2.2.2 
Hypotheses for the PrEP Comparison Component ............................................. 6 
2.3 
Primary and Secondary Study Objectives ................................................................... 6 
2.3.1 
Primary Study Objective for the PK Component .................................................. 6 
2.3.2 
Secondary Study Objective for the PK Component ............................................. 7 
2.3.3 
Primary Study Objectives for PrEP Comparison Component .............................. 7 
2.4 
Overview of Sample Size Considerations .................................................................... 7 
2.4.1 
PK Component: .................................................................................................... 7 
2.4.2 
PrEP Comparison Component: ............................................................................ 7 
2.5 
Overview of Formal Interim Monitoring ........................................................................ 7 
3 
OUTCOME MEASURES ........................................................................................................... 8 
3.1 
Primary and Secondary Outcome Measure for PK Component ................................ 8 
3.2 
Primary Outcome Measure(s) for PrEP Comparison Component ............................. 9 
4 
DEFINITIONS ............................................................................................................................ 9 
5 
GENERAL CONSIDERATIONS – PREP COMPARISON COMPONENT ............................. 10 
6 
ESTIMANDS AND ESTIMATION ............................................................................................ 11 
6.1 
Primary Estimand PK Component: ............................................................................. 11 
6.2 
Secondary Estimand – PK Component ...................................................................... 12 
6.3 
Primary Estimand(s) - PrEP Comparison Component .............................................. 13 
6.3.1 
First Primary Estimand ....................................................................................... 13 
6.3.2 
Second Primary Estimand .................................................................................. 16 
6.3.3 
Third Primary Estimand ...................................................................................... 17 
6.3.4 
Fourth Primary Estimand ................................................................................... 18 
6.3.5 
Fifth Primary Estimand ....................................................................................... 19 
7. REPORT CONTENTS ............................................................................................................. 20 
8 
ASSOCIATED DOCUMENTS ................................................................................................. 21 
9 
APPENDIX: ADHERENCE INTERPRETATIONS .................................................................. 22 


IMPAACT 2009 Version 3.0  
Primary Statistical Analysis Plan v2.0 
 
22 October 2024 
 
Page 2 of 22 
 
Appendix Table 1: Pregnant Women TFV-DP Concentrations in DBS at <=6 Weeks on 
PrEP and >6 Weeks and Beyond ..................................................................... 22 
Appendix Table 2: Postpartum Women TFV-DP concentrations in DBS at <=6 Weeks on 
PrEP and >6 Weeks and Beyond ..................................................................... 22 
 
 
 


IMPAACT 2009 Version 3.0  
Primary Statistical Analysis Plan v2.0 
 
22 October 2024 
 
Page 3 of 22 
 
Version History 
 
Version 
Changes Made 
Date Finalized 
1 
Original Version 
January 12 2022 
2.0 
Added PK Component text 
October 22 2024 
 
 
 


IMPAACT 2009 Version 3.0  
Primary Statistical Analysis Plan v2.0 
 
22 October 2024 
 
Page 4 of 22 
 
1 
Introduction 
1.1 
Purpose 
This Primary Statistical Analysis Plan (SAP) describes the primary estimands and primary 
outcome measures that will address primary study objectives and interim monitoring of IMPAACT 
2009. The Primary SAP includes general analytic approaches for all primary estimands, and 
primary outcome measures in the primary manuscript(s) or submitted to ClinicalTrials.gov 
(regardless of the reporting timeline). The Primary SAP facilitates discussion of the statistical 
analysis components among the lead study investigators and statisticians, helping them agree on 
the statistical analyses to be performed and presented in the primary analysis report. 
The Analysis Implementation Plan (AIP) provides detailed outlines of tables, figures, and coding 
descriptions. A separate SAP will provide outlines of analyses for other objectives and outcome 
measures not included in the Primary SAP. 
1.2 
Version History 
Not applicable; original version  
2 
Study Overview 
2.1 
Overview of Study Design 
2.1.1 
PK Component Study Design 
The IMPAACT 2009 PK Component aims to establish drug thresholds for adequate adherence in 
pregnancy and postpartum when FTC/TDF is administered daily during pregnancy and in the 
postpartum period under directly observed conditions. All maternal participants will be 
administered once daily FTC/TDF. All doses will be directly observed for the 12-week duration. 
DBS specimens will be collected at weekly intervals for analysis.  
The study population includes pregnant or postpartum women 16-24 years of age who are HIV 
negative and their infants: Group 1: Enrolled during singleton pregnancy at 14-24 weeks’ 
gestation; Group 2: Enrolled postpartum within 6-12 weeks after delivery. The PK Component will 
enroll 40 women and their infants (20 mother-infant pairs in each Group). A total of 40 maternal 
participants will be recruited to obtain at least 30 evaluable maternal participants with 20 
participants recruited in the antepartum group (14-24 weeks of gestation) (Group 1), and 20 
recruited in the postpartum group (6-12 weeks postpartum) (Group 2). Participants agree to take 
once daily oral PrEP (FTC/TDF) under direct observation daily for 12 weeks. Dried blood spot 
(DBS) specimens will be collected at weekly intervals for analysis. Five sites across four countries 
(Malawi, South Africa, Uganda, and Zimbabwe) participate in the IMPAACT 2009 PK component.  
A maternal participant is considered evaluable if she fulfils the following criteria; a) completes PK 
Component follow-up, b) has adequate documentation that PrEP doses were directly observed, 
c) has demonstrated adequate adherence to PrEP, defined as no more than 12 total directly 
observed doses missed over 12 weeks (maternal participants with more than three consecutively 
missed doses will be reviewed by the CMC to determine evaluability), and (d) had adequate DBS 
samples shipped to the PK testing laboratory, defined as no more than one missed specimen in 


IMPAACT 2009 Version 3.0  
Primary Statistical Analysis Plan v2.0 
 
22 October 2024 
 
Page 5 of 22 
 
any given two-week interval over 12 weeks with a minimum of  seven samples correctly collected, 
processed, handled and shipped. The rationale for this design is to collect as many weekly 
measurements as feasible to enable the most robust estimates, but also to allow flexibility for 
occasional missed visits and doses to enable practicability for participants and sites.  
2.1.2 
PrEP Comparison Component Study Design 
The IMPAACT 2009 PrEP Comparison Component is a parallel observational cohort study. It will 
assess feasibility, acceptability, adherence to, and safety of PrEP during pregnancy and in the 
postpartum period among adolescents and young women who are HIV-negative. Women will be 
screened prior to 32 weeks’ gestation and subsequently enrolled in two cohorts: those who 
choose to initiate PrEP at enrollment (Cohort 1) and those who decline (Cohort 2). Infants will be 
enrolled in utero at the same time the woman is enrolled. A randomized trial in which women 
were assigned to an arm that would not receive PrEP would be unethical at this time due to the 
overwhelming evidence supporting the efficacy of PrEP to prevent HIV infection. All women 
enrolled in the study will receive a standard of care package of HIV prevention services and a 
study-specific behavioral risk reduction intervention. Additionally, all women will receive support 
for antenatal, delivery and early infant care through brief motivational-interviewing informed 
counseling at each study visit and one-way mHealth messaging services. Women who choose to 
initiate PrEP will be provided PrEP as well as drug-level informed adherence support intervention.  
Approximately 350 women will be enrolled to achieve at least 300 evaluable women (200 in 
Cohort 1 and 100 in Cohort 2) and their infants, defined as completing the week 26 postpartum 
visit. Women will be accrued over a 12-month period (from the date of first enrollment) and 
followed through 26 weeks postpartum. For each woman, the duration of follow-up is expected to 
range from seven to 12 months depending on gestational age at entry. For each infant, the 
expected duration of follow-up is approximately six months.  
Regardless of cohort, all maternal participants will follow similar schedules of evaluations through 
the course of pregnancy and in the 26 weeks following delivery. Women in Cohort 2 may choose 
to initiate PrEP at any stage following study entry, and triggers for change in PrEP perceptions 
and acceptability over time will be recorded to better understand women’s motivation to seek 
additional HIV prevention services. As Cohort 2 is not exposed to antiretroviral agents during 
pregnancy or postpartum, its unexposed time period will serve as a comparison group for 
estimates of incidence and prevalence of maternal and infant safety outcomes including a) 
pregnancy outcomes, b) maternal adverse events, and c) infant growth and development 
between the two exposure groups.  
The primary objectives focus on women who initiate PrEP during pregnancy and continue through 
the first 26 weeks postpartum (Cohort 1). Adherence to PrEP will be assessed by measuring 
TFV-DP drug levels in dried blood spots. Participants in this arm will receive an intervention 
designed to provide participant-centered support, including support for PrEP use/adherence, 
comprised of a) two-way SMS messaging related to PrEP adherence, and b) targeted adherence 
counseling guided by TFV-DP drug levels.  
Maternal participants who change their intent regarding PrEP will be allowed to do so. 
Participants in Cohort 1 who choose to stop PrEP will continue in follow-up. Maternal participants 


IMPAACT 2009 Version 3.0  
Primary Statistical Analysis Plan v2.0 
 
22 October 2024 
 
Page 6 of 22 
 
in Cohort 2 who subsequently choose to initiate PrEP will undergo a Step Change, and will be 
referred to as Cohort 2/Step 2 and will follow the procedures for Cohort 1/Cohort 2 Step 2. While 
a formal step change will only be required when those originally declining PrEP later chose to 
initiate it, there is no upper limit set on the number of switches allowed for each participant. 
Switching will be closely monitored as part of feasibility and adherence outcomes. 
There will be no randomization for this study. To monitor the balance of the maternal participants 
enrolled among various groups, the enrollment will be stratified by: 
• 
Cohort: PrEP vs. No PrEP at enrollment 
• 
Trimester of enrollment during pregnancy: 1st or 2nd trimester vs. 3rd trimester 
• 
Country 
• 
Age at enrollment: 16-17 years vs. 18 years of age and older 
Stratifying by the above factors in this non-randomized study is for the purpose of monitoring the 
accrual to ensure that there are not large differences between the two cohorts (PrEP and No 
PrEP) in the proportion of women who are 16-17 years old, who are from a specific country, or 
who enroll in the 1st or 2nd (vs. 3rd) trimester of pregnancy, and to ensure a proportion of enrolled 
women are in the 16-17 year old age group. The team will be closely monitoring and adjusting 
enrollment to ensure this balance. 
The primary analysis for this study will take place after follow-up of all participants in the study 
has concluded.  
2.2 
Hypotheses  
2.2.1 
Hypothesis for the PK Component 
In the context of monitored daily administration of PrEP, a TFV-DP threshold can be determined 
to track adequate adherence during pregnancy and breastfeeding. 
2.2.2 
Hypotheses for the PrEP Comparison Component 
1. At least 75% of women who opt to initiate PrEP will achieve a high level of 
adherence throughout pregnancy, as measured by optimal TFV-DP 
concentrations in DBS specimens. 
 
2. The rate of maternal and infant adverse events (including adverse pregnancy 
outcomes) will be higher among mother-infant pairs in which the mother 
initiates PrEP during pregnancy or postpartum than in pairs in which the 
mother declines PrEP. 
2.3 
Primary and Secondary Study Objectives 
2.3.1 
Primary Study Objective for the PK Component 
• 
To determine the concentration of tenofovir diphosphate (TFV-DP) associated with 
adequate adherence to FTC/TDF among women observed ingesting daily oral 
PrEP during pregnancy and postpartum. 
 


IMPAACT 2009 Version 3.0  
Primary Statistical Analysis Plan v2.0 
 
22 October 2024 
 
Page 7 of 22 
 
2.3.2 
Secondary Study Objective for the PK Component 
• 
To compare TFV-DP concentrations observed in pregnant and postpartum women. 
2.3.3 
Primary Study Objectives for PrEP Comparison Component 
This Primary SAP addresses the following primary objectives in the study protocol. Other study 
objectives in the protocol will be addressed in subsequent analysis plans.  
• 
To characterize PrEP adherence among HIV-uninfected young women during pregnancy 
and for twenty-six weeks postpartum, when provided with enhanced adherence support 
through mobile technology and counseling based on observed drug levels.  
• 
To assess the safety of FTC/TDF for PrEP during pregnancy and postpartum by 
comparing pregnancy outcomes and maternal and infant safety between PrEP-exposed 
and PrEP unexposed groups.  
The Primary SAP includes objectives, estimands and outcome measures to be addressed in the 
primary analysis report for the PrEP Comparison Component. The analysis or monitoring reports 
prepared by the SDMC for IMPAACT 2009 will include monthly monitoring reports, annual and ad 
hoc SMC reports, and a final report to be prepared after all participants have completed their last 
follow up visit.  
2.4 
Overview of Sample Size Considerations 
2.4.1 
PK Component:  
The PK Component will enroll a total of 40 women (20 in Group 1 and 20 in Group 2) to achieve a 
sample size of at least 30 evaluable participants, accounting for attrition. 
2.4.2 
PrEP Comparison Component:  
The PrEP Comparison Component will enroll a total of 350 (233 in Cohort 1 and 117 in Cohort 2) 
women over a 12-month period. Women will be followed through 26 weeks postpartum. Sample 
size and power calculations assume a final analysis sample of 300 women (200 in Cohort 1 and 
100 in Cohort 2) with follow-up through 26 weeks postpartum. The primary reason for the 2:1 
enrollment into the two cohorts was to balance the need for a “No PrEP” comparison group (to 
provide the background rates for safety outcome measures) with the need for a large enough 
PrEP group to examine outcomes that would be restricted to women in that group and the periods 
when they were prescribed PrEP (Adherence). To achieve this sample size at the analysis phase, 
this study will enroll approximately 350 women to accommodate a decrease of an estimated 15% 
due to maternal attrition. This is an abbreviated summary of details in the study protocol; refer to 
the IMPAACT 2009 protocol for additional details. 
2.5 
Overview of Formal Interim Monitoring 
PK Component and PrEP Comparison Component: The Clinical Monitoring Committee (CMC) 
on behalf of the Protocol Team will closely monitor study progress, safety, quality of study 
conduct, and participant accrual and retention based on reports that will be generated at least 


IMPAACT 2009 Version 3.0  
Primary Statistical Analysis Plan v2.0 
 
22 October 2024 
 
Page 8 of 22 
 
monthly by the SDMC. In addition, an independent IMPAACT Study Monitoring Committee (SMC) 
will review this study regularly, following policies described in the IMPAACT Manual of 
Procedures. The composition of the SMC will include the SMC Chair; IMPAACT Chair or Vice-
Chair; IMPAACT HIV Treatment Scientific Committee representative; representatives of the 
IMPAACT Operations Center and Statistical and Data Management Center; and representatives 
of NIAID and NICHD.  
SMC reviews will occur at least annually and on a more frequent or ad hoc basis if any safety 
issues or concerns arise. Ad hoc reviews may also be triggered per the safety monitoring 
guidelines specified below. Based on any of its reviews, the SMC may recommend that the study 
proceed as currently designed, proceed with design modifications, or be discontinued. The SMC 
may also provide operational recommendations to help address any study implementation 
challenges that may be identified during their reviews.  
The SMC will monitor study progress, quality of study conduct, and participant safety. The SMC 
will generally review the same types of data reports as the Protocol Team and CMC. For ad hoc 
or triggered safety reviews, more limited data may be reviewed, focusing on the events that 
triggered the reviews.  
PrEP Comparison Component Only: Adverse events in both groups and the proportion of 
women with Week 12 TFV-DP drug levels below the limit of quantification in Cohort 1 (as well as 
decisions to initiate PrEP after study entry among women in Cohort 2) will be monitored and 
summaries prepared at regular intervals for review by the SMC. The following events will trigger a 
SMC review. 
• 
Monitoring the proportion of women in Cohort 1 without quantifiable levels of TFV-DP at 
Week 12 (excluding women who have decided to stop PrEP): 
o 
At any site, if this proportion at Week 12 is greater than 40% after 15 maternal 
participants in Cohort 1 have completed that study visit and have TFV-DP specimen 
data available for that visit, the CMC will review the data and consult with site 
investigators, and make a recommendation to the SMC regarding the need for 
remedial actions or discontinuation of enrollment at the site. The SMC will convene to 
consider the CMC’s recommendation.  
• 
Monitoring participant safety outcomes (for women or infants in Cohort 1 and Cohort 2, Step 
2). Ad hoc SMC reviews will be convened:   
o 
If the proportion of women experiencing Grade 3 or higher adverse events is greater 
than 15%, after 50 women have been enrolled  
o 
If the rate of adverse pregnancy outcomes is greater than 20%, after 25% of 
pregnancies have been completed.  
o 
If the proportion of livebirth infants experiencing Grade 3 or higher adverse events is 
greater than 15%, after 50 completed pregnancies resulting in live births. 
3 
Outcome Measures 
3.1 
Primary and Secondary Outcome Measure for PK Component 
• 
Maternal Steady state TFV-DP concentration levels at Week 12. 


IMPAACT 2009 Version 3.0  
Primary Statistical Analysis Plan v2.0 
 
22 October 2024 
 
Page 9 of 22 
 
3.2 
Primary Outcome Measure(s) for PrEP Comparison Component 
PrEP adherence:  
• 
TFV-DP drug concentration level in Dried Blood Spots (DBS)  
Maternal Adverse Events:  
• 
Maternal Grade 3 or higher adverse events (signs, symptoms, labs, and diagnoses) 
• 
Maternal Grade 2 or higher chemistry abnormalities  
Adverse Pregnancy Outcomes:  
Composite outcome of  
• 
Spontaneous abortion (occurring at <20 weeks gestation) 
• 
Stillbirth (occurring at ≥20 weeks gestation) 
• 
Preterm delivery (<37 completed weeks’ gestation) 
• 
Small for gestational age (<10th percentile using INTERGROWTH-21st norms and 
ultrasound derived gestational age at delivery) 
Infant Safety: 
Infant Adverse Events 
• 
Infant death within the first 26 weeks of life 
• 
Infant Grade 3 or higher adverse events (signs, symptoms, labs, diagnoses) reported 
between birth and 26 weeks postpartum 
Infant Growth and Development 
• 
Infant bone mineral content based on DXA scan of the whole body (WB-BMC) at birth 
and lumbar spine (LS-BMC) at birth and 26 weeks postpartum  
• 
Infant creatinine and CrCl rate at birth and 26 weeks postpartum measured by Schwartz 
equation 
• 
Infant length for age z-score at birth and 26 weeks postpartum 
4 
Definitions 
Baseline 


IMPAACT 2009 Version 3.0  
Primary Statistical Analysis Plan v2.0 
 
22 October 2024 
 
Page 10 of 22 
 
Maternal baseline is defined as the measurement on or closest to the study entry date, and 
infant baseline is defined as the measurement at birth. For the PrEP Comparison 
Component analyses characterizing the proportion with optimal adherence to PrEP among 
women in Cohort 2 who subsequently decide to initiate PrEP, baseline is defined as the date 
initiating PrEP. 
Visit Windows for Analysis 
All analyses summarizing or referring to data by visit week include a visit window around the 
applicable study visit week. For maternal antepartum study visit weeks 4, 8, and 12 the visit 
window is +/- 14 days. The visit window is +/- 21 days for antepartum visit weeks 24 and 36. 
The Labor and Delivery/Infant birth visit may occur as soon as possible after delivery through 
21 days postpartum. The visit window is +/- 21 days for the maternal and infant 6- week 
postpartum, 14-week postpartum, and 26-week postpartum visits.  
Analysis Sets 
PK Component: 
• 
PK Adherence Set: All maternal participants on PrEP, including those in Group 1 
and those in Group 2 
PrEP Comparison Component: 
• 
Adherence Set: All maternal participants on PrEP, including those in Cohort 1 and 
those in Cohort 2 who later decide to formally initiate PrEP. All visits/periods where 
maternal participants are actively prescribed PrEP. 
• 
Maternal Safety Set: All maternal participants in Cohort 1 or Cohort 2, starting at 
enrollment 
• 
Infant Safety Set: All liveborn infants in Cohort 1 or Cohort 2, starting at birth 
5 
General Considerations – PrEP Comparison Component 
The primary analyses to address the primary objectives of the PK Component and the PrEP 
Comparison Component are outlined below. For a more detailed description of the analyses to be 
conducted, please refer to the Analysis Implementation Plan (AIP). 
Categorical variables will be summarized as N (%), with corresponding 95% confidence intervals 
where applicable. Continuous variables will be summarized with means and standard deviations, 
medians and IQR (Q1, Q3), as well as min, max. 
Descriptive summaries: 
 
PK Component: We will summarize and compare demographic and clinical characteristics at 
enrollment between maternal PK Component Group 1 (enrolled in pregnancy) and maternal PK 


IMPAACT 2009 Version 3.0  
Primary Statistical Analysis Plan v2.0 
 
22 October 2024 
 
Page 11 of 22 
 
Component Group 2 (enrolled postpartum). We will use Fisher’s exact test to estimate differences 
in proportions and t tests or Wilcoxon rank-sum tests (as appropriate) for continuous measures.  
 
PrEP Comparison Component: Entry demographic, pregnancy, pregnancy history, 
psychosocial, sexual behavior and partner characteristics of women in Cohort 1 and Cohort 2 will 
be summarized and compared using chi square tests (or Fishers exact test as appropriate) for 
discrete variables and t-tests or Wilcoxon tests for continuous variables.  
 
6 
Estimands and Estimation 
6.1 
Primary Estimand PK Component: 
Primary Objective 1: To determine the concentration of tenofovir diphosphate (TFV-DP) 
associated with adequate adherence to FTC/TDF among women observed ingesting daily oral 
PrEP during pregnancy and postpartum. 
Estimand 
description 
Maternal Steady state TFV-DP concentrations at Week 12 
Treatment 
1. 
Daily oral PrEP (200 mg FTC/ 300 mg TDF) during pregnancy and/or 
postpartum administered through direct observation. 
Target population  
Analysis set  
Women who are pregnant and test HIV-negative, 
are16-24 years of age, enrolled during a singleton 
pregnancy at 14-24 weeks’ gestation or postpartum 
within 6-12 weeks after delivery, and express 
willingness to take daily oral PrEP under direct 
observation for 12 weeks  
PK Adherence set: Women initiating PrEP  
 
 
Variable(s) 
Outcome measure(s)  
TFV-DP drug concentration level 
1. TFV-DP drug concentration level from Dried 
Blood Spots (DBS) measured at week 12 among 
pregnant women 
2. TFV-DP drug concentration level from Dried 
Blood Spots (DBS) measured at week 12 among 
postpartum women. 
 
Handling of intercurrent events  
Handling of missing data 


IMPAACT 2009 Version 3.0  
Primary Statistical Analysis Plan v2.0 
 
22 October 2024 
 
Page 12 of 22 
 
• 
Discontinuation of PrEP: Only visits 
occurring prior to discontinuation of PrEP 
will be included. (While on treatment 
strategy) 
 
Missing data could occur in the following 
situations:  
• 
Missing visit(s) when DBS would have been 
collected 
• 
Missing drug concentration results due to 
sample collection or processing issues. 
If a single specimen is missing at week 12, and a 
specimen is available at week 11, sensitivity 
analyses will be conducted including the results 
from the analysis of the 11-week specimen. 
Population-level summary measure 
Analysis approach 
1. 
Median and IQR TFV-DP concentration levels at 
Week 12 in pregnant and postpartum groups. 
 
 
In each of the two groups (antepartum and 
postpartum groups), the median and IQR of 
steady state concentration (Css), defined as the 
TFV-DP concentration observed at week 12 
corresponding to 6-7 day/week adherence 
(“optimal adherence”), will be calculated for each 
group. Predicted TFV-DP concentration levels for 
each maternal participant will be obtained using a 
population PK model, and descriptive statistics 
will be generated. The estimated steady-state 
TFV‐DP concentration thresholds for optimal 
adherence during pregnancy and postpartum will 
be based on the 25th percentile for 7 doses per 
week. 
 
6.2 
Secondary Estimand – PK Component 
Secondary Objective 1: To compare TFV-DP concentrations observed in pregnant and 
postpartum women 
Estimand 
description 
Maternal Steady state TFV-DP concentrations at Week 12 
Treatment 
1. 
Daily oral PrEP (200 mg FTC/ 300 mg TDF) during pregnancy and/or 
postpartum administered through direct observation. 
Target population  
Analysis set  
Women who are pregnant and test HIV-negative, are 
16-24 years of age, enrolled during a singleton 
pregnancy at 14-24 weeks’ gestation or postpartum 
within 6-12 weeks after delivery, and express 
willingness to take daily oral PrEP under direct 
observation for 12 weeks  
PK Adherence set: Women initiating PrEP  
 
 
Variable(s) 
Outcome measure(s)  


IMPAACT 2009 Version 3.0  
Primary Statistical Analysis Plan v2.0 
 
22 October 2024 
 
Page 13 of 22 
 
TFV-DP drug concentration level 
1. TFV-DP drug concentration level from Dried 
Blood Spots (DBS) measured at week 12 among 
pregnant women 
2. TFV-DP drug concentration level from Dried 
Blood Spots (DBS) measured at week 12 among 
postpartum women. 
 
Handling of intercurrent events  
Handling of missing data 
Discontinuation of PrEP: Only visits occurring prior to 
discontinuation of PrEP will be included. (While on 
treatment strategy) 
 
Missing data could occur in the following 
situations:  
• 
Missing visit(s) when DBS would have been 
collected 
• 
Missing drug concentration results due to 
sample collection or processing issues. 
If a single specimen is missing at week 12, and a 
specimen is available at week 11, sensitivity 
analyses will be conducted including the results 
from the analysis of the 11-week specimen. 
Population-level summary measure 
Analysis approach 
Difference in median TFV-DP concentration levels at 
Week 12 between pregnant (Group 1) and 
postpartum (Group 2) groups. 
 
 
In each of the two groups (antepartum and 
postpartum groups), the median and IQR of 
steady state concentration (Css), defined as the 
TFV-DP concentration observed at week 12 
corresponding to 6-7 day/week adherence 
(“optimal adherence”), will be calculated for each 
group. Differences in median Css between the 
antepartum and postpartum groups will be 
evaluated using Wilcoxon Rank Sum tests.  
 
6.3 
Primary Estimand(s) - PrEP Comparison Component 
6.3.1 
First Primary Estimand 
Primary Objective 1: To characterize PrEP adherence among HIV-uninfected young women 
during pregnancy and for twenty-six weeks postpartum, when provided with enhanced 
adherence support through mobile technology and counseling based on observed drug levels. 
Estimand 
description 
The probability that pregnant and postpartum HIV-uninfected women will have optimal 
adherence to daily oral PrEP 1) at defined timepoints; 2) during pregnancy and 
postpartum (through twenty-six weeks) as measured in TFV-DP concentration levels 
in dried blood spots during periods when women are formally prescribed PrEP 


IMPAACT 2009 Version 3.0  
Primary Statistical Analysis Plan v2.0 
 
22 October 2024 
 
Page 14 of 22 
 
Treatment 
1. 
Daily oral PrEP (200 mg FTC/ 300 mg TDF) during pregnancy and/or 
postpartum. 
2. 
Enhanced adherence support, including SMS messaging and feedback of 
drug levels with tailored counseling. 
3. 
Behavioral HIV risk reduction package 
Target population  
Analysis set  
Women who are pregnant and HIV-uninfected,16-
24 years of age, with a confirmed singleton 
pregnancy of 32 weeks’ gestation or less and who 
have access to a mobile phone, are able to receive 
and read SMS messages, and express willingness to 
take PrEP anytime between pregnancy and 26 
weeks postpartum  
Adherence set: Women initiating PrEP  
 
 
Variable(s) 
Outcome measure(s)  
TFV-DP drug concentration level 
 
 
1. TFV-DP drug concentration level from Dried 
Blood Spots (DBS) measured in pregnancy at 4, 
8, 12, 24, 36 week study visits, Labor and 
Delivery, and postpartum at 6, 14, and 26 week 
study visits during the periods that participants 
are receiving PrEP. A binary indicator, “optimal 
adherence” will be defined as TFV-DP levels 
meeting or exceeding the threshold of consistent 
dosing of PrEP (“Green Zone”) determined in the 
PK Component (Appendix Tables 1-2). For 
women who are pregnant the threshold is 600 
fmol/punch if on PrEP <=6 weeks and 650 
fmol/punch if >6 weeks; for women who are not 
pregnant the threshold is 700 fmol/punch if on 
PrEP <=6 weeks and 1050 fmol/punch if on PrEP 
>6 weeks. 
 
2. Visits with optimal adherence according to 
TFV-DP level during pregnancy and during 
postpartum  
Handling of intercurrent events  
Handling of missing data 
• 
Failure to start PrEP (in Cohort I or Cohort 
2/Step 2) (Treatment policy strategy) 
• 
Discontinuation of PrEP: Only visits occurring 
prior to discontinuation of PrEP will be included. 
(While on treatment strategy) 
• 
HIV seroconversion: Only visits occurring up to 
the later of the date of first positive HIV test or 
date when PrEP is discontinued will be included. 
(While on treatment strategy) 
Missing data could occur in the following 
situations:  
• 
Missing visit(s) when adherence would have 
been assessed 
• 
Missing drug concentration results due to 
sample collection or processing issues. 
Visits without adherence data will be excluded. 
Sensitivity analyses will be conducted imputing 
“suboptimal adherence” for each missed 
visit/concentration result 
Population-level summary measure 
Analysis approach 
1. 
Probability of optimal adherence according to 
TFV-DP levels in DBS at defined times during 
pregnancy and postpartum 
 
2. 
Probability of optimal adherence while pregnant 
and up to 26 weeks postpartum  
1. 
At each visit that TFV-DP levels are 
obtained, the binomial proportion of women 
with optimal adherence will be calculated 
bounded by an exact (Clopper-Pearson) 
95% confidence interval. 
 
2. 
The binomial proportion of visits with optimal 
adherence in pregnancy and postpartum 
periods during periods when women are 


IMPAACT 2009 Version 3.0  
Primary Statistical Analysis Plan v2.0 
 
22 October 2024 
 
Page 15 of 22 
 
formally prescribed PrEP will be calculated 
with exact (Clopper-Pearson) 95% 
confidence intervals.  
Supplemental Analyses: 
• 
Exploratory longitudinal analyses identifying baseline and time-varying predictors of 
optimal adherence will be conducted with multivariable regression models which 
account for repeated measures across time for each participant.  
• 
Adherence (as measured in TFV-DP levels) will also be summarized as a continuous 
outcome measure (median, IQR and mean [SD]) at each time point noted above 
when drug levels are measured, and “average” drug concentrations across 
pregnancy and postpartum periods, will be calculated, using generalized estimating 
equations as appropriate. Log transformation of this outcome will be considered if the 
distribution is not normal. 
• 
Other approaches to summarizing the adherence outcome will be considered. This 
includes an ordinal variable with categories corresponding to different dosing levels 
(e.g., Below limit of quantification (BLQ), Red, Yellow, Green). For this type of 
outcome, at each visit that drug levels are measured in DBS, descriptive analyses will 
summarize the proportion of women in each adherence category (refer to categories 
in the appendix tables 1-2). For the interim analysis the proportion of women with 
TFV-DP levels below the limit of quantification (BLQ) at the week 12 visit will be 
estimated. Additional analyses with other cutpoints (e.g., below vs. above the limit of 
quantification; red vs. not red) will be considered. 
• 
Women in Cohort 2 who later decide to initiate PrEP will be included in the main 
estimand. In addition, baseline characteristics, and patterns of adherence and 
duration on PrEP will be summarized separately for women in Cohort 1 and women 
in Cohort 2 who later decide to initiate PrEP using the approaches outlined above. 
• 
The following additional descriptive statistics will be calculated: The proportion of 
women a) with at least one visit with TFV-DP levels corresponding to optimal 
adherence, b) who had TFV-DP levels corresponding to optimal adherence at all 
visits while formally prescribed PrEP, c) who had no detectable TFV-DP levels at any 
visit while formally prescribed PrEP d) who formally stopped PrEP among those who 
had initiated, including reasons for stopping, characterizing those who stop vs 
continue. In addition, mean follow-up time and % of follow-up time on PrEP will be 
summarized.  
 
 
 


IMPAACT 2009 Version 3.0  
Primary Statistical Analysis Plan v2.0 
 
22 October 2024 
 
Page 16 of 22 
 
6.3.2 
Second Primary Estimand 
Primary Objective 2: To assess the safety of FTC/TDF for PrEP during pregnancy and 
postpartum by comparing pregnancy outcomes and maternal and infant safety between 
cohorts. 
Estimand 
description 
Incidence rate ratio of cumulative  adverse events (AEs) up to 26 weeks postpartum 
among PrEP exposed  vs. PrEP unexposed women  
Treatment 
1. 
Daily oral PrEP (200 mg FTC/ 300 mg TDF) throughout follow-up. 
2. 
Enhanced adherence support, including SMS messaging and feedback of 
drug levels with tailored counseling. 
3. 
Behavioral HIV risk reduction package 
Target population  
Analysis set  
Women who are pregnant and HIV-uninfected,16-24 
years of age, with a confirmed singleton pregnancy 
of 32 weeks’ gestation or less and who have access 
to a mobile phone and are able to receive and read 
SMS messages  
Maternal Safety Set:  all enrolled maternal 
participants 
 
Variable(s) 
Outcome measure(s)  
Occurrence of at least one of the following maternal 
AEs  up to 26 weeks postpartum 
• 
Grade 3 or higher adverse events  
• 
Grade 2 or higher chemistry abnormalities  
 
Outcome measures as defined by the variables 
(graded according to the NIAID DAIDS Table for 
Grading the Severity of Adult and Pediatric 
Adverse Events). 
• 
The start of person-time for the PrEP-
exposed group is study entry for Cohort 1 and 
Cohort 2/Step 2 entry for Cohort 2;  
• 
The start of person-time for the PrEP 
unexposed group is study entry (for Cohort 2 
only; person-time is censored when initiating 
PrEP for participants enrolled in Cohort 
2/Step 2) 
Handling of intercurrent events  
Handling of missing data 
• 
Failure to start PrEP (in Cohort I or Cohort 
2/Step 2) (Treatment policy strategy) 
 
• 
Premature discontinuation of PrEP  (Treatment 
policy strategy) 
 
 
Participants who discontinue follow-up before the 
26-week postpartum visit will have their outcome 
determined based on data available until the time 
of discontinuation (i.e., a participant who 
discontinued follow-up without a prior AE is 
assumed not to have an AE had they been 
observed for the intended duration). 
Population-level summary measure 
Analysis approach 
Incidence rate ratio (among PrEP exposed  vs. 
PrEP unexposed women) of  cumulative adverse 
events up to 26 weeks postpartum  
 
 
Incidence rate ratio of cumulative AEs up to the 
week-26 postpartum visit (among PrEP exposed 
vs. PrEP unexposed women) estimated based on 
Poisson distribution (with 95% Wald CI).  
 
Supplemental Analyses: 
• 
Analyses will be repeated stratified by time period (i.e., antepartum (AP) and postpartum 
(PP), and within AP stratified by gestational age category of enrollment).  
• 
Rates of maternal adverse events in AP and PP periods will also be calculated and 
compared across levels of PrEP adherence (based on TFV-DP levels in dried blood 
spots). Models will be fit adjusting for potential confounders. 


IMPAACT 2009 Version 3.0  
Primary Statistical Analysis Plan v2.0 
 
22 October 2024 
 
Page 17 of 22 
 
• 
To compare time to first adverse event in PrEP exposed vs. PrEP unexposed women, the 
hazard ratio (95% CI) will be estimated with Logrank test p-value from Cox proportional 
hazards regression on time to first AE with PrEP exposure as a time-varying covariate. 
6.3.3 
Third Primary Estimand 
Primary Objective 2: To assess the safety of FTC/TDF for PrEP during pregnancy and 
postpartum by comparing pregnancy outcomes and maternal and infant safety between 
cohorts. 
Estimand 
description 
The probability of an adverse pregnancy outcome among HIV-uninfected pregnant 
women who are PrEP exposed compared to women who are PrEP unexposed during 
pregnancy. 
Treatment 
1. 
Daily oral PrEP (200 mg FTC/ 300 mg TDF) throughout follow-up. 
2. 
Enhanced adherence support, including SMS messaging and feedback of 
drug levels with tailored counseling. 
3. 
Behavioral HIV risk reduction package 
Target population  
Analysis set  
Women who are pregnant and HIV-uninfected,16-24 
years of age, with a confirmed singleton pregnancy 
of 32 weeks’ gestation or less and who have access 
to a mobile phone and are able to receive and read 
SMS messages  
Maternal Safety Set:  all enrolled maternal 
participants  
 
Women in Cohort 1 (all) and Cohort 2/step 2 (if 
enrolled to Step 2 during pregnancy) are in PrEP 
exposed group;  
Women in Cohort 2 (remained in step 1 during 
pregnancy) are in PrEP unexposed group. 
Variable(s) 
Outcome measure(s)  
Composite adverse pregnancy outcomes of  
• 
Spontaneous abortion (occurring at <20 
weeks gestation 
• 
Stillbirth (occurring at ≥20 weeks gestation) 
• 
Preterm delivery (<37 completed weeks’ 
gestation) 
• 
Small for gestational age (<10th percentile 
using INTERGROWTH-21st norms and 
ultrasound derived gestational age at 
delivery) 
Outcome measure as defined by the variable. 
 
Handling of intercurrent events  
Handling of missing data 
• 
Failure to start PrEP (in Cohort I or Cohort 
2/Step 2) (Treatment policy strategy) 
• 
Premature discontinuation ofPrEP during 
pregnancy (Treatment policy strategy) 
Women without a pregnancy outcome will be 
excluded from the analysis, with an assumption 
that data are missing completely at random.  
Population-level summary measure 
Analysis approach 
Odds ratio of an adverse pregnancy outcome 
among PrEP exposed women during pregnancy vs. 
adverse pregnancy outcomes among PrEP 
unexposed women in pregnancy  
Odds ratio (and exact 95% CI) will be estimated 
and Fisher’s exact test p-value will be used to 
evaluate differences in the proportion with at least 
one adverse pregnancy outcome among women 
who are PrEP-exposed vs. women who are PrEP 
unexposed during pregnancy. 
Supplemental Analyses: 
• 
Univariable and multivariable logistic regression methods will be used to evaluate 
associations of PrEP use and the composite outcome indicating presence vs. absence of 
any adverse pregnancy outcomes, controlling for potential confounders. The same 
analyses will be conducted for each of the pregnancy outcomes which comprise the 


IMPAACT 2009 Version 3.0  
Primary Statistical Analysis Plan v2.0 
 
22 October 2024 
 
Page 18 of 22 
 
composite outcome separately. Analyses of small-for-gestational age births will be 
restricted to live births. 
 
6.3.4 
Fourth Primary Estimand 
Primary Objective 2: To assess the safety of FTC/TDF for PrEP during pregnancy and 
postpartum by comparing pregnancy outcomes and maternal and infant safety between 
cohorts. 
Estimand 
description 
Incidence rate ratio of cumulative adverse events up to the age 26-week visit among 
PrEP exposed  vs. PrEP unexposed infants  
Treatment 
Infants exposed to the following maternal treatment in utero and/or through 
breastfeeding: 
1. 
Daily oral PrEP (200 mg FTC/ 300 mg TDF) throughout follow-up. 
2. 
Enhanced adherence support, including SMS messaging and feedback of drug 
levels with tailored counseling. 
3. 
Behavioral HIV risk reduction package 
Target population  
Analysis set  
Infants born to women who are pregnant and HIV-
uninfected, 16-24 years of age, with a confirmed 
singleton pregnancy of 32 weeks’ gestation or less 
and who have access to a mobile phone and are 
able to receive and read SMS messages 
Infant Safety Set: all enrolled infants 
 
Variable(s) 
Outcome measure(s)  
Infant adverse events: 
• 
Infant death within the first 26 weeks of life 
• 
Infant Grade 3 or higher adverse events 
reported between birth and the age 26-
week visit. 
 
Outcome measures as defined by the variable 
(graded according to the NIAID DAIDS Table for 
Grading the Severity of Adult and Pediatric 
Adverse Events). 
The start of person-time for the PrEP-exposed 
group is birth for Cohort 1 and birth or Cohort 
2/step 2 entry (whichever is later) for Cohort 2;  
The start of person-time for the PrEP unexposed 
group is birth (Cohort 2 participants only; person-
time is censored when initiating PrEP for 
participants enrolled in Cohort 2/Step 2). 
Handling of intercurrent events  
Handling of missing data 
• 
Mother’s failing to start PrEP (in Cohort I or 
Cohort 2/Step 2) (Treatment policy strategy) 
 
• 
Mother’s discontinuation of PrEP (Treatment 
policy strategy) 
 
Participants who discontinue follow-up before the 
age 26-week visit will have their outcome 
determined based on data available until the time 
of discontinuation (i.e., a participant who 
discontinued follow-up without a prior AE is 
assumed not to have an AE had they been 
observed for the intended duration). 
Population-level summary measure 
Analysis approach 
• 
Incidence rate ratio  (among PrEP exposed  vs. 
PrEP unexposed infants) of  cumulative 
adverse events up to the age 26-week visit  
 
• 
Incidence rate ratio of cumulative adverse 
events up to the age 26-week visit (among 
PrEP exposed vs. PrEP unexposed infants) 
estimated based on Poisson distribution (with 
95% Wald CI).  
 
 
 
 
 
 


IMPAACT 2009 Version 3.0  
Primary Statistical Analysis Plan v2.0 
 
22 October 2024 
 
Page 19 of 22 
 
Supplemental Analyses: 
• 
Analyses will be repeated stratifying by time of infant drug exposure (i.e., antepartum 
(AP) and postpartum (PP), and within AP stratified by gestational age category of 
maternal enrollment).  
• 
Rates of infant adverse events will also be calculated and compared across levels of 
maternal PrEP adherence (based on TFV-DP levels in dried blood spots). Models will be 
fit adjusting for potential confounders. 
• 
To compare time to first infant adverse event in PrEP exposed vs. PrEP unexposed 
infants, the hazard ratio (95% CI) will be estimated with Logrank test p-value from Cox 
proportional hazards regression on time to first AE with PrEP exposure as a time-varying 
covariate. 
 
6.3.5 
Fifth Primary Estimand 
Primary Objective 2: To assess the safety of FTC/TDF for PrEP during pregnancy and 
postpartum by comparing pregnancy outcomes and maternal and infant safety between 
cohorts. 
Estimand 
description 
Difference in mean infant growth and development outcomes at birth and age 26 
weeks among PrEP exposed and PrEP unexposed infants;  
 
Treatment 
Infants exposed to the following maternal treatment in utero and/or through 
breastfeeding: 
1. 
Daily oral PrEP (200 mg FTC/ 300 mg TDF) throughout follow-up. 
2. 
Enhanced adherence support, including SMS messaging and feedback of drug 
levels with tailored counseling. 
3. 
Behavioral HIV risk reduction package 
Target population  
Analysis set  
Infants born to women who are pregnant and HIV-
uninfected, 16-24 years of age, with a confirmed 
singleton pregnancy of 32 weeks’ gestation or less 
and who have access to a mobile phone and are 
able to receive and read SMS messages 
Infant Safety Set: growth and development 
 
Infants of women who have ever used PrEP (in 
Cohort 1 or Cohort 2 Step 2) will be considered 
PrEP exposed. Infants of women who have never 
used PrEP will be considered PrEP unexposed. If 
PrEP exposure occurs prior to the outcome 
measurement of interest then the infant will be 
considered PrEP exposed. 
 
Variable(s) 
Outcome measure(s)  
Infant growth and development outcomes 
The following will be calculated to evaluate infant 
safety outcomes: 
• 
Infant bone mineral content (grams) by dual 
energy X-ray absorptiometry (DXA) scan of 
the whole body (WB-BMC) at birth and 
lumbar spine (LS-BMC) at birth and 26 weeks  
• 
Infant creatinine and CrCl rate measured by 
Schwartz equation at birth and at 26 weeks  
• 
Infant length-for-age z-score at birth and at 26 
weeks 
The week 26 measurement will be at the Week 26 
study visit 


IMPAACT 2009 Version 3.0  
Primary Statistical Analysis Plan v2.0 
 
22 October 2024 
 
Page 20 of 22 
 
Handling of intercurrent events  
Handling of missing data 
• 
Mother’s failure to start PrEP (in Cohort I or 
Cohort 2/Step 2) (Treatment policy strategy) 
 
• 
Mother’s discontinuation of PrEP(Treatment 
policy strategy) 
Sensitivity analysis: for infants discontinuing study 
prior to the 26 weeks of age, use the last value 
carried forward for the 26 weeks visit. 
Population-level summary measure 
Analysis approach 
Difference in mean infant growth and development  
outcomes between PrEP exposed (in Cohort 1 and 
Cohort 2 step 2) and PrEP unexposed infants 
(infants in Cohort 2) at birth and 26 weeks of age 
Means will be estimated and compared between 
PrEP-exposed and PrEP unexposed infants using 
two sample t-tests at each time point of 
evaluation, or Wilcoxon rank sum tests as 
appropriate to evaluate differences in these 
endpoints between PrEP-exposed and PrEP 
unexposed infants. 
7. 
Report Contents 
An overview of the contents of the final analysis report for the PrEP Comparison Component is 
outlined below. Additional details of the final analysis report contents are provided in the AIP.  
• 
CONSORT diagram  
• 
Study entry:  
o 
Screening 
o 
Accrual 
o 
Eligibility 
• 
Baseline characteristics (reported in ClinicalTrials.gov) 
o 
Maternal characteristics at baseline 
o 
Infant characteristics at birth 
• 
Study retention (reported in ClinicalTrials.gov) 
o 
By Cohort and study visit 
• 
Treatment status:  
o 
By Cohort (Cohort 1-PrEP, Cohort 2-No PrEP) 
o 
Frequency and Timing of switching from No PreP to PrEP (i.e., Cohort 2 step 
change) 
• 
PrEP discontinuation, and PrEP restart (if applicable) 
o 
PrEP discontinuation reasons 
• 
PrEP adherence:  
o 
N (%) with optimal adherence at each visit, overall, during pregnancy, and 
postpartum, and by gestational age group at enrollment 
o 
Number and timing of visits missed when assessment of PrEP adherence was 
expected 
• 
Maternal safety outcomes  
o 
By PrEP exposure 
o 
During pregnancy and postpartum 
• 
Pregnancy Outcomes 
o 
Overall and by PrEP exposure  
• 
Infant safety outcomes  
o 
Overall, by PrEP exposure   


IMPAACT 2009 Version 3.0  
Primary Statistical Analysis Plan v2.0 
 
22 October 2024 
 
Page 21 of 22 
 
8 
Associated Documents 
 
Attachment 1: Timetable for Primary Analysis and Manuscript  
Event 
Responsible party 
Weeks from primary 
completion date (PCD) 
Primary completion date (PCD) 
 
PCD 
Clinical data entry termination 
Sites 
PCD + 4 weeks 
Initial database clean-up complete, including 
- 
DAERS reconciliation complete 
- 
TSDV complete 
 
PDM and LDM 
PCD + 12 weeks 
Clinical database closure/freeze complete/eCRF sign-
off by site investigators 
PDM and Sites 
PCD + 15 weeks 
SDTM ARMCD populated 
SDTM Specialist 
PCD + 16 weeks 
Complete SDTM on production server 
SDTM Specialist 
PCD + 16 weeks 
Clinical database lock and primary laboratory database 
lock 
Chief Data Manager 
and LDM Leadership 
PCD + 17 weeks 
Final SDTM on production server 
SDTM Specialist 
PCD + 18 weeks 
Primary analysis report to Protocol Chairs/Writing 
Team 
Protocol statisticians 
PCD + 22 weeks 
 
 
 
 
 


IMPAACT 2009 Version 3.0  
Primary Statistical Analysis Plan v2.0 
 
22 October 2024 
 
Page 22 of 22 
 
9 
Appendix: Adherence Interpretations 
 
The following Appendix Tables are adherence interpretations and categories based on TFV-DP 
Concentration (fmol/punch) in Dried Blood Spots (DBS) from the PK Component. 
 
Appendix Table 1: Pregnant Women TFV-DP Concentrations in DBS at <=6 Weeks on PrEP 
and >6 Weeks and Beyond  
 
Interpretation 
≤ 6 Weeks  
on PrEP 
> 6 Weeks  
on PrEP and Beyond 
Green Zone 
Consistent with Highest levels of 
protection 
≥600 
≥650 
Yellow Zone 
Consistent with some but 
incomplete levels of protection 
150-599 
200-649 
Red Zone 
Consistent with low to no levels of 
protection 
<150 
<200 
 
Appendix Table 2: Postpartum Women TFV-DP concentrations in DBS at <=6 Weeks on 
PrEP and >6 Weeks and Beyond  
 
Interpretation 
≤ 6 Weeks  
on PrEP 
> 6 Weeks  
on PrEP and Beyond 
Green Zone 
Consistent with Highest levels of 
protection 
≥700 
≥1050 
Yellow Zone 
Consistent with some but 
incomplete levels of protection 
200-699 
300-1049 
Red Zone 
Consistent with low to no levels of 
protection 
<200 
<300