Long-Term Clinical, Immunologic, and Virologic Profiles of Children Who Received Early Treatment for HIV
Conditions: HIV Infection
Sponsor: International Maternal Pediatric Adolescent AIDS Clinical Trials Group

 
 
IMPAACT 2028 
Long-Term Clinical, Immunologic, and Virologic Profiles of 
Children who Received Early Treatment for HIV 
 
 
Non-IND Study  
DAIDS ES # 38693 
 
 
This file contains the current IMPAACT 2028 protocol, 
which is comprised of the following documents, 
presented in reverse chronological order: 
 
• Letter of Amendment #1, dated 10 February 2023  
• Clarification Memorandum #1, dated 26 April 2021 
• Protocol Version 1.0, dated 23 December 2020 
 
 
 
 

Letter of Amendment #1 for  
Page 1 of 4 
10 February 2023 
IMPAACT 2028 Protocol Version 1.0 
Letter of Amendment #1 for:  
 
IMPAACT 2028 
Long-Term Clinical, Immunologic, and Virologic Profiles of 
Children who Received Early Treatment for HIV 
 
Version 1.0, dated 23 December 2020 
 
DAIDS Study ID #38693 
 
Letter of Amendment Date: 10 February 2023 
 
 
Information/Instructions to Study Sites from the Division of AIDS 
 
The information contained in this Letter of Amendment (LoA) affects the IMPAACT 2028 study and 
must be submitted to site Institutional Review Boards and/or Ethics Committees (IRBs/ECs) as soon as 
possible for their review and approval. Approval must also be obtained from other site regulatory entities 
if applicable per the policies and procedures of the regulatory entities. All applicable IRB/EC and 
regulatory entity requirements must be followed.  
 
Upon obtaining all required IRB/EC approvals and any other applicable regulatory entity approvals, each 
site should immediately begin implementing this LoA. Sites are required to submit an LoA registration 
packet to the DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory Support Center. Sites 
will receive a registration notification for the LoA after the DAIDS PRO verifies that all required 
registration documents have been received and are complete. Sites should not await this notification 
before implementing this LoA.  
 
Please file this LoA, all associated IRB/EC and regulatory entity correspondence, and all correspondence 
with the DAIDS PRO in your essential document files for IMPAACT 2028. If the IMPAACT 2028 
protocol is amended in the future, the contents of this LoA will be incorporated into the next version of 
the protocol. 
 
 
 
 
 
 
 

Letter of Amendment #1 for  
Page 2 of 4 
10 February 2023 
IMPAACT 2028 Protocol Version 1.0 
IMPAACT 2028 
Long-Term Clinical, Immunologic, and Virologic Profiles of 
Children who Received Early Treatment for HIV 
 
DAIDS Study ID #38693 
 
Version 1.0, Letter of Amendment #1 
Letter of Amendment Signature Page 
 
 
I will conduct this study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with United States (US) Health and 
Human Service regulations (45 CFR 46); applicable US Food and Drug Administration regulations; 
standards of the International Council for Harmonisation Guideline for Good Clinical Practice (ICH E6); 
Institutional Review Board/Ethics Committee determinations; all applicable in-country, state, and local 
laws and regulations; and other applicable requirements (e.g., US National Institutes of Health, Division 
of AIDS) and institutional policies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator of Record 
  
 
Date 
 
 
 
 
 
 
 
 
 
 
 
Name of Investigator of Record  
 
(printed) 
 
 
 
 

Letter of Amendment #1 for  
Page 3 of 4 
10 February 2023 
IMPAACT 2028 Protocol Version 1.0 
Summary of Modifications and Rationale 
 
The purpose of this LoA is to permit an exemption from storage of peripheral blood mononuclear cells 
(PBMCs) at sites where the local laboratory does not participate in the DAIDS immunology quality 
assurance (IQA) program. Updates of the protocol team and study site rosters are also included in this 
LoA. 
 
Implementation 
 
A. Exemption from Storage of PBMCs 
 
Protocol Section 5.8.2 specifies that PBMCs stored for this study must be processed and cryopreserved by 
an IQA-approved laboratory. In the event that DAIDS determines a site laboratory cannot be added to the 
IQA program, on a case-by-case basis, the protocol team may exempt the site from PBMC storage. If this 
option is implemented, this will be documented in a memorandum from the protocol team that should be 
filed in the relevant site’s essential document files for IMPAACT 2028.  
 
B. Protocol Team Roster Updates 
 
To reflect current Protocol Team membership, Jason Rippe is removed (deletions not shown); Jared 
Kneebone and Christina Reding are replaced by Andi Ace; and Colleen Foley is replaced by Laura 
Hovind. Contact details are shown below.  
 
Andi Ace, MEd 
Frontier Science Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900, x7269 
Email: ace@frontierscience.org 
 
Laura Hovind, MS 
Frontier Science Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900, x7468 
Email: hovind@frontierscience.org
C. Study Site Roster Updates 
 
The investigator at Clinical Research Site 5048 has determined that the site is not expected to enroll any 
participants in this study; as such, this site is removed from the roster (deletions not shown). 
 
To reflect recent staffing changes, LaTeshia Thomas Seaton is replaced by Sierra Jordan-Thompson as 
the Study Coordinator at Site 5030; Kathleen Graham is replaced by Paulino Four Castro as the Study 
Coordinator at Site 5055; Jullapong Achalapong is replaced by Pradthana Ounchanum as the Investigator 
of Record at site 5116; Nastassja Ramsagar is replaced by Deirdre Josipovic as the Study Coordinator at 
Site 8052; Portia Kamthunzi is replaced by Tisungane Mvalo as the Investigator of Record at site 12001; 
and Barbara Pahud is replaced by James Christopher Day as the Investigator of Record at Site 32017. 
Contact details are shown below. 
 
5030, Emory University School of Medicine Clinical Research Site 
Sierra Jordan-Thompson  
Study Coordinator 
Phone: 404-616-9839 
Email: sierra.jordan@emory.edu 
 
 
 

Letter of Amendment #1 for  
Page 4 of 4 
10 February 2023 
IMPAACT 2028 Protocol Version 1.0 
5055, South Florida CDTC Fort Lauderdale Clinical Research Site 
Paulino Four Castro 
Study Coordinator 
Phone: 954-712-5052 
Email: pfourcastro@browardhealth.org 
 
8052 Soweto Clinical Research Site 
Deirdre Josipovic  
Study Coordinator 
Phone: 27-11-989-9700 
Email: josipovicd@phru.co.za> 
 
12001, Malawi Clinical Research Site 
Tisungane Mvalo  
Investigator of Record 
Phone: 265-1-755-056 
Email: tmvalo@unclilongwe.org 
 
32017, Children's Mercy Hospital Clinical Research Site 
James Christopher Day 
Investigator of Record 
Phone: 816-234-3207 
Email: ccday@cmh.edu 
 
In addition, a site is added:  
 
5072, Hospital Federal dos Servidores do Estado Clinical Research Site 
Rua Sadadura Cabral 178 
Rio de Janeiro, Brazil 
 
Esau Joao Filho 
Investigator of Record 
Phone: 55-21-223-31551 
Email: esaujoao@gmail.com 
 
Lean Sidi 
Study Coordinator 
Phone: 55-21-223-30018 
Email: leon@diphse.com.br 
 
 

Clarification Memorandum #1 for  
Page 1 of 4 
26 April 2021  
IMPAACT 2028 Protocol Version 1.0 
Clarification Memorandum #1 for:  
 
IMPAACT 2028 
Long-Term Clinical, Immunologic, and Virologic Profiles of 
Children who Received Early Treatment for HIV 
 
Version 1.0, dated 23 December 2020 
 
DAIDS Study ID #38693 
 
Clarification Memorandum Date: 26 April 2021 
 
 
Summary of Clarifications and Rationale 
 
This Clarification Memorandum (CM) updates protocol specifications to reflect current policies of the 
Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases (NIAID), and National 
Institutes of Health (NIH). It also updates the protocol team and study site rosters and adds guidance for 
collection of nasopharyngeal and rectal swabs in the event that supplies required for collection of these 
specimens are not available. 
 
 
Implementation 
 
Institutional Review Board/Ethics Committee (IRB/EC) approval of this CM is not required by the study 
sponsor prior to implementation; however, sites may submit it to IRBs/ECs for their information or, if 
required by the IRBs/ECs, for their approval prior to implementation.  
 
IRBs/ECs may have acknowledged and/or approved remote site monitoring strategies prior to the 
issuance of this CM. If so, documentation of the acknowledgement and/or approval should be filed in 
your essential document files for IMPAACT 2028. This CM and any applicable IRB/EC correspondence 
should also be filed in your essential document files for IMPAACT 2028. 
 
The information included in this memorandum will be incorporated into the next protocol amendment. 
 
A. DAIDS Policy Updates  
 
1. Protocol Section 9 is updated to reflect current DAIDS policies for clinical site monitoring, which do 
not require monitoring for non-IND studies and allow for monitoring, when performed, to be 
performed on-site or remotely. The prior contents of this section are replaced with the following:  
 
Under contract to DAIDS or NICHD, site monitors may inspect study site facilities and review 
participant study records — including informed consent and assent forms, paper-based CRFs 
(if used), eCRFs, medical records, and laboratory records — to ensure protection of study 
participants, compliance with the IRB/EC approved protocol, and accuracy and completeness 
of records. Monitors also may review essential document files to ensure compliance with all 
applicable regulatory requirements. Site investigators will make study facilities and documents 
available for inspection by monitors. 
 

Clarification Memorandum #1 for  
Page 2 of 4 
26 April 2021  
IMPAACT 2028 Protocol Version 1.0 
Monitoring visits may be conducted on-site or remotely. Remote visits may include remote 
source document verification using methods specified for this purpose by DAIDS or NICHD. 
Remote monitoring visits may be performed in place of, or in addition to, onsite visits to ensure 
the safety of study participants and data integrity (1). Site investigators will make study 
documents available for site monitors to review utilizing a secure platform that is HIPAA 
compliant. Potential platform options include: Veeva SiteVault, Medidata Rave Imaging 
Solution, Medidata Remote Source Review, site-controlled SharePoint or cloud-based portal, 
and direct access to electronic medical records. Other secure platforms that are HIPAA 
compliant may be utilized, as allowed by DAIDS or NICHD. 
 
Reference:  
1. FDA Guidance on Conduct of Clinical Trials of Medical Products During the COVID-19 
Public Health Emergency: Guidance for Industry, Investigators, and Institutional Review 
Boards, March 2020, Updated on January 27, 2021. Accessed at: 
https://www.fda.gov/media/136238/download 
 
2. Protocol Section 11.5 refers to the DAIDS policy on identification and classification of critical 
events. This policy has been retired. Section 11.5 is removed from the protocol and Section 10.1 has 
been updated to refer to the reporting requirements that still apply for sites conducting this study. The 
prior contents of the first paragraph in Section 10.1 are replaced with the following:  
 
Prior to study initiation, site investigators must obtain IRB/EC review and approval of this 
protocol and site-specific informed consent and assent forms in accordance with 45 CFR 46; 
subsequent to initial review and approval, IRBs/ECs must review the study at least annually. 
Site investigators must promptly report to the IRBs/ECs any changes in the study and must 
comply with the requirements of 45 CFR 46.108(a)(4) for promptly reporting the following: 
unanticipated problems involving risks to participants or others; serious or continuing 
noncompliance with applicable regulations or the requirements or determinations of their 
IRBs/ECs; and any suspension or termination of IRB approval. 
 
3. Protocol Sections 8.1, 8.2, 8.3, 10.2, 10.7, 11.3, and 11.4 refer to the following DAIDS policies: 
 
• 
Requirements for Essential Documents at Clinical Research Sites Conducting DAIDS Funded 
and/or Sponsored Clinical Trials  
• 
Requirements for Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials  
• 
Requirements for Clinical Quality Management Plans 
• 
Requirements for Manual of Operational Procedures 
• 
Enrolling Children (including Adolescents) in Clinical Research: Clinical Site Requirements  
 
These policies have been retired and replaced with instructions for sites that are now contained in the 
DAIDS Site Clinical Operations and Research Essentials (SCORE) Manual. Throughout the protocol, 
references to the above-listed policies are replaced with requirements specified in the DAIDS SCORE 
Manual (edits not shown here). The SCORE Manual is available at: 
https://www.niaid.nih.gov/research/daids-clinical-site-implementation-operations 
 
 
 

Clarification Memorandum #1 for  
Page 3 of 4 
26 April 2021  
IMPAACT 2028 Protocol Version 1.0 
B. Protocol Team Roster Updates 
 
To reflect current protocol team membership, Michael Whitton is added as a Clinical Trials Specialist; 
Yvonne Woolwine-Cunningham is replaced by Rebecca Dirschberger as a Protocol Data Manager; Scott 
Watson is replaced by Aundria Charles as the Westat Representative; and address information is updated 
for Diane Costello. Contact details are shown below. Michael Whitton is also added as a Clinical Trials 
Specialist on the protocol cover page. 
 
Clinical Trials Specialists 
Michael Whitton, BA 
IMPAACT Operations Center 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 22701 
Phone: 919-544-7040 
Email: mwhitton@fhi360.org 
 
Protocol Data Managers 
Rebecca Dirschberger, MPH 
Frontier Science Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900, x7268 
Email: dirsch@frontierscience.org 
Westat Representative 
Aundria Charles, RN, BSN, CCRP 
Westat, Inc. 
1600 Research Boulevard 
WB Building, Room 403 
Rockville, MD 20850 
Phone: 240-453-2758 
Email: aundriacharles@westat.com 
 
Laboratory Center Representative 
Diane Costello, BS 
University of California at Los Angeles  
MacDonald Research Laboratory (MRL) 
675 Charles East Young Drive, South 
MRL 4-629 
Los Angeles, CA 90095 
Phone: 703-862-0820 
Email: dcostello@milabcentral.org
 
C. Study Site Roster Updates 
 
The investigator at Clinical Research Site 4001 has determined that the site is not expected to enroll any 
participants in this study; as such, this site is removed from the roster (deletions not shown). 
 
To reflect recent administrative changes, the site number assigned to the Texas Children’s Hospital 
Clinical Research Site is changed from 3801 to 5128; the site number assigned to the Pediatric Perinatal 
HIV Clinical Trials Unit Clinical Research Site is changed from 4201 to 5127; and Feiona Heaven is 
replaced by Kathleen Graham as the Study Coordinator at Site 5055 (contact details are shown below).  
 
5055, South Florida CDTC Fort Lauderdale Clinical Research Site 
Kathleen Graham 
Study Coordinator 
Phone: 954-728-1111 
Email: kgraham@browardhealth.org 
 
In addition, two sites are added:  
 
5030, Emory University School of Medicine Clinical Research Site 
Department of Pediatrics  
Division of Infectious Diseases 
2015 Uppergate Drive 
Atlanta, GA, USA 
 

Clarification Memorandum #1 for  
Page 4 of 4 
26 April 2021  
IMPAACT 2028 Protocol Version 1.0 
Andres Camacho-Gonzalez  
Investigator of Record 
Phone: 404-727-5642 
Email: acamac2@emory.edu 
 
Lateshia Thomas-Seaton 
Study Coordinator 
Phone: 404-616-5936 
Email: lseaton@emory.edu 
 
32017, Children's Mercy Hospital Clinical Research Site 
2401 Gillham Road 
Kansas City, MO, USA 
 
Barbara Pahud 
Investigator of Record 
Phone: 816-234-3061 
Email: bapahud@cmh.edu 
 
Connie Haney 
Study Coordinator 
Phone: 816-601-4526 
Email: cjhaney@cmh.edu 
 
D. Additional Guidance for Specimen Collection During the COVID-19 Pandemic 
 
Protocol Appendix VI provides operational guidance for study implementation at sites experiencing 
operational disruptions due to COVID-19. Clinical and laboratory supplies required for specimen 
collection and storage are in short supply globally; as such, procurement delays and stock-outs may occur. 
The following guidance is added as the fourth bullet point under Prioritization of Study Visit Procedures: 
 
• 
In the event that required specimen collection supplies are not available at a visit when 
nasopharyngeal and rectal swabs are specified to be collected and stored, this specimen 
collection may be deferred until the next visit occurring after the required supplies are 
available.  

 
 
IMPAACT 2028 
 
Long-Term Clinical, Immunologic, and Virologic Profiles of 
Children who Received Early Treatment for HIV 
 
 
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 
 
 
 
 
DAIDS Study ID #38693 
Non-IND Study 
 
 
 
 
Protocol Chair: 
Shaun Barnabas, MD, PhD 
 
NIAID Medical Officers:  
Hans Spiegel, MD, PhD 
 
Dwight Yin, MD, PhD 
 
NICHD Program Officers: 
Eric Lorenzo, PhD 
 
Sai Majji, PhD 
 
Clinical Trials Specialist: 
Anne Coletti, MS 
 
 
 
 
FINAL Version 1.0 
23 December 2020 
 

IMPAACT 2028, FINAL Version 1.0 
Page 2 of 82 
23 December 2020 
IMPAACT 2028 
Long-Term Clinical, Immunologic, and Virologic Profiles of  
Children who Received Early Treatment for HIV 
 
TABLE OF CONTENTS 
 
PROTOCOL SIGNATURE PAGE .............................................................................................. 4 
ABBREVIATIONS AND ACRONYMS ....................................................................................... 5 
PROTOCOL TEAM ROSTER .................................................................................................... 7 
STUDY SITE ROSTER .............................................................................................................10 
SCHEMA ..................................................................................................................................21 
1 
INTRODUCTION ...........................................................................................................22 
1.1 
Background ....................................................................................................................... 22 
1.2 
Rationale ........................................................................................................................... 26 
2 
OBJECTIVE ..................................................................................................................30 
3 
STUDY DESIGN ...........................................................................................................31 
4 
STUDY POPULATION ..................................................................................................31 
4.1 
Inclusion Criteria .............................................................................................................. 31 
4.2 
Exclusion Criteria ............................................................................................................. 32 
4.3 
Co-Enrollment Considerations.......................................................................................... 32 
4.4 
Recruitment, Screening, and Enrollment Process ............................................................. 32 
4.5 
Participant Retention ......................................................................................................... 33 
4.6 
Participant Withdrawal or Termination from the Study ................................................... 33 
5 
STUDY VISITS AND PROCEDURES ...........................................................................34 
5.1 
Screening and Entry Visit ................................................................................................. 35 
5.2 
Semi-Annual Follow-Up Visits ........................................................................................ 36 
5.3 
Interim Clinical Care Visits .............................................................................................. 37 
5.4 
Medical and Medications Histories .................................................................................. 37 
5.5 
Feeding History ................................................................................................................. 40 
5.6 
Physical Examinations ...................................................................................................... 40 
5.7 
Laboratory Evaluations ..................................................................................................... 41 
5.8 
Additional Considerations for Laboratory Procedures ..................................................... 41 
5.9 
Maternal Data Collection .................................................................................................. 42 
6 
PARTICIPANT MONITORING, REPORTING, AND MANAGEMENT ...........................43 
7 
STATISTICAL CONSIDERATIONS ..............................................................................43 
7.1 
General Design Issues ....................................................................................................... 43 
7.2 
Outcome Measures ........................................................................................................... 44 
7.3 
Randomization and Stratification ..................................................................................... 45 
7.4 
Sample Size and Accrual .................................................................................................. 45 
7.5 
Monitoring ........................................................................................................................ 48 
7.6 
Analyses ............................................................................................................................ 49 
8 
DATA HANDLING AND RECORD KEEPING ...............................................................50 
8.1 
Data Management Responsibilities ................................................................................... 50 
8.2 
Essential and Source Documents and Access to Source Data .......................................... 50 
8.3 
Quality Control and Quality Assurance ............................................................................ 51 
9 
CLINICAL SITE MONITORING .....................................................................................51 
10 
HUMAN SUBJECTS PROTECTIONS...........................................................................51 
10.1 
Institutional Review Board/Ethics Committee Review and Approval ............................. 51 
10.2 
Vulnerable Participants ..................................................................................................... 52 
10.3 
Informed Consent and Assent ........................................................................................... 52 

IMPAACT 2028, FINAL Version 1.0 
Page 3 of 82 
23 December 2020 
10.4 
Potential Benefits .............................................................................................................. 54 
10.5 
Potential Risks .................................................................................................................. 54 
10.6 
Reimbursement/Compensation ......................................................................................... 54 
10.7 
Privacy and Confidentiality .............................................................................................. 54 
10.8 
Communicable Disease Reporting .................................................................................... 55 
10.9 
Management of Incidental Findings ................................................................................. 55 
10.10 Management of New Information Pertinent to Study Participation.................................. 55 
11 
ADMINISTRATIVE PROCEDURES ..............................................................................55 
11.1 
Regulatory Oversight ........................................................................................................ 55 
11.2 
Protocol Registration ........................................................................................................ 56 
11.3 
Study Implementation ....................................................................................................... 56 
11.4 
Protocol Deviation Reporting ........................................................................................... 56 
11.5 
Critical Event Reporting ................................................................................................... 57 
11.6 
ClinicalTrials.gov ............................................................................................................. 57 
12 
PUBLICATIONS ...........................................................................................................57 
13 
REFERENCES ..............................................................................................................57 
Appendix I: Schedule of Evaluations ...............................................................................................61 
Appendix II: WHO Clinical Stage 3 and Stage 4 Conditions and Other Medical Conditions of Interest for 
IMPAACT 2028..................................................................................................................62 
Appendix III: Sample Informed Consent Form for Study Participation ....................................................64 
Appendix IV: Sample Assent Form for Study Participation ..................................................................74 
Appendix V: Sample Informed Consent Form for Maternal Data Collection .............................................77 
Appendix VI: Operational Guidance for Study Implementation at Sites Experiencing Operational Disruptions 
Due to COVID-19 ...............................................................................................................81 
 
 
LIST OF TABLES 
 
Table 1 Potential Enrollment from Parent Studies ...................................................................................... 26 
Table 2 Potential Investigations using Specimens Collected and Stored in IMPAACT 2028.................... 28 
Table 3 Detectable Effects at 80% Power Assuming Exposure is Associated with Increased Risk and a 
Sample Size of 250 ..................................................................................................................................... 47 
Table 4 Detectable Effects at 80% Power Assuming Exposure is Associated with Decreased Risk and a 
Sample Size of 250 ..................................................................................................................................... 47 
Table 5 Detectable Mean Differences Between Exposed and Unexposed Assuming Unequal Variances 
and a Sample Size of 250 ............................................................................................................................ 48 
 
 
 

IMPAACT 2028, FINAL Version 1.0 
Page 4 of 82 
23 December 2020 
IMPAACT 2028 
Long-Term Clinical, Immunologic, and Virologic Profiles of  
Children who Received Early Treatment for HIV 
 
DAIDS Study ID #38693 
 
 
Version 1.0 
PROTOCOL SIGNATURE PAGE 
 
 
 
 
I will conduct this study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with United States (US) Health and 
Human Service regulations (45 CFR 46); applicable US Food and Drug Administration regulations; 
standards of the International Council for Harmonisation Guideline for Good Clinical Practice (E6); 
Institutional Review Board/Ethics Committee determinations; all applicable in-country, state, and local 
laws and regulations; and other applicable requirements (e.g., US National Institutes of Health, Division 
of AIDS) and institutional policies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator of Record 
  
 
Date 
 
 
 
 
 
 
 
 
 
 
 
Name of Investigator of Record  
 
(printed) 
 
 
 
 

IMPAACT 2028, FINAL Version 1.0 
Page 5 of 82 
23 December 2020 
IMPAACT 2028 
Long-Term Clinical, Immunologic, and Virologic Profiles of 
Children who Received Early Treatment for HIV 
 
ABBREVIATIONS AND ACRONYMS 
 
AIDS  
Acquired immune deficiency syndrome 
ART  
Antiretroviral therapy 
ARV  
Antiretroviral 
bNAb  
Broadly neutralizing monoclonal antibody 
CFR  
Code of Federal Regulations 
CI  
Confidence interval 
CLIA  
Clinical Laboratory Improvement Amendments 
CRF  
Case report form 
CRS  
Clinical research site 
DAIDS  
Division of AIDS 
DAIDS PRO  
Division of AIDS Protocol Registration Office 
ddPCR  
Droplet digital polymerase chain reaction 
DMC  
Data Management Center 
DNA  
Deoxyribonucleic acid 
DTaP  
Diphtheria, tetanus, and pertussis vaccine 
EC  
Ethics committee 
eCRF  
Electronic case report form 
GLP  
Good Laboratory Practice 
HIV  
Human immunodeficiency virus 
HLA  
Human leukocyte antigen 
ICF  
Informed consent form 
IMPAACT  
International Maternal Pediatric Adolescent AIDS Clinical Trials Group 
IQA  
DAIDS Immunology Quality Assurance program 
IRB  
Institutional Review Board 
LDMS  
Laboratory Data Management System 
LPC  
Laboratory Processing Chart 
mAb  
Monoclonal antibody 
NIAID  
National Institute of Allergy and Infectious Diseases 
NICHD  
Eunice Kennedy Shriver National Institute of Child Health and Human 
Development 
NIMH 
National Institute of Mental Health 
NIH  
United States National Institutes of Health 
PBMC  
Peripheral blood mononuclear cells 
PCR  
Polymerase chain reaction 
PID  
Participant Identification Number 
RNA  
Ribonucleic acid 
RR 
Risk ratio 
RSC  
Regulatory Support Center 
SD  
Standard deviation 
SDMC  
Statistical and Data Management Center 
SES  
Subject Enrollment System 
SID  
Study Identification Number 
sIRB 
Single Institutional Review Board 
SMC  
Study Monitoring Committee 

IMPAACT 2028, FINAL Version 1.0 
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23 December 2020 
SOP  
Standard operating procedure 
TB  
Tuberculosis 
US  
United States 
VQA  
DAIDS Virology Quality Assurance program 
WHO 
World Health Organization 
 
 

IMPAACT 2028, FINAL Version 1.0 
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IMPAACT 2028 
Long-Term Clinical, Immunologic, and Virologic Profiles of 
Children who Received Early Treatment for HIV 
 
PROTOCOL TEAM ROSTER 
 
Protocol Chair 
Shaun Barnabas, MD, PhD 
Department of Paediatrics and Child Health 
FAMCRU, Stellenbosch University 
PO Box 19063 
Tygerberg, 7505 
South Africa 
Phone: 27-21-938-4153 
Email: barnabas@sun.ac.za 
 
Protocol Vice Chairs 
Samantha Fry, MD, MMed (Paed) 
Department of Paediatrics and Child Health 
FAMCRU, Stellenbosch University 
PO Box 19063 
Tygerberg, 7505 
South Africa 
Phone: 27-21-938-4153 
Email: fry@sun.ac.za 
 
Julia Rosebush, DO, FAAP 
Department of Pediatrics 
Section of Infectious Diseases 
The University of Chicago 
5841 South Maryland Avenue 
Room C-623B, MC 6054 
Chicago, IL 60637 
Phone: 773-834-8518 
Email: jrosebush@peds.bsd.uchicago.edu 
 
Clinical Trials Specialist 
Anne Coletti, MS 
IMPAACT Operations Center 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 22701 
Phone: 919-544-7040 x11238 
Email: acoletti@fhi360.org 
 
 
 
 
 
 
NIAID Medical Officers 
Hans ML Spiegel, MD, PhD 
Preclinical Microbicide and Prevention Research 
Branch, Prevention Sciences Program  
DAIDS, NIAID, NIH 
5601 Fishers Lane Room 8B51A 
Rockville, MD 20852 
Phone: 240-292-4633 
Email: hans.spiegel@nih.gov 
 
Dwight Yin, MD, PhD 
Maternal Adolescent and Pediatric Research 
Branch, Prevention Sciences Program  
DAIDS, NIAID, NIH 
5601 Fishers Lane Room 8B25 
Rockville, MD 20852 
Phone: 301-761-5006 
Email: dwight.yin@nih.gov 
 
NICHD Program Officers 
Eric Lorenzo, PhD 
Maternal and Pediatric Infectious Disease Branch 
Eunice Kennedy Shriver National Institute of 
Child Health and Human Development 
6710B Rockledge Drive Room 2159C 
Bethesda, MD 20817 
Phone: 301-443-4993 
Email: eric.lorenzo@nih.gov 
 
Sai Majji, PhD 
Maternal and Pediatric Infectious Disease Branch 
Eunice Kennedy Shriver National Institute of 
Child Health and Human Development 
6710B Rockledge Drive Room 2159C 
Bethesda, MD 20817 
Phone: 301-402-8048 
Email: sai.majji@nih.gov 
 
 
 
 

IMPAACT 2028, FINAL Version 1.0 
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23 December 2020 
Protocol Investigators 
Ellen Chadwick, MD 
Northwestern University Feinberg School of 
Medicine, Division of Infectious Diseases 
Ann & Robert H Lurie Children’s Hospital of 
Chicago 
225 East Chicago Avenue 
Chicago, IL 60611 
Phone: 312-227-4080 
Email: egchadwick@luriechildrens.org 
 
Mark Cotton, MMed, PhD 
Department Paediatrics and Child Health 
FAMCRU, Stellenbosch University 
PO Box 19063 
Tygerberg, 7505 
South Africa 
Phone: 27-21-938-4219 
Email: mcot@sun.ac.za 
 
Theodore Ruel, MD 
Division of Pediatric Infectious Diseases and  
Global Health, Department of Pediatrics 
Benioff Chidren’s Hospital, San Francisco 
University of California, San Francisco  
550 16th Street, Box 0434  
San Francisco, CA 94158-0434  
Phone: 415 476-9197  
E-mail: theodore.ruel@ucsf.edu 
 
Protocol Virologist 
Deborah Persaud, MD 
Johns Hopkins University 
Department of Pediatric Infectious Diseases 
720 Rutland Avenue, Ross Building, Room 1170 
Baltimore, MD 21205 
Phone: 443-287-3733 
Email: dpers@jhmi.edu 
 
Protocol Immunologists 
Alka Khaitan, MD 
Indiana University School of Medicine 
Department of Pediatric Infectious Diseases 
705 Riley Hospital Drive, Room 5862 
Indianapolis, IN 46202 
Phone: 317.944.3698 
Email: akhaita@iu.edu 
 
 
 
 
Adriana Weinberg, MD 
Departments of Pediatrics, Medicine, and 
Pathology 
University of Colorado Denver 
Mail Stop 8604 
12700 E. 19th Avenue, Room 11126 
Aurora, CO 80045 
Phone: 303-724-4480 
Email: adriana.weinberg@cuanschutz.edu 
 
Protocol Data Managers 
Jared Kneebone, PhD 
Frontier Science Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900, x7263 
Email: kneebone@frontierscience.org 
 
Christina Reding, MPH 
Frontier Science Foundation  
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900, x7339 
Email: reding@frontierscience.org  
 
Yvonne Woolwine-Cunningham 
Frontier Science Foundation  
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900, x7332 
Email: woolwine@frontierscience.org 
 
Laboratory Data Manager 
Colleen Foley 
Frontier Science Foundation  
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900, x7267 
Email: foley@frontierscience.org 
 
Protocol Epidemiologist 
Kunjal Patel, DSc, MPH 
Department of Epidemiology 
Statistical & Data Analysis Center  
Harvard TH Chan School of Public Health  
Kresge Building Room 817C 
677 Huntington Avenue 
Boston, MA 02115 
Phone: 617-432-3174  
Email: kpatel@hsph.harvard.edu 
 

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Protocol Statistician 
Bryan Nelson, BA  
Statistical & Data Analysis Center  
Harvard TH Chan School of Public Health  
FXB Building Room 543  
651 Huntington Avenue  
Boston, MA 02115 
Phone: 617-432-7130 
Email: bnelson@sdac.harvard.edu 
 
Laboratory Center Representative 
Diane Costello, BS 
University of California at Los Angeles 
11075 Santa Monica Boulevard, Suite #200 
Los Angeles, CA 90095 
Phone: 703-862-0820 
Email: dcostello@milabcentral.org 
 
Laboratory Technologists 
Paul Harding, MS 
Pediatric Infectious Disease 
University of Colorado Denver 
Mail Stop 8604 Building P15 
12700 E. 19th Avenue Room 11460-A 
Aurora, CO 80045 
Phone: 303-724-3404 or 303-724-3407 
Email: paul.harding@cuanschutz.edu 
 
Jason Rippe, JD 
Special Infectious Diseases 
Ann & Robert H Lurie Children’s Hospital of 
Chicago 
2515 North Clark, Deming Room 3012, Box 155 
Chicago, IL 60614 
Phone: 312-227-6290 
Email: jrippe@luriechildrens.org 
 
Westat Representative 
Scott Watson 
Westat, Inc. 
1441 West Montgomery Avenue 
Rockville, MD 20850 
Phone: 415-494-5575 
Email: scottwatson@westat.com 
 
 
 
 
 
 

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IMPAACT 2028 
Long-Term Clinical, Immunologic, and Virologic Profiles of 
Children who Received Early Treatment for HIV 
 
STUDY SITE ROSTER 
 
Botswana 
12701, Gaborone Clinical Research Site 
Botswana Harvard AIDS Institute Partnership 
Princess Marina Hospital 
Plot 2403 Hospital Way 
Gaborone, Botswana 
 
Gaerolwe Masheto 
Investigator of Record 
Phone: 267-390-2671 
Email: gmasheto@bhp.org.bw 
 
Mpho Rasesi 
Study Coordinator 
Phone: 267-393-0335 
Email: mraesi@bhp.org.bw 
 
12702, Molepolole Clinical Research Site 
Botswana Harvard AIDS Institute Partnership 
Scottish Livingstone Hospital 
Gaborone-Molepolole Road 
Molepolole, Botswana 
 
Gaerolwe Masheto 
Investigator of Record 
Phone: 267-390-2671 
Email: gmasheto@bhp.org.bw 
 
Mpho Rasesi 
Study Coordinator 
Phone: 267-393-0335 
Email: mraesi@bhp.org.bw 
 
Brazil 
5071, Instituto de Puericultura e Pediatria Martagao Gesteira Clinical Research Site 
Rua Bruno Lobo n° 50 
Ilha do Fundão 
Rio de Janeiro, Brazil 
 
Cristina Hofer  
Investigator of Record 
Phone: 55-21-3148-2255 
Email: cbhofer@hucff.ufrj.br 
 

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Lorena Pestana  
Study Coordinator 
Phone: 55-21-3148-2255 
Email: lorena.pestana@gmail.com 
 
5073, School of Medicine Federal University Minas Gerais Clinical Research Site 
Avenue Alfredo Balena 190 
Belo Horizonte, Minas Gerais, Brazil 
 
Jorge Pinto 
Investigator of Record 
Phone: 55-31-3409-9822 
Email: jorgeandradepinto@gmail.com 
 
Flavia Ferriera 
Study Coordinator 
Phone: 55-31-3409-9111 
Email: flaviafaleiro@medicina.ufmg.br 
 
5074, University of Sao Paulo Clinical Research Site 
Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto 
Avenue Bandeirantes 3900 
São Paulo, Brazil 
 
Marisa Mussi 
Investigator of Record 
Phone: 55-16-3602-2807 
Email: mmmpinha@fmrp.usp.br 
 
Fernanda Sturzbecher 
Study Coordinator 
Phone: 55-16-3602-2925 
Email: fersiltome@yahoo.com.br 
 
5097, Hospital Geral De Nova Igaucu Clinical Research Site 
Avenida Henrique Duque Estrada Mayer 953 
Alto da Posse 
Nova Iguacu 
Rio de Janeiro, Brazil 
 
Ivete Gomes 
Investigator of Record 
Phone: 55-21-2667-3022 
Email: ivetegomes63@gmail.com 
 
Jorgiane Faria 
Study Coordinator 
Phone: 55-21-2667-6059 
Email: ge.ffaria@gmail.com 
 
 
 

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Haiti 
30022, Les Centres GHESKIO Clinical Research Site 
33 Boulevard Harry Truman 
Port-au-Prince, Haiti 
 
Jean William Pape 
Investigator of Record 
Phone: 509-2940-1431 
Email: jwpape@gheskio.org 
 
Vanesa Rouzier 
Investigator of Record 
Phone: 509-2940-1431 
Email: vrouzier@gheskio.org 
 
Elsie Jean 
Study Coordinator 
Phone: 509-2942-6327 
Email: drlysie@gmail.com 
 
Kenya 
5121, Kenya Medical Research Institute/Walter Reed Project Clinical Research Center 
Kericho Clinical Research Site 
Hospital Road 
PO Box 1357 
Kericho, Kenya 
 
Josphat Kosgei 
Investigator of Record 
Phone: 254-522-030-686 
Email: josphat.kosgei@usamru-k.org 
 
David Wekulo 
Study Coordinator 
Phone: 254-522-030-686 
Email: david.wekulo@usamru-k.org 
 
Malawi 
12001, Malawi Clinical Research Site 
UNC Project-Lilongwe 
Tidziwe Centre 
100 Mzimba Road 
Lilongwe, Malawi 
 
Portia Kamthunzi 
Investigator of Record 
Phone: 265-955-3034 
Email: portia85117@yahoo.co.uk 
 
 
 

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Lucky Makonakaya 
Study Coordinator 
Phone: 265-175-0610 
Email: lmakonokaya@unclilongwe.org 
 
30301, Blantyre Clinical Research Site 
Johns Hopkins Research Project 
Queen Elizabeth Central Hospital 
Chipatala Avenue  
  
Blantyre, Malawi 
 
Macpherson Mallewa 
Investigator of Record 
Phone: 265-187-5129 
Email: mmallewa@medcol.mw 
 
Rachel Chihana-Kawalazira 
Study Coordinator 
Phone: 265-187-4885 
Email: rkawalazira@jhu.medcol.mw 
 
South Africa 
8051, Wits RHI Shandukani Research Centre Clinical Research Site 
Wits Reproductive Health and HIV Institute 
2nd floor, Hillbrow Health Precinct 
Corner Esselen and Klein Street 
Hillbrow, Johannesburg, Gauteng, South Africa 
 
Faeezah Patel 
Investigator of Record 
Phone: 27-11-358-5500 
Email: fpatel@wrhi.ac.za 
 
Phato (Sibongile) Mncube 
Study Coordinator 
Phone: 27-11-358-5500 
Email: smncube@wrhi.ac.za 
 
8052 Soweto Clinical Research Site 
Perinatal HIV Research Unit 
Chris Hani Baragwanath Academic Hospital 
12th Floor, New Nurses Home 
Chris Hani Road 
Diepkloof, Johannesburg, Gauteng, South Africa 
 
Avy Violari 
Investigator of Record 
Phone: 27-11-989-9703 
Email: violari@mweb.co.za 
 
 
 

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Nastassja Ramsagar 
Study Coordinator 
Phone: 27-11-989-9858 
Email: choonilaln@phru.co.za  
 
8950, FAMCRU Clinical Research Site 
Tygerberg Hospital, Ward J8 
Francie van Zijl Drive 
Parow Valley, Tygerberg, Western Cape, South Africa 
 
Shaun Barnabas 
Investigator of Record 
Phone: 27-21-938-4153 
Email: barnabas@sun.ac.za 
 
Anita Janse van Rensburg  
Study Coordinator 
Phone: 27-21-938-4295  
Email: ajvanr@sun.ac.za 
 
30300, Umlazi Clinical Research Site 
Prince Mshiyeni Memorial Hospital 
1358 Mangosuthu Highway 
Umlazi, Durban, KwaZulu-Natal, South Africa 
 
Kimesh Naidoo 
Investigator of Record 
Phone: 27-31-260-4350  
Email: naidook9@ukzn.ac.za 
 
Thandeka Nkosi 
Study Coordinator 
Phone: 27-31-260-1985 
Email: nkosit@ukzn.ac.za  
 
Tanzania 
5118, Kilimanjaro Christian Medical Centre Clinical Research Site 
Box 3010 
Sokoine Road 
Moshi, Tanzania 
 
James Ngocho 
Investigator of Record 
Phone: 255-78-464-0164 
Email: jamesngocho08@gmail.com 
 
Boniface Njau 
Study Coordinator 
Phone: 255-75-493-3559 
Email: bnneneu@yahoo.com 
 

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Thailand 
5115, Siriraj Hospital Mahidol University Clinical Research Site 
Department of Pediatrics 
Faculty of Medicine Siriraj Hospital 
Mahidol University 
2 Wanglang Road 
Bangkok, Bangkoknoi, Thailand 
 
Kulkanya Chokephaibulkit 
Investigator of Record 
Phone: 66-2-419-7000 x5671 
Email: kulkanya.cho@mahidol.ac.th 
 
Watcharee Lermankul 
Study Coordinator 
Phone: 66-2-419-7000 x5695 
Email: watchareeped@gmail.com 
 
5116, Chiangrai Prachanukroh Hospital Clinical Research Site 
1039 Sathanpayaban Road 
Muang, Chiangrai, Thailand 
 
Jullapong Achalapong  
Investigator of Record 
Phone: 66-81-950-0707 
Email: jullapong.achalapong@phpt.org 
 
Timothy Cressey 
Study Coordinator 
Phone: 66-89-634-1672 
Email: tim.cressey@phpt.org 
 
Uganda 
31798, Baylor-Uganda Clinical Research Site 
Baylor College of Medicine Children's Foundation Uganda 
Block 5 Mulago Hospital 
PO Box 72052 
Clock Tower 
Kampala, Uganda 
 
Adeodata Kekitiinwa  
Phone: 256-417-119-200 
Email: akekitiinwa@baylor-uganda.org 
 
Mary Agatha Nanyonjo 
Study Coordinator 
Phone: 256-417-119-200 
Email: mnanyonjo@baylor-uganda.org 
 
 
 

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United States 
3801, Texas Children’s Hospital Clinical Research Site 
6621 Fannin, Suite 630 
Houston, TX, USA 
 
Mary Paul 
Investigator of Record 
Phone: 832-824-1143 
Email: mepaul@texaschildrens.org 
 
Ruth Eser-Jose 
Study Coordinator 
Phone: 832-824-1333 
Email: rjeser@texaschildrens.org 
 
4001, Lurie Children’s Hospital of Chicago Clinical Research Site 
Ann & Robert H Lurie Children's Hospital of Chicago 
2515 North Clark Street, 9th Floor 
Chicago, IL, USA 
 
Ellen Chadwick 
Investigator of Record 
Phone: 312-2276280 
Email: egchadwick@luriechildrens.org 
 
Emanuela Lartey 
Study Coordinator 
Phone: 312-227-8266 
 
4201, Pediatric Perinatal HIV Clinical Trials Unit Clinical Research Site 
University of Miami School of Medicine 
Pediatric Infectious Diseases and Immunology 
Batchelor Children's Research Institute 
1580 NW 10th Avenue   
Miami, FL, USA 
 
Charles Mitchell 
Investigator of Record 
Phone: 305-243-2755 
Email: cmitchel@med.miami.edu 
 
Grace Alvarez 
Study Coordinator 
Phone: 305-243-4447 
Email: galvarez2@miami.edu 
 
 
 

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4601, University of California, San Diego Clinical Research Site 
Mother-Child-Adolescent HIV Program 
4076 Third Avenue Suite 301 
San Diego, CA, USA 
 
Stephen Spector 
Investigator of Record 
Phone: 858-534-7055 
Email: saspector@ucsd.edu 
 
Megan Loughran 
Study Coordinator 
Phone: 858-534-9218 
Email: meloughran@ucsd.edu 
 
5048, University of Southern California Clinical Research Site 
Maternal, Child, and Adolescent Adult Center 
LAC+USC Medical Center 
1640 Marengo Street, Suite 300 
Los Angeles, CA, USA 
 
James Homans  
Phone: 323-865-1585 
Email: homans@usc.edu 
 
Yvonne Morales 
Study Coordinator 
Phone: 323-865-1561 
Email: ytr@usc.edu 
 
5051, University of Florida, Jacksonville Clinical Research Site 
Department of Pediatrics, Rainbow Center 
655 West 8th Street 
Clinical Center 3rd Floor 
Jacksonville, FL, USA 
 
Mobeen Rathore  
Investigator of Record 
Phone: 904-789-4179 
Email: mobeen.rathore@jax.ufl.edu 
 
Saniyyah Mahmoudi 
Study Coordinator 
Phone: 904-244-5331 
Email: saniyyah.mahmoudi@jax.ufl.edu 
 
 
 

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5052, University of Colorado, Denver Clinical Research Site 
Department of Pediatrics 
13123 E. 16th Avenue B055 
Aurora, CO, USA 
 
Elizabeth McFarland 
Investigator of Record 
Phone: 303-724-3447 
Email: betsy.mcfarland@cuanschutz.edu  
 
Emily Barr 
Study Coordinator 
Phone: 720-777-6752 
Email: emily.barr@childrenscolorado.org  
 
5055, South Florida CDTC Fort Lauderdale Clinical Research Site 
Children's Diagnostic and Treatment Center, Inc. 
1401 South Federal Highway 
Fort Lauderdale, FL, USA 
 
Lisa-Gay Robinson 
Investigator of Record 
Phone: 954-728-1136 
Email: lerobinson@browardhealth.org 
 
Feiona Heaven 
Study Coordinator 
Phone: 954-728-1054 
Email: fheaven@browardhealth.org 
 
5092, Johns Hopkins Clinical Research Site 
Harriet Lane Clinic 
200 North Wolfe Street 
Baltimore, MD, USA 
 
Alison Agwu 
Investigator of Record 
Phone: 410-614-3917 
Email: ageorg10@jhmi.edu 
 
Aleisha Collinson-Streng 
Study Coordinator 
Phone: 443-801-7301 
Email: acolli14@jhmi.edu 
 
 
 

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5112, David Geffen School of Medicine at UCLA Clinical Research Site 
University Of California, Los Angeles 
Department of Pediatrics, Division of Infectious Diseases 
10833 Le Conte Avenue, MDCC 22-442 
Los Angeles, CA, USA 
 
Jaime Deville  
Investigator of Record 
Phone: 310-825-9660 
Email: jdeville@mednet.ucla.edu 
 
Michele Carter  
Study Coordinator 
Phone: 310-206-6369 
Email: mfcarter@mednet.ucla.edu 
 
5114, Bronx Lebanon Hospital Center Clinical Research Site 
Division of Pediatrics 
1650 Selwyn Avenue 
Bronx, NY, USA 
 
Murli Purswani 
Investigator of Record 
Phone: 718-960-1010 
Email: mpurswan@bronxleb.org 
 
Martha Cavallo 
Study Coordinator 
Phone: 718-960-1010 
Email: mcavallo@bronxleb.org 
 
6501, St Jude Children’s Research Hospital Clinical Research Site 
262 Danny Thomas Place 
Memphis, TN, USA 
 
Katherine Knapp 
Investigator of Record 
Phone: 901-448-4774 
Email: katherine.knapp@stjude.org 
 
Ryan Heine 
Study Coordinator 
Phone: 901-595-6549 
Email: ryan.heine@stjude.org 
 
 
 

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Zimbabwe 
30303, Saint Mary’s Clinical Research Site 
Saint Mary’s Clinic 
Ingwe Road 
Chitungwiza, Zimbabwe 
 
Lynda Stranix-Chibanda 
Investigator of Record 
Phone: 263-772-246-011 
Email: lstranix@uz-ctrc.org  
 
Suzen Maonera 
Study Coordinator 
Phone: 263-772-288-160 
Email: smaonera@uz-ctrc.org 
 
30306, Seke North Clinical Research Site 
Makoni Primary Health Care Clinic, Unit G 
Jenje Road 
Chitungwiza, Zimbabwe 
 
Teacler Nematadzira 
Investigator of Record 
Phone: 263-772-288-155 
Email: tnematadzira@uz-ctrc.org 
 
Barbara Masango 
Study Coordinator 
Phone: 263-772-750-840 
Email: bmasango@uz-ctrc.org 
 
31890, Harare Family Care Clinical Research Site 
Parirenyatwa Hospital 
Mazowe Street 
Harare, Zimbabwe 
 
Mutsawashe Bwakura-Dangarembizi 
Phone: 263-772-601-735 
Email: mbwakura@uz-ctrc.org 
 
Sukunena Maturure  
Study Coordinator 
Phone: 263-712-437-682 
Email: smaturure@uz-ctrc.org 
 
 

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IMPAACT 2028 
Long-Term Clinical, Immunologic, and Virologic Profiles of 
Children who Received Early Treatment for HIV  
 
SCHEMA 
 
Purpose: 
To characterize a cohort of early treated children who may 
participate in future research related to HIV remission or cure  
 
Design: 
Observational prospective cohort study 
 
Study Population: 
Children living with perinatally-acquired HIV who received 
early treatment in IMPAACT network studies or other research 
studies sponsored by the United States National Institutes of 
Health. Early treatment is defined as treatment with at least three 
antiretroviral agents from at least two classes of antiretroviral 
therapy initiated within 12 weeks of birth. Early treatment 
regimens may also include broadly neutralizing antibodies (in 
addition to at least three antiretroviral agents). Within the overall 
study population, children who initiated treatment within 48 
hours of birth will be classified as having received very early 
treatment.  
 
Sample Size: 
Up to approximately 250 participants 
 
Study Intervention: 
No intervention is provided in this study  
 
Study Duration: 
Approximately seven years 
 
Objective: 
To characterize the long-term clinical, immunologic, and 
virologic profiles of children who received early treatment for 
perinatally-acquired HIV 
 
 
 
 
 

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1 
INTRODUCTION 
 
1.1 
Background 
 
In 2013, the World Health Organization (WHO) recommended antenatal HIV testing and 
immediate initiation of antiretroviral therapy (ART) for all pregnant women living with HIV, 
resulting in a dramatic decline in perinatal HIV transmission (1). Nevertheless, there were still 
160,000 new pediatric HIV infections in 2018, with only 50% of these children accessing ART 
(2), thus emphasizing the need for HIV remission and cure research in this age group. 
 
During acute infection, HIV establishes a latent reservoir in long-lived resting memory CD4+ T 
cells (3). These latent cells harboring integrated, intact provirus are susceptible to reactivation and 
virus production during ART administration. Treatment interruption results in rebound viremia 
(4) and presents one of the main barriers to cure. Untreated perinatal HIV infection is 
characterized by high levels of viremia that takes years to reach steady-state levels (5) compared 
to the rapid reduction, within weeks, seen in adult infection (6) and that reflects the delayed 
development of HIV-specific CD8+ T cell responses in perinatal infection (7). Early and very 
early ART (defined as treatment within 12 weeks or 48 hours of birth, respectively) is lifesaving 
as 50% of untreated infants living with HIV in Africa die by age two (8). Early and very early 
ART also limits latent reservoir size and reduces the persistence of long-lived HIV- infected cells 
(9). Additionally, virologically suppressed adolescents with controlled HIV replication from 
infancy due to effective ART have a lower reservoir size than adolescents in whom HIV 
replication was poorly controlled until later in childhood (10). Achieving low HIV reservoir size 
through early or very early ART provides a permissive state for HIV ART-free remission or cure. 
 
With effective early or very early treatment of perinatal HIV infection, there is a lack of HIV- 
specific immune responses and very low reservoir size (11-13). The “Mississippi baby” was the 
first case of perinatal ART-free remission in which persistent viral suppression was seen for 27.6 
months after ART interruption. This child initiated very early ART, by 30 hours of life, with viral 
suppression achieved by day 28. After unplanned treatment interruption at 18 months of age, a 
prolonged period of HIV remission was observed. The rebounding virus was confirmed by 
phylogenetic analysis to be maternal transmitted. This delayed re-emergence of transmitted virus 
supports the idea that prolonged viral remission is achievable through time-limited very early 
ART initiation after perinatal infection, but does not signify cure. This case formed the basis for 
IMPAACT P1115, Very Early Treatment of HIV-Infected Infants to Achieve Remission, the 
Treating Infants Early Study (TIES), the Latency and Early Neonatal Provision of Antiretroviral 
Drugs (LEOPARD) (all described below), and the Early Infant Treatment study in Botswana 
(14). 
 
Following the case description of the “Mississippi baby,” long-term remission was also reported 
in the “South African child,” identified at 9.5 years of age, who initiated early ART. This child’s 
viral load was less than 50 copies/mL by week 24 of treatment and less than 20 copies/mL by 
week 50. He underwent planned ART interruption at week 50 of treatment and had sustained viral 
suppression through 9.5 years of age, with no HIV-specific antibody responses, apart from weak 
CD4+ T cell responses to Gag and gp120 and a very strong anti-CD16 induced natural killer cell 
response (15). Similarly, a French teenager who initiated early ART at three months of age and 
underwent unplanned treatment interruption between 5.8 and 6.8 years of age has maintained 
viral suppression more than 12 years off treatment with a viral load less than 50 copies/mL, in 
association with weak HIV-specific CD8+ T-cell responses and low level T-cell activation (16). 
None of these three cases exhibited the HLA-alleles associated with the elite controller status 

IMPAACT 2028, FINAL Version 1.0 
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23 December 2020 
seen in adults (15), confirming that in a subset of children with perinatally-acquired HIV, early 
ART may promote ART-free remission. 
 
Early and continued treatment provides immunologic and virologic benefits to infants living with 
perinatally-acquired HIV. ART initiated within eight days of life can produce viral suppression as 
early as six days after initiation, with continued viral decay of cellular reservoirs over twelve 
months (17). Viral decay in early and continuously treated infants occurs more rapidly than with 
delayed treatment or among those who initiated treatment early but underwent interruption and 
then recommenced treatment (18). Notably, very early treatment demonstrated a more rapid 
decline of intact HIV DNA sequences compared to the decline of defective virus (14), potentially 
decreasing the likelihood of continued effective viral replication after treatment interruption. 
Altogether, these findings indicate that early treatment of perinatally-acquired HIV alters the 
establishment and dynamics of HIV reservoir in infancy. Further, there is evidence that early 
ART preserves immunity and vaccine responses to routine childhood vaccines, supporting the 
notion that these children may be ideal candidates for cure or remission-targeted trials. 
 
The number of ARV drugs available for treating HIV in infancy is extremely limited; however, 
treatment options may be expanded through the use of injectable, long-acting broadly neutralizing 
monoclonal antibodies (bNAbs). The antiviral properties of bNAbs are largely mediated through 
virus neutralization, although immune-enhancing effects have been seen in non-human primates 
(with enhanced endogenous neutralizing antibody responses and decreased disease progression) 
and in adults living with HIV (with increased antibody breadth and/or potency and an increase in 
heterologous neutralizing activity), raising the possibility of a “vaccinal effect” with enhancement 
of HIV-specific immune responses (19-22). The effects of combining early ART with bNAbs on 
HIV reservoir size and HIV-specific immune responses are being studied in IMPAACT P1115 
and IMPAACT 2008. The long-term immune effects of early ART or bNAbs in the treatment of 
HIV infection through childhood have not yet been described and will be examined in this study. 
 
IMPAACT P1115 
This study is currently ongoing. Enrollment under protocol Version 1.0 occurred between 
January 2015 and December 2017 (54 infants with in utero HIV infection were enrolled). 
Enrollment under protocol Version 2.0 is expected to continue through 2023 (45 infants with in 
utero HIV infection are expected to be enrolled). Follow-up of participants enrolled under 
Version 1.0 and Version 2.0 is expected to continue through 2027. All infants with in utero 
infection receive very early treatment in this study. 
 
The primary objective of IMPAACT P1115 (NCT02140255) is to assess HIV remission among 
neonates with in utero HIV infection who initiate very early intensive ART within 48 hours of 
birth. In Version 1.0 of this study, infants at high risk for in utero infection, i.e., those born to 
mothers with presumed or confirmed HIV who did not receive ARVs during pregnancy, were 
enrolled in Cohort 1 within 48 hours of birth and started nevirapine-based ART while being 
evaluated for in utero HIV transmission. If in utero transmission was excluded, these infants were 
switched to standard of care perinatal prophylaxis and exited the study at four weeks of age. 
Infants who had initiated an ART regimen within 48 hours of life outside of the study but were 
confirmed to have in utero transmission were enrolled in Cohort 2 within the first 10 days of life.  
 
Cohort 1 and Cohort 2 infants with confirmed in utero HIV infection entered Step 2 of the study 
and continued nevirapine-based ART. Lopinavir/ritonavir was added after 42 weeks 
postmenstrual age for a four-drug ART regimen. Nevirapine was withdrawn once virologic 
suppression for at least 12 consecutive weeks was confirmed. If virologic suppression was 
achieved by Week 24 and maintained to Week 48 and beyond, evaluation for potential treatment 

IMPAACT 2028, FINAL Version 1.0 
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23 December 2020 
cessation began. If strict protocol-specified criteria are met at or after Week 96 (e.g., no 
detectable HIV DNA by droplet digital PCR (ddPCR), negative HIV antibody by fourth 
generation ELISA), infants enter Step 3 of the study for ART cessation. In this study, remission is 
defined as having no confirmed plasma HIV RNA greater than or equal to the limit of detection 
(LOD) of the assay through 48 weeks of ART cessation. If viral rebound occurs in Step 3, 
participants enter Step 4, resume ART, and are followed through five years of age.  
IMPAACT P1115 participants who do not achieve undetectable HIV RNA between Week 48 and 
Week 192 are not eligible for treatment cessation and exit the study. Participants who maintain 
undetectable HIV RNA but do not enter Step 3 by Week 192 also exit the study. All participants 
with confirmed in utero HIV infection who have exited from Version 1.0 will be eligible for 
IMPAACT 2028 (23). 
 
In P1115 Version 2.0, participants are treated with raltegravir, nevirapine, and two nucleoside 
reverse transcriptase inhibitors, with or without the bNAb VRC01. Infants in whom in utero HIV 
infection is not confirmed transition to standard of care prophylaxis by two weeks of age and are 
followed for 12 weeks before exiting the study; any of these infants identified with HIV infection 
acquired through the 12-week follow-up period will be eligible for IMPAACT 2028 if they 
initiated treatment, with at least three ARV agents from at least two classes of ART, within 12 
weeks of life. 
 
Infants in P1115 Version 2.0 with confirmed in utero transmission progress through Steps 2-4 as 
described above for Version 1.0. However, regardless of viral RNA suppression status, these 
infants will be followed on P1115 for at least 192 weeks (approximately four years); after exiting 
P1115, they will be eligible for IMPAACT 2028.  
 
IMPAACT 2008 
This study is currently ongoing. Enrollment occurred between August 2018 and March 2020 (61 
infants were enrolled, all received early treatment). Follow-up is expected to continue through 
March 2021.  
 
IMPAACT 2008 (NCT03208231) is evaluating the safety and antiviral activity of the bNAb 
VRC01 in combination with ART to promote HIV clearance in infants. The study population 
includes 61 infants who began ART within 12 weeks of birth at IMPAACT sites in Botswana, 
Brazil, Malawi, and Zimbabwe. Approximately half of the enrolled infants were randomly 
assigned to receive VRC01 in addition to ART at study entry and weeks 2, 6, and 10. All infants 
are followed for 48 weeks.  
 
Pharmacokinetics, safety, development of anti-VRC01 antibodies, time to viral suppression, 
biomarkers of viral persistence and immune responses are also evaluated in this study. Given the 
48-week follow-up period, capacity to examine the long-term virologic and immunologic effects 
of this novel therapeutic approach is limited; long-term evaluation will be facilitated in 
IMPAACT 2028. 
 
The participants in both IMPAACT P1115 and IMPAACT 2008 are unique with respect to their 
treatment intervention and anticipated low reservoir diversity and size. They will have well-
characterized early virologic and immune measurements collected and stored. It is important to 
better understand the longer-term effects of these novel interventions on HIV reservoirs and on 
immune and viral profiles to inform future interventions. 
 

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Latency and Early Neonatal Provision of Antiretroviral Drugs (LEOPARD)  
This study was conducted between August 2015 and April 2020. Seventy-three infants were 
enrolled; 46 received very early treatment, 27 received early treatment.  
 
The LEOPARD study (NCT02431975) identified infants in South Africa with in utero 
transmission of HIV and initiated nevirapine-based ART within 14 days of life. At 42 weeks 
postmenstrual age, nevirapine was changed to lopinavir/ritonavir per the local standard of care. 
The study examined changes to the viral reservoir and detection of HIV-specific antibody 
responses over time, with a primary outcome of identifying the percent of participants with viral 
suppression (plasma HIV RNA less than 400 copies/mL by 24 weeks after ART and less than 50 
copies/mL by 48 weeks of age and no confirmed viral load greater than 50 copies/mL after 
suppression was attained). The study also aimed to determine the relationship between markers of 
neonatal immune quiescence, the extent of seeding, and rate of decline of the viral reservoir in 
early treated infants. During the first year of treatment, ART initiated within 48 hours after birth 
(i.e., very early treatment as defined for IMPAACT 2028) was observed as a significant 
contributory predictor of proviral DNA reservoir size, when compared to later ART initiation 
(24). Data published from this cohort in early 2020 examined the effects of early and very early 
treatment (as defined for IMPAACT 2028) on the potential for HIV remission (25). The study 
team concluded that decisions regarding ART initiation should be based on the optimization of 
clinical outcomes rather than the achievement of disease remission as few infants met the defined 
laboratory criteria for treatment interruption. LEOPARD study participants will be eligible for 
IMPAACT 2028.  
 
Treating Infants Early Study (TIES) 
This study is currently ongoing. Enrollment occurred between December 2015 and September 
2020 (15 infants were enrolled, 13 received early treatment, 2 received very early treatment). 
Follow-up is expected to continue through December 2020. 
 
The Treating Infants Early Study is an observational study of infants living with HIV in the US 
who initiated early ART with at least three ARVs within the first six weeks of life. The primary 
objective is to assess the safety of initiating ART and characterize the decline in HIV RNA over 
time. In addition, biological samples have been collected and stored for future studies of HIV 
reservoirs and HIV immune responses. These children will be eligible for IMPAACT 2028.  
 
Children with HIV Early Antiretroviral (CHER) Trial  
This study was conducted between July 2005 and January 2013. Three hundred and seventy-
seven infants were enrolled; all received early treatment.  
 
In the CHER trial (NCT00102960), South African infants living with HIV 6-12 weeks of age 
with a CD4+ cell percentage greater than 25% were randomly assigned to receive ART when the 
CD4+ cell percentage decreased to less than 20% (or less than 25% if the child was younger than 
one year) or when clinical criteria were met (the deferred therapy group) or to immediate ART 
initiation until either one or two years of age (the early ART groups). Two hundred and fifty-two 
infants received early therapy at a median of 7.4 weeks of age, which reduced early infant 
mortality by 76% and HIV progression by 75% when compared with infants in the deferred 
therapy group (26, 27). An additional 34 infants were randomized to early limited ART for either 
one or two years but were not included in the primary analysis. The CHER children are now 12-
14 years of age and are eligible for IMPAACT 2028. 
 

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In the remainder of this protocol, the term “parent study” is used to refer to the IMPAACT 
P1115, IMPAACT 2008, CHER, LEOPARD, and TIES studies, from which participants in 
IMPAACT 2028 will be drawn. Table 1 presents the number of participants enrolled in each 
parent study (projected for IMPAACT P1115) and the Protocol Team’s estimate of the 
approximate number of children who may be enrolled in IMPAACT 2028 from each parent 
study. These estimates reflect allowances for loss-to-follow-up during the parent studies and 
estimates of the likelihood of re-contact following the last contact for the parent study. Because 
the likelihood of re-contact cannot be estimated with certainty, the total of 250 reflects that the 
maximum number that may be enrolled rather than a target number to be enrolled.  
 
Table 1 
Potential Enrollment from Parent Studies 
Parent Study 
dates of study 
implementation 
 
Number Enrolled 
in Parent Study 
Number Who  
May Enroll in 
IMPAACT 2028  
 
Number Very 
Early Treated 
 
Number 
Received bNAb  
IMPAACT P1115 
January 2015 to 
present (ongoing) 
99 
64 
64 
15 
IMPAACT 2008 
August 2018 to 
present (ongoing) 
61 
61 
0 
30 
CHER 
July 2005 to  
January 2013 
377 
70 
0 
0 
LEOPARD 
August 2015 to  
April 2020 
73 
40 
25 
0 
TIES 
December 2015 to 
December 2020  
15 
15 
2 
0 
Total 
625 
250 
91 
45 
 
1.2 
Rationale 
 
Early treatment of infants living with HIV offers a unique population in which to investigate 
long-term clinical, immunologic, and virologic outcomes and to better characterize how early 
ART impacts HIV infection over time. The overarching goals of IMPAACT 2028 are to establish 
long-term follow-up of participants who received early treatment for future interventional cure 
and/or remission trials and to establish a unique biorepository from which additional scientific 
questions can be answered. In lower and middle-income settings, where the majority of these trial 
participants live, the significant mobility of enrolled participants may reduce access for future 
studies, particularly if they are currently not receiving care at a clinical research site. The 
durability of early treatment, the effect of acquired co-infections on reservoir dynamics, the long-
term effects of ART and/or bNAbs on a maturing immune system and on the evolution of HIV-
specific neutralizing antibodies, cell-mediated immunity, systemic immune activation, 
inflammation, and the predictive value of biomarkers associated with increased morbidity and 
mortality in adults are poorly understood in children. It is thus anticipated that IMPAACT 2028 
will longitudinally track these participants while simultaneously advancing our understanding of 
the long-term effects of early ART and/or bNAb initiation through establishing a biorepository to 
address scientific questions and promote innovation in this field.  

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Study Design and Population 
This is an observational prospective cohort study characterizing and establishing a biorepository 
of early treated children who may participate in future research related to HIV remission or cure. 
Early treatment is defined as treatment with at least three ARV agents from at least two classes of 
ART initiated within 12 weeks of birth. Within the overall study population, for descriptive and 
analysis purposes, children who initiated treatment within 48 hours of birth will be classified as 
having received very early treatment. A subset of children will have received bNAbs as part of 
their treatment regimens.  
 
This study design was chosen to facilitate rollover from US and international studies of early 
treatment to gain a longer-term perspective on clinical, virologic, and immunologic trajectories, 
as well as to identify participants for inclusion in future cure and/or remission studies. Although it 
is anticipated that many participants will have achieved viral suppression owing to their 
participation in prior studies, current detectable viremia is not exclusionary. This will allow for 
examination of differences in trajectories based on the presence or absence of viral suppression 
and permit identification of comparison groups within the cohort. Likewise, participants may 
receive any ART or bNAbs prior to or following enrollment, potentially permitting inquiry into 
whether particular drug combinations influence clinical, virologic, or immunologic responses. 
 
Up to approximately 250 children living with HIV who received early treatment in IMPAACT 
network studies or other research studies sponsored by the US National Institutes of Health (NIH) 
will be enrolled and followed semi-annually for up to seven years. Clinical, virologic, and 
immunologic evaluations will be performed semi-annually at each study visit, and specimens will 
be collected for the study’s biorepository for future investigations. This sample size is based on 
ongoing or completed studies of infants who received early treatment and feasibility of enrolling 
these infants into a long-term study. Given the lack of longitudinal data on this group, the 
development of a biorepository will address scientific questions and contribute to the literature on 
early ART and its impact on HIV reservoir size in this unique population.  
 
Real Time and Batched Laboratory Evaluations  
CD4+ and HIV-1 RNA assays will be performed in real time at each study visit. ARV resistance 
assays will also be run in real time when clinically indicated. The results of these clinically 
relevant assays will be provided to participants/parents/guardians and to participants’ primary 
care providers.  
 
HIV-1 DNA and HIV-1 antibody assays will be performed in batches approximately every six 
months. The results of these assays will establish basic virologic and immunologic biomarker 
profiles for the study cohort and provide snapshots of the state of HIV persistence in the cohort 
over time. The results will also inform hypotheses to be investigated with use of specimens stored 
in the study repository. For researchers developing future studies of interventions for HIV-1 
remission and cure, results may serve to guide study eligibility criteria. 
 
Selection and optimization of assays to quantify the size of the HIV reservoir is an active area of 
HIV-1 cure-related research. The single-amplicon HIV-1 DNA ddPCR assay was selected for use 
in this study because it offers a feasible approach to rapidly characterize large numbers of 
participants with different HIV-1 subtypes for whom reservoir size may be quite small due to 
receipt of early or very early ART. The assay is fully validated and CLIA-certified, and can be 
performed with non-viable PBMCs that do not require liquid nitrogen for transport. Although this 
assay may overestimate the size of the replication competent reservoir due to the preponderance 
of defective HIV-1 genomes (28), it provides a benchmark biomarker to which the results of other 
measures of replication competence can be referenced.  

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Other HIV-1 DNA assays, for example the intact proviral DNA assay, which allows quantitation 
of intact and defective genomes, may be performed with specimens stored in the study repository. 
As assay development and validation for different HIV-1 subtypes progresses over time, the 
Protocol Team may choose to replace the single amplicon HIV-1 DNA ddPCR assay with an 
alternative assay. When such a choice is made, a protocol clarification memorandum will be 
issued to specify the new assay to be performed.  
 
Specimen Repository 
Specimens for biorepository storage will be collected throughout the study follow-up period. 
Plasma, PBMCs, and serum will be collected at each visit; nasopharyngeal and rectal swabs will 
be collected once, at the first visit occurring after the participant has reached three years of age 
(28). These specimens will be used in investigations related to the clinical, immunologic, and 
virologic effects of early treatment. Specimens may be accessed by investigators via a 
competitive proposal-based process. For illustrative purposes, a listing of potential investigations 
is provided in Table 2.  
 
Table 2 
Potential Investigations using Specimens Collected and Stored in IMPAACT 2028 
Illustrative Hypotheses 
Illustrative Outcome Measures 
Immunologic 
Very early compared to early ART will 
lead to improved immune health and 
lower levels of immune activation and 
exhaustion 
• CD4+ and CD8+ cell counts and 
percentages 
• Expanded T cell immunophenotyping  
• HIV-1 antibody profiles 
Addition of a bNAb to very early and 
early ART will lead to improved immune 
outcomes 
• CD4+ cell counts and percentages 
• CD8+ cell counts and percentages 
• Expanded B and T cell 
immunophenotyping  
Very early compared to early ART will 
lead to more durable responses to routine 
childhood vaccines  
• Durable antibody responses to routine 
childhood vaccines 
Addition of a bNAb to very early and 
early ART will induce a vaccinal effect 
and manifest as durable HIV-1-specific 
responses 
• Breadth of HIV-specific humoral and 
cellular immune responses  
Very early compared to early ART will 
lead to less gut dysbiosis 
• Microbiome differences in very early 
versus early ART 
A healthy microbiome is correlated with 
immune health in perinatal HIV infection  
• Expanded B and T cell 
immunophenotyping  
• Vaccine responses 
Intermittent episodes of viremia may 
boost autologous HIV-1 neutralization 
antibody responses and HIV-1 cellular 
immune responses 
• In-depth profiling of functional HIV-1 
specific immune responses  
Virologic 
Very early compared to early treatment 
will lead to sustained lower reservoir size 
including lower intact proviral reservoir 
size 
• Reservoir size as measured by total 
HIV-1 DNA  
• Composition of HIV-1 reservoir by 
intact and defective genomes 

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Addition of a bNAb to very early and 
early ART will lead to lower intact 
proviral reservoir size 
• Composition of HIV reservoir by intact 
and defective genomes 
Addition of a bNAb to very early and 
early ART will modify the reservoir 
composition 
• HIV-1 env analyses for sequence 
diversity and neutralization 
Intermittent episodes of viremia may 
lead to clonal amplification or depletion 
of HIV-1 reservoir cells  
• Changes in HIV-1 reservoir size and 
composition with near full-length 
sequencing  
• Changes in the proportion of intact and 
defective genomes, degree of clonal 
expansion, and contribution of reservoir 
cells to rebound virus 
 
As part of the informed consent and assent (if applicable) process, participants/parents/guardians 
will be informed that specimens collected for the repository may be used for testing related to 
HIV or other diseases with opt in or opt out choices for genetic testing of these specimens.  
 
Collection of Nasopharyngeal and Rectal Swab Specimens 
Gut mucosal damage, associated with HIV infection, is characterized by CD4+ T cell depletion, 
immune activation and translocation of microbial products (30). HIV infection influences the 
composition of the gut microbiome with recent HIV infection associated with transient loss of 
bacterial taxonomic richness, while chronic infection showed a depletion of Akkermansia, 
Anaerovibrio, Bifidobacterium, and Clostridium (30). Further, children with HIV have an 
increased alpha-diversity and higher inflammatory plasma factors than children without HIV, 
which is associated with specific microbiome profiles (32). Cotrimoxazole therapy alters the gut 
microbiome of children living with HIV and decreases inflammation (32). The interaction 
between the gut microbiome, immune system, and inflammation in children living with HIV is 
complex and has not yet been fully characterized. 
 
The composition of the gut microbiome influences the development of the immune system (33, 
34). Some of the individual variation in vaccination response is thought to be secondary to gut 
microbial changes. In 2018, a systematic review of one adult and three infant studies examined 
the association between the composition of the gut microbiome and vaccine responses. A higher 
relative abundance of Actinobacteria and Firmicutes was associated with increased humoral and 
cellular vaccine responses, while increased Proteobacteria and Bacteroidetes decreased responses 
(35-37). The lipopolysaccharide derived from several Bacteroidetes species is less immunogenic 
or possibly immune-inhibitory and may cause the decreased responses seen (38). A relative 
abundance of Bifidobacterium in early infancy was associated with increased CD4 T-cell 
responses to BCG, tetanus toxoid, and hepatitis B vaccines (39). Moreover, interventions that 
changed the gut microbiome composition were associated with altered immune responses to the 
influenza vaccine (40). There is a paucity of data on the impact of ART on the microbiome of 
early treated children that warrants further research (41). In adult studies, ART administration 
was associated with decreased alpha diversity when compared to people living with HIV who are 
not on ART.  
 
Much less is known about the interactions of the respiratory microbiome and the immune system. 
However, there is growing evidence of a bidirectional interaction between the two (41-44).  

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Murine studies have shown that bacterial load in the lungs increases during the first two weeks of 
life with changes in the microbiota associated with accumulation of a PD-L1-dependent T 
regulatory cell population (45). The acquisition of a normal lung microbiome has been shown as 
important in protecting the lung from harmful responses to inhaled antigens (45). 
 
In asymptomatic humans an increased abundance of Prevotella and Veillonella species has been 
associated with higher levels of lymphocyte and neutrophil inflammation in bronchoalveolar 
lavage fluid (47), while in chronic lung disease, the ability of lung microbiota to modulate local 
inflammatory responses may influence disease progression (47). Moreover, a recent study 
utilizing PET-MR technology scan with HIV-env specific monoclonal antibody VRC01 
demonstrated a significant presence of HIV within nasal turbinates suggestive of an HIV 
reservoir site, which increases interest in evaluating a respiratory microbiome that may be an HIV 
reservoir site (49). 
 
The gut microbiome may also influence respiratory health via the gut-lung axis with oral 
probiotics shown to be beneficial in preventing ventilator-assisted pneumonia and upper 
respiratory tract infections in adults (49, 50). There appears to be a complex interplay between the 
development of the gastrointestinal and respiratory microbiota and the regulation of immune 
function with bacterial metabolites, such as short-chain fatty acids, influencing respiratory health 
(52). This lung-gut axis may be bi-directional, with mouse studies showing that exposure of the 
lungs to lipopolysaccharide results in changes to the bowel flora (52). 
 
There is a growing interest in understanding the role of the human microbiome in child health, as 
dysbiotic microbial communities have been implicated in a variety of adverse outcomes. HIV 
infection is known to influence both microbial composition and systemic immunity, while 
immunity in both the gut and the lung is affected by changes in the local microbiome. Thus, a 
better understanding of these interactions could help explain some of the alterations in immunity 
that are seen in children living with HIV.  
  
Summary 
This study aims to characterize the long-term clinical, immunologic, and virologic profiles of 
children who received early treatment for HIV. Secondarily, it will establish a pediatric cohort 
who received early treatment for HIV and may be eligible for future studies of interventions for 
HIV remission or cure. Lastly, it will establish a biorepository for further investigation of the 
long-term effects of early ART and the developing immune system. This study is crucial to the 
evolution of the scientific community’s understanding of the longitudinal effects of early 
treatment on the progression of HIV. This unique population will add to the body of literature 
supporting early infant interventions and has the potential to provide novel and innovative 
insights into HIV cure and remission. 
 
2 
OBJECTIVE 
 
The objective of this study is to characterize the long-term clinical, immunologic, and virologic 
profiles of children who received early treatment for perinatally-acquired HIV.  
 
 
 
 

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3 
STUDY DESIGN 
 
This is an observational prospective cohort study to characterize the long-term clinical, 
immunologic, and virologic profiles of early treated children who may participate in future 
research related to HIV remission or cure. Up to approximately 250 children who received early 
treatment for perinatally-acquired HIV in IMPAACT network studies or other research studies 
sponsored by the US NIH will be enrolled and followed semi-annually for up to seven years. As 
shown in Appendix I and detailed in Section 5, clinical, virologic, and immunologic evaluations 
will be performed at each study visit; specimens will be collected for the study’s biorepository at 
each visit.  
 
Early treatment is defined as treatment with at least three ARV agents from at least two classes of 
ART initiated within 12 weeks of birth. Early treatment regimens may also include bNAbs. 
Within the overall study population, for descriptive and analysis purposes, children who initiated 
treatment within 48 hours of birth will be classified as having received very early treatment. Data 
analyses planned to fulfill the primary study objective are described in Section 7. 
 
Data and specimens collected in this study will be utilized for additional research related to HIV 
remission or cure via a competitive proposal-based process. Proposals for use of data and/or 
specimens will be solicited and reviewed on a routine basis following a process described in the 
study-specific manual of procedures. Proposals received from early career investigators will be 
prioritized for approval. 
 
 
4 
STUDY POPULATION 
 
Children will be selected for this study according to the criteria in Sections 4.1 and 4.2 and the 
guidelines in Section 4.3. The study-specific approach to recruitment, screening, and enrollment 
is described in Section 4.4. Considerations related to participant retention and withdrawal from 
the study are provided in Sections 4.5 and 4.6, respectively. 
 
4.1 
Inclusion Criteria 
 
4.1.1 
Participated in one of the parent studies listed in Table 1 on page 26 (documentation 
should be obtained from parent study records and should minimally include the date of 
enrollment and date of final visit in the parent study).  
 
4.1.2 
Confirmed HIV-1 infection based on documented nucleic acid testing of two blood 
samples collected at different time points (documentation should be obtained from parent 
study records and should minimally include dates of specimen collection, tests 
performed, and test results) 
 
4.1.3 
Received early treatment for HIV-1 infection, defined as treatment with at least three 
ARV agents from at least two classes of ART, initiated within 12 weeks of birth 
(documentation should be obtained from parent study records and should minimally 
include the date of initiation of the early treatment regimen and each agent in the 
regimen) 
 
4.1.4 
Based on parent or guardian report at entry, child is expected to be available for at least 
24 months of follow-up  

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23 December 2020 
 
4.1.5 
Parent or guardian is willing and able to provide written informed consent for child’s 
study participation and, when applicable per institutional review board/ethics committee 
(IRB/EC) policies and procedures, child is willing and able to provide written assent for 
study participation 
 
Note: All sites must follow all applicable IRB/EC policies and procedures; for US sites, 
this includes single IRB (sIRB) policies and procedures.  
 
4.2 
Exclusion Criteria 
 
Potential participants who meet the following criterion will be excluded from the study: 
 
4.2.1 
Has any documented or suspected clinically significant medical condition or any other 
condition that, in the opinion of the site investigator, would make participation in the 
study unsafe or otherwise interfere with completing study procedures 
 
Note: Periods of treatment interruption are not exclusionary.  
 
4.3 
Co-Enrollment Considerations 
 
Co-enrollment in other studies, concurrent with participation in IMPAACT 2028, is not 
precluded, although careful consideration must be given to visit burden, blood draw volumes, and 
interpretation of outcome data across studies.  
 
Participants enrolled in this study will ideally be eligible for future studies of interventions for 
HIV remission or cure. For participants who become eligible for interventional studies, every 
effort will be made to accommodate co-enrollment in the interventional study and IMPAACT 
2028. For example, study sites would be encouraged to abstract clinical findings and laboratory 
test results from interventional study records for entry into IMPAACT 2028 electronic case report 
forms (eCRFs), rather than duplicate these evaluations for IMPAACT 2028. Further operational 
guidance on managing periods of co-enrollment will be provided in the study-specific manual of 
procedures. 
 
Regardless of the type of studies in which participants may be co-enrolled, co-enrollment must be 
approved in advance by the Protocol Teams of both studies; requests for approval should be 
emailed to the IMPAACT 2028 Protocol Team (impaact.team2028@fstrf.org). 
 
4.4 
Recruitment, Screening, and Enrollment Process 
 
Participant recruitment methods for this study may vary across sites but are generally expected to 
rely on referrals to study staff from the parent studies listed in Section 1. 
 
Upon identification of a potentially eligible child, study staff will provide information about the 
study to the potential participant and/or the potential participant’s parent or guardian as 
appropriate based on the age and maturity of the potential participant, guided by site SOPs and 
applicable IRB/EC policies and procedures. Potential participants/parents/guardians who 
expresses interest in learning more about the study will be provided additional information, 
education, and counseling as part of the study informed consent and assent processes. The 
informed consent process will include detailed review of the study informed consent form (ICF), 

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23 December 2020 
time to address any questions or concerns the participant/parent/guardian may have, and an 
assessment of understanding before proceeding to the informed consent decision. Potential 
participants who meet applicable IRB/EC criteria for provision of assent will undergo an age-
appropriate assent process. Informed consent and assent processes will be fully documented, 
consistent with the Division of AIDS (DAIDS) policies referenced in Section 8.2. Refer to 
Section 10.3 for further information on informed consent and assent procedures for this study. 
 
Eligibility screening will be initiated after written informed consent, and assent if applicable, are 
obtained (i.e., informed consent, and assent if applicable, must be obtained before any study-
specific screening procedures are performed). For potential participants who are found to be 
eligible, it is generally expected that screening and enrollment procedures will be completed at a 
single visit. However, multiple visits may be conducted. When more than one visit is required, all 
procedures must be performed within 60 days, counted from the date of informed consent. If the 
60-day period is exceeded, the screening process may be repeated; in this case, most but not all 
screening evaluations must be repeated, as specified in Section 5.1. 
 
Each site must establish standard operating procedures (SOPs) for eligibility determination that 
describe where and when screening procedures will be performed; roles and responsibilities for 
performing the required procedures; roles and responsibilities for assessing and confirming 
eligibility; and procedures for documenting the process, taking into consideration the required 
timing of enrollment.  
 
The IMPAACT Data Management Center (DMC) Subject Enrollment System (SES) will be used 
to enroll participants in this study. When informed consent is obtained, a participant identification 
number (PID) will be assigned to the participant by study staff. For children found to be eligible, 
enrollment will occur upon successful entry of required eligibility data into the SES. Successful 
entry into the SES will generate a study identification number (SID). Refer to Section 7.5 for 
more information on monitoring participant accrual in this study. 
 
4.5 
Participant Retention 
 
Study staff will make every effort to retain each enrolled child in follow-up for the protocol-
specified duration of follow-up, thereby minimizing potential biases and loss of precision 
associated with loss-to-follow-up. Each site must establish SOPs for participant retention that 
describe procedures for retention-related activities such as collecting locator information, 
providing visit reminders, and taking action on missed visits in a timely manner. Given that study 
visits will occur relatively infrequently, procedures for between-visit contacts to verify locator 
information and other strategies to avoid loss-to-follow-up between visits should also be 
described. Refer to Section 7.5 for more information on monitoring participant retention in this 
study. 
 
4.6 
Participant Withdrawal or Termination from the Study 
 
Regardless of the participant retention procedures referenced above, participants may be 
voluntarily withdrawn from the study by their parents or guardians; participants who meet 
IRB/EC criteria for providing assent may also withdraw from the study themselves. Participants 
may be terminated from the study by the site investigator or designee under the following 
circumstances: 
 

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• 
Participant re-locates away from the study site (with no options to transfer to another site), is 
otherwise unable to attend study visits, or is determined to be lost-to-follow-up 
• 
Investigator or designee determines 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 
• 
The study is stopped or canceled by the sponsors or government or regulatory authorities 
• 
Site participation in the study is canceled by the sponsors, government or regulatory 
authorities, the sIRB (for US sites), or site IRBs/ECs (for non-US sites) 
 
For any participant who is withdrawn or terminated from the study prior to scheduled completion 
of follow-up, study staff will document the reason for the withdrawal or termination in detail and 
will make every effort to complete final evaluations for the study, following the procedures 
shown in Section 5.2. If the circumstances that led to a participant’s withdrawal or termination 
change (e.g., he or she returns to the study site area after having re-located previously), the site 
investigator or designee should contact the Protocol Team to discuss options for resuming follow-
up. 
 
5 
STUDY VISITS AND PROCEDURES 
 
An overview of the study visit and evaluation schedule is provided in Appendix I; blood draw 
volumes for each visit are also detailed in Appendix I. Presented in this section is additional 
information on visit-specific study procedures.  
 
In addition to the protocol-specified procedures listed in this section, study staff may complete 
other tasks consistent with site SOPs, including but not limited to collecting, reviewing, and 
updating demographic and locator information; reviewing elements of informed consent and 
assent; scheduling visits; providing instructions for contacting study staff between visits; 
providing visit reminders; and following up on missed visits. Locator contacts are encouraged 
between scheduled visits to maximize participant retention. All such tasks should be documented 
consistent with site SOPs.  
 
Study staff should inform participants/parents/guardians of clinically meaningful physical exam 
findings and laboratory test results when available; given the semi-annual study visit schedule, 
site SOPs should specify expectations and procedures for providing results between scheduled 
visits when applicable. Study staff should provide results to participants’ primary care providers 
when applicable and provide referrals to non-study sources of medical care or other services 
when clinically indicated.  
 
Follow-up visits should be conducted as close as possible to target visit dates and within targeted 
visit windows (±4 weeks) whenever possible. When visits cannot be conducted within the 
targeted windows, care should be taken to conduct sequential visits at least 12 weeks apart. Visits 
may be split, with required procedures performed on more than one day within the allowable visit 
window if necessary.  
 
All visits and procedures must be documented in accordance with the DAIDS policies for source 
documentation; refer to Section 8 for more information on documentation requirements and entry 
of eCRFs.  
 
Note: For sites that may experience operational disruptions due to COVID-19, guidance for study 
implementation during periods of disruption is provided in Appendix VI.  

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5.1 
Screening and Entry Visit 
 
It is generally expected that all screening (eligibility determination) and enrollment procedures 
required for this study will be completed at a single visit. However, multiple visits may be 
conducted. When more than one visit is required, all procedures must be performed within 60 
days, counted from the date of informed consent.  
 
Informed consent must be obtained before any study-specific procedures are performed. 
Procedures that may provide information relevant to eligibility — including all administrative and 
regulatory procedures and the physical examination shown below — should be performed prior to 
enrollment. Clinical procedures may be performed before or after enrollment. Blood should be 
collected for laboratory evaluations and specimen storage after enrollment. Nasopharyngeal and 
rectal swabs should be collected after enrollment. 
 
Note: Participants are considered enrolled in the study upon successful entry of required 
eligibility data into the SES. 
 
Screening and Entry Visit Procedures 
Administrative 
and Regulatory 
 
• Obtain written informed consent for child study participation; 
additionally obtain written assent if applicable per IRB/EC 
policies and procedures 
• Assign PID 
• Review parent study records and available medical records as 
needed in relation to study eligibility criteria 
• Assess expected availability for study participation in relation to 
study eligibility criteria 
• Complete final eligibility determination and confirmation 
• Complete paper-based eligibility checklist, enter checklist data 
into SES to enroll the participant, print and file a copy of the 
confirmation file 
Clinical 
 
• Collect baseline medical and medications history (see Section 
5.4.1); includes ascertainment of gender identity if applicable) 
• Collect feeding history (see Section 5.5) 
• Perform physical examination (see Section 5.6) 
Laboratory 
 
• Collect blood for: 
– HIV-1 RNA PCR 
– HIV-1 DNA ddPCR 
– CD4+ and CD8+ cell counts and percentages 
– HIV-1 antibody 
– Serum, plasma, and peripheral blood mononuclear cell 
(PBMC) storage 
– ARV resistance testing if clinically indicated (following 
consultation with the Protocol Team) 
• If child is three years of age or older, collect nasopharyngeal and 
rectal swabs for storage 
 
Note: Gender identity should be ascertained for participants who are 12 years of age and older as 
part of the medical and medications history obtained at this visit. However, this procedure should 
not be performed at sites that have formally opted out of collection of gender identity data, in 
accordance with policies specified in the IMPAACT Manual of Procedures. Gender identity data 
should be collected from participants in private, without a parent or guardian present. 
 

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If the 60-day screening period is exceeded before an eligible participant can be enrolled, the 
screening process may be repeated. In this case, all screening procedures listed above must be 
repeated, except that a new PID should not be assigned. Previously documented medical and 
medications history information should be reviewed and updated through the date of re-screening 
(it is not necessary to re-record history information that was previously documented). 
 
5.2 
Semi-Annual Follow-Up Visits 
 
Follow-up visits are targeted to occur every 24 weeks, counted from the date of enrollment as 
Day 0, with a targeted window of ±4 weeks and an allowable window of ±12 weeks. Every effort 
should be made to conduct each visit within the targeted window; however, visits may be 
conducted on any day within the allowable window. When visits cannot be conducted within the 
targeted windows, care should be taken to conduct sequential visits at least 12 weeks apart. There 
is no required sequencing of procedures at these visits. 
 
Note: For any participant who is withdrawn or terminated from the study prior to scheduled 
completion of follow-up, a final study visit should be performed, if possible, following the 
procedures described in this section. However, this visit need not be performed if a scheduled 
visit was completed within four weeks prior to the participant’s withdrawal or termination. 
 
Semi-Annual Visit Procedures (Q24 Weeks ±4 weeks targeted, ±12 weeks allowed) 
Clinical 
• Collect interval medical and medications history (see Section 5.4.2; 
includes ascertainment of gender identity if applicable) 
• If applicable, collect feeding history (see Section 5.5) 
• Perform physical examination (see Section 5.6) 
Laboratory 
• Collect blood for: 
– HIV-1 RNA PCR 
– HIV-1 DNA ddPCR 
– CD4+ and CD8+ cell counts and percentages 
– HIV-1 antibody (Q48 weeks) 
– Serum, plasma, and PBMC storage 
– ARV resistance testing if clinically indicated (following 
consultation with the Protocol Team) 
• If child has reached three years of age since the last visit, and has 
not previously had swabs collected, collect nasopharyngeal and 
rectal swabs for storage 
 
Note: Gender identity should be ascertained for participants who were younger than 12 years of 
age at entry who subsequently reach 12 years of age while on study; this ascertainment should 
occur at the first follow-up visit after the participant reaches 12 years of age and should not be 
repeated thereafter. However, this procedure should not be performed at sites that have formally 
opted out of collection of gender identity data, in accordance with policies specified in the 
IMPAACT Manual of Procedures. Gender identity data should be collected from participants in 
private, without a parent or guardian present. 
 
 
 

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5.3 
Interim Clinical Care Visits 
 
Participants may return to the study site between scheduled follow-up visits for a variety of 
reasons. Participants needing clinical care are generally expected to be managed consistent with 
local clinical practice standards. When clinical care visits occur between scheduled study visits, 
study procedures are not expected to be performed and study data are not expected to be 
collected. Rather, the study visit and data collection schedule should be maintained, with clinical 
information of interest for the study (as indicated in Section 5.4.2) ascertained as part of the 
interval medical and medications history performed at the next scheduled visit.  
 
5.4 
Medical and Medications Histories 
 
Medical and medication history information is collected at each scheduled visit. A baseline 
history is established at the Screening and Entry Visit and interval (since the last visit) histories 
are obtained at follow-up visits.  
 
Note: The term “written records” is used in this section to refer to parent study records and/or 
non-study medical records. If a discrepancy is identified between data recorded in parent study 
records and data recorded in non-study medical records, data recorded in parent study records 
will be used. 
 
5.4.1 
Baseline Medical and Medications History 
 
At the Screening and Entry Visit, the medical and medications history elements listed below 
should be source documented; all should also be entered into eCRFs. 
 
Baseline History Element 
Data Collection Details 
Name of parent study, date of enrollment in 
parent study, identification number assigned in 
parent study, date of final visit in parent study, 
whether early or very early treatment was 
received 
Must be abstracted from parent study records 
Date of birth and sex at birth 
 
Should be based on written records to the 
extent possible; may be based on participant or 
caregiver report  
Gender identity (if applicable) 
 
Must be based on participant report  
(if 12 years of age and older at entry) 
Mode of delivery (vaginal delivery or 
Cesarean section) 
Must be based on written records 
Gestational age at birth and method of 
determination if available 
Must be based on written records 
Weight, length, and head circumference at 
birth 
Must be based on written records 
Weight and length/height at approximately 
two, four, and six months after birth and every 
six months thereafter 
Must be based on written records; record 
documented measurements dated as close as 
possible to the targeted timepoints 
Head circumference approximately two, four, 
and six months after birth and every six 
months thereafter through 24 months 
Must be based on written records; record 
documented measurements dated as close as 
possible to the targeted timepoints 

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Baseline History Element 
Data Collection Details 
Diagnostic HIV testing details (specimen 
collection date, specimen collection time if 
available, test type, and result of initial 
positive test and of confirmatory test) 
Must be based on written records 
Date of early treatment initiation 
 
Must be based on written records 
Receipt of ARVs (all approved/licensed and 
investigational agents received for prophylaxis 
and/or treatment with start and stop dates since 
birth and reason for each ARV change) 
Should be based on written records to the 
extent possible; may be based on or 
supplemented with participant or caregiver 
report  
Any periods of planned ARV treatment 
interruption (relevant dates since birth) 
Must be based on written records 
Receipt of other HIV treatment agents (all 
approved/licensed and investigational agents 
received with start and stop dates since birth) 
Must be based on written records 
Receipt of immunizations (agents received 
with administration dates since birth) 
Must be based on written records 
Receipt of investigational vaccines or 
investigational agents for indications other 
than HIV  
Must be based on written records 
Receipt of TB prophylaxis or treatment 
(agents received with start and stop dates  
since birth) 
Must be based on written records 
Receipt of blood products (e.g., blood or 
plasma transfusions, immune globulins)  
(agents received with start and stop dates since 
birth) 
Must be based on written records 
Receipt of any antibiotic or antiprotozoal 
within the 30 days prior to microbiome swab 
collection (agents received and dates of 
receipt) 
Should be based on written records to the 
extent possible; may be based on or 
supplemented with participant or caregiver 
report 
Date and result of all documented CD4+ and 
CD8+ counts and percentages since birth 
Must be based on written records 
Date and result of all documented HIV-1 RNA 
tests since birth  
Must be based on written records 
Any documented ARV resistance  
(since birth) 
Must be based on written records 
WHO clinical stage at entry in IMPAACT 
2028 
Should be based on site investigator review of 
all available clinical and laboratory 
information from all sources 
Any WHO clinical Stage 3 or Stage 4 
condition or other medical condition of 
interest as listed in Appendix II (since birth) 
Should be based on site investigator review of 
all available clinical and laboratory 
information from all sources 
Any medical condition that required inpatient 
hospitalization or prolongation of existing 
hospitalization, resulted in persistent or 
significant disability or incapacity, or was life-
threatening (since birth) 
Should be based on site investigator review of 
all available clinical and laboratory 
information from all sources 
 

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5.4.2 
Interval Medical and Medications History 
 
At Semi-Annual Follow-Up Visits, the medical and medications history elements listed below 
should be source documented; all should also be entered into eCRFs. 
 
Interval History Element 
Data Collection Details 
If co-enrolled in an interventional study, name 
of interventional study, date of enrollment in 
interventional study, and date of final visit in 
interventional study 
Should be abstracted from interventional study 
records if possible; may be based on 
communications from interventional study 
staff and/or participant or caregiver report 
Gender identity (if applicable) 
 
Must be based on participant report  
(if 12 years of age and older and not 
previously collected) 
Receipt of ARVs (all approved/licensed and 
investigational agents received with start and 
stop dates and reason for each ARV change) 
Should be based on written records to the 
extent possible; may be based on or 
supplemented with participant or caregiver 
report  
Any periods of non-adherence when no ARVs 
were taken for seven consecutive days or 
longer (relevant dates) 
Should be based on written records to the 
extent possible; may be based on or 
supplemented with participant or caregiver 
report 
Any periods of planned ARV treatment 
interruption (relevant dates) 
Must be based on written records  
Receipt of other HIV treatment agents  
(all approved/licensed and investigational 
agents received with start and stop dates) 
Must be based on written records 
Receipt of immunizations  
(agents received with administration dates) 
Must be based on written records 
Receipt of investigational vaccines or 
investigational agents for indications other 
than HIV  
Must be based on written records 
Receipt of TB prophylaxis or treatment 
(agents received with start and stop dates) 
Must be based on written records 
Receipt of blood products (e.g., blood or 
plasma transfusions, immune globulins)  
(agents received with start and stop dates) 
Must be based on written records 
Receipt of any antibiotic or antiprotozoal 
within the 30 days prior to microbiome swab 
collection (agents received and dates of 
receipt) 
Should be based on written records to the 
extent possible; may be based on or 
supplemented with participant or caregiver 
report 
Receipt of blood products (e.g., blood or 
plasma transfusions, immune globulins)  
(agents received with start and stop dates) 
Must be based on written records 
Use of contraceptive methods 
 
Should be based on written records to the 
extent possible; may be based on or 
supplemented with participant or caregiver 
report 
Date and result of any documented non-study 
CD4+ and CD8+ cell counts and/or 
percentages 
Must be based on written records 
Date and result of any documented non-study 
HIV-1 RNA tests  
Must be based on written records 

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Interval History Element 
Data Collection Details 
Any documented ARV resistance (based on 
non-study testing) 
Must be based on written records 
Any WHO clinical Stage 3 or Stage 4 
condition or other medical condition of 
interest as listed in Appendix II 
Should be based on site investigator review of 
all available clinical and laboratory 
information from all sources 
Any medical condition that required inpatient 
hospitalization or prolongation of existing 
hospitalization, resulted in persistent or 
significant disability or incapacity, was life-
threatening, or resulted in death 
Should be based on site investigator review of 
all available clinical and laboratory 
information from all sources 
For participants who die, date of death, cause 
of death, and other narrative details pertaining 
to death 
Should be based on site investigator review of 
all available clinical and laboratory 
information from all sources 
For participants who become pregnant, 
Date of first day of last menstrual period prior 
to pregnancy, pregnancy outcome, date of 
pregnancy outcome 
Should be based on site investigator review of 
all available clinical and laboratory 
information from all sources 
 
5.5 
Feeding History  
 
At the Screening and Entry Visit, the following should be source documented and entered into 
eCRFs: whether the child was ever formula fed, date of first and last exposure to formula if 
applicable, whether the child was ever breastfed, date of first and last exposure to breast milk if 
applicable, and date of first exposure to complementary foods. For children who are formula 
feeding or breastfeeding at the Screening and Entry Visit, date of last exposure to formula or 
breast milk will be recorded (source documented and entered into eCRFs) at a subsequent Semi-
Annual Follow-up Visit. These data should be collected based on written records to the extent 
possible and may be supplemented with caregiver report.  
 
5.6 
Physical Examinations 
 
A physical examination is required at each scheduled visit. At each visit, examinations should 
include the following:  
 
• 
Assessment of vital signs: temperature, heart rate, respiratory rate, and blood pressure 
• 
Measurement of height and weight 
• 
If two years of age or younger, measurement of head circumference 
• 
Examination of: 
– General appearance 
– Head, eyes, ears, nose, neck, mouth, and throat 
– Lymph nodes 
– Lungs 
– Heart 
– Abdomen 
– Extremities 
– Skin 
– Neurologic 
– Sexual maturity 
– Other body systems if clinically indicated 
 

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At all visits, additional assessments may be performed at the discretion of the examining 
clinician.  
 
All exam findings should be source documented; weight, height, head circumference, and sexual 
maturity rating will be entered into eCRFs. Findings may also contribute to identification of 
clinical events of interest, as listed in Section 5.4.  
 
5.7 
Laboratory Evaluations  
 
HIV-1 RNA PCR assays and CD4+ and CD8+ cell counts and percentages will be performed in 
real time for this study locally; results of these study tests will be entered into eCRFs or 
transferred to the DMC via the Laboratory Data Management System (LDMS). ARV resistance 
tests will be performed in real time for this study locally, regionally, or centrally; results will be 
entered into eCRFs. 
 
Note: HIV-1 RNA PCR assays, CD4+ and CD8+ cell counts and percentages, and ARV 
resistance tests may also be performed outside of the study; results of adequately documented 
non-study tests will be noted as part of the medical and medications histories described in Section 
5.4 and will be entered into eCRFs. 
 
HIV-1 DNA ddPCR and HIV-1 antibody (fourth generation or higher) assays will be performed 
in batches at designated testing laboratories. Results will be electronically transferred to the 
DMC.  
 
5.8 
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 
 
5.8.1 
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 study-specific website: https://impaactnetwork.org/studies/IMPAACT2028.asp 
 
In accordance with 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-1 RNA 
PCR, (2) CD4+ and CD8+ cell counts and percentages, (3) ARV resistance testing, (4) HIV-1 
DNA ddPCR, (5) HIV-1 antibody, (6) stored plasma, serum, and PBMCs.  
 
5.8.2 
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 5.8, site and local laboratory 
SOPs, and the LPC. The frequency of specimen collection and testing will be directed by the 
Schedule of Evaluations. The LDMS will be used to document specimen collection, testing, 
storage, and shipping as specified in LPC.  

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HIV-1 RNA PCR assays must be performed in a CLIA-certified or equivalent laboratory (for US 
sites) or a VQA-certified laboratory (for non-US sites). CD4+ and CD8+ cell counts and 
percentages must be performed in a CLIA-certified or equivalent laboratory (for US sites) or an 
IQA-certified laboratory (for non-US sites). PBMCs must be processed and cryopreserved by an 
IQA-approved laboratory (for all sites) consistent with the HIV/AIDS Network Coordination 
Cross-Network PBMC Processing SOP, which is available at: 
https://www.hanc.info/labs/labresources/procedures/Pages/pbmcSop.aspx  
 
Specimens collected, processed, and stored at site laboratories are expected to be shipped to 
designated repositories approximately every six months. Specimens collected for HIV-1 DNA 
and HIV-1 antibody assays are expected to be shipped to the designated testing laboratories 
approximately every six months, either from the study sites or from the repositories. Alternative 
specimen shipping arrangements may be specified by the Protocol Team as needed. Refer to the 
LPC for detailed shipping instructions. Sites based in locations where local policies or regulations 
do not allow specimen storage in repositories will retain specimens locally until requested for 
testing.  
 
5.8.3 
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, collection of nasopharyngeal and 
rectal swabs, and shipping and handling of all specimens for this study as currently recommended 
by the US Centers for Disease Control and Prevention, NIH, and other applicable agencies. All 
specimens will be shipped using packaging that meets requirements specified by the International 
Air Transport Association Dangerous Goods Regulations for UN 3373, Biological Substance, 
Category B, and Packing Instruction 650. Culture isolates, if obtained in this study, are to be 
shipped as specified for UN 2814 Category A Infectious Substances. 
 
5.9 
Maternal Data Collection  
 
Most but not all children enrolled in this study are expected to be in the care of their biological 
mothers and in many cases informed consent for child participation in the study will be provided 
by the biological mother. When biological mothers are available, they will also be asked to 
provide written informed consent for collection of limited maternal data for study purposes. For 
consenting mothers, the following will be source documented and entered into eCRFs:  
 
• 
ARV use during pregnancy and breastfeeding (may be based on maternal report or written 
records) 
• 
HIV viral load at delivery and during breastfeeding (must be based on written records) 
• 
CD4+ cell count at delivery (must be based on written records) 
 
These data should ideally be collected concurrent with the child’s entry into the study but may be 
collected thereafter if applicable. For example, additional time may be needed to contact and 
complete the informed consent process with the biological mother and/or to obtain maternal 
medical records. It may also be necessary to collect maternal data at multiple timepoints to 
capture all applicable information through cessation of breastfeeding. 
 
 

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6 
PARTICIPANT MONITORING, REPORTING, AND MANAGEMENT 
 
This observational study does not involve the use of any investigational agents or interventions. It 
also does not involve any investigational procedures; all procedures are common minimal risk 
procedures. As such, requirements for safety monitoring and reporting are limited. Adverse event 
and expedited adverse event reporting are not required for this study. Participant management 
will be guided by local clinical practice standards. 
 
Site investigators are responsible for monitoring the safety of study participants and alerting the 
Protocol Team if unexpected concerns arise. Site investigators are also responsible for prompt 
reporting of any unanticipated problems involving risks to participants or others to all applicable 
IRBs/ECs and other applicable review bodies, per the procedures of each applicable review body.  
 
Data collection for this study will include source documentation and entry into eCRFs of the 
clinical events of interest specified in Section 5.4. Management of any such events will be at the 
direction of participants’ primary care providers. Depending on the local context, participants 
may receive their primary care at the study site or from non-study care providers; for participants 
who receive their primary care from non-study providers, study staff will actively communicate 
and coordinate with the non-study providers when clinically indicated. Study staff will also refer 
participants to non-study sources of further evaluation and/or management when applicable. 
Study staff will similarly provide counseling and support to participants/parents/guardians when 
applicable.  
 
Site investigators will monitor participants’ HIV-1 RNA results and take action as needed in 
response to these results. When ARV resistance is suspected, the site investigator will coordinate 
with the participant’s primary care providers and consult with the Protocol Team to review the 
participant’s history and determine whether resistance testing should be performed through the 
study. When resistance testing is performed, the site investigator will provide results to the 
participant’s primary care providers, who will ultimately be responsible for any ARV regimen 
management decisions. 
 
Site investigators may also consult with the Protocol Team regarding any other participant 
management issues, questions, or concerns that may arise during follow-up.  
 
 
7 
STATISTICAL CONSIDERATIONS 
 
7.1 
General Design Issues 
 
This is an observational prospective cohort study to characterize the long-term clinical, 
immunologic, and virologic profiles of early treated children who may participate in future 
research related to HIV remission or cure. Early treatment is defined as treatment with at least 
three ART agents from at least two classes of ART initiated within 12 weeks of birth. Early 
treatment regimens may also include bNAbs. Within the overall study population, for descriptive 
and analysis purposes, children who initiated treatment within 48 hours of birth will be classified 
as having received very early treatment. Enrolled participants will complete semi-annual follow-
up for up to seven years. Clinical, virologic, and immunologic evaluations will be performed at 
each study visit; specimens will be collected for the study’s biorepository at each visit. 
 

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The cohort of participants enrolled in this study may represent a specific subset of the parent 
study populations, which raises the potential for selection bias in IMPAACT 2028 analyses. For 
example, long-term survivors may be overrepresented, particularly among CHER participants 
who are now 12-14 years of age. Infants in IMPAACT P1115 with sustained virological 
suppression will remain in that study and not enroll in IMPAACT 2028. The direction and 
magnitude of potential selection bias will depend on where these participants fall within exposure 
groups and their likelihood of outcomes of interest. Adjusting for this type of selection bias at 
enrollment would depend on having access to data from all participants in the parent studies to 
estimate the probability of being enrolled in IMPAACT 2028. As the IMPAACT 2028 Protocol 
Team is unlikely to have full access to these data, analytic methods will be used to estimate the 
direction of potential selection bias and put bounds around the magnitude of the bias (54). To 
inform these sensitivity analyses, the Protocol Team will compare the characteristics of 
participants enrolled in IMPAACT 2028 with those reported in parent study publications. This 
will allow evaluation of the robustness of the effect estimates observed in IMPAACT 2028 
analyses and the strength of conclusions drawn from these analyses. Efforts to minimize the 
magnitude of potential selection bias will also be explored. This may include, for example, 
collaborating with parent study teams to include all parent study participants in analyses.  
 
Because this is an observational study without any exposure assignment, comparisons should be 
carefully interpreted for confounding effects. Additionally, analyses within participant subgroups 
will have smaller sample sizes and will therefore provide less precise estimates. 
 
Although this study is observational, study participation itself, with access to the expertise of 
study investigators, may result in stricter ARV adherence and more frequent monitoring of HIV 
disease parameters and complications than would occur outside the study. This may impact the 
generalizability of study findings. 
 
All potential biases and limitations, including selection bias, unmeasured confounding, and 
limited generalizability as described above, will be acknowledged in study publications. 
Discussion will include the impact of such potential biases and limitations on the reported 
conclusions. 
 
7.2 
Outcome Measures 
 
Corresponding to the primary objective of the study, the clinical, immunologic, and virologic 
outcome measures listed below will be analyzed to characterize participants at study entry and 
during follow-up. The timeframe for ascertainment of all primary outcome measures is through 
the end of scheduled follow-up.  
 
Clinical Outcome Measures 
• Somatic growth indicators:  
– Weight, height, and weight-for-height Z score  
– Head circumference and head circumference-for-age Z score (through 2 years of age) 
• WHO clinical Stage 3 or Stage 4 conditions (see Appendix II) 
• Other medical conditions of interest (see Appendix II) 
• Medical conditions that required inpatient hospitalization or prolongation of existing 
hospitalization, resulted in persistent or significant disability or incapacity, were life-
threatening, or resulted in death 
• Mortality 

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Immunologic Outcome Measures 
• CD4+ cell counts and percentages 
• CD8+ cell counts and percentages 
• HIV-1 antibody status 
Virologic Outcome Measures 
• HIV-1 RNA in plasma 
• HIV-1 DNA concentration in PBMCs 
• HIV-1 ARV resistance mutations 
 
7.3 
Randomization and Stratification 
 
This is not a randomized study. To monitor accrual from each of the parent studies, participants 
will be stratified at entry by parent study. 
 
7.4 
Sample Size and Accrual 
 
7.4.1 
Sample Size 
 
Up to approximately 250 children will be enrolled in this study. Refer to Table 1 on page 26 for 
estimated numbers of participants who may be enrolled from each parent study.  
 
Data and specimens collected in this study will be used for additional research related to HIV 
remission or cure via a competitive proposal-based process. Most analyses performed for this 
study are expected to be based on proposals approved through the process noted in Section 3. 
More detailed power calculations relevant to specific analyses may be conducted within 
individual proposals. In proposed analyses, outcome measure data may be analyzed categorically 
or continuously. 
 
Table 3, Table 4, and Table 5 present general calculations for a binary or continuous outcome 
measure under varying assumptions of underlying event rates and distributions across a range of 
two-group comparison sample sizes (e.g., exposure, no exposure) to inform feasibility of future 
analysis proposals. For all calculations, the maximum sample size of 250 participants is assumed, 
with a two-sided α=0.05. With this sample size, the calculations represent the highest power and 
precision achievable in this study. Depending on analysis objectives, sample sizes for some 
outcome measures may be smaller, with corresponding lower precision. 
 
Categorical Outcome Measures 
 
For simplicity, it is assumed that for a given exposure, a comparison of interest is the proportion 
of exposed participants with an event versus the proportion of unexposed participants with the 
event measured in terms of a risk ratio (RR). For example, there may be interest in comparing the 
RR of a WHO Stage 3 or Stage 4 event in very early versus early treated infants. If 30% of the 
study population is very early treated and 70% is early treated with a 5% event probability among 
the very early treated children, then the study has 80% power to detect a RR of 3.28 (Table 3), 
which implies early treated children have 3.28 times the risk of a WHO Stage 3 or Stage 4 event 
compared to very early treated children (corresponding to a 16.4% event probability in early 
treated). 
 

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Table 3 presents the minimum detectable RR at 80% power assuming that exposure increases the 
risk of an event (RR>1). The RRs range from 1.57 to 19.61 depending on the underlying event 
probability and the percent of the population in the unexposed group.  
 
A similar summary is presented in Table 4, but under the assumption that exposure is protective 
(RR<1). Table 4 presents the maximum detectable RR at 80% power assuming that exposure 
decreases the risk of an event. The RRs range from 0.04 to 0.51 depending on the underlying 
event probability and the percent of the population in the unexposed group. 
 
With a maximum sample size of 250, rare events are unlikely to be observed in this study. If 
exposure increases the risk of an event, reasonably small effect sizes (RR between 1.5 and 3.5) 
may be detected if the probability of the event in the unexposed group is 10% or greater. For rare 
events (≤5% probability in the unexposed group), only very large associations would be 
detectable (Table 3). If exposure is protective, reasonable effect sizes (RR between 0.46 and 0.51) 
would be detectable if the probability of the event is greater than 30% with 30-70% of the 
population in the unexposed group. For less frequent events (<30%), only quite large associations 
would be detectable (Table 4). 
 
Continuous Outcome Measures 
 
Additional primary outcome measures of interest may be continuous, such as weight-for-height 
Z-score. For example, if the comparison of interest is having received bNAbs versus not having 
received bNAbs, and 20% of participants have received bNAbs, the study has 80% power to 
detect a mean difference of 0.40 standard deviations (Table 5).  
 
Table 5 presents the minimum detectable mean differences comparing two groups of with a t-test 
(unequal variances) at 80% power. These differences range from 0.40 to 0.60 standard deviations 
depending on the percent of the population in the unexposed group. 
 
 
 
 

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Table 3 
Detectable Effects at 80% Power 
Assuming Exposure is Associated with Increased Risk and a Sample Size of 250 
Event Probability  
in Unexposed 
Percent of Population  
in Unexposed Group 
Minimum Detectable RR for 
for Exposed vs Unexposed* 
1% 
90% 
12.52 
70% 
8.65 
50% 
8.53 
30% 
10.32 
10% 
19.61 
5% 
90% 
4.51 
70% 
3.28 
50% 
3.16 
30% 
3.51 
10% 
5.48 
10% 
90% 
3.15 
70% 
2.40 
50% 
2.31 
30% 
2.50 
10% 
3.51 
20% 
90% 
2.30 
70% 
1.86 
50% 
1.79 
30% 
1.88 
10% 
2.40 
30% 
90% 
1.94 
70% 
1.62 
50% 
1.57 
30% 
1.63 
10% 
1.96 
*Based on Mantel-Haenszel test. Calculations performed using PASS 15 (NCSS, 2017).  
 
Table 4 
Detectable Effects at 80% Power 
Assuming Exposure is Associated with Decreased Risk and a Sample Size of 250 
Event Probability 
(in Unexposed) 
Percent of Population 
in Unexposed Group 
Maximum Detectable RR for 
Exposed vs Unexposed* 
10% 
90% 
N/A 
70% 
0.09 
50% 
0.17 
30% 
0.16 
10% 
0.04 
20% 
90% 
0.06 
70% 
0.33 
50% 
0.39 
30% 
0.36 
10% 
0.19 
30% 
90% 
0.22 
70% 
0.46 
50% 
0.51 
30% 
0.48 
10% 
0.30 
*Based on Mantel-Haenszel test. Calculations performed using PASS 15 (NCSS, 2017).  

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Table 5 
Detectable Mean Differences Between Exposed and Unexposed 
Assuming Unequal Variances and a Sample Size of 250 
Percent of Population  
in Unexposed Group 
Minimum Detectable Mean Difference  
In Standard Deviations  
Between Exposed and Unexposed* 
50% 
0.40 
40% or 60% 
0.40 
30% or 70% 
0.40 
20% or 80% 
0.40 
10% or 90% 
0.60 
*Based on two-sample t-test allowing for unequal variances. Calculations performed 
using PASS 15 (NCSS, 2017).  
 
7.4.2 
Accrual 
 
Accrual into this study will remain open for the duration of follow-up (or until the maximum 
sample size of 250 is met). Accrual of participants recruited from the IMPAACT P1115 (Version 
1.0), IMPAACT 2008, CHER, LEOPARD, and TIES study populations is expected to take 
approximately 6-12 months at each site. Because IMPAACT P1115 will be conducted 
concurrently with IMPACT 2028, accrual of participants from IMPAACT P1115 is expected 
throughout the duration of IMPAACT 2028. 
 
7.5 
Monitoring 
 
Implementation of this study will be monitored at multiple levels, consistent with standard 
IMPAACT procedures. A study monitoring plan that details monitoring roles and responsibilities 
and data to be reviewed at each level will be prepared before the study opens to accrual. Sections 
8 and 9 provide for more information on on-site monitoring and quality management at the site 
level; see also Section 6. Further information on monitoring of study progress and the quality of 
study conduct across sites is provided below. 
 
7.5.1 
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.  
 
The Protocol Team will closely monitor participant accrual based on reports that will be 
generated by the SDMC. The pace and completeness of accrual will be monitored relative to the 
projections specified in Section 7.4.2; however, no minimum accrual target is applicable, and 
accrual will continue until the maximum sample size is enrolled or through the duration of the 
study. The Protocol Team will actively communicate with site investigators regarding the 
progress of accrual at each site and determine when accrual should be discontinued at each site.  
 
In addition to participant accrual, the Protocol Team will monitor participant retention and other 
key indicators of the quality of study conduct (e.g., data quality, data and specimen completeness) 
based on reports generated by the SDMC. The team will take action with study sites as needed to 
ensure high quality study conduct throughout the period of study implementation. The Protocol 
Team will also monitor aggregate clinical, immunologic, and virologic parameters over time 
based on reports generated by the SDMC. 
 

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Data reports required for the team’s monitoring will be generated at least monthly during the 
early period of study implementation. Thereafter, reports will be generated on a frequency 
specified in the study monitoring plan.  
 
7.5.2 
Monitoring by the Study Monitoring Committee (SMC) 
 
An independent IMPAACT SMC will review this study regularly, following policies described in 
the IMPAACT Manual of Procedures.  
 
SMC reviews will occur at least annually or on a more frequent or ad hoc basis if any issues or 
concerns arise. 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 and the quality of study conduct, and will review summary 
clinical, immunologic, and virologic data. The SMC will generally review the same types of data 
reports as the Protocol Team (e.g., participant accrual, participant retention, data quality, data and 
specimen completeness). For ad hoc reviews, more limited data may be reviewed, focusing on the 
issues or concerns that necessitated the reviews. Beginning approximately two years after study 
initiation (first enrollment), the SMC will also review information pertaining to the productivity 
of the proposal-based process for use of study data and stored specimens. 
 
7.6 
Analyses 
 
The primary analysis to characterize the IMPAACT 2028 cohort will describe clinical, 
immunologic, and virologic characteristics at enrollment, and from birth (as available), as well as 
at early follow-up, by very early (within 48 hours of age) versus early (between 48 hours and 12 
weeks of age) treatment and by receipt of bNAbs as part of treatment. This analysis will be 
descriptive and will present point estimates of summary statistics with associated confidence 
intervals or selected quantiles as appropriate. This analysis is expected to be performed once the 
Protocol Team determines that all participants expected to be enrolled from the parent studies, 
except IMPAACT P1115 Version 2.0 participants, have been enrolled. This analysis will be 
described in the reference publication for the study and will inform subsequent analysis 
proposals, along with study monitoring reports that summarize additional data during the study 
follow-up period.  
 
Additional analyses will be performed after the primary analysis, based on approved proposals, 
during follow-up and after follow-up has been completed. Such analyses may be cross-sectional 
or longitudinal depending on available data and may explore exposures other than very early 
versus early treatment or receipt of bNAbs, such as: 
 
• 
Male versus female 
• 
In utero versus intrapartum or postpartum HIV transmission 
• 
Breastfed versus formula fed 
• 
Have versus have not had exposure to HIV during breastfeeding (as indicated by maternal 
ARV use and maternal viral load during breastfeeding) 
• 
Have versus have not maintained virologic suppression 
 

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The analysis approach will be tailored to the type of outcome measure of scientific interest. For 
categorical data, RRs will be estimated using modified Poisson models or log-binomial models. 
For continuous measures (e.g., CD8+ percentage), linear regression will be used. For longitudinal 
outcomes, mixed effects models and generalized estimating equations may be used to evaluate 
associations of interest. Time-to-event outcome measures will be analyzed using survival 
methods for failure time data such as Kaplan-Meier, log rank tests, and proportional hazards 
regression models, with consideration for competing events, time-varying covariates, and the 
non-informative censoring assumption, as appropriate. For count data, Poisson regression may be 
used.  
 
A detailed statistical analysis plan will be developed for the primary analysis and separately for 
each approved proposal. As needed, analysis plans will specify the covariates for regression 
models. Covariate data may include those collected as history and at study entry.  
 
 
8 
DATA HANDLING AND RECORD KEEPING 
 
8.1 
Data Management Responsibilities 
 
As described in Section 4.4, eligibility and enrollment data will be collected using the DMC SES.  
 
Study sites must maintain adequate and accurate research records containing all information 
pertinent to the study for all screened and enrolled participants, including paper-based CRFs (if 
used), eCRFs, and supporting source data. In maintaining these records, sites must comply with 
the standards of source documentation specified in the DAIDS policy on Requirements for 
Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials (available on the 
website referenced in Section 8.2). 
 
eCRFs and an eCRF completion guide will be made available to study sites by the DMC. Study 
site staff will enter required data into eCRFs, with system checks applied and data queries 
generated immediately upon saving the entered data. Data must be entered within timeframes 
specified by the DMC; queries must also be resolved in a timely manner. Selected laboratory data 
will be transferred electronically to the DMC through the LDMS.  
 
Further information on eCRFs and IMPAACT data management procedures will be provided by 
the DMC. A User Manual for the SES is available on the DMC portal at: 
https://www.frontierscience.org 
 
8.2 
Essential and Source Documents and Access to Source Data 
 
All DAIDS policies referenced in this section are available at: 
https://www.niaid.nih.gov/research/daids-clinical-site-implementation-operations 
 
Study sites must comply with DAIDS policies on Requirements for Essential Documents at 
Clinical Research Sites Conducting DAIDS Funded and/or Sponsored Clinical Trials and 
Requirements for Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials. In 
its policy on Requirements for Manual of Operational Procedures, DAIDS requires sites to 
establish SOPs for maintaining essential and source documents in compliance with these policies. 
Site SOPs should be updated and/or supplemented as needed to describe roles, responsibilities, 
and procedures for this study, and site SOPs should be followed throughout the study.  

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Per the DAIDS policy on Storage and Retention of Clinical Research Records, study records must 
be stored in a manner that ensures privacy, confidentiality, security, and accessibility during the 
conduct of the study and after the study is completed. Records must be retained for a minimum of 
three years after the completion of the study.  
 
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, site IRBs/ECs, the sIRB (for US sites), the Office for Human Research 
Protections, and other US, local, and international regulatory entities. Records must be kept on-
site throughout the period of study implementation; thereafter, instructions for off-site storage 
may be provided by the National Institute of Allergy and Infectious Diseases (NIAID) or National 
Institute of Child Health and Human Development (NICHD). No study records may be removed 
to an off-site location or destroyed prior to receiving approval from NIAID or NICHD.  
 
8.3 
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 
 
 
9 
CLINICAL SITE MONITORING 
 
Site monitors under contract to NIAID or NICHD will visit study sites to inspect study facilities 
and review participant study records — including informed consent and assent forms, paper-
based CRFs (if used), eCRFs, medical records, and laboratory 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.  
 
 
10 
HUMAN SUBJECTS PROTECTIONS 
 
10.1 
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 informed consent and assent forms in accordance with 45 CFR 46; 
subsequent to initial review and approval, IRBs/ECs must review the study at least annually. Site 
investigators must also promptly report to the IRBs/ECs any changes in the study and any 
unanticipated problems involving risks to participants or others. 
 
Non-US sites are frequently overseen by more than one IRB/EC. US sites are overseen by an 
sIRB, with additional review by local IRBs if required per their agreements with the sIRB. Site 
investigators are responsible for awareness of and adherence to the policies and procedures of all 
applicable IRBs/ECs. All such policies and procedures must be followed and complete 
documentation of all correspondence to and from all applicable IRBs/ECs must be maintained in 
site essential document files. Sites must submit documentation of both initial review and approval 

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and continuing review to the DAIDS Protocol Registration Office (PRO) in accordance with the 
DAIDS Protocol Registration Manual (see also Section 11.2). 
 
10.2 
Vulnerable Participants 
 
The NIH is mandated by law to ensure that children are included in clinical research when 
appropriate (55). This study responds to that mandate.  
 
Nonetheless, the children enrolled in this study are considered vulnerable participants per 45 CFR 
46 Subpart D. IRBs/ECs must consider the potential benefits, risks, and discomforts of the study 
children and assess the justification for their inclusion in this study. As part of this assessment, 
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 11.2, and the risk category assigned by the IRB/EC 
determines the parental informed consent requirements for the study at each site. Per 45 CFR 
46.408 (b), the IRB/EC may find that the consent of one parent is sufficient for research to be 
conducted under 46.404 or 46.405. If the IRB/EC finds that the research is covered by 46.406 or 
46.407, both parents must give their consent, unless one parent is deceased, unknown, 
incompetent, or not reasonably available or when only one parent has legal responsibility for the 
care and custody of the child (as determined locally). IRBs/ECs must document their risk 
determination, and study sites should adapt the signature pages of their site-specific ICF 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: Clinical Site Requirements, which is available at:  
https://www.niaid.nih.gov/research/daids-clinical-site-implementation-operations 
 
In addition to the US regulations cited above, sites in countries other than the US must also 
comply with all applicable local and national guidelines and regulations. 
 
10.3 
Informed Consent and Assent 
 
Refer to Section 4.4 and the study-specific manual of procedures for further information on 
informed consent and assent procedures for this study. Refer to Appendix III and Appendix IV 
for sample informed consent and assent forms, respectively, for child study participation. Refer to 
Appendix V for the sample ICF for maternal data collection.  
 
10.3.1 Informed Consent and Assent for Child Study Participation 
 
Written informed consent for study participation will be obtained from each child’s parent or 
guardian before any study-specific procedures are performed. It is generally expected that the 
consent of one parent (or guardian) will be sufficient for child participation in this study. 
However, consenting requirements at each site will depend on the IRB/EC risk determination as 
described in Section 10.2; all applicable IRB/EC requirements must be followed. When 
applicable per IRB/EC policies and procedures, written assent will also be obtained from each 
child before any study-specific procedures are performed. For participants who do not meet 
IRB/EC criteria for providing assent at the time of screening and enrollment, if such criteria are 
met during follow-up, assent should be obtained at the next study visit after the criteria are met. 

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Likewise, informed consent should be obtained from participants who reach the legal age or 
circumstance of consent.  
 
The informed consent process will include information exchange, detailed discussion, and 
assessment of understanding of all required elements of informed consent, including the potential 
risks, benefits, and alternatives to study participation. The process will describe expectations for 
abstraction of information from parent study records and recording of information from non-study 
medical records. The assent process will include a similar but age-appropriate discussion. The 
amount of information and level of detail provided as part of the assent process should be tailored 
to the age and maturity of the potential participant, guided by applicable IRB/EC policies and 
procedures. The extent to which HIV status is disclosed as part of the assent process should also 
be guided by applicable IRB/EC policies and procedures. When preparing site-specific assent 
forms, sites may remove or modify the wording included in the sample form (see Appendix IV) 
in order to provide the most appropriate information and level of detail, consistent with IRB/EC 
policies and procedures. This may include preparing site-specific form versions that do not 
disclose HIV status. 
 
Participants/parents/guardians will be asked whether they agree to collection, storage, and future 
research use of biological specimens (serum, plasma, PBMCs, nasopharyngeal swabs, rectal 
swabs) as applicable. This is optional and may be declined with no impact on other aspects of 
study participation. Consent for genetic testing of these specimens is also optional.  
 
Should the consenting parent or guardian of an enrolled child die or no longer be available for 
any reason, all applicable IRB/EC policies and procedures should be followed. Study-specific 
evaluations should not be performed until informed consent for continued study participation is 
obtained from the child’s authorized guardian, as defined locally. If an authorized guardian 
cannot be identified, or if the guardian does not consent to continued study participation, the child 
must be withdrawn from the study. In accordance with the DAIDS policy on Enrolling Children 
(including Adolescents) in Clinical Research: Clinical Site Requirements, all sites must establish 
and maintain written procedures describing the standards that will be followed to identify who 
may serve as guardian for an enrolled child, reflective of applicable IRB/EC guidance for conduct 
of human subjects research within the context of available local law, regulation, or government 
policy. 
 
10.3.2 Informed Consent for Maternal Data Collection 
 
See also Section 5.9. When available, the biological mothers of enrolled children will be asked to 
provide written informed consent for collection of limited maternal data for study purposes. This 
informed consent process should be conducted in a manner similar to the process for child study 
participation, including information exchange, detailed discussion, and assessment of 
understanding of all required elements of informed consent. The process should ideally be 
conducted such that, for consenting mothers, maternal data can be collected concurrent with the 
child’s entry into the study. However, this is not required; the process may be conducted any time 
after informed consent for child study participation is obtained. In addition, consent for maternal 
data collection is optional; this consent may be declined with no impact on child study 
participation. 
 

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10.4 
Potential Benefits 
 
There may be no direct benefit to participants in this study. However, it is possible that 
information learned in this study may be of benefit to participants and others in the future. 
Participants and their families may appreciate the opportunity to contribute to HIV-related 
research. Evaluations such as HIV-1 RNA assays and CD4+ and CD8+ cell counts and 
percentages may be performed more frequently in this study than is standard in some settings and 
the results of these and other evaluations (e.g., physical examinations) may provide information 
to guide aspects of participants’ clinical care and management.  
 
10.5 
Potential Risks  
 
The potential risks of participation in this study include the minimal risks associated with 
common medical procedures. Blood collection may cause pain, bruising, swelling, and fainting. 
There is a very small risk of infection where the needle is inserted. Nasopharyngeal and rectal 
swab collection may cause discomfort. 
 
Refer to Section 10.7 for further information on privacy and confidentiality. Despite efforts to 
maintain confidentiality, children’s involvement in this study could become known to others, 
possibly leading to unfair treatment, discrimination, or other social impacts (e.g., because 
participants could become known as having HIV). For example, children could be treated unfairly 
or discriminated against or could have problems being accepted by their families and/or 
communities. Every effort will be made to protect children’s information, but this cannot be 
guaranteed. 
 
10.6 
Reimbursement/Compensation 
 
Pending IRB/EC approval, participants will be reimbursed for costs associated with completing 
study visits (e.g., transport costs). Reimbursement amounts will be specified in site-specific ICFs 
and/or other materials per applicable IRB/EC policies and procedures.  
 
10.7 
Privacy and Confidentiality 
 
Study procedures will be conducted in private and every effort will be made to protect participant 
privacy and confidentiality to the extent possible. Site staff will follow applicable institutional 
and IRB/EC policies with respect to information-sharing with the parents or guardians of study 
participants. Participant information will not be released without written permission to do so 
except as necessary for review, monitoring, and/or auditing as described in Section 8.2. 
 
All study-related information will be stored securely. Participant research records will be stored 
in locked areas with access limited to study staff. All laboratory specimens, CRFs, and other 
documents that may be transmitted off-site 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.  

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In addition to the above, a Certificate of Confidentiality has been deemed issued for the 
IMPAACT Network by the US Department of Health and Human Services. This certificate 
protects study staff from being compelled to disclose study-related information by any US 
Federal, state, or local civil, criminal, administrative, legislative, or other proceedings. It thus 
serves to protect the identity and privacy of study participants. Because the certificate cannot be 
enforced outside of the US, however, it applies only to US sites and participants. 
 
10.8 
Communicable Disease Reporting 
 
Study staff will comply with local requirements to report communicable diseases identified 
among study participants to health authorities. Participants/parents/guardians will be made aware 
of applicable reporting requirements as part of the study informed consent process. 
 
10.9 
Management of Incidental Findings 
 
Site clinicians will inform participants/parents/guardians of all clinically meaningful physical 
exam findings and laboratory test results, including CD4+ and CD8+ cell counts and percentages, 
HIV-1 RNA PCR results, and ARV resistance test results. Site clinicians will provide results to 
participants’ primary care providers when applicable and will provide referrals to non-study 
sources of medical care for further evaluation and/or treatment of study-related findings when 
clinically indicated.  
 
The results of other tests that may be performed using specimens collected in this study are not 
planned to be provided to participants/parents/guardians, as these are considered research tests 
that are not expected to be relevant to clinical care and management. If, however, new 
information becomes available indicating that the results of any tests are of clinical relevance, the 
results will be provided. 
 
10.10 Management of New Information Pertinent to Study Participation 
 
Study staff will provide participants/parents/guardians with any new information learned over the 
course of the study that may affect their willingness to continue study participation. 
 
 
11 
ADMINISTRATIVE PROCEDURES 
 
11.1 
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 US National Institutes of 
Health (NIH). 
 
Within the NIAID, DAIDS is responsible for regulatory oversight of this study.  
 
NIAID and NICHD provide funding to the clinical research sites at which this study will be 
conducted. Each institute contracts with independent clinical site monitors who will perform 
monitoring visits as described in Section 9. As part of these visits, monitors will inspect study-
related documentation to ensure compliance with all applicable US, local, and international 
regulatory requirements. 

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11.2 
Protocol Registration 
 
Prior to implementation of this protocol, and any subsequent full version amendments, each site 
must have the protocol and the study informed consent and assent forms approved, as appropriate, 
by applicable IRBs/ECs, and any other applicable regulatory entities; for US sites, this includes 
the sIRB. 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 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 
 
11.3 
Study Implementation 
 
This study will be conducted in accordance with the protocol, international good clinical practice 
guidelines, and all applicable US and local regulations. Study implementation will also be guided 
by the IMPAACT Manual of Procedures, study-specific manual of procedures, LPC, and other 
study implementation materials, which will be available on the study-specific website: 
https://impaactnetwork.org/studies/IMPAACT2028.asp 
 
Study implementation at each site will also be guided by site-specific SOPs. The DAIDS policy 
on Requirements for Manual of Operational Procedures specifies the minimum set of SOPs that 
must be established at sites conducting DAIDS funded and/or sponsored clinical trials (available 
on the website referenced in Section 8.2). These SOPs should be updated and/or supplemented as 
needed to describe roles, responsibilities, and procedures for this study. 
 
11.4 
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 8.2), 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.  
 

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Deviations should be reported to applicable IRBs/ECs and other applicable review bodies in 
accordance with the policies and procedures of these review bodies; for US sites, this includes the 
sIRB, per the requirements available at the website cited in Section 6. 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. 
 
11.5 
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 
 
11.6 
ClinicalTrials.gov 
 
This observational study is not subject to the Food and Drug Administration Amendments Act of 
2007 or the NIH Policy on Dissemination of NIH-funded Clinical Trial Information. However, it 
will be registered in ClinicalTrials.gov to meet International Committee of Medical Journal 
Editors requirements. 
 
 
12 
PUBLICATIONS 
 
All presentations and publications of data collected in this study are governed by IMPAACT 
policies, which are available in the IMPAACT Manual of Procedures.  
 
 
13 
REFERENCES 
 
1. 
Organization WH. Consolidated guidelines on the use of antiretroviral drugs for treating and 
preventing HIV infection Recommendations for a public health approach In: Organization WH, 
editor. 30 June 2013 ed2013. p. 272. 
2. 
UNAIDS. Fact Sheet - World AIDS Day 2019 [Available from: 
https://www.unaids.org/sites/default/files/media_asset/UNAIDS_FactSheet_en.pdf. 
3. 
Mzingwane ML, Tiemessen CT. Mechanisms of HIV persistence in HIV reservoirs. Rev Med 
Virol. 2017;27(2). 
4. 
Sengupta S, Siliciano RF. Targeting the Latent Reservoir for HIV-1. Immunity. 2018;48(5):872-
95. 
5. 
Shearer WT, Quinn TC, LaRussa P, Lew JF, Mofenson L, Almy S, et al. Viral load and disease 
progression in infants infected with human immunodeficiency virus type 1. Women and Infants 
Transmission Study Group. NEnglJMed. 1997;336(19):1337-42. 
6. 
Kaufmann GR, Cunningham P, Kelleher AD, Zaunders J, Carr A, Vizzard J, et al. Patterns of 
viral dynamics during primary human immunodeficiency virus type 1 infection. The Sydney 
Primary HIV Infection Study Group. J Infect Dis. 1998;178(6):1812-5. 
7. 
Luzuriaga K, Holmes D, Hereema A, Wong J, Panicali DL, Sullivan JL. HIV-1-specific cytotoxic 
T lymphocyte responses in the first year of life. JImmunol. 1995;154(1):433-43. 

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8. 
Newell ML, Coovadia H, Cortina-Borja M, Rollins N, Gaillard P, Dabis F. Mortality of infected 
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Persaud D, Gay H, Ziemniak C, Chen YH, Piatak M, Jr., Chun TW, et al. Absence of detectable 
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Moragas M, Distefano M, Mecikovsky D, Arazi Caillaud S, Cernadas C, Bologna R, et al. Impact 
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infected children with long-term sustained virological suppression: A longitudinal study. PLoS 
One. 2018;13(10):e0205579. 
11. 
Martinez-Bonet M, Puertas MC, Fortuny C, Ouchi D, Mellado MJ, Rojo P, et al. Establishment 
and Replenishment of the Viral Reservoir in Perinatally HIV-1-infected Children Initiating Very 
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12. 
Luzuriaga K, McManus M, Catalina M, Mayack S, Sharkey M, Stevenson M, et al. Early therapy 
of vertical human immunodeficiency virus type 1 (HIV-1) infection: control of viral replication 
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13. 
Zanchetta M, Anselmi A, Vendrame D, Rampon O, Giaquinto C, Mazza A, et al. Early therapy in 
HIV-1-infected children: effect on HIV-1 dynamics and HIV-1-specific immune response. 
Antivir Ther. 2008;13(1):47-55. 
14. 
Garcia-Broncano P, Maddali S, Einkauf KB, Jiang C, Gao C, Chevalier J, et al. Early 
antiretroviral therapy in neonates with HIV-1 infection restricts viral reservoir size and induces a 
distinct innate immune profile. Sci Transl Med. 2019;11(520). 
15. 
Violari A, Cotton MF, Kuhn L, Schramm DB, Paximadis M, Loubser S, et al. A child with 
perinatal HIV infection and long-term sustained virological control following antiretroviral 
treatment cessation. Nature communications. 2019;10(1):412. 
16. 
Frange P, Faye A, Avettand-Fenoel V, Bellaton E, Descamps D, Angin M, et al. HIV-1 
virological remission lasting more than 12 years after interruption of early antiretroviral therapy 
in a perinatally infected teenager enrolled in the French ANRS EPF-CO10 paediatric cohort: a 
case report. Lancet HIV. 2016;3(1):e49-54. 
17. 
Veldsman KA, Maritz J, Isaacs S, Katusiime MG, Janse van Rensburg A, Laughton B, et al. 
Rapid decline of HIV-1 DNA and RNA in infants starting very early antiretroviral therapy may 
pose a diagnostic challenge. AIDS. 2018;32(5):629-34. 
18. 
Veldsman KA, Janse van Rensburg A, Isaacs S, Naidoo S, Laughton B, Lombard C, et al. HIV-1 
DNA decay is faster in children who initiate ART shortly after birth than later. J Int AIDS Soc. 
2019;22(8):e25368. 
19. 
Haigwood NL, Montefiori DC, Sutton WF, McClure J, Watson AJ, Voss G, et al. Passive 
immunotherapy in simian immunodeficiency virus-infected macaques accelerates the 
development of neutralizing antibodies. J Virol. 2004;78(11):5983-95. 
20. 
Ng CT, Jaworski JP, Jayaraman P, Sutton WF, Delio P, Kuller L, et al. Passive neutralizing 
antibody controls SHIV viremia and enhances B cell responses in infant macaques. Nat Med. 
2010;16(10):1117-9. 
21. 
Jaworski JP, Kobie J, Brower Z, Malherbe DC, Landucci G, Sutton WF, et al. Neutralizing 
polyclonal IgG present during acute infection prevents rapid disease onset in simian-human 
immunodeficiency virus SHIVSF162P3-infected infant rhesus macaques. J Virol. 
2013;87(19):10447-59. 
22. 
Schoofs T, Klein F, Braunschweig M, Kreider EF, Feldmann A, Nogueira L, et al. HIV-1 therapy 
with monoclonal antibody 3BNC117 elicits host immune responses against HIV-1. Science. 
2016;352(6288):997-1001. 
23. 
Persaud D, Chadwick EG, Tierney C, Nelson B, Cotton M, Coletti A, et al. Virologic response to 
very early ART in neonates with in utero HIV: IMPAACT P1115. Conference on Retroviruses 
and Opportunistic Infections; 2019 March 4-7; Seattle, WA2019. 

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Paximadis M, Dias BDC, Mncube S, Strehlau R, Shen Y, Shiau S, et al. Predictors of the 
persisting viral reservoir in very early treated infants. Conference on Retroviruses and 
Opportunistic Infections; Boston, MA2020. 
25. 
Kuhn L, Strehlau R, Shiau S, Patel F, Shen Y, Technau KG, et al. Early antiretroviral treatment of 
infants to attain HIV remission. EClinicalMedicine. 2020;18:100241. 
26. 
Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn J, Madhi SA, et al. Early antiretroviral 
therapy and mortality among HIV-infected infants. N Engl J Med. 2008;359(21):2233-44. 
27. 
Cotton MF, Violari A, Otwombe K, Panchia R, Dobbels E, Rabie H, et al. Early time-limited 
antiretroviral therapy versus deferred therapy in South African infants infected with HIV: results 
from the children with HIV early antiretroviral (CHER) randomised trial. Lancet. 
2013;382(9904):1555-63. 
28. 
Stewart CJ, Ajami NJ, O'Brien JL, Hutchinson DS, Smith DP, Wong MC, et al. Temporal 
development of the gut microbiome in early childhood from the TEDDY study. Nature. 
2018;562(7728):583-8. 
29. 
Crakes KR, Jiang G. Gut Microbiome Alterations During HIV/SIV Infection: Implications for 
HIV Cure. Front Microbiol. 2019;10:1104. 
30. 
Rocafort M, Noguera-Julian M, Rivera J, Pastor L, Guillen Y, Langhorst J, et al. Evolution of the 
gut microbiome following acute HIV-1 infection. Microbiome. 2019;7(1):73. 
31. 
Sessa L, Reddel S, Manno E, Quagliariello A, Cotugno N, Del Chierico F, et al. Distinct gut 
microbiota profile in antiretroviral therapy-treated perinatally HIV-infected patients associated 
with cardiac and inflammatory biomarkers. AIDS. 2019;33(6):1001-11. 
32. 
Bourke CD, Gough EK, Pimundu G, Shonhai A, Berejena C, Terry L, et al. Cotrimoxazole 
reduces systemic inflammation in HIV infection by altering the gut microbiome and immune 
activation. Sci Transl Med. 2019;11(486):eaav0537. 
33. 
Marchesi JR, Adams DH, Fava F, Hermes GD, Hirschfield GM, Hold G, et al. The gut 
microbiota and host health: a new clinical frontier. Gut. 2016;65(2):330-9. 
34. 
Zeevi D, Korem T, Segal E. Talking about cross-talk: the immune system and the microbiome. 
Genome Biol. 2016;17:50. 
35. 
Harris VC, Armah G, Fuentes S, Korpela KE, Parashar U, Victor JC, et al. Significant Correlation 
Between the Infant Gut Microbiome and Rotavirus Vaccine Response in Rural Ghana. J Infect 
Dis. 2017;215(1):34-41. 
36. 
Eloe-Fadrosh EA, McArthur MA, Seekatz AM, Drabek EF, Rasko DA, Sztein MB, et al. Impact 
of oral typhoid vaccination on the human gut microbiota and correlations with s. Typhi-specific 
immunological responses. PLoS One. 2013;8(4):e62026. 
37. 
Mullie C, Yazourh A, Thibault H, Odou MF, Singer E, Kalach N, et al. Increased poliovirus-
specific intestinal antibody response coincides with promotion of Bifidobacterium longum-
infantis and Bifidobacterium breve in infants: a randomized, double-blind, placebo-controlled 
trial. Pediatr Res. 2004;56(5):791-5. 
38. 
Vatanen T, Kostic AD, d'Hennezel E, Siljander H, Franzosa EA, Yassour M, et al. Variation in 
Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans. Cell. 
2016;165(4):842-53. 
39. 
Huda MN, Ahmad SM, Alam MJ, Khanam A, Kalanetra KM, Taft DH, et al. Bifidobacterium 
Abundance in Early Infancy and Vaccine Response at 2 Years of Age. Pediatrics. 2019;143(2). 
40. 
Hagan T, Cortese M, Rouphael N, Boudreau C, Linde C, Maddur MS, et al. Antibiotics-Driven 
Gut Microbiome Perturbation Alters Immunity to Vaccines in Humans. Cell. 2019;178(6):1313-
28 e13. 
41. 
Li SX, Armstrong A, Neff CP, Shaffer M, Lozupone CA, Palmer BE. Complexities of Gut 
Microbiome Dysbiosis in the Context of HIV Infection and Antiretroviral Therapy. Clin 
Pharmacol Ther. 2016;99(6):600-11. 
42. 
O'Dwyer DN, Dickson RP, Moore BB. The Lung Microbiome, Immunity, and the Pathogenesis 
of Chronic Lung Disease. J Immunol. 2016;196(12):4839-47. 

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43. 
Lynch JP, Sikder MA, Curren BF, Werder RB, Simpson J, Cuiv PO, et al. The Influence of the 
Microbiome on Early-Life Severe Viral Lower Respiratory Infections and Asthma-Food for 
Thought? Front Immunol. 2017;8:156. 
44. 
Wypych TP, Wickramasinghe LC, Marsland BJ. The influence of the microbiome on respiratory 
health. Nat Immunol. 2019;20(10):1279-90. 
45. 
Gollwitzer ES, Saglani S, Trompette A, Yadava K, Sherburn R, McCoy KD, et al. Lung 
microbiota promotes tolerance to allergens in neonates via PD-L1. Nat Med. 2014;20(6):642-7. 
46. 
Segal LN, Alekseyenko AV, Clemente JC, Kulkarni R, Wu B, Gao Z, et al. Enrichment of lung 
microbiome with supraglottic taxa is associated with increased pulmonary inflammation. 
Microbiome. 2013;1(1):19. 
47. 
O'Dwyer DN, Dickson RP, Moore BB. The Lung Microbiome, Immunity, and the Pathogenesis 
of Chronic Lung Disease. J Immunol. 2016;196(12):4839-47. 
48. 
Henrich TJ, Beckford-Vera D, Martinez-Ortiz E, Aslam M, Thanh C, Kumar S, et al., editors. 
Whole-body PET imaging of the HIV reservoir using radiolabeled VRC01. Conference on 
Retroviruses and Opportunistic Infections (CROI); 2020; Boston, MA. 
49. 
Morrow LE, Kollef MH, Casale TB. Probiotic prophylaxis of ventilator-associated pneumonia: a 
blinded, randomized, controlled trial. Am J Respir Crit Care Med. 2010;182(8):1058-64. 
50. 
Popova M, Molimard P, Courau S, Crociani J, Dufour C, Le Vacon F, et al. Beneficial effects of 
probiotics in upper respiratory tract infections and their mechanical actions to antagonize 
pathogens. J Appl Microbiol. 2012;113(6):1305-18. 
51. 
Warner BB, Hamvas A. Lungs, microbes and the developing neonate. Neonatology. 
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52. 
Sze MA, Tsuruta M, Yang SW, Oh Y, Man SF, Hogg JC, et al. Changes in the bacterial 
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53. 
National Institutes of Health. NIH Policy and Guidelines on the Inclusion of Children as 
Participants in Research Involving Human Subjects. 1998 March 6. 
 
 
  
 
 

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Appendix I: Schedule of Evaluations 
 
 
Screening and Entry 
Day 0 
Semi-Annual Follow-Up 
Q24 weeks 
ADMINISTRATIVE, REGULATORY, AND CLINICAL EVALUATIONS 
Assess expected availability for study participation 
for eligibility determination 
X 
 
Review parent study records and available medical 
records for eligibility determination 
X 
 
Collect baseline medical and medications history 
 
X 
 
Collect interval medical and medications history 
 
 
X 
Collect feeding history1  
X 
[X] 
Perform physical examination 
 
X 
X 
LABORATORY EVALUATIONS 
 
 
HIV-1 RNA PCR2 
(quantitative, performed locally) 
3 mL 
3 mL 
HIV-1 DNA ddPCR2 
(performed centrally) 
3 mL 
3 mL 
CD4+ and CD8+ cell counts and percentages3 
(performed locally) 
1-2 mL 
1-2 mL 
HIV-1 antibody2 
(performed centrally) 
1.5 mL 
1.5 mL  
Q48 only 
Plasma and PBMC storage (stored locally)2 
 
 
‒ Less than 5 kg 
5 mL 
5 mL 
‒ 5 to less than 10 kg 
7 mL 
7 mL 
‒ 10 to less than 15 kg 
12 mL 
12 mL 
‒ 15 kg or greater 
17 mL 
17 mL 
Serum storage 
(stored locally) 
3 mL 
3 mL 
ARV resistance testing if clinically indicated2 
(performed locally, regionally, or centrally) 
3 mL 
3 mL 
If child is three years of age, nasal and rectal swab 
storage (stored locally)4 
[X]4 
[X]4 
 
Total Blood Volume  
19.5-32.5 mL 
18.0-32.5 mL 
1Collect for all participants at Screening and Entry Visit. Collect at Semi-Annual Follow-up Visit(s) only if 
needed to record date of last exposure to formula and/or date of last exposure to breast milk if applicable.  
2To maximize specimen yields, whenever possible, blood volumes collected for HIV-1 RNA PCR, HIV-1 
DNA ddPCR, HIV-1 antibody, and/or ARV resistance testing should be processed for PBMC storage; all 
residual plasma should also be stored. Refer to the LPC for detailed guidance on specimen collection, 
processing, and storage. 
3At sites where a complete blood count with white blood cell differential is needed to obtain CD4+ and 
CD8+ cell counts and percentages, up to 2 mL of blood may be collected; otherwise, 1 mL should be 
collected. 
4One nasopharyngeal swab and one rectal swab should be collected from each participant once he or she 
has reached three years of age. For participants who are three years of age or older at study entry, the swabs 
should be collected at study entry. Otherwise, the swabs should be collected at the first follow-up visit 
occurring after the participant has reached three years of age. 
 

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Appendix II: WHO Clinical Stage 3 and Stage 4 Conditions 
and Other Medical Conditions of Interest for IMPAACT 2028 
 
WHO Stage 3 Conditions for Participants  
15 Years of Age and Older 
• Unexplained severe weight loss (>10% of presumed or 
measured body weight) 
• Unexplained chronic diarrhoea for longer than 1 month 
• Unexplained persistent fever (intermittent or constant 
for longer than 1 month) 
• Persistent oral candidiasis 
• Oral hairy leukoplakia 
• Pulmonary tuberculosis 
• Severe bacterial infections (such as pneumonia, 
empyema, pyomyositis, bone or joint infection, 
meningitis, bacteraemia) 
• Acute necrotizing ulcerative stomatitis, gingivitis or 
periodontitis 
• Unexplained anaemia (<8 g/dl), neutropaenia (<0.5 x 
109/l) and/or chronic thrombocytopaenia (<50 x 109/l) 
 
WHO Stage 3 Conditions for Participants  
Less than 15 Years of Age 
• Unexplained moderate malnutritionb not adequately 
responding to standard therapy 
• Unexplained persistent diarrhoea (14 days or more)  
• Unexplained persistent fever (above 37.5°C, 
intermittent or constant, for longer than one 1 month)  
• Persistent oral candidiasis (after first 6 weeks of life)  
• Oral hairy leukoplakia  
• Lymph node tuberculosis  
• Pulmonary tuberculosis  
• Severe recurrent bacterial pneumonia  
• Acute necrotizing ulcerative gingivitis or periodontitis  
• Unexplained anaemia (<8 g/dl), neutropaenia (<0.5 x 
109/l) or chronic thrombocytopaenia (<50 x 109/l) 
• Symptomatic lymphoid interstitial pneumonitis  
• Chronic HIV-associated lung disease, including 
bronchiectasis 
WHO Stage 4 Conditionsc for Participants  
15 Years of Age and Older 
• HIV wasting syndrome 
• Pneumocystis (jirovecii) pneumonia 
• Recurrent severe bacterial pneumonia 
• Chronic herpes simplex infection (orolabial, genital or 
anorectal of more than 1 month’s duration or visceral 
at any site) 
• Oesophageal candidiasis (or candidiasis of trachea, 
bronchi or lungs) 
• Extrapulmonary tuberculosis 
• Kaposi sarcoma 
• Cytomegalovirus infection (retinitis or infection of 
other organs) 
• Central nervous system toxoplasmosis 
• HIV encephalopathy 
• Extrapulmonary cryptococcosis, including meningitis 
• Disseminated nontuberculous mycobacterial infection 
• Progressive multifocal leukoencephalopathy 
• Chronic cryptosporidiosis 
• Chronic isosporiasis 
• Disseminated mycosis (extrapulmonary 
histoplasmosis, coccidioidomycosis) 
• Lymphoma (cerebral or B-cell non-Hodgkin) 
• Symptomatic HIV-associated nephropathy or 
cardiomyopathy 
• Recurrent septicaemia (including nontyphoidal 
Salmonella) 
• Invasive cervical carcinoma 
• Atypical disseminated leishmaniasis 
WHO Stage 4 Conditionsc for Participants  
Less than 15 Years of Age 
• Unexplained severe wasting, stunting or severe 
malnutritiond not responding to standard therapy 
• Pneumocystis (jirovecii) pneumonia 
• Recurrent severe bacterial infections (such as 
empyema, pyomyositis, bone or joint infection, 
• meningitis, but excluding pneumonia) 
• Chronic herpes simplex infection (orolabial or 
cutaneous of more than 1 month’s duration or 
• visceral at any site) 
• Oesophageal candidiasis (or candidiasis of trachea, 
bronchi or lungs) 
• Extrapulmonary tuberculosis 
• Kaposi sarcoma 
• Cytomegalovirus infection (retinitis or infection of 
other organs with onset at age more than 1 month) 
• Central nervous system toxoplasmosis (after the 
neonatal period) 
• HIV encephalopathy 
• Extrapulmonary cryptococcosis, including meningitis 
• Disseminated nontuberculous mycobacterial infection 
• Progressive multifocal leukoencephalopathy  
• Chronic cryptosporidiosis (with diarrhoea) 
• Chronic isosporiasis 
• Disseminated endemic mycosis (extrapulmonary 
histoplasmosis, coccidioidomycosis, penicilliosis) 

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Other Medical Conditions of Interest 
• Asthma 
• Hepatitis (includes viral hepatitis as well as clinical hepatitis) 
• Congenital cytomegalovirus 
• Measles 
• Chickenpox 
• Insulin resistance 
• Diabetes 
• Lipodystrophy 
• Lipoatrophy 
• Hyperlipidemia 
• Other metabolic syndrome 
• Anemia 
• Leukopenia 
• Thrombocytopenia  
• Decreased bone mineral density 
• Bone fracture 
• Allergy or hypersensitivity to medication (specify medication; at follow-up visits, also specify type of 
reaction) 
• Autoimmune disorder 
• Malignancy 
Source: Adapted from Annex 1, WHO clinical staging of HIV disease in adults, adolescents and children, of the 
Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, recommendations for 
a public health approach; World Health Organization; June 2013. 
 
b For children younger than 5 years, moderate malnutrition is defined as weight-for-height <–2 z-score or mid-upper arm 
circumference ≥115 mm to <125 mm. 
c Some additional specific conditions can be included in regional classifications, such as penicilliosis in Asia, HIV-
associated rectovaginal fistula in southern Africa and reactivation of trypanosomiasis in Latin America. 
d For children younger than 5 years of age, severe wasting is defined as weight-for-height <–3 z-score; stunting is defined 
as length-for-age/height-for-age <–2 z-score; and severe acute malnutrition is defined as either weight for height <–3 z-
score or mid-upper arm circumference <115 mm or the presence of oedema. 
 

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Appendix III: Sample Informed Consent Form for Study Participation 
 
IMPAACT 2028 
Long-Term Clinical, Immunologic, and Virologic Profiles of  
Children who Received Early Treatment for HIV 
 
Version 1.0, 23 December 2020 
 
Introduction 
 
This form is for the parent or guardian of a child who is being asked to participate in the research study 
named above.  
 
Participants in this study may be young babies, older children, or adolescents. In this form, participants 
are referred to as “children” regardless of their age. For most participants, it is expected that a parent or 
guardian will provide informed consent for participation in the study. This form refers to “your child” 
with the expectation that parents and guardians will be reading the form. However, some adolescents may 
qualify to provide informed consent for themselves. For these adolescents, when reading this form, “your 
child” refers to the adolescent who is providing informed consent.  
 
This form gives information about the study. Please read it or have it read to you. Ask any questions you 
may have. We will take as much time as needed for you to fully understand the study. We will ask you 
questions to see if we have explained the study clearly. 
 
Here is a summary of important information about the study: 
 
• 
The study is to learn more about children who started treatment for HIV soon after birth. 
• 
Children will be in the study for up to 7 years. During this time, children will have clinic visits every 
6 months (2 times per year). Clinic visits will include physical examinations and blood collection for 
tests.  
• 
There are possible risks for children in the study. However, these risks are minimal.  
• 
There may be no benefits for children in the study. However, information learned in this study may 
benefit other children with HIV in the future. 
• 
Your decision on your child’s participation in the study will have no effect on the medical care your 
child receives. Your child’s access to services, and the benefits and rights he or she normally has, will 
not be affected.  
 
More information about the study is given in this form. You should feel that you understand the study 
before deciding whether your child will participate. If you decide that your child will participate, you will 
be asked to sign or make your mark on this form. You will be offered a copy to keep. 
 
About the study 
 
The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) and <<site 
name>> are doing this study. The person in charge of the study at <<site name>> is <<Investigator of 
Record name>>. 
 
The study is for children who have been in other studies of treatment for HIV started within 12 weeks of 
birth. The study will include up to 250 children from many countries, including Brazil, Botswana, Haiti, 
Malawi, South Africa, Thailand, Uganda, Zimbabwe, and the United States.  

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The United States National Institutes of Health is paying for the study. 
 
1. The study is to learn more about children who started treatment for HIV soon after birth. 
 
Many studies are being done to learn about treatments for children with HIV. Starting treatment early (as 
soon as possible after birth) can help children stay healthy. Starting treatment early may also help control 
the amount of HIV in a child’s body.  
 
There is still much to be learned about treatment for children with HIV. For example, how well do 
children who started treatment early grow? What health problems do they have or not have as they get 
older?  
 
There is also much to be learned about how the immune system works in children who started treatment 
early. The immune system is the part of the body that fights infections. HIV attacks the immune system. 
Learning more about the immune system may help researchers understand what is needed for better 
treatments for children with HIV.  
 
2. Only children who qualify can participate in the study. 
 
If you decide to have your child join this study, we will first check whether your child qualifies. More 
information about this is given in #4. If your child qualifies, he or she will be entered in the study. If your 
child does not qualify, he or she cannot be entered in the study. 
 
3. It is your decision whether to have your child participate in the study. 
 
Deciding to have your child to join the study is voluntary (your choice). You are free to have your child 
join or not join. If you decide to have your child join, you can change your mind and take your child off 
the study. Your decisions will have no effect on the medical care your child receives. Your child’s access 
to services, and the benefits and rights he or she normally has, will not be affected.  
 
Take your time and consider your decision carefully. If you wish, you can talk to other people about the 
study before you decide. You can bring other people here to learn about the study with you. 
 
Finding out if your child qualifies 
 
4. We will review your child’s records, ask questions, and examine your child. 
 
To find out if your child qualifies, we will: 
 
• 
Review your child’s records. This includes records from the study your child was in before this one. It 
also includes other medical records such as from the clinic where your child receives treatment for 
HIV. In order for your child to be in this study, you will need to give us permission to review these 
records. If information needed for this study is available in your child’s records, we will record that 
information.  
• 
Ask questions about your child’s health and medications.  
• 
Give your child a physical examination.  
• 
Talk with you about the study requirements and if your child will be able to meet the requirements. 
 
These procedures will take about 2 hours. After the procedures are done, we will tell you if your child 
qualifies for the study.  

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Entering the study 
 
5. If your child qualifies, he or she will enter the study. 
 
If your child qualifies for the study, we will collect additional information from your child’s records.  
 
<<Sites may remove assessment of gender identity if there are any significant concerns about participant 
safety or may insert locally appropriate language as needed>> If your child is 12 years of age or older, 
we will ask your child about gender identity. Gender identity is the internal sense people have of whether 
they are male, female, or something in between. A person’s gender identity may be different from their 
sex at birth. We will ask your child about gender identity in private, without you being present.  
 
We will also draw your child’s blood for tests. About 13 mL or 3 teaspoons will be drawn for tests of: 
 
• 
Your child’s CD4 and CD8 cells. These cells are part of the immune system. They help fight HIV and 
other infections. The number of CD4 and CD8 cells should go up and stay up when your child is 
taking anti-HIV medicines (ARVs). 
• 
The amount of HIV in your child’s blood. This is called your child’s “viral load.” The viral load 
should go down and stay down when your child is taking ARVs. 
• 
The amount of HIV in your child’s cells. Researchers have learned that HIV can hide inside cells in 
the body. The cells that HIV can hide in are inactive. However, these cells can later become active. 
When these cells become active, the HIV inside the cells also becomes active and starts making more 
copies of itself. The inactive cells that HIV hides in are called the “reservoir.” Little is known about 
the reservoir in children. Tests done in this study will help researchers learn more about this. 
• 
Whether your child has antibodies to HIV. Antibodies are substances made by the immune system to 
help fight infection. Researchers have learned that antibodies may help control the amount of HIV in 
the body. However, little is known about the effects of antibodies in children. Tests done in this study 
will help researchers learn more about this.  
 
We may also do tests for resistance to ARVs. If your child has resistance, some ARVs may not work well 
against the HIV in his or her body. As a result, your child’s viral load may go up. If we think your child 
may have resistance to ARVs, we will test for this.  
 
We would also like to draw blood from your child to be stored for future tests. If you agree to this, the 
amount drawn will depend on your child’s weight. Less blood is drawn while children are younger and 
smaller. More blood is drawn as children get older and bigger. The amount drawn will be between 8 mL 
(less than 2 teaspoons) and 20 mL (about 4 teaspoons). More information on blood stored for future tests 
is given in #8. 
 
During the study 
 
6. Your child will have clinic visits every 6 months.  
 
Your child will have visits here every 6 months (2 times per year) while in the study. The study is 
expected to go on for 7 years. Depending on when your child joins the study, he or she may have up to 14 
visits.  
 
Each visit will take about 2 hours. At these visits we will:  
 

IMPAACT 2028, FINAL Version 1.0 
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• 
Review your child’s records. If information needed for this study is available in your child’s records, 
we will record that information. 
• 
Ask questions about your child’s health and medicines. If your child becomes pregnant, this will 
include asking questions about the pregnancy.  
• 
Ask questions about any new studies your child has joined. 
• 
<<Sites may remove assessment of gender identity if there are any significant concerns about 
participant safety or may insert locally appropriate language as needed>> If your child reaches 12 
years of age while in the study, we will ask your child about gender identity. This will be done in 
private, without you being present.  
• 
Give your child a physical examination.  
• 
Draw your child’s blood for tests. About 8 mL or 2 teaspoons will be drawn to for tests of: 
– Your child’s CD4 and CD8 cells. 
– Your child’s viral load. 
– The amount of HIV in your child’s cells 
– Whether your child has antibodies to HIV 
If we think your child may have resistance to ARVs, we will also test for this.  
 
If you agree, we will also collect blood (up to 20 mL or about 4 teaspoons) for future tests. More 
information on blood stored for future tests is given in #8. 
 
7. Other types of samples will be collected. 
 
We would like to collect a sample from your child’s nose and a sample from your child’s rectum to be 
stored for future tests. These samples are collected with a swab. One swab is inserted in the nose. Another 
swab is inserted in the rectum. Each swab is inserted for about 5-10 seconds. If you agree, these samples 
will be collected only once, after your child has reached 3 years of age.  
 
These samples will be used for tests of the bacteria living in your child’s body. All people have bacteria 
living on their skin and in the mouth, nose, and gut. These bacteria can have helpful effects. For example, 
they help with digesting food. They may affect body weight, functioning of the brain, and mood. 
Researchers have learned that these bacteria may also affect the immune system. However, little is known 
about this in children. Researchers would especially like to learn more about whether changes in these 
bacteria make it more or less likely for children with HIV to have certain illnesses. Tests done in this 
study will help researchers learn more about this.  
 
More information on samples stored for future tests is given in #8. 
 
8. Different tests will be done at different laboratories at different times. 
 
Testing During the Study 
We will do tests of your child’s viral load and CD4 and CD8 counts here at our laboratory. Tests for 
resistance to ARVs may be done here or at laboratories in other locations. We will give you the results of 
these tests and explain the results to you. We will also give the results to your child’s medical care 
providers. This study cannot provide ARVs or medical care to your child. However, if test results show 
that your child may need different ARVs or other medical care, we will tell you where you can go for this 
care. 
 
Tests of HIV in cells and of antibodies to HIV will be done at laboratories in the United States or South 
Africa. These tests are for research purposes only. The results are not expected to give information 
relevant to your child’s health. Therefore, the results will not be given to you.  

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Future Testing 
Permission for different types of sample collection and future testing is requested at the end of this form. 
 
<<Sites insert one of the following two paragraph options. Non-US sites should select the option that 
applies based on whether local regulations do or do not permit specimen storage for future research in 
the US; if local regulations do not permit specimen storage for future research, this section of the form 
should be deleted.>> 
 
If you agree to have samples collected for future testing, the samples will be collected during your child’s 
visits and kept in a repository. A repository is a secure facility used to store samples. The IMPAACT 
Network repository is in the United States. If you agree to have your child’s extra samples stored, the 
samples will be kept in this repository. There is no limit on how long the samples will be kept. <<Sites 
may modify the preceding sentence to specify time limits or additional site-specific requirements if 
required by local authorities.>> 
 
If you agree to have samples collected for future testing, the samples will be collected during your child’s 
visits and kept in a repository. A repository is a secure facility used to store samples. The IMPAACT 
Network repository is in the United States. However, our regulations require that samples be stored in our 
country. Therefore, if you agree to have your child’s specimens stored, they will be kept here at our 
laboratory. There is no limit on how long the samples will be kept. <<Sites may modify the preceding 
sentence to specify time limits or additional site-specific requirements if required by local authorities.>> 
 
The samples may be used for future testing related to HIV or other diseases. Because children in this 
study started treatment for HIV early, testing of these samples may help researchers learn more about 
treatment for HIV and control of HIV in the body. The testing may be done in laboratories in the United 
States or in other countries. 
 
The samples may also be used for tests of your child’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 child’s samples may be tested for 
specific genes, such as genes related to HIV. Samples may also be tested for genes related to other 
diseases. Testing of all your child’s genes, which is sometimes called whole genome sequencing, may 
also be done. 
 
Future testing may not give information that is directly relevant to your child’s health. For this reason, the 
results of future tests may not be given to you. If any results that are relevant to your child’s health 
become available while your child is in the study, those results will be given to you. Results that become 
available after your child is no longer in the study are not expected to be given to you.  
 
9. We may take your child off the study. 
 
Children are expected to stay in the study for up to 7 years. However, we may take your child off the 
study early if: 
 
• 
The study is stopped for any reason. 
• 
We determine that your child cannot meet the study requirements. 
• 
We determine that staying in the study might harm your child. 
 

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10. Please tell us if you want your child to leave the study. 
 
You are free to take your child off the study at any time for any reason. You are also free to change your 
mind about collection and future testing of your child’s samples. The medical care your child receives 
will not be affected by your decisions, but it is important that we know your decisions. We will record 
your decisions and ensure they are followed. 
 
If your child leaves the study early, we will ask your child to complete one last visit. At this visit, we will 
perform the same procedures described in #6. We will answer any questions you may have and tell you 
how to contact us in the future, if you wish.  
 
If your child leaves the study early, we will still use the information and samples already collected from 
your child. However, if you do not agree to this, you can tell us and your decisions will be followed. 
 
Risks of the study 
 
11. There is little risk from the study procedures. 
 
Most procedures done in this study are routine medical procedures, with little risk to your child. Drawing 
blood can cause fainting, pain, swelling, bruising, or bleeding where the needle is inserted. Rarely, 
drawing blood can cause fainting or infection. Collection of samples from your child’s nose and rectum 
can cause discomfort. Your child may feel nervous or embarrassed when answering questions for the 
study.  
 
12. There may be risks of disclosure of your child’s information. 
 
We will make every effort to keep your child’s information private and confidential. Study records and 
samples will be kept in secure locations. All samples and most records will be labeled only with a code 
number. However, your and your child’s name will be written on some records.  
 
<<US sites insert this paragraph>> Your child’s privacy may also be protected by a Certificate of 
Confidentiality that helps us avoid being forced to release information that may identify your child, such 
as by the courts or police. The certificate cannot be used in all situations, but it can be used to resist 
demands for information that would identify your child. The certificate does not protect against requests 
for information from the United States federal government. Regardless of the certificate, you can release 
information about your child’s participation in the study to others, if you wish. 
 
The information we collect about your child for this study will be combined with information collected 
from all other children in the study. This will be done at an organization called a statistical and data 
management center. The IMPAACT Network statistical and data management center is in the United 
States. We will send your child’s information to this center. The information will be sent securely, 
following applicable laws and policies. Your child’s name and other information that could personally 
identify your child will not be sent.  
 
Information and samples collected for this study may be used for other research in the future. Any such 
research must be approved by the IMPAACT Network. Information and samples used for approved 
research will be labeled with a code number only. The only link between the code number and your 
child’s name will be kept here at this clinic. Your child’s name and other information that could 
personally identify your child will not be given to other researchers.  
 

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Despite our best efforts to keep your child’s information private, it is possible that your child’s 
information could be obtained by someone who should not have it. If this were to happen, your child 
could be treated badly or unfairly.  
 
Benefits of the study 
 
13. There may be no benefit from being in the study. 
 
By joining the study, your child will be part of research for children with HIV. Being in this study is not 
expected to benefit your child directly. However, information learned may benefit other children with 
HIV in the future.  
 
Your child will have regular visits here, with physical examinations and laboratory tests. This study 
cannot provide medical care to your child. However, if study procedures show that your child may need 
medical care, we will tell you where you can go for the care your child needs. This may help your child 
stay healthy. 
 
Other information about the study 
 
14. There are no costs to you for your child being in the study. 
 
There are no costs to you or your child for study visits or procedures.  
 
If you agree to have blood, nose, and rectal samples collected for future research, there is no cost to you 
or your child for this. The samples will not be sold, and you will not be paid for 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 child.  
 
<<Sites insert information about compensation/reimbursement, for example>> You will be reimbursed 
for the cost of transport to study visits. For each visit, you will be given [specify amount].>> 
 
15. Your child’s records may be reviewed by study staff and groups that oversee the study. 
 
Groups that oversee the study include: 
 
• 
<<US sites insert single IRB>>  
• 
<<All sites insert applicable local IRBs/ECs>> 
• 
<<All sites insert other applicable regulatory entities>> 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Office for Human Research Protections 
• 
Other United States, local, and international regulatory entities 
• 
The IMPAACT Network that is coordinating the study 
 
Like the study staff, these groups are required to make efforts 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 child’s name or identify your child personally. The same is true for research done in the 
future with stored samples.  
 

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A description of this study will be available on ClinicalTrials.gov. This website will not include 
information that can identify your child. At most, the website will include a summary of the results. You 
can search this website at any time. 
 
Your child’s study information may be disclosed to other authorities if required by law. <<Sites may add 
other applicable local reporting requirements in this section.>>  
 
16. If your child gets sick or injured, please contact us.  
  
Your child’s health is important to us. If your child gets sick or injured, contact us immediately. We will 
make every effort to protect your child’s well-being and minimize risks. It is possible, however, that your 
child could have an illness or injury that is study-related. This means that 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 your child or tell you where you can get the treatment your 
child needs. 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 
 
If you have questions, concerns, or problems at any time, use these contacts. 
 
• 
If you have questions about the study:  
<<Name, phone number, and other relevant contact details of investigator or other study staff>> 
 
• 
If you have questions about future use of blood, nose, or rectal samples: 
<<Name, phone number, and other relevant contact details of investigator or other study staff>> 
 
• 
If you have questions about your child’s rights as a study participant, or problems or concerns about 
how your child is being treated in the study:  
<<Name, phone number, and other relevant contact details of IRB/EC contact person or other 
appropriate person or organization>> 
 
• 
If your child has any health or other problems that may be related to study participation: 
<<Name, phone number, and other relevant contact details of investigator or other study staff>> 
 
• 
If you want your child to leave the study: 
<<Name, phone number, and other relevant contact details of investigator or other study staff>> 
 
Signatures 
 
If you decide to have your child join this study, please sign or make your mark below. 
 
Before deciding whether to have your child join this study, make sure you have read this form or had it 
read to you. Make sure all 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 child. 

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We will tell you any new information from this study or other studies that may affect your willingness to 
keep your child in the study. You are welcome to ask questions or request more information at any time.  
 
You do not give up any rights by signing this form. 
 
<<Sites insert initial and signature blocks as required by IRB/EC and institutional policies. Separate 
consent decisions must be documented for genetic testing of stored samples.>> 
 
For participation in the study (all three should be initialed/marked for participants to be enrolled) 
 
 
__________ 
I agree to have my child join this study.  
 
 
__________ 
I agree that my child’s previous study records may be reviewed and that information from 
these records can be recorded for this study.  
 
 
__________ 
I agree that my child’s medical records may be reviewed and that information from these 
records can be recorded for this study.  
 
For collection of blood samples for future research (one of the three choices should be initialed/ 
marked) 
 
 
__________ 
I allow blood to be collected from my child for future research. I also allow my child’s 
blood to be used for tests of his or her genes. 
 
__________ 
I allow blood to be collected from my child for future research. I do not allow my child’s 
blood to be used for tests of his or her genes. 
 
__________ 
I do not allow blood to be collected from my child for future research. 
 
 
For collection of nose samples for future research (one of the two choices should be initialed/marked) 
 
 
__________ 
I allow a sample to be collected from my child’s nose for future research.  
 
__________ 
I do not allow a sample to be collected from my child’s nose for future research. 
 
 
For collection of rectal samples for future research (one of the two choices should be initialed/marked) 
 
 
__________ 
I allow a sample to be collected from my child’s rectum for future research.  
 
__________ 
I do not allow a sample to be collected from my child’s rectum for future research. 
 
 
 

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Name of Participant  
 
 
Participant Signature 
  
 
Date 
(print)  
 
 
 
(only for those who reach the legal age or circumstance to provide  
independent consent) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Parent or Guardian 
 
Parent or Guardian Signature 
  
Date 
(print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Witness Signature 
 
 
Date 
(if applicable, print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Staff Conducting  
 
Study Staff Signature 
 
 
Date 
Consent Process Name (print) 
 
 
 
 

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Appendix IV: Sample Assent Form for Study Participation 
 
IMPAACT 2028 
Long-Term Clinical, Immunologic, and Virologic Profiles of  
Children who Received Early Treatment for HIV 
 
Version 1.0, 23 December 2020 
 
<<The amount of information and level of detail provided in site-specific assent forms should be tailored 
to the age and maturity of study participants, guided by applicable IRB/EC policies and procedures. Sites 
may develop multiple assent forms, if desired, in anticipation of different information needs across the 
study age range. When preparing site-specific assent forms, the wording included in this sample form 
may be modified, added to, or removed in order to provide the most appropriate information and level of 
detail for participants, consistent with IRB/EC policies and procedures. This may include preparing site-
specific form versions that do not disclose HIV status.>> 
 
Introduction 
 
You are being asked to take part in a research study. For you to take part, you must give your permission. 
Your parent or guardian must also give permission.  
 
This form gives information about the study. Please read it or have it read to you. Ask any questions you 
may have. After we talk about the study, you will record your decisions at the end of this form. You will 
be offered a copy to keep. 
 
Your rights  
 
It is up to you and your parent or guardian to decide if you will take part in the study. You can say yes or 
no. If you say yes now, you can change your mind later. Your decision will have no effect on your 
medical care. 
 
About the study 
 
The study is to learn about children who started taking medicines for HIV soon after being born. Studies 
of these medicines have been done in the past, but there is still more to learn. For example, we would like 
to learn more about how well children who take these medicines grow. We would also like to learn about 
health problems children may have as they get older. 
 
What happens in the study 
 
We will first ask some questions, review your records, and examine you (check your body) to see if you 
qualify for the study.  
 
If you qualify, you will enter the study and have visits here every 6 months for up to 7 years. The visits 
will take about 2 hours. We will ask questions about your health and the medicines you take. We will 
examine you and see how much you have grown. We will draw blood for tests. This will be done with a 
needle in your arm.  
 

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We would also like to take sample from your nose and a sample from your rectum for tests. If you agree, 
we will take the samples with a cotton swab that is placed in the nose or rectum for 5-10 seconds. If you 
do not agree, these samples will not be taken. 
 
Some tests will check on your health. These will be done right away after each visit. We will tell you and 
your parent or guardian the results of these tests. Other tests will be done in the future. These tests are not 
expected to give information that is important for your health. The results will not be given to you or your 
parent or guardian. 
 
We will tell you as much information as you want about the study. Please ask any questions you may 
have. Please tell us if anything bothers you or scares you. We will do our best to explain the study and 
help you feel more comfortable.  
 
What good and bad effects could happen  
 
By taking part in the study, you will be helping to learn more about medicines for children with HIV. This 
may not have any benefits (good effects) for you. However, information learned in the study may have 
good effects for other children with HIV in the future.  
 
Having your blood drawn may hurt. This may also cause fainting, bleeding, bruising, swelling, or 
infection where the needle goes in your arm. Having samples collected from your nose or rectum may 
hurt. You may feel nervous or embarrassed when answering questions for the study. 
 
There could be other bad effects. For example, other people could find out that you are in the study or 
learn other information about you. We will do all we can to keep this from happening. For example, most 
of the records we keep here for the study will be labeled with a code number (not your name). We will 
share information about you, including information that you tell us, with your parent or guardian. We will 
not share your information with other people unless you or your parent or guardian ask us to.  
 
Who to contact 
 
You and your parent or guardian can contact us at any time. Please talk to your parent or guardian and to 
us about any questions or problems you may have.  
 
• 
If you have questions about the study:  
<<Name, phone number, and other relevant contact details of investigator or other study staff>> 
 
• 
If you have problems related to being in the study: 
<<Name, phone number, and other relevant contact details of investigator or other study staff>> 
 
• 
If you have questions about your rights or how you are treated in the study:  
<<Name, phone number, and other relevant contact details of IRB/EC contact person or other 
appropriate person or organization>> 
 
• 
If you want to leave the study: 
<<Name, phone number, and other relevant contact details of investigator or other study staff>> 
 
 
 

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Signatures 
 
Before deciding whether to take part in the study, make sure you have read this form or had it read to you. 
Make sure all your questions have been answered. 
 
<<Sites insert initial and signature blocks as required by IRB/EC and institutional policies.>> 
 
Please write your initials or make your mark next to your choices.  
 
 
__________ 
I agree to take part in the study.  
 
 
__________ 
I do not agree to take part in the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Participant (print) 
 
Signature of Participant   
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Study Staff Conducting 
Signature of Study Staff  
 
Date 
Assent Process Name (print) 
 
 

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Appendix V: Sample Informed Consent Form for Maternal Data Collection 
 
IMPAACT 2028 
Long-Term Clinical, Immunologic, and Virologic Profiles of  
Children who Received Early Treatment for HIV 
 
Version 1.0, 23 December 2020 
 
Introduction 
 
Your child is taking part in the research study named above. The study is to learn more about children 
who started treatment for HIV soon after birth. You are being asked for permission to collect information 
about you to be combined with information about your child for the study. You are not being asked to 
join the study. 
 
Here is a summary of important information: 
 
• 
If you agree, information about you will be collected for the study by asking you questions and 
reviewing your medical records.  
• 
There is little risk to you from having information collected for the study. 
• 
There may be no benefit to you from having information collected for this study. 
• 
Your decision on having your information collected will have no effect on your child’s participation 
in the study. Your decision will have no effect on the medical care you or your child receive. Your 
and your child’s access to services, and the benefits and rights you normally have, will not be 
affected. 
 
More information is given in the rest of this form. Please read it or have it read to you. Ask any questions 
you may have. We will take as much time as needed for you to fully understand the information. We will 
ask you questions to see if we have explained the information clearly. 
 
If you decide to have information about you collected for the study, you will be asked to sign or make 
your mark on this form. You will be offered a copy to keep. 
 
About the study  
 
The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) and <<site 
name>> are doing this study. The person in charge of the study at <<site name>> is <<Investigator of 
Record name>>. The United States National Institutes of Health is paying for the study. 
 
The study will include up to 250 children from many countries, including Brazil, Botswana, Haiti, 
Malawi, South Africa, Thailand, Uganda, Zimbabwe, and the United States. 
 
To learn more about children who started treatment for HIV soon after birth, we would like to collect 
some information about the biological mothers of children taking part in this study. If you agree, we will 
ask you questions and review your medical records to collect information on: 
 
• 
The anti-HIV medications (ARVs) you took while pregnant and breastfeeding (if you breastfed) 
• 
The amount of HIV in your blood when you gave birth and while breastfeeding (if you breastfed) 
• 
Your CD4+ cell count when you gave birth 
 

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Deciding to have your information collected for the study is voluntary (your choice). You are free to say 
yes or no. If you say yes now, you can change your mind later. Your decisions will have no effect on your 
child’s participation in the study. Your decisions will have no effect on the medical care you or your child 
receive. Your and your child’s access to services, and the benefits and rights you normally have, will not 
be affected.  
 
Possible benefits  
 
There may be no benefit to you from having information collected for this study. By having your 
information collected, you will be part of research for children with HIV. Although this is not expected to 
benefit you directly, information learned in the study may benefit children with HIV in the future.  
 
Possible risks 
 
There is little risk to you from having information collected for the study. We will make every effort to 
keep your information private and confidential. Study records will be kept in secure locations. Most 
records will be labeled only with a code number. However, your name will be written on some records.  
 
<<US sites insert this paragraph>> Your privacy may also be protected by a Certificate of 
Confidentiality that helps us avoid being forced to release information that may identify you, such as by 
the courts or police. The certificate cannot be used in all situations, but it can be used to resist demands 
for information that would identify you. The certificate does not protect against requests for information 
from the United States federal government. Regardless of the certificate, you can release your information 
to others, if you wish. 
 
The information we collect about you for the study will be combined with information collected about all 
other children in the study, and their mothers. This will be done at an organization called a statistical and 
data management center. The IMPAACT Network statistical and data management center is in the United 
States. We will send your information to this center. The information will be sent securely, following 
applicable laws and policies. Your name and other information that could personally identify you will not 
be sent.  
 
Information collected for this study may be used for other research in the future. Any such research must 
be approved by the IMPAACT Network. Information used for approved research will be labeled with a 
code number only. The only link between the code number and your name will be kept here at this clinic. 
Your name will not be given to other researchers.  
 
Despite our best efforts to keep your information private, it is possible that your information could be 
obtained by someone who should not have it. If this were to happen, you could be treated badly or 
unfairly.  
 
Costs to you 
 
There are no costs to you for having your information collected for the study.  
 
<<Sites insert information about compensation/reimbursement, for example>> You will be reimbursed 
for the cost of transport to study visits. For each visit, you will be given [specify amount].>> 
 

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Review of study records 
 
The records that contain the information collected from you for the study may be reviewed by study staff 
and groups that oversee the study. Groups that oversee the study include: 
 
• 
<<US sites insert single IRB>>  
• 
<<All sites insert applicable local IRBs/ECs>> 
• 
<<All sites insert other applicable regulatory entities>> 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Office for Human Research Protections 
• 
Other United States, local, and international regulatory entities 
• 
The IMPAACT Network that is coordinating the study 
 
Like the study staff, these groups are required to make efforts 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 identify you personally.  
 
A description of this study will be available on ClinicalTrials.gov. This website will not include 
information that can identify you. At most, the website will include a summary of the results. You can 
search this website at any time. 
 
Your information may be disclosed to other authorities if required by law. <<Sites may add other 
applicable local reporting requirements in this section.>>  
 
Who to contact 
 
• 
If you have questions about the study or the information collected from you for the study, contact:  
<<Name, phone number, and other relevant contact details of investigator or other study staff>> 
 
• 
If you change your mind about having information collected for the study, contact:  
<<Name, phone number, and other relevant contact details of investigator or other study staff>> 
 
• 
If you have questions about your rights or problems or concerns about how your information is being 
used in the study:  
<<Name, phone number, and other relevant contact details of IRB/EC contact person or other 
appropriate person or organization>> 
 
Signatures 
 
If you decide to have your information collected for the study, please sign or make your mark below. 
 
Before deciding whether to have your information collected, make sure you have read this form or had it 
read to you. Make sure all your questions have been answered.  
 
We will tell you any new information from this study or other studies that may affect your willingness to 
have your information used for the study. You are welcome to ask questions or request more information 
at any time.  
 

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You do not give up any rights by signing this form. 
 
<<Sites insert signature blocks as required by IRB/EC and institutional policies.>> 
 
 
 
 
 
 
 
 
Name of Child  
Participating in Study (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Mother (print)  
 
Mother Signature 
  
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Witness Signature 
 
 
Date 
(if applicable, print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name Study Staff Conducting  
Study Staff Signature 
 
 
Date 
Consent Process  
With Mother (print) 
 
 
 

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Appendix VI: Operational 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 2028 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 
• 
Sites are advised to make use of the allowable visit windows specified in Section 5 when scheduling 
study visits during periods of operational disruption. For example, sites that are able to anticipate 
operational disruptions are advised to conduct study visits early in the allowable visit window before 
the disruption occurs. Visits conducted outside of allowable windows are also preferred to missed 
visits. In the event of a missed visit (i.e., visit not conducted before the allowable window closes) or 
in situations that may result in conducting more than one visit within a given window, the Protocol 
Team should be contacted for guidance on visit completion on a case-by-case basis. 
 
Prioritization of Study Visit Procedures 
• 
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 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 clinical events or social impacts that may occur 
during the visits. If clinical 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.  
• 
Sites with limited capacity to conduct in-person visits should refer to the prioritization provided in 
Section 5.8.1. HIV-1 RNA and CD4+ and CD8+ assays are of highest priority. If these assays cannot 
be performed consistent with a site’s Protocol Analyte List, the tests may be performed in alternate 
laboratories using alternate assays (alternate laboratories must adhere to local regulations for clinical 
laboratory testing). Specimens should also be collected for storage whenever possible, assuming 
laboratory staff and facilities are available to process and store specimens consistent with the 
Laboratory Processing Chart. When necessary, medical and medication histories as well as feeding 
histories can be obtained from participants or caregivers remotely. Written records that supplement 
participant and caregiver report may be collected at a later date (when it is feasible to do so). 
 

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Documentation 
• 
Site-specific contingency plans, and the implementation thereof, should be documented in essential 
document files for IMPAACT 2028. 
• 
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 
• 
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.