Observational Cohort to Assess Therapeutic Efficacy and Emergence of HIV Drug Resistance Following Initiation of Tenofovir-Lamivudine-Dolutegravir (TLD) for First- or Second-Line ART or With Rifampin-Containing TB Treatment: The Hakim Study
Conditions: HIV-1-infection
Sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections

 
 
A5381 
 
Observational Cohort to Assess Therapeutic Efficacy and 
Emergence of HIV Drug Resistance Following Initiation of 
Tenofovir-Lamivudine-Dolutegravir (TLD) for First- or 
Second-Line ART or with Rifampicin-Containing TB 
Treatment: 
The Hakim Study 
 
 
A Limited-Center Study of the AIDS Clinical Trials Group 
(ACTG) 
 
 
NIAID CRMS # 38564 
 
 
 
This file contains the current ACTG A5381 protocol, which 
includes the following document:  
 
• Protocol Version 2.0, dated 5 Mar 2021  
 

 
A5381 
 
 
Observational Cohort to Assess Therapeutic Efficacy and Emergence of HIV Drug 
Resistance Following Initiation of Tenofovir-Lamivudine-Dolutegravir (TLD) for 
First- or Second-Line ART or with Rifampicin-Containing TB Treatment:  
The Hakim Study 
 
 
A Limited-Center Study of the AIDS Clinical Trials Group (ACTG) 
 
 
 
 
 
 
 
 
Sponsored by: 
 
National Institute of Allergy 
and Infectious Diseases 
 
In Collaboration with:  
United States President’s Emergency Plan for AIDS Relief (PEPFAR) 
 
Non-IND Protocol 
 
 
 
The Antiretroviral Therapy Strategies  
Transformative Science Group:  
 
 
Charles Flexner, MD, Chair 
 
 
Protocol Chair: 
 
 
 
 
Cissy Kityo, MBChB, MSc, PhD  
 
DAIDS Clinical Representative: 
 
 
Lawrence Fox, MD, PhD 
 
Clinical Trials Specialist: 
 
 
 
Elizabeth Woolley, MPH 
 
 
 
 
FINAL Version 2.0 
March 05, 2021

 
 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
Observational Cohort to Assess Therapeutic Efficacy and Emergence of HIV Drug Resistance 
Following Initiation of Tenofovir-Lamivudine-Dolutegravir (TLD) for First- or Second-Line ART or 
with Rifampicin-Containing TB Treatment: The Hakim Study 
 
SIGNATURE PAGE 
 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable US Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
 
 
 
 
 
Principal Investigator: _______________________________________________ 
Print/Type 
 
 
 
 
 
Signed: ___________________________________ Date: _____________ 
 Name/Title 
 
 
 

A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
 
TABLE OF CONTENTS 
Page 
SIGNATURE PAGE .................................................................................................................... 2 
SITES PARTICIPATING IN THE STUDY .................................................................................... 5 
PROTOCOL TEAM ROSTER ..................................................................................................... 6 
STUDY MANAGEMENT ........................................................................................................... 11 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ..................................................................... 13 
SCHEMA .................................................................................................................................. 14 
1.0 
HYPOTHESES AND STUDY OBJECTIVES.................................................................. 16 
1.1 
Hypotheses ........................................................................................................ 16 
1.2 
Primary Objectives ............................................................................................. 16 
1.3 
Secondary Objectives ........................................................................................ 17 
1.4 
Exploratory Objectives ....................................................................................... 17 
2.0 
INTRODUCTION ........................................................................................................... 18 
2.1 
Background ........................................................................................................ 18 
2.2 
Rationale ........................................................................................................... 20 
3.0 
STUDY DESIGN ........................................................................................................... 23 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................ 25 
4.1 
Inclusion Criteria ................................................................................................ 25 
4.2 
Exclusion Criteria ............................................................................................... 27 
4.3 
Study Enrollment Procedures............................................................................. 27 
4.4 
Co-enrollment Guidelines ................................................................................... 28 
5.0 
STUDY TREATMENT ................................................................................................... 29 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................... 30 
6.1 
Schedule of Evaluations (SOE) .......................................................................... 30 
6.2 
Timing of Evaluations ......................................................................................... 33 
6.3 
Instructions for Evaluations ................................................................................ 35 
7.0 
ADVERSE EVENTS AND STUDY MONITORING ......................................................... 42 
7.1 
Adverse Event Collection Requirements for this protocol ................................... 42 
7.2 
Study Monitoring ................................................................................................ 42 
8.0 
CLINICAL MANAGEMENT ISSUES .............................................................................. 43 
8.1 
Toxicity .............................................................................................................. 43 
8.2 
Pregnancy.......................................................................................................... 43 
8.3 
Breastfeeding ..................................................................................................... 43 

A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
CONTENTS (Cont’d) 
Page 
 
9.0 
CRITERIA FOR DISCONTINUATION ........................................................................... 43 
9.1 
Permanent and Premature Treatment Discontinuation ....................................... 43 
9.2 
Premature Study Discontinuation ....................................................................... 43 
10.0 
STATISTICAL CONSIDERATIONS ............................................................................... 44 
10.1 
General Design Issues ....................................................................................... 44 
10.2 
Outcome Measures ............................................................................................ 44 
10.3 
Randomization and Stratification ........................................................................ 47 
10.4 
Sample Size and Accrual ................................................................................... 47 
10.5 
Data and Safety Monitoring ................................................................................ 50 
10.6 
Analyses ............................................................................................................ 52 
11.0 
PHARMACOLOGY PLAN .............................................................................................. 54 
11.1 
Pharmacology Objectives .................................................................................. 54 
11.2 
Pharmacology Study Design .............................................................................. 54 
11.3 
Primary and Secondary Data, Modeling, and Data Analysis .............................. 55 
11.4 
Anticipated Outcomes ........................................................................................ 56 
12.0 
DATA COLLECTION AND MONITORING ..................................................................... 56 
12.1 
Records to Be Kept ............................................................................................ 56 
12.2 
Role of Data Management ................................................................................. 56 
12.3 
Clinical Site Monitoring and Record Availability .................................................. 56 
13.0 
PARTICIPANTS ............................................................................................................ 57 
13.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 57 
13.2 
Participant Confidentiality ................................................................................... 57 
13.3 
Study Discontinuation ........................................................................................ 57 
14.0 
PUBLICATION OF RESEARCH FINDINGS .................................................................. 57 
15.0 
BIOHAZARD CONTAINMENT ...................................................................................... 57 
16.0 
REFERENCES .............................................................................................................. 58 
APPENDIX I: SAMPLE INFORMED CONSENT ....................................................................... 61 
APPENDIX II: SAMPLE PARENTAL INFORMED CONSENT ................................................... 74 
APPENDIX III: SAMPLE ASSENT FORM ................................................................................. 88 
 

 
5 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
SITES PARTICIPATING IN THE STUDY 
 
A5381 will be open to ACTG clinical research sites (CRSs) in Haiti, Kenya, Malawi, South 
Africa, Uganda, Zimbabwe, the Philippines, and Vietnam. 
 
A participating CRS must be a PEPFAR-supported site or able to collaborate with a PEPFAR 
supported site to implement, enroll, and monitor participants.  
 
To participate in Group 1, sites must be able to enroll participants switching from first-
line ART with HIV-1 RNA >1000 copies/mL. To participate in Group 2, sites must be able 
to enroll participants switching from second-line ART with HIV-1 RNA >1000 copies/mL. 
These restrictions may change after a review of enrollment targets. 
 
 

 
6 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
PROTOCOL TEAM ROSTER 
 
Chair 
Cissy Kityo, MBChB, MSc, PhD 
Joint Clinical Research Center 
(JCRC)/Kampala CRS 
Research and Clinical Services 
Butikiro House 
P.O. Box 10005 
Plot 893 Ring Road 
Kampala, 10005 
UGANDA 
Phone: 256-41-4201145 
E-mail: ckityo@jcrc.org.ug 
 
Vice Chairs 
Charles Flexner, MD 
The Johns Hopkins Baltimore-Washington-
India (BWI) CTU 
Division of Clinical Pharmacology 
600 North Wolfe Street-Osler 527 
Baltimore, MD 21287-5554 
Phone: 410-955-9712 
E-mail: flex@jhmi.edu 
 
John Mellors, MD 
Pitt-Ohio State CTU 
School of Medicine 
3550 Terrace Street, Suite 818 
Pittsburgh, PA 15261 
Phone: 412-624-8512 
E-mail: jwm1@pitt.edu 
 
DAIDS Clinical Representative  
Lawrence Fox, MD, PhD 
DAIDS/NIAID/NIH/HIVRB 
NIH, NIAID, DAIDS, TRP, HIVRB 
5601 Fishers Lane 
Room 9E41A 
Rockville, MD 20852 
Phone: 240-627-3069 
Fax: 240-627-3106 
E-mail: lfox@niaid.nih.gov
Clinical Trials Specialist 
Elizabeth Woolley, MPH 
ACTG Network Coordinating Center 
Social & Scientific Systems, a DLH 
Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: 301-628-3000 
E-mail: elizabeth.woolley@dlhcorp.com 
 
Statisticians 
Michael Hughes, PhD 
Statistical and Data Analysis Center 
Harvard School of Public Health 
Building 2, Room 439A 
655 Huntington Avenue 
Boston, MA 02115-6017 
Phone: 617-432-3161 
E-mail: mhughes@sdac.harvard.edu 
 
Caitlyn McCarthy, MA 
Statistical and Data Analysis Center 
Harvard School of Public Health 
FXB 535 
Boston, MA 02115 
Phone: 617-432-7524 
E-mail: cmccarth@sdac.harvard.edu 
 
Data Managers 
Kathleen Donahue, MA 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 Ext. 7329 
E-mail: donahue@frontierscience.org 
 
Data Managers (cont’d)  
Autumn Rolack, MPH 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 Ext. 7406 
E-mail: rolack@frontierscience.org 
 

 
7 
A5381 
 
 
FINAL Version 2.0 
 
PROTOCOL TEAM ROSTER (Cont'd) 
03/05/21 
 
Virologists  
Urvi Parikh, PhD 
University of Pittsburgh School of Medicine 
Department of Infectious Diseases 
3550 Terrace Street 
S804 Scaife Hall 
Pittsburgh, PA 15261 
Phone: 412-648-3103 
E-mail: ump3@pitt.edu 
 
Carole Wallis, MSc MED, PhD 
BARC-SA and Lancet Laboratories 
Lancet Corner, Corner of Stanley and 
Menton 
11 Napier Road 
Richmond 
Johannesburg, Gauteng, 2193 
SOUTH AFRICA 
Phone: 27-11-3580816 
E-mail: carole.wallis@lancet.co.za 
 
Pharmacologists 
Kelly Dooley, MD, PhD 
Johns Hopkins University CRS 
Osler 527 
600 North Wolfe Street 
Baltimore, MD 21287 
Phone: 410-955-3100 
E-mail: kdooley1@jhmi.edu 
 
Pharmacologists (cont’d) 
Gary Maartens, MBChB, MMed 
University of Cape Town 
Division of Clinical Pharmacology 
Observatory 
Anzio Road 
Cape Town, 7925 
SOUTH AFRICA 
Phone: 27-21-4066286 
E-mail: gary.maartens@uct.ac.za 
 
Investigators  
Joseph Sean Cavanaugh, MD  
3707 35th ST NW 
Washington, DC 20016 
Phone: 240-281-5773 
E-mail: JCavanaugh@hivresearch.org 
  
Investigators (Cont'd)  
Peter Ehrenkranz, MD, MPH 
Bill and Melinda Gates Foundation 
500 5th Avenue N 
Seattle, WA 98119 
Phone: 253-243-5122 
E-mail: 
peter.ehrenkranz@gatesfoundation.org 
 
Catherine Godfrey, MD, FRACP 
Senior Technical Advisor HIV Care and 
Treatment 
PEPFAR/Office of the Global AIDS 
Coordinator 
Department of State 
1800 G Street NW, Suite 10300  
Washington, DC 20006 
Phone: 202-663-3413 
E-mail: qea0@cdc.gov 
 
Mina C. Hosseinipour, MD 
University of North Carolina Global HIV 
Prevention and Treatment CTU 
Kamuzu Central Hospital 
Tidziwe Centre 
Private Bag A-104 
100 Mzimba Road 
Lilongwe 
MALAWI 
Phone: 265-888202153 
E-mail: mina_hosseinipour@med.unc.edu  
 
Abraham Katana, MD 
Kenya Medical Research Institute/Centers 
for Disease Control (KEMRI/CDC) CRS 
Division of Global HIV/AIDS, CDC Kenya 
KEMRI HQ, Mbagathi Road, Off Mbagathi 
Way 
P.O. Box 606 
Village Market 
Nairobi, 00621 
KENYA 
Phone: 254-20286700  
E-mail: akatana@cdc.gov

 
8 
A5381 
 
 
FINAL Version 2.0 
 
PROTOCOL TEAM ROSTER (Cont'd) 
03/05/21 
 
Investigators (Cont'd)  
Serena Koenig, MD, MPH 
Les Centres Gheskio (Gheskio-INLR) CRS 
Brigham and Women’s Hospital 
75 Francis Street 
Boston, MA 02115 
Phone: 617-413-4090 
E-mail: skoenig@bwh.harvard.edu 
 
Deborah Langat, MBChB, MSc 
Kenya Medical Research Institute/Walter 
Reed Project Clinical Research Center 
(KEMRI/WRP) CRS 
P.O. Box 1357 
Hospital Road 
Kericho, Rift Valley, 20200 
KENYA 
Phone: 254-52-2020946 
E-mail: deborah.langat@usamru-k.org 
 
Yukari Manabe, MD 
Johns Hopkins University CRS 
Center for Global Health 
1830 East Monument Street, Room 443 
Baltimore, MD 21205 
Phone: 410-955-8571  
E-mail: ymanabe@jhmi.edu 
 
Rosie Mngqibisa, MB, ChB, MPH 
Durban International CRS 
Enhancing Care Foundation 
16 Charles Strachan 
Westridge 
Durban RSA, 4091 
SOUTH AFRICA 
Phone: 27-31-2611093 
E-mail: mngqibisa@ecarefoundation.com 
 
Mulinda Nyirenda, FCP(SA), MMED, MBBS 
Blantyre CRS 
John Hopkins Research Project 
Chipatala Avenue 
P.O. Box 1131 
Blantyre, 265 
MALAWI 
Phone: 265-999946026 
E-mail: mnyirenda@jhu.medcol.mw
Investigators (Cont'd)  
Elliot Raizes, MD 
US Centers for Disease Control and 
Prevention 
1600 Clifton Road 
P.O. Box: MS US1-1 
Atlanta, GA 30329 
Phone: 404-639-6408 
E-mail: gwq0@cdc.gov 
 
Mohammed Rassool, MD 
University of the Witwatersrand Helen 
Joseph (WITS HJH) CRS 
Perth Road, Westdene 
Johannesburg, Gauteng 2092 
SOUTH AFRICA 
Phone: 27-11-2768800 
E-mail: mrassool@witshealth.co.za 
 
Vanessa Rouzier, MD 
Les Centres Gheskio (Gheskio-INLR) CRS 
33 Boulevard Harry Truman 
Port-au-Prince, HT-6110 
HAITI 
Phone: 509-37014593 
E-mail: vrouzier@gheskio.org 
 
Damocles Patrice Severe, MD 
Les Centres Gheskio (Gheskio-INLR) CRS 
Cite de l'Exposition, Bicentenaire 
33 Boulevard Harry Truman 
Port au Prince, HT-6110 
HAITI 
Phone: 509-29401431 
E-mail: patsevere@gheskio.org 
 
Sarita Shah, MD, MPH 
Hubert Department of Global Health 
Rollins School of Public Health 
Emory University 
1518 Clifton Road, CNR 6009 
Atlanta, GA  30322 
Phone: 404-727-7326 
E-mail: sarita.shah@emory.edu

 
9 
A5381 
 
 
FINAL Version 2.0 
 
PROTOCOL TEAM ROSTER (Cont'd) 
03/05/21 
 
Investigators (Cont'd)  
George Siberry, MD, MPH 
Adult Clinical Branch, Office of HIV/AIDS  
United States Agency for International  
Development (USAID) 
Workstation 9040-B 
2100 Crystal Drive 
Arlington, VA 22202 
Phone: 571-551-7473 
E-mail: gsiberry@usaid.gov  
 
Isaac Tsikhutsu, MBChB, MMED 
Kenya Medical Research Institute/Walter 
Reed Project Clinical Research Center 
(KEMRI/WRP) CRS, P.O. Box 1357 
Kericho, 
KENYA 
Phone: 25-452-2020419 
E-mail: isaac.tsikhutsu@usamru-k.org 
 
Field Representatives 
Ruth Luhanga, RN 
Blantyre CRS 
Queen Elizabeth Central Hospital 
P.O. Box 1131, Chipatala Avenue 
Blantyre, 265 
MALAWI 
Phone: 265-1875129 
E-mail: rluhanga@jhu.medcol.mw 
 
Rachel Mahachi, MNS, BN 
Parirenyatwa CRS 
15 Philips Avenue 
Belgravia, Harare, 00263 
ZIMBABWE 
Phone: 263-4-701356 
E-mail: rmahachi@uzcrc.co.zw 
 
Laboratory Technologists 
Cheryl Jennings, BS 
Northwestern University CRS 
Clinical Retrovirology Research 
Laboratory 
1121 Jelke Building 
1750 West Harrison Street 
Chicago, IL 60612 
Phone: 312-942-5954 
E-mail: cheryl_jennings@rush.edu 
Laboratory Technologists (cont’d) 
Jennifer Norman, MSc 
University of Cape Town, ACTG 
International HIV/AIDS Pharmacology 
Specialty Laboratory 
K50 Division of Clinical Pharmacology 
Old Main Building 
Groote Schuur Hospital 
Cape Town, Western Cape 7925 
SOUTH AFRICA 
Phone: 27-21-4047695 
E-mail: jennifer.norman@uct.ac.za 
 
Sasiwimol Ubolyam, MSc 
Thai Red Cross AIDS Research Center 
Treatment (TRC-ARC Treatment) CRS 
104 Rajdamri Road 
Patumwan, Bangkok, 10330 
THAILAND 
Phone: 66-2-2564648 
E-mail: sasiwimol.u@hivnat.org 
 
Community Scientific Subcommittee (CSS) 
Representative 
George Kukhala 
Blantyre CRS 
P.O. Box 1131 
Blantyre 
MALAWI 
Phone: 265-888-208172 
E-mail: gkukhala@gmail.com 
 
ACTG International Site Specialist 
Mary Allegra Cermak, MFA 
ACTG Network Coordinating Center 
Social & Scientific Systems, a DLH 
Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: 301-628-3312 
E-mail: allegra.cermak@dlhcorp.com

 
10 
A5381 
 
 
FINAL Version 2.0 
 
PROTOCOL TEAM ROSTER (Cont'd) 
03/05/21 
 
Laboratory Data Manager 
Colleen Foley, MS 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY  14226-1056 
Phone: 716-834-0900 Ext. 7267 
E-mail: foley@fstrf.org 
 
Kathleen Trabert, BS 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Rd 
Amherst, NY 14226-1056 
Phone: 716-834-0900 Ext. 7373 
E-mail: trabert@frontierscience.org 
 
Laboratory Specialist 
Frances Whalen, MPH, MT(ASCP) 
ACTG and IMPAACT Laboratory Center 
University of California Los Angeles  
11075 Santa Monica Boulevard, Suite 200  
Los Angeles, CA 90025 
Phone: 704-422-4055 
E-mail: fwhalen@milabcentral.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
11 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
STUDY MANAGEMENT 
 
All general questions concerning this protocol should be sent to actg.teamA5381@fstrf.org via 
e-mail. The appropriate team member will respond with a "cc" to actg.teamA5381@fstrf.org. A 
response should generally be received within 24 hours (Monday through Friday). 
 
Protocol E-mail Group 
Sites should contact the User Support Group at the Data Management Center (DMC) as soon 
as possible to have the relevant personnel at the site added to the actg.protA5381 e-mail group. 
Include the protocol number in the e-mail subject line.  
• 
Send an e-mail message to actg.user.support@fstrf.org.  
 
Clinical Management  
For questions concerning entry criteria, toxicity management, concomitant medications, and co-
enrollment, contact the core protocol team.  
• 
Send an e-mail message to actg.coreA5381@fstrf.org. Include the protocol number, patient 
identification number (PID), and a brief relevant history. 
 
Laboratory 
For questions specifically related to virologic or pharmacologic laboratory tests, contact the 
Protocol Virologists or Pharmacologist.  
• 
Send an e-mail message to actg.teamA5381@fstrf.org (ATTENTION: Urvi Parikh, Carole 
Wallis, Kelly Dooley, and Gary Maartens). 
 
Data Management 
• 
For nonclinical questions about transfers, inclusion/exclusion criteria, electronic case report 
forms (eCRFs), randomization/registration, and other data management issues, contact the 
data manager. Completion guidelines for eCRFs and participant-completed CRFs can be 
downloaded from the FSTRF website at www.frontierscience.org. 
• 
For transfers, reference the Study Participant Transfer SOP 119, and contact Kathleen 
Donahue and Autumn Rolack directly.  
• 
For other questions, send an e-mail message to actg.teamA5381@fstrf.org (ATTENTION: 
Kathleen Donahue and Autumn Rolack).  
• 
Include the protocol number, PID, and a detailed question. 
 
Participant Registration  
For participant registration questions or problems and study identification number SID lists:  
• 
Send an e-mail message to rando.support@fstrf.org or call the DMC Randomization Desk at 
716-834-0900, extension 7301.  
 
DMC Portal and Medidata Rave Problems  
Contact DMC User Support. 
• 
Send an e-mail message to actg.user.support@fstrf.org or call 716-834-0900 x7302. 
 

 
12 
A5381 
 
 
FINAL Version 2.0 
 
STUDY MANAGEMENT (Cont'd) 
03/05/21 
 
Protocol Document Questions 
For questions concerning the protocol document, contact the Clinical Trials Specialist.  
• 
Send an e-mail message to actg.teamA5381@fstrf.org (ATTENTION: Elizabeth Woolley). 
 
Copies of the Protocol 
To request a hard copy of the protocol, send an e-mail message to ACTGNCC@dlhcorp.com. 
Electronic copies can be downloaded from the ACTG website at https://www.actgnetwork.org. 
 
Product Package Inserts and/or Investigator Brochures 
To request copies of product package inserts or investigator brochures, contact the Division of 
AIDS (DAIDS) Regulatory Support Center (RSC) at RIC@tech-res.com or call 301-897-1708. 
 
Protocol Registration 
For protocol registration questions, send an e-mail message to Protocol@tech-res.com or call 
301-897-1707.  
 
Protocol Activation 
For questions related to protocol activation at non-US sites, contact the ACTG Site Coordination 
Group.  
• 
Send an e-mail message to actgsitecoordination@dlhcorp.com. 
 
Telephone Calls 
Sites are responsible for documenting telephone calls made to A5381 team members.  
• 
Send an e-mail message to actg.teamA5381@fstrf.org. 
 
Protocol-Specific Web Page 
Additional information about management of the protocol can be found on the protocol-specific 
web page (PSWP). 

 
13 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
3TC 
lamivudine 
AE 
adverse event 
ART 
antiretroviral therapy 
ATV/r 
atazanavir/ritonavir 
BMI 
body mass index 
DBS 
dried blood spot 
DDIs 
drug-drug interactions 
DTG 
 
 
dolutegravir 
EFV 
efavirenz 
FDA 
US Food and Drug Administration 
GCLP 
Good Clinical Laboratory Practices 
INSTI 
integrase strand transfer inhibitor 
LMIC 
low- and middle-income countries 
LPV/r 
lopinavir/ritonavir 
NNRTI 
non-nucleoside reverse transcriptase inhibitor 
NTD 
neural tube defects 
NRTI 
nucleoside reverse transcriptase inhibitors 
NVP 
nevirapine 
PEPFAR 
 
United States President’s Emergency Plan for AIDS Relief 
PI 
 
 
protease inhibitor 
PLHIV  
 
people living with HIV 
PSWP  
 
protocol-specific web page 
RIF 
 
 
rifampicin 
TB 
 
 
tuberculosis 
TFV 
 
 
tenofovir 
TLD 
 
 
tenofovir disoproxil fumarate/lamivudine/dolutegravir 
TFV-DP 
 
tenofovir-diphosphate 
WHO  
 
World Health Organization 

 
14 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
SCHEMA 
 
 
A5381 
 
Observational Cohort to Assess Therapeutic Efficacy and Emergence of HIV Drug Resistance 
Following Initiation of Tenofovir-Lamivudine-Dolutegravir (TLD) for First- or Second-Line ART or 
with Rifampicin-Containing TB Treatment: The Hakim Study 
 
DESIGN 
This is an observational, longitudinal prospective cohort study to assess 
therapeutic efficacy and emergence of HIV drug resistance following initiation 
of tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD) for first- or 
second-line antiretroviral therapy (ART), or start of concomitant TLD and 
rifampicin (RIF)-containing tuberculosis (TB) treatment. To the greatest extent 
possible, participants will be managed according to local standards of care, 
and preferably in accordance with current World Health Organization (WHO) 
Guidelines for HIV and TB treatment and monitoring. Participants will be 
divided into four study groups for enrollment: 
 
Group 1: Participants switching to TLD from a first-line regimen containing a 
non-nucleoside reverse transcriptase inhibitor (NNRTI). These participants 
will be divided into two subgroups based upon their HIV-1 RNA level in a 
sample obtained at entry, before starting TLD. Group 1a will include 
participants with viremia (HIV-1 RNA >1000 copies/mL at start of TLD) and 
Group 1b will include participants with suppressed viremia (HIV-1 RNA ≤1000 
copies/mL at start of TLD). 
 
 
 
Group 2: Participants switching to TLD from a second-line regimen containing 
a boosted protease inhibitor (PI). These participants will be divided into two 
subgroups based upon their HIV-1 RNA level in a sample obtained at entry, 
before starting TLD. Group 2a will include participants with viremia (HIV-1 
RNA >1000 copies/mL at start of TLD) and Group 2b will include participants 
with suppressed viremia (HIV-1 RNA ≤1000 copies/mL at start of TLD). 
 
 
 
Group 3: Participants initiating concomitant TLD and RIF-containing TB 
treatment, with an additional daily dose of dolutegravir (DTG) 50mg. For 
participants already on RIF-containing TB treatment when TLD treatment is 
started, TLD treatment must be started within 8 weeks (56 days) of the start 
of RIF-containing TB treatment. Group 1, 2, or 4 participants who start RIF-
containing TB treatment after enrollment will have additional evaluations at 
the start and end of concomitant HIV and TB treatment but will not be co-
enrolled in Group 3 (their additional evaluations will, however, be considered 
when analyzing data from Group 3).    
 
Group 4: ART-naïve participants initiating therapy with TLD. 
 

 
15 
A5381 
 
 
FINAL Version 2.0 
 
SCHEMA (Cont'd) 
03/05/21 
 
DURATION 
Each participant will be followed for 36 months. 
 
SAMPLE SIZE  
Approximately 1350 participants: 540 in Group 1 with the goal of at least 180 
in Group 1a, 540 in Group 2 with the goal of at least 180 in Group 2a, 90 in 
Group 3, and 180 in Group 4. Participants in Group 3 who were already 
taking TLD at the time of study entry and who are found to have HIV-1 RNA 
>1000 copies/mL from the entry HIV-1 RNA test will be discontinued from the 
study and will be replaced. 
 
In each group, there is a goal of enrolling 10% of participants who are 
adolescents aged 10 to 19 years. In Group 1a, there is also a goal to enroll 
45 participants with nevirapine (NVP)-based first-line ART exposure.  
 
POPULATION  
HIV-infected adults and adolescents (>30 kg, ≥10 years of age) initiating or 
switching to TLD and receiving care through a President’s Emergency Plan 
for AIDS Relief (PEPFAR)-supported treatment program. 
 
REGIMEN 
Observational study, no treatments are provided through A5381.  
 
Qualifying treatment (initiated within 7 days after study entry): 
 
For Groups 1, 2, and 4: Co-formulated tenofovir disoproxil fumarate 300 
mg/lamivudine 300 mg/dolutegravir 50 mg (TLD) taken once daily. 
 
For Group 3: During TB treatment and for 2 weeks following completion of 
rifampicin-containing TB treatment, TLD taken once daily with an additional 
daily dose of DTG 50 mg such that DTG is taken twice daily. TB treatment 
will follow WHO Guidelines.  

 
16 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
1.0 
HYPOTHESES AND STUDY OBJECTIVES 
 
1.1 
Hypotheses 
 
1.1.1 Among participants still on tenofovir disoproxil fumarate/lamivudine/dolutegravir 
(TLD) at 6 months of followup, the proportion achieving virologic success (HIV-1 
RNA ≤1000 copies/mL) at that time will be high, specifically: 
• 
≥85% among participants switching from first-line non-nucleoside reverse 
transcriptase inhibitor (NNRTI)-containing and second-line protease inhibitor 
(PI)-containing therapy with HIV-1 RNA >1000 copies/mL at start of TLD 
(Groups 1a and 2a); 
• 
≥90% among participants switching from first-line NNRTI-containing and 
second-line PI-containing therapy with HIV-1 RNA ≤1000 copies/mL at start 
of TLD (Groups 1b and 2b); 
• 
≥85% among participants who are ART-naïve when starting TLD (Group 4); 
and the proportion with new dolutegravir (DTG) resistance mutations will be 
low (<5%).  
 
1.1.2 Among participants in Group 3, the proportion achieving virologic success (HIV-1 
RNA ≤1000 copies/mL) at the end of concomitant TLD (including an additional 
daily dose of DTG 50 mg) and rifampicin (RIF)-containing TB treatment will be 
high (≥85%) and the proportion with new DTG resistance mutations will be low 
(<5%).  
1.2 
Primary Objectives 
 
1.2.1 Among participants still on TLD at 6 months of followup, to estimate the 
proportion achieving virologic success (HIV-1 RNA ≤1000 copies/mL) and the 
proportion with new DTG resistance mutations in each of the following groups: 
• 
Participants switching from first-line NNRTI-containing therapy with HIV-1 
RNA >1000 copies/mL at start of TLD (Group 1a); 
• 
Participants switching from second-line PI-containing therapy with HIV-1 RNA 
>1000 copies/mL at start of TLD (Group 2a); 
• 
Participants switching from first-line NNRTI-containing therapy with HIV-1 
RNA ≤1000 copies/mL at start of TLD (Group 1b); 
• 
Participants switching from second-line PI-containing therapy with HIV-1 RNA 
≤1000 copies/mL at start of TLD (Group 2b); 
• 
Participants who are ART-naïve when starting TLD (Group 4).  
 
1.2.2 Among participants taking concomitant TLD (including an additional daily dose of 
DTG 50 mg) and RIF-containing TB treatment (Group 3), to estimate the 
proportion achieving virologic success (HIV-1 RNA ≤1000 copies/mL) and the 
proportion with new DTG resistance mutations at the end of concomitant 
treatment.   
 

 
17 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
1.3 
Secondary Objectives 
 
1.3.1 To describe treatment outcomes at 6 months, 12 months, 24 months, and 36 
months after starting TLD according to the US Food and Drug Administration 
(FDA) Snapshot algorithm using a threshold of ≤1000 copies/mL for virologic 
suppression in each of Groups, 1a, 1b, 2a, 2b, and 4; and at the end of 
concomitant TLD and RIF-containing TB treatment, 12 months, 24 months, and 
36 months after starting concomitant TLD and RIF-containing TB treatment in 
Group 3. 
 
1.3.2 To assess the long-term durability of TLD (up to 36 months) in suppressing 
viremia in each of the study groups/subgroups.  
 
1.3.3 To assess drug resistance and accumulation of drug resistance mutations over 
time (up to 36 months) in the participants experiencing virologic failure in each of 
the study groups/subgroups.  
 
1.3.4 To describe the frequency of toxicities leading to discontinuation of the TLD 
regimen in each of the study groups/subgroups. 
 
1.3.5 To assess change in quality of life after starting TLD in each of the study 
groups/subgroups. 
 
1.3.6 To describe the frequency of clinical events relevant for TLD in each of the study 
groups/subgroups. 
 
1.3.7 To assess virologic success, accumulation of drug resistance mutations, 
frequency of toxicities leading to discontinuation of TLD, change in quality of life, 
and frequency of clinical events relevant for TLD over time by gender in each of 
the study groups/subgroups. 
 
1.4 
Exploratory Objectives 
 
1.4.1 To assess virologic success, accumulation of drug resistance mutations, 
frequency of toxicities leading to discontinuation of TLD, change in quality of life, 
and frequency of clinical events relevant for TLD over time, specifically among 
participants switching from first-line nevirapine (NVP)-containing ART. 
 
1.4.2 To assess virologic success, accumulation of drug resistance mutations, 
frequency of toxicities leading to discontinuation of TLD, change in quality of life, 
and frequency of clinical events relevant for TLD over time, specifically in 
adolescents (using the World Health Organization (WHO) definition of anyone 
aged 10 to 19 years). 
 
1.4.3 To assess virologic success, accumulation of drug resistance mutations, 
frequency of toxicities leading to discontinuation of TLD, change in quality of life, 

 
18 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
frequency of clinical events relevant for TLD over time, and pregnancy outcomes 
in women who are pregnant while receiving TLD. 
 
1.4.4 To identify baseline predictors of virologic success including CD4+ cell count, 
HIV-1 RNA, and drug resistance mutations. 
 
1.4.5 To assess the relationship between tenofovir-diphosphate (TFV-DP) in dried 
blood spot (DBS) sampling, and months 6, 12, 24, and 36 virologic failure and 
development of integrase inhibitor resistance mutations on TLD. 
 
1.4.6 To estimate the rate of successful suppression of plasma HIV-1 RNA to three 
thresholds: ≤1000, ≤200, and <50 copies/mL at 6, 12, 24, and 36 months after 
starting TLD in each of the study groups/subgroups, and to compare these rates:  
 
(a) between participants with viremia (HIV-1 RNA >1000 copies/mL) versus 
suppressed viremia (HIV-1 RNA ≤1000 copies/mL) at start of TLD among 
those switching from first-line NNRTI-containing ART (Group 1) and among 
those switching from second-line PI-containing ART (Group 2); and  
 
(b) among participants with suppressed viremia (HIV-1 RNA ≤1000 copies/mL at 
start of TLD) switching from first-line NNRTI-containing ART (Group 1b) and 
among participants with suppressed viremia switching from second-line PI-
containing ART (Group 2b) to that achieved among ART-naïve participants 
starting TLD (Group 4).  
 
1.4.7 To assess change in body mass index (BMI) over time (up to 36 months) after 
starting TLD. 
 
1.4.8 In each study group/subgroup, to describe the proportion of females of 
reproductive potential starting TLD who are receiving contraceptives. 
 
1.4.9 In each study group, to describe the reproductive potential, number of live 
births, and fertility desires of females starting TLD.   
 
1.4.10 To assess the metabolic complications of DTG, including hyperglycemia 
and hyperlipidemia. 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
By mid-2017, there were 20.9 million people living with HIV (PLHIV) on antiretroviral 
therapy (ART) worldwide [1], the majority of these being from HIV high-burden countries. 
The rapid rollout of ART in these countries has been made possible through support 
from the United States President’s Emergency Plan for AIDS Relief (PEPFAR), the 
Global Fund, other agencies, and from in-country resources. With an HIV population of 
36.7 million [1], the 90-90-90 targets (identifying 90% of PLHIV, 90% of these on ART 

 
19 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
and achieving a viral suppression rate of 90% of those on treatment), and the ambitious 
target of ending the AIDS epidemic by 2030 [2], there is urgent need to identify and 
promote ART regimens and strategies that include drugs that can be co-formulated and 
have high potency, high genetic barrier to resistance, proven safety, and no food or 
other restrictions. Integrase strand transfer inhibitor (INSTI)-based regimens, especially 
those including DTG, have emerged as highly attractive regimens for ART-naïve and 
ART-experienced patients. Nevertheless, the recent observation of a possible increase 
in the risk of neural tube defects (NTD) in children born to mothers exposed to DTG 
during conception underscores the need to carefully monitor DTG regimens that are 
rolled out, irrespective of strong attributes demonstrated in clinical trials. 
 
Antiretroviral therapy, comprising a backbone of two nucleoside reverse transcriptase 
inhibitors (NRTIs) plus a NNRTIs or boosted PI, is the recognized standard of care for 
treatment of HIV-1 infection. These combinations have helped extend the life expectancy 
of many PLHIV [3-6], and are still being used as first- and second-line regimens in many 
countries.  
 
In clinical trials, DTG-containing first-line ART has been better tolerated, has higher 
virologic efficacy, fewer drug-drug interactions (DDIs), and less frequent emergence of 
HIV drug resistance than efavirenz (EFV)-containing ART [7]. In August 2017, the 
decision was made to support rapid adoption of the single-tablet regimen of TLD as first-
line and second-line ART for adults and adolescents in PEPFAR programs, with rollout 
starting in 2018. Countries are encouraged to include HIV-1 positive pregnant women, 
breastfeeding women, adolescents (from age 10 years and body weight >30 kg), and 
patients requiring treatment for TB (for whom an additional DTG 50 mg dose is used with 
RIF-based treatment) in their TLD transition planning.  
 
In the Tsepamo study, an ongoing birth outcome surveillance study conducted in 
Botswana, 4 cases of NTD have been reported in 426 infants born to women who took 
DTG as part of combined ART at the time of conception. This represents an incidence of 
about 0.9% compared with an expected background rate of about 0.1% in infants born to 
women taking other ART at the time of conception [8]. 
 
Non-communicable diseases are becoming a significant concern in individuals 
living with HIV including in resource-limited settings. Obesity, especially visceral fat, 
is emerging as a key risk factor for several non-infectious comorbidities such as 
cardiovascular disease, diabetes, certain cancers, and neurocognitive disorders. There 
is growing recognition that obesity is prevalent in sub-Saharan Africa, with southern 
Africa having the highest prevalence of overweight individuals, women being more 
affected than men [9, 10]. Obesity is emerging as a problem for HIV-infected individuals 
in both resource rich and resource poor environments [11, 12]. There is a growing body 
of data suggesting that the use of INSTIs may have a negative impact on BMI [13-15]. 
There is little prospective data on the effects of INSTIs in diverse settings among diverse 
populations. It is unknown whether obesity in the setting of the use of these drugs 
is associated with metabolic consequences. Emerging evidence suggests that the 
presentation of metabolic complications may be different in sub-Saharan Africa. 
 

 
20 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
2.2 
Rationale 
 
TLD Rollout 
There is limited data on the performance and emergence of resistance to TLD in diverse 
settings. Understanding the risks and benefits of TLD rollout is a priority research 
question, as many programs in low- and middle-income countries (LMIC) may not use 
viral load testing in the transition to DTG-based, first-line ART and will not have the 
benefit of individual resistance testing to guide ART optimization. It is critical to monitor 
programmatic and clinical outcomes for patients initiating or transitioning to TLD. 
Consequently, to better inform policy and clinical practice moving forward, we propose to 
enroll a cohort study at AIDS Clinical Trial Group (ACTG) sites coincident with TLD 
rollout to systematically track clinical and virologic outcomes, HIV drug resistance, 
adverse events (AEs), and drug toxicities among diverse participant groups. The study 
will also actively and closely monitor birth outcomes, particularly amongst women who 
conceive while receiving TLD to confirm safety in pregnancy as part of the TLD rollout, 
as well as TB outcomes for TB patients treated with TLD while on TB therapy. 
 
Neuropsychiatric symptoms are common with EFV. It is postulated that switching to a 
DTG-containing regimen will result in improved quality of life, adherence, and retention 
in care in support of viral suppression. 
 
TLD as first-line ART  
TLD is being recommended by PEPFAR for all first-line ART initiations. In randomized 
clinical trials, DTG has shown higher efficacy and lower overall risks of AEs than the 
NNRTI EFV (in the SINGLE trial [7]), and the protease inhibitors darunavir/ritonavir 
(DRV/r; in the FLAMINGO study [16]), atazanavir/ritonavir (ATV/r; in the ARIA trial [17]) 
and lopinavir/ritonavir (LPV/r; in the DAWNING trial [18]). Furthermore, the ARIA trial 
was composed entirely of women, and it confirmed that AE profiles were similar in men 
and women. DTG has shown similar rates of AEs to the integrase inhibitors raltegravir 
(in the SPRING-2 trial [19]) and bictegravir (in the Gilead 1489 and 1490 trials [20, 21]). 
 
TLD as second-line ART 
The current WHO guidelines for second-line treatment recommend two NRTIs and 
LPV/r, ATV/r, or DTG after failure of an NNRTI-based first-line regimen [22]. The most 
significant challenges with this current WHO recommendation are side effects and DDIs. 
In an effort to simplify treatment and minimize or avoid long term toxicities, various 
studies have been performed or are currently underway to determine alternatives to the 
currently recommended second-line regimens [23]. The search continues for durable 
regimens that are simple, safe and tolerable, provide superior virologic efficacy, and 
have less frequent emergence of resistance. Initial data from the ViiV-sponsored 
DAWNING study of best available NRTIs plus DTG in participants on failing first-line, 
NNRTI-containing ART showed excellent virologic efficacy, tolerability, and superiority to 
2 NRTI + LPV/r, although at least one active NRTI by genotype analysis was required for 
study entry [18]. TLD is likely to be used as a second-line regimen in most PEPFAR-
supported countries regardless of resistance to NRTIs. However, current WHO 
guidelines [22] recommend that patients who received TDF/emtricitabine (XTC) in first-
line ART should switch to azidothymidine (AZT)/XTC for second-line treatment; if the 

 
21 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
recycled TDF/3TC backbone is found to be virologically effective, TLD would be 
preferable to AZT/3TC/DTG, due to lower toxicity and single tablet formulations. A switch 
to TLD is also being considered for individuals on second-line ART with 2 NRTI + LPV/r 
or ATV/r. Use of TLD in both treatment-naïve and treatment-experienced PLHIV is 
programmatically very attractive because it facilitates distribution of drug, thus 
minimizing supply chain interruptions and lowering cost compared to current first- or 
second-line regimens. 
 
HIV Resistance to Dolutegravir 
HIV drug resistance is an important consideration when contemplating DTG for 
treatment. Use of DTG for second-line treatment when extensive NRTI resistance is 
present may increase the risk of development of HIV drug resistance. DTG without an 
effective NRTI agent has been recently reported to incompletely suppress viremia and 
select for DTG resistance in at least 10% of individuals [24, 25]. Many studies in LMIC 
have shown that prolonged failure of first-line NNRTI-containing ART can cause 
extensive NRTI resistance, including tenofovir (TFV) and lamivudine (3TC) resistance, 
which could increase the risk of both TLD failure and the emergence and spread of DTG 
resistance. The ACTG A5288 study of people failing second-line ART showed triple 
class mutations in 27% of participants, and 22% of participants had three or more 
thymidine analog mutations (TAMS). This level of resistance could increase the risk of 
TLD failure. Importantly, the effect of some common drug-resistance mutations (K65R, 
M184 I/V, TAMs) in combination is unknown, and must be evaluated for their impact on 
response to TLD, although recent subanalyses [26] from the DAWNING study are 
reassuring that DTG-containing regimens perform well regardless of prior NRTI 
exposure when WHO recommended NRTIs were used in combination. Furthermore, 
some of these mutations (K65R, M184I/V) reduce viral fitness; this may result in high 
DTG efficacy, even if both NRTIs are compromised. Nevertheless, TLD for second-line 
ART requires additional study of outcomes among groups at higher potential risk of TLD 
failure in LMIC.  
 
In addition, RIF-containing therapy for TB co-infection complicates the use of TLD 
because of DDIs potentially affecting TFV and DTG pharmacokinetics, drug exposure, 
and efficacy.  
 
Cohort Rationale 
This cohort study will provide critical information on the frequency of treatment failure 
and new drug resistance rates after initiation of TLD in higher-risk groups (Groups 1, 2, 
and 3). The study could identify patient groups with suboptimal responses to TLD, which 
could be studied in a subsequent randomized comparison of alternative ART regimens. 
 
Adolescents on ART pose a special concern because of issues related to adherence, 
use of substances, and mental health. These issues impact viral suppression rates and 
treatment outcomes. This study is not more than minimal risk, as enrolled adolescents 
must be receiving a DTG-containing regimen as part of their medical care, and a small 
volume of blood will be collected per the Schedule of Evaluations (SOE) to assess 
primary endpoints. There are no additional procedures. 
 

 
22 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
Group 1: Individuals switching to TLD from a first-line regimen containing an NNRTI 
Among individuals taking NNRTI-based first-line ART, some will be suppressed and 
others will be viremic. Patients who are viremic may have NRTI resistance and be at risk 
of functional DTG monotherapy after switching to TLD with the potential to fail on TLD 
with emergence of DTG resistance. Studies in LMIC have shown that prolonged failure 
of first-line, NNRTI-containing ART can cause extensive NRTI resistance, including TFV 
and 3TC resistance [26-29]. DTG monotherapy has been reported to incompletely 
suppress viremia and select for DTG resistance in at least 10% of individuals [24, 25]. 
However, it is not known if DTG monotherapy carries the same resistance risk as DTG 
plus 2 NRTIs with genotypic evidence of resistance to those NRTIs, as this has never 
been investigated prospectively. High quality evidence demonstrating the long-term 
efficacy of DTG alongside a compromised NRTI backbone is also lacking. There is 
evidence from A5353 that dual therapy with DTG and emtricitabine is efficacious in 
individuals with VL < 100000 c/ml. This provides some reassurance that even in the 
setting of some resistance a TLD combination will be effective. Group 1 will include 
individuals who are viremic or have unknown plasma HIV-1 RNA status as well as those 
who are known to have suppressed plasma HIV-1 RNA to facilitate comparison of 
outcomes between these subgroups. 
 
Group 2: Individuals switching to TLD from a second-line regimen containing a boosted 
PI 
Individuals on a second-line regimen containing a boosted PI may have viremia, HIV-1 
RNA suppression, or unknown HIV-1 RNA status. It is unknown if patients with prior first-
line regimen failure but current suppression on a second-line boosted PI regimen will 
maintain virologic suppression if they are switched to DTG with the same or different 
NRTI. In addition, there is currently no data on DTG use for patients not suppressed on 
a second-line, PI-containing regimen. This group will provide longitudinal data and 
critical information about the frequency of treatment failure and drug resistance after 
switching to TLD, comparing the subgroup that is suppressed to the subgroup that is not 
virologically suppressed on a second-line boosted PI regimen.  
 
Group 3: Participants initiating concomitant TLD (including an additional daily dose of 
DTG 50 mg) and RIF-containing TB treatment 
RIF is a critical component of first-line TB treatment. RIF induces hepatic drug 
metabolizing enzymes and drug transport proteins. It increases clearance of many 
drugs, including DTG. In healthy volunteers, RIF reduced DTG levels by about 30%. 
This reduction can be overcome by giving DTG 50 mg twice a day. In the INSPIRING 
trial, Dooley et al. demonstrated that DTG 50 mg twice a day, given during concomitant 
RIF-based therapy achieved target trough concentrations, was safe, and demonstrated 
high HIV treatment efficacy and a good immunologic response through week 48 [30-32]. 
The study provides evidence that DTG is effective and well tolerated in adults with 
HIV/TB coinfection who are receiving RIF-based TB treatment. WHO currently 
recommends that the dose of DTG be increased to 50 mg BID for patients who are on 
concurrent RIF-based TB regimen. As TLD is widely rolled out and DTG is administered 
with RIF-based TB regimens, there is need for data on effectiveness of TLD with an 
additional dose of DTG 50 mg with RIF in patients with TB/HIV co-infection in different 
clinical settings, including among individuals with low CD4 count. 

 
23 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
Perinatal outcomes are negatively affected by concomitant TB and HIV infections.  
Moreover, there is growing evidence that RIF affects the exposure of several commonly 
used contraceptive agents potentially making them less effective.  Sites should follow 
local guidelines with respect to contraceptive counseling.   
 
Group 4: Treatment-naïve individuals initiating therapy with TLD 
Treatment-naïve individuals initiating therapy with TLD will serve as a parallel 
comparator group for treatment-experienced individuals who switch to TLD, and for 
individuals who switch to or start TLD and require RIF-based treatment for TB. 
 
3.0 
STUDY DESIGN 
 
A5381 is an observational, longitudinal prospective cohort study to assess therapeutic 
efficacy and emergence of HIV drug resistance following initiation of TLD for first- or 
second-line ART provided through PEPFAR-supported sites. Participants will be 
managed according to local standards of care, and preferably in accordance with current 
WHO Guidelines for HIV and TB treatment and monitoring. Participants will be divided 
into four study groups for enrollment and analysis: 
 
Group 1: Participants switching to TLD from a first-line regimen containing an NNRTI. 
These participants will be divided into two subgroups based upon their HIV-1 
RNA level in a sample obtained at entry, before starting TLD: Group 1a will 
include participants with viremia (HIV-1 RNA >1000 copies/mL at start of TLD), 
and Group 1b will include participants with suppressed viremia (HIV-1 RNA 
≤1000 copies/mL at start of TLD). 
 
Group 2: Participants switching to TLD from a second-line regimen containing a boosted 
PI. These participants will be divided into two subgroups based upon their HIV-
1 RNA level in a sample obtained at entry, before starting TLD: Group 2a will 
include participants with viremia (HIV-1 RNA >1000 copies/mL at start of TLD), 
and Group 2b will include participants with suppressed viremia (HIV-1 RNA 
≤1000 copies/mL at start of TLD). 
 
Group 3: Participants who are initiating concomitant TLD and RIF-containing TB 
treatment with an additional daily dose of DTG 50 mg within 7 days after entry. 
This includes: 
• 
Participants on TLD at screening, and initiating RIF-containing TB treatment 
within 7 days after entry. For these participants to be eligible, TLD 
treatment must have been taken for at least 6 consecutive calendar months 
before initiation of RIF-containing TB treatment. 
• 
Participants on RIF-containing TB treatment at screening, and initiating TLD 
within 7 days after entry. These participants may be ART-naïve, or may be 
switching from a first- or second-line ART regimen. TLD treatment must be 
started within 8 weeks (56 days) of the start of RIF-containing TB treatment. 
• 
Participants who are initiating both TLD and RIF-containing TB treatment 
within 7 days after entry. These participants may be ART-naïve, or may be 
switching from a first- or second-line ART regimen.   

 
24 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
NOTE: Participants who are enrolled in Groups 1, 2, or 4 and start RIF-
containing TB treatment while on study will have additional evaluations at the 
start and end of concomitant treatment. These participants will not be co-
enrolled in Group 3 (their additional evaluations will however be considered 
when analyzing data from Group 3).    
 
Group 4: ART-naïve participants initiating therapy with TLD.  
 
The study will enroll approximately 1350 participants: 540 in Group 1 with the goal of at 
least 180 in Group 1a, 540 in Group 2 with the goal of at least 180 in Group 2a, 90 in 
Group 3, and 180 in Group 4. 
 
The 90 participants in Group 3 do not include those already enrolled in Group 1, 2, or 4. 
Participants in Groups 1, 2, and 4 who start RIF-containing treatment during followup will 
have additional samples obtained at the start and end of concomitant treatment and will 
also be included in the Group 3 analysis. 
 
There are additional enrollment goals to provide information about outcomes on TLD in 
adolescents and individuals with NVP-based first-line ART exposure. In each group, 
there is a goal of enrolling 10% of participants who are adolescents aged 10 to 19 years. 
In Group 1a, there is also a goal to enroll 45 participants with NVP-based first-line ART 
exposure.  
 
Visits will include collection of plasma and DBS samples, and collection of medical 
history, safety (including pregnancy outcomes) and tolerability data. Plasma HIV-1 RNA 
will be batch tested regularly (e.g., monthly) in samples obtained per the SOE, and will 
be collected for retrospective testing per the SOE. Given reports of incomplete CD4+T-
cell recovery on DTG-containing regimens [33], CD4+/CD8+ testing will be done per the 
SOE in section 6.1. 
 
Confirmed virologic failure is defined as HIV-1 RNA >1000 copies/mL based on two 
consecutive plasma HIV-1 RNA viral load measurements at or after 6 months from 
starting TLD. If virologic failure occurs, on-treatment samples will be analyzed for 
evidence of immunologic failure, for TFV-DP levels in DBS, and genotypic and 
phenotypic analysis will be performed retrospectively on paired samples (entry and 
virologic failure) to assess the emergence of new drug resistance including to DTG. 
 
To support generalizability of results, to the extent practically possible, sites will 
approach all individuals starting TLD within the PEPFAR program for screening to 
determine eligibility and study participation. However, recognizing that testing of samples 
to determine HIV-1 RNA at start of TLD will be done after enrollment, enrollment may be 
restricted to selected sites as the study proceeds to achieve the targeted sample sizes of 
all Groups and subgroups. Specifically, a review of the relative enrollment into Group 1a 
versus 1b, and into Group 2a versus 2b, will be undertaken when 25% and 50% of the 
planned enrollment has been reached in Group 1 and Group 2. After these reviews, 
enrollment may be restricted to selected sites if this might help achieve the targeted 

 
25 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
sample sizes. For example, enrollment to Group 1 (or to Group 2) may need to be 
restricted to sites with higher proportions of participants with elevated HIV-1 RNA levels 
identified in samples obtained at the start of TLD. In addition, enrollment may be 
increased over the targets to facilitate reaching the enrollment goals for adolescents and 
participants switching from NVP-based first-line ART. To participate in Group 1, sites 
must be able to enroll participants switching from first-line ART with HIV-1 RNA 
>1000 copies/mL. To participate in Group 2, sites must be able to enroll 
participants switching from second-line ART with HIV-1 RNA >1000 copies/mL. 
These restrictions may change after a review of enrollment targets.   
  
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria 
 
4.1.1 Receiving care at a PEPFAR-supported site. 
 
4.1.2 Documentation of HIV-1 infection acceptable to the local PEPFAR-supported 
program to allow antiretroviral (ARV) treatment to be initiated or continued. 
 
4.1.3 Age ≥10 years. 
 
4.1.4 Ability and willingness of participant or legal guardian/representative to provide 
informed consent to participate in the study. 
 
4.1.5 Expectation that the participant will receive care within the local PEPFAR-
supported program and will be able to be followed for study evaluations for at 
least 6 months and ideally for 36 months. 
 
4.1.6 Group 1 participants:  
Receipt of an NNRTI-containing first-line ARV regimen from a clinic in a 
PEPFAR-supported country for at least 6 consecutive calendar months prior to 
study entry. 
 
NOTE: ARV treatment gaps are allowed, but treatment gaps should not exceed 
14 consecutive days in the 6 calendar months prior to study entry. 
 
Group 2 participants:   
Receipt of a boosted PI-containing second-line ARV regimen from a clinic in a 
PEPFAR-supported country for at least 6 consecutive calendar months prior to 
study entry. 
 
NOTE: ARV treatment gaps are allowed, but treatment gaps should not exceed 
14 consecutive days in the 6 calendar months prior to study entry. 
 
Group 4 participants:   
No current or prior ARV treatment. 
 

 
26 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
NOTE: Women who received ARV regimens only during pregnancy and/or 
breastfeeding for prevention of mother-to-child transmission but who have not 
taken any ARV drugs for at least 6 calendar months immediately prior to study 
entry will be allowed. 
 
4.1.7 For Group 1, 2, and 4 participants, expected initiation of TLD taken once daily 
within 7 days after study entry. 
 
NOTE: Group 1, 2, and 4 participants may not be on, or expected to start, RIF-
containing TB treatment at the time of study entry. 
 
4.1.8 For Group 3 participants already on RIF-containing TB treatment but not on TLD 
at study entry, expected initiation of TLD taken once daily with an additional daily 
dose of DTG 50 mg. This must be started within 7 days after study entry AND 
within 56 days after the start of RIF-containing TB treatment. These participants 
may be ART-naïve, or may be switching from a first- or second-line ART 
regimen. 
 
NOTE: For ART-naïve participants who start RIF-containing TB treatment first 
and then start TLD at a later date, screening must occur within 14 days before 
the intended TLD start date. 
 
4.1.9 For Group 3 participants not already on RIF-containing TB treatment but already 
on TLD at study entry, receipt of TLD for at least 6 consecutive calendar months 
prior to study entry AND expected initiation of RIF-containing TB treatment within 
7 days after study entry. 
 
4.1.10  For Group 3 participants not already on RIF-containing TB treatment or TLD at 
study entry, expected initiation of TLD and RIF-containing TB treatment within 7 
days after study entry. These participants may be ART-naïve, or may be 
switching from a first- or second-line ART regimen.   
 
4.1.11 For Group 1 participants, HIV-1 RNA >1000 copies/mL obtained as part of 
standard of care or with a real-time test within 12 weeks prior to study entry 
at any network-approved non-US laboratory that operates in accordance 
with Good Clinical Laboratory Practices (GCLP) and participates in 
appropriate external quality assurance programs. 
 
4.1.12 For Group 2 participants, HIV-1 RNA obtained as part of standard of care or 
with a real-time test within 12 weeks prior to study entry at any network-
approved non-US laboratory that operates in accordance with Good 
Clinical Laboratory Practices (GCLP) and participates in appropriate 
external quality assurance programs. 
a. If Group 2b reaches its enrollment target of 360 participants, the 
protocol team will notify sites that the following criteria will be 
implemented: For Group 2 participants, an HIV-1 RNA >1000 copies/mL 

 
27 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
will need to be obtained as part of standard of care or with a real-time 
test within 12 weeks prior to study entry. 
b. If Group 2a reaches its enrollment target of 180 participants, the 
protocol team will notify sites that the following criteria will be 
implemented: For Group 2 participants, an HIV-1 RNA ≤1000 copies/mL 
will need to be obtained as part of standard of care or with a real-time 
test within 12 weeks prior to study entry. 
 
4.2 
Exclusion Criteria 
 
4.2.1 Weight ≤30 kg. 
 
4.2.2 For participants already on ART in Groups 1, 2, and 3, known to have had an 
ART interruption encompassing the entire 14 day window (≥14 consecutive days) 
immediately prior to study entry.  
 
4.2.3 For Group 3, if a participant is already taking TLD at the time of study entry, HIV-
1 RNA >1000 copies/mL within the past 9 months while taking TLD with no 
subsequent HIV-1 RNA ≤1000 copies/mL. 
 
4.2.4 Prior enrollment in any group in this study. 
 
4.2.5 For Group 3 participants, already on concomitant TLD and RIF-containing TB 
treatment prior to study entry.    
 
4.2.6 For Group 2 participants with HIV-1 RNA >1000 copies/mL from a host 
country in which treatment guidelines require a genotypic test prior to 
switching patients on a boosted PI-containing second-line ARV regimen to 
TLD, 65R RT mutation within 12 weeks prior to study entry. 
 
4.3 
Study Enrollment Procedures 
 
4.3.1 Prior to implementation of this protocol, and any subsequent full version 
amendments, each site must have the protocol and the protocol consent form(s) 
approved, as appropriate, by their local institutional review board (IRB)/ethics 
committee (EC) and any other applicable regulatory entity (RE). Upon receiving 
final approval, sites will submit all required protocol registration documents to the 
Division of AIDS (DAIDS) Protocol Registration Office (PRO) at the Regulatory 
Support Center (RSC). The DAIDS PRO will review the submitted protocol 
registration packet to ensure that all of the required documents have been 
received.  
 
Site-specific informed consent forms (ICFs) WILL NOT be reviewed or approved 
by the DAIDS PRO. Sites will receive an Initial Registration Notification when the 
DAIDS PRO receives a complete registration packet. Receipt of an Initial 
Registration Notification indicates successful completion of the protocol 
registration process. Sites will not receive any additional notifications from the 

 
28 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
DAIDS PRO for the initial protocol registration. A copy of the Initial Registration 
Notification should be retained in the site's regulatory files.  
 
Upon receiving final IRB/EC and any other applicable RE approvals for an 
amendment, 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 ICF(s) 
WILL NOT be reviewed or approved by the DAIDS PRO. 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.  
 
Once a candidate for study entry has been identified, details will be carefully 
discussed with the participant. The participant (or, when necessary, the parent or 
legal representative if the participant is younger than 18 years of age or under 
guardianship) will be asked to read and sign the approved protocol consent form. 
For those under the age of consent, assent will also be obtained according to the 
local IRB requirements and regulations. 
 
Participants from whom a signed informed consent has been obtained may be 
screened and enrolled, if they otherwise qualify. An ACTG Screening Checklist 
must be entered through the DMC Study Enrollment System. 
 
4.3.2 Protocol Activation 
 
Prior to enrollment, sites must complete the Protocol Activation Checklist found 
on the ACTG Member website. This checklist must be approved prior to any 
screening of participants for enrollment.  
 
4.3.3 Participant Registration 
 
For participants from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the protocol, an ACTG Screening 
Failure Results form must be completed and keyed into the database.  
Participants who meet the enrollment criteria will be registered to the study 
according to standard ACTG DMC procedures.  
 
4.4 
Co-enrollment Guidelines  
• 
Non-US sites are encouraged to co-enroll participants in A5243, “Plan for Obtaining 
Human Biological Samples at Non-U.S. Clinical Research Sites for Currently 
Unspecified Genetic Analyses.” Co-enrollment in A5243 does not require permission 
from the A5381 protocol chairs.  

 
29 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
• 
For specific questions and approval for co-enrollment in other studies, sites should 
first check the PSWP or contact the protocol team via e-mail as described in the 
Study Management section. 
 
5.0 
STUDY TREATMENT  
 
This is an observational study; no treatment is provided.  
 
Qualifying treatment (initiated within 7 days after study entry): 
 
For Groups 1, 2, and 4: Co-formulated tenofovir disoproxil fumarate 300 mg/Lamivudine 
300 mg/Dolutegravir 50 mg (TLD) taken once daily. 
 
For Group 3: During TB treatment and for 2 weeks following completion of rifampicin-
containing TB treatment, TLD taken once daily with an additional daily dose of DTG 50 
mg such that DTG is taken twice daily. TB treatment will follow WHO Guidelines. 

 
30 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Evaluations (SOE) 
 
Table 6.1-1: Schedule of Evaluations for Participants Who Enter the Study in Group 1, 2, or 4 
Evaluation 
Screening 
Entry 
Post Entry Evaluations 
(Months) 
Virologic Failure 
Confirmation 
 
Initiating  
Concomitant 
TLD/RIF-
Based 
Treatment  
Ending 
Concomitant 
TLD/RIF-
Based 
Treatment 
Premat
ure 
TLD 
Disc. 
Evals 
Premature 
Study 
Disc. 
Evals 
- 2 Weeks 
Day 
0 
3 
6 
12 
18 
24 
30 
36 
≤ 6 Months After 
Initial Failing 
Viral Load 
- 1 Week Prior 
to Starting RIF 
+ 4 Weeks 
+ 4 
Weeks 
± 2 
Weeks 
± 4 Weeks 
Documentation 
of HIV 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ART, TB, & 
Contraception 
Medication 
History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adherence 
Assessment 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical 
Assessments 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BMI  
X 
 
 
X 
X 
 
X 
 
X 
 
 
 
 
X 
Quality of Life 
Questionnaire 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Fertility Desires 
Questionnaire 
 
X 
See section 6.3.8 
 
 
 
 
 
CD4+/CD8+ 
 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
X 
HIV-1 RNA, 
Real-Time For 
Groups 1 and 2 
Only 
X 
See section 
6.3.10  
 
 
 
 
 
 
 
 
 
 
 
 
 

 
31 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
Evaluation 
Screening 
Entry 
Post Entry Evaluations 
(Months) 
Virologic Failure 
Confirmation 
 
Initiating  
Concomitant 
TLD/RIF-
Based 
Treatment  
Ending 
Concomitant 
TLD/RIF-
Based 
Treatment 
Premat
ure 
TLD 
Disc. 
Evals 
Premature 
Study 
Disc. 
Evals 
- 2 Weeks 
Day 
0 
3 
6 
12 
18 
24 
30 
36 
≤ 6 Months After 
Initial Failing 
Viral Load 
- 1 Week Prior 
to Starting RIF 
+ 4 Weeks 
+ 4 
Weeks 
± 2 
Weeks 
± 4 Weeks 
HIV-1 RNA, 
Batch Test 
Monthly  
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
HIV-1 RNA, 
Retrospective 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
Plasma 
Resistance 
Testing - 
Standard 
Genotype  
Group 2 
Only; 
See section 
6.3.10 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
 
Plasma 
Resistance 
Testing - Next 
Generation 
Sequencing 
Genotype 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
 
Plasma 
Resistance 
Testing - 
Phenotype 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
 
DBS for TFV-DP 
 
 
 
X 
X 
 
X 
 
X 
X 
 
 
X 
X 
Stored Plasma  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Stored Whole 
Blood 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Stored Serum 
 
X 
 
X 
X 
 
X 
 
X 
 
 
 
 
 
Remote data 
collection 
 
 
When necessary; see section 
6.2.2 
 
 
 
 
 
 

 
32 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
Table 6.1-2: Schedule of Evaluations for Participants Who Enter the Study in Group 3 
Evaluation 
Screening 
Entry 
Ending 
Concomitant 
TLD/RIF 
Treatment 
Post Entry Evaluations 
(Months) 
Virologic Failure 
Confirmation 
Premat
ure 
TLD 
Disc. 
Evals 
Premature 
Study Disc. 
Evals 
- 2 Weeks 
Day 0 
+ 4 Weeks 
12 
18 
24 
30 
36 
≤ 6 Months After 
Initial Failing Viral 
Load 
+ 4 
Weeks 
± 4 Weeks 
Documentation of HIV 
X 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
ART, TB, & Contraception 
Medication History 
X 
X 
 
 
 
 
 
 
 
 
 
Adherence Assessment 
X 
X 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BMI  
X 
 
X 
X 
 
X 
 
X 
 
 
X 
Quality of Life Questionnaire 
 
X 
X 
 
 
 
 
 
 
 
 
Fertility Desires Questionnaire 
 
X 
See section 6.3.8 
 
 
 
CD4+/CD8+ 
 
X 
 
 
 
 
 
X 
X 
X 
X 
HIV-1 RNA, Batch Test Monthly  
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
HIV-1 RNA, Retrospective 
 
 
 
 
X 
 
X 
 
 
 
 
Plasma Resistance Testing - 
Standard Genotype  
 
X 
 
 
 
 
 
 
X 
X 
 
Plasma Resistance Testing - 
Next Generation Sequencing 
Genotype 
 
X 
 
 
 
 
 
 
X 
X 
 
Plasma Resistance Testing - 
Phenotype 
 
X 
 
 
 
 
 
 
X 
X 
 
DBS for TFV-DP 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
Stored Plasma  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Stored Whole Blood 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Stored Serum 
 
X 
X 
X 
 
X 
 
X 
 
 
 
Remote data collection 
 
 
When necessary; see section 6.2.2 
 
 
 
 

 
33 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
Table 6.1-3: Schedule of Site Evaluations 
Evaluation 
Timepoint 
Documentation of PEPFAR Site 
SOC  
Annually at each site, beginning with enrollment of its 
first participant 
 
6.2 
Timing of Evaluations 
 
6.2.1 Screening and Entry Evaluations  
 
Screening evaluations must be completed within 14 days prior to study entry 
unless otherwise specified (see sections 4.1 and 4.2). Screening and entry 
evaluations can be done on the same day or on different days. 
 
NOTE: For ART-naïve participants who start RIF-containing TB treatment first 
and then start TLD at a later date, screening should be delayed until within 14 
days before the intended TLD start date. 
 
In addition to data being collected on participants who enroll into the study, 
demographic and clinical data on screening failures will be captured in a 
Screening Failure Results form and entered into the ACTG database.  
 
For participants who are starting TLD:  
• 
Screening and entry evaluations must occur before the participant starts TLD. 
• 
Participants must begin TLD treatment within 7 days after entry. 
• 
If, immediately prior to starting TLD, the participant is known to have missed 
≥14 consecutive days of the prescribed first- or second-line ART, any 
remaining entry evaluations should not be performed and the participant 
should be discontinued from the study (refer to sections 6.2.3 and 9.2). 
 
For Group 3 participants already on TLD and are starting RIF-containing TB 
treatment:  
• 
Screening and entry evaluations must occur before the participant starts RIF-
containing TB treatment. 
• 
Participants must begin RIF-containing TB treatment within 7 days after entry. 
 
6.2.2 Post Entry Evaluations 
 
Post Entry Evaluations  
All participants will be followed for 36 months, with evaluations per the SOE 
irrespective of changes in ART.  
 
Post entry evaluations are calculated from the date of study entry and are 
targeted to be scheduled per the SOE. Data and samples that cannot be 
collected during the appropriate visit window, as specified in the SOE, can be 
collected outside of the window during an unscheduled visit. 
 

 
34 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
Virologic Failure Confirmation 
If a failing HIV-1 RNA sample is collected as part of standard of care 6 or more 
months after TLD initiation (or, in Group 3, after the end of concomitant TLD and 
RIF-containing TB treatment), then virologic failure confirmation evaluations 
should occur within 6 months or earlier, to be consistent with country guidelines, 
after the collection of that initial failing HIV-1 RNA sample. Adherence counseling 
may occur as part of standard of care between the visit at which the initial failing 
HIV-1 RNA sample was drawn and the confirmatory virologic failure visit. 
  
If possible, the virologic failure confirmation evaluations should coincide with the 
next scheduled study visit. If these do coincide, required evaluations should be 
conducted only once, even when evaluations are listed for both time points. For 
example, if the participant has a viral load result indicating viremia (HIV-1 RNA 
>1000 copies/mL) from the 12 month visit, then the virologic failure confirmation 
evaluations and the 18 month evaluations should be done once at the 18 month 
visit.  
 
If the participant has been switched to a new therapy prior to the virologic failure 
confirmation visit, then record the medication modifications per section 6.3.5, and 
continue the virologic failure confirmation visit per the SOE. 
 
Initiating Concomitant TLD/RIF-Containing TB Treatment, for Participants Who 
Enter the Study in Group 1, 2, or 4 
Evaluations for initiating concomitant TLD/RIF-containing TB treatment are 
performed only for participants who initiated concomitant TLD/RIF-containing TB 
treatment after study entry. These evaluations must be performed within one 
week prior to the participant starting RIF-containing TB treatment. 
 
Ending Concomitant TLD/RIF-Containing TB Treatment 
Evaluations for ending concomitant TLD/RIF-containing TB treatment must be 
performed within 4 weeks after the end of concomitant treatment. 
 
NOTE: For Group 3 participants, the Ending Concomitant TLD/RIF-Containing 
TB Treatment visit is expected to occur within the first year on study. 
 
Premature TLD Discontinuation Evaluations 
Participants who permanently discontinue TLD while on the study will have the 
TLD discontinuation evaluations performed within 4 weeks after TLD 
discontinuation. Participants who discontinue TLD will continue to be followed on 
study. 
 
Remote Data Collection 
Study visits may be conducted remotely (e.g., telephone, telehealth) in the 
following situations:  
• 
A participant is unable to attend a visit because of personal illness, 
illness among others in his or her home, or local conditions or 
guidelines restricting travel to the clinic.  

 
35 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
• 
The site is temporarily unable to conduct non-essential visits in the 
clinic; the site must inform the core team (actg.corea5381@fstrf.org) 
once when it has to stop non-essential visits. 
 
Regardless of the situation, sites should document which visits were 
conducted remotely, attempt to obtain as much of the visit-specific 
required information, based on the SOE, as possible, and record it. The 
impacted visits and rationale must be reported and documented, following 
instructions provided by the team or network leadership.  
 
The need for remote data collection, whether by site or across the network, 
is expected to be time-limited in relation to the COVID-19 pandemic. Each 
site should inform the core team when it is able to return to the conduct of 
non-essential visits. In consultation with ACTG Network leadership and the 
study sponsor, the protocol team may determine when remote data 
collection across the network is no longer required. When such a 
determination is made, study sites will be formally notified.  In all cases, it 
is the sites’ responsibility to inform their IRBs/ECs as needed. 
 
6.2.3 Premature Study Discontinuation Evaluations 
 
Premature Study Discontinuation Evaluations for Registered Participants Who 
Do NOT Start TLD (Groups 1, 2, and 4) or Who Do NOT Start Concomitant TLD 
and RIF-Containing Treatment (Group 3) 
All eCRFs must be keyed for the period up to and including the entry visit, but 
further followup is not required for these participants. 
 
Premature Study Discontinuation Evaluations for Participants Who Started TLD 
(Groups 1, 2, and 4) or Who Started Concomitant TLD and RIF-Containing 
Treatment (Group 3) 
Participants will have the premature study discontinuation evaluations performed 
prior to being taken off the study. 
 
6.3 
Instructions for Evaluations 
 
Each study site and laboratory involved in this study will comply with the DAIDS 
policy on Requirements for Laboratories Performing Testing for DAIDS-Supported 
and/or Sponsored Clinical Trials, which is available at: 
https://www.niaid.nih.gov/sites/default/files/laboratorypolicy1.pdf. 
 
All clinical and laboratory information required by this protocol is to be present in the 
source documents. Sites must refer to the Source Document Guidelines on the DAIDS 
website for information about what must be included in the source document: 
https://www.niaid.nih.gov/sites/default/files/daids-sourcedocpolicy.pdf. 
 
All stated evaluations are to be recorded on the eCRF unless otherwise specified. Refer 
to section 7.0 for information on the Division of AIDS Table for Grading the Severity of 

 
36 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
Adult and Pediatric Adverse Events (DAIDS AE Grading Table), and AE and toxicity 
reporting requirements. 
 
6.3.1 Documentation of HIV-1 
 
Section 4.1.2 specifies requirements for HIV-1 documentation. HIV-1 
documentation is not recorded on the eCRF. 
 
For participants who are <25 years of age at the time of study entry, document if 
the participant acquired HIV-1 infection perinatally.  
 
6.3.2 Medical History 
 
Medical history is performed per the SOE. The medical history must include all 
signs and symptoms regardless of grade and all diagnoses identified by the 
ACTG criteria for clinical events and other diagnoses regardless of grade within 
the past 30 days. In addition, the following diagnoses should be recorded 
regardless of when the diagnosis was made: 
• 
AIDS-defining conditions 
• 
Bone fractures (verbal history accepted) 
• 
Coronary heart disease 
• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Diabetes 
• 
Tuberculosis 
• 
Chronic hepatitis C 
• 
Chronic hepatitis B 
• 
HIV-associated nephropathy 
 
Any allergies to any medications and their formulations must also be 
documented.  
 
6.3.3 ART, TB, and Contraception Medication History 
 
ART and TB Medication History is performed per the SOE. A medication history 
must be present, including start and stop dates. The table below lists the 
medications that must be included in the history.  
 
Contraceptive Medication History is performed at entry for females of 
reproductive potential only. 
 
NOTE: Start and stop dates are not recorded for Contraceptive Medication 
History. 
 

 
37 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
Table 6.3.3-1:  Medication History 
Medication Category 
Complete History or Timeframe 
Antiretroviral therapy 
Complete History 
TB treatment 
For Group 3 Participants, History of the 
Current Period of TB Treatment 
Contraceptives expected to 
be effective at the present 
time 
Last 6 Months 
 
6.3.4 Adherence Assessment 
 
At screening, entry, and within 24 hours prior to TLD initiation (If TLD is initiated 
>24 hours after entry), assess adherence to prescribed ART medications over 
the prior 14 days. The adherence assessment evaluation should be conducted 
just once if screening, entry, and TLD initiation occur on the same day.  
 
Document if an adherence assessment was performed post-entry as part of the 
participant’s clinical care. 
 
Detailed adherence assessments are not recorded on the eCRF. 
 
See sections 4.2.2 and 9.2 for adherence requirements. 
 
6.3.5 Clinical Assessments  
 
Documentation of Clinical Events 
See section 8.2 for collection requirements for pregnancy. 
 
Breastfeeding is not recorded on the eCRF. 
 
Post-entry, record the following targeted events regardless of grade: 
• 
AIDS-defining conditions 
• 
Bone fractures (verbal history accepted) 
• 
Coronary heart disease 
• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Death 
• 
Depression 
• 
Diabetes 
• 
Immune Reconstitution Inflammatory Syndrome (IRIS) conditions 
• 
Suicidal ideation 
• 
Suicide attempt 
• 
Tuberculosis 
• 
HIV-associated nephropathy 
 

 
38 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
All clinical events that are recorded must have their severity graded. To grade 
clinical events, site must refer to the DAIDS AE Grading Table, corrected Version 
2.1, July 2017, which can be found on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-
tables. 
 
Refer to section 7.1 for AE collection requirements. 
 
Gynecological History 
At entry, all female participants will be asked about reproductive potential, 
including history of bilateral oophorectomy and hysterectomy, and 
postmenopausal status. Female participants of reproductive potential will 
be asked about their last menstrual period, history of intermenstrual 
bleeding, number of live births, and year of births.  
 
NOTE: “Postmenopausal” is defined as amenorrhea for at least 12 
consecutive months prior to study entry (in the absence of medications 
known to induce amenorrhea), and have a documented follicle-stimulating 
hormone (FSH) release factor measurement >40 mIU/mL or a result in the 
testing laboratory’s menopausal range. If an FSH level is not available, 
“postmenopausal” is defined as 24 consecutive months of amenorrhea 
prior to study entry (in the absence of medications known to induce 
amenorrhea). Follicle-stimulating hormone documentation is not reported 
on an eCRF. 
 
Documentation of Creatinine Results  
At entry and post-entry, record serum creatinine test results from any testing 
performed as part of the participant’s clinical care or as part of another ACTG or 
non-ACTG study.  
 
ART Treatment Modifications 
At entry and post-entry, record all ART medication modifications, including initial 
doses, participant-initiated modifications, and inadvertent and deliberate 
interruptions of more than 14 consecutive days since the last visit. Record any 
permanent discontinuation of treatment. 
 
TB Medication Modifications  
At entry and post-entry, record all TB medication modifications, including initial 
doses, participant-initiated modifications, and inadvertent and deliberate 
interruptions of more than 14 consecutive days since the last visit. Record any 
permanent discontinuation of treatment. 
 
6.3.6 BMI 
 
At screening, record height and weight for all participants.  
 
NOTE: Only weight is an exclusionary criterion (see section 4.2.1). 

 
39 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
Post entry, record weight for all participants. Record height only for participants 
who were age 10-19 years at study entry.  
 
6.3.7 Quality of Life Questionnaire 
 
The quality of life questionnaire will be administered per the SOE. The 
questionnaire is administered by the site staff, and requires an additional 10 
minutes of the participant’s time. 
 
The quality of life questionnaire includes the ACTG SF-21 questionnaire 
and additional questions. The questionnaire is posted on the DMC Portal in the 
Forms Management Utility. 
 
6.3.8  Fertility Desires Questionnaire 
 
The fertility desires questionnaire will be administered for female 
participants of reproductive potential who are ≥18 years of age. The 
questionnaire will be administered at entry. If a participant is already 
enrolled by the time the questionnaire is added to the SOE, then the 
questionnaire will be administered at the next scheduled study visit. The 
questionnaire is posted on the DMC Portal in the Forms Management 
Utility. 
 
6.3.9 Immunologic Studies 
 
CD4+/CD8+ 
Record absolute CD4+/CD8+ counts per the SOE. If available, also record 
CD4+/CD8+ percentages per the SOE. For entry and post-entry evaluations, all 
laboratories must possess DAIDS Immunology Quality Assessment (IQA) 
certification. CD4+/CD8+ results will only be shared with the treatment site if the 
evaluation at the time point is part of standard of care, as described in the 
national guidelines followed by the treatment site. Refer to the Manual of 
Procedures (MOPS) for additional instructions for sharing CD4+/CD8+ results. 
 
6.3.10 Virologic Studies 
 
HIV-1 RNA 
Plasma HIV-1 RNA must be obtained by a laboratory that possesses DAIDS 
Virology Quality Assurance (VQA) certification.   
 
Batch test and retrospective HIV-1 RNA results will only be shared with the 
treatment site if the evaluation at the time point is part of standard of care, as 
described in the national guidelines followed by the treatment site. HIV-1 RNA 
results will be shared with the treatment site and participant if the participant is 
prematurely discontinued from the study as a direct consequence of the HIV-1 

 
40 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
RNA test result, as described in section 9.2. Refer to the MOPS for additional 
instructions for sharing HIV-1 RNA results. 
 
HIV-1 RNA, Real-Time For Groups 1 and 2 Only  
Plasma HIV-1 RNA may be performed in real-time at screening within 12 
weeks prior to study entry for participants who are being screened for 
Groups 1 or 2. The real-time screening plasma HIV-1 RNA must be 
performed after confirmation that the participant meets all other eligibility 
criteria for Group 1 or 2 (see sections 4.1 and 4.2, and the MOPS). 
Screening plasma HIV-1 RNA testing must be done at a network-approved 
non-US laboratory that operates in accordance with Good Clinical 
Laboratory Practices (GCLP) and participates in appropriate external 
quality assurance programs. 
 
Plasma HIV-1 RNA, Batch Test Monthly  
Plasma HIV-1 RNA for monthly batch testing is collected per the SOE.  
 
Plasma HIV-1 RNA, Retrospective 
Plasma HIV-1 RNA will be collected per the SOE, and tested retrospectively. 
 
Plasma Resistance Testing – Standard Genotype, Next Generation Sequencing 
Genotype (NGS), and Phenotype 
Standard genotype, NGS genotype, and phenotype plasma resistance samples 
will be collected for all participants per the SOE.  
 
For participants in screening for Group 2a in countries that require 
exclusion of the 65R RT mutation before switching to TLD, standard 
genotype testing will be performed in real-time after confirmation of 
eligibility for Group 2 and HIV-1 RNA >1000 copies/mL within 12 weeks 
prior to study entry (see sections 4.1 and 4.2, and the MOPS). 
 
For participants with viremia (HIV-1 RNA >1000 copies/mL) at the 6 month 
visit (for Groups 1, 2, and 4) or at the Ending Concomitant TLD/RIF 
Treatment (for Group 3), standard genotype testing will be performed near-
time using a stored plasma sample.  
 
For participants with confirmed viremia (HIV-1 RNA >1000 copies/mL at the 
virologic failure confirmation visit), the following standard genotype samples that 
were drawn per the SOE will be batch tested near-time, and the NGS genotype 
and phenotype samples that were drawn per the SOE will be batch tested 
retrospectively: 
• 
The virologic failure plasma resistance sample 
• 
The entry plasma resistance samples will be tested at the same time as the 
virologic failure sample only if the participant had HIV-1 RNA >1000 
copies/mL at entry  
• 
The Premature TLD Discontinuation visit plasma resistance sample (for 
participants who have this visit) 

 
41 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
• 
The Initiating Concomitant TLD/RIF-Based Treatment plasma resistance 
sample (for participants who have this visit) 
 
Standard genotype and NGS genotype testing results will be shared with the 
treatment site in aggregate, if requested, 6 months after the end of the study.  
 
Phenotype testing will not be shared with the treatment site or the participant.  
 
Standard genotype, NGS genotype, and phenotype resistance testing results will 
be submitted to the DMC by the testing lab and will not be collected on an eCRF. 
 
DBS for TFV-DP 
Two dried blood spot samples for TFV-DP will be collected at the virologic failure 
confirmation timepoint. One DBS sample will be collected at all other timepoints 
indicated in the SOE. Dried blood spot samples for TFV-DP will be used to 
perform intracellular TFV-DP concentration measurements as a quantitative 
assessment of adherence in patients who fail therapy, for use as matched 
controls in the pharmacology nested case-control study (refer to section 11.3), 
and for future tests.  
 
Dried blood spot for TFV-DP results will not be shared with the treatment site or 
the participant. Dried blood spot for TFV-DP results will not be recorded on an 
eCRF. Refer to section 11.0 for additional pharmacology plan details. 
 
Stored Plasma 
Stored plasma will be collected per the SOE, and stored for future protocol-
required tests. 
 
6.3.11 Stored Whole Blood 
 
Whole blood will be collected per the SOE, and stored for retrospective 
hemoglobin A1c testing. 
 
6.3.12 Stored Serum 
 
Serum will be collected per the SOE, and stored for retrospective lipid and 
chemistry testing. 
 
6.3.13 Documentation of PEPFAR Site SOC 
 
Each site will record a description of SOC at the PEPFAR site and submit 
relevant country guidelines per the Schedule of Site Evaluations (Table 6.1-3). 
Refer to the MOPS for additional instructions. 
 

 
42 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
7.0 
ADVERSE EVENTS AND STUDY MONITORING 
 
7.1 
Adverse Event Collection Requirements for this protocol 
 
A5381 is an observational study and does not require Expedited Adverse Event (EAE) 
reporting to DAIDS via the DAIDS Adverse Experience Reporting System (DAERS). 
 
All AEs must be recorded on the eCRFs if the following criteria has been met. 
• 
All events, regardless of grade, that caused a change in TLD or TB 
medications, and that are considered to be related to TLD or TB medications.  
 
All AEs must have their severity graded. To grade AEs, sites must refer to the DAIDS 
AE Grading Table, corrected Version 2.1, July 2017, which can be found on the DAIDS 
RSC website at https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-
grading-tables. 
 
For reporting purposes, a voluntary MedWatch form may be submitted to the FDA by the 
site investigator for all TLD or TB related side effects that are “unexpected” per the latest 
version of the package insert. This protocol will use form FDA 3500 for voluntary 
reporting of adverse events. Instructions for completing MedWatch Form 3500 are found 
at https://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm. 
Sites are requested to forward the MedWatch report to the RSC. A copy of the 
MedWatch report should be sent to the DAIDS clinical representative via the RSC Safety 
Office. Upon submission of such a report to the regulatory authority, a copy of the report 
should be provided to the Protocol Team and DAIDS RSC via email.   
 
Site investigators are required to report to the site IRB as per the IRB requirements. Site 
investigators are responsible for following the in-country regulatory authority’s reporting 
requirements for observational studies. 
 
7.2 
Study Monitoring 
 
The Protocol Core Team will monitor the conduct of the study via regular summaries of 
accrual, study discontinuation, and data completeness, as appropriate.   
 
The study will undergo interim review as described in section 10.5.  
 
Detailed plans for study monitoring will be outlined in a Study Monitoring Plan developed 
by the Statistical and Data Management Center (SDMC) prior to enrollment of the first 
participant. 
 
 

 
43 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
8.0 
CLINICAL MANAGEMENT ISSUES 
 
8.1 
Toxicity  
 
Toxicity will be managed by the primary care provider per standard of care. 
 
8.2 
Pregnancy  
 
Pregnancy and pregnancy outcome will be recorded on the eCRFs. Pregnancies that 
occur on study should be reported prospectively to The Antiretroviral Pregnancy 
Registry. More information is available at www.apregistry.com. Telephone: 910-679-
1598; Fax: 44-1628-789-666 or 910-256-0637.  
 
Pregnancy Outcomes and Reporting 
If a woman has completed the study or chooses to discontinue from the study before the 
end of the pregnancy, then site staff should request permission to contact her regarding 
pregnancy outcomes at the end of pregnancy. If the information is obtained, pregnancy 
outcomes will be submitted on an eCRF at the end of the pregnancy.  
 
Pregnant women will continue on study and will follow the schedule outlined in section 
6.0. Pregnancy outcome will be submitted on an eCRF at the end of the pregnancy. 
 
8.3 
Breastfeeding 
 
Sites should follow local guidelines to prevent mother-to-child transmission during 
breastfeeding.   
 
9.0 
CRITERIA FOR DISCONTINUATION 
 
9.1 
Permanent and Premature Treatment Discontinuation 
 
This study is observational. All decisions about TLD discontinuation will be made by the 
participant’s primary care provider.  
 
9.2 
Premature Study Discontinuation 
 
The intent of the study is to follow all participants for 36 months irrespective of changes 
in ART. The following are therefore reasons for participant discontinuation from the 
study: 
• 
For Groups 1 and 2, and Group 3 if the participant is on ART prior to entry, 
participant is known to have had an ART interruption encompassing the entire 14 
day window (≥14 consecutive days) of prescribed first- or second-line ART 
immediately prior to initiating TLD. 
• 
Participant does not start taking TLD or RIF (if already taking TLD at study entry) 
within 7 days after the entry visit. 

 
44 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
• 
For Group 3 participants who were already taking TLD at the time of study entry, 
HIV-1 RNA >1000 copies/mL from the entry HIV-1 RNA test. These participants will 
be replaced. 
• 
Request by the participant to withdraw. 
• 
Request of the primary care provider if she or he thinks the study is no longer in the 
best interest of the participant. 
• 
At the discretion of the IRB/EC, National Institute of Allergy and Infectious Diseases 
(NIAID), Office for Human Research Protections (OHRP), PEPFAR, other 
government agencies as part of their duties, or investigator.  
 
10.0 
STATISTICAL CONSIDERATIONS  
 
10.1 
General Design Issues 
 
This is an observational, longitudinal prospective cohort study to assess therapeutic 
efficacy and emergence of HIV drug resistance following initiation of TLD for first- or 
second-line ART, or start of concomitant TLD and RIF-containing TB treatment. 
Participants will be enrolled into Groups 1, 2, 3, or 4 (see section 3.0 for definitions). 
However, for analysis purposes, Groups 1 and 2 will each be subdivided into two 
subgroups according to the results of HIV-1 RNA testing on samples obtained at the 
time of start of TLD: Groups 1a and 2a will include participants with viremia (HIV-1 RNA 
>1000 copies/mL) and Groups 1b and 2b will include participants with suppressed 
viremia (HIV-1 RNA ≤1000 copies/mL).  
 
The design of this study is driven by a desire to estimate the virologic success rate at 6 
months after starting TLD (Groups 1a, 1b, 2a, 2b, and 4), and at the end of concomitant 
TLD and RIF-containing TB treatment (Group 3), with good precision and to identify high 
rates of virologic failure with new drug resistance mutations in each of the 
group/subgroups as quickly as possible. Therefore, enrollment will proceed as quickly as 
possible, regardless of site distribution. As such, it is recognized that the study 
population will be a convenience sample of people starting TLD. 
 
However, recognizing that testing of samples to determine HIV-1 RNA at start of TLD will 
be done after enrollment, enrollment may be restricted to selected sites as the study 
proceeds in order to achieve the targeted sample sizes (refer to section 3.0).  
 
10.2 
Outcome Measures 
 
The following outcome measures will be evaluated for the purposes of characterizing 
outcomes in each of the study groups. 
 

 
45 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
10.2.1 
Primary Outcome Measures  
 
10.2.1.1 For Groups 1, 2, and 4: 
 
Virologic success, defined as suppression of plasma HIV-1 RNA to 
≤1000 copies/mL, at 6 months after starting TLD. This will be based 
on the measurement closest to exactly 6 months (i.e., 183 days) after 
the date of start of TLD, within the window of 6 months ±3 months 
(specifically 92 to 274 days, inclusive).  
 
For participants experiencing virologic failure (HIV-1 RNA >1000 
copies/mL) at 6 months after starting TLD, new DTG resistance 
mutations defined as those present at the time of the failing 
measurement that were not present at the time of starting TLD. 
 
10.2.1.2 For Group 3: 
 
Virologic success, defined as suppression of plasma HIV-1 RNA to 
≤1000 copies/mL, at the end of concomitant TLD (including an 
additional daily dose of DTG 50 mg such that DTG is taken twice 
daily) and RIF-containing TB treatment. This will be the measurement 
closest to the end of concomitant treatment within the window of 4 
weeks (28 days) before the end to 6 months (183 days) after the end, 
inclusive. 
 
For participants experiencing virologic failure (HIV-1 RNA >1000 
copies/mL) at the end of concomitant TLD (including an additional 
daily dose of DTG 50 mg such that DTG is taken twice daily) and 
RIF-containing TB treatment, new DTG resistance mutations defined 
as those present at the time of the failing measurement that were 
not present at the time of starting TLD.  
 
10.2.2 
Secondary Outcome Measures  
 
10.2.2.1 Treatment outcome measure based on the FDA Snapshot algorithm 
at 6 months, 12 months, 24 months, and 36 months after starting 
TLD in each of Groups, 1a, 1b, 2a, 2b, and 4; and at the end of 
concomitant TLD and RIF-containing TB treatment, 12 months, 24 
months, and 36 months after starting concomitant TLD and RIF-
containing TB treatment in Group 3. 
 
Based on the FDA Snapshot algorithm, participants’ outcomes will be 
grouped into the following three categories: 
• 
HIV-1 RNA ≤1000 copies/mL 
• 
HIV-1 RNA >1000 copies/mL (also includes participants who 
discontinued study/TLD for Other Reasons [e.g., withdrew 

 
46 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
consent, loss to followup, moved, etc.] while >1000 copies/mL; 
and participants who changed ART)   
• 
No Virologic Data (participants will be grouped by the following 
reasons: on study but missing data in window; discontinued 
study/TLD due to AE or death; discontinued study/TLD for other 
reasons [e.g., withdrew consent, loss-to-followup]) 
 
10.2.2.2 Suppression of plasma HIV-1 RNA to ≤1000 copies/mL at months 12, 
24, and 36.   
 
10.2.2.3 Time to confirmed virologic failure (VF), defined as the time from start 
of TLD to the first HIV-1 RNA >1000 copies/mL at or after 6 months 
which is confirmed by the next HIV-1 RNA measurement also being 
>1000 copies/mL (irrespective of the time between the initial and 
confirmatory measurements provided that they are obtained on 
different days, and irrespective of ART being received at the times of 
these measurements).  
 
10.2.2.4 Time to confirmed virologic failure (as defined above) with a new 
DTG resistance-associated mutation detected in population-based 
sequencing (i.e., one not present in the last population-based 
sequence obtained prior to initiating TLD). 
 
10.2.2.5 Time from start of TLD to TLD discontinuation.  
 
10.2.2.6 Time from start of TLD to TLD discontinuation due to toxicity. 
 
10.2.2.7 Summary score of quality of life measure.   
 
10.2.2.8 Time from start of TLD to first occurrence of a targeted clinical event 
(a list of targeted clinical events to be considered is provided in 
section 6.3.5). 
 
10.2.3 
Exploratory Outcome Measures 
 
10.2.3.1 Suppression of plasma HIV-1 RNA to three thresholds: ≤1000, ≤200, 
and <50 copies/mL at months 6, 12, 24, and 36   
 
10.2.3.2 Change in CD4+ cell count from entry to 36 months.  
 
10.2.3.3 TFV-DP levels in DBS. 
 
10.2.3.4 BMI. For adolescents, WHO BMI z-score will be used.  
 
10.2.3.5 Change in HbA1C from study entry at each measurement time 
during follow-up. 
 

 
47 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
10.2.3.6 Change in lipid measurements from study entry at each 
measurement time during follow-up. 
 
10.3 
Randomization and Stratification 
 
There is no randomization in this study. 
 
10.4 
Sample Size and Accrual 
 
A sample size of 180 participants each in Groups 1a, 2a, and 4; 360 participants each in 
Groups 1b and 2b; and 90 participants in Group 3 has been chosen to address the 
primary objectives. It is expected that accrual will take approximately 18 months after the 
first participant enrolls into the study.  
 
NOTE: The 90 participants in Group 3 does not include those already enrolled in Groups 
1, 2, or 4. Participants in Groups 1, 2, and 4 who start RIF-containing treatment during 
followup will have additional samples obtained at start and end of concomitant treatment 
and will be included also in the Group 3 analysis. In addition, Group 3 participants who 
were already taking TLD at the time of study entry and who were found to have HIV-1 
RNA >1000 copies/mL from the entry HIV-1 RNA test will be discontinued from the study 
and replaced. 
 
The larger sample sizes of 360 participants (with HIV-1 RNA ≤1000 copies/mL at start of 
TLD) in each of Groups 1b and 2b reflect the overall goal of enrolling 180 participants in 
each of Groups 1a and 2a (with HIV-1 RNA >1000 copies/mL at start of TLD), 
recognizing that testing of samples to determine HIV-1 RNA at start of TLD will be done 
after enrollment. The sample size of 360 participants is therefore an estimate which 
assumes that about one-third of participants in each of Groups 1 and 2 have HIV-1 RNA 
>1000 copies/mL at the start of TLD. Enrollment may be restricted to selected sites as 
the study proceeds in order to achieve the targeted sample sizes. The study design 
includes a review after 25% and 50% of the targeted sample size has been achieved in 
Group 1b and Group 2b to allow for the possibility that enrollment will need to be 
restricted to sites which enable the relative numbers in Groups 1a versus 1b, or 2a 
versus 2b, to be achieved.   
 
The sample size goals are driven by a desire to estimate the virologic success rate at 6 
months after starting TLD among those still on TLD at 6 months in each of Groups 1a, 
1b, 2a, 2b and 4 or at the end of concomitant TLD and RIF-containing TB treatment in 
Group 3 with good precision. Table 10.4-1 shows two-sided 95% confidence intervals 
(CI) and precision for selected observed virologic success rates and sample sizes. 
 
For Groups 1a, 2a, and 4, with the planned sample size of 180 participants in each, the 
width of a 95% CI will be approximately ±5.2% if the success rate is 85% as 
hypothesized (maximally, the width would be ±7.3% if the success rate was 50%). Even 
if as many as 20% of participants are lost to followup or discontinue TLD before 6 
months, the precision of the estimated success rate among those remaining on TLD at 

 
48 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
that time will still be good: 95% CI width of ±5.9% for success rate of 85% based on 144 
participants on TLD (maximally ±8.2% if the success rate is 50%). 
   
For Groups 1b and 2b, with the planned sample size of 360 participants in each, the 
width of a 95% CI will be approximately ±3.1% if the success rate is 90% as 
hypothesized (maximally, the width would be ±5.2% if the success rate was 50%).  Even 
if as many as 20% of participants are lost to followup or discontinue TLD before 6 
months, the precision of the estimated success rate among those remaining on TLD at 
that time will still be good: 95% CI width of ±3.5% if the success rate is 90% based on 
288 participants on TLD (maximally ±5.8% if the success rate is 50%). 
 
For Group 3, with the planned sample size of 90 participants, the width of a 95% CI will 
be approximately ±7.4% if the success rate is 85% as hypothesized (maximally, the 
width would be ±10.4% if the success rate was 50%). Even if as many as 20% of 
participants are lost to followup or discontinue TLD before the end of concomitant TLD 
and RIF-containing TB treatment in Group 3, the precision of the estimated success rate 
among those remaining on TLD at that time will still be good: 95% CI width of ±8.3% if 
the success rate is 85% based on 72 participants on TLD (maximally ±11.6% if the 
success rate is 50%). 
 
As a point of reference, the following are results based on the FDA Snapshot algorithm 
in DTG-containing arms from previous clinical trials: 
 
• 
STRIIVING: Among participants who were virally suppressed (HIV-1 RNA <50 
copies/mL) on first-line ART, 85% of the participants on DTG-containing ART 
achieved HIV-1 RNA <50 copies/mL at 24 weeks.  
• 
DAWNING: Among participants failing (HIV-1 RNA ≥400 copies/mL) first-line NNRTI-
containing ART, 82% of participants on DTG-containing ART achieved HIV-1 RNA 
<50 copies/mL at 24 weeks. 
• 
INSPIRING: Among HIV/TB coinfected ART-naïve participants, 81% of the 
participants on DTG-containing ART achieved HIV-1 RNA <50 copies/mL at 24 
weeks. 
• 
SINGLE: Among ART-naïve participants, 92% of the participants on DTG-containing 
ART achieved HIV-1 RNA <50 copies/mL at 24 weeks. 
 
NOTE: Instead of using the FDA Snapshot approach, our target for the primary outcome 
of the proportion with virologic success (HIV-1 RNA ≤1000 copies/mL) in each 
group/subgroup are restricted to those on TLD at 6 months. 
 

 
49 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
Table 10.4-1: Two-Sided 95% Confidence Interval (CI) and Precision for Selected 
Observed Virologic Success Rates and Sample Sizes 
Number of 
Participants in 
Group 
Observed 
Virologic 
Success Rate 
Two-Sided 95% CI* 
Precision 
90 
50% 
[39.7%, 60.3%] 
±10.4% 
 
70% 
[60.5%, 79.5%] 
±9.5% 
 
75% 
[66.1%, 83.9%] 
±9.0% 
 
80% 
[71.7%, 88.3%] 
±8.3% 
 
85% 
[77.6%, 92.4%] 
±7.4% 
 
90% 
[83.8%, 96.2%] 
±6.2% 
 
 
 
 
180 
50% 
[42.7%, 57.3%] 
±7.3% 
 
70% 
[63.3%, 76.7%] 
±6.7% 
 
75% 
[68.7%, 81.3%] 
±6.4% 
 
80% 
[74.2%, 85.8%] 
±5.9% 
 
85% 
[79.8%, 90.2%] 
±5.2% 
 
90% 
[85.6%, 94.4%] 
±4.4% 
 
 
 
 
360 
50% 
[44.8%, 55.2%] 
±5.2% 
 
70% 
[65.3%, 74.7%] 
±4.8% 
 
75% 
[70.5%, 79.5%] 
±4.5% 
 
80% 
[75.9%, 84.1%] 
±4.2% 
 
85% 
[81.3%, 88.7%] 
±3.7% 
 
90% 
[86.9%, 93.1%] 
±3.1% 
*Confidence Interval based on Wald (normal approximation to the binomial) Method 
 
We expect the proportion of participants experiencing virologic failure (HIV-1 RNA >1000 
copies/mL) with new DTG resistance mutations to be low at 6 months after starting TLD. 
As a point of reference, no participants in the DTG-containing arms of the above clinical 
trials had detectable treatment-emergent resistance-associated mutations at week 24. 
Table 10.4-2 shows 95% two-sided CIs and precision for selected sample sizes and 
observed cumulative proportions with virologic failure and new drug resistance 
mutations. 
 
NOTE: Many of the participants in the aforementioned clinical trials had screening 
resistance testing and were susceptible to at least one NRTI. Individuals eligible for this 
study may be failing for a longer time without regular virologic monitoring and have more 
accumulated resistance. 
 

 
50 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
Table 10.4-2: Two-Sided 95% Confidence Interval (CI) and Precision for Selected 
Sample Sizes and Observed Cumulative Proportions with Virologic Failure and New 
DTG Resistance Mutations 
Number of 
Participants in 
Group 
Observed Cumulative 
Proportion with Virologic 
Failure and New DTG 
Resistance Mutations 
Two-Sided 95% CI* 
Precision 
90 
1% 
[0.0%, 5.8%] 
±2.9% 
 
5% 
[1.5%, 11.7%] 
±5.1% 
 
10% 
[4.7%, 18.1%] 
±6.8% 
 
15% 
[8.3%, 24.1%] 
±7.9% 
 
20% 
[12.3%, 29.8%] 
±8.7% 
 
25% 
[16.5%, 35.2%] 
±9.4% 
 
 
 
 
180 
1% 
[0.1%, 3.8%] 
±1.9% 
 
5% 
[2.3%, 9.3%] 
±3.5% 
 
10% 
[6.0%, 15.3%] 
±4.7% 
 
15% 
[10.1%, 21.1%] 
±5.5% 
 
20% 
[14.4%, 26.6%] 
±6.1% 
 
25% 
[18.9%, 32.0%] 
±6.6% 
 
 
 
 
360 
1% 
[0.2%, 2.7%] 
±1.2% 
 
5% 
[3.0%, 7.8%] 
±2.4% 
 
10% 
[7.1%, 13.6%] 
±3.3% 
 
15% 
[11.5%, 19.1%] 
±3.8% 
 
20% 
[16.0%, 24.5%] 
±4.3% 
 
25% 
[20.6%, 29.8%] 
±4.6% 
*Confidence Interval based on Exact (Clopper-Pearson) Method 
 
10.5 
Data and Safety Monitoring  
 
This study will be reviewed by the ACTG ARTS TSG Study Monitoring Committee 
(SMC). The first review of virologic and safety outcomes will occur approximately 12 
months after the enrollment of the first participant. Thereafter, reviews will be completed 
every 6 months until all participants should have completed the 6 month visit (Groups 1, 
2, and 4) or the “ending concomitant TLD/RIF-based treatment” visit (Group 3). 
Thereafter, reviews will be completed every 12 months. Throughout, the SMC may 
request additional reviews but the study will be reviewed by the SMC at least annually. A 
review may also be convened if a concern is identified by the DAIDS clinical 
representative, the study chairs, or study statisticians in consultation with the team. 
 

 
51 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
At each interim review, safety outcomes in all groups/subgroups will be reviewed, and 
virologic outcomes in groups/subgroups with at least 25% of the planned enrollment 
having HIV-1 RNA results at 6 months of followup (Groups 1a, 1b, 2a, 2b, and 4) or at 
the end of concomitant TLD/RIF-based treatment (Group 3) will be reviewed to ensure 
participants’ safety.  
 
Efficacy outcome data will only be provided to the SMC while the study is ongoing 
(unless otherwise recommended by the SMC) except that results may be made 
available for public dissemination when 50% of the targeted accrual in a particular 
group/subgroup have completed the 6 month time point (for Groups 1, 2, and 4) or 
the Ending Concomitant TLD/RIF Treatment (for Group 3) (including from standard 
resistance testing), and when follow up is complete for all participants in a particular 
group/subgroup through to key time points, specifically 6, 12, 24, and 36 months 
(including from standard resistance testing). Group 1a results may also be made 
available for public dissemination when 50% of the targeted accrual to Group 1b 
have completed the 6 month time point. Similarly, Group 2a results 
may also be made available for public dissemination when 50% of the targeted 
accrual to Group 2b have completed the 6 month time point.  
The primary role of the interim reviews is to evaluate whether there are any 
unexpectedly high failure or HIV resistance rates, or safety concerns. In addition, the 
reviews will evaluate whether there are any issues with study conduct (e.g., low data 
completeness or unexpectedly high rate of loss to followup).  
 
Interim results provided at each SMC review will include: accrual, loss to followup, data 
completeness for primary outcomes, mortality, TLD discontinuations, AEs associated 
with TLD discontinuation, birth outcomes, primary virologic outcome measure, HIV 
resistance, the secondary treatment outcome measure based on the FDA Snapshot 
algorithm, and confirmed virologic failure. Results will be provided by group/subgroup. 
 
The study team will monitor the conduct of the study via regular summaries of accrual, 
study discontinuation, and data completeness. In the event that the study team becomes 
aware of a possible safety issue during the study, the study team including the DAIDS 
clinical representative may refer the issue to the SMC for review.  
 
10.5.1 Guideline for Monitoring Virologic Outcomes 
 
As a guideline for monitoring the primary outcome of virologic suppression at 6 
months after starting TLD (Groups 1a, 1b, 2a, 2b, and 4), and at the end of 
concomitant TLD and RIF-containing TB treatment (Group 3), a possible efficacy 
concern will be triggered if the upper bound of the two-sided 95% repeated CI for 
the proportion suppressed among those still on TLD at the measurement time is 
below the targeted proportion for the relevant group/subgroup as specified in the 
study hypotheses (see section 1.0). The repeated CI takes account of the 
multiple interim analyses that may be undertaken and will be calculated using the 
Lan and DeMets method with an O’Brien and Fleming spending function. Since 
early interim analyses (i.e., based on <50% information) can be extremely 
conservative, the nominal confidence level used at any interim analysis will be 

 
52 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
capped at 99.9%. If there is a possible efficacy concern, the SMC may make a 
recommendation to release the interim information for the affected 
group/subgroup to the study team and sponsors. In making a recommendation, 
the SMC may consider findings for other outcome measures and in specific 
subpopulations (e.g., the type of NNRTI-containing therapy in Groups 1a and 
1b). Table 10.5-1 illustrates potential observed proportions with virologic success 
at 6 months after starting TLD (Groups 1a, 1b, 2a, 2b, and 4) or at the end of 
concomitant TLD and RIF-containing TB treatment (Group 3), where the upper 
bound of the two-sided 95% repeated CI is below the pre-specified hypothesized 
proportion for the relevant group/subgroup at interim analyses with 25% and 50% 
information on the primary outcomes. 
 
Table 10.5-1: Observed Proportions with Virologic Success at 6 Months After 
Starting TLD (Groups 1a, 1b, 2a, 2b and 4) or at the End of Concomitant TLD 
and RIF-containing TB Treatment (Group 3) with the Upper Bound of the Two-
Sided 95% Repeated CI Is Below the Pre-Specified Hypothesized Proportion for 
the Relevant Group/Subgroup at an Interim Analyses with 25% or 50% 
Information on the Primary Outcomes. 
Percentage of 
Participants 
Evaluated at 
6 Months 
Group / 
Subgroup 
Number 
Evaluated  
Observed 
Proportion 
with Virologic 
Success 
95% Repeated CI* 
25% 
1a 
45 
61% 
[37.1%, 84.9%] 
1b 
90 
74% 
[58.8%, 89.2%] 
2a 
45 
61% 
[37.1%, 84.9%] 
2b 
90 
74% 
[58.8%, 89.2%] 
3 
23 
50% 
[15.7%, 84.3%] 
4 
45 
61% 
[37.1%, 84.9%] 
50% 
1a 
90 
71% 
[57.2%, 84.8%] 
1b 
180 
81% 
[72.6%, 89.4%] 
2a 
90 
71% 
[57.2%, 84.8%] 
2b 
180 
81% 
[72.6%, 89.4%] 
3 
45 
64% 
[43.3%, 84.7%] 
4 
90 
71% 
[57.2%, 84.8%] 
*Based on the O’Brien and Fleming stopping guideline assuming four equally 
spaced analyses, 99.9% (using a standard cap 99.9%) and 99.61% nominal 
confidence levels are used at interim analyses where 25% and 50%, 
respectively, of the planned enrollment have completed the 6 month visit (Groups 
1a, 1b, 2a, 2b, 4) or ending concomitant TLD/RIF-based treatment visit (Group 
3). 
 
10.6 
Analyses 
 
A detailed Statistical Analysis Plan for addressing the primary and secondary outcomes 
will be developed prior to enrollment of participants. The following provides a brief 
overview of the general approach. 

 
53 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
As noted above, efficacy outcome data will only be provided to the SMC while the study 
is ongoing (unless otherwise recommended by the SMC) except that results may be 
made available for public dissemination when 50% of the targeted accrual in a 
particular group/subgroup have completed the 6 month time point (for Groups 1, 
2, and 4) or the Ending Concomitant TLD/RIF Treatment (for Group 3) (including 
from standard resistance testing), and when follow up is complete for all participants 
in a particular group/subgroup through to key time points, specifically 6, 12, 24, and 36 
months (including from standard resistance testing). Group 1a results may also be 
made available for public dissemination when 50% of the targeted accrual to 
Group 1b have completed the 6 month time point. Similarly, Group 2a results 
may also be made available for public dissemination when 50% of the targeted 
accrual to Group 2b have completed the 6 month time point.  
 
10.6.1 Primary Analyses  
 
The primary objectives regarding virologic success rates will be addressed by 
computing the proportion of participants in each study group/subgroup for whom 
virologic success has been achieved (based on the primary outcome measure) 
together with the associated two-sided 95% Wald CI. To account for multiple 
interim analyses that may be undertaken, a 95% repeated CI will be calculated 
using the Lan and DeMets method with an O’Brien and Fleming spending 
function.  
 
The primary objective regarding drug resistance will be addressed by computing 
the cumulative proportion of participants in each study group with virologic failure 
and new DTG drug resistance mutations together with the associated two-sided 
95% CI. The two-sided 95% CI will be calculated using the Exact method since 
the proportion experiencing VF with new drug resistance mutations is expected 
to be low.   
 
The primary analysis will be restricted to participants who have not permanently 
discontinued TLD prior to the time of the qualifying HIV-1 RNA measurement, but 
the reasons for discontinuation of TLD beforehand will also be documented 
(including the possibility that discontinuation was motivated by efficacy failure 
though this is considered unlikely during the first 6 months of TLD as HIV-1 RNA 
and CD4 count monitoring is not generally conducted with such frequency in 
programs with PEPFAR-supported treatment). Although this is a reasonable 
presumption, if it is not the case, a sensitivity analysis will be undertaken to take 
account of such discontinuations in calculating the proportion.      
 
10.6.2 Secondary Analyses  
 
Virologic success at scheduled visit weeks will be analyzed using the same 
approach for the primary analysis and summaries of plasma HIV-1 RNA results 
will be provided. 
 

 
54 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
The proportion of participants in each of the treatment outcome categories as 
defined by FDA Snapshot algorithm will be calculated together with the 
associated two-sided 95% Wald CI. 
 
Patterns of drug resistance mutations at study entry and failure will be 
summarized for participants who experienced virologic failure. 
 
Reported toxicities will be tabulated. Premature treatment discontinuation will be 
summarized with detailed reasons provided.  
 
For time to event outcome measures, Kaplan-Meier estimates will be used to 
characterize the distribution of time to the event; the Kaplan-Meier estimate with 
the event will be obtained together with the associated 95% CI calculated using 
the Greenwood variance. For analyses of time to VF, the analysis will be based 
on the discrete scheduled measurement times and will be censored after the last 
scheduled HIV-1 RNA measurement; for other “time to event” analyses, time will 
be considered as continuous and censoring will be at the time of the last time of 
contact with the participant that provides the necessary evaluations to define the 
outcome measure. Sensitivity analyses will be undertaken to evaluate whether 
censoring due to participant loss to followup affects the conclusions that might be 
drawn from the analysis. 
 
Comparisons between groups with respect to the primary outcome measure will 
be based on estimating the difference in proportions with the associated 95% CI. 
Comparisons adjusted for baseline characteristics will also be undertaken. 
However, it is a recognized limitation of the study that enrollment to different 
groups may be differential among sites, and there may be unmeasured 
confounding variables that might influence the interpretation of the differences 
between groups. 
 
Comparisons by gender for primary and secondary outcome measures will also 
be undertaken within each group/subgroup. Details will be described in the 
Statistical Analysis Plan. It is recognized that this comparison may have limited 
precision and that it will be important to consider differential representation of 
males versus females among sites. 
 
11.0 
PHARMACOLOGY PLAN 
 
11.1 
Pharmacology Objectives 
 
Refer to section 1.4.5.  
 
11.2 
Pharmacology Study Design 
 
Dried blood spot samples will be collected for all study participants per the SOE (section 
6.1) and Instructions for Evaluations (section 6.3.9). Dried blood spot samples will be 
collected, stored, and shipped as per the LPC. 

 
55 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
11.2.1 Methods and Timing for Assessing, Recording, and Analyzing PK Outcome 
Measures 
 
Sparse sampling will be performed as per the SOE in section 6.1. A single pre-
dose PK sample will be collected at each visit, approximately 24 hours following 
the preceding day’s dose. The time of the sample collection as well as the last 
dose time will be strictly recorded.   
 
11.2.2 Pharmacokinetics: Blood Collection, Processing, and Storage 
 
The blood sample for measurement of TFV-DP concentrations will be collected 
by direct venipuncture. Whole blood will be spotted from the tube onto a 
Whatman 903 DBS card. Detailed blood processing, handling, and storage 
procedures can be found in the A5381 Laboratory Processing Chart (LPC).  
 
11.2.3 Laboratory Performing the Assays 
 
Intracellular TFV-DP concentrations from whole blood DBS samples will be 
determined by a validated high-performance liquid chromatography procedure 
performed according to written standard operating procedures. The intraday 
accuracy and intraday precision will be obtained with quality control samples, 
which will be analyzed concurrently with each set of volunteer samples. Quality 
control procedures will be in place to ensure stability of sample materials. 
 
11.3 
Primary and Secondary Data, Modeling, and Data Analysis 
 
To assess the relationship between TFV-DP in DBS and virologic failure at month 6, 12, 
24, and 36 on TLD, a nested case control study will be done by randomly selecting one 
control for each case of virologic failure on TLD (defined as HIV-1 RNA >1000 
copies/mL). Controls (defined as HIV-1 RNA ≤1000 copies/mL) will be matched for 
group, site, and duration on TLD. TFV-DP concentrations will be analyzed as continuous 
variables and as one of five categories developed from a healthy volunteer study [34]. 
For continuous variable analyses TFV-DP concentrations below the limit of quantification 
of the assay will be assigned a value of 0.5 × lower limit of quantification. Distribution of 
TFV-DP concentrations will be compared for cases and controls. C-statistic will be 
calculated to assess discrimination. Thresholds will be determined using the five 
categories of TFV-DP and from continuous variable analyses. Multivariable models will 
be developed to adjust for other factors predictive of virologic failure (age, sex, duration 
on ART, nadir CD4 count, group).   
 
An exploratory analysis will be done to assess the relationship between TFV-DP in DBS 
and emergence of integrase inhibitor resistance mutations in cases with virologic failure 
at month 6, 12, 24, and 36 on TLD who have had resistance testing done. 
 

 
56 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
11.4 
Anticipated Outcomes 
 
An overall virologic failure rate of 10% is expected. DBS samples from these participants 
will be used to estimate adherence, and the quantitative relationship between TLD 
adherence and virologic failure will be explored. 
 
There will be no overall correlation between DBS TFV-DP concentrations and virologic 
outcomes; however, at any given visit, absence of drug at one or more of the 
participant’s preceding visits will be associated with HIV-1 RNA >1000 copies/mL. 
 
12.0 
DATA COLLECTION AND MONITORING  
 
 
12.1 
Records to Be Kept 
 
Electronic case report form screens will be made available to sites for data entry. 
Participants must not be identified by name on any data submitted to the DMC. 
Participants will be identified by the patient identification number (PID) and study 
identification number (SID) provided by the ACTG DMC upon registration. 
 
12.2 
Role of Data Management 
 
12.2.1 Instructions concerning entering study data on eCRFs will be provided by the 
ACTG DMC. Each Clinical Research Site is responsible for keying the data in a 
timely fashion. 
 
12.2.2 It is the responsibility of the ACTG DMC to assure the quality of computerized 
data for each ACTG study. This role extends from protocol development to 
generation of the final study databases. 
 
12.3 
Clinical Site Monitoring and Record Availability 
 
12.3.1 Site monitors under contract to the NIAID will visit participating clinical research 
sites to review the individual participant records, including consent forms, eCRFs, 
supporting data, laboratory specimen records, and medical records (physicians’ 
progress notes, nurses’ notes, individuals’ hospital charts), to ensure protection 
of study participants, compliance with the protocol, and accuracy and 
completeness of records. The monitors also will inspect sites’ regulatory files to 
ensure that regulatory requirements are being followed and sites’ pharmacies to 
review product storage and management. 
 
12.3.2 The site investigator will make study documents (e.g., consent forms, drug 
distribution forms, eCRFs) and pertinent hospital or clinic records readily 
available for inspection by the local IRB, the site monitors, the NIAID, the OHRP, 
PEPFAR, and other local, US, and international regulatory entities for 
confirmation of the study data.  
 

 
57 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
13.0 
PARTICIPANTS 
 
13.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent documents (Appendices I, II, and III) and any 
subsequent modifications will be reviewed and approved by the IRB or EC responsible 
for oversight of the study. A signed consent form will be obtained from the participant (or 
parent, legal guardian, or person with power of attorney for participants who cannot 
consent for themselves, such as those below the legal age of consent). The consent 
form will describe the purpose of the study, the procedures to be followed, and the risks 
and benefits of participation. A copy of the consent form will be given to the participant, 
parent, or legal guardian, and this fact will be documented in the participant’s record. 
 
13.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the ACTG, IRB/EC, NIAID, OHRP, 
PEPFAR, and other local, US, and international regulatory entities as part of their duties, 
or designee.  
 
13.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, NIAID, OHRP, 
PEPFAR, or other country-specific government agencies as part of their duties to ensure 
that research participants are protected. 
 
14.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this study will be governed by ACTG policies. Any 
presentation, abstract, or manuscript will be made available for review by PEPFAR prior 
to submission.  
 
15.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the CDC and the 
National Institutes of Health. 
 
All dangerous goods and materials, including diagnostic specimens and infectious 
substances, must be transported using packaging mandated by CFR 42 Part 72. Please 
refer to instructions detailed in the International Air Transport Association (IATA) 
Dangerous Goods Regulations.  

 
58 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
16.0 
REFERENCES 
 
1. 
UNAIDS. Fact sheet - Latest global and regional statistics on the status of the AIDS 
epidemic. Geneva: Joint United Nations Programme on AIDS (UNAIDS); July 2018. 
http://www.unaids.org/sites/default/files/media_asset/UNAIDS_FactSheet_en.pdf. 
2. 
UNAIDS. 90–90–90: An ambitious treatment target to help end the AIDS epidemic. 
Geneva: Joint United Nations Programme on AIDS (UNAIDS); 2014. 
http://www.unaids.org/sites/default/files/media_asset/90-90-90_en.pdf. 
3. 
May MT, Gompeis M, Delpech V, et al. mpact on life expectancy of HIV-1 positive 
individuals of CD4+ cell count and viral load response to antiretroviral therapy. AIDS 
2014;28:1193-202. 
4. 
Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on 
combination antiretroviral therapy in high-income countries: a collaborative analysis of 
14 cohort studies. Lancet 2008;372:293-9. 
5. 
van Sighem AI, Gras LA, Reiss P, Brinkman K, de Wolf F; ATHENA National 
Observational Cohort Study Life expectancy of recently diagnosed asymptomatic HIV-
infected patients approaches that of uninfected individuals. AIDS 2010;24:1527-35. 
6. 
Samji H, Cescon A, Hogg RS, et al.; North American AIDS Cohort Collaboration on 
Research and Design (NA-ACCORD) of IeDEA  Closing the gap: increases in life 
expectancy among treated HIV-positive individuals in the United States and Canada. 
PLoS ONE 2013;8:e81355. 
7. 
Walmsley S, Baumgarten A, Berenguer J, et al. Dolutegravir plus abacavir/lamivudine 
for the treatment of HIV-1 infection in antiretroviral therapy-naive patients: week 96 and 
week 144 results from the SINGLE randomized clinical trial. J Acquir Immune Defic 
Syndr 2015;70:515-19. 
8. 
Zash R, Jacobson D, Mayondi G, et al. Dolutegravir / tenofovir / emtricitabine 
(DTG/TDF/FTC) started in pregnancy is as safe as efavirenz / tenofovir / emtricitabine 
(EFV/TDF/FTC) in nationwide birth outcomes surveillance in Botswana. [Abstract]. IAS 
2017: Conference on HIV Pathogenesis Treatment and Prevention, July 23-26, 2017, 
Paris, France. 
9. 
Agyemang C, Boatemaa S, Agyemang Frempong G, de-Graft Aikins A. Obesity in sub-
Saharan Africa. In Ahima RS (ed). Metabolic Syndrome. Springer, Cham; 2015.  
10. Bares SH, Smeaton LM, Xu A, Godfrey C, McComsey GA. HIV-infected women gain 
more weight than HIV-infected men following the initiation of antiretroviral therapy. J 
Womens Health (Larchmt) 2018; Apr 2. doi: 10.1089/jwh.2017.6717. 
11. Erlandson KM, Fiorillo SP, Cardoso SW, et al. Insulin-like growth factor is associated 
with changes in body composition with antiretroviral therapy initiation. AIDS Res Hum 
Retroviruses 2017;33:929-34.  
12. Kazooba P, Kasamba I, Mayanja BN, et al. Cardiometabolic risk among HIV-POSITIVE 
Ugandan adults: prevalence, predictors and effect of long-term antiretroviral therapy. 
Pan Afr Med J 2017;27:40. 
13. Menard A, Meddab L, Tissot-Dupont H, et al. Dolutegravir and weight gain: an 
unexpected bothering side effect? AIDS 2017;31:1499-500. 

 
59 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
14. Norwood J, Turner M, Bofill C, et al. Brief report: Weight gain in persons with HIV 
switched from efavirenz-based to integrase strand transfer inhibitor-based regimens. J 
Acquir Immune Defic Syndr 2017;76:527-31. 
15. Bakal DR, Coelho LE, Luz PM, et al. Obesity following ART initiation is common and 
influenced by both traditional and HIV-/ART-Specific Risk Factors. J Antimicrob 
Chemother 2018;73:2177-85. 
16. Clotet B, Feinberg J, van Lunzen J, et al. Once-daily dolutegravir versus darunavir plus 
ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results 
from the randomised open-label phase 3b study. Lancet 2014;383:2222-31. 
17. Orrell C, Hagins D, Belonosova E, et al. 2016. Superior Efficacy of 
Dolutegravir/Abacavir/Lamivudine Fixed Dose Combination Compared With Ritonavir 
Boosted Atazanavir Plus Tenofovir/Emtricitabine in Treatment-Naive Women With HIV-
1 Infection (ARIA Study). [Abstract 136]. 2016 Australasian HIV & AIDS Conference, 
November 16-18, 2016, Adelaide, South Australia.  
18. Aboud M, Kaplan R, Lombaard J, et al. Dolutegravir versus ritonavir-boosted lopinavir 
both with dual nucleoside reverse transcriptase inhibitor therapy in adults with HIV-1 
infection in whom first-line therapy has failed (DAWNING): an open-label, non-
inferiority, phase 3b trial. Lancet Infect Dis 2019; pii S1473-3099(19)30036-2. 
19. Raffi F, Jaeger H, Quiros-Roldan E, et al. Once-daily dolutegravir versus twice-daily 
raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 Study): 96 week 
results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis 
2013;13:927-35. 
20. Gallant J, Lazzarin A, Mills A, et al. Bictegravir, emtricitabine, and tenofovir alafenamide 
versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-
US-380-1489): a double-blind, multicentre, phase 3, randomised controlled non-
inferiority trial. Lancet 2017;390:2063-72. 
21. Sax PE, Pozniak A, Montes ML, et al. Coformulated bictegravir, emtricitabine, and 
tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, 
for initial treatment of HIV-1 infection (GS-US-380-1490): a randomised, double-blind, 
multicentre, phase 3, non-inferiority trial. Lancet 2017;390:2073-82. 
22. WHO. Updated Recommendations on First-Line and Second-Line Antiretroviral 
Regimens and Post-Exposure Prophylaxis and Recommendations on Early Infant 
Diagnosis of HIV. Geneva: World Health Organization; 2018. 
23. WHO. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and 
Preventing Hiv Infection : Recommendations for a Public Health Approach. Geneva: 
World Health Organization; 2016. 
24. Wijting I, Rokx C, Boucher C, et al. Dolutegravir as maintenance monotherapy for HIV 
(DOMONO): a phase 2, randomised non-inferiority trial. Lancet HIV;2017:4:e547-e554. 
25. Trevillyan JM, Hoy JF. Dolutegravir monotherapy as maintenance ART bites the dust. 
Lancet HIV 2017;4:e531-e532. 
26. Aboud M, Brites C, Hongzhou L, et al. DTG versus LPV/R in second line (DAWNING): 
Outcomes by WHO-Recommended NRTI Backbone. [Abstract 508]. Conference on 
Retroviruses and Opportunistic Infections (CROI 2018), March 4-7, 2018, Boston, MA.  

 
60 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
27. Sigaloff KC, Ramatsebe T, Viana R, de Wit TF, Wallis CL, Stevens WS. Accumulation 
of HIV drug resistance mutations in patients failing first-line antiretroviral treatment in 
South Africa. AIDS Res Hum Retroviruses 2012;28:171-5. 
28. Boender TS, Kitvo CM, Boerma RS, et al. Accumulation of HIV-1 drug resistance after 
continued virological failure on first-line ART in adults and children in sub-Saharan 
Africa. J Antimicrob Chemother 2016;71:2918-27. 
29. Hunt GM, Dokubo EK, Takuva S, et al. Rates of virological suppression and drug 
resistance in adult HIV-1-positive patients attending primary healthcare facilities in 
KwaZulu-Natal, South Africa. J Antimicrob Chemother 2017;72:3141-8. 
30. Gregson J, Tang M, Ndembi N, et al.; TenoRes Study Group. Global epidemiology of 
drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 
infection: a multicentre retrospective cohort study. Lancet Infect Dis 2016;16:565-75. 
31. Dooley KE, Sayre P, Borland J, et al. Safety, tolerability, and pharmacokinetics of the 
HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with 
rifabutin. J Acquir Immune Defic Syndr 2013;62:21-7. 
32. Dooley KE, Kaplan R, Mwelase N, et al. Safety and efficacy of dolutgravir-based ART in 
TB/HIV co-infected adults at week 48. [Abstract 33]. Conference on Retroviruses and 
Opportunistic Infections (CROI 2018), March 4-7, 2018, Boston, MA. 
33. Blanco JR, Alejos B, Moreno S. Impact of dolutegravir and efavirenz on immune 
recovery markers: results from a randomized clinical trial. Clin Microbiol Infect 
2018;24:900-77. 
34. Anderson PL, Liu AY, Castillo-Mancilla JR, et al. Intracellular tenofovir-diphosphate and 
emtricitabine-triphosphate in dried blood spots following directly observed therapy. 
Antimicrob Agents Chemother 2017;62(1):e01710-17. 

 
61 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
APPENDIX I: SAMPLE INFORMED CONSENT 
 
DIVISION OF AIDS 
AIDS CLINICAL TRIALS GROUP (ACTG) 
SAMPLE INFORMED CONSENT 
For protocol: A5381 
 
Observational Cohort to Assess Therapeutic Efficacy and Emergence of HIV Drug Resistance 
Following Initiation of Tenofovir-Lamivudine-Dolutegravir (TLD) for First- or Second-Line ART or 
with Rifampicin-Containing TB Treatment: The Hakim Study 
 
FINAL Version 2.0, 03/05/21 
 
 
SHORT TITLE FOR THE STUDY: Assess Therapeutic Efficacy and Emergence of HIV Drug 
Resistance Following Initiation of TLD 
 
 
SUMMARY 
 
This study is research. Your participation is voluntary. If you choose not to participate, it will not 
change your medical care or your access to antiretroviral (ARV) HIV medication.  
 
PURPOSE: The purpose of this observational study is to see how successful the ARV drug 
combination called Tenofovir-Lamivudine-Dolutegravir (TLD) is at treating HIV.  
 
NUMBER OF PARTICIPANTS: About 1350 people will take part in this study 
 
LENGTH OF STUDY: You will be in this study for about 3 years. 
 
REQUIRED ACTIVITIES: At every visit, you will have blood collected from a vein in your arm. 
You will also be asked questions about your current anti-HIV and anti-tuberculosis (TB) 
medications, and about any new HIV or TB diagnoses. 
 
RISKS: Taking blood may cause some discomfort, bleeding, or bruising where the needle 
enters the body, lightheadedness, and in rare cases, fainting or infection.  
 
This is an observational study of the antiretroviral HIV medication that you are receiving locally. 
So, the risks of taking those medications are not part of this study. Your medical provider should 
give you that information. 
 
BENEFITS: There will be no direct benefit to you if you take part in this study. 
 
 

 
62 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
INTRODUCTION 
 
You are being asked to take part in this research study because: 
 
1. 
You are living with human immunodeficiency virus (HIV-1), and you will soon start taking 
the antiretroviral (ARV) drug combination called Tenofovir-Lamivudine-Dolutegravir (TLD).  
 
OR 
 
2. 
You are living with HIV-1 and tuberculosis (TB), you have started or will soon start taking 
the ARV drug combination TLD, and you have started or will soon start taking the TB 
medication that includes the drug rifampicin. 
 
You are encouraged to discuss the risks and benefits of TLD with your clinician. 
 
This study is sponsored by the National Institutes of Health (NIH). The doctor in charge of this 
study at this site is: (insert name of Principal Investigator). Before you decide if you want to be a 
part of this study, we want you to know about the study.  
 
This is a consent form. It gives you information about this study. The study staff will talk with you 
about this information. You are free to ask questions about this study at any time. If you agree to 
take part in this study, you will be asked to sign this consent form. You will get a copy to keep. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
TLD is being used more widely across the world to treat HIV. This is an observational study (a 
type of study in which participants are observed and certain outcomes are measured). The aim 
of this study is to observe how successful TLD is at treating HIV, in the following groups of 
people: 
• 
People switching to TLD, after taking anti-HIV medication that contains a NNRTI drug (non-
nucleoside reverse transcriptase inhibitor, such as Efavirenz or Nevirapine) (Group 1). 
• 
People switching to TLD, after taking anti-HIV medication that contains a PI drug (protease 
inhibitor, such as Lopinavir or Atazanavir) (Group 2). 
• 
People taking TLD and receiving medication for TB that includes the drug rifampicin (Group 
3). These people must be starting one or both of these medications when they enter the 
study. 
• 
People starting TLD who have not taken anti-HIV medication before (Group 4). 
  
Another goal of this study is to use genetic testing of the virus (HIV) to see how often HIV is 
resistant to TLD. Genetic testing of the virus is one way to see if the TLD medication is not 
working to treat your HIV infection. 
 
The United States Food and Drug Administration (US FDA) has approved Tenofovir, 
Lamivudine, and Dolutegravir for treatment of HIV. 

 
63 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
If you enter the study 
If you decide to take part in this research study, after you have read and signed this informed 
consent form, you will come to the clinic for a screening visit to make sure you meet the 
requirements for joining the study. If you are eligible for the study and you choose to enroll, you 
will have the entry evaluations done. You have to start taking TLD or rifampicin (if you are 
already taking TLD) within 7 days after this entry visit to remain on the study. You will have up to 
7 scheduled visits on this study. Your last visit will be about 3 years after you enter the study.  
• 
You will be seen at the clinic 3 months and 6 months after your screening and entry visit.  
• 
Or, if you are receiving treatment for TB when you start the study, you will have one visit 
within 4 weeks after you finish taking your TB treatment. This visit will be in the first year 
after your screening and entry visit. 
• 
You will then be seen at the clinic about once every 6 months.  
 
Study visits may be conducted remotely (like over the telephone) if you are unable to 
attend a visit for any of the following reasons: 
• 
You are sick.  
• 
Someone in your home is sick.  
• 
Local conditions or guidelines restrict travel to the clinic. 
• 
The site is temporarily unable to have these visits in the clinic. 
 
If any of the following events occur, you may have to come back to the clinic for an additional 
visit. If possible, these visits will coincide with your next scheduled visit. 
• 
Virologic failure confirmation: If a test to see how much HIV is in your blood shows that your 
anti-HIV medication might not be helping you, you will have a visit about 6 months later.  
• 
Starting rifampicin-Based TB treatment: If you start taking TB medicine that includes 
rifampicin while also taking TLD for HIV, you will have a study visit. 
• 
Ending rifampicin-Based TB Treatment: If you finish taking TB medicine that includes 
rifampicin while also taking TLD for HIV, you will have a study visit. 
• 
TLD Discontinuation: If you stop taking TLD while on the study, you will have a study visit, 
and then continue on study. 
• 
Early Study Discontinuation (Leaving the Study Early): If you leave the study early, you will 
be asked to return to the clinic for one final visit. 
 
If you do not enroll into the study 
If you decide not to take part in this study or if you do not meet the eligibility requirements, we 
will still use some of your information. As part of this screening visit, some demographic (for 
example, age, gender, race), clinical (for example, disease condition, diagnosis), and laboratory 
(for example, CD4 cell count, viral load) information is being collected from you so that AIDS 
Clinical Trial Group (ACTG) researchers may help determine whether there are patterns or 
common reasons why people do not join a study. 
 
Information Collected at Screening 

 
64 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
There is some information that we collect on everyone who is screened for an ACTG 
study. As part of your screening visit, some demographic (for example, age, gender, 
race), clinical (for example, disease condition, diagnosis), and laboratory (for example, 
CD4 cell count, viral load) information will be collected from you. 
  
We will collect this information even if you do not enroll in this study. This information is 
collected so that ACTG researchers may determine whether there are patterns and/or 
common reasons why people do not join a study. 
CAN I CHOOSE THE TYPES OF RESEARCH THAT MY SAMPLES AND INFORMATION 
ARE USED FOR? 
 
Some of your blood will be stored and used to check the level of anti-HIV medications in your 
blood, and for immunologic and viral testing that is required for this study.   
 
Samples collected from you will be stored in the United States. Identifiers will be removed 
from your samples and from any private information that has been collected about you. 
This means that no one looking at the labels or at other information will be able to know 
that the samples or information came from you.  
 
All information collected about you as part of the study will be sent securely to the ACTG 
statistical and data management center in the United States for combining with 
information from other study participants and statistical analysis of study results. Your 
name and other personal identifiers will not be sent. Your research site is responsible for 
sending your information in accordance with the laws, regulations and policies of your 
country and research site. 
 
The tests described above are required by this study. If you do not agree to the storage 
or testing that has been described above, you should not join this study.  
 
Please refer to Attachment I-A to consent for use of your samples in other studies. 
 
 
A5381 Study Visits 
The study staff can answer any questions you have about individual study visits, and how long 
they will last, or about the tests that will occur. The table below can be used as a quick 
reference for you, along with the explanations that follow. 
 
Appendix I Table 1:  Study Schedule for Groups 1, 2, and 4. You will follow this study schedule 
if you are not receiving treatment for TB when you start the study. 

 
65 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
Evaluation 
Screening Visit 
Entry Visit 
Post Entry Visits (Months) 
Unscheduled Visits 
3 
6 
12 
18 
24 
30 
36 
Virologic 
Failure 
Confirmation 
Starting 
Rifampicin-
Based TB 
Treatment 
Ending 
Rifampicin-
Based TB 
Treatment 
TLD 
Discontinuation 
Early Study 
Discontinuation 
Documentation of 
HIV Status 
√ 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
Medical & 
Medication 
History 
√ 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
Adherence 
Assessment 
√ 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical 
Evaluations 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Height & Weight 
√ 
 
 
√ 
√ 
 
√ 
 
√ 
 
 
 
 
√ 
Quality of Life 
Questionnaire 
 
√ 
 
√ 
 
 
 
 
 
 
 
 
 
 
Fertility Desires 
Questionnaire 
 
√ 
At one visit if you did not have 
the questionnaire at Entry 
 
 
 
 
 
Blood Collection 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Appendix I Table 2:  Study Schedule for Group 3. You will follow this study schedule if you are 
receiving treatment for TB when you start the study. 
Evaluation 
Screening Visit 
Entry Visit 
Post Entry 
Visit 
Post Entry Visits 
(Months) 
Unscheduled Visits 
Ending 
Rifampicin-
Based TB 
Treatment 
12 
18 
24 
30 
36 
Virologic 
Failure 
Confirmation 
TLD 
Discontinuation 
Early Study 
Discontinuation 
Documentation of HIV Status 
√ 
√ 
 
 
 
 
 
 
 
 
 
Medical & Medication History 
√ 
√ 
 
 
 
 
 
 
 
 
 
Adherence Assessment 
√ 
√ 
 
 
 
 
 
 
 
 
 
Clinical Evaluations 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Height & Weight 
√ 
 
√ 
√ 
 
√ 
 
√ 
 
 
√ 
Quality of Life 
Questionnaire 
 
√ 
√ 
 
 
 
 
 
 
 
 
Fertility Desires 
Questionnaire 
 
√ 
At one visit if you did not have the 
questionnaire at Entry 
 
 
 
Blood Collection 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 

 
66 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
Description of Study Procedures 
Documentation of HIV Status: Your HIV infection status will be documented.  
 
Medical & Medication History: You will be asked questions about your medical and medication 
history, and you will be asked about past and current anti-HIV and anti-TB medications that you 
have taken or are taking. 
 
Adherence Assessment: You will be asked about adherence to your anti-HIV or anti-TB 
medications (how you are currently taking your medications). 
 
Clinical Evaluations: You will be asked questions about any new HIV and TB diagnoses, and 
you will be asked about any changes in the anti-HIV and anti-TB medications that you are 
taking. Other health events will be reviewed. This information will be shared with you, if 
applicable. 
 
Height & Weight: Your height and weight will be measured. If you are over 19 years old when 
you enter the study, your height will only be measured at screening. 
 
Quality of Life Questionnaire: You will be asked questions about how you feel and how you 
have been sleeping. 
 
Fertility Desires Questionnaire: If you can become pregnant, you will be asked at entry 
about your plans for having children. If you are already in the study when this 
questionnaire is added, then at your next scheduled study visit, you will be asked about 
your plans for having children. 
 
Blood Collection: You will have between about 10 mL (1 tablespoon) and about 52 mL (3.5 
tablespoons) of blood drawn at each visit for some or all of the following tests: 
 
• 
To test how much HIV is in your blood (viral load). 
• 
To test how many CD4/CD8 cells (infection-fighting cells) are in your blood. 
• 
For genetic testing of the virus (HIV). This testing is done to see if the TLD medication is a 
good choice of medication to treat your HIV infection.  
• 
For a dried blood spot. The dried blood spot test will be used to test how much anti-HIV 
medication is in your blood, or will be stored for future tests.  
• 
To be stored for future tests. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 1350 people will take part in this study 
 
 

 
67 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for about 3 years.  
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
 
• 
The study is stopped or cancelled.  
• 
You are not able to attend the study visits as required by the study. 
• 
You are taking HIV medications before switching to TLD, and you missed 14 or more days 
in a row of those medications immediately before switching to TLD. 
• 
You do not start taking TLD or rifampicin (if you are already taking TLD when you enter the 
study) within 7 days after the entry visit. 
• 
If all three of these things are true: You have a viral load (how much HIV is in your blood) 
that is more than 1000 copies/mL at your study entry visit, and you are receiving medication 
for TB that includes the drug rifampicin, and you started taking TLD before entering the 
study.  
• 
Your primary care doctor requests that you be taken off the study. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
Risks of Drawing Blood 
Taking blood may cause some discomfort, bleeding, or bruising where the needle enters the 
body, lightheadedness, and in rare cases, fainting or infection. 
 
Risks of Social Harm 
It is possible that participating in this study will make it difficult for you to keep your HIV or TB 
status secret from people close to you. This may include your parent or guardian if you are 
under 18 years old. This may lead to unwelcome discussions about or reactions to your HIV or 
TB status. Please talk with the study staff if you have any concerns about this. 
 
Risks of ARV Medications 
This is an observational study of the ARV treatment that you are receiving locally. So, the risks 
of taking those medications are not included in this study. Your medical provider should give 
you that information. 
 
 
WHAT HAPPENS IF I BECOME PREGNANT WHILE TAKING PART IN THIS STUDY? 
 
If you become pregnant while on study, the study staff would like to obtain information from you 
about the outcome of the pregnancy (even if it is after your participation in the study ends). You 
will continue on the study. If you are taking anti-HIV drugs when you become pregnant, your 

 
68 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
pregnancy will be reported to an international database that collects information about 
pregnancies in women taking anti-HIV drugs. This report will not use your name or other 
information that could be used to identify you. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you take part in this study, there will be no direct benefit to you. Information learned from this 
study may help others who have HIV. 
 
You may receive ancillary benefit from taking part in this study, such as receiving test results as 
described in the next section. 
  
 
WILL I RECEIVE THE RESULTS OF ANY TESTS? 
 
You will receive the result of tests that are performed as part of the recommended medical care 
for HIV or TB in your country (for example, some viral load and CD4 count tests). (Site to insert 
site-specific information about CD4 count and viral load test results participants will receive as 
part of standard of care; if the site is in a country in which treatment guidelines require a 
genotypic test prior to switching patients on a boosted PI-containing second-line ARV 
regimen to TLD, include: “If genetic testing of the virus (HIV) is done at your screening 
visit, you will receive the result of that test.”)  
 
Some tests are done only for research purposes, to improve the care of people living with 
HIV/AIDS. This includes tests done with dried blood spots and genetic testing of the virus (HIV). 
This also includes some of the tests in this study that are not part of recommended medical care 
for HIV or TB in your country. You and your treatment provider will not receive the result of 
these tests. (Site to insert site-specific information about CD4 and viral load test results that are 
not part of standard of care, which participants will not receive.) 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
We will do everything we can to protect your privacy. In addition to the efforts of the study staff 
to help keep your personal information private, we have gotten a Certificate of Confidentiality 
from the US Federal Government. This certificate means that researchers cannot be forced to 
tell people who are not connected with this study, such as the court system, about your 
participation. Also, any publication of this study will not use your name or identify you 
personally.  
 
Your records may be reviewed by the ACTG, United States President’s Emergency Plan for 
AIDS Relief (PEPFAR), the US Office for Human Research Protections (OHRP), or other local, 
US, and international regulatory entities as part of their duties (insert name of site) institutional 
review board (IRB) or Ethics Committee (a committee that protects the rights and safety of 
participants in research), the NIH, study staff, study monitors, and their designees. Having a 

 
69 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
Certificate of Confidentiality does not prevent you from releasing information about yourself and 
your participation in the study. 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities. 
 
A description of this clinical trial 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.  
 
 
WHAT ARE THE COSTS TO ME? 
 
Taking part in this study may lead to added costs to you and your insurance company. In some 
cases, it is possible that your insurance company will not pay for these costs because you are 
taking part in a research study. (If applicable to your site. Delete if this does not apply.) 
 
Anti-HIV and anti-TB medicines will not be provided by the study. 
 
 
WILL I RECEIVE ANY PAYMENT? 
 
You may be reimbursed for your time and travel expenses as part of your participation in this 
study. (Site to insert site-specific information about payment.) 
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of being in this study, you will be given immediate treatment for 
your injuries.  
 
[Sites: Please modify (if necessary) and insert one of these two statements, as appropriate to 
your site. If your site is required to carry CTI, this must be indicated in the informed consent.] 
• 
This site has clinical trials insurance. This insurance will allow the site to provide you with 
monetary compensation if you suffer harm as a result of participating in this research study.  
• 
The cost for this treatment will be charged to you or your insurance company. There is no 
program for compensation either through this institution or the NIH.  
 
You will not be giving up any of your legal rights by signing this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. Your decision will not have any impact on your participation in 

 
70 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
other studies conducted by NIH and will not result in any penalty or loss of benefits to which you 
are otherwise entitled. 
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. If you want the results of the study, let the study staff 
know. 
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
 
• 
Name of the investigator or other study staff 
• 
Telephone number of above  
 
For questions about your rights as a research participant, contact: 
 
• 
Name or title of person on the Institutional Review Board (IRB) or other organization 
appropriate for the site 
• 
Telephone number of above 
 

 
71 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
SIGNATURE PAGE 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to take part in this study, please sign your name below. 
 
 
 
 
____________________________ __________________________________ 
Participant’s Name (print) 
 
Participant’s Signature and Date 
 
 
____________________________ __________________________________ 
Participant’s Legally Authorized 
Legally Authorized Representative 
Representative (print) Signature  
and Date 
(As appropriate) 
 
 
____________________________ __________________________________ 
Study Staff Conducting 
 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
____________________________ __________________________________ 
Witness’s Name (print) 
 
Witness’s Signature and Date 
(As appropriate) 
 
 
 
 

 
72 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
ATTACHMENT I-A:  CONSENT FOR USE OF SAMPLES IN OTHER STUDIES 
 
When samples are no longer needed for this study, the ACTG may want to use them in 
other studies and share them with other researchers. These samples are called “extra 
samples.” The ACTG will only allow your extra samples to be used in other studies if 
you agree to this. If you have any questions, please ask. 
 
Identifiers will be removed from your samples and from any private information that has 
been collected about you. This means that no one looking at the labels or at other 
information will know that the samples or information came from you.  
 
Extra samples are stored in a secure central place called a repository. Your samples 
will be stored in the ACTG repository located in the United States. 
 
There is no limit on how long your extra samples will be stored.  
[Site: Revise the previous sentence to insert limits if your regulatory authority imposes 
them.] 
 
When a researcher wants to use your samples and information, their research plan must 
be approved by the ACTG. Also, the researcher’s institutional review board (IRB) or 
ethics committee (EC) will review their plan. [Site: If review by your institution’s 
IRB/EC/RE is also required, insert a sentence stating this.] IRBs/ECs protect the rights 
and well-being of people in research. If the research plan is approved, the ACTG will 
send your samples to the researcher’s location. This means that researchers who are not 
part of the protocol team may use your samples without asking you again for your 
consent.  
 
You will not be paid for your samples. Also, a researcher may make a new scientific 
discovery or product based on the use of your samples. If this happens, there is no 
plan to share any money with you.  
 
You may withdraw your consent for research on your extra samples at any time, and the 
specimens will be discarded. 
 
Please choose the response that matches what you want by putting your initials in the 
space provided. Please ask the staff any questions that you have before you indicate 
your selection. 
 
Research without Human Genetic Testing  
If you agree, your extra samples may be stored (with usual protection of your identity) 
and used for ACTG-approved HIV-related research that does not include human genetic 
testing. 
 
____ (initials) I understand and I agree to this storage and possible use of my samples  
 
OR 

 
73 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
____ (initials) I understand but I do not agree to this storage and possible use of my 
samples 
 
Research with Human Genetic Testing  
Your extra samples will not be used for human genetic testing.  
 
The ACTG has a different study that collects samples for genetic testing. This study is 
called ACTG A5243, Plan for Obtaining Human Biological Samples at Non-US Clinical 
Research Sites for Currently Unspecified Genetic Analyses. 
 
Your site might ask you if you would like to participate in this study if it is being done 
where you live. If you would like to participate, you will sign a separate consent form. 

 
74 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
APPENDIX II: SAMPLE PARENTAL INFORMED CONSENT 
 
DIVISION OF AIDS 
AIDS CLINICAL TRIALS GROUP (ACTG) 
SAMPLE INFORMED CONSENT 
For protocol: A5381 
 
Observational Cohort to Assess Therapeutic Efficacy and Emergence of HIV Drug Resistance 
Following Initiation of Tenofovir-Lamivudine-Dolutegravir (TLD) for First- or Second-Line ART or 
with Rifampicin-Containing TB Treatment: The Hakim Study 
 
FINAL Version 2.0, 03/05/21 
 
 
SHORT TITLE FOR THE STUDY: Assess Therapeutic Efficacy and Emergence of HIV Drug 
Resistance Following Initiation of TLD 
 
 
SUMMARY 
 
This study is research. Your child’s participation is voluntary. If you choose not to let your child 
participate, it will not change your child’s medical care or his/her access to antiretroviral (ARV) 
HIV medication.  
 
PURPOSE: The purpose of this observational study is to see how successful the antiretroviral 
(ARV) drug combination called Tenofovir-Lamivudine-Dolutegravir (TLD) is at treating HIV. 
 
NUMBER OF PARTICIPANTS: About 1350 people will take part in this study 
 
LENGTH OF STUDY: Your child will be in this study for about 3 years. 
 
REQUIRED ACTIVITIES: At every visit, your child will have blood collected from a vein in his or 
her arm. You or your child will also be asked questions about his or her current anti-HIV and 
anti-tuberculosis (TB) medications, and about any new HIV or TB diagnoses. 
 
RISKS: Taking blood may cause some discomfort, bleeding, or bruising where the needle 
enters the body, lightheadedness, and in rare cases, fainting or infection. 
 
This is an observational study of the HIV medication that your child is receiving locally. So, the 
risks of taking those medications are not included in this study. Your child’s medical provider 
should give you that information. 
 
BENEFITS: There will be no direct benefit to your child if he or she takes part in this study. 
 
 

 
75 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
INTRODUCTION 
 
You are being asked to let your child take part in this research study because your child is at 
least 10 years old and: 
 
1. Your child is living with human immunodeficiency virus (HIV-1), and your child will soon start 
taking the antiretroviral (ARV) drug combination called Tenofovir-Lamivudine-Dolutegravir 
(TLD).  
 
OR 
 
2. Your child is living with HIV-1 and tuberculosis (TB), your child has started or will soon start 
taking the ARV drug combination TLD, and your child has started or will soon start taking 
the TB medication that includes the drug rifampicin. 
 
You are encouraged to discuss the risks and benefits of TLD with your child’s clinician. 
 
This study is sponsored by the National Institutes of Health (NIH). The doctor in charge of this 
study at this site is: (insert name of Principal Investigator). Before you decide if you want to let 
your child be a part of this study, we want you to know about the study.  
 
This is a consent form for your child to participate in this study. It gives you information about 
this study. The study staff will talk with you about this information. You are free to ask questions 
about this study at any time. If you agree to let your child take part in this study, you will be 
asked to sign this consent form. You will get a copy to keep. We will also talk to your child about 
the study and ask him/her if he/she agrees to participate in the study. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
TLD is being used more widely across the world to treat HIV. This is an observational study (a 
type of study in which participants are observed and certain outcomes are measured). The aim 
of this study is to observe how successful TLD is at treating HIV, in the following groups of 
people: 
 
• 
People switching to TLD, after taking anti-HIV medication that contains a NNRTI drug (non-
nucleoside reverse transcriptase inhibitor, such as Efavirenz or Nevirapine) (Group 1). 
• 
People switching to TLD, after taking anti-HIV medication that contains a PI drug (protease 
inhibitor, such as Lopinavir or Atazanavir) (Group 2). 
• 
People taking TLD and receiving medication for TB that includes the drug rifampicin (Group 
3). These people must be starting one or both of these medications when they enter the 
study. 
• 
People starting TLD who have not taken anti-HIV medication before (Group 4). 
  

 
76 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
Another goal of this study is to use genetic testing of the virus (HIV) to see how often HIV is 
resistant to TLD. Genetic testing of the virus is one way to see if the TLD medication is not 
working to treat your child’s HIV infection. 
 
The United States Food and Drug Administration (US FDA) has approved Tenofovir, 
Lamivudine, and Dolutegravir for treatment of HIV. 
 
 
WHAT DOES MY CHILD HAVE TO DO IF MY CHILD IS IN THIS STUDY? 
 
If your child enters the study 
If you decide to let your child take part in this research study, after you have read and signed 
this informed consent form, a screening visit will be done to make sure your child meets the 
requirements for joining the study. If your child is eligible for the study and you choose to let 
your child enroll, your child will have the entry evaluations done. Your child has to start taking 
TLD or rifampicin (if your child is already taking TLD) within 7 days after this entry visit to remain 
on the study. Your child will have up to 7 scheduled visits on this study. Your child’s last visit will 
be about 3 years after your child enters the study.  
 
• 
Your child will be seen at the clinic 3 months and 6 months after the screening and entry 
visit.  
• 
Or, if your child is receiving treatment for TB when he or she starts the study, your child will 
have one visit within 4 weeks after he/she finishes taking TB treatment. This visit will be in 
the first year after the screening and entry visit. 
• 
Your child will then be seen at the clinic about once every 6 months.  
 
Study visits may be conducted remotely (like over the telephone) if your child is unable 
to attend a visit for any of the following reasons: 
• 
Your child is sick.  
• 
Someone in your child’s home is sick.  
• 
Local conditions or guidelines restrict travel to the clinic. 
• 
The site is temporarily unable to have these visits in the clinic. 
 
If any of the following events occur, your child may have to come back to the clinic for an 
additional visit. If possible, these visits will coincide with your child’s next scheduled visit. 
 
• 
Virologic failure confirmation: If a test to see how much HIV is in your child’s blood shows 
that your child’s anti-HIV medication might not be helping him or her, your child will have a 
visit about 6 months later.  
• 
Starting rifampicin-Based TB treatment: If your child starts taking TB medicine that includes 
rifampicin while also taking TLD for HIV, your child will have a study visit. 
• 
Ending rifampicin-Based TB Treatment: If your child finishes taking TB medicine that 
includes rifampicin while also taking TLD for HIV, your child will have a study visit. 
• 
TLD Discontinuation: If your child stops taking TLD while on the study, your child will have a 
study visit, and then continue on study. 

 
77 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
• 
Early Study Discontinuation (Leaving the Study Early): If your child leaves the study early, 
your child will be asked to return to the clinic for one final visit. 
 
If your child does not enroll into the study 
If you decide not to let your child take part in this study or if your child does not meet the 
eligibility requirements, we will still use some of your child’s information. As part of this 
screening visit, some demographic (for example, age, gender, race), clinical (for example, 
disease condition, diagnosis), and laboratory (for example, CD4 cell count, viral load) 
information is being collected from your child so that AIDS Clinical Trial Group (ACTG) 
researchers may help determine whether there are patterns or common reasons why people do 
not join a study. 
 
Information Collected at Screening 
There is some information that we collect on everyone who is screened for an ACTG 
study. As part of your child’s screening visit, some demographic (for example, age, 
gender, race), clinical (for example, disease condition, diagnosis), and laboratory (for 
example, CD4 cell count, viral load) information will be collected from your child.  
  
We will collect this information even if your child does not enroll in this study. This 
information is collected so that ACTG researchers may determine whether there are 
patterns and/or common reasons why people do not join a study. 
 
 
CAN I CHOOSE THE TYPES OF RESEARCH THAT MY SAMPLES AND INFORMATION 
ARE USED FOR? 
 
Some of your child’s blood will be stored and used to check the level of anti-HIV medications in 
his or her blood, and for immunologic and viral testing that is required for this study. 
 
Samples collected from your child will be stored in the United States. Identifiers will be 
removed from your child’s samples and from any private information that has been 
collected about your child. This means that no one looking at the labels or at other 
information will be able to know that the samples or information came from your child.  
 
All information collected about your child as part of the study will be sent securely to the 
ACTG statistical and data management center in the United States for combining with 
information from other study participants and statistical analysis of study results. Your 
child’s name and other personal identifiers will not be sent. Your child’s research site is 
responsible for sending her information in accordance with the laws, regulations and 
policies of your country and research site. 
 
The tests described above are required by this study. If you do not agree to the storage 
or testing that has been described above, your child should not join this study.  
 
Please refer to Attachment II-A to consent for use of your child’s samples in other 
studies. 

 
78 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
 
 
A5381 Study Visits 
The study staff can answer any questions you have about individual study visits, and how long 
they will last, or about the tests that will occur. The table below can be used as a quick 
reference for you, along with the explanations that follow. 
 
 

 
79 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
Appendix II Table 1:  Study Schedule for Groups 1, 2, and 4. Your child will follow this study 
schedule if your child is not receiving treatment for TB when he or she starts the study. 
Evaluation 
Screening Visit 
Entry Visit 
Post Entry Visits (Months) 
Unscheduled Visits 
3 
6 
12 
18 
24 
30 
36 
Virologic 
Failure 
Confirmation 
Starting 
Rifampicin-
Based TB 
Treatment 
Ending 
Rifampicin-
Based TB 
Treatment 
TLD 
Discontinuation 
Early Study 
Discontinuation 
Documentation of 
HIV Status 
√ 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
Medical & 
Medication History 
√ 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
Adherence 
Assessment 
√ 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Evaluations 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Height & Weight 
√ 
 
 
√ 
√ 
 
√ 
 
√ 
 
 
 
 
√ 
Quality of Life 
Questionnaire 
 
√ 
 
√ 
 
 
 
 
 
 
 
 
 
 
Blood Collection 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Appendix II Table 2:  Study Schedule for Group 3. Your child will follow this study schedule if 
your child is receiving treatment for TB when he or she starts the study. 
Evaluation 
Screening Visit 
Entry Visit 
Post Entry 
Visit 
Post Entry Visits 
(Months) 
Unscheduled Visits 
Ending 
Rifampicin-
Based TB 
Treatment 
12 
18 
24 
30 
36 
Virologic 
Failure 
Confirmation 
TLD 
Discontinuation 
Early Study 
Discontinuation 
Documentation of HIV Status 
√ 
√ 
 
 
 
 
 
 
 
 
 
Medical & Medication History 
√ 
√ 
 
 
 
 
 
 
 
 
 
Adherence Assessment 
√ 
√ 
 
 
 
 
 
 
 
 
 
Clinical Evaluations 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Height & Weight 
√ 
 
√ 
√ 
 
√ 
 
√ 
 
 
√ 
Quality of Life 
Questionnaire 
 
√ 
√ 
 
 
 
 
 
 
 
 
Blood Collection 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 

 
80 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
Description of Study Evaluations 
Documentation of HIV Status: Your child’s HIV infection status will be documented.  
 
Medical & Medication History: You or your child will be asked questions about his or her medical 
and medication history, and about past and current anti-HIV and anti-TB medications that your 
child has taken or is taking. 
 
Adherence Assessment: Your child will be asked about adherence to his or her anti-HIV or anti-
TB medications (how your child is currently taking his or her medications). 
 
Clinical Evaluations: You or your child will be asked questions about any new HIV and TB 
diagnoses, and about any changes in the anti-HIV and anti-TB medications that your child is 
taking. Other health events will be reviewed. This information will be shared with you, if 
applicable. 
 
Height & Weight: Your child’s height and weight will be measured. 
 
Quality of Life Questionnaire: Your child will be asked questions about how he or she feels, 
and about how he or she has been sleeping. 
 
Blood Collection: Your child will have between about 10 mL (1 tablespoon) and about 52 mL 
(3.5 tablespoons) of blood drawn at each visit for some or all of the following tests: 
 
• 
To test how much HIV is in your child’s blood (viral load). 
• 
To test how many CD4/CD8 cells (infection-fighting cells) are in your child’s blood. 
• 
For genetic testing of the virus (HIV). This testing is done to see if the TLD medication is a 
good choice of medication to treat your child’s HIV infection).  
• 
For a dried blood spot. The dried blood spot test will be used to test how much anti-HIV 
medication is in your child’s blood, or will be stored for future tests.  
• 
To be stored for future tests. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 1350 people will take part in this study 
 
HOW LONG WILL MY CHILD BE IN THIS STUDY? 
 
Your child will be in this study for about 3 years.  
 
 

 
81 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
WHY WOULD THE DOCTOR TAKE MY CHILD OFF THIS STUDY EARLY? 
 
The study doctor may need to take your child off the study early without your permission if: 
 
• 
The study is stopped or cancelled  
• 
Your child is not able to attend the study visits as required by the study 
• 
Your child is taking HIV medications before switching to TLD, and your child missed 14 or 
more days in a row of those medications immediately before switching to TLD. 
• 
Your child does not start taking TLD or rifampicin (if your child is already taking TLD when 
he or she enters the study) within 7 days after the entry visit. 
• 
If all three of these things are true: Your child has a viral load (how much HIV is in your 
child’s blood) that is more than 1000 copies/mL at his/her study entry visit, and your child is 
receiving medication for TB that includes the drug rifampicin, and your child started taking 
TLD before entering the study. 
• 
Your child’s primary care doctor requests that your child be taken off the study 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
Risks of Drawing Blood 
Taking blood may cause some discomfort, bleeding, or bruising where the needle enters the 
body, lightheadedness, and in rare cases, fainting or infection. 
 
Risks of Social Harm 
It is possible that participating in this study will make it difficult for you or your child to keep your 
child’s HIV or TB status secret from people close to you. This may lead to unwelcome 
discussions about or reactions to your child’s HIV or TB status. Please talk with the study staff if 
you have any concerns about this. 
 
Risks of ARV Medications 
This is an observational study of the ARV treatment that your child is receiving locally. So, the 
risks of taking those medications are not included in this study. Your child’s medical provider 
should give you that information. 
 
 
WHAT HAPPENS IF MY CHILD BECOMES PREGNANT WHILE TAKING PART IN THIS 
STUDY? 
 
If your child becomes pregnant while on study, the study staff would like to obtain information 
from your child about the outcome of the pregnancy (even if it is after your child’s participation in 
the study ends). Your child will continue on the study. If your child is taking anti-HIV drugs when 
she becomes pregnant, your child’s pregnancy will be reported to an international database that 
collects information about pregnancies in women taking anti-HIV drugs. This report will not use 
your child’s name or other information that could be used to identify her. 
 

 
82 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If your child takes part in this study, there will be no direct benefit to him or her. Information 
learned from this study may help others who have HIV.  
 
Your child may receive ancillary benefit from taking part in this study, such as receiving test 
results as described in the next section.  
 
 
WILL I RECEIVE THE RESULTS OF ANY TESTS? 
 
You will receive the result of tests that are performed as part of the recommended medical care 
for HIV or TB in your country (for example, some viral load and CD4 count tests). (Site to insert 
site-specific information about CD4 count and viral load test results participants will receive as 
part of standard of care; if the site is in a country in which treatment guidelines require a 
genotypic test prior to switching patients on a boosted PI-containing second-line ARV 
regimen to TLD, include: “If genetic testing of the virus (HIV) is done at your child’s 
screening visit, you will receive the result of that test.”) 
 
Some tests are done only for research purposes, to improve the care of people living with 
HIV/AIDS. This includes tests done with dried blood spots and genetic testing of the virus (HIV). 
This also includes some of the tests in this study that are not part of recommended medical care 
for HIV or TB in your country. You and your child’s treatment site will not receive the result of 
these tests. (Site to insert site-specific information about CD4 and viral load test results that are 
not part of standard of care, which participants will not receive) 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
We will do everything we can to protect your child’s privacy. In addition to the efforts of the study 
staff to help keep your child’s personal information private, we have gotten a Certificate of 
Confidentiality from the US Federal Government. This certificate means that researchers cannot 
be forced to tell people who are not connected with this study, such as the court system, about 
your child’s participation. Also, any publication of this study will not use your child’s name or 
identify your child personally. 
 
Your child’s records may be reviewed by the ACTG, United States President’s Emergency Plan 
for AIDS Relief (PEPFAR), the US Office for Human Research Protections (OHRP), or other 
local, US, and international regulatory entities as part of their duties (insert name of site) 
institutional review board (IRB) or Ethics Committee (a committee that protects the rights and 
safety of participants in research), the NIH, study staff, study monitors, and their designees. 
Having a Certificate of Confidentiality does not prevent you from releasing information about 
your child and his or her participation in the study. 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to your child or others, we will be required to tell the proper authorities. 

 
83 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
 
A description of this clinical trial 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.  
 
 
WHAT ARE THE COSTS TO ME? 
 
Taking part in this study may lead to added costs to you and your insurance company. In some 
cases, it is possible that your insurance company will not pay for these costs because your child 
is taking part in a research study. (If applicable to your site. Delete if this does not apply.) 
 
Anti-HIV and anti-TB medicines will not be provided by the study. 
 
 
WILL I RECEIVE ANY PAYMENT? 
 
You may be reimbursed for your time and travel expenses as part of your child’s participation in 
this study. (Site to insert site-specific information about payment.) 
 
 
WHAT HAPPENS IF MY CHILD IS INJURED? 
 
If your child is injured as a result of being in this study, your child will be given immediate 
treatment for his or her injuries.  
 
[Sites: Please modify (if necessary) and insert one of these two statements, as appropriate to 
your site. If your site is required to carry CTI, this must be indicated in the informed consent.] 
• 
This site has clinical trials insurance. This insurance will allow the site to provide you with 
monetary compensation if your child suffers harm as a result of participating in this research 
study.  
• 
The cost for this treatment will be charged to you or your insurance company. There is no 
program for compensation either through this institution or the NIH.  
 
You will not be giving up any of your legal rights by signing this consent form. 
 
 
WHAT ARE MY CHILD’S RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to let your child take part 
in this study or to remove your child from this study at any time. Your decision will not have any 
impact on your child’s participation in other studies conducted by NIH and will not result in any 
penalty or loss of benefits to which your child are otherwise entitled. 
 

 
84 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
We will tell you about new information from this or other studies that may affect your child’s 
health, welfare, or willingness to let your child stay in this study. If you want the results of the 
study, let the study staff know. 
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
• 
Name of the investigator or other study staff 
• 
Telephone number of above  
 
For questions about your child’s rights as a research participant, contact: 
• 
Name or title of person on the Institutional Review Board (IRB) or other organization 
appropriate for the site 
• 
Telephone number of above 

 
85 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
SIGNATURE PAGE 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered, and you agree to let your child to take part in this study, please sign your name 
below. 
 
 
 
____________________________ 
__________________________________ 
Child Participant’s Name (print) 
Child Participant’s Date of Birth 
 
 
____________________________ 
__________________________________ 
Parent/Legal Guardian Name (print) 
Parent/Legal Guardian Signature and Date 
(As appropriate) 
 
 
____________________________ 
__________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
 
____________________________ 
__________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 

 
86 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
ATTACHMENT II-A:  CONSENT FOR USE OF SAMPLES IN OTHER STUDIES 
 
When samples are no longer needed for this study, the ACTG may want to use them in 
other studies and share them with other researchers. These samples are called “extra 
samples.” The ACTG will only allow your child’s extra samples to be used in other 
studies if you agree to this. If you have any questions, please ask. 
 
Identifiers will be removed from your child’s samples and from any private information 
that has been collected about your child. This means that no one looking at the labels or 
at other information will know that the samples or information came from your child.  
 
Extra samples are stored in a secure central place called a repository. Your child’s 
samples will be stored in the ACTG repository located in the United States. 
 
There is no limit on how long your child’s extra samples will be stored.  
[Site: Revise the previous sentence to insert limits if your regulatory authority imposes 
them.] 
 
When a researcher wants to use your child’s samples and information, their research 
plan must be approved by the ACTG. Also, the researcher’s institutional review board 
(IRB) or ethics committee (EC) will review their plan. [Site: If review by your institution’s 
IRB/EC/RE is also required, insert a sentence stating this.] IRBs/ECs protect the rights 
and well-being of people in research. If the research plan is approved, the ACTG will 
send your child’s samples to the researcher’s location. This means that researchers who 
are not part of the protocol team may use your child’s samples without asking you or 
your child again for consent.  
 
Your child will not be paid for her samples. Also, a researcher may make a new 
scientific discovery or product based on the use of your child’s samples. If this 
happens, there is no plan to share any money with your child.  
 
You may withdraw your consent for research on your child’s extra samples at any time, 
and the specimens will be discarded. 
 
Please choose the response that matches what you want by putting your initials in the 
space provided. Please ask the staff any questions that you have before you indicate 
your selection. 
 
Research without Human Genetic Testing  
If you agree, your child’s extra samples may be stored (with usual protection of your 
child’s identity) and used for ACTG-approved HIV-related research that does not include 
human genetic testing. 
 
____ (initials) I understand and I agree to this storage and possible use of my child’s 
samples  
 

 
87 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
OR 
 
____ (initials) I understand but I do not agree to this storage and possible use of my 
child’s samples 
 
Research with Human Genetic Testing  
Your child’s extra samples will not be used for human genetic testing.  
 
The ACTG has a different study that collects samples for genetic testing. This study is 
called ACTG A5243, Plan for Obtaining Human Biological Samples at Non-US Clinical 
Research Sites for Currently Unspecified Genetic Analyses. 
 
Your site might ask you if you would like your child to participate in this study if it is 
being done where you live. If you would like your child to participate, you will sign a 
separate consent form. 
 
 

 
88 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
APPENDIX III: SAMPLE ASSENT FORM 
 
DIVISION OF AIDS 
AIDS CLINICAL TRIALS GROUP (ACTG) 
SAMPLE INFORMED CONSENT 
For protocol: A5381 
 
Observational Cohort to Assess Therapeutic Efficacy and Emergence of HIV Drug Resistance 
Following Initiation of Tenofovir-Lamivudine-Dolutegravir (TLD) for First- or Second-Line ART or 
with Rifampicin-Containing TB Treatment: The Hakim Study 
 
FINAL Version 2.0, 03/05/21 
 
 
SHORT TITLE FOR THE STUDY: Assess Therapeutic Efficacy and Emergence of HIV Drug 
Resistance Following Initiation of TLD 
 
 
INTRODUCTION 
 
We are asking you to take part in this research study. We are doing this study to find out if the 
human immunodeficiency virus (HIV-1) medication called Tenofovir-Lamivudine-Dolutegravir 
(TLD) is successful at treating HIV for you and for other people in this study. 
 
Another goal of this study is to use genetic testing of the virus (HIV) to see how often HIV 
is resistant to TLD. Genetic testing of the virus is one way to see if the TLD medication is 
not working to treat your HIV infection. 
 
Your parent/guardian will be informed about this study and asked to sign a separate form giving 
their consent for you to take part. As a participant in this study, we would like you to know about 
the study too, and to be given a chance to ask any questions you may have about it. You will be 
asked to sign this assent form. You will get a copy to keep. 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
People who take part in this study will be asked to be part of it for 3 years. You will be seen at 
the clinic about every 6 months (for a total of about seven study visits). You may also have extra 
study visits, if any of the following things happen.  
• 
If a test to see how much HIV is in your blood shows that your HIV medicine might be 
failing to help you, you will have a study visit about 6 months later.  
• 
If you start or stop taking medicine for tuberculosis (TB), you will have a study visit.  
• 
If your HIV medicine is changed, you will have a study visit.  
• 
If you leave the study early, you will be asked to have one last study visit. 
 

 
89 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
Study visits may be conducted remotely (like over the telephone) if you are unable to 
attend a visit for any of the following reasons: 
• 
You are sick.  
• 
Someone in your home is sick.  
• 
Local conditions or guidelines restrict travel to the clinic. 
• 
The site is temporarily unable to have these visits in the clinic. 
 
At these study visits, the study staff will talk with you and your parent or legal guardian about 
your health and the medicines you are taking. You will have blood collected for testing.  
 
The study staff can tell you more about the study visits and what exactly will be done at the 
study visits. 
 
We would also like you to know that information collected in this study will be kept confidential 
(private) and only those people who are doing the study and are overseeing the study will be 
able to see your information. [Sites should also include a statement here describing the extent 
to which information reported by children/adolescents will be shared with their 
parents/guardians]. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
Risks of Blood Collection 
Blood collection may cause some discomfort, bleeding, or bruising where the needle 
enters the body, lightheadedness, and in rare cases, fainting or infection. 
 
Risks of Social Harm 
It is possible that participating in this study will make it difficult for you to keep your HIV 
or TB status secret from people close to you. This may include your parent or guardian. 
This may lead to unwelcome discussions about or reactions to your HIV or TB status. 
Please talk with the study staff if you have any concerns about this. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you take part in this study, there will be no direct benefit to you. Information learned 
from this study may help others who have HIV. You may indirectly benefit from taking 
part in this study. For example, you may receive some test results. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is your choice. This means you can say yes or no to being part of the 
study. No matter what decision you make, and even if your decision changes, nothing bad will 

 
90 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
happen to you or your family. You will not lose medical care, legal rights, or any benefits that 
you are otherwise entitled to. 
 

 
91 
A5381 
 
 
FINAL Version 2.0 
 
 
03/05/21 
 
 
SIGNATURE PAGE 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to take part in this study, please sign your name below. 
 
____________________________________ 
Child Participant’s Name and Surname (print) 
 
 
 
_____________________________________  
Child Participant’s Date of Birth  
 
 
 
_____________________________________  
Child Participant’s Signature and Date 
 
 
 
 
 
 
____________________________ 
_________________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Assent Discussion (print)  
 
 
 
____________________________ 
_________________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate)