A Phase III Study to Evaluate Long-Acting Antiretroviral Therapy in Non-Adherent HIV-Infected Individuals
Phase: PHASE3
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
 
 
 
 
A5359 
 
The LATITUDE Study 
Long-Acting Therapy to Improve Treatment SUccess in Daily LifE 
 
A Phase III Study to Evaluate Long-Acting Antiretroviral Therapy in Non-adherent 
HIV-Infected Individuals 
 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
 
Sponsored by: 
The National Institute of Allergy and Infectious Diseases 
 
In Collaboration with: 
The National Institute of Mental Health 
The National Institute on Drug Abuse 
 
Industry Support Provided by: 
ViiV 
Janssen  
 
IND # 138754 
 
Antiretroviral Therapy Strategies  
Transformative Science Group (ARTS TSG): 
Timothy Wilkin, MD, MPH, Chair 
  
 
Protocol Co-Chairs:  
 
 
 
Jose Castillo-Mancilla, MD  
 
 
 
 
 
 
Aadia Rana, MD  
 
Protocol Co-Vice Chairs:   
 
 
Raphael Landovitz, MD, MSc 
 
 
 
 
 
 
Karen Tashima, MD  
 
DAIDS Clinical Representatives:   
 
Tia Morton, RN, MS 
 
 
 
 
 
 
Lawrence Fox, MD, PhD 
 
 
Clinical Trials Specialist:   
 
 
Chanelle Wimbish, BS, CCRP 
 
 
FINAL Version 3.0  
December 05, 2022 

 
A5359 
 
 
FINAL Version 3.0 
05Dec2022 
 
A5359 
 
The LATITUDE Study 
Long-Acting Therapy to Improve Treatment SUccess in Daily LifE 
 
A Phase III Study to Evaluate Long-Acting Antiretroviral Therapy in Non-adherent HIV-
Infected Individuals 
 
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 (eg, US National Institutes of Health, Division of AIDS) and institutional 
policies. 
 
 
 
 
 
Principal Investigator: _______________________________________________ 
Print/Type 
 
 
 
 
 
Signed: ___________________________________ Date: _____________ 
Name/Title 
 
 

 
A5359 
 
 
FINAL Version 3.0 
05Dec2022 
 
TABLE OF CONTENTS 
Page 
SIGNATURE PAGE .................................................................................................................... 2 
SITES PARTICIPATING IN THE STUDY .................................................................................... 6 
PROTOCOL TEAM ROSTER ..................................................................................................... 7 
STUDY MANAGEMENT ........................................................................................................... 11 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ..................................................................... 13 
SCHEMA .................................................................................................................................. 15 
1.0 
HYPOTHESIS AND STUDY OBJECTIVES ................................................................... 18 
1.1 
Hypothesis ......................................................................................................... 18 
1.2 
Primary Objective ............................................................................................... 18 
1.3 
Secondary Objectives ........................................................................................ 18 
1.4 
Exploratory Objectives ....................................................................................... 18 
2.0 
INTRODUCTION ........................................................................................................... 20 
2.1 
Background ........................................................................................................ 20 
2.2 
Rationale ........................................................................................................... 24 
3.0 
STUDY DESIGN ........................................................................................................... 24 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................ 26 
4.1 
Step 1 Inclusion Criteria ..................................................................................... 26 
4.2 
Step 1 Exclusion Criteria .................................................................................... 28 
4.3 
Step 2 Inclusion Criteria ..................................................................................... 30 
4.4 
Step 2 Exclusion Criteria .................................................................................... 30 
4.5 
Step 3 Inclusion Criteria ..................................................................................... 30 
4.6 
Step 3 Exclusion Criteria .................................................................................... 30 
4.7 
Step 4 Inclusion Criteria ..................................................................................... 31 
4.8 
Step 4 Exclusion Criteria .................................................................................... 31 
4.9 
Study Enrollment Procedures............................................................................. 31 
4.10 
Co-enrollment Guidelines ................................................................................... 32 
5.0 
STUDY TREATMENT ................................................................................................... 32 
5.1 
Study Product .................................................................................................... 33 
5.2 
Study Product Regimens, Administration, and Duration ..................................... 33 
5.3 
Study Product Preparation, and Formulation ...................................................... 37 
5.4 
Pharmacy: Product Supply, Distribution, and Accountability .............................. 44 
5.5 
Concomitant Medications ................................................................................... 45 
5.6 
Adherence ......................................................................................................... 47 
5.7  
Conditional Economic Incentives (CEI) .............................................................. 48 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................... 50 
6.1 
Schedule of Evaluations..................................................................................... 50 
6.2 
Timing of Evaluations ......................................................................................... 66 
6.3 
Instructions for Evaluations ................................................................................ 78 
6.4 
Visit Windows .................................................................................................... 85 

A5359 
 
 
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TABLE OF CONTENTS (Cont’d) 
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Page 
 
 
 
7.0 
ADVERSE EVENTS AND STUDY MONITORING ......................................................... 85 
7.1 
Definition of Adverse Events .............................................................................. 85 
7.2 
Adverse Event Collection Requirements for this Protocol ................................... 85 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS ........................................ 86 
7.4 
Study Monitoring ................................................................................................ 87 
8.0 
CLINICAL MANAGEMENT ISSUES .............................................................................. 88 
8.1 
Toxicity Management ......................................................................................... 88 
8.2 
Grade 1 or 2 ....................................................................................................... 89 
8.3 
Grade 3 .............................................................................................................. 89 
8.4 
Grade 4 .............................................................................................................. 89 
8.5 
Rash (with or without systemic symptoms or mucosal or target lesions) ............ 90 
8.6 
Skin Hyperpigmentation ..................................................................................... 93 
8.7 
Creatinine Clearance ......................................................................................... 93 
8.8 
Nausea (with or without vomiting) and/or Diarrhea ............................................. 93 
8.9 
Hypertriglyceridemia/Hyperlipidemia .................................................................. 94 
8.10 
Liver Enzymes ................................................................................................... 94 
8.11 
Hyperglycemia ................................................................................................... 94 
8.12 
CPK Elevation .................................................................................................... 94 
8.13 
Prolonged QTc ................................................................................................... 95 
8.14 
Hyperlactatemia/Lactic Acidosis ......................................................................... 95 
8.15 
Lipase Elevations and Pancreatitis .................................................................... 96 
8.16 
Anemia/Neutropenia .......................................................................................... 97 
8.17 
Peripheral Neuropathy ....................................................................................... 97 
8.18 
Injection Site Reactions...................................................................................... 98 
8.19 
Seizure .............................................................................................................. 98 
8.20 
Drug Substitutions .............................................................................................. 98 
8.21 
Immune Reconstitution Inflammatory Syndrome (IRIS) ...................................... 98 
8.22 
Pregnancy.......................................................................................................... 98 
9.0 
CRITERIA FOR DISCONTINUATION ......................................................................... 100 
9.1 
Permanent and Premature Treatment Discontinuation ..................................... 100 
9.2 
Premature Study Discontinuation ..................................................................... 100 
10.0 
STATISTICAL CONSIDERATIONS ............................................................................. 100 
10.1 
General Design Issues ..................................................................................... 100 
10.2 
Outcome Measures .......................................................................................... 102 
10.3 
Randomization ................................................................................................. 105 
10.4 
Sample Size and Accrual ................................................................................. 106 
10.5 
Data and Safety Monitoring .............................................................................. 107 
10.6 
Analyses .......................................................................................................... 110 
11.0 
PHARMACOLOGY PLAN ............................................................................................ 112 
11.1 
Pharmacology Objectives ................................................................................ 112 
11.2 
Pharmacology Study Design ............................................................................ 112 
11.3 
Primary and Secondary Data, Modeling, and Data Analysis ............................ 113 
11.4 
Anticipated Outcomes ...................................................................................... 114 

A5359 
 
 
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TABLE OF CONTENTS (Cont’d) 
05Dec2022 
 
Page 
 
 
 
12.0 
DATA COLLECTION AND MONITORING ................................................................... 114 
12.1 
Reporting Protocol Deviations .......................................................................... 114 
12.2 
Records to Be Kept .......................................................................................... 114 
12.3 
Role of Data Management ............................................................................... 114 
12.4 
Clinical Site Monitoring and Record Availability ................................................ 114 
13.0 
PARTICIPANTS .......................................................................................................... 115 
13.1 
Institutional Review Board (IRB) Review and Informed Consent ...................... 115 
13.2 
Participant Confidentiality ................................................................................. 115 
13.3 
Study Discontinuation ...................................................................................... 115 
14.0 
PUBLICATION OF RESEARCH FINDINGS ................................................................ 115 
15.0 
BIOHAZARD CONTAINMENT .................................................................................... 116 
16.0 
REFERENCES ............................................................................................................ 117 
APPENDIX I: INFORMED CONSENT FORM ......................................................................... 120 
ATTACHMENT A: CONSENT FOR USE OF SAMPLES IN OTHER STUDIES ..................... 149 
APPENDIX II: INFORMED CONSENT FOR PARTICIPANTS WHO BECOME 
PREGNANT WHILE ON STUDY ................................................................................. 151 
 
 

 
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SITES PARTICIPATING IN THE STUDY 
 
A5359 is a multicenter study open to all ACTG US clinical research sites (CRSs) including 
Puerto Rico. 
 
 
 
 
 
 
 

 
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PROTOCOL TEAM ROSTER 
 
Co-Chairs 
Jose Castillo-Mancilla, MD  
University of Colorado Hospital CRS 
Infectious Diseases/Medicine 
12700 East 19th Avenue, B168 
Aurora, CO 80045 
Phone: 303-724-4934 
E-mail: jose.castillo-mancilla@cuanschutz.edu 
 
Aadia Rana, MD 
Alabama CTU 
845 19th Street South, BBRB 206 
Birmingham, AL 35205 
Phone: 205-934-1268 
E-mail: airana@uabmc.edu 
 
Co-Vice Chairs 
Raphael Landovitz, MD, MSc 
University of California, Los Angeles CARE 
Center CRS 
Center for Clinical AIDS Research & 
Education 
911 Broxton Avenue, Suite 200 
Los Angeles, CA 90024 
Phone: 310-825-3782 
E-mail: rlandovitz@mednet.ucla.edu 
 
Karen Tashima, MD 
The Miriam Hospital (TMH) CRS 
M-974112 
164 Summit Avenue 
Providence, RI 02906 
Phone: 401-793-4089 
Phone: 401-793-4979 
E-mail: ktashima@lifespan.org 
 
DAIDS Clinical Representatives  
Lawrence Fox, MD, PhD 
TRP/DAIDS/NIAID/NIH 
HIV Research Branch 
5601 Fishers Lane 
Room 9E41 
Rockville, MD 20852 
Phone: 240-627-3069 
E-mail: lfox@niaid.nih.gov 
 
Tia Morton, RN, MS 
DAIDS/NIAID/NIH/HIVRB 
5601 Fishers Lane 
Room 9E48 
Rockville, MD 20852 
Phone: 240-627-3073 
E-mail: frazierti@niaid.nih.gov 
 
Clinical Trials Specialist 
Chanelle Wimbish, BS, CCRP  
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc.,  
A DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910 
Phone: 301-628-3367 
E-mail: chanelle.wimbish@dlhcorp.com 
 
Statisticians 
Irena Brates, MSPH 
Statistical and Data Analysis Center 
Harvard T.H. Chan School of Public Health 
FXB Building, Room 625 
651 Huntington Avenue 
Boston, MA 02115-6017 
Phone: 617-432-2809 
E-mail: ibrates@sdac.harvard.edu

 
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PROTOCOL TEAM ROSTER (Cont’d) 
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Statisticians (Cont’d) 
Ellen S. Chan, MSc 
Statistical and Data Analysis Center 
Harvard T.H. Chan School of Public Health 
651 Huntington Avenue 
FXB 539 
Boston, MA 02115 
Phone: 617-432-4879 
E-mail: echan@sdac.harvard.edu 
 
Lu (Summer) Zheng, PhD 
Statistical and Data Analysis Center 
Harvard T.H. Chan School of Public Health 
FXB Building, Room 613 
651 Huntington Avenue 
Boston, MA 02115-6017 
Phone: 617-432-3021 
E-mail: szheng@sdac.harvard.edu 
 
Data Manager 
Sara Sieczkarski, PhD 
ACTG Data Management Center 
Frontier Science and Technology Research 
Foundation, Inc.  
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 x7372 
E-mail: sieczka@frontierscience.org 
 
Primary DAIDS Pharmacist 
Katherine Shin, PharmD, RPh 
OCSO/DAIDS/NIAID/NIH 
Pharmaceutical Affairs Branch 
5601 Fishers Lane 
Room 9D30 
Rockville, MD 20852 
Phone: 240-627-3047 
E-mail: kashin@niaid.nih.gov 
 
DAIDS Pharmacist 
Cynthia Parker, PharmD, RPh 
OSCO/DAIDS/NIAID/NIH 
Pharmaceutical Affairs Branch 
5601 Fishers Lane, 9D37 
Rockville, MD 20852 
Phone: 301-761-7199 
E-mail: cindy.parker@nih.gov 
Pharmacologists 
Ed Acosta, PharmD 
Alabama Therapeutics CRS 
University of Alabama at Birmingham 
School of Medicine 
1670 University Boulevard 
Volker Hall, Room 258 
Birmingham, AL 35294-0019 
Phone: 205-934-2655 
E-mail: eacosta@uab.edu 
 
Jennifer Kiser, PharmD 
University of Colorado Hospital CRS 
Pharmaceutical Sciences 
12850 E. Montview Boulevard, C238 
Aurora, CO 80045 
Phone: 303-724-6131 
E-mail: jennifer.kiser@ucdenver.edu 
 
Charles Venuto, PharmD 
University of Rochester Adult HIV 
Therapeutic Strategies Network CRS 
265 Crittenden Boulevard 
Rochester, NY 14642 
Phone: 585-276-5622 
E-mail: charles.venuto@chet.rochester.edu 
 
Virologist 
Jonathan Li, MD, MMSc 
Brigham and Women’s Hospital 
Harvard Medical School 
65 Landsdowne Street, Room 435 
Cambridge, MA 02139 
Phone: 617-768-8476 
E-mail: jli@bwh.harvard.edu 
 
Investigators 
Omar Galarraga, PhD 
The Miriam Hospital (TMH) CRS 
121 South Main Street, 
G-S121-7 
Providence, RI 02912 
Phone: 401-863-2331 
E-mail: omar_galarraga@brown.edu

 
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PROTOCOL TEAM ROSTER (Cont’d) 
05Dec2022 
 
Investigators (Cont’d) 
Steven Shoptaw, PhD 
UCLA Vine Street Clinic CRS 
10880 Wilshire Boulevard, Suite 1800 
Los Angeles, CA 90024 
Phone: 310-794-6206 
E-mail: sshoptaw@mednet.ucla.edu 
 
Michael Stirratt, PhD 
NIMH Division of AIDS Research 
5601 Fishers Lane, Rm 9G28, MSC 9830 
Bethesda, MD 20892 
Phone: 240-627-3875 
E-mail: stirrattm@mail.nih.gov 
 
David Wohl, MD 
Chapel Hill CRS 
Suite 2100, Bioinformatics Building 
130 Mason Farm Road 
Chapel Hill, NC 27514 
Phone: 919-843-2723 
E-mail: wohl@med.unc.edu 
 
Field Representative 
Romina Chinchay Collahua, MSc, MBA 
Houston AIDS Research Team CRS 
6431 Fannin Street 
Houston, TX 77030 
Phone: 713-500-5589 
E-mail: 
romina.chinchaycollahua@uth.tmc.edu 
 
Laboratory Technologist 
Cheryl Jennings, BS 
Rush University Medical Center 
Clinical Retrovirology Research 
Laboratory 
859 Jelke Building 
1750 West Harrison Street 
Chicago, IL 60612 
Phone: 312-942-5954 
E-mail: cheryl_jennings@rush.edu
Community Scientific Subcommittee (CSS) 
Representative 
Michael Dorosh, MA 
University of Colorado Hospital CRS 
38 W. Maple Avenue 
Denver, CO 80223-1839 
Phone: 303-777-5737 
E-mail: michael@ontheten.org 
 
Industry Representatives  
Ronald D'Amico, DO, MSc 
Five Moore Drive 
Research Triangle Park 
Durham, NC 27709 
Phone: 919-315-7489 
E-mail: Ronald.d.damico@viivhealthcare.com 
 
Kimberly Smith, MD, MPH 
ViiV Healthcare 
Five Moore Drive 
P.O. Box 13398 
Durham, NC 27709 
Phone: 919-491-2167 
E-mail: kimberly.y.smith@viivhealthcare.com 
 
Kati Vandermeulen, MSc 
Janssen Pharmaceuticals Inc.  
Turnhoutseweg 30 
Beerse, 2340 
Belgium 
Phone: 324-735-31109 
E-mail: kvanderm@its.jnj.com 
 
Rodica Van Solingen-Ristea, MD 
Janssen R&D 
Turnhoutseweg 30 
Beerse, 2340 
Belgium  
Phone: +32 478-63-2199 
E-mail: rvsolin1@its.jnj.com 

 
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PROTOCOL TEAM ROSTER (Cont’d) 
05Dec2022 
 
Industry Representatives (Cont’d) 
Paul Wannamaker 
ViiV Healthcare 
5 Moore Drive 
Mail Stop 5.3C 
Research Triangle Park, NC 27709 
Phone: 919-259-2554 
E-mail: paul.g.wannamaker@viivhealthcare.com 
 
Laboratory Data Managers 
Frederic Bone 
Frontier Science & Technology Research 
Foundation, Inc.  
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 
E-mail: bone@frontierscience.org 
 
Kathleen Shepherd, MPH 
Frontier Science Foundation, Inc.  
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 x7370 
E-mail: kshepherd@frontierscience.org 
 
Laboratory Specialists 
Ceora Beijer, BS 
ACTG Laboratory Center at UCLA (ALC-UCLA) 
675 Charles E. Young Drive S 
Los Angeles, CA 90095 
Phone:  
E-mail: cbeijer@milabcentral.org 
 
Kathie Ferbas, PhD 
ACTG Laboratory Center at UCLA (ALC-UCLA) 
675 Charles E. Young Drive South 
Los Angeles, CA 90095  
Phone: 310-780-3639 
E-mail: kferbas@milabcentral.org 
 

 
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STUDY MANAGEMENT 
 
All questions concerning this protocol should be sent to actg.leada5359@fstrf.org via email. The 
appropriate team member will respond with a "cc" to actg.leada5359@fstrf.org. A response 
should generally be received within 24 hours (Monday-Friday). 
 
Protocol Email 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.prota5359 email group. 
Include the protocol number in the email subject line.  
• 
Send an email message to actg.user.support@fstrf.org  
 
Clinical Management  
For questions concerning entry criteria, toxicity management, concomitant medications, and 
coenrollment, contact the protocol team. 
• 
Send an email message to actg.leada5359@fstrf.org. Include the protocol number, patient 
identification number (PID), and a brief relevant history. 
 
Laboratory 
For questions specifically related to pharmacologic laboratory tests, contact the protocol 
pharmacologists.  
• 
Send an email message to actg.leada5359@fstrf.org (ATTN: Ed Acosta, Jen Kiser, and 
Charles Venuto).  
 
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 Sara 
Sieczkarski directly.  
• 
For other questions, send an email message to actg.leada5359@fstrf.org (ATTN: Sara 
Sieczkarski).  
• 
Include the protocol number, PID, and a detailed question. 
 
Randomization/Participant Registration 
For randomization/participant registration questions or problems and study identification number 
SID lists.  
• 
Send an email 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. 
 

 
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STUDY MANAGEMENT (Cont'd) 
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Computer and Screen Problems  
Contact the User Support Group at the Data Management Center (DMC). 
• 
Send an email message to actg.user.support@fstrf.org or call 716-834-0900 x7302. 
 
Protocol Document Questions 
For questions concerning the protocol document, contact the clinical trials specialist.  
• 
Send an email message to actg.leada5359@fstrf.org (ATTN: Chanelle Wimbish). 
 
Copies of the Protocol 
To request a hard copy of the protocol, send a message to ACTGNCC@dlhcorp.com via email. 
Electronic copies can be downloaded from the ACTG Web site (https://www.actgnetwork.org). 
 
Product Package Inserts and/or Investigator Brochures 
To request copies of product package inserts or investigator brochures, contact the DAIDS 
Regulatory Support Center (RSC) at RIC@tech-res.com or call 301-897-1708. 
 
Protocol Registration 
For protocol registration questions, send an email message to Protocol@tech-res.com or call 
301-897-1707.  
 
Protocol Activation 
For questions related to protocol activation, contact the clinical trials specialist Chanelle 
Wimbish at chanelle.wimbish@dlhcorp.com. 
 
Study Product 
For questions or problems regarding study product, dose, supplies, records, and returns, email 
Katherine Shin and Cynthia Parker, protocol pharmacists, at kashin@niaid.nih.gov and 
cindy.parker@nih.gov.  
 
Study Drug Orders 
Call the Clinical Research Products Management Center (CRPMC) at 301-294-0741. 
 
IND (Investigational New Drug) Number or Questions  
The IND number is available on the PSWP. For any questions related to the IND submission, 
contact the DAIDS RSC at Regulatory@tech-res.com or call 301-897-1706. 
 
Expedited Adverse Event (EAE) Reporting/Questions  
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or 301-897-1709; or fax 1-800-275-7619 or 301-897-1710.  
 
Phone Calls 
Sites are responsible for documenting any phone calls made to A5359 team members. 
• 
Send an email to actg.leada5359@fstrf.org. 
 
Protocol-Specific Web Page 
Additional information about management of the protocol can be found on the protocol-specific 
web page (PSWP). 

 
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GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
ABC 
AE 
abacavir  
adverse event 
AIDS 
acquired immunodeficiency syndrome 
ALT 
ANC 
alanine aminotransferase 
absolute neutrophil count  
ART 
ARV 
antiretroviral therapy 
antiretroviral 
AST 
aspartate aminotransferase 
BUN 
CAB 
blood urea nitrogen 
cabotegravir (GSK1265744) 
CDC 
CEI 
CKD-Epi 
CLIA 
Centers for Disease Control and Prevention 
conditional economic incentives 
Chronic Kidney Disease Epidemiology Collaboration equation 
Clinical Laboratory Improvement Amendments 
CRPMC 
NIAID Clinical Research Products Management Center  
DAERS 
DBS 
DAIDS Adverse Events Reporting System 
dried blood spots 
DMC 
Data Management Center 
EAE 
expedited adverse event 
EC 
Ethics Committee 
eCRF 
electronic case report form 
FDA 
GCLP 
Food and Drug Administration 
Good Clinical Laboratory Practice 
HCV 
HRU 
IM 
IND 
INSTI 
hepatitis C virus 
healthcare resource utilization 
intramuscular 
investigational new drug 
integrase strand transfer inhibitor  
IQA 
IRB 
Immunology Quality Assurance 
Institutional Review Board 
IRC 
infusion report card  
ISR 
injection site reaction  
IUD 
intrauterine device 
IV 
intravenous 

 
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GLOSSARY OF PROTOCOL-SPECIFIC TERMS (Cont'd) 
05Dec2022 
 
LA 
long-acting 
LPC 
mg 
laboratory processing chart 
milligram  
MOPS 
OHRP 
Manual of Procedures  
Office for Human Research Protections  
OLI 
oral lead-in 
PBMC 
PI/cobi 
peripheral blood mononuclear cell 
boosted protease inhibitor 
PID 
PK 
patient identification number 
pharmacokinetics 
PSWP 
RPV 
protocol specific webpage 
rilpivirine  
RSC 
Regulatory Support Center 
SAE 
serious adverse event 
SID 
SOE 
SOC 
study identification number 
schedule of evaluations 
standard of care  
VL 
viral load 
WBC 
white blood cell 
WHO 
World Health Organization 

 
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SCHEMA 
 
A5359 
 
The LATITUDE Study 
Long-Acting Therapy to Improve Treatment SUccess in Daily LifE 
 
A Phase III Study to Evaluate Long-Acting Antiretroviral Therapy in Non-adherent HIV-Infected 
Individuals 
 
DESIGN 
A phase III, prospective, randomized, open-label trial comparing Long-
Acting (LA) Antiretroviral therapy (ART) with rilpivirine (RPV) LA and 
cabotegravir (CAB) LA versus Standard of Care (SOC) in previously 
non-adherent individuals. The study has four steps.  
 
In Step 1, participants will be initiated on a SOC oral induction regimen 
consisting of a ≥3-drug ART regimen with ≥2 drugs predicted to be fully 
active including a boosted protease inhibitor (PI/cobi) and/or an 
integrase strand transfer inhibitor (INSTI) for up to 24 weeks. 
Participants who achieve milestones will be eligible to receive conditional 
economic incentives (CEI) at Step 1 (section 5.7).  
 
Step 1 participants are eligible to enter Step 2 if virologic suppression 
criteria for randomization are met at or after Step 1, week 4 (but before 
Step 1, week 24). Virologic suppression criteria are defined as: a) HIV-1 
RNA ≤200 copies/mL or b) HIV-1 RNA of 201-399 copies/mL followed by 
HIV-1 RNA ≤200 copies/mL prior to Step 1, week 24. Eligible participants 
will enter Step 2 and be randomized 1:1 to switch to oral RPV + oral 
CAB for 4 weeks (optional) followed by RPV-LA + CAB-LA every 4 
weeks (Q4) until the end of Step 2 or to continue on SOC for 52 weeks 
(see Table 5.2.1-2).  
 
At the completion of Step 2, eligible participants randomized to SOC will 
have the option to register to Step 3 and cross over to the LA strategy, 
which includes oral RPV + oral CAB for 4 weeks (optional see section 
5.2.1) followed by RPV-LA + CAB-LA Q4 weeks until the end of Step 3; 
participants already on RPV-LA + CAB-LA in Step 2 will continue on this 
regimen in Step 3 for 52 weeks (see Table 5.2.1-3).  
 
At the completion of Step 3, participants will transition to locally sourced 
RPV-LA + CAB-LA, (if possible and available) and will no longer be 
followed on study. If access to locally sourced RPV-LA + CAB-LA cannot 
be attained or participant requests to switch to oral ART, those 
participants will enter Step 4 and be followed for 52 weeks on locally 
sourced oral ART. If the participant can access LA ART during follow-
up in Step 4, and the participant and provider decide to restart LA ART, 

 
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they will be allowed to do so. In that case, the participants will not be 
followed by the study after restarting LA ART.  
 
In addition, any participant who receives at least one dose of CAB-LA or 
RPV-LA, and prematurely discontinues study treatment prior to the end 
of Step 3, will complete their Step (2 or 3) off treatment, and then register 
to Step 4 to be followed on locally sourced oral ART for 52 weeks after 
his or her last dose of any LA injectable.  
 
DURATION 
Up to 180 weeks (up to 24 weeks in Step 1, 52 weeks in Step 2, 52 
weeks in Step 3, and up to 52 weeks in Step 4). 
 
SAMPLE SIZE 
A maximum of 640 participants in Step 1 for Step 2 to achieve an accrual 
target of 320 participants (160 in each arm). 
 
POPULATION 
ART-experienced, non-pregnant people with HIV-1 who are ≥18 years 
of age with: 
• 
Evidence of non-adherence according to at least one of the following 
criteria:  
o Poor virologic response within 18 months prior to study entry 
(defined as <1 log10 decrease in HIV-1 RNA or HIV-1 RNA >200 
copies/mL at two time points at least 4 weeks apart) in individuals 
who have been prescribed ART for at least 6 consecutive 
months. 
o Loss to clinical follow-up within 18 months prior to study entry 
with ART non-adherence for ≥6 consecutive months. Lost to 
clinical follow-up is defined as either no contact with provider or 
missed 2 or more appointments in a 6-month period. ART non-
adherence is defined as a lapse in ART ≥7 days (consecutive or 
non-consecutive), in the 6-month period where they were lost to 
clinical follow-up per participant report. 
• 
No evidence of any clinically relevant RPV or INSTI resistance-
associated mutations through commercially available resistance 
testing analyses (historically or upon screening). 
• 
Ability of site clinician, in conjunction with participant, to construct a 
≥3-drug ART regimen with ≥2 drugs predicted to be fully active, 
including a boosted PI/cobi and/or an INSTI. Drugs for oral regimens 
will be made available to study participants according to PSWP. 
 
REGIMEN 
Step 1, Induction: All participants will receive SOC (oral induction ART 
regimen) with CEI for up to 24 weeks. 
 
Step 2, Randomization: Participants who achieve virologic suppression 
criteria at or after Step 1, week 4, will be randomized to Step 2 in a 1:1 
ratio to either of the two treatment arms: 
 

 
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• 
Arm A: Oral RPV + oral CAB for 4 weeks (optional) followed by RPV-
LA + CAB-LA Q4 weeks until the end of Step 2 (Table 5.2.1-2). 
 
• 
Arm B: Continuation of SOC for 52 weeks.  
 
Step 3, Continuation/Crossover: 
  
• 
Arm A participants (LA ART arm) will continue on RPV-LA + CAB-LA 
Q4 weeks for 52 weeks until completion of Step 3.  
 
• 
Arm B participants (SOC arm) who are virologically suppressed (HIV-
1 RNA ≤200 copies/mL) at Step 2, week 48, or HIV-1 RNA of 201-399 
copies/mL at Step 2, week 48, followed by HIV-1 RNA ≤200 
copies/mL by Step 2, week 52, will have the option to switch to oral 
RPV + oral CAB for 4 weeks (optional) followed by RPV-LA + CAB-LA 
Q4 weeks until the end of Step 3 (Table 5.2.1-3).  
 
Step 4, Observation: All participants who enter Step 4, as outlined in 
study design above, will be followed until they complete 52 weeks on 
locally sourced oral ART or restart LA ART if it becomes available. 
 
Standardized adherence support will be provided by sites throughout 
each step of the study (refer to the Manual of Procedures [MOPS]).  
 
Schema Figure 1: Schema Diagram 
 

 
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1.0 
HYPOTHESIS AND STUDY OBJECTIVES 
 
1.1 
Hypothesis 
 
After achieving suppression during a period of incentivized standard of care (SOC) (up 
to 24 weeks), long-acting (LA) antiretroviral therapy (ART) consisting of RPV-LA + CAB-
LA will be a more successful therapy compared to a SOC regimen in keeping previously 
non-adherent persons with HIV on treatment and virologically suppressed.  
 
1.2 
Primary Objective 
 
To compare regimen efficacy of LA ART (using RPV-LA and CAB-LA) to SOC in 
previously non-adherent persons with HIV by 48 weeks of follow-up after an incentivized 
oral induction period.  
 
1.3 
Secondary Objectives 
 
1.3.1 To compare virologic efficacy between LA ART using RPV-LA and CAB-LA and 
SOC at 48 weeks following an incentivized oral induction period in previously 
non-adherent persons with HIV. 
 
1.3.2 To assess the safety and tolerability of the LA ART regimen versus the SOC 
regimen in previously non-adherent persons with HIV after an incentivized oral 
induction period. 
 
1.3.3 To estimate the HIV-1 RNA viral decline at 4, 8, 12, 16 and 20 weeks after 
initiation of oral ART in Step 1 in previously non-adherent persons with HIV 
utilizing CEI to promote adherence. 
 
1.3.4 To assess participant acceptability and treatment satisfaction with LA ART 
versus SOC. 
 
1.3.5 To assess adherence (self-reported, self-efficacy, and missed or delayed 
injections [defined as 8 days beyond scheduled injection day] for LA ART), 
among previously non-adherent persons with HIV randomized to LA ART versus 
SOC. 
 
1.3.6 To compare the rates of new drug-resistance mutation development in 
individuals who develop virologic failure between the LA ART versus SOC and 
determine factors associated with emerging drug resistance. 
 
1.4 
Exploratory Objectives 
 
1.4.1 To assess long-term durability of LA ART in Step 3 for persons with HIV with a 
history of non-adherence randomized to LA ART. 

 
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1.4.2 To assess virologic efficacy of returning to an oral ART regimen after receiving at 
least one dose of LA ART. 
 
1.4.3 To evaluate factors associated with viral suppression during Step 1 including 
socio-demographic, substance abuse, health, and behavioral health-related 
measures.  
 
1.4.4 To evaluate factors associated with maintenance of virologic suppression at Step 2, 
week 48, including socio-demographic, substance abuse, health, and behavioral 
health- related measures within each arm. 
 
1.4.5 To evaluate factors associated with virologic suppression at Step 3, week 48, 
including socio-demographic, substance abuse, health, and behavioral health 
measures.  
 
1.4.6 To evaluate factors associated with virologic suppression at Step 4, week 48, 
including socio-demographic, substance abuse, health, and behavioral health 
measures.  
 
1.4.7 To develop a repository of biologic samples (i.e., plasma and hair) for future 
research on ART adherence (e.g., ART concentration in dried blood spots (DBS) 
and hair), inflammation and immune activation in previously non-adherent 
persons with HIV. 
 
1.4.8 To assess cost-effectiveness of an LA ART strategy with an incentivized oral 
induction period versus SOC in previously non-adherent persons with HIV. 
 
1.4.9 To assess quality of life in participants randomized to LA ART versus SOC. 
 
1.4.10 To assess stigma associated with HIV in participants randomized to the LA ART 
versus SOC.  
 
1.4.11 To assess healthcare resource utilization (HRU) in Steps 1 through 3.  
 
1.4.12 To assess efficacy of LA ART, effect of CEI or adherence and behavioral 
measures specifically in young adults with HIV (18-24 years old) with a history of 
non-adherence. 
 
1.4.13 To examine the association of HIV treatment outcomes, including virologic 
failure, at Step 2 and Step 3 with corresponding CAB-LA and RPV-LA pre-dose 
trough concentrations.  
 
1.4.14 To examine relationship between the hair and DBS concentrations of ARTs with 
self-reported adherence measures.  
 

 
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2.0 
INTRODUCTION 
 
2.1 
Background 
 
Durable viral suppression remains the main objective of ART for individuals with HIV. 
However, achieving an undetectable viral load (VL) continues to be a challenge for many 
individuals in clinical practice [1, 2]. Among the obstacles that hinder ART success, 
suboptimal drug adherence is responsible for most episodes of failure to achieve and 
maintain virologic suppression. Up to 25% of individuals on chronic ART may experience 
episodes of non-adherence, and only a small proportion of adults with HIV in the US are 
virologically suppressed [3], a suboptimal outcome from both an individual and public 
health perspective. Thus, improving ART adherence remains of critical importance in 
HIV treatment. 
 
Rationale for the use of LA ART as an alternative for individuals in whom oral ART is a 
challenge 
Despite the potency of currently available orally administered ART regimens, high levels 
(≥80-85%) of adherence to daily dosing are still necessary to maintain viral suppression 
[2, 4]. Although ideal, this level of adherence is unachievable in some individuals due to 
a wide range of structural, behavioral, social and clinical barriers including patient 
recollection of scheduled doses, competing priorities (i.e., employment, child care, 
transportation) stigma, and active mental illness or substance use [5, 6, 7]. Newer LA 
ART regimens offer the possibility of improving virologic suppression outcomes in 
previously non-adherent individuals, given the benefits associated with infrequent dosing 
and the opportunity to implement directly-observed therapy in this population [8, 9]. 
Recent modeling data have also demonstrated that LA ART could improve survival in 
non-adherent individuals, while offering a significant cost advantage when compared to 
SOC [10].  
 
Currently, the combination of GSK1265744 LA (CAB-LA) plus rilpivirine (RPV) LA is the 
only LA regimen being evaluated for the treatment of HIV infection [8, 11, 12]. CAB-LA is 
a novel INSTI that can be administered orally or as a LA intramuscular injection [12]. Its 
oral formulation has been evaluated in an ongoing phase II dose-ranging study 
randomizing participants to three doses of oral CAB in combination with 2 nucleoside 
reverse transcriptase inhibitors (NRTIs) in a 24-week lead-in period followed by two-drug 
maintenance with once-daily oral CAB and RPV versus 2 NRTIs plus once-daily 
efavirenz (EFV) in treatment-naïve, persons with HIV (LATTE trial) [8, 9]. Recently 
published 96-week data demonstrated comparable rates of virologic suppression 
between all CAB dosing arms vs. EFV, with similar incidence of adverse events and the 
identification of 30 mg/day as the oral CAB dose for further study [13]. Based on these 
results, the CAB-LA nanoformulation (half-life ~20-50 days) [12], is currently undergoing 
evaluation in combination with RPV-LA (half-life ~35 days) [14] after a 20-week induction 
period with oral CAB plus abacavir/lamivudine versus continuation of oral induction in 
treatment-naïve, persons with HIV (LATTE-2, NCT02120352). Results from this trial 
demonstrate high levels of viral suppression with CAB-LA and RPV-LA at 96 weeks with 
comparable response rates among those injected every 4 and 8 weeks (87% in Q4W vs. 
94% in Q8W maintained HIV-1 RNA <50 c/mL at W96 compared to 84% on PO) [14].  

 
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The First Long-Acting Injectable Regimen (FLAIR; NCT02938520) study is a Phase III 
non-inferiority study that enrolled 629 treatment-naïve persons with HIV. Participants 
who achieved viral suppression to <50 copies/mL after 20 weeks of oral daily ART 
induction with ABC/3TC/DTG were randomized 1:1 to continuation of this oral regimen 
or switch to IM CAB-LA 400 mg + RPV-LA 600 mg Q4W [15]. The 48-week results from 
FLAIR demonstrated that 94% of participants in the IM CAB-LA + RPV-LA arm 
maintained viral suppression to <50 copies/mL, in comparison with 93% of participants in 
the continuation of daily oral ABC/3TC/DTG arm. This met the pre-specified non-
inferiority margin for CAB-LA + RPV-LA, which was set at 6%. Safety and tolerability of 
IM CAB-LA + RPV-LA were similar to oral daily ABC/3TC/DTG, with 3% versus 1% of 
adverse events leading to discontinuation in the IM and SOC arms, respectively. 
Regarding participant preferences, 99% of respondents preferred the IM CAB-LA + 
RPV-LA over the daily oral therapy. In total, three participants randomized to IM CAB-LA 
+ RPV-LA (all with HIV-1 subtype A1) had confirmed virologic failure with evidence of 
treatment-emergent resistance for non-nucleoside reverse transcriptase inhibitor 
(NNRTI) (E138E/A/K/T, K101E) and INSTI (L74I, G140R, Q148R) [15].  
 
The Antiretroviral Therapy as Long-Acting Suppression (ATLAS; NCT02951052) study is 
also a non-inferiority, randomized phase III study that is evaluating continuation of daily 
oral SOC ART versus CAB-LA 400 mg IM + RPV-LA 600 mg IM Q4W in persons with 
HIV with long-standing virologic suppression on a standard-of-care oral regimen [16]. In 
ATLAS, 616 persons with HIV with at least 6 months of virologic suppression were 
randomized 1:1 to each arm. At 48 weeks, 92% versus 95% of participants in the LA IM 
and SOC arms, respectively, maintained viral suppression <50 copies/mL, 
demonstrating non-inferiority of IM CAB-LA + RPV-LA Q4W in comparison with the SOC 
arm (similar to FLAIR, a 6% non-inferiority margin was pre-specified). Similar to FLAIR, 
tolerability and safety were comparable between both arms (2% adverse events in the 
SOC arm versus 3% in the IM arm, with 1% of injection site reactions [ISRs] leading to 
discontinuation in the IM arm), with higher participant satisfaction in the CAB-LA + RPV-
LA arm [16]. Virologic failure with NNRTI (E138E/A/K, V108I) and/or INSTI (L74I, 
N155H) -associated mutations was confirmed in three participants in the CAB-LA+ RPV-
LA arm, two had A/A1 and one had subtype AG), two of which had NNRTI resistance-
associated mutations at baseline (demonstrated by archived HIV-1 DNA).  
 
ATLAS-2M (NCT03299049) randomized approximately 1,020 persons with HIV with 
virologic suppression receiving oral daily SOC ART or IM CAB 400 mg LA + RPV 600 
mg LA Q4W (as part of ATLAS) to either IM CAB-LA + RPV-LA Q4W or Q8W. Similar to 
ATLAS, this study was designed to demonstrate non-inferiority and safety and tolerability 
of IM CAB 600 mg LA + RPV 900 mg LA Q8W compared to Q4W IM CAB 400 mg LA + 
RPV 600 mg LA, which was confirmed to be non-inferior to SOC in ATLAS and FLAIR 
after a 48-week follow-up [17]. 
 
Based on the results of FLAIR and ATLAS, a New Drug Application (NDA) seeking 
approval for CAB-LA 400 mg + RPV-LA 600 mg IM Q4W was submitted to the FDA on 
April 29, 2019. On December 21, 2019, the FDA provided a Complete Response Letter 
to this application citing reasons related to the Chemistry Manufacturing and Controls, 
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In addition to the registrational phase III studies, data on the compassionate use program 
of CAB-LA + RPV-LA IM in 35 patients from 10 countries have recently become available. 
This program, which used the same dosing as the FLAIR/ATLAS studies (including a 
one-month oral lead-in [OLI] in some cases), enrolled patients with advanced disease 
who required parenteral ART and had no key CAB or RPV-associated mutations. From 
the 28 patients who entered the compassionate use with detectable viremia (10 without 
administration of oral CAB + RPV lead-in period), 16 (57%, 4/10 without OLI) achieved 
virologic suppression (<50 copies/mL) with CAB + RPV LA IM, with a median (range) 
duration of follow-up of 11 (1-47) months, and a median (range) time to virologic 
suppression of 6 (1-31) months. At the time of last follow-up, 22/35 (63%) remained 
virologically suppressed to <50 copies/mL. Of the 7/35 patients who were virologically 
suppressed at the time of initiation of oral CAB + RPV, 6/7 remained suppressed at their 
last follow-up. Among five (14%) patients who had incomplete virologic responses and 
stopped CAB-LA + RPV-LA IM treatment, four had NNRTI resistance-associated 
mutations and two had INSTI resistance-associated mutations at failure [18].  
 
In Phase III studies, virologic failure was confirmed in ~1% of study participants 
across FLAIR, ATLAS, and ATLAS-2M. In multivariate analysis of pooled data from 
those three studies, BMI ≥30 kg/m2, HIV-1 subtype A6/A1, the presence of RPV-
associated mutations, and lower week 8 RPV trough concentrations were all 
significantly associated with increased odds of virologic failure in 13 out of 1039 
participants. While less than 1% of participants with zero or one of those risk 
factors at baseline had virologic failure, this was confirmed in 25% of participants 
who had at least two baseline factors and in one participant who had all three 
factors at baseline [19]. 
 
Regarding safety in the compassionate use program, the most common adverse events 
reported were ISRs, but no patients discontinued CAB-LA + RPV-LA due to these. Five 
patients reported serious adverse events (one of them treatment related), but all 
continued CAB-LA + RPV-LA IM. In this cohort, three patients died, but none of these 
events were related to treatment. 
 
Direct-to-Inject 
Data on the use of CAB-LA + RPV-LA without the CAB + RPV OLI have also become 
recently available. Within the FLAIR study, 111 participants transitioned from oral ART to 
CAB-LA + RPV-LA without the use of the OLI (i.e., direct-to-inject), while 121 received 
the OLI. At week 124, one participant in each arm had HIV‐1 RNA ≥50 copies/mL, and 
one participant in the direct-to-inject group developed confirmed virologic failure at week 
112. Regarding safety, adverse events leading to withdrawal were infrequent, and the 
number of participants experiencing serious adverse events was comparable between 
arms. One participant in the direct-to-inject arm had a Grade 4 drug-related adverse 
event (mixed cellularity Hodgkin's lymphoma) [20]. 
 
On January 21, 2021, the US Food and Drug Administration (FDA) approved injectable 
CAB and RPV for the treatment of adults living with HIV-1 who are virologically 
suppressed on a stable ART regimen with no known or suspected resistance to either 
CAB or RPV or a history of treatment failure. The FDA approved the injectable 

 
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combination to be administered once a month. Oral CAB was also approved to be used 
in combination with oral RPV for 1 month prior to starting treatment with the injectable 
[21].  
 
Although these are encouraging and supportive results, none of these studies or the 
FDA approval relate to the use of LA ART regimens in previously non-adherent 
individuals. Since non-adherent individuals are one of the main population targets of 
these LA formulations, addressing this gap is of critical importance to accelerate 
implementation of these new regimens in the individuals who might benefit from them 
most. 
 
Rationale for the use of short-term CEI to support adherence with LA ART  
Although infrequent dosing will be a very attractive treatment option for many persons 
with HIV on ART, achieving viral suppression through a short-acting “conventional” oral 
ART regimen (i.e., dosed daily) is still required prior to transitioning to a maintenance 
strategy using LA ART. The need for stable and suppressive oral ART represents a 
major hurdle to the use of an LA ART strategy in those who have challenges to 
adherence. Thus, useful interventions to improve adherence during this period will still 
be required. 
 
While a wide variety of interventions have been shown to improve adherence to ARTs, 
no optimal strategy is applicable to all populations. Evidence-based strategies to 
address ART adherence include adherence counseling, interactive text messaging, and 
efforts to address mental health and substance abuse in concert with adherence 
support. Behavioral interventions have been found to have a modest effect on ART 
adherence in meta-analyses and are commonly used to varying degrees in standard 
clinical practice. Behavior modifications through economic incentives have had positive 
results in studies done for smoking cessation, weight loss, medication adherence, and 
illicit drug abstinence [22-25], particularly if the reward is temporally proximate to the 
behavior change [26, 27]. In the HIV arena, CEI have resulted in improvement in ART 
adherence in substance users [28-34], retention in care, and viral suppression [35, 36]. 
A potential drawback to the use of CEI has been the durability and sustainability of their 
beneficial effect, limiting their utility to promote high-level adherence over a prolonged 
horizon and beyond the incentive period [26, 27, 35]. To date, data have demonstrated 
that CEI are successful in promoting adherence for up to 48 weeks, mainly while the 
incentives remain in place [33]. Project Hope, a completed three-arm randomized 
controlled trial (RCT), tested 6 months of patient navigation (PN) and PN plus 
contingency management (PN+CM) versus treatment as usual (TAU) on 12-month viral 
suppression rates [37]. Average payment to an incentivized PN+CM participant was 
$668. While there was no difference in viral suppression at 12 months among the three 
arms, attendance at an HIV care visit at 6 months was highest in the PN+CM arm 
(PN=79%, PN+CM=87%, TAU=69%, p(PN vs TAU)=.003); p(PN+CM vs PN)=.014) at 6 
months and was significantly different between arms. If used as a time-limited 
intervention to support a short-term behavior, CEI could prove highly effective to 
optimize adherence and achieve viral suppression in preparation to the use of LA ARV in 
previously non-adherent individuals. Currently, no data on the efficacy of this approach 

 
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are available; however, a substantial analogy to short-term potent effects exists across a 
wide variety of medical and social contexts [35, 38, 39]. 
 
The CEI sizes in this protocol are comparable to what has been demonstrated 
successful among previously non-adherent patients with $100/quarter [32, 40] for VL 
reductions and suppression. In HPTN-065 trial, a multi-site RCT testing CEI on linkage 
to care and viral suppression, a $70 gift certificate to attain VL was associated with 10% 
higher proportion of patients with an undetectable VL at care clinics, where fewer than 
65% of patients had an undetectable VL at the start of the study [36].  
 
Reflecting the myriad barriers that patients with challenges to adherence may face, 
studies evaluating CEI also included additional strategies to promote adherence 
including reinforcement of the behavior based on a standard measure and delivered in 
close proximity with the successful behavior; medication counseling or coaching [33]; 
digital reminders and pill organizers [33]; and case management and substance abuse 
counseling as indicated [30, 37]. Similarly, an approach using CEI in this setting will also 
need to incorporate evidence-based strategies such as case management support and 
patient-navigation to enhance treatment and care adherence [41, 42]. 
 
To address the above-mentioned gaps, we propose a randomized study that will 
compare an LA ART therapeutic strategy to best current practice in previously non-
adherent persons with HIV. Given the need to achieve and sustain viral suppression 
using an oral, short-acting regimen before transitioning to maintenance LA ART therapy, 
in this strategy we also propose to implement CEI as an intervention aimed at reinforcing 
early adherence to oral ARTs during the Step 1 OLI phase only (see Design section of 
the Schema). The CEI program will be complemented by an array of other evidence-
based behavioral support approaches for adherence. Each study site is required to 
create a site-specific adherence intervention plan. The protocol team will assist in 
developing, implementing and monitoring the adherence intervention plan for each study 
site. 
 
2.2 
Rationale 
 
The proposed study seeks to compare the efficacy, safety, and durability of two different 
strategies to treat participants with a history of sub-optimal adherence and control of 
their HIV infection: LA ART versus all-oral SOC/Best Available Regimen after an 
incentivized induction period of all oral ART. The main advantages of LA ART in this 
population include infrequent dosing and directly observed therapy during the LA ART 
phase. To assess the safety and efficacy of this strategy we propose a comparator arm 
that consists of the best available therapy in the absence of LA ART.  
 
3.0 
STUDY DESIGN 
 
This is a phase III, four-step, randomized, open label, controlled study that will assess if 
LA ART therapy is effective in persons with HIV with a prior history of non-adherence 
compared to SOC. 
 

 
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Step 1, Induction 
Previously non-adherent individuals will be enrolled and undergo a period (up to 24 
weeks) of induction SOC ART regimen using conditional economic incentives (CEI). 
Participants who achieve virologic suppression criteria at or after Step 1, week 4, defined 
as: a) HIV-1 RNA ≤200 copies/mL or b) HIV-1 RNA of 201-399 copies/mL followed by 
HIV-1 RNA ≤200 copies/mL by Step 1, week 24, will be eligible to enter Step 2. 
 
NOTE A: CEI to support adherence will be provided to all participants during Step 1 oral 
induction phase only. Participants will continue to receive study visit remuneration as per 
usual site practice throughout study participation (Steps 1-4).  
 
 
NOTE B: Participants who do not achieve virologic suppression will complete study at 
Step 1, week 24. 
 
Step 2, Randomization 
Eligible participants will be randomized at Step 2 entry in a 1:1 ratio to either of the two 
treatment arms:  
 
Arm A (LA ART):  A combination of oral RPV + oral CAB for 4 weeks (optional) followed 
by the LA ART Phase, consisting of a two-drug regimen using RPV-
LA + CAB-LA Q4 weeks until the end of Step 2 (Table 5.2.1-2). The 
option to initiate LA ART at the Step 2 Randomization visit without oral 
RPV + oral CAB is at the discretion of the site investigator of Record 
(IoR) and participant (see section 2.1, Direct-to-Inject). 
 
Arm B (SOC):  
Continuation of the SOC for 52 weeks.  
 
Step 3, Continuation/Crossover 
Arm A participants will continue on RPV-LA + CAB-LA Q4 weeks for 52 weeks until the 
end of Step 3. Arm B participants (continuation of SOC) who achieve virologic 
suppression (HIV-1 RNA ≤200 copies/mL) at Step 2, week 48, or HIV-1 RNA of 201-399 
copies/mL at Step 2, week 48, followed by HIV-1 RNA ≤200 copies/mL by Step 2, week 
52, will have the option to cross over at the end of Step 2 to oral RPV + oral CAB for 4 
weeks (optional) followed by RPV-LA + CAB-LA every 4 weeks until the end of Step 3 
(Table 5.2.1-3). Arm B participants who do not wish or are not eligible to cross over will 
complete study follow-up at Step 2, week 52.  
 
If RPV-LA + CAB-LA becomes available before a participant finishes Step 3, and the 
participant chooses to continue RPV-LA + CAB-LA as part of their clinical care, their 
follow-up in the study will end at the completion of Step 3. If for some reason the 
participant chooses not to continue LA ART at the end of Step 3 or if LA ART is not 
available, the participant will register to Step 4 and will be followed on locally sourced 
oral ARV for 52 weeks. 
 

 
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Step 4, Observation 
Participants who register to Step 4 will be followed for up to 52 weeks on oral ART. In 
addition, any participant who receives at least one dose of CAB-LA or RPV-LA at any 
step, and prematurely discontinues the LA ART prior to end of Step 3, will complete  
their respective Step (either Step 2 or 3) on study/off study treatment, and will register to 
Step 4 and followed to complete 52 weeks total on oral ART after their last dose of any 
LA injectable.  
 
If LA ART becomes available during follow-up in Step 4, and the participant and provider 
decide to restart LA ART, they will be allowed to do so. In that case, the participants will 
not be followed by the study after restarting LA ART.  
 
Justification for Step 4: Given the long pharmacokinetic tail of the LA ART formulations, 
Step 4 has been implemented to ensure ongoing ART and virologic suppression during 
a period of potential vulnerability when participants could have drug concentrations that 
may be below the necessary therapeutic thresholds for virologic suppression. 
 
Standardized adherence support will be provided by sites throughout each step of the 
study (refer to MOPS). 
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Step 1 Inclusion Criteria 
 
4.1.1 HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry 
and confirmed by a licensed Western blot or a second antibody test by a method 
other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 
RNA viral load. 
 
NOTE: The term “licensed” refers to a US FDA-approved kit, which is required for 
all IND studies.  
 
WHO (World Health Organization) and CDC (Centers for Disease Control and 
Prevention) guidelines mandate that confirmation of the initial test result must 
use a test that is different from the one used for the initial assessment. A reactive 
initial rapid test should be confirmed by either another type of rapid assay or an 
E/CIA that is based on a different antigen preparation and/or different test 
principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 
RNA viral load. 
 
4.1.2 HIV-1 Plasma VL >200 copies/mL within 12 months prior to study entry by 
any US laboratory that has a Clinical Laboratory Improvement 
Amendments (CLIA) certification or its equivalent, unless participant has 
been lost to clinical follow-up (see 4.1.3 NOTE) and no viral load result is 
available within the last 12 months. 
 

 
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4.1.3 Evidence of non-adherence to ART according to at least one of the following 
criteria: 
 
4.1.3.1 Poor virologic response within 18 months prior to study entry (defined as 
<1 log10 decrease in HIV-1 RNA or HIV-1 RNA >200 copies/mL at two 
time points at least 4 weeks apart) in individuals who have been 
prescribed ART for at least 6 consecutive months.  
 
4.1.3.2 Lost to clinical follow-up within 18 months prior to study entry with ART 
non-adherence for ≥6 consecutive months. 
 
NOTE: Lost to clinical follow-up is defined as either no contact with provider or 
missed ≥1 appointment in a 6-month period. ART non-adherence is defined as a 
lapse in ART ≥7 days (consecutive or non-consecutive), in the 6-month period 
where they were lost to clinical follow-up per participant report. 
 
4.1.4 No evidence of any clinically relevant RPV or INSTI resistance-associated 
mutations (see MOPS for list of exclusionary mutations) through commercially 
available genotypic (or phenotypic if available) analyses from any laboratory that 
has a CLIA certification or equivalent within 60 days of study entry, nor history of 
such mutations on review of prior HIV-1 drug resistance tests by the site 
investigator. For participants in whom a screening HIV-1 conventional 
genotype cannot be resulted by the testing laboratory, review of historical 
genotypes and treatment history by the IoR can be used to satisfy this 
criterion (see section 6.3.8). 
 
4.1.5 Ability of site clinician, in conjunction with participants, to construct an oral 
induction ARV regimen that must include at least three ARVs of which at least 
two must be predicted to be fully active. The regimen must, include PI/cobi 
and/or an INSTI based on screening and/or historic resistance testing.  
 
4.1.6 Laboratory values obtained within 60 days prior to study entry by any laboratory 
that has a CLIA certification or its equivalent: 
• 
Hemoglobin 9.0 g/dL 
• 
Absolute neutrophil count (ANC) 600/mm3 
• 
Alanine aminotransferase (ALT) ≤3 x ULN 
• 
Creatinine Clearance (CrCl) ≥50 mL/min estimated by Chronic Kidney 
Disease Epidemiology Collaboration equation (CKD-Epi) 
 
4.1.7 For participants of reproductive potential, negative serum or urine pregnancy test 
with a sensitivity of ≤25 mIU/mL at screening. This will be repeated again at 
study entry.  
 
NOTE: Participants are considered to be NOT of reproductive potential if: 1) they 
have had amenorrhea for at least 12 consecutive months prior to study entry 
(i.e., who have had no menses within 12 months prior to study entry), and have a 

 
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documented FSH >40 IU/mL; OR 2) an FSH level is not available, but they have 
had 24 consecutive months of amenorrhea (in the absence of medications known 
to induce amenorrhea); OR 3) they report having undergone surgical sterilization 
(e.g., hysterectomy, or bilateral oophorectomy, or bilateral tubal 
ligation/hysteroscopic tubal occlusion). 
 
4.1.8 Contraception Requirements 
 
Participants of Reproductive Potential 
Participants of reproductive potential, who are participating in sexual activity that 
could lead to pregnancy, must agree to use at least one of the listed highly 
effective methods for contraception from 30 days prior to the first dose of study 
medication, while receiving the study drugs, and for 30 days after stopping oral 
medications, or the duration specified in the product label if receiving study drugs 
not supplied by the study, or 52 weeks after stopping RPV-LA or CAB-LA. 
Acceptable methods of contraception include: 
• 
Contraceptive subdermal implant 
• 
Intrauterine device or intrauterine system 
• 
Combined estrogen and progestogen oral contraceptive 
• 
Injectable progestogen  
• 
Contraceptive vaginal ring  
• 
Percutaneous contraceptive patches  
 
Participants Who Are Not of Reproductive Potential 
Participants who are not of reproductive potential are eligible to start study drugs 
without requiring the use of contraceptives. Any statement of self-reported 
sterility or that of her partner’s must be entered in the source documents.  
 
NOTE A: Acceptable documentation of lack of reproductive potential is the 
participant’s self-reported history of surgical sterilization, menopause, 
or male partner’s azoospermia. 
 
NOTE B: ALL participants in the study should be counseled on safer sexual 
practices including the use and benefit/risk of effective barrier methods 
(e.g., male condom) and on the risk of HIV transmission to a partner 
without HIV. 
 
4.1.9 Age ≥18 years.  
 
4.1.10 Ability and willingness of participant or legal guardian/representative to provide 
written informed consent. 
 
4.2 
Step 1 Exclusion Criteria 
 
4.2.1 Currently pregnant, planning to become pregnant during the study period, or 
currently breastfeeding. 

 
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4.2.2 Participants determined by the Site Investigator to have a high risk of seizures, 
including participants with an unstable or poorly controlled seizure disorder.  
 
NOTE: A participant with a prior history of seizure may be considered for 
enrollment if the Investigator believes the risk of seizure recurrence is low. All 
cases of prior seizure history should be discussed with the A5359 protocol 
leadership team (actg.leada5359@fstrf.org) prior to enrollment. 
 
4.2.3 Advanced liver disease (as defined by any of the following: presence of ascites, 
encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, 
or persistent jaundice), known biliary abnormalities (with the exception of 
Gilbert's syndrome or asymptomatic gallstones) OR history of liver cirrhosis.  
 
4.2.4 History of or current active hepatitis B (HBV) infection defined as positive HBV 
surface antigen test or any detectable HBV DNA in participants with isolated 
HBcAb and HBV DNA as follows: 
 
4.2.4.1 Participants positive for HBsAg are excluded 
 
4.2.4.2 Participants negative for anti-HBs but positive for anti-HBc (negative 
HBsAg status) and any detectable HBV DNA are excluded 
 
NOTE: Participants positive for anti-HBc (negative HBsAg status) and positive for 
anti-HBs (past and/or current evidence) are immune to HBV and are not 
excluded. If prior documentation of immunity is available, repeat testing at 
screening is not required. 
 
4.2.5 Current or anticipated need for chronic anti-coagulation therapy.  
 
4.2.6 Unwilling to receive injections, or unable to receive gluteal injections. 
 
4.2.7 Tattoo or other condition over gluteus region, which may interfere with 
interpretation of injection site reaction. 
 
4.2.8 Previous use of CAB. 
 
4.2.9 Any acute or serious illness, within 7 days prior to entry, requiring systemic 
treatment and/or hospitalization that may render the participant unable to 
receive study medication, in the opinion of the site investigator. 
 
4.2.10 Any serious medical or psychiatric condition, which may render the participant 
unable to receive study medication in the opinion of the site investigator. 
 
4.2.11 Known allergy/sensitivity or any hypersensitivity to components of study drug(s) 
or their formulation. 
 
4.2.12 Requirement for any medication that is prohibited with a study medication. 

 
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4.3 
Step 2 Inclusion Criteria 
 
Meeting virologic suppression criteria at or after Step 1, week 4, defined as:  
a) HIV-1 RNA ≤200 copies/mL 
 
OR  
 
b) HIV-1 RNA of 201-399 copies/mL followed by HIV-1 RNA ≤200 copies/mL by Step 1, 
week 24  
 
NOTE: The HIV-1 RNA viral load that will be used to determine eligibility for 
randomization must have been collected within 4 weeks (28 days) of the Step 2 
randomization visit. 
 
4.4 
Step 2 Exclusion Criteria 
 
4.4.1 Permanent discontinuation of study treatment for any reason during Step 1. 
 
4.4.2 Participants who never started study treatment in Step 1 (see section 6.2.4). 
 
4.4.3 Currently pregnant, planning to become pregnant during the study period, or 
currently breastfeeding. 
 
4.5 
Step 3 Inclusion Criteria 
 
4.5.1 Willingness to continue for those in Arm A or begin to receive LA ART for those 
in Arm B.  
 
4.5.2 Arm B participants: HIV-1 RNA ≤200 copies/mL at Step 2, week 48, or HIV-1 
RNA of 201-399 copies/mL at Step 2, week 48, followed by HIV-1 RNA ≤200 
copies/mL by Step 2, week 52.  
 
NOTE: For Arm B participants continuing on to Step 3, the HIV-1 RNA viral load 
that will be used to determine eligibility for Step 3 registration must have been 
collected within 4 weeks (28 days) of the Step 3 registration visit. 
 
4.6 
Step 3 Exclusion Criteria 
 
4.6.1 Permanent discontinuation of study treatment (LA ART for Arm A and oral ART 
for Arm B) for any reason during Step 2. 
 
4.6.2 Confirmed Virologic Failure during Step 2. 
 
4.6.3 (Only for Arm B in Step 2) Currently pregnant, planning to become pregnant 
during the study period, or currently breastfeeding. 
 

 
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4.7 
Step 4 Inclusion Criteria 
 
4.7.1 Any participant who has received at least one dose of CAB-LA or RPV-LA AND 
does not have access to available LA ART through their provider. 
 
OR 
 
4.7.2 Does not wish to continue LA ART. 
 
4.8 
Step 4 Exclusion Criteria 
 
There are no exclusion criteria for Step 4. 
 
4.9 
Study Enrollment Procedures 
 
4.9.1 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 
DAIDS Protocol Registration Office (DAIDS 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 be reviewed and approved by 
the DAIDS PRO, and sites will receive an Initial Registration Notification from the 
DAIDS PRO that indicates successful completion of the protocol registration 
process. A copy of the Initial Registration Notification should be retained in the 
site's regulatory files. 
 
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 the required documents have been received. Site-specific ICF(s) 
WILL NOT be reviewed and approved by the DAIDS PRO, and sites will receive 
an Amendment Registration Notification when the DAIDS PRO receives a 
complete registration packet. A copy of the Amendment Registration Notification 
should be retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific 
documents required for initial and amendment registrations, refer to the current 
version of the DAIDS Protocol Registration Manual.  
 
Once a candidate for study entry has been identified, details will be carefully 
discussed with the participant. The participant (or, when necessary, the legal 
representative if the participant is under guardianship) will be asked to read and 

 
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sign the approved protocol consent form.  
 
For participants from whom a signed informed consent has been obtained, an 
ACTG Screening Checklist must be entered through the Data Management 
Center (DMC) Subject Enrollment System.  
 
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.  
 
4.9.2 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.  
 
4.9.3 Randomization/Participant Registration 
 
For participants from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the initial protocol step, 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.  
 
4.10 
Co-enrollment Guidelines  
 
• 
US sites are encouraged to co-enroll participants in A5128, “Plan for Obtaining 
Informed Consent to Use Stored Human Biological Materials (HBM) for Currently 
Unspecified Analyses.” Co-enrollment in A5128 does not require permission from the 
A5359 protocol chairs.  
• 
For specific questions and approval for co-enrollment in other studies, sites should 
first check the PSWP or contact the protocol team via email as described in the 
Study Management section. 
 
5.0 
STUDY TREATMENT  
 
Study treatment is defined as oral cabotegravir (CAB), cabotegravir long-acting 
injectable (CAB-LA), oral rilpivirine (RPV), rilpivirine long-acting injectable (RPV-LA), and 
the oral ARVs (abacavir (ABC)/lamivudine (3TC), ABC/dolutegravir (DTG)/3TC, 
darunavir (DRV)/cobicistat (cobi), DTG, emtricitabine (FTC)/tenofovir alafenamide (TAF) 
that are provided through the study and any locally sourced oral antiretroviral product 
prescribed in Step 1 and Step 2.   
 
 
 
 

 
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5.1 
Study Product 
 
Site pharmacists should consult the Pharmacy Guidelines and Instructions for DAIDS 
Clinical Trials Networks for standard pharmacy operations. Refer to the Schema section 
for an overview of steps and study design, and to the investigator’s brochures (IBs) for 
further information about the study products. 
 
5.2 
Study Product Regimens, Administration, and Duration 
 
5.2.1 Regimen 
 
Step 1: Induction  
All participants who meet eligibility criteria will initiate an ART regimen of ≥3 
drugs with ≥2 drugs predicted to be fully active. The regimen must include a 
boosted PI/cobi and/or an INSTI. Oral antiretroviral study products provided 
through the study are included in Table 5.2.1-1 below. If it is determined that it is 
in a participant’s best interest to be prescribed a regimen that is not included in 
Table 5.2.1-1, locally sourced antiretroviral products are allowed. Please note 
that, if the oral antiretroviral product is provided through the study (i.e., included 
in Table 5.2.1-1), participants MUST use the study supply. All participants are 
eligible to receive CEI for achieving visit and virologic benchmarks at Step 1 
(Table 5.7-1).  
 
Table 5.2.1-1: Oral ART for Step 1 and Arm B of Step 2 Provided Through the 
Study 
Single Tablet Regimen 
1. ABC/DTG/3TC 600 mg/50 mg/300 mg (Triumeq®) one tablet orally once daily 
with or without food  
Combination Regimen 
2. FTC/ TAF 200 mg/25 mg (Descovy®) one tablet orally once daily with or 
without food + DTG 50 mg (Tivicay®) one tablet orally once daily with or without 
food 
3. FTC/ TAF 200 mg/25 mg (Descovy®) one tablet orally once daily with or 
without food + DRV/cobi 800 mg/150 mg (Prezcobix®) one tablet orally once 
daily with food 
4. FTC/ TAF 200 mg/25 mg (Descovy®) one tablet orally once daily with or 
without food + DTG 50 mg (Tivicay®) one tablet orally once daily with or without 
food + DRV/cobi 800 mg/150 mg (Prezcobix®) one tablet orally once daily with 
food 
5. ABC/ 3TC 600 mg/300 mg (Epzicom®) one tablet orally once daily with or 
without food + DRV/cobi 800 mg/150 mg (Prezcobix®) one tablet orally once 
daily with food 
6. ABC/ DTG/3TC 600 mg/50 mg/300 mg (Triumeq®) one tablet orally once daily 
with or without food + DRV/cobi 800 mg/150 mg (Prezcobix®) one tablet orally 
once daily with food 

 
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7. RPV 25 mg (Edurant®) one tablet once daily with a meal + DRV/cobi 800 
mg/150 mg (Prezcobix®) one tablet orally once daily with food + NRTI (FTC/TAF 
200 mg/25 mg or abacavir/3TC 600 mg/300 mg) one tablet orally once daily with 
or without food) 
8. RPV 25 mg (Edurant®) one tablet once daily with a meal + DTG 50 mg 
(Tivicay®) one tablet orally once daily with or without food + NRTI (FTC/TAF 200 
mg/25 mg or ABC/3TC 600 mg/300 mg) one tablet orally once daily with or 
without food 
 
Step 2: Randomization 
At Step 2 randomization, eligible participants will be randomized 1:1 to one of the 
following two arms (see Table 5.2.1-2):  
 
Arm A (LA ART):  
Participants will discontinue Step 1 ART regimen and receive RPV plus CAB 
orally once daily for 4 weeks followed by RPV-LA plus CAB-LA Q4 weeks for 48 
weeks. 
 
RPV 25 mg orally once daily and CAB 30 mg orally once daily for 4 weeks 
followed by: 
 
RPV-LA 900 mg Loading Dose and CAB-LA 600 mg Loading Dose IM followed in 
4 weeks by: 
 
RPV-LA 600 mg Maintenance Dose and CAB-LA 400 mg Maintenance Dose IM 
every 4 weeks for 44 weeks.  
 
Alternatively, participants may initiate Long-Acting (LA) injectable ART at the 
Step 2 Randomization visit without oral RPV+ oral CAB at the discretion of the 
site IoR and participant. In this case, the participant will initiate RPV-LA 900 mg 
Loading Dose and CAB-LA 600 mg Loading Dose IM at the Step 2 
Randomization visit, followed in 4 weeks by RPV-LA 600 mg Maintenance Dose 
and CAB-LA 400 mg Maintenance Dose IM every 4 weeks for 48 weeks. 
 
Arm B (SOC): 
Participants will continue their SOC oral ART regimen for 52 weeks.  
 
Table 5.2.1-2: Dosing Regimen in Step 2 
 
Registration 
Week 4b 
Weeks 8-52 
Step 2: Arm A (LA ART) 
Regimen 
Optional Oral Lead-in 
(OLI): 
RPV 25 mg orally 
once daily and CAB 30 
mg orally once daily 
for 4 weeks 
LA ART Loading 
Dose: 
RPV-LA 900 mg and 
CAB-LA 600 mg IM  
LA ART 
Maintenance Dose: 
RPV-LA 600 mg and 
CAB-LA 400 mg IM 
every 4 weeks  

 
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Alternative 
Regimen 
Dosing 
LA ART Loading 
Dose: 
RPV-LA 900 mg and 
CAB-LA 600 mg IM  
LA ART Maintenance Dose: 
RPV-LA 600 mg and CAB-LA 400 mg IM 
every 4 weeks 
Step 2: Arm B (SOC) 
Regimen 
SOC 
 
Step 3: Continuation/Crossover  
Participants randomized to LA ART in Step 2 will continue RPV-LA + CAB-LA Q4 
weeks for 52 weeks. In addition, eligible participants randomized to SOC in Step 
2 will initiate oral RPV + CAB for 4 weeks (optional) followed by RPV-LA + CAB-
LA Q4 weeks until the end of Step 3. 
 
Arm A: 
Participants in Arm A in Step 2 will continue RPV-LA 600 mg Maintenance Dose 
and CAB-LA 400 mg Maintenance Dose IM every 4 weeks for 52 weeks.  
 
Arm B: 
Participants in Arm B in Step 2 will switch from SOC oral ART to:  
 
RPV 25 mg orally once daily and CAB 30 mg orally once daily for 4 weeks 
followed by: 
 
RPV-LA 900 mg Loading Dose and CAB-LA 600 mg Loading Dose IM followed in 
4 weeks by: 
 
RPV-LA 600 mg Maintenance Dose and CAB-LA 400 mg Maintenance Dose IM 
every 4 weeks for 44 weeks. 
 
Alternatively, Step 2, Arm B, participants may initiate LA ART at the Step 3 
registration visit without oral RPV + oral CAB at the discretion of the site IoR and 
participant. In this case, the participant will initiate RPV-LA 900 mg Loading Dose 
and CAB-LA 600 mg Loading Dose IM at Step 3 Registration visit, followed in 4 
weeks by RPV-LA 600 mg Maintenance Dose and CAB-LA 400 mg Maintenance 
Dose IM every 4 weeks until the end of Step 3. 
 
Table 5.2.1-3: Dosing Regimen in Step 3 
 
Registration 
Week 4b 
Weeks 8-52 
Step 3: Arm A (LA ART) 
Regimen  
LA ART Maintenance Dose: 
RPV-LA 600 mg and CAB-LA 400 mg IM every 4 weeks  
Step 3: Arm B (SOC) Crossover Regimen 
Regimen  
Optional OLI: 
RPV 25 mg orally 
once daily and CAB 
LA ART Loading 
Dose: 
RPV-LA 900 mg and 
LA ART 
Maintenance 
Dose: 

 
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Registration 
Week 4b 
Weeks 8-52 
30 mg orally once 
daily for 4 weeks 
CAB-LA 600 mg IM  
RPV-LA 600 mg 
and CAB-LA 400 
mg IM every 4 
weeks  
Alternative 
Regimen 
Dosing  
LA ART Loading 
Dose: 
RPV-LA 900 mg and 
CAB-LA 600 mg IM  
LA ART Maintenance Dose: 
RPV-LA 600 mg and CAB-LA 400 mg IM 
every 4 weeks 
 
Step 4: Observation 
Any participant who has completed Step 3 and does not have access to locally 
sourced available LA ART (CAB-LA and RPV-LA) will register to Step 4 for 52 
weeks. Any participant who has received at least one dose of CAB-LA or RPV-
LA and withdraws from LA dosing during the study will be followed on oral ART 
for 52 weeks after their last dose of any LA injectable. Oral ART (SOC) in Step 4 
will be locally sourced and will not be provided by the study.  
 
Prescriptions 
A new prescription that includes the patient identification number (PID) and study 
identification number (SID) and signed by an authorized prescriber must be 
provided to the site pharmacist before the pharmacist prepares and dispenses 
study product.   
 
Quantity of Oral Study Product Supply to Dispense  
The site pharmacist should dispense enough oral study products so the 
participant has about 1 month of buffer supply. The oral study products should be 
prepared and dispensed by the site pharmacist in original whole bottles. The oral 
tablets should not be transferred from the original bottle to a prescription vial for 
dispensation by the site pharmacist. 
 
Drug substitutions 
Drug substitutions, if deemed appropriate by the site investigator, will be 
permitted during Step 1 and in the Step 2, Arm B (SOC arm). All substitutions 
and indications for the substitutions are to be recorded on the eCRFs. The site 
pharmacist must be informed in writing that the previous regimen is to be 
discontinued.   
 
5.2.2 Administration  
 
• 
CAB 30 mg administered as one 30 mg tablet orally once daily, with or 
without food for 4 weeks (optional).  
• 
CAB-LA 600 mg loading dose administered as one 3 mL (600 mg) IM 
injection in the gluteal muscle once at the Step 2 randomization if no OLI, or 
at Step 2, week 4, visit after 4 weeks of oral CAB + RPV therapy. 

 
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• 
CAB-LA 400 mg maintenance dose administered as one 2 mL (400 mg) IM 
injection in the gluteal muscle starting 4 weeks after the CAB-LA 600 mg 
loading dose and then every 4 weeks until the end of the Step.    
• 
RPV 25 mg administered as one 25 mg tablet orally once daily, with a meal 
for 4 weeks (optional). 
• 
RPV-LA 900 mg loading dose administered as one 3 mL (900 mg) IM 
injections in the gluteal muscle once at the Step 2 randomization if no OLI, or 
at Step 2, week 4, visit after 4 weeks of oral CAB + oral RPV therapy. 
• 
RPV-LA 600 mg maintenance dose administered as one 2 mL (600 mg) IM 
injection in the gluteal muscle starting 4 weeks after the RPV-LA 900 mg 
loading dose and then every 4 weeks until the end of the step.    
• 
CAB-LA and RPV-LA injections will be administered by study staff in a clinical 
setting during the same clinic visit. 
• 
ART in Step 1 and Arm B of Step 2 – The site clinician, in conjunction with 
participant, should determine the optimal ART regimen per protocol for each 
participant and dosed per package insert and site clinician’s discretion. 
 
NOTE: If the participant misses an injection and the time since the last RPV-LA 
and CAB-LA injection was greater than 8 weeks (56 days) from the previous 
injection, the participant will need to be administered a new loading dose of both 
RPV-LA (900 mg) and CAB-LA (600 mg) prior to continuing the maintenance dose. 
If the last injection of RPV-LA and CAB-LA occurred less than or equal to 8 weeks 
(56 days) from the previous injection, the participant will be continued on the 
maintenance dose of RPV-LA (600 mg) and CAB-LA (400 mg).  
 
5.2.3 Study Duration 
 
Participants will be followed for a maximum duration of 180 weeks with up to 24 
weeks in Step 1, 52 weeks in Step 2, 52 weeks in Step 3, and up to 52 weeks in 
Step 4 (if LA ART is not locally accessible and/or if participant has received at 
least one dose of LA ART and does not wish to continue LA ART).   
 
5.3 
Study Product Preparation, and Formulation  
 
5.3.1 Preparation of Injectable Study Products 
 
The Pharmacist of Record must be proficient in the preparation of study products 
using aseptic technique under a pharmacy Biological Safety Cabinet (BSC) Class 
II or better. For individual protection measures such as personal protective 
equipment (PPE), local requirements and regulations are to be followed. PPE 
may include disposable gloves, gowns, respirator and safety glasses. 
 
5.3.1.1 
CAB-LA Injectable Study Product Preparations 
 
Materials required for preparation and administration of CAB-LA 600 
mg (3 mL) and CAB-LA 400 mg (2 mL) dose: 

 
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1. CAB-LA 600 mg/3 mL vial or CAB-LA 400 mg/2 mL vial(s) 
o For CAB-LA 600 mg/3 mL Loading Dose, one (1) CAB-LA 600 
mg/3 mL vial or two (2) CAB-LA 400 mg/2 mL vials are needed 
o For CAB-LA 400 mg/2 mL Maintenance Dose, one (1) CAB-LA 
600 mg/3 mL vial or one (1) CAB-LA 400 mg/2 mL vial is 
needed 
 
2. Becton Dickinson (BD) 3-mL size syringe, Luer-Lok Tip, Product 
No.: 309657 or equivalent 
 
3. Becton Dickinson (BD) 5-mL size syringe, Luer-Lok Tip, Product 
No.: 309646 or equivalent 
 
4. Needle for aspiration: BD general use sterile hypodermic needle, 
21G x 1½ inch (e.g., Precision Glide Needle, Product No.: 305165 
or equivalent) 
 
5. Needle for intramuscular injection: BD IM sterile hypodermic 
needle, 23G x 1½ inch (e.g., Precision Glide Needle, Product No.: 
305194 or equivalent). Longer needle lengths may be needed for 
participants based on body habitus and/or with higher body mass 
indexes (BMIs, example >30), to ensure that injections are 
administered intramuscularly as opposed to subcutaneously. 
  
Preparation Steps: 
1. Remove required vial(s) of CAB-LA from storage. If the vials are 
stored in the refrigerator (2°C to 8°C), remove vial(s) from the 
refrigerator and wait at least 15 minutes to equilibrate to room 
temperature. If stored refrigerated, record for each individual CAB-
LA vial the point in time that the vial has been taken out of the 
refrigerator on the participant’s pharmacy log. 
 
o For CAB-LA 600 mg/3 mL Loading Dose, remove one (1) 600 
mg/3 mL vial or two (2) 400 mg/2 mL vials from storage  
o For CAB-LA 400 mg/2 mL Maintenance Dose, remove one (1) 
600 mg/3 mL vial or one (1) 400 mg/2 mL vials from storage  
 
2. Vigorously shake the vial(s) for a full 10 seconds by shaking the 
vial(s) with long arm movements.  
 
3. Invert the vial(s) and inspect to ensure uniform suspension. If solid 
remains undispersed, repeat Steps 2-3 until all material is 
uniformly suspended. 
 
NOTE: It is normal to see small air bubbles at the end of shaking 
the vial for resuspension. 

 
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4. Using aseptic technique under a pharmacy BSC/isolator, flip off the 
plastic cap from the vial. Wipe the top of the vial with an alcohol 
pad (isopropyl alcohol 70% or similar) and allow to dry. Do not 
touch the rubber stopper at any time. 
 
5. Remove a 3 mL or 5 mL size syringe and 21G x 1½ inch (or 
equivalent) needle for aspiration. Attach the needle to the Luer 
connection of the syringe. 
 
6. With the needle sheath on, pull the syringe plunger rod to allow 
approximately 1 mL of air into the syringe. Remove the needle 
sheath. 
 
7. With the vial in the inverted position and the syringe with the 
needle in the upright position, push the needle through the vial 
stopper and inject approximately 1 mL of air into the vial. 
 
8. While keeping the syringe with the needle in the upright position, 
withdraw needed volume of CAB-LA suspension from the vial(s) 
into the syringe. 
o For CAB-LA 600 mg/3 mL Loading Dose, withdraw total of 3 
mL (600 mg) of CAB-LA suspension from the vial(s) into a 
syringe. 
o If using two CAB-LA 400 mg/2 mL vials to prepare the dose, a 
second new aspiration needle should be used to withdraw 
suspension from the second vial. Remove the first needle that 
was used to withdraw the suspension out of the first vial and 
discard properly. Attach the new 21G x 1½ inch needle to the 
syringe already containing suspension per instructions in Step 5 
and repeat Steps 6 through 8 to withdraw the remaining needed 
volume from the second vial. 
o For CAB-LA 400 mg/2 mL Maintenance Dose, withdraw a total 
of 2 mL (400 mg) of CAB-LA suspension from the vial into a 
syringe. 
 
Since the suspension can contain some air after having shaken the 
vial, withdraw enough suspension from the vial in order to be able 
to de-aerate the syringe properly. 
 
9. Remove the needle that was used to withdraw the suspension out 
of the vial and discard the needle properly. 
 
10. Attach a 23G x 1½ inch (or equivalent) needle to the Luer 
connection of the prepared CAB-LA syringe for IM injection for the 
participant. Alternatively, the site pharmacist can attach a syringe 
cap to the prepared syringe. The study staff can then attach the 

 
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appropriate needle for administration to the prepared syringe in the 
clinic before administration. 
 
NOTE: The participant-specific prepared CAB-LA in a syringe is to 
be de-aerated by administrator prior to injection so that the correct 
volume can be administered. 
 
De-aerate the syringe by first tapping with a finger against the 
syringe and then by moving the plunger rod carefully forward with 
the needle in an upright position until the first drop of suspension 
appears. Remove the excess suspension in order to administer the 
correct volume. If needed, collect the excess suspension in a 
beaker to avoid spilling. 
 
11. Record the time the suspension was withdrawn from the vial and 
into the syringe in the participant’s pharmacy log. This is the time 
of preparation. 
 
12. Label the prepared syringe as CAB-LA 600 mg (3mL) for the 
Loading Dose or as CAB-LA 400 mg (2 mL) for the Maintenance 
Dose. Also include on the label the participant’s PID, route of 
administration (IM), date and time of preparation, and date and 
time of expiration. Follow the DAIDS Pharmacy Guidelines and 
local regulations for preparing participant specific labels. 
 
13. After withdrawal of the CAB-LA suspension from the vial into a 
syringe, it is recommended to inject the suspension immediately. 
Do not exceed 2 hours between withdrawing the contents of the 
vial(s) into a syringe (Step 8) and administering to the study 
participant.  
 
14. The prepared CAB-LA study product in a syringe must be stored at 
controlled room temperature between 20°C to 25°C (68°F to 77°F) 
from the time it is withdrawn into a syringe to the time it is 
administered. 
 
15. Any entered vials or expired filled syringes should be disposed of 
in accordance with institutional or pharmacy policy. 
 
5.3.1.2 
RPV-LA Injectable Study Product Preparations 
 
Materials required for preparation and administration of RPV-LA 900 
mg (3 mL) and RPV-LA 600 mg (2 mL) dose: 
 
1. 
RPV-LA 900 mg/3 mL vial or RPV-LA 600 mg/2 mL vial(s) 
o For RPV-LA 900 mg/3 mL Loading dose, one (1) RPV-LA 900 
mg/3 mL vial or two (2) RPV-LA 600 mg/2 mL vials are needed 

 
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o For RPV-LA 600 mg/2 mL Maintenance dose, one (1) RPV-LA 
900 mg/3 mL vial or one (1) RPV-LA 600 mg/2 mL vials is 
needed 
 
2. 
Becton Dickinson (BD) 3-mL size syringe, Luer-Lok Tip, Product 
No.: 309657 or equivalent 
 
3. 
Becton Dickinson (BD) 5-mL size syringe, Luer-Lok Tip, Product 
No.: 309646 or equivalent 
 
4. 
Needle for aspiration: BD general use sterile hypodermic needle, 
21G x 1½ inch (e.g., Precision Glide Needle, Product No.: 305165 
or equivalent) 
 
5. 
Needle for intramuscular injection: BD IM sterile hypodermic 
needle, 23G x 1½ inch (e.g., Precision Glide Needle, Product No.: 
305194 or equivalent)   
 
Preparation Steps: 
6. 
Remove required vial(s) of RPV-LA from the refrigerator and wait 
15 minutes to equilibrate to room temperature. Record for each 
individual RPV-LA vial the point in time that the vial has been 
taken out of the refrigerator on the participant’s pharmacy log. The 
maximum time out of the refrigerator is 24 hours at a maximum 
temperature of 25ºC. 
o For RPV-LA 900 mg/3 mL Loading Dose, remove one (1) 900 
mg/3 mL vial or two (2) 600 mg/2 mL vials from storage  
o For RPV-LA 600 mg/2 mL Maintenance Dose, remove one (1) 
900 mg/3 mL vial or one (1) 600 mg/2 mL vial from storage  
 
7. 
Hand-shake the vial(s) moderately for a minimum of 10 seconds 
to ensure a homogeneous suspension. After resuspending, it is 
recommended to use the suspension immediately.  
 
8. 
Invert the vial to inspect for any sediment. If sediment is observed, 
repeat Step 2. 
 
9. 
Using aseptic technique under a pharmacy Biological Safety 
Cabinet or isolator, flip off the plastic cap from the vial. Wipe the 
top of each vial with a single-use sterile alcohol pad of isopropyl 
alcohol 70% and allow the alcohol to dry. Do not touch the rubber 
stopper at any time. 
 
10. Remove a 3 mL or a 5 mL size syringe from the blister pouch and 
appropriate aspiration needle to withdraw the suspension from the 
vial. Attach the needle to the Luer connection of the syringe.  
 

 
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11. Remove needle sheath and, with vial in the upright position, push 
the needle through the vial stopper and inject the amount of air 
equal to the needed amount of suspension into the vial.  
 
12. Withdraw needed volume of RPV-LA suspension from the vial(s) 
into the syringe. 
o For RPV-LA 900 mg/3 mL Loading Dose, withdraw total of 3 
mL (900 mg) of RPV-LA suspension from the vial(s) into a 
syringe. 
o If using two RPV-LA 600 mg/2 mL vials to prepare the dose, a 
second new aspiration needle should be used to withdraw 
suspension from the second vial. Remove the first needle that 
was used to withdraw the suspension out of the first vial and 
discard properly. Attached a new needle to the syringe already 
containing suspension per instructions in Step 5 and repeat 
Steps 6 and 7 to withdraw the remaining needed volume from 
the second vial. 
o For RPV-LA 600 mg/2 mL Maintenance Dose, withdraw a total 
of 2 mL (600 mg) of RPV-LA suspension from the vial into a 
syringe. 
 
13. Since the suspension can contain some air after having shaken 
the vial, withdraw enough suspension from the vial in order to be 
able to de-aerate the syringe properly. 
 
14. Remove the needle that was used to withdraw the suspension out 
of the vial and discard the needle properly. 
 
15. Attach a 23G x 1½ inch (or equivalent) needle to the Luer 
connection of the prepared RPV-LA syringe for IM injection for the 
participant. Alternatively, the site pharmacist can attach a syringe 
cap to the prepared syringe. The study staff can then attach the 
appropriate needle for administration to the prepared syringe in 
the clinic before administration. 
 
NOTE: The participant-specific prepared RPV-LA in a syringe is to 
be de-aerated by administrator prior to injection so that the correct 
volume can be administered. 
 
16. De-aerate the syringe by first tapping with a finger against the 
syringe and then by moving the plunger rod carefully forward with 
the needle in an upright position until the first drop of suspension 
appears. Remove the excess suspension in order to administer 
the correct volume. If needed, collect the excess suspension in a 
beaker to avoid spilling. 
 

 
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17. Record the time the suspension was withdrawn from the vial and 
into the syringe in the participant’s pharmacy log. This is the time 
of preparation. 
 
18. Label the prepared syringe as RPV-LA 900 mg (3 mL) for the 
Loading Dose or as RPV-LA 600 mg (2 mL) for the Maintenance 
Dose. Also include on the label the participant’s PID, route of 
administration (IM), date and time of preparation, and date and 
time of expiration. Follow the DAIDS Pharmacy Guidelines and 
local regulations for preparing participant specific labels. 
 
19. After withdrawal of the RPV-LA suspension from the vial into a 
syringe, it is recommended to inject the suspension immediately. Do 
not exceed 2 hours between withdrawing the contents of the vial(s) 
into a syringe (Step 7) and administering to the study participant.   
 
20. The prepared RPV-LA study product in a syringe must be stored 
at controlled room temperature between 20°C to 25°C (68°F-77°F) 
from the time it is withdrawn into a syringe to the time it is 
administered. 
 
Any entered vials or expired filled syringes should be disposed of in 
accordance with institutional or pharmacy policy. 
 
5.3.2 Study Product Formulation 
 
• 
CAB 30 mg oral tablet in bottles is to be stored up to 30°C (86°F) in the 
original container and protected from moisture. 
• 
CAB-LA injectable suspension in single use vial containing 400 mg/2 mL or 
600 mg/3 mL is to be stored up to 30°C (up to 86°F). Do not freeze. The 
concentration of CAB-LA for both 2 mL and 3 mL filled vials is 200 mg/mL. 
• 
RPV 25 mg oral tablet (Edurant®) in bottles is to be stored in the original 
bottle protected from light at 25°C (77°F); excursions permitted to 15° to 30°C 
(59° to 86°F) [See USP Controlled Room Temperature]. 
• 
RPV-LA injectable suspension in single use vial containing 600 mg/2 mL or 
900 mg/3 mL is to be stored in the original container protected from light 
between 2°C to 8°C (36°F to 46°F). Do not freeze. The concentration of RPV-
LA for both 2 mL and 3 mL filled vials is 300 mg/mL. 
• 
Emtricitabine and tenofovir alafenamide 200 mg/25 mg tablet (Descovy®) is 
to be stored below 30°C (86°F). Keep container tightly closed. Dispense only 
in original container. 
• 
Abacavir and lamivudine(3TC) 600 mg/300 mg tablet (Epzicom®) is to be 
stored at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See 
USP Controlled Room Temperature]. 

 
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• 
Darunavir and cobicistat 800 mg/150 mg tablet (Prezcobix®) is to be stored 
at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 
86°F) [See USP Controlled Room Temperature]. 
• 
Dolutegravir 50 mg tablet (Tivicay®) is to be stored at 25°C; excursions 
permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room 
Temperature]. 
• 
Abacavir, dolutegravir, and lamivudine(3TC) 600 mg/50 mg/300 mg 
(Triumeq®) is to be stored at 25°C; excursions permitted to 15° to 30°C (59° 
to 86°F) [See USP Controlled Room Temperature]. Dispense in the original 
package, protected from moisture with the bottle tightly closed. Do not 
remove desiccant. 
 
5.4 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.4.1 Study Product Acquisition/Distribution 
 
All oral ART provided through the study for Steps 1 and 2 (see Table 5.2.1-1), 
oral CAB, oral RPV, CAB-LA and RPV-LA for Steps 2 and 3 will be provided by 
ViiV and will be available through the NIAID Clinical Research Products 
Management Center (CRPMC). The site pharmacist should obtain the study 
drug(s) for this protocol by following the instructions in the manual Pharmacy 
Guidelines and Instructions for DAIDS Clinical Trials Networks.  
 
5.4.2 Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all study drugs 
received from the NIAID CRPMC and subsequently dispensed. All unused study 
drugs in US CRSs must be returned to the NIAID CRPMC (or as otherwise 
directed by the sponsor) after the study is completed or terminated. The 
procedures to be followed are in the manual Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks.  
 
5.4.3 Ensuring Study Product Supply during the COVID-19 Pandemic or Other 
Extenuating Circumstances as Approved by Protocol Team Leadership  
 
Notify the site Pharmacist of Record (PoR) and provide a prescription for any 
participant randomized to the long-acting injectable arm in Step 2 that may require 
oral bridging therapy (up to 1 month is allowed) with oral cabotegravir/rilpivirine 
(CAB/RPV) due to a missed visit (either anticipated or already missed). The site 
PoR can order 1-month supplies of oral CAB and oral RPV from the CRPMC via 
the online ordering system per PID per order. The site PoR should notify both 
protocol pharmacists, Katherine Shin (kashin@niaid.nih.gov) and Cynthia Parker 
(cindy.parker@nih.gov), for each PID in need of oral bridging therapy. The 
protocol pharmacists will work with the site pharmacist to provide assistance. 
 
If oral CAB/RPV is unavailable or more than 1 month of oral bridging is needed 
by a participant, sites should instruct the participant to reinitiate his or her 

 
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regimen from Step 1. The oral study products provided through the study via 
CRPMC may be limited in supply during the COVID-19 pandemic. In rare 
circumstances, additional consideration for the use of oral bridging may be 
appropriate; contact the study leadership team (actg.leada5359@fstrf.org) for 
individual circumstances, such as limited site study product supply, anticipated 
prolonged absence, or other unpredictable  instances (see also section 6.2.3.1) . 
In emergency situations, such as the COVID-19 pandemic, the Pharmacy 
Guidelines and Instructions for DAIDS Clinical Trials Networks permits shipment 
or courier of study product from the site directly to participants. The pharmacist 
should refer to the section on “Shipping Study Product to a Participant” in this 
manual for detailed procedures. If this method is to be implemented, each site 
pharmacist must develop appropriate procedures for the shipment or courier of 
study product to the identified participant in accordance with these guidelines, 
and must include appropriately documented chain of custody. This method 
should only be used if permissible per local institutional and IRB/EC policies. 
 
All questions related to study product management should be directed to the 
protocol pharmacists, Katherine Shin and Cynthia Parker. 
 
If sites cannot, at minimum, dispense oral study products and maintain contact 
with the participant to assess safety because of institutional or local guidelines 
related to the response to the COVID-19 pandemic, then participants should be 
referred back to their local clinical providers to obtain local SOC ARVs and 
medical care. 
 
5.5 
Concomitant Medications 
 
Whenever a concomitant medication or study agent is initiated or a dose changed, 
investigators must review the concomitant medication’s and study agent’s most recent 
package insert, Investigator’s Brochure, or updated information from DAIDS to obtain the 
most current information on drug interactions, contraindications, and precautions. 
 
Additional drug information may be found on the ACTG Precautionary and Prohibited 
Medications Database located at: http://tprc.pharm.buffalo.edu/home/di_search/. 
 
5.5.1 Required Medications 
 
Prophylaxis for those who are at risk for opportunistic infections is strongly 
recommended. Investigators should refer to the US Public Health 
Service/Infectious Diseases Society of America "Guidelines for Prevention and 
Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents 
(https://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf).” Although 
recommended as an alternative in the guidelines, rifabutin for the prophylaxis of 
Mycobacterium avium-intracellulare complex should be avoided. 
 
 
 

 
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5.5.2 Prohibited Medications 
 
The following concomitant medications or therapies are not permitted at any time 
during the study regardless of randomized treatment arm: 
 
o HIV immunotherapeutic vaccines or monoclonal antibodies. 
o Other experimental agents, ARV drugs not otherwise specified in the 
protocol, cytotoxic chemotherapy, or radiation therapy (see Exclusion Criteria: 
section 5.2). 
o Systemically administered immunomodulators (such as interleukin and 
interferon agents). Including interferon for treatment of HCV infection. This 
includes topical agents with substantial systemic exposure and systemic 
effects. Use of topical imiquimod is permitted. 
o Chronic use of systemic (oral or parenteral) glucocorticoids at doses above 
physiologic replacement must be avoided due to their immunosuppressive 
effect; however, short treatment courses with oral prednisone/ 
prednisolone/methylprednisolone (e.g., adjunctive treatment of pneumocystis 
pneumonia with ≤21 days of tapering prednisone) are allowed. A single dose 
of systemic dexamethasone is permitted (more than a single dose in a 
treatment course may cause significant decrease in RPV plasma 
concentration and is prohibited). Topical, inhaled, or intranasal use of 
glucocorticoids will be allowed. 
 
Prohibited Medications with Concurrent Use of CAB or RPV: 
For participants receiving either formulation of CAB and RPV, the following 
medications could significantly decrease the levels of CAB and/or RPV due to 
enzyme induction and therefore are prohibited and must not be administered 
concurrently: 
o Carbamazepine 
o Oxcarbazepine 
o Phenobarbital 
o Phenytoin 
o Rifabutin 
o Rifampicin / Rifampin 
o Rifapentine 
o St. John’s wort (Hypericum perforatum) 
 
Hepatitis C infection therapy with direct-acting agents (DAA) is allowed during the 
entire study. However, participants on an HIV ART regimen in Step 1 or Step 2 
that contains a protease inhibitor (PI) are prohibited from co-administration of 
anti-HCV PI as part of their DAA regimen either alone or as part of a fixed-dose 
combination (e.g., Ombitasvir/Paritaprevir/RTV plus Dasabuvir). Please refer to 
DHHS guidelines Table 15 
(https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/AdultandAdole
scentGL.pdf). 
 
 

 
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Prohibited Medications with Concurrent Use of Oral RPV: 
Participants must discontinue the following (or change to an allowable 
alternative) while receiving treatment with oral RPV: 
o Proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, 
pantoprazole, rabeprazole 
o Systemic dexamethasone (more than a single dose) 
 
If the participant cannot discontinue use or change to an allowable alternative 
while receiving treatment with RPV, the participant should not be randomized into 
the study. 
 
Prohibited Medications with Concurrent Use of Either Long-acting Agent: 
In addition, for participants receiving CAB-LA and RPV-LA, use of 
anticoagulation agents for greater than 14 days is prohibited, with the exception 
of the use of anticoagulation for deep vein thrombosis (DVT) prophylaxis (e.g., 
postoperative DVT prophylaxis) or the use of low-dose  
acetylsalicylic acid (≤325 mg). Systemic anticoagulation (including prophylaxis 
doses) on the day of an IM injection should be avoided. 
 
NOTE: Any prohibited medications that decrease CAB or RPV concentrations 
should be discontinued for a minimum of 4 weeks or a minimum of three half-
lives (whichever is longer) prior to the first dose, and any other prohibited 
medications should be discontinued for a minimum of 2 weeks or a minimum of 
three half-lives (whichever is longer) prior to the first dose. 
 
5.5.3 Precautionary Medications 
 
A full list of precautionary medications will be listed in the PSWP.  
 
5.6 
Adherence  
 
5.6.1 Adherence Assessment  
 
Adherence to all oral study medications will be assessed by a validated 
adherence assessment at the intervals indicated in section 6.1, Schedule of 
Evaluations (SOE). In addition to self-report, ART adherence and drug exposure 
will also be evaluated through drug concentrations in hair and DBS. These 
matrices provide a quantitative measure of cumulative drug exposure (usually 
weeks or months) that complement plasma drug levels (which are subject to 
white coat adherence) and are predictive of viral suppression in diverse 
populations (refer to the MOPS).  
 
5.6.2 Adherence Monitoring and Support 
 
This study seeks to enroll participants with a history of non-adherence to 
medications, a group not traditionally targeted for recruitment in ACTG trials. 
Since CEI alone might not be sufficient to encourage adherence, addressing the 

 
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challenges to adherence in this study population will be imperative to ensure 
study retention and allow for complete interpretation of study results. 
 
In addition to the CEI used during the induction period, sites will be required to 
develop a multi-component adherence support protocol utilizing the framework of 
the Guidelines for Improving Entry Into and Retention in Care and ARV Adherence 
for Persons With HIV: Evidence-Based Recommendations From an International 
Association of Physicians in AIDS Care Panel, with a focus on the 
recommendations to promote adherence to visits and improve adherence to ART 
(see MOPS) [43]. In addition, multiple methods of participant recruitment and 
retention will be utilized, including appointment reminder via phone call, email, SMS 
and social media in a HIPAA-compliant fashion. We expect these recommendations 
will enhance current study adherence and retention efforts by ACTG sites.  
 
The A5359 MOPS will provide recommendations on frequency of between-visit 
contact with study participants. Recommendations for best practices for 
addressing toxicity and adherence barriers will also be outlined in the MOPS.  
 
5.7  
Conditional Economic Incentives (CEI) 
 
Adherence benchmarks using study visit and HIV-1 RNA decline will be evaluated during 
Step 1 and CEI will be provided to participants if the predetermined milestones are met 
during this period (Table 5.7-1). As described above, the rationale behind limiting the 
cash incentives to the induction phase is to utilize them as a time-limited intervention to 
support adherence to oral therapy in individuals with a history of sub-optimal adherence 
to oral medications and to improve the chance that viral suppression will be achieved 
before transitioning to LA ART.  
 
Participants are eligible to receive CEI totaling up to $675 for completion of Step 1. At 
Step 1, week 2, a $75 incentive will be provided for completion of a return study visit. At 
Step 1, weeks 4 and 8, participants who have a decrease of >1 log10 and >2 log10 in HIV-
1 RNA compared to HIV-1 RNA at entry, respectively, or achieve an HIV-1 RNA decline 
to ≤200 copies/mL, or complete a virtual visit under COVID-19 pandemic guidelines, will 
be incentivized $75 for each milestone met.  
 
Starting at Step 1, week 4, participants who achieve an HIV-1 RNA ≤200 copies/mL will be 
eligible to receive the remainder of the CEI scheduled for Step 1 and proceed to Step 2 
randomization (Table 5.7-1). As an example, if a participant meets virologic suppression 
criteria for randomization at Step 1, week 12, the CEI for week 12+16+20 ($450) will be 
disbursed at that time and the participant will proceed to Step 2 randomization; or if a 
participant meets virologic suppression criteria for randomization at Step 1, week 16, the 
CEI for week 16+20 ($300) will be disbursed at that time and the participant will proceed to 
Step 2 randomization. If the Step 1, week 4, 8, 12, 16, or 20, HIV-1 RNA is 201-399 
copies, the participant will not receive CEI at that visit, but can be incentivized if the 
confirmation viral load visit is ≤200 copies/mL. This confirmation visit needs to be 
completed before Step 1, week 24. 
 

 
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If a participant skips visit(s), he or she can be eligible for an incentive not received in a 
previous missed visit; e.g., if participant misses the Step 1, week 8, visit, he or she can 
be eligible for the $75 incentive of dropping more than 2 log10 copies in HIV RNA at 
Step 1, week 9, 10, or 11, visits. 
 
Participants who do not achieve the benchmarks at any point will not receive the CEI.  
 
Table 5.7-1: 
CEI from Entry to Week 20, and Additional Continuity Visits Due to the 
COVID-19 Pandemic 
Step 1, Week 
Milestone 
Incentive 
2 
Completed visit (in person or virtual) 
$75.00 
4 
HIV-1 RNA >1 log10 drop or HIV-1 RNA 
≤200 copies/mL or completed virtual 
visit 
$75.00* 
8 (if needed) 
HIV-1 RNA >2 log10 drop or HIV-1 RNA 
≤200 copies/mL or completed virtual 
visit 
$75.00* 
12 (if needed) 
HIV-1 RNA ≤200 copies/mL or 
completed virtual visit 
$150.00* 
16 (if needed) 
HIV-1 RNA ≤200 copies/mL or 
completed virtual visit 
$150.00* 
20 (if needed), 
or 
Confirmation viral load after week 20 (but 
prior to week 24) 
HIV-1 RNA ≤200 copies/mL 
$150.00 
Additional Continuity Visits during the 
COVID-19 pandemic (only applicable if in-
person visits are not permitted by the site’s 
institution) 
HIV-1 RNA ≤200 copies/mL or 
completed virtual visit 
$150.00 
* NOTE: Virally suppressed participants (≤200 copies/mL) who receive CEI at week 4, 8, 
12, or week 16 will be eligible for randomization into Step 2 and should not continue 
further visits in Step 1, and will additionally receive the CEI that would have been 
distributed at the later Step 1 visits.  
 
All CEIs will be additional to site’s usual compensation for participation in the study (i.e., 
attending study visits and completing assessments). Since there will be a short lapse 
between study visits and virologic assay results, incentives may be provided using a 
debit card system, which will allow for funds to be added remotely once the data become 
available, although in person incentive distribution will also be permitted. Study 
participants will be notified immediately via phone call, text SMS, email, or other 
preferred communication method after their benchmark is achieved.  
 
No other steps will be incentivized financially beyond standard site-specific 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Evaluations 
 
Table 6.1-1: Step 1: Induction 
Evaluations 
Screening 
Entry (0) 
Step 1, Week 2 
Step 1, Week 4 
Step 1, Week 8 
Step 1, Week 12 
Step 1, Week 16 
Step 1, Week 20 
Visit to confirm  
HIV-1 RNA if  
Week 4, 8, 12, 16, or 
20  
HIV-1 RNA = 201-399
Step 1, Week 24A 
Premature Treatment 
DiscontinuationB  
Premature Study 
Discontinuation  
Visit Window 
Within 60 
days prior 
to entry 
Within 72 
hours after 
registration 
±1 Week 
Before Step 
1, Week 24 
±1 
Week 
Within 
14 
days 
Within 
14 
days 
SOC (All Participants) 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Documentation of HIV-1 
X 
 
 
 
 
 
 
 
 
 
 
 
Baseline Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
X 
 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Complete Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
Targeted Physical Exam 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Hematology 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Blood Chemistries, including Cr 
Clearance 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 

 
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Evaluations 
Screening 
Entry (0) 
Step 1, Week 2 
Step 1, Week 4 
Step 1, Week 8 
Step 1, Week 12 
Step 1, Week 16 
Step 1, Week 20 
Visit to confirm  
HIV-1 RNA if  
Week 4, 8, 12, 16, or 
20  
HIV-1 RNA = 201-399
Step 1, Week 24A 
Premature Treatment 
DiscontinuationB  
Premature Study 
Discontinuation  
Visit Window 
Within 60 
days prior 
to entry 
Within 72 
hours after 
registration 
±1 Week 
Before Step 
1, Week 24 
±1 
Week 
Within 
14 
days 
Within 
14 
days 
Liver Function Tests 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Fasting Lipid Profile 
 
X 
 
 
 
 
 
 
 
X 
 
 
Urinalysis 
X 
 
If clinically indicated (see section 6.3.6) 
 
 
Pregnancy Test 
X 
X 
If 
suspect
ed 
XC 
XC 
XC 
XC 
X 
 
XC 
X 
X 
Urine Drug Toxicology 
 
XD 
X 
X 
X 
X 
X 
X 
 
 
 
 
CD4+/CD8+ 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
HIV-1 RNAE 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV-1 GenotypeE 
X 
If Clinically Indicated (see section 6.3.8) 
DBS (venipuncture) for 
participants on TAF, 3TC, FTC or 
ABC  
 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
Stored plasma and PBMCs 
from Whole Blood 
 
X 
 
 
X 
X 
 
 
 
X 
X 
X 
Hepatitis B and C Serology 
XR 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 

 
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Evaluations 
Screening 
Entry (0) 
Step 1, Week 2 
Step 1, Week 4 
Step 1, Week 8 
Step 1, Week 12 
Step 1, Week 16 
Step 1, Week 20 
Visit to confirm  
HIV-1 RNA if  
Week 4, 8, 12, 16, or 
20  
HIV-1 RNA = 201-399
Step 1, Week 24A 
Premature Treatment 
DiscontinuationB  
Premature Study 
Discontinuation  
Visit Window 
Within 60 
days prior 
to entry 
Within 72 
hours after 
registration 
±1 Week 
Before Step 
1, Week 24 
±1 
Week 
Within 
14 
days 
Within 
14 
days 
Hair Collection (optional) 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Sociodemographic Questionnaire 
 
X 
 
 
 
 
 
 
 
 
 
 
C-SSRS, DVST, HIV Stigma 
Mechanism Measure 
Questionnaires 
 
X 
 
 
 
 
 
 
 
 
X 
X 
HRU Questionnaire 
 
X 
 
 
 
X 
 
 
 
 
 
 
GAD-7, HIV-ASES, PHQ-9 
Questionnaires 
 
X 
 
 
 
X 
 
X 
 
 
X 
X 
Self-Report of Adherence 
Questionnaire 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Documentation of Site 
Adherence and Retention 
Support 
 
Every six months at each site beginning with enrollment of its first 
participant 
 
 
 
AUDIT-C, DUDIT, Smoking 
Questionnaires 
X 
 
 
 
 
X 
 
X 
 
 
X 
X 
Conditional Economic Incentives 
 
 
X 
X 
X 
X 
X 
X 
XF 
 
 
 
 
Refer to the SOE FOOTNOTES section for the footnote explanations. 
 
NOTE: Once a participant meets eligibility criteria for randomization (at or after Step 1, week 4) subsequent visits for Step 1 should not be 
completed and they should proceed to the Step 2 randomization visit. 
 

 
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Table 6.1-2: Step 2: Randomization to LA ART vs. Oral SOC – Arm A 
Evaluations 
Step 2, RandomizationG 
Step 2, Week 4aH 
Step 2, Week 4b 
Step 2, Week 8 
Step 2, Week 12 
Step 2, Week 16 
Step 2, Week 20 
Step 2, Week 24 
Step 2, Week 28 
Step 2, Week 32 
Step 2, Week 36 
Step 2, Week 40 
Step 2, Week 44 
Step 2, Week 48 
Step 2, Week 52 
Confirmation of  
Virologic Failure 
Premature Treatment 
Discontinuation 
Premature Study 
Discontinuation 
Visit Window Arm A 
 
±4 Days 
for non-
OLI;  
+1 week 
for OLI 
+6 
Days 
±4 
Days 
±1 Week 
for non-
OLI; 
±4 days for 
OLI  
±1 Week 
±1 
Wee
k 
7-21 
Days 
after 
HIV VL 
>200 
Within 
14 
days 
Within 
14 
days 
Dispense Oral RPV + CAB  
XI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RPV-LA + CAB-LA Injection  
XJ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Clinical Assessments  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
Targeted Physical Exam  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
Injection Site Evaluation  
XJ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Hematology 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Blood Chemistries, including 
Cr Clearance 
 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Liver Function Tests 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Fasting Lipid Profile 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Urinalysis 
 If clinically indicated (see section 6.3.6) 
 
Urine Pregnancy Test (pre-
dose) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Urine Drug Toxicology   
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 

 
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Evaluations 
Step 2, RandomizationG 
Step 2, Week 4aH 
Step 2, Week 4b 
Step 2, Week 8 
Step 2, Week 12 
Step 2, Week 16 
Step 2, Week 20 
Step 2, Week 24 
Step 2, Week 28 
Step 2, Week 32 
Step 2, Week 36 
Step 2, Week 40 
Step 2, Week 44 
Step 2, Week 48 
Step 2, Week 52 
Confirmation of  
Virologic Failure 
Premature Treatment 
Discontinuation 
Premature Study 
Discontinuation 
Visit Window Arm A 
 
±4 Days 
for non-
OLI;  
+1 week 
for OLI 
+6 
Days 
±4 
Days 
±1 Week 
for non-
OLI; 
±4 days for 
OLI  
±1 Week 
±1 
Wee
k 
7-21 
Days 
after 
HIV VL 
>200 
Within 
14 
days 
Within 
14 
days 
CD4+/CD8+ 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
HIV-1 RNAE 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
HIV-1 GenotypeE 
If Clinically Indicated (see section 6.3.8) 
X 
If clinically 
indicated 
(see section 
6.3.8) 
Stored plasma and PBMCs 
from Whole BloodK 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
PK Trough SampleL 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Hair Collection (optional) 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
Pill Counts  
 
XI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sociodemographic 
Questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
HIVTSQs-status 
QuestionnaireM 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
HIVTSQc-change 
QuestionnaireM 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 

 
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Evaluations 
Step 2, RandomizationG 
Step 2, Week 4aH 
Step 2, Week 4b 
Step 2, Week 8 
Step 2, Week 12 
Step 2, Week 16 
Step 2, Week 20 
Step 2, Week 24 
Step 2, Week 28 
Step 2, Week 32 
Step 2, Week 36 
Step 2, Week 40 
Step 2, Week 44 
Step 2, Week 48 
Step 2, Week 52 
Confirmation of  
Virologic Failure 
Premature Treatment 
Discontinuation 
Premature Study 
Discontinuation 
Visit Window Arm A 
 
±4 Days 
for non-
OLI;  
+1 week 
for OLI 
+6 
Days 
±4 
Days 
±1 Week 
for non-
OLI; 
±4 days for 
OLI  
±1 Week 
±1 
Wee
k 
7-21 
Days 
after 
HIV VL 
>200 
Within 
14 
days 
Within 
14 
days 
Dichotomous Preference 
Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
CEI Withdrawal Questionnaire 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS, DVST, HIV Stigma 
Mechanism Measure 
Questionnaires 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
HRU Questionnaire 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
GAD-7, HIV-ASES, PHQ-9 
Questionnaires 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
Documentation of Site 
Adherence and Retention 
Support 
Every six months at each site beginning with enrollment of its first participant. 
 
 
 
AUDIT-C, DUDIT, Smoking 
Questionnaires 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
Refer to the SOE FOOTNOTES section for the footnote explanations. 
 
 

 
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Table 6.1-3: Step 2: Randomization to LA ART vs. Oral SOC – Arm B 
Evaluations 
Step 2, Randomization 
Step 2, Week 4aH 
Step 2, Week 8 
Step 2, Week 12N 
Step 2, Week 16 
Step 2, Week 20N 
Step 2, Week 24 
Step 2, Week 28N 
Step 2, Week 32N 
Step 2, Week 36 
Step 2, Week 40N 
Step 2, Week 44N 
Step 2, Week 48 
Visit to confirm  
HIV-1 RNA if  
Step 2, Week 48  
HIV-1 RNA = 201-399 
Step 2, Week 52 
Confirmation of  
Virologic Failure 
Premature Treatment 
DiscontinuationB 
Premature Study 
Discontinuation 
Visit Window Arm B 
 
±1 
Week 
±1 Week 
Before 
Step 2, 
Week 52 
±1 
Wee
k 
7-21 
Days 
after HIV 
VL >200 
Within 
14 
days 
Within 
14 
days 
Dispense Oral SOC 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Clinical Assessments 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
Targeted Physical Exam 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
Hematology 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Blood Chemistries, including 
Cr Clearance 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Liver Function Tests 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Fasting Lipid Profile 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Urinalysis 
If clinically indicated (see section 6.3.6) 
 
Urine Pregnancy Test  
X 
X 
X 
XN 
X 
XN 
X 
XN 
XN 
X 
XN 
XN 
X 
 
X 
 
X 
X 
Urine Drug Toxicology  
X 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
CD4+/CD8+ 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 

 
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Evaluations 
Step 2, Randomization 
Step 2, Week 4aH 
Step 2, Week 8 
Step 2, Week 12N 
Step 2, Week 16 
Step 2, Week 20N 
Step 2, Week 24 
Step 2, Week 28N 
Step 2, Week 32N 
Step 2, Week 36 
Step 2, Week 40N 
Step 2, Week 44N 
Step 2, Week 48 
Visit to confirm  
HIV-1 RNA if  
Step 2, Week 48  
HIV-1 RNA = 201-399 
Step 2, Week 52 
Confirmation of  
Virologic Failure 
Premature Treatment 
DiscontinuationB 
Premature Study 
Discontinuation 
Visit Window Arm B 
 
±1 
Week 
±1 Week 
Before 
Step 2, 
Week 52 
±1 
Wee
k 
7-21 
Days 
after HIV 
VL >200 
Within 
14 
days 
Within 
14 
days 
HIV-1 RNAE 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
HIV-1 GenotypeE 
If Clinically Indicated (see section 6.3.8) 
 
X 
If clinically 
indicated (see 
section 6.3.8) 
DBS (venipuncture) on TAF, 
3TC, FTC, or ABC  
X 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Stored plasma and PBMCs 
from Whole BloodK 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Hair Collection (optional) 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Sociodemographic 
Questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
HIVTSQs-status 
QuestionnaireM 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
CEI Withdrawal Questionnaire 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS, DVST, HIV Stigma 
Mechanism Measure 
Questionnaires 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
HRU Questionnaire 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 

 
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Evaluations 
Step 2, Randomization 
Step 2, Week 4aH 
Step 2, Week 8 
Step 2, Week 12N 
Step 2, Week 16 
Step 2, Week 20N 
Step 2, Week 24 
Step 2, Week 28N 
Step 2, Week 32N 
Step 2, Week 36 
Step 2, Week 40N 
Step 2, Week 44N 
Step 2, Week 48 
Visit to confirm  
HIV-1 RNA if  
Step 2, Week 48  
HIV-1 RNA = 201-399 
Step 2, Week 52 
Confirmation of  
Virologic Failure 
Premature Treatment 
DiscontinuationB 
Premature Study 
Discontinuation 
Visit Window Arm B 
 
±1 
Week 
±1 Week 
Before 
Step 2, 
Week 52 
±1 
Wee
k 
7-21 
Days 
after HIV 
VL >200 
Within 
14 
days 
Within 
14 
days 
GAD-7, HIV-ASES, PHQ-9 
Questionnaires 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
Self-Report of Adherence 
Questionnaire  
X 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
Documentation of Site 
Adherence and Retention 
Support 
Every six months at each site beginning with enrollment of its first participant. 
 
 
 
AUDIT-C, DUDIT, Smoking 
Questionnaires 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
 
Refer to the SOE FOOTNOTES section for the footnote explanations. 

 
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Table 6.1-4: Step 3: LA ART Continuation/Crossover to LA ARV 
Evaluations 
Step 3, RegistrationO 
Step 3, Week 4aH 
Step 3, Week 4b  
(All Participants) 
Step 3, Week 8 
Step 3, Week 12 
Step 3, Week 16 
Step 3, Week 20 
Step 3, Week 24 
Step 3, Week 28 
Step 3, Week 32 
Step 3, Week 36 
Step 3, Week 40 
Step 3, Week 44 
Step 3, Week 48 
Confirmation of 
Virologic Failure 
Step 3, Week 52 
Premature Treatment 
Discontinuation 
Premature Study 
Discontinuation 
Visit Window (Arm A) 
 
±1 Week 
 
±1 Week 
7-21 
Days 
after 
HIV VL 
>200 
±1 
Week 
Within 
14 
days 
Within 
14 
days 
Visit Window (Arm B) 
 
±4 Days for 
non-OLI;  
+1 week for 
OLI 
+6 
Days 
±4 
Days 
±1 Week 
for non-
OLI; 
±4 days for 
OLI 
±1 Week 
7-21 
Days 
after 
HIV VL 
>200 
±1 
Week 
Within 
14 
days 
Within 
14 
days 
Dispense Oral RPV + CAB  
(Arm B) 
XI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RPV-LA + CAB-LA Injection 
XJ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Clinical Assessments 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Targeted Physical Exam 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Injection Site Evaluation 
XJ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Hematology 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
Blood Chemistries, including Cr 
Clearance 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
Liver Function Tests 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
Fasting Lipid Profile 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 

 
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Evaluations 
Step 3, RegistrationO 
Step 3, Week 4aH 
Step 3, Week 4b  
(All Participants) 
Step 3, Week 8 
Step 3, Week 12 
Step 3, Week 16 
Step 3, Week 20 
Step 3, Week 24 
Step 3, Week 28 
Step 3, Week 32 
Step 3, Week 36 
Step 3, Week 40 
Step 3, Week 44 
Step 3, Week 48 
Confirmation of 
Virologic Failure 
Step 3, Week 52 
Premature Treatment 
Discontinuation 
Premature Study 
Discontinuation 
Visit Window (Arm A) 
 
±1 Week 
 
±1 Week 
7-21 
Days 
after 
HIV VL 
>200 
±1 
Week 
Within 
14 
days 
Within 
14 
days 
Visit Window (Arm B) 
 
±4 Days for 
non-OLI;  
+1 week for 
OLI 
+6 
Days 
±4 
Days 
±1 Week 
for non-
OLI; 
±4 days for 
OLI 
±1 Week 
7-21 
Days 
after 
HIV VL 
>200 
±1 
Week 
Within 
14 
days 
Within 
14 
days 
Urinalysis 
If clinically indicated (see section 6.3.6) 
 
Urine Pregnancy Test  
(pre-dose) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Urine Drug Toxicology 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
CD4+/CD8+ 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
HIV-1 RNAE 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
HIV-1 GenotypeE 
If Clinically Indicated (see section 6.3.8) 
X 
If Clinically Indicated 
(see section 6.3.8) 
Stored Plasma and PBMCs from 
Whole BloodK 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
PK Trough SampleL 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Hair Collection (optional) 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
X 
X 

 
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Evaluations 
Step 3, RegistrationO 
Step 3, Week 4aH 
Step 3, Week 4b  
(All Participants) 
Step 3, Week 8 
Step 3, Week 12 
Step 3, Week 16 
Step 3, Week 20 
Step 3, Week 24 
Step 3, Week 28 
Step 3, Week 32 
Step 3, Week 36 
Step 3, Week 40 
Step 3, Week 44 
Step 3, Week 48 
Confirmation of 
Virologic Failure 
Step 3, Week 52 
Premature Treatment 
Discontinuation 
Premature Study 
Discontinuation 
Visit Window (Arm A) 
 
±1 Week 
 
±1 Week 
7-21 
Days 
after 
HIV VL 
>200 
±1 
Week 
Within 
14 
days 
Within 
14 
days 
Visit Window (Arm B) 
 
±4 Days for 
non-OLI;  
+1 week for 
OLI 
+6 
Days 
±4 
Days 
±1 Week 
for non-
OLI; 
±4 days for 
OLI 
±1 Week 
7-21 
Days 
after 
HIV VL 
>200 
±1 
Week 
Within 
14 
days 
Within 
14 
days 
Pill Counts (Arm B) 
 
XI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIVTSQs-status QuestionnaireM 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
HIVTSQs-change Questionnaire (Arm 
B only)M 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Dichotomous Preference 
Questionnaire (Arm B) 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
C-SSRS, DVST, HIV Stigma 
Mechanism Measure Questionnaires 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
HRU Questionnaire 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
GAD-7, HIV-ASES, PHQ-9 
Questionnaires 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
Documentation of Site Adherence 
and Retention Support 
Every six months at each site beginning with enrollment of its first participant 
X 
X 
AUDIT-C, DUDIT, Smoking 
Questionnaires 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
Refer to the SOE FOOTNOTES section for the footnote explanations. 
 

 
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Table 6.1-5: Step 4: Observation on SOC (Oral ART locally sourced, not provided by study). Participants Who Received at Least 
One Dose of LA ART 
Evaluations 
Step 4 - Observation 
Study D/C or  
Premature 
DiscontinuationQ 
Step 4, 
RegistrationP 
Step 4, Week 
24 
Step 4, Week 
52 
Confirmation of 
Virologic Failure 
Premature 
Treatment 
DiscontinuationB 
Visit Window 
±4 Weeks 
7-21 Days 
after HIV VL 
>200 
Within 14 days 
Within 14 days 
Clinical Assessments 
X 
X 
X 
 
X 
X 
Targeted Physical Exam 
X 
X 
X 
 
X 
X 
Injection Site Evaluation 
X 
 
 
 
 
 
Hematology 
X 
X 
X 
 
X 
X 
Blood Chemistries, including Cr Clearance 
X 
X 
X 
 
X 
X 
Liver Function Tests 
X 
X 
X 
 
X 
X 
Fasting Lipid Profile 
X 
 
X 
 
X 
X 
Urinalysis 
If clinically indicated (see section 6.3.6) 
 
Pregnancy Test 
If suspected. Participants of Child Bearing Potential on DTG must have a pregnancy test 
monthly. 
 
CD4+/CD8+ 
X 
 
X 
X 
X 
X 
HIV-1 RNAE 
X 
X 
X 
X 
X 
X 
HIV-1 GenotypeE 
If Clinically Indicated (see section 6.3.8) 
X 
If Clinically Indicated  
(see section 6.3.8) 
Stored Plasma and PBMCs from Whole 
BloodK 
X 
X 
X 
 
X 
X 
PK Trough Sample for storage only 
X 
 
 
X 
X 
X 

 
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Evaluations 
Step 4 - Observation 
Study D/C or  
Premature 
DiscontinuationQ 
Step 4, 
RegistrationP 
Step 4, Week 
24 
Step 4, Week 
52 
Confirmation of 
Virologic Failure 
Premature 
Treatment 
DiscontinuationB 
Visit Window 
±4 Weeks 
7-21 Days 
after HIV VL 
>200 
Within 14 days 
Within 14 days 
HIVTSQ Questionnaire 
 
 
 
 
 
X 
GAD-7, HIV-ASES, PHQ-9 Questionnaires 
 
 
 
 
 
X 
Documentation of Site Adherence and 
Retention Support 
Every six months at each site beginning with 
enrollment of its first participant. 
 
 
 
C-SSRS, DVST, HIV Stigma Mechanism 
Measure 
 
 
 
X 
AUDIT-C, DUDIT, Smoking 
Questionnaires 
 
 
 
 
 
X 
 
Refer to the SOE FOOTNOTES section for the footnote explanations. 
 
 
 

 
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SOE FOOTNOTES: 
A For participants who are not eligible or choose not to continue onto Step 2 only. 
B The treatment discontinuation visit should only be completed if the participant discontinues oral ART including study provided 
and/or locally sourced ART. 
C For participants of child-bearing potential who are on a DTG-containing regimen, perform a pregnancy test at the visits indicated. 
For all other participants of child-bearing potential, pregnancy test is performed only if clinically suspected. 
D Only Step 1, Entry urine drug toxicology screen results will be returned to the participant for purposes of referral (see section 6.3.6). 
E HIV-1 RNA and HIV-1 genotype testing to be done at local or central laboratory. Refer to the A5359 LPC for more information. 
F Only if not provided at Step 1, week 20.  
G Step 2 randomization will occur after Step 1, week 4, if the participant has met virologic suppression criteria for randomization. The 
HIV-1 RNA viral load that will be used to determine eligibility for randomization must have been collected within 4 weeks (28 days) 
of the randomization visit. Participant must begin treatment within 72 hours after Step 2 randomization. 
H Participants who are randomized to LA ART in Step 2, or crossing over from SOC to LA ART in Step 3, and who are opting to start 
oral CAB and RPV at the Step 2 Randomization visit or Step 3 Registration visit, must have results from the week 4a clinical and 
laboratory evaluations available and reviewed by the IoR or their designee prior to the injections. Week 4 evaluations may be 
combined to occur on the same day if safety lab results (all except HIV-1 RNA) are available, or over several days. Participants 
continuing LA ART in Step 3 can combine Step 3 weeks 4a/4b evaluations on the same visit. 
I Only for participants opting to start oral CAB and RPV at the Step 2 Randomization visit or Step 3 Registration visit (see section 
6.2.3). 
J Only for participants opting to start LA ART injections at Step 2 Randomization visit OR Step 3 Registration visit (see section 6.2.3). 
These participants must combine the weeks 4a and 4b visits. 
K Stored plasma and PBMCs from whole blood will NOT be collected for people who become and remain pregnant during Steps 2 
and 3 (section 8.22). 
L A pre-dose trough sample will also be obtained for storage at study visits in which a participant missed a prior scheduled study 
visit. 
M For those randomized to Arm A, the “HIVTSQ change” questionnaire will be administered at the Step 2, week 48, visit. For those 
randomized to Arm B, the “HIVTSQ change” questionnaire will be administered at the Step 3, week 48, visit. For all other visits, the 
“HIVTSQ status” questionnaire will be administered. 
N Only people of child bearing potential on a DTG-containing regimen must attend visit weeks 12, 20, 28, 32, 40, and 44. 
O Participants may register to Step 3 immediately following their Step 2, week 52 visit. The HIV-1 RNA viral load that will be used to 
determine eligibility for Step 3 registration for participants randomized to Arm B in Step 2 must have been collected within 4 weeks 
(28 days) of their Step 3 registration visit. Participants randomized to Arm B must begin study treatment within 72 hours after 
registration to Step 3. 

 
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P Participants who received at least one dose of CAB-LA or RPV-LA will register to Step 4 after completing Step 2 per the SOE or 
after completing Step 3 per the SOE. Visits in Step 4 must be scheduled ±4 weeks. 
Q Participants who complete 52 weeks of oral ART after their last dose of LA ART, but prior to Step 4, week 52, will need to complete 
a study discontinuation visit. 
R  If the last negative HBV test is more than 6 months prior to enrollment, then repeat testing should be performed at screening.

 
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6.2 
Timing of Evaluations 
 
6.2.1 Screening Evaluations  
 
Screening evaluations must occur prior to the participant starting any study 
medications, treatments, or interventions. 
 
Screening 
Screening evaluations to determine eligibility must be completed within 60 days 
prior to study entry unless otherwise specified. In addition to data being collected 
on participants who enroll into the study, demographic, clinical, and laboratory 
data on participants who do not enroll will be captured in a Screening Failure 
Results form and entered into the ACTG database.  
 
On March 18, 2020, the ACTG leadership placed a temporary pause on 
enrollment due to the COVID-19 pandemic. Participants who were in screening 
or completed screening prior to the pause in enrollment, but have exceeded the 
screening window, could be rescreened after the pause was lifted by the ACTG 
leadership on August 11, 2020. 
 
6.2.2 Entry Evaluations 
 
Entry evaluations may occur on the same day as screening. Participant must 
begin treatment within 72 hours after registration to Step 1.  
 
6.2.3 Post-Entry Evaluations  
 
6.2.3.1 On-Treatment Evaluations 
 
Step 1: 
Evaluations must occur after the entry visit. The Step 1, week 2, through 
Step 1, week 24, visits should be scheduled per the window in the SOE.  
 
Step 1, week 24, evaluations are only performed for those participants 
who are not eligible or choose not to move onto Step 2. 
 
Step 2: 
Participants will be randomized in Step 2 after they meet the virologic 
suppression criteria for randomization at or after Step 1 week 4 (see 
SOE, Table 6.1-2). The HIV-1 RNA viral load that will be used to 
determine eligibility for randomization must have been collected within 4 
weeks (28 days) of the randomization visit. Participant must begin 
treatment within 72 hours after Step 2 randomization. After 
randomization, for Arm A participants, the visits for the second and third 
CAB-LA/RPV-LA dose (Step 2, week 8, and Step 2, week 12, visits for 
OLI participants; Step 2, week 4, and Step 2, week 8, for non-OLI 

 
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participants) should be scheduled per the window in the SOE and 
section 6.4. All subsequent CAB-LA/RPV-LA injections visits in Step 2 
should be scheduled per the window in the SOE. For Arm B participants, 
all study visits should be scheduled per the window in the SOE.  
 
Step 2 LA ART Initiation with CAB + RPV OLI Step 2, Week 4a, or Step 
3, Week 4a, Visit 
Participants who are randomized to Arm A in Step 2 and participants 
who are crossing over to LA ART in Step 3 and initiating oral CAB + 
RPV, must have results from the Step 2, week 4a, or Step 3, week 4a, 
visit, respectively. Clinical and laboratory evaluations results must be 
reviewed by the IoR or their designee prior to the injections. Week 4a 
evaluations may occur on a single day or over several days in 
accordance with the visit windows. 
 
Participants who are randomized to Arm A and are continuing on LA 
ART in Step 3 do not need to wait for laboratory evaluations results 
before receiving their injections. 
 
Step 2, Week 4b, and Step 3, Week 4b, Visits with CAB + RPV OLI 
Participants who are randomized to Arm A in Step 2, will receive 
additional evaluation and LA ART injection per the window in the SOE. 
Clinical and laboratory evaluations results must be reviewed by the IoR 
or their designee prior to the injections.  
 
Participants who are randomized to Arm B in Step 2 and are 
transitioning to LA ART in Step 3, will receive additional evaluation and 
LA ART injection per the window in the SOE and must have results from 
the week 4a visit. Clinical and laboratory evaluations results must be 
reviewed by the IoR or their designee prior to the injections.   
 
Step 2 LA ART Initiation without CAB + RPV OLI 
At the discretion of the site IoR, a participant may opt to forgo the oral 
CAB + oral RPV, and proceed directly to injection at the Step 2 
randomization visit. In this case, the first injections are administered at 
the Step 2 randomization visit. The next injections will be administered 
at Step 2, week 4a. The Step 2, weeks 4a and 4b, visits are combined. 
Please refer to SOE Table 6.1-2 Step 2: Randomization to LA ART vs. 
Oral SOC – Arm A footnotes (I, J).  
 
In exceptional circumstances, the protocol team may authorize the use 
of oral CAB and oral RPV as a short-term “bridging” strategy for 
participants who have begun CAB-LA/RPV-LA (for COVID-19 pandemic 
bridging instructions, please refer to section 6.2.3.3 below). This 
strategy would only be employed to address any potential gap in CAB-
LA + RPV-LA dosing due to the COVID-19 pandemic and other 

 
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extenuating circumstances (see section 5.4.3) as approved by the 
A5359 team leadership such as limited site study product supply, 
anticipated prolonged absence, or other unpredictable or unforeseen 
events. Should a participant need “oral bridging,” sites must contact the 
protocol leadership team at actg.leada5359@fstrf.org for authorization 
and guidance for treatment strategies prior to a missed CAB-LA + RPV-
LA dose. Should a participant not notify the site in advance, the protocol 
leadership team must be contacted for further treatment guidance. 
 
In Clarification Memo #2, for Version 1.0, dated April 13, 2020, sites 
were instructed to defer entry into Step 2 following the ACTG 
leadership’s temporary pause on enrollment due to the COVID-19 
pandemic. The ACTG leadership lifted this pause in August 2020. 
 
Transition from Step 2, Week 52, to Step 3 Registration 
Participants can register to Step 3 immediately following their Step 2, 
week 52, visit. Participants who were randomized to Arm A in Step 2 
should continue their study visits as outlined in the SOE. Participants 
who were randomized to Arm B in Step 2 must begin study treatment 
within 72 hours after registration to Step 3. The HIV-1 RNA viral load 
that will be used to determine eligibility for Step 3 registration for 
participants randomized to Arm B in Step 2 must have been collected 
within 4 weeks (28 days) of their Step 3 registration visit. Step 2, week 
52, evaluations and results do not need to be repeated nor keyed at the 
Step 3 registration study visit (if completed on the same day).  
 
Step 3 LA ART Initiation with CAB + RPV OLI 
In Step 3, for participants who were randomized to Step 2, Arm B, visits 
for the second and third CAB-LA/RPV-LA dose (Step 3, week 8, and 
Step 3, week 12) should be scheduled per the window in the SOE and 
section 6.4. All subsequent CAB-LA/RPV-LA injection visits in Step 3 
should be scheduled per the window in the SOE. 
 
Step 3 LA ART Initiation without CAB + RPV OLI 
At the discretion of the site IoR and study participant, a Step 2, Arm B, 
participant crossing over to LA ART in Step 3 may opt to forgo the oral 
CAB + oral RPV, and proceed directly to injection at the Step 3 
registration visit. In this case, the first injections are administered at the 
Step 3 registration visit. The next injections will be administered at Step 
3, week 4a. The Step 3, week 4a and 4b, visits are combined. Please 
refer to SOE Table 6.1-4 Step 3: LA ART Continuation/Crossover to LA 
ART. 
 
Transition from Step 2, Week 52, to Step 4 Registration 
Participants who received at least one dose of CAB-LA or RPV-LA can 
register to Step 4 immediately or within 4 weeks (28 days) following their 

 
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Step 2, week 52 visit. Follow-up within Step 2 after the last injection will 
count towards follow-up in Step 4. 
 
Transition from Step 3, Week 52, to Step 4 Registration 
Participants who received at least one dose of CAB-LA or RPV-LA can 
register to Step 4 immediately or within 4 weeks (28 days) following their 
Step 3, week 52, visit. Follow-up within Step 3 after the last injection will 
count towards follow-up in Step 4. 
 
6.2.3.2 Event-Driven Evaluations  
 
Step 1: 
At Step 1, weeks 4, 8, 12, 16, and 20, if HIV-1 RNA is between 201-399 
copies/mL, a repeat HIV-1 RNA will be performed at a laboratory that 
possesses a CLIA certification or equivalent by Step 1, week 24. If the 
repeat HIV-1 RNA is ≤200 copies/mL, then the participant is eligible for 
randomization.  
 
Step 2: 
For participants who randomized to Arm B, if their Step 2, week 48, 
sample is between 201-399 copies/mL, a repeat HIV-1 RNA will be 
performed at a laboratory that possesses a CLIA certification or 
equivalent by Step 2, week 52. If the repeat HIV-1 RNA is ≤200 
copies/mL, then the participant is eligible to register for Step 3 to cross 
over to LA ART. 
 
Steps 2 through 4: Confirmation of Virologic Failure 
Virologic failure is defined as follows: 
 
• 
Confirmed HIV-1 RNA >200 copies/mL after Step 2 
randomization. 
 
Participants in whom virologic failure is suspected (HIV-1 VL >200 
copies/mL at any visit after the Step 2 randomization visit) should return 
to the clinic for evaluations per the SOE within 7-21 days after the date 
of the initial plasma HIV-1 RNA >200 copies/mL.  
 
If the initial sample was collected during a treatment interruption, sites 
are encouraged to address toxicity or adherence issues before taking 
the confirmatory sample, if possible, within the allowed window. If the 
evaluations at the time of confirmed virologic failure coincide with a 
regularly scheduled visit, the evaluations should be combined.  
 

 
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For participants who enter Step 3 from Step 2 SOC arm, Step 3 
virologic failure is defined as confirmed HIV-1 RNA >200 copies/mL 
after Step 3, week 0. 
 
If the initial sample was collected during a treatment interruption, sites 
are encouraged to address toxicity or adherence issues before taking 
the confirmatory sample, if possible, within the allowed window. If the 
evaluations at the time of confirmed virologic failure coincide with a 
regularly scheduled visit, the evaluations should be combined.  
 
If virologic failure is confirmed, management of ART will be left to the 
discretion of the site investigator. If stopping study treatment, the 
participant will complete the Premature Treatment Discontinuation 
evaluations and continue to be followed on study/off study treatment or 
be followed on study/on oral ART if they received at least one dose of 
CAB-LA/RPV-LA per section 6.2.4. Refer to the A5359 LPC for testing 
requirements. 
 
6.2.3.3 COVID-19 Pandemic Guidance 
 
Study Visits during the COVID-19 Pandemic Restrictions 
The study team recognizes that each site’s situation will be unique 
regarding the timing of reopening for study visits and procedures (if 
these were affected), and the extent to which they will be implemented. 
The study team suggests that sites should not resume regular 
operations unless: 
• 
Local governance bodies allow the reinitiation of in-person research 
activities, 
AND 
• 
The site has the capacity to perform monthly visits, specimen 
collection, and injection administration. 
 
NOTE: Please refer to DAIDS memorandum “Guidance for Resuming 
ACTG Clinical Research Activities Post-COVID-19 Restrictions” dated 
May 29, 2020 for additional instructions and recommendations. 
 
Data Collection during the COVID-19 Pandemic “Stay-At-Home” Order 
Study visits may be conducted remotely (e.g., telephone, telehealth) in 
the following situations: 
• 
A participant is unable to attend a visit because of illness, inability to 
travel, or concern for potential exposure to COVID-19. 
• 
The site is temporarily unable to conduct non-essential visits in the 
clinic. 
 

 
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Sites should document which visits were conducted remotely, attempt to 
obtain as much of the visit-specific required information as possible, 
based on the SOE, and record the information on the relevant eCRF. 
The impacted visits and rationale must be reported and documented 
following instructions provided by the team or network leadership. Both 
the team and IRB must be apprised of overall strategies that are 
employed at the site, and these documents should be placed in the 
regulatory binder for the study. The individual research participant’s 
chart will contain information about what assessments were done 
remotely, or were missed, or other deviations because of COVID-19. 
 
For all visits, site staff should not inactivate eCRFs but should follow 
guidelines provided by the DMC regarding documentation of missed 
evaluations due to COVID-19. 
 
Step 1: 
Step 1 participants should be maintained on their Step 1 regimen (if 
possible). Study visits should be conducted as per local institutional 
guidelines (this could include implementing virtual and over-the-phone 
visits to provide adherence support and completion of study 
questionnaires). Study labs may be deferred unless the IoR considers 
them critical to assess safety. 
 
Conditional Economic Incentives (CEIs) should be deployed as per the 
protocol and subsequent LOAs if the participant:  
1) Meets the criteria as outlined in the protocol (Table 5.7-1) if the site 
is still conducting visits, or  
2) Completes virtual or over-the phone visits as per the institution’s 
current research visits policy. 
 
If a participant has not yet reached the virologic suppression criteria for 
randomization in Step 1, continue to conduct study visits per the SOE 
through week 16. At these visits, record data in the corresponding visit 
week folder. For in-person evaluations that cannot be completed, please 
follow the guidelines provided by the DMC regarding documentation. 
These guidelines are located under “Medidata Rave Resources” on the 
DMC Portal. 
 
After a participant completes the Step 1, week 16, visit, continue to 
conduct visits every 4 weeks and perform the week 16 evaluations (per 
Table 6.1-1) at each visit until the COVID-19 restrictions are lifted. 
 
NOTE: Do not perform the Step 1, week 20, evaluations indicated in 
Table 6.1-1 (Step 1: Induction). 
 

 
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Record the Step 1 visits conducted every 4 weeks after week 16 in an 
Unscheduled Visit folder. Continue to count visit weeks from Entry for 
the source documents. On the eCRFs, you will be asked the date of the 
visit when using the Unscheduled Visit folder. Contact the DMC if 
additional eCRFs are required. Include “COVID-19” when indicating the 
reason for an unscheduled visit. 
 
For participants who have completed the Step 1, week 20, visit: 
If the participant’s HIV-1 RNA viral load was ≥400 copies/mL, the participant 
should complete the Step 1, week 24, visit as scheduled (remotely, as 
needed). If the participant’s HIV-1 RNA viral load is <400 copies/mL, 
continue to conduct visits every 4 weeks, performing the Step 1, week 16, 
evaluations per the SOE. Record these visits in an Unscheduled Visit folder. 
Include “COVID-19” when indicating the reason for an unscheduled visit. 
 
Participants are eligible to receive both CEIs as outlined above in Table 5.7-1 
AND study visit compensation for every visit conducted while in Step 1. 
 
Once the COVID-19 restrictions are lifted, the participants enrolled in Step 1 
who were undergoing repeated week 16 evaluations (i.e., those who 
completed Step 1, week 16) will return for a study visit where the Step 1, 
week 20, evaluations will be conducted or be randomized to Step 2, if eligible 
as above. For participants who already completed Step 1, week 20, 
evaluations prior to the pause in study visits, they may proceed with 
randomization provided their HIV-1 RNA was ≤200 copies/mL and that this 
was obtained within 4 weeks (28 days). If HIV-1 RNA was obtained >4 weeks 
(28 days), repeat testing will be necessary. 
 
Step 2 (Both Arms): 
During special operations instituted under the national emergency 
declaration for the COVID-19 pandemic, sites will continue to collect and 
process for HIV-1 RNA evaluation for all Step 2 visits that are completed 
in person by a local CLIA-approved laboratory.  
 
Step 2 (Arm A): 
If injections can be administered safely at the institution for those 
participants randomized to Arm A, injections should be continued after 
documentation of a negative pregnancy test. Sites could consider 
minimizing contact during these visits by conducting study questionnaires 
and performing telehealth evaluations for injection site reactions (if 
available and per institutional policies).  
 
Laboratory assessments may be limited to safety labs at the discretion 
of the IoR and per local institutional guidance. 
 

 
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If injections cannot be provided for any reason, consider bridging with 1 month 
of oral CAB/RPV or Step 1 regimen (see above in section 5.4.3). Participants 
currently receiving the CAB/RPV OLI should be transitioned to their Step 1 
regimen. Participants in this group (receiving CAB/RPV OLI and then 
transitioned to their previous Step 1 regimen) will continue follow-up visits 
monthly and have assessments performed according to the SOE (as possible). 
Data should be recorded in the corresponding visit week folder. 
 
Sites should inform the A5359 protocol team leadership 
(actg.leada5359@fstrf.org) when initiating participants on oral bridging 
therapy during the COVID-19 pandemic per section 6.2.3, On-Treatment 
Evaluations, Step 2, week 4b, and Step 3, week 4b, Visit, in the 
protocol. Sites may also consider reinitiating the ART regimen used in 
Step 1 if injections cannot be provided. 
 
If study visits in Step 2 are curtailed, continue to conduct safety follow-up 
visits (per the Step 2, Arm A, SOE) by phone or telehealth to determine if 
a participant receiving site-prescribed study products has had adverse 
events (AEs) or serious adverse events (SAEs) that require medical 
follow-up. Study questionnaires can be administered over the phone per 
the SOE. Timely medical follow-up is still required for participants 
experiencing AEs or SAEs. SAEs will need to be reported to DAIDS via 
DAERS as per guidelines. 
 
Once the COVID-19 restrictions are lifted, the participants enrolled in Step 2, 
Arm A, will return for a study visit where the next scheduled evaluations will 
be conducted (i.e., participants will be treated as if this upcoming visit were 
their next scheduled injection visit after discontinuation of injections). Prior to 
the reinitiation of injectable LA CAB + RPV, participants will need to have 
documentation of viral suppression (HIV-1 RNA ≤200 copies/mL). If HIV-1 
RNA is >200 copies/mL, a repeat HIV-1 RNA can be obtained within 14 days 
to assess if reinitiating injectable LA CAB + RPV is appropriate. Refer to the 
subsection, Data Collection after Resumption of In-Person Clinical Research 
Activities Post-COVID-19 Restrictions, below for further guidance. 
 
Step 2 (Arm B): 
Arm B visits may be treated as other non-essential study visits at some 
sites in accordance with their local institutional guidance/policies during 
the COVID-19 pandemic. In these situations, study visits should be 
conducted according to local institutional guidance and policies. 
Research personnel can conduct all study visits by phone or telehealth 
to determine if a participant receiving site-prescribed study products has 
had AEs or SAEs that require medical follow-up and EAE reporting. 
Study questionnaires can be administered over the phone. 
 

 
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If study visits in Step 2 are curtailed, conduct safety follow-up visits by 
phone or telehealth to determine if a participant has had an AE or SAE. 
Study questionnaires can be administered over the phone per the SOE. 
Timely medical follow-up is still required for participants experiencing  
AEs or SAEs. SAEs will need to be reported to DAIDS via DAERS as 
per guidelines. 
 
NOTE: The CEIs will not be extended to participants in Step 2. 
 
Step 3 
Please refer to instructions for Step 2 (Arm A).  
 
Data Collection after Resumption of In-Person Clinical Research 
Activities Post-COVID-19 Restrictions 
 
Step 1: (including transition from Step 1 into Step 2) 
If a site was able to continue with study visits throughout the COVID-19 
“stay-at-home” orders, the site may continue to conduct study visits and 
procedures per the SOE. 
 
If a participant was maintained on their Step 1 study-supplied regimen, 
they should continue this regimen. 
 
If a participant was required to switch to locally sourced ART due to 
barriers accessing study-supplied regimen, the study team will allow 
continuation of this locally sourced ART. Any ART changes will need to 
be properly documented in the corresponding eCRF. 
 
If a site was unable to conduct in-person study visits or virtual visits for a 
participant, the study team would recommend that participants resume 
study visits and procedures in accordance to what would have been 
their next scheduled visit (per the SOE). 
 
If any participant was required to repeat Step 1 visits due to site 
restrictions, the participant can now proceed to the next scheduled visit 
to determine eligibility for transition and randomization to Step 2, or be 
randomized to Step 2, if eligible. If the participant was determined to be 
eligible for randomization prior to suspension of Step 1 to Step 2 
transition, they can proceed to randomization, provided the last HIV-1 
RNA was obtained ≤4 weeks (28 days) prior to the visit and was ≤200 
copies/mL. If the HIV-1 RNA was obtained >4 weeks (28 days) prior,  
this will need to be repeated and confirmed ≤200 copies/mL prior to 
transition to Step 2. 
 
Sites should confirm the availability of LA ART and oral SOC supply with 
their site PoR. The site PoR should notify both protocol pharmacists, 

 
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Katherine Shin (kashin@niaid.nih.gov) and Cynthia Parker 
(cindy.parker@nih.gov), for any additional need of study products. The 
protocol pharmacists will work with the site PoR to provide assistance. 
 
As of August 11, 2020, Step 1 progression may resume. This will allow 
participants to transition from Step 1 into Step 2 as follows: 
 
Step 2 (Arm A): 
If a site was able to continue with study visits throughout the COVID-19 
“stay-at-home” order, the sites may continue to conduct study visits and 
procedures per the SOE. 
 
If a participant was required to transition back to either their Step 1 oral 
SOC regimen or received/remained on oral CAB/RPV bridging, 
resumption or initiation of injections will be based on the timing of the 
last HIV-1 RNA and the timing of the last injection. 
 
HIV-1 RNA: 
If the last HIV-1 RNA was obtained ≤4 weeks (28 days) prior to the visit 
AND was ≤200 copies/mL, the participant can resume injections based 
on the timing of their last injection (outlined below). 
 
If the last HIV-1 RNA was obtained >4 weeks (28 days) prior to the visit, 
the site should obtain an HIV-1 RNA (which can be performed at a local 
lab) and proceed with reinitiation of injectable LA ART if it is ≤200 
copies/mL. If the HIV-1 RNA is >200 copies/mL, the site should follow 
the confirmation of virologic failure procedures outlined in section 6.2.3. 
If the confirmation HIV-1 RNA is ≤200 copies/mL, proceed with injection. 
 
NOTE: See section 6.3.8 regarding collection of viral loads. 
 
Timing of the last injection: 
If the last injection occurred <8 weeks prior to the visit, participants may 
resume maintenance dose of injectable RPV 600 mg/CAB 400 mg. 
 
If the last injection occurred ≥8 weeks prior to the visit, participants will 
require a new loading dose of IM RPV 900 mg/CAB 600 mg, which will 
be followed by the maintenance dose of injectable RPV 600 mg/CAB 
400 mg 4 weeks later (in a similar fashion as when they initiated 
injectable ART in Step 2). 
 
Step 2 (Arm B): 
If a site was able to continue with study visits throughout the COVID-19 
“stay-at-home” order, the site may continue to conduct study visits and 
procedures per the SOE. 
 

 
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When in-person visits resume, sites should continue to conduct study 
visits and procedures per the SOE. 
 
6.2.4 Discontinuation Evaluations 
 
Evaluations for Participants Who Do Not Start Study Treatment in Step 1 
Participants who do not begin study treatment in Step 1 will be followed on 
study/off study treatment until Step 1, week 24, and then be taken off study. 
Participants will not have Step 1 evaluations performed per protocol 
requirements; however, their clinical chart will be abstracted for CD4+/CD8+, and 
plasma HIV-1 RNA assessments until Step 1, week 24, i.e., the equivalent of end 
of Step 1. Participants who do not wish to be followed on study should have 
screening and entry forms completed and keyed and then be taken off study.  
 
Evaluations for Randomized Participants Who Do Not Start Study Treatment in Step 2 
Participants who do not begin study treatment in Step 2, will be followed on 
study/off study treatment until Step 2, week 52, and then be taken off study. 
However, they will only be required to have clinical assessments, CD4+/CD8+ 
and plasma HIV-1 RNA performed per protocol requirements until Step 2, week 
52, i.e., the equivalent of end of Step 2. If applicable, they may also have a urine 
pregnancy test at the treatment discontinuation visit. 
 
Evaluations for Participants Who Do Not Start Injectable Study Treatment in Step 3 
Participants randomized to SOC (Arm B) in Step 2 who do not wish to begin study 
treatment in Step 3 will be taken off study with no further evaluations required. 
 
Participants randomized to CAB-LA/RPV-LA (Arm A) in Step 2 and who received 
at least one dose of CAB-LA/RPV-LA in Step 2, who do not wish to continue 
study treatment in Step 3 will register to Step 4 at the completion of Step 2.  
 
Evaluations for Participants Who Do Not Start oral ART in Step 4 
Participants who do not begin oral ART in Step 4, will be followed on study/off 
study treatment until Step 4, week 52, and then be taken off study. Participants 
will not have Step 4 evaluations performed per protocol requirements; however, 
their clinical chart will be abstracted for CD4+/CD8+ and plasma HIV-1 RNA 
assessments until Step 4, week 52, i.e., the equivalent of end of Step 4. 
 
Premature Discontinuation of Study Treatment  
Discontinuation of study treatment is defined as following: 
 
Step 1 participants: discontinuation of all oral ART regimen (this includes study 
provided and/or locally sourced ART). 
 
Step 2, Arm A, participants: Discontinuation of oral CAB/RPV and not initiating 
LA injections, or discontinuation of LA injections. 
 

 
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Step 2, Arm B, participants: Discontinuation of all oral ART regimen (including 
study provided and/or locally sourced ART). 
 
NOTE: Switching oral ART from study provided to locally sourced is NOT 
considered as discontinuation of study treatment.  
 
Step 3 participants: Discontinuation of oral CAB/RPV and not initiating LA 
injections, or discontinuation of LA injections. 
 
Step 4 participants: Discontinuation of all oral ART regimen. 
 
Participants who prematurely discontinue treatment at any step will have the 
Premature Treatment Discontinuation evaluations performed within 14 days after 
stopping study treatment per the SOE. 
 
Participants who prematurely discontinue study treatment during Step 1 are 
encouraged to be followed on study/off study treatment per the SOE until the end 
of Step 1.  
 
Arm B participants who permanently discontinue all oral ART regimen prematurely 
during Step 2 should be followed on study/off study treatment per the SOE until 
the end of Step 2; Arm A participants should be followed on study/on oral ART per 
the SOE until the end of Step 2 and then register to Step 4. Arm A participants will 
be followed until the participant completes 52 weeks on oral ART after their last 
dose of LA ART, which could include weeks accrued during Step 2 for a total of 
52 weeks.  
 
Participants who prematurely discontinue study treatment during Step 3 should 
be followed on study/on oral ART per the SOE until the end of Step 3 and then 
register to Step 4. Participants will be followed until the participant completes 52 
weeks on oral ART after their last dose of LA ART, which could include weeks 
accrued during Step 3 for a total of 52 weeks. 
 
Participants who prematurely discontinue oral ART on Step 4, are encouraged to 
be followed on study/off oral ART per SOE until the end of Step 4. 
 
Premature Study Discontinuation Evaluations 
Participants who prematurely discontinue participation in the study should report 
to the clinic to have the Premature Study Discontinuation evaluations performed 
within 14 days.  
 
Participants who complete 52 weeks of oral ART after their last dose of LA ART, 
but prior to Step 4, week 52, will need to complete a study discontinuation visit. 
 

 
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Study Completion Evaluations  
Participants who are not eligible to enter Step 2 will have final study visit at Step 1, 
week 24. 
 
Step 2, Arm A participants who are not eligible or choose not to continue on LA 
ART in Step 3 will register to Step 4 at the completion of Step 2 and will be 
followed until they complete 52 weeks on locally sourced oral ART. 
 
Step 2, Arm B participants who are not eligible or choose not to crossover to LA 
ART in Step 3 will have their final study visit at Step 2, week 52.  
 
Participants who complete Step 3 and choose not to continue (or cannot access) 
LA ART at the end of Step 3, will register to Step 4 and have their final study visit 
at Step 4, week 52.  
 
If participants can access LA ART during follow-up in Step 4, and the participant 
and provider decide to restart LA ART prior to Step 4, week 52, they will 
discontinue study follow up and complete a study discontinuation visit before 
restarting LA ART. 
 
6.3 
Instructions for Evaluations 
 
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/score-source-documentation-
requirements.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 
Adult and Pediatric Adverse Events (DAIDS AE Grading Table), and AE reporting of 
adverse events requirements. 
 
The protocol team and/or study monitoring entity (e.g., SMC) may determine that 
additional source data associated with procedures or evaluations performed per protocol 
should be entered into eCRFs so that the data can be used for analysis or to otherwise 
assist with interpretation of study findings. In such cases, sites will be officially instructed 
to enter the additional data into eCRFs from available source documentation. 
 
6.3.1 Documentation of HIV-1 
 
Section 4.1.1 specifies assay requirements for HIV-1 documentation. HIV-1 
documentation is not recorded on the eCRF. 
 

 
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6.3.2 Medical History 
 
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 (refer to the CDC HIV Classification and the WHO 
Staging System for HIV Infection and Disease) 
• 
Bone fractures (verbal history accepted) 
• 
Coronary heart disease 
• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Diabetes 
• 
Tuberculosis 
• 
Chronic hepatitis C 
• 
Chronic hepatitis B  
• 
History of SARS-CoV-2 infection or COVID-19 
 
Any allergies to any medications and their formulations must also be documented.  
 
6.3.3 Medication History 
 
A medication history must be present, including start and stop dates. The table 
below lists the medications that must be included in the history:  
 
Table 6.3.3-1: Medication History 
Medication Category 
Time Frame 
ART 
Complete History 
Immune-based therapy 
Within 12 months prior to study entry 
Blinded study treatment 
Within 12 months prior to study entry 
HIV-1-related vaccines 
Complete History 
Prescription drugs for treatment of 
opportunistic infections 
Within 30 days prior to study entry 
Prescription drugs for prophylaxis of 
opportunistic infections 
Within 30 days prior to study entry 
Prescription drugs (other) 
Within 30 days prior to study entry 
Alternative therapies 
Within 30 days prior to study entry 
Dietary supplements 
Within 30 days prior to study entry 
Sex-hormone medications or sex-
hormone analogues or antagonists* 
 Within 12 months prior to study entry 
except as noted below 
*Includes hormone-releasing IUDs (e.g., Mirena inserted in the last 5 years); oral, 
injectable, implanted, or patch contraceptives; vaginal ring, creams, or inserts; 
estrogen, progesterone, or testosterone therapy; leuprolide or other synthetic 
gonadotropin-releasing hormone; tamoxifen, raloxifene, aromatase inhibitors, or 
any other androgen, estrogen, or progesterone analogue or antagonist therapy. 

 
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6.3.4 Clinical Assessments 
 
Complete Physical Exam 
A complete physical examination, at screening, is to include at a minimum an 
examination of the skin, head, mouth, and neck; auscultation of the chest; 
cardiac exam; abdominal exam; and examination of the lower extremities for 
edema. The complete physical exam will also include signs and symptoms, 
diagnoses, and vital signs (temperature, pulse, respiration rate, and blood 
pressure), height, and weight for BMI calculation. 
 
Targeted Physical Exam 
A targeted physical examination will be performed per the SOE and is to include 
vital signs (weight, temperature, pulse, respiration rate, and blood pressure) and 
is to be driven by any previously identified or new adverse events/targeted 
events (as described in below bullets), that the participant has experienced since 
the last visit or at this visit. 
 
Injection Site Reaction 
Injections will start in Step 2. For those randomized to Arm A in Step 2, and for all 
participants in Step 3, evaluate each injection site immediately after injection and 
at each subsequent visit and describe per section 8.18.  
 
Refer to section 7.2 for AE collection requirements. 
 
Concomitant Medications 
Post-entry, the following new and discontinued concomitant medications must be 
recorded on the eCRFs: 
• 
Sex-hormone medications or sex-hormone analogues or antagonists (see 
section 6.3.3 for examples). 
• 
Any new or discontinued prescription medications, especially those listed in 
section 6.3.3, including lipid-lowering agents, contraceptives, systemic 
steroids, other immune modulatory drugs, investigational drugs, and study-
prohibited medications taken since the last study visit, including actual or 
estimated start dates and stop dates. 
 
Study Treatment Modifications 
Record all study drug modifications, including initial doses, participant-initiated 
and/or protocol-mandated modifications, inadvertent and deliberate oral ART 
interruptions of more than 7 consecutive days, missed or delayed LA injections 
(defined as 8 days beyond scheduled injection day) since the last visit. Record 
any permanent discontinuation of treatment.  
 

 
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6.3.5 Procedures 
 
Intramuscular LA ART injection: 
Starting in Step 2, Arm A, at study visits (dosing interval of Q4 weeks) and for all 
participants in Step 3.  
  
6.3.6 Laboratory Evaluations 
 
At screening and entry for each step, all laboratory values must be recorded on 
the eCRF. For post-entry assessments, record on the eCRF all laboratory values 
for ALT, AST, alkaline phosphatase, total bilirubin, total cholesterol, HDL 
cholesterol, low density lipoprotein (LDL) cholesterol (calculated), triglycerides, 
and glucose regardless of grade as indicated on SOE; record abnormal 
laboratory findings as per section 7.2.  
 
Hematology (CBC) 
Hemoglobin, hematocrit, white blood cell count (WBC), differential WBC, ANC, 
and platelet count will be performed in real time at the local laboratory. 
 
Blood Chemistries (Basic Metabolic Panel) 
Blood urea nitrogen (BUN), creatinine, glucose, and electrolytes (sodium, 
potassium, chloride, and CO2/bicarbonate) will be performed in real time at the 
local laboratory. 
 
Calculated CrCl is required as estimated by the CKD-Epi (refer to section 4.1.6). 
This requires the recording of all values of serum creatinine regardless of grade. 
 
Liver Function Tests (LFTs) 
Total bilirubin, direct bilirubin, AST (SGOT), ALT (SGPT), and alkaline 
phosphatase will be performed in real time at the local laboratory. 
 
NOTE A: If participant develops symptoms suggestive of hepatitis, perform LFTs 
within 2 weeks of visit.   
 
NOTE B: Indirect bilirubin should be calculated from the total and direct bilirubin 
values. Indirect bilirubin should be reported according to protocol 
reporting requirements. Direct bilirubin does not need to be reported.   
 
Fasting Lipid Profile 
Total cholesterol, HDL cholesterol, low density lipoprotein (LDL) cholesterol 
(calculated), triglycerides, will be obtained and all values will be recorded in the 
eCRFs regardless of grade.  
 
Participants will be fasting (nothing to eat or drink except water, decaffeinated 
black coffee without sugar, and required prescription medications for at least 8 

 
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hours). If participants are in a non-fasting state, they must come back within 96 
hours for a fasting blood draw and evaluation. 
 
Urinalysis 
Urinalysis will be performed at Screening. Post-entry, urinalysis will only be 
performed if clinically indicated. Perform a microscopic examination if dipstick 
urinalysis is abnormal or when deemed necessary by the investigator.  
  
Pregnancy Test 
For participants of reproductive potential: serum or urine -HCG. Pregnancy tests 
must have a sensitivity of ≤25 mIU/mL. Pregnancy testing will be repeated as 
indicated in the SOEs. Refer to section 8.0 for pregnancy and pregnancy 
outcome reporting requirements. 
 
For Step 1, Step 2, and Step 4, all participants of child bearing potential who are on a 
DTG-containing regimen must have a pregnancy test performed at least monthly. If a 
pregnancy test cannot be performed because the participant is unable to attend study 
visits, the IoR has the discretion either to continue the DTG-containing regimen or to 
switch the participant to another regimen. 
 
NOTE: In Step 2 and Step 3, participants of reproductive potential must have a 
negative pregnancy test result prior to initiating LA ART. 
 
Urine Drug Toxicology  
Urine drug toxicology will be performed at entry for purposes of referral for support 
if indicated. Urine drug toxicology screens will be collected per the SOE but 
results will not be returned to the participant (except the test performed at entry). 
The specimen will be checked for: cocaine, amphetamines, methamphetamines, 
barbiturates, benzodiazepines, marijuana (THC), opiates (including morphine and 
oxycodone), PCP, methadone. The specimen will also be checked for quality 
assurance by measuring the specimen temperature at the time of collection with 
an acceptable range of 92-96°F at time of collection.   
 
6.3.7 Immunologic Studies 
 
CD4+/CD8+ 
Obtain absolute CD4+/CD8+ T-cell count and percentages within 60 days prior to 
entry from a laboratory that possesses a CLIA certification or equivalent. During the 
study, CD4+/CD8+ T-cell count and percentage assays must be performed as 
indicated in the SOE by a laboratory that possesses a CLIA certification or equivalent. 
 

 
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6.3.8 Virologic Studies 
 
HIV-1 RNA 
Screening HIV-1 RNA must be performed within 60 days prior to study entry at a 
laboratory that possesses a CLIA certification or equivalent. Eligibility will be 
determined based on the screening value.  
 
Specimens for entry and all post-entry HIV-1 RNA, will also be performed at 
a laboratory that possesses a CLIA certification or equivalent as outlined in 
the A5359 LPC. 
 
HIV-1 Genotype 
All participants will have HIV genotype testing (including NRTI, NNRTI, PI, and 
INI resistance) within 60 day prior to study entry. For the screening genotype, 
previous results verifiable by reports from a CLIA-certified laboratory (refer to 
Department of Health and Human Services (DHHS) Guidelines for the use of 
antiretroviral agents in HIV-1-infected adults and adolescents, June 2021: 
(https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/adult-
adolescent-arv/guidelines-adult-adolescent-arv.pdf) obtained within 60 days 
prior to screening are acceptable as long as the results are available prior to entry.  
 
A conventional genotype is recommended for HIV-1 drug resistance testing for 
all participants. For participants in whom an HIV-1 RNA conventional genotype 
cannot be resulted by the testing laboratory, review of historical genotypes 
and treatment history by the IoR can be used to satisfy this criterion. 
 
When a participant is suspected to have virologic failure, a specimen for HIV-1 
RNA and HIV-1 genotyping will be collected. If virologic failure is confirmed, the 
HIV-1 genotype will be tested according to the A5359 LPC. 
 
Stored Plasma and PBMCs from Whole Blood  
Whole blood will be collected and processed into stored plasma and PBMCs 
according to the A5359 LPC. 
 
Hepatitis B and C Serology 
For participants with known HBV immunity, prior documentation of positive HBsAb is 
acceptable. If documentation is not available, HBsAb, HBsAg, and HBcAb will be 
obtained at screening. Negative HBV tests (i.e., negative HBsAb, HBsAg, and 
HBcAb) performed within 6 months prior to enrollment need not be repeated. If the 
last negative test result is more than 6 months prior to enrollment, then testing should 
be performed at screening. Results must be available prior to study entry so that 
participants who have active HBV can be excluded from participating in the study.  
 

 
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Participants who have positive HBcAb but negative HBsAg and HBsAb (isolated 
HBcAb positive status) must have HBV DNA PCR performed and confirmed as 
negative for participant to be eligible for A5359.  
 
Hepatitis C antibody testing will be done per the SOE. See sections 4.2.4 and 
4.2.5 for details.  
 
6.3.9 Other Laboratory Studies 
 
Electrocardiogram (ECG) 
ECG for corrected QT (QTc) measurement will be obtained per the SOE (see 
section 8.13). 
 
6.3.10 Adherence Assessments  
• 
Dried Blood Spots (DBS) cards will be created and stored for participants on 
TAF, FTC, 3TC or ABC. Refer to the A5359 LPC. 
• 
Hair collection (100 strands) per SOE (Optional). Refer to the A5359 MOPS 
and A5359 LPC. 
• 
Pill Counts conducted per SOE (Step 2, week 4, Arm A/Step 3, week 4, Arm B, 
for participants who initiated oral RPV/CAB). 
 
6.3.11 Questionnaires (see MOPS for details and when a referral for psychiatric care or 
drug treatment is warranted) 
• 
Sociodemographic Self-Report Questionnaire 
• 
The Alcohol Use and Disorders Identification Test (AUDIT – C) 
• 
Drug Use Disorders Identification Test (DUDIT) 
• 
Smoking Questionnaire 
• 
Patient Health Questionnaire – 9 (PHQ-9) 
• 
General Anxiety Disorder Assessment (GAD-7) 
• 
HIV Treatment Adherence Self-Efficacy Scale (HIV-ASES) 
• 
HIV Stigma Mechanism Measure 
• 
HIV Treatment Satisfaction Questionnaires (HIVTSQs-status and HIVTSQc-change) 
• 
Self-Report of Adherence 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Domestic Violence Screen Tool: (DVST) 
• 
Health Resource Utilization Questionnaire (HRUQ) 
• 
Conditional Economic Incentive Withdrawal Questionnaire (CEI Withdrawal) 
• 
Dichotomous Preference Questionnaire 
• 
Checklist of Adherence/Retention Measures (at site level only) 
 
6.3.12 Incentives  
 
CEI will be paid to participants according to Table 5.7-1 and Step 1 SOE. 
 

 
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6.3.13 Pharmacokinetic Studies (refer to section 11.0) 
 
Refer to the A5359 LPC for collection, processing, storage, and shipping details. 
 
The date and time of the last three doses of oral ARV taken or last dose of RPV-LA 
and CAB-LA injected prior to each pharmacokinetic (PK) sample must be recorded. 
PK specimens consist of dried blood spots, hair, and plasma for PK trough levels. 
 
6.4 
Visit Windows 
 
The target visit windows for all visits, including injection visits, are outlined in the SOE 
(section 6.1). Visits conducted outside of the target visit windows are allowable with the 
following instructions for those receiving RPV-LA and CAB-LA:  
 
If the time since the last RPV-LA and CAB-LA injection was greater than 8 weeks (56 
days) from the previous injection, a participant will need to be administered a new 
loading dose of both RPV-LA (900 mg) and CAB-LA (600 mg) prior to continuing the 
maintenance dose. If the last injection of RPV-LA and CAB-LA occurred less than or 
equal to 8 weeks from the previous injection, the participant will be continued on the 
maintenance dose of RPV-LA (600 mg) and CAB-LA (400 mg).  
 
The reason for any injection received outside the injection target window will be 
recorded on the eCRF. Per protocol, for non-OLI participants, the target window 
for the week 4b and week 8 injections is 24-32 days since the previous injection. 
The target window for the week 12 injection is 21-35 days since the previous 
injection. For OLI participants, the target window for the week 8 and week 12 
injections is 24-32 days since the previous injection. The target window for all 
other injections for all participants is 21-35 days since the previous injection. 
 
7.0 
ADVERSE EVENTS AND STUDY MONITORING 
 
7.1 
Definition of Adverse Events 
 
An adverse event (AE) is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or diagnosis that occurs in a study participant during the 
conduct of the study REGARDLESS of the attribution (i.e., relationship of event to medical 
treatment/study product/device or procedure/intervention). This includes any occurrence 
that is new in onset or aggravated in severity or frequency from the baseline condition.  
 
7.2 
Adverse Event Collection Requirements for this Protocol 
 
All AEs must be recorded on the eCRF if any of the following criteria have been met. 
• 
All Grade ≥3 AEs 
• 
All AEs that led to a change in study treatment/ intervention regardless of grade 
• 
All AEs meeting SAE definition or EAE reporting requirement  

 
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• 
New diagnosis of hepatitis B 
• 
New diagnosis of hepatitis C 
• 
All Grade ≥2 neurologic and psychiatric events  
• 
All seizure regardless of grade   
• 
Any bone fracture 
• 
New onset of Diabetes or preexisting Diabetes with Grade ≥2 Diabetes AE 
• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Tuberculosis  
• 
ALT ≥3x ULN AND total bilirubin ≥2x ULN  
• 
New diagnosis of COVID-19 or SARS-CoV-2 infection, regardless of grade 
 
NOTE A: Uterine pregnancy does not require reporting as an AE (unless other SAE 
criteria are met), but must still be recorded in the eCRFs.  
 
NOTE B: SAEs or events meeting EAE reporting requirements should also be entered into 
the DAIDS Adverse Experience Reporting System DAERS system as indicated. 
 
All AEs recorded must have their severity (grade) defined. 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. 
 
Serious Adverse Events (SAEs) 
An SAE is defined as any untoward medical occurrence that: 
• 
Results in death 
• 
Is life-threatening 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity  
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event (that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the participant or may require 
intervention to prevent one of the other outcomes listed in the definition above).  
 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS 
 
7.3.1 Expedited Reporting of Adverse Event to DAIDS 
 
Requirements, definitions and methods for expedited reporting of Adverse 
Events (AEs) are outlined in Version 2.0 of the DAIDS EAE Manual, which is 
available on the RSC website at https://rsc.niaid.nih.gov/clinical-research-
sites/manual-expedited-reporting-adverse-events-daids. 
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based 
reporting system, must be used for EAE reporting to DAIDS. In the event of 
system outages or technical difficulties, EAEs may be submitted using the DAIDS 

 
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EAE Form. This form is available on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting. 
 
For questions about DAERS, please contact NIAID CRMS Support at 
CRMSSupport@niaid.nih.gov. Please note that site queries may also be sent 
from within the DAERS application itself. 
 
For questions about expedited reporting, please contact the DAIDS RSC Safety 
Office at (DAIDSRSCSafetyOffice@tech-res.com). 
 
7.3.2 Reporting Requirements for this Study 
 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE manual, 
will be used for this study (the definition of an SAE is also included in the manual).  
 
The study agents for the purposes of EAE reporting are:  
• 
Oral CAB 30 mg oral tablet 
• 
CAB LA injectable suspension (200 mg/mL) 
• 
Oral RPV 25 mg tablet 
• 
RPV LA injectable suspension (300 mg/mL) 
• 
DTG 50 mg as either Tivicay or Triumeq 
• 
In participants for whom a protease inhibitor-based regimen is chosen: 
DRV/cobi as Prezcobix 
• 
In participants for whom a non-nucleoside-based regimen is chosen: RPV (Edurant) 
• 
Additionally, regimens would include separate NRTIs as either Epzicom or 
Descovy (except in those participants who receive Triumeq) 
• 
FDA approved oral therapy used to construct SOC (locally sourced) 
 
7.3.3 Expedited AE Reporting Period 
• 
The expedited AE reporting period for this study is as per the EAE manual. 
• 
After the protocol-defined AE reporting period, unless otherwise noted, only 
suspected, unexpected serious adverse reactions (SUSARs), as defined in Version 
2.0 of the EAE Manual, will be reported to DAIDS if the study staff become aware of 
the events on a passive basis (from publicly available information). 
 
7.4 
Study Monitoring 
 
The Protocol Leadership Team will monitor the conduct and safety of the study via 
regular summaries of accrual, study discontinuation (Step 1 only), protocol deviations, 
data completeness and adverse events pooled across treatment arms, as appropriate.  
 
The DAIDS clinical representative will review and assess select EAE reports for potential 
impact on the study participant safety and protocol conduct as per DAIDS policies, 
guidance documents, and SOPs as applicable.  
 

 
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The study will undergo interim review at least annually by a DAIDS-appointed Data 
Safety Monitoring Board (DSMB). The first interim review will occur approximately 6 
months after the enrollment of the first study participant. An interim 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. See section 10.0 for statistical and 
other considerations related to interim monitoring.  
 
Detailed plans for study monitoring will be outlined in a Study Progress Data and Safety 
Monitoring Plan (SPDSMP) developed by Statistical and Data Management Center 
(SDMC) prior to enrollment of the first participant. 
 
8.0 
CLINICAL MANAGEMENT ISSUES 
 
8.1 
Toxicity Management 
 
8.1.1 Only toxicities related to study medications provided through this study (CAB-LA, 
RPV-LA, other oral regimens) or required for certain arms of this study (oral CAB, 
oral RPV) will be considered in the Toxicity Management section. The grading 
system is located in the DAIDS AE Grading Table, corrected Version 2.1, July 
2017: https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse event-
grading-tables. 
 
8.1.2 For toxicities attributed to one or more of the study medications, the following 
dosing modifications can be considered: 
• 
All study medications may be held 
• 
One or more of the study drugs may be switched per section 5.0 
 
If there is interruption of one of the study drugs for which no immediate 
substitution is possible, then all ART drugs should be interrupted. 
 
Participants who have switched to any non-study ART drug should manage 
toxicity for that drug per SOC. 
 
If there is a treatment-limiting toxicity resulting from one of the drugs in the fixed-
dose combination of FTC/TAF the individual formulations of FTC or TAF can be 
given along with a drug substitution (see section 5.2.1), if necessary.  
 
NOTE: The study leadership team must be notified by e-mail regarding toxicities 
that result in a change in regimen (actg.leada5359@fstrf.org).  
 
Dosage reductions for oral ART administered in the study in Step 1 and Step 2 
are permitted with guidance from the package insert for the respective agent. 
 
There will be no dose reduction for CAB-LA or RPV-LA. 
 

 
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8.2 
Grade 1 or 2 
 
Participants who develop a Grade 1 or 2 AE or toxicity may continue study medications 
without alteration of the dosage, except as stated in sections 8.5-8.22. For participants 
experiencing Grade 1 or 2 AEs who choose to discontinue all study medications, the site 
investigator should complete premature discontinuation of study therapy evaluations, 
contact the study leadership team (actg.leada5359@fstrf.org), and the participant should 
be encouraged to complete follow-up protocol study evaluations. 
 
NOTE: If participants discontinue study medications due to experiencing Grade 1 or 2 
AEs, this should be noted in the eCRF as the reason for discontinuation.  
 
8.3 
Grade 3 
 
If the investigator has evidence that the AE has not been caused by study medications, 
dosing may continue. Participants who develop a Grade 3 AE or toxicity thought to be 
related to a study medication, except as stated in sections 8.5 -8.22 below, should have 
an ART drug substitution or their study medications withheld, at the site investigator’s 
discretion. The participant should be reevaluated weekly until the AE returns to Grade ≤2 
or baseline, at which time the study medications may be reintroduced, at the discretion 
of the site investigator or according to standard practice.  
 
If the same Grade 3 AE, excluding those AEs noted in the following sections, recurs 
within 4 weeks of restarting treatment, the suspected study medication must be 
permanently discontinued. However, if the same Grade 3 AE recurs after 4 weeks, the 
management scheme outlined above may be repeated. 
 
Participants experiencing Grade 3 AEs requiring permanent discontinuation of all study 
medications should be followed weekly until resolution of the AE and should be encouraged to 
complete the premature study treatment discontinuation evaluations and be followed on study/off 
study treatment (see section 6.2.4). The study leadership team (actg.leada5359@fstrf.org) must 
be notified, and drug substitution can be considered as discussed in section 5.0. 
 
8.4 
Grade 4  
 
Participants who develop a Grade 4 symptomatic AE or toxicity related to study product, 
will have all study medications permanently discontinued, except as stated in sections 
8.5-8.22 below. Participants experiencing Grade 4 AEs requiring permanent 
discontinuation of all study medications should be followed weekly until resolution of the 
AE and encouraged to complete the premature study treatment discontinuation 
evaluations and be followed on study/off study treatment (see section 6.2.4). 
 
The study leadership team (actg.leada5359@fstrf.org) must be notified by e-mail 
regarding toxicities that result in a change in regimen.  
 

 
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8.5 
Rash (with or without systemic symptoms or mucosal or target lesions) 
 
In the event that a participant experiences rash (with or without systemic symptoms), 
they should be evaluated for the possibility of a cutaneous AE associated with DRV or 
other medications.  
 
8.5.1 Grade 2 Rash 
 
If thought to be related to the study medications, antihistamines, topical 
corticosteroids, or a brief course of systemic corticosteroids, at the discretion of 
the site investigator, may be prescribed and participants may continue all study 
medications. If the rash progresses, then manage as per section 8.5.2 or 8.5.3. 
 
If the rash is considered to be most likely due to concomitant illness then that 
illness should be managed as per SOC. If the rash is considered to be due to a 
non-protocol medication, discontinuation of the likely causative agent should be 
undertaken. If no other causative factor is found after clinical evaluation, the 
participant should be treated symptomatically until the rash resolves.  
 
8.5.2 Grade 3 Rash  
 
If thought to be related to the study medications, participants should either 
discontinue all drugs or consider switching from the likely causative agent. If the  
rash progresses and all study medications have not yet been stopped, then 
manage as per section 8.5.3. 
 
8.5.3 Grade 4 Rash  
 
Participants should discontinue all study medications. If the site investigator 
establishes that there is a definitive alternate explanation for the Grade 4 rash, 
other than the protocol medications, then the protocol medications may be 
restarted once the rash has resolved to Grade 2 or less. Otherwise, the 
participant should have their ART changed to alternate medications. 
 
8.5.4 Abacavir Hypersensitivity Reaction (HSR) 
 
It is required that investigators screen for the HLA-B*5701 allele in any 
participant for whom an abacavir (ABC)-containing product will be used as part of 
their best-available NRTI regimen and for whom HLA-B*5701 status is unknown 
(even if the participant has previously tolerated ABC). Use of ABC in participants 
known to carry this allele is not allowed. For all participants, appropriate 
counseling and monitoring for any signs of HSR should be instituted in 
conjunction with local guidelines.  
 
In any participant treated with ABC, the clinical diagnosis of suspected HSR must 
remain the basis of clinical decision-making. Even in the absence of the HLA-

 
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B*5701 allele, participants developing signs and symptoms suggestive of a 
systemic HSR after initiation of an ABC-containing regimen should discontinue all 
study drugs and seek medical evaluation immediately. The study leadership 
team should be notified of a clinically suspected HSR as soon as possible and 
subsequent management should be discussed with the leadership. Withholding 
ABC should not be delayed, however and ABC must not be reinitiated due to the 
potential for a severe or even fatal reaction. After resolution of the signs and 
symptoms, sites can reinitiate a regimen that contains the best NRTI combination 
that does not include ABC. 
 
All clinically-suspected ABC HSR events must be reported to DAIDS as an EAE 
(see section 7.3.2). 
  
Clinical Description 
The diagnosis of hypersensitivity to ABC remains a clinical diagnosis. There is no 
pathognomonic clinical sign or laboratory finding that suggests or confirms the 
diagnosis. Overall, in clinical studies conducted before the introduction of 
screening for the HLA-B*5701 allele, approximately 5% of participants receiving 
ABC develop an HSR that in rare cases has proved fatal. HSR is characterized 
by the appearance of symptoms indicating multi-organ/body system involvement. 
Symptoms usually appear within the first 6 weeks of starting treatment with ABC 
(median time to onset is 9 days), but may occur at any time while on therapy, and 
most often include fever, rash, gastrointestinal symptoms (nausea, vomiting, 
diarrhea, or abdominal pain), respiratory symptoms (dyspnea, sore throat, 
cough), and lethargy or malaise. Other signs and symptoms may include 
musculoskeletal symptoms (myalgia, rarely myolysis, and arthralgia), headache, 
paresthesia, and edema. Respiratory tract symptoms (dyspnea, sore throat, and 
cough) have been observed in approximately 20% of participants who 
experience HSR. Some participants with HSRs were initially thought to have 
respiratory tract disease (pneumonia, bronchitis, pharyngitis) or a flu-like illness.  
 
Physical findings may include lymphadenopathy and, occasionally, mucous 
membrane lesions (conjunctivitis and/or mouth ulceration). The rash is variable 
and may be absent, but often appears maculopapular or urticarial. Laboratory 
abnormalities that may accompany ABC hypersensitivity include elevated 
transaminases, CK, or creatinine or lymphopenia. 
 
The misattribution of the symptoms of HSR to another medical condition or delay 
in diagnosis of hypersensitivity has resulted in ABC being continued or 
reintroduced, leading to more severe presentation of HSR or death. Therefore, the 
diagnosis of HSR should be carefully considered for participants presenting with 
symptoms of these diseases, even if another medical diagnosis seems likely.  
 
Symptoms related to HSR worsen with continued therapy and usually resolve 
upon discontinuation of ABC. Restarting ABC following an HSR results in a 
prompt return of symptoms within hours. This recurrence of the HSR may be 

 
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more severe than on initial presentation and may include life-threatening 
anaphylaxis, hypotension, liver, renal and respiratory failure, and death. 
Regardless of their HLA-B*5701 status, participants who develop this HSR must 
discontinue ABC and MUST NOT be rechallenged with any ABC-containing 
product (e.g., Ziagen, Epzicom, or Triumeq). 
 
Management of HSR 
Symptoms usually start to resolve (within 24 hours) after stopping therapy. 
Symptomatic support, such as intravenous fluids for those who develop 
hypotension, is advised. There are no clinical data demonstrating the benefit of 
antihistamines or corticosteroids in the management of hypersensitivity. 
Nevertheless, symptomatic and/or supportive treatment may be reasonable 
following ABC discontinuation. Laboratory and other investigations which may be 
useful in the evaluation and treatment of ABC HSR include, but may not be 
limited to, measurement of ALT, AST, CK, serum creatinine, WBC differential 
count, and chest x-ray, if respiratory symptoms are present.  
 
Regardless of their HLA-B*5701 status, participants who have had a clinically 
suspected HSR must be advised to never again take an ABC-containing product 
(e.g., Ziagen, Epzicom, or Triumeq). ABC therapy SHOULD NOT be restarted 
following a clinically suspected HSR, because more severe symptoms will occur 
within hours and may include life-threatening hypotension and death. Fatal HSRs 
have been associated with re-initiation of ABC therapy. Participants, who develop 
signs or symptoms of HSR, MUST contact their doctor immediately for advice. 
The site investigator must be notified and provide sign-off for those participants 
who discontinue ABC due to HSR. In order to avoid restarting the ABC-
containing product, participants who have experienced a clinically suspected 
HSR should be asked to return the remaining tablets to the pharmacy.  
 
There have been infrequent reports of HSR following reintroduction of ABC, 
where the interruption was preceded by a single key symptom of hypersensitivity 
(rash, fever, malaise/fatigue, gastrointestinal symptoms or a respiratory 
symptom). If a decision is made to restart ABC in these participants in 
consultation with the study leadership team, this should be done only under 
direct medical supervision. 
 
On very rare occasions, hypersensitivity reactions have been reported in patients 
who have restarted therapy and who had no preceding symptoms of a 
hypersensitivity reaction. If a decision is made to restart ABC, this must be done 
only if medical care can be accessed readily by the participant. 
 
NOTE: HLA B*5701 screening will not be provided by the study.  
 

 
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8.6 
Skin Hyperpigmentation 
 
Changes in skin hyperpigmentation, if assessed as being related to FTC, can be 
followed without modification of therapy, at the discretion of the site investigator. If the 
participant is on his/her initial regimen and the skin hyperpigmentation is felt to be 
toxicity limiting, sites may replace FTC with 3TC. 
 
8.7 
Creatinine Clearance 
 
Any participant experiencing a calculated CrCl <50 mL/min should have the value 
confirmed within 14 days. For those participants being treated with 3TC or FTC as part of 
their oral regimen who experience a confirmed (2 consecutive) reduction in CrCl to <50 
mL/min, 3TC or FTC should be dose reduced as indicated by the package insert. For a 
confirmed CrCl to <30 mL/min, TAF should be discontinued with substitution as 
recommended in section 5.0. If the site investigator determines that another condition 
caused the decrease in CrCl, then TAF may be restarted if approved by the protocol team. 
Participants should be followed as medically indicated until the serum creatinine clearance 
returns to Grade ≤2. If 3TC or FTC is to be continued, dosing will need to be adjusted per 
the package insert. For those participants being treated with a co-formulated regimen 
containing TAF, the TAF containing regimen should be discontinued with substitution as 
recommended in section 5.0. If the site investigator determines that another condition 
caused the decrease in CrCl, then TAF may be restarted if approved by the protocol team. 
Participants should be followed as medically indicated until the serum creatinine returns to 
Grade ≤2. If 3TC or FTC is to be continued, dosing will need to be adjusted per the 
package insert.  
 
8.8 
Nausea (with or without vomiting) and/or Diarrhea 
 
Although common, nausea following initiation of therapy with study medications usually 
subsides or resolves during the first few weeks of treatment. 
 
With the onset of Grade ≥1 nausea, advise participants to take study medications with 
food. Participants may also be treated as needed with anti-emetics given orally or by 
suppository. 
 
In participants with persistent nausea, consideration should be given for evaluation of 
pancreatitis, hepatitis, or hyperlactatemia/lactic acidosis, with evaluation for each if 
clinically indicated. 
 
For Grade 1 or 2 diarrhea, therapy should be continued with symptomatic treatment that 
may include antimotility agents. If Grade ≥3 diarrhea occurs and is unresponsive to 
antimotility agents, and for which an alternative etiology (e.g., infectious diarrhea) is not 
established, all study medications should be interrupted until resolution of diarrhea to Grade 
≤2 or return to baseline. If Grade ≥3 diarrhea recurs upon the resumption of the study 
medications, all study medications should be interrupted and study drugs can be selectively 
substituted or alternative ART can be selected, at the discretion of the site investigator. 

 
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8.9 
Hypertriglyceridemia/Hyperlipidemia 
 
If elevated triglyceride or lipid levels are measured in a non-fasting blood draw, repeat the 
draw after an 8-hour fast. Only levels done in a fasting state should be used to determine 
toxicity management. Participants with asymptomatic Grade ≥3 triglyceride, total 
cholesterol, or LDL elevations may continue ART, at the discretion of the site investigator. 
Please see the recent recommendations of the ACTG Cardiovascular Disease Focus 
Group (https://www.actgnetwork.org/members/download/other/lipid901.pdf) for full 
discussion of management of hyperlipidemia in the context of HIV-1 disease. 
 
8.10 
Liver Enzymes 
 
ALT Elevations 
All study medications may be continued for asymptomatic Grade ≤3 ALT elevations, at 
the discretion of the site investigator. Careful assessments should be done to rule out 
the use of alcohol, non-study drug-related drug toxicity, or viral hepatitis as the cause of  
Grade 3 elevations. The possibility of hyperlactatemia/lactic acidosis syndrome should 
also be explored (see section 8.15).  
 
All study medications should be held for symptomatic Grade 3 and all Grade 4 
elevations until the symptoms resolve and toxicity grade returns to Grade ≤2. 
Participants will be followed with weekly ALT assessments until they return to Grade ≤2.  
 
For confirmed Grade 4 elevation in ALT, all study medications should be held and ALT 
followed weekly until the toxicity grade returns to Grade ≤2 or baseline.  
 
In the individuals who are receiving the LA ART regimen, RPV-LA + CAB-LA will be 
stopped if any of the following liver chemistry criteria are met: 
• 
ALT ≥3x ULN and total bilirubin ≥2x ULN  
• 
ALT ≥8x ULN 
• 
ALT ≥3x baseline ALT with signs/symptoms of acute hepatitis 
• 
ALT ≥5x ULN that persists >2 weeks 
 
8.11 
Hyperglycemia 
 
Participants with Grade ≥3 hyperglycemia may continue their study medications at the 
discretion of the site investigator and be managed with oral hypoglycemic medications or 
insulin, but this should be discussed with the study leadership team. 
 
8.12 
CPK Elevation 
 
A CPK can be checked in cases of suspected rhabdomyolysis. Grade 3 or 4 elevation in 
CPK should result in a repeat assessment within 4 weeks after the participant has 
abstained from exercise for ≥72 hours to ensure the result is transient or due to exercise 
and will not require a change in study treatment. A history regarding use of drugs known 

 
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to cause increase of CPK (such as statins), physical activity or exercise preceding the 
CPK evaluation should be obtained.  
 
For persistent Grade 4 CPK elevations that are considered possibly or probably related 
to the study medications, study medications should be discontinued and the participant 
will be followed on study/off study treatment. 
 
8.13 
Prolonged QTc 
 
A participant that meets either criterion below will have study medications stopped, but will 
remain in study follow-up. The QT correction formula (Bazett or Fridericia) used to determine 
study medications discontinuation should be the same one used throughout the study. 
 
8.13.1 
Change from baseline: QTc >60 ms 
 
Study medications discontinuation decisions are to be determined by the site 
investigators in consultation with the study leadership team. A decision to 
permanently discontinue study product will be based on an average QTc value 
of triplicate ECGs. If an ECG demonstrates a prolonged QT interval, obtain two 
more ECGs within one hour, and then use the averaged QTc values of the 
three ECGs to determine whether the participant should permanently 
discontinue study product.   
 
8.14 
Hyperlactatemia/Lactic Acidosis 
 
The relevance of asymptomatic lactic acid elevations is unclear, and lactates are not part 
of the routine safety evaluations for this study. Routine lactate monitoring is not currently 
recommended. 
 
A sometimes-fatal syndrome of lactic acidosis, often associated with evidence of hepatic 
steatosis, is a recognized but rare complication of NRTI therapy. This syndrome is felt to 
be secondary to mitochondrial toxicity induced by the inhibitory effect of NRTIs on DNA 
polymerase gamma, a key enzyme needed for mitochondrial DNA synthesis. Current 
knowledge regarding this syndrome is incomplete. Obesity and prolonged NRTI exposure 
may be risk factors. Symptoms of lactic acidosis frequently involve non-specific symptoms 
such as fatigue, weakness, and fever, but in the majority of cases also involve symptoms 
suggestive of hepatic dysfunction such as nausea, vomiting, abdominal or epigastric 
discomfort, abdominal distension, hepatomegaly, and new onset of elevated liver 
enzymes. A high index of suspicion may be required to diagnose this condition. 
 
The following case definition of symptomatic hyperlactatemia/lactic acidosis will be used 
in this protocol: 
 
Symptomatic Hyperlactatemia/Lactic Acidosis  
New, otherwise unexplained and persistent (≥2 weeks) occurrence of one or more of the 
following symptoms: 

 
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• 
Nausea and vomiting 
• 
Abdominal pain or gastric discomfort 
• 
Abdominal distention 
• 
Elevated LFTs 
• 
Unexplained fatigue 
• 
Dyspnea 
 
AND 
 
Lactate level >2x ULN confirmed by repeat lactate level analysis. 
 
NOTE: All lactates >2x ULN should be repeated as soon as possible, generally within 1 
week. If the second result confirms hyperlactatemia (>2x ULN), participants should 
immediately discontinue their study medications and the study leadership team 
(actg.leada5359@fstrf.org) should be contacted to plan further treatment. See the ACTG 
Web site for guidelines for the collection of lactate specimens:   
https://www.actgnetwork.org/members/download/other/Metabolic/VenousLactate SOP.doc  
 
8.15 
Lipase Elevations and Pancreatitis 
 
Pancreatitis will be reported as either clinical (i.e., symptomatic) or chemical (i.e., 
persistent elevation in enzymes without any symptoms). The principal enzyme 
abnormality that will be used for making diagnoses is the lipase level, as this is the most 
specific. If obtained, amylase determinations will be recorded on the eCRF. For both 
symptomatic and asymptomatic participants suspected of having pancreatitis, 
triglyceride levels should be drawn with lipase values.  
 
In cases where study medications are temporarily held, re-challenge with study 
medications may be performed (with permission from the study leadership team). Re-
challenge will occur after complete resolution of the episode in a setting in which other 
concomitant illness or drugs might have reasonably contributed to the development of 
pancreatitis. Upon re-challenge, lipase determinations should be performed every 2 weeks 
for at least 6 weeks after reinitiation (see allowable drug substitutions in section 5.0). Any 
elevation of lipase of Grade ≥2 or any recurrence of symptoms during this period will lead 
to permanent discontinuation of the suspected study medications. 
 
8.15.1  Symptomatic Elevations in Lipase (gastrointestinal symptoms, particularly 
abdominal pain).   
 
The severity of clinical pancreatitis will be recorded as the highest severity level 
of any of the associated clinical signs and symptoms.  
 

 
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8.15.1.1 Grade 1 or 2 
 
Participants may continue study medications at the discretion of the site 
investigator. Repeat lipase within 2 weeks. If lipase remains elevated but is 
Grade <3 and symptoms persist, order a computed tomography (CT) scan (or 
other radiologic test). If pancreatic enlargement and/or peripancreatic 
inflammation is demonstrated, diagnose clinical pancreatitis. If the CT scan (or 
other radiologic test) shows no evidence of pancreatitis, continue to monitor 
lipase every 2 weeks until symptoms and lipase abnormalities resolve. 
 
8.15.1.2 Grade ≥3 
 
Exclude other possible diagnoses (e.g., renal insufficiency causing 
false elevations in lipase). If none are found, diagnose as clinical 
pancreatitis. 
 
8.15.2 Asymptomatic Elevations in Lipase 
 
For those without symptoms that are incidentally found to have lipase of Grade 
≥3, repeat testing within 2 weeks will be performed. Persistence of asymptomatic 
elevation of lipase of Grade ≥3 will qualify as a diagnosis of chemical 
(asymptomatic) pancreatitis. For a diagnosis of asymptomatic chemical 
pancreatitis, at the discretion of the study leadership team 
(actg.leada5359@fstrf.org), it may be decided that all study medications should 
be held. Asymptomatic, chemical pancreatitis will be listed as mild, regardless of 
enzyme elevation. Further details regarding the definitions of pancreatitis and the 
proposed management of drug regimens in the setting of pancreatitis can be 
found on the ACTG Web site at: 
https://www.actgnetwork.org/members/download/other/pancdefv2.doc. 
 
8.16 
Anemia/Neutropenia 
 
If a participant experiences treatment-limiting (in the opinion of the site investigator) 
anemia or neutropenia, substitution with an alternative drug can be requested. 
Alternatively, anemia may be managed by transfusions and recombinant erythropoietin, 
and neutropenia may be managed with granulocyte-colony stimulating factor (G-CSF) or 
granulocyte-macrophage colony-stimulating factor (GM-CSF), at the discretion of the 
investigator. Once the anemia or neutropenia has returned to baseline, all study 
medications can be restarted. 
 
8.17 
Peripheral Neuropathy 
 
Participants should be monitored for the development of peripheral neuropathy, which is 
usually characterized by numbness, tingling, and/or pain in the feet or hands. If a participant 
without previous history of neuropathy develops Grade ≥2 neuropathy and the investigator 
attributes the neuropathy to a study NRTI, that NRTI may be replaced with an alternative 

 
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NRTI. Similarly, if a participant with history of neuropathy develops worsening neuropathy 
Grade ≥3 that is attributed to a study NRTI by the study investigator, that NRTI may be 
replaced with and alternative NRTI. If the neuropathy is attributed to CAB, CAB-LA, or RPV-
LA the investigator should contact the study leadership team for instructions. Treatment of 
the peripheral neuropathy should be defined by the clinician. 
 
8.18 
Injection Site Reactions 
 
Injection Site Reaction (ISR) will be assessed at every study visit in Step 2 for participants 
randomized to Arm A and for all participants in Step 3.The study leadership team must be 
informed of all Grade 3 or 4 ISRs to determine etiology and assess appropriate continued 
study participation. ISR discomfort can be managed symptomatically (e.g., cold/warm 
compress, acetaminophen, ibuprofen) if the reaction is interfering with the participant’s ability 
to perform activities of daily living. ISR grading will be done according to the DAIDS AE 
Grading Table referenced above. 
 
8.19 
Seizure 
 
Any seizure event will result in permanent discontinuation of LA therapy.  
 
8.20 
Drug Substitutions 
 
Drug substitutions, if deemed appropriate by the site investigator, will be permitted 
during Step 1 and in the SOC arm (Arm B) for Step 2. All substitutions and indications 
for the substitutions are to be recorded on the eCRFs. The site PoR must be informed in 
writing that the previous regimen is to be discontinued.   
 
8.21 
Immune Reconstitution Inflammatory Syndrome (IRIS) 
 
IRIS events are not caused by a specific or individual drug, but rather are the result of 
being on a successful ARV treatment regimen. Management of events judged by the site 
investigator to be IRIS may be managed at the discretion of the site investigator. IRIS 
events should be recorded in the eCRFs, however, no EAE reporting is required, unless 
the event meets the criteria for “serious” as discussed in section 7.3. Further details 
regarding IRIS can be found on the ACTG Web site at: 
https://www.actgnetwork.org/members/download/other/iris.doc. 
 
8.22 
Pregnancy 
 
Step 1: 
Participants who become and remain pregnant during Step 1 will be followed on study, 
until Step 1, week 24, and blood collections should be limited to safety labs (including 
HIV viral load). Oral ART regimen will be determined by local provider. These 
participants will not be eligible to enroll into Step 2. 
 

 
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If the pregnancy results in early termination or loss, the participant can continue on study 
and advance to Step 2 (if eligible).  
 
Step 2 and Step 3: 
Given the anticipated long pharmacokinetic tail of CAB-LA and RPV-LA (resulting in 
continued exposure in these participants, even after one single dose), participants who 
become pregnant during Step 2, Arm A, or Step 3 who have already received at least 
one dose of RPV-LA + CAB-LA injection will be able to continue on study treatment if the 
benefit of treatment is deemed to be higher than the potential risk in the opinion of the 
IoR, and the participant wishes to continue LA ART. These participants could move onto 
the next study step upon completion of their current Step (if eligible).  
 
Although the use of combination ART during pregnancy significantly decreases the 
risk of vertical transmission, data for CAB-LA and RPV-LA in pregnant individuals 
remain limited. Thus, participants randomized to Step 2, Arm A, or Step 3 who become 
pregnant while receiving oral CAB + RPV (but have not received any CAB-LA/RPV-LA) will 
have to discontinue study treatment and will need a new regimen in accordance with current 
guidelines for treatment of persons with HIV who become pregnant while on ART. These 
participants can remain on study but will not be eligible to enroll into the next study step.  
 
Participants who become pregnant while in Step 2, Arm B, can remain on study until 
Step 2, week 52. Oral ART regimen will be determined by local provider. Only those 
participants in Step 2, Arm B, who are not pregnant (including those whose pregnancy 
results in early termination or loss in Step 2) at the time of their Step 3 Registration visit 
would be considered eligible for crossover.  
 
Blood collections for participants who become and remain pregnant during Steps 2 and 3 
should continue as per the SOE with the exception of Stored Plasma and PBMCs from 
Whole Blood. 
 
Step 4: 
Participants who become pregnant during Step 4 may continue study visits as outlined in 
the SOE. Oral ART regimen will be determined by local provider. 
 
All participants who become pregnant while on study will be followed through the 
postpartum period to determine the effects of the study regimens on birth outcomes in the 
exposed infants. For participants who become pregnant while receiving CAB, DTG, or 
within one year of the last dose of CAB-LA, please see the MOPs for further management. 
 
Participants who become pregnant, and who have access to an International Maternal 
Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) trial site, should be 
encouraged to enroll in the P1026s Pregnancy PK study.  
 
The intrapartum complications, pregnancy, and pregnancy outcome will be recorded on 
the eCRFs. Pregnancies that occur on study should be reported prospectively to The  

 
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Antiretroviral Pregnancy Registry. More information is available at www.apregistry.com. 
Phone: 800-258-4263; Fax: 800-800-1052.  
 
Pregnancy Reporting 
Any intrapartum complications, pregnancy, and pregnancy outcome (including 
pregnancy loss) for the participant and infant (if known) for any participant who becomes 
pregnant at any step should be recorded on the eCRFs. If a participant has completed 
the study or chooses to discontinue from the study before the end of the pregnancy, then 
site staff should complete a study discontinuation visit within 2 weeks and request 
permission to contact her regarding pregnancy outcomes at the end of pregnancy.  
 
9.0 
CRITERIA FOR DISCONTINUATION 
 
9.1 
Permanent and Premature Treatment Discontinuation 
 
• 
Drug-related toxicity (see section 8.1 Toxicity) 
• 
Requirement for prohibited concomitant medications (see section 5.4) 
• 
Pregnancy during Step 2 or Step 3 CAB-RPV oral induction (if applicable). See 
section 8.22. 
• 
Breastfeeding at any time 
• 
Completion of treatment as defined in the protocol 
• 
Request by participant to terminate treatment 
• 
Clinical reasons believed life threatening by the physician, even if not addressed in 
the Toxicity section of the protocol 
 
9.2 
Premature Study Discontinuation 
 
• 
Failure by the participant to attend three consecutive study visits; this criteria needs 
to be discussed with the Study Leadership Team (actg.leada5359@fstrf.org) prior to 
discontinuation. (For participants in Step 2, please see section 6.2.4 for more 
details.) 
• 
Request by the participant to withdraw 
• 
Request of the primary care provider if s/he thinks the study is no longer in the best 
interest of the participant 
• 
At the discretion of the IRB/Ethics Committee, Food and Drug Administration (FDA), 
NIAID, Office for Human Research Protections (OHRP), other government agencies 
as part of their duties, investigator, or industry supporter 
 
10.0 
STATISTICAL CONSIDERATIONS  
 
10.1 
General Design Issues 
 
A5359 is a phase III, four-step, randomized, open-label study that will assess if LA ART 
is efficacious compared to a SOC in persons with HIV with prior history of non-
adherence who achieve viral suppression during the oral induction period. In Step 1, 

 
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previously non-adherent individuals will be enrolled and undergo a brief period (up to 24 
weeks) of all-oral induction using incentivized adherence. If participants achieve virologic 
suppression (HIV-1 RNA ≤200 copies/mL) at or after Step 1, week 4, they will register to 
Step 2 and be randomized 1:1 to switch to LA ART (oral RPV + CAB for 4 weeks 
followed by RPV-LA + CAB-LA Q4 weeks for 48 weeks or direct injection of RPV-LA + 
CAB-LA for 52 weeks). At the completion of Step 2, eligible participants randomized to 
SOC will have the option to register to Step 3 and cross over to the LA ART (oral RPV + 
CAB for 4 weeks followed by RPV-LA + CAB-LA Q4 weeks for 48 weeks or direct 
injection of RPV-LA + CAB-LA for 52 weeks); participants randomized to LA ART arm in 
Step 2 will have the option to register to Step 3 and continue the LA ART for another 52 
weeks. At the completion of Step 3, participants will transition to RPV-LA + CAB-LA, if 
possible and available. If access to RPV-LA + CAB-LA cannot be attained or participant 
requests to switch to oral ART, those participants will register to Step 4 and be followed 
for 52 weeks on oral ART. In addition, any participant who receives at least one dose of 
CAB-LA or RPV-LA, and prematurely discontinues LA ART prior to end of Step 3, will be 
followed on oral ART for 52 weeks after their last dose of any LA injectable. 
 
The primary analyses of efficacy and safety for the study will be performed after the last 
participant completes Step 2 follow-up. Efficacy analyses will use an intention-to-treat 
(ITT) approach including all participants who are randomized to the treatment arms, 
regardless of status on randomized treatment. To assess the robustness of the efficacy 
results, sensitivity analyses will be performed based on a modified ITT approach 
including all participants who were randomized to the treatment arms and received at 
least one dose of study treatment at/or after randomization and an as-treated analysis 
restricting to participants who remained on randomized treatment. Safety analyses will 
be as-treated, with participant follow-up censored at treatment discontinuation. The 
results of the primary analysis at the end of Step 2 follow-up will be published following 
the ACTG publication SOP. Step 1 results may be summarized and shared with the 
study team upon last participants’ completion of Step 1. Analysis of long-term outcome 
measures will be performed upon completion of the study.  
 
The primary efficacy outcome measure of the study is regimen failure, which is a 
composite outcome measure of virologic failure and discontinuation of randomized 
treatment. This outcome measure was chosen for the following reasons. First, A5359 is 
a strategy trial to assess whether LA ART treatment is more successful in keeping 
participants who are previously non-adherent virologically suppressed and in the 
treatment program than the standard of care oral regimen. Secondly, LA ART requires 
regular injections, hence tolerability to the regimen/injectable is considered to be 
essential to efficacy. Finally, given the study population of participants with history of 
non-adherence, participants in the LA ART arm will be exposed to the significantly 
increased risk of developing drug resistance if they are lost to follow-up and do not 
obtain oral ART coverage for the long half-life of LA ART. Although it is felt that regimen 
failure is the appropriate outcome measure to understand the efficacy of the study 
regimen, pure virologic failure as well as treatment-related failure secondary outcome 
measures are also central in interpreting study results. Assessing similarity or 
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(ITT vs. modified ITT vs. as-treated) will help understand the relative performance of the 
regimens and help clinicians weigh the efficacy/tolerability trade-offs and apply them to 
clinical practice.  
 
10.2 
Outcome Measures 
 
Primary and secondary outcomes listed below will be addressed in the study's primary 
Statistical Analysis Plan, which will define the content of the Primary Analysis Report. 
This report will form the basis for the primary study manuscript(s) and results reporting to 
ClinicalTrials.gov. Outcomes related to other objectives intended for subsequent 
publications are listed under Other Outcome Measures. 
 
10.2.1 
Primary Outcome Measure 
 
Occurrence of regimen failure in Step 2.  
 
NOTE A: Regimen failure is defined as the occurrence of the first of the 
following two events at any time post randomization and Step 2, 
week 48, visit: 
• 
Virologic failure (as defined in sections 6.2.3 and 10.2.2.1) 
• 
Permanent discontinuation of randomized study treatment 
 
NOTE B: Permanent discontinuation of randomized study treatment is defined 
as the first of the following events: 
• 
Participants randomized to LA ART arm prematurely discontinue oral RPV 
or CAB before Step 2, week 4. 
• 
Participants randomized to LA ART arm never initiate RPV or CAB injectable. 
• 
Participants randomized to LA ART arm prematurely discontinue RPV or 
CAB injectable. 
• 
Participants randomized to SOC arm prematurely discontinue oral ART 
regimen. Switching to another oral ARV is not considered treatment 
discontinuation.  
• 
Participants prematurely discontinue study treatment/participation for any 
reason including death and loss to follow-up.  
 
NOTE C: Participants who complete randomized study treatment without 
experiencing a virologic failure on Step 2 will be censored at Step 2, 
week 48, visit.  
 
NOTE D: To assess the robustness of the results, sensitivity analyses will be 
performed in which all participants (regardless of randomized 
treatment received) who become pregnant without experiencing a 
virologic failure or permanent discontinuation of study treatment 
before confirmation of pregnancy will be censored at the study visit 
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NOTE E: During the COVID-19 pandemic, clinical research operation might be 
disrupted or affected at sites. At sites where a COVID-19 disruption is 
determined, participants randomized prior to the COVID-19 pandemic 
will have their follow-up time censored at the start of the disruption 
period.   
 
10.2.2 
Secondary Outcome Measures  
 
10.2.2.1 Occurrence of virologic failure in Step 2 at any time post 
randomization and week 48 visit. 
 
NOTE A: Time will be measured from the Step 2 randomization. 
 
NOTE B: Virologic failure confirmation will be determined based on 
any two consecutive evaluations meeting the virologic 
failure criterion regardless of the time between them. 
NOTE C: Participants discontinuing the study/Step 2 (for any reason, 
including death and end of study step) will be handled as 
follows: 
• 
Participants with an unconfirmed virologic failure (HIV-1 RNA 
>200 copies/mL) will be considered as virologic failure at the 
study visit week of the unconfirmed value. 
• 
All remaining participants will have their follow-up time censored 
at the study week of the last measured plasma HIV-1 RNA 
sample on Step 2.  
• 
For as-treated analysis, a participant’s follow-up time will be 
censored at discontinuation of randomized treatment.  
 
NOTE D: Same as NOTE E in section 10.2.1  
 
10.2.2.2 Occurrence of treatment-related failure in Step 2 at any time post 
randomization and week 48 visit 
 
NOTE A: Time will be measured from the Step 2 randomization. 
 
NOTE B: Treatment-related failure is defined as the first of the 
following events: 
• 
Virologic failure (as defined in sections 6.2.3 and 
10.2.2.1) 
• 
Treatment discontinuation due to AE 
 
NOTE C: For participants who do not experience treatment-
related failure, their follow-up time will be censored at 
the last study visit week on Step 2 up to week 48 visit. 

 
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For as-treated analysis, their follow-up time censored at 
discontinuation of randomized treatment.  
 
NOTE D: Same as NOTE E in section 10.2.1  
 
10.2.2.3 Virologic non-success (defined by FDA Snapshot algorithm) at Step 2, 
week 48 
 
10.2.2.4 Plasma HIV-1 RNA level < 50 copies/mL and ≤200 copies/mL at 
scheduled study visits on Steps 1 and 2 
 
10.2.2.5 Occurrence of adverse event (as defined in section 7.2) during Steps 
1 and 2 
 
10.2.2.6 Occurrence of discontinuation of randomized treatment in Step 2 at 
any time post randomization and week 48 visit 
 
10.2.2.7 Summary score of HIV Treatment Satisfaction Questionnaire 
(HIVTSQ) in Step 2 
 
10.2.2.8 Occurrence of missed or delayed (defined as 8 days beyond 
scheduled injection day) injections for participants who received LA 
ART in Step 2  
 
10.2.2.9 Summary scores of HIV Treatment Adherence Self-Efficacy Scale in 
Step 1 and Step 2. 
 
10.2.2.10 New drug-resistance mutation in participants with virologic failure in 
Step 2 
 
10.2.2.11 Occurrence of Injection Site Reactions (ISR) during Step 2 
 
10.2.2.12 Participant self-reported dichotomous preference questionnaire 
 
10.2.3 
Other Outcome Measures 
 
10.2.3.1 Time to regimen failure in Step 3. 
 
NOTE: Time will be measured from Step 3 entry until the first of 
virologic failure and discontinuation of study treatment. Participants 
who complete Step 3 on study treatment without experiencing 
virologic failure will be censored at Step 3, week 48, visit. 
 

 
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10.2.3.2 Occurrence of virologic failure on LA ART in Steps 2 and 3. 
 
NOTE: Time will be measured from initial dose of RPV + CAB until 
virologic failure up to Step 3, week 48, visit.  
 
10.2.3.3 Plasma HIV-1 RNA level <50 copies/mL and ≤200 copies/mL at 
scheduled study visits on Steps 3 and 4. 
 
10.2.3.4 Occurrence of AEs (as defined in section 7.2) during Step 3. 
 
10.2.3.5 Summary scores of HIV stigma measures. 
 
10.2.3.6 Summary score of QOL measure.  
 
10.2.3.7 Counts of the following HRU units: hospitalizations for any reason 
(ward, length of stay), emergency room visits for any reason, 
additional clinician office visits for any reason (participant self-report). 
 
10.2.3.8 Participants’ self-reported opinions (e.g., dissatisfaction) about CEI withdrawal.  
 
10.2.3.9 Occurrence of Injection Site Reactions (ISR) during Step 3. 
 
10.2.3.10 Summary scores of substance abuse, health and behavioral-health 
measures. 
 
10.2.3.11 Summary of socio-demographics measures 
 
10.2.3.12 Self-reported adherence in Step 1 
 
10.2.3.13 Self-reported adherence for participants who randomized to SOC 
arm in Step 2   
 
10.2.3.14 Occurrence of missed or delayed (defined as 8 days beyond 
scheduled injection day) injections for participants who received LA 
ART in Step 3  
 
10.2.3.15 Site Adherence/Retention Measures in Steps 1 and 2 
 
10.3 
Randomization 
 
There is no randomization in Step 1. In Step 2, eligible participants will be randomized 
1:1 to each of the two arms of the study. Randomization will be carried out using 
permuted blocks across sites with dynamic balance within site via a computer algorithm 
at the SDMC. There is no randomization in Step 3 and Step 4. 
 

 
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10.4 
Sample Size and Accrual  
 
Superiority of the LA ART (oral induction followed by CAB LA + RPV LA) compared to 
SOC will be assessed based on the primary comparison of the cumulative probability of 
regimen failure by Step 2, week 48.  
 
A maximum of 640 participants need to be enrolled in Step 1, for Step 2 to achieve an 
accrual target of 320 participants (160 in each arm). Screening and enrollment into Step 1 
will stop when 320 participants have enrolled into Step 2. The sample size estimation is 
based on the following considerations: 
• 
The study should have approximately 80% power to show superiority of the LA ART 
compared to daily SOC with respect to the Step 2, week 48, cumulative probability of 
regimen failure (defined in section 10.2.1). 
• 
The study should have at least 80% power to show superiority of the LA ART 
compared to daily SOC with respect to the Step 2, week 48, cumulative probability of 
virologic failure (defined in section 10.2.2.1). 
• 
The cumulative probability of virologic failure by Step 2, week 48, is estimated to be 
25% for the SOC arm and 9% for the LA ART strategy. The reference rate for the 
SOC is based on ACTG A5241 study of HIV salvage therapy in treatment-
experienced participants with cumulative virologic failure rate at week 48 of 24.9% in 
the add-NRTIs arm and 24.6% in the omit-NRTIs arm [44]. The estimated rate for the 
LA ART strategy is based on LATTE-2 Q4W results (<1% with HIV-1 RNA <50 
copies/mL at week 48 and <1% with virologic failure) while taking into consideration 
of treatment-experienced study population with history of non-adherence.  
• 
The cumulative probability of regimen failure by Step 2, week 48, is estimated to be 
50% for the SOC arm and 34% for the LA ART strategy assuming 5% treatment-
related failures other than virologic in both arms. 
• 
The lost to follow-up rate (non-treatment related) will be constant during the study 
follow-up with a Step 2, week 48, cumulative lost to follow-up rate of 25% for each 
arm taking into consideration of possible impact of COVID-19 pandemic on clinical 
research activities. 
• 
Sample size inflation of 2% is allowed to account for interim monitoring. 
• 
PASS 15 [PASS 15 Power Analysis and Sample Size Software (2017). NCSS, LLC. 
Kaysville, Utah, USA, ncss.com/software/pass] was used to calculate the sample 
size requirement with above parameter settings for an O’Brien-Fleming group-
sequential design with two interim reviews comparing two independent proportions 
using a two-sided Fisher’s exact test at a significance level of 0.05.  
• 
Sample size may be further adjusted to account for potential censoring due to 
COVID-19 disruption. 
 

 
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Table 10.4-1: Power to Claim Superiority Based on Step 2 Sample Size of 320 (N=160 
per arm) with 25% Lost to Follow-up Rate Assuming Various Underlying 
Week 48 Cumulative Failure Rates 
Outcome 
Measure 
Step 2, Week 48 
Cumulative Failure Rates 
Power to Claim 
Superiority of 
LA ART 
Compared to 
SOC 
LA ART 
SOC 
Regimen 
Failure 
35% 
50% 
73% 
34% 
50% 
79% 
30% 
46% 
80% 
Virologic 
Failure 
11% 
25% 
75% 
9% 
25% 
88% 
7% 
23% 
91% 
 
Table 10.4-2: Sample Size Required to Provide 80% Power to Assess Superiority of LA 
ART Compared to SOC Assuming Various Underlying Step 2, Week 48, 
Cumulative Regimen Failure Rates 
Effect Size 
Cumulative Probability 
of Regimen Failure by 
Step 2, Week 48 
Step 2 
Total N 
Step 1 Total N (to account for LOFU 
and failure to suppress) 
SOC 
LA ART 
40% LOFU and 
failure to suppress 
50% LOFU and 
failure to suppress 
16% 
50% 
34% 
320 
534 
640 
 
Given the targeted study population of previously non-adherent, persons with HIV, it is 
further assumed that 50% of participants who enroll in Step 1 will be lost to follow-up 
and/or ineligible to enter Step 2. This rate was revised up based on limited data observed 
prior to the COVID-19 pandemic. In the March 2020 DSMB review, based on data 
entered as of February 24, 2020, the observed failure rate to enroll to Step 2 was 43% 
with 95% CI of 33-54%. Furthermore, the team took into account the potential continued 
impact of the COVID-19 pandemic on clinical research operations. Thus, the study 
targets to enroll a maximum of 640 participants in Step 1 to achieve the accrual goal for 
Step 2. Depending on the actual proportion of the Step 1 participants eligible to enroll in 
Step 2, the accrual to Step 1 may be closed earlier prior to reaching 640 participants. 
 
It is anticipated that the study will meet its Step 2 accrual target in 36 to 48 months after 
sites are enrolling excluding the period when study enrollment was paused due to the 
COVID-19 pandemic.  
 
10.5 
Data and Safety Monitoring 
 
The study will be reviewed by DSMB appointed by DAIDS. The first review will occur 
approximately 6 months after the accrual of the first participant. Subsequent reviews will 

 
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take place at approximately yearly intervals after the first review, or per request by the 
DSMB. These reviews will assess study conduct and safety. Two interim efficacy 
reviews are planned when approximately 33% and 67% of the total information on the 
primary outcome measure is anticipated to be available. Interim efficacy analyses will be 
based on group-sequential repeated confidence intervals for the difference between 
treatment groups, using the Lan-DeMets approach with an O’Brien-Fleming spending 
function. Table 10.5-1 below gives examples of extreme results that might lead to DSMB 
action at each scheduled review. Each scenario assumes between a 20%-28% 
cumulative probability of failure by week 48 in the superior group. If the confidence 
interval excludes zero, demonstrating that one arm is superior to the other, or if external 
results convincingly establish the superiority of one arm over the other, consideration 
should be given to recommending modification of the study. Interpretation and the 
consistency of the primary analysis with the results for secondary efficacy outcome 
measures and safety should be considered by the DSMB prior to recommending 
stopping a study arm.  
 
Table 10.5-1: Examples of Extreme Results Based on the Proposed Timing of the 
Interim Review Using O’Brien-Fleming Spending Function 
Interim 
Review # 
Confidence 
Level 
Anticipated 
Number of 
Participants in 
Each Group at 
or after Step 
2, Week 48 
Number (%) Failures 
Estimated CI on the 
Difference of 
Cumulative Regimen 
Failure 
Superior 
Group 
Inferior Group 
1 
99.98% 
50 
10 (20%) 
27 (54%) 
[0.4%, 67.6%] 
 
 
 
13 (26%) 
31 (62%) 
[1.6%, 70.4%] 
2 
98.8% 
100 
30 (30%) 
48 (48%) 
[1.0%, 35.0%] 
 
 
 
39 (39%) 
57 (57%) 
[0.5%, 35.5%] 
 
At each interim efficacy review, we will also assess whether there is an unacceptable 
increase in AEs in the LA ART arm compared to the SOC arm. This interim safety 
analysis will be based on a 95% confidence interval of the difference between the 
treatment groups (LA ART – SOC) in the cumulative probability of adverse event by 
week 48. If the lower bound of the 95% confidence interval is greater than 15%, 
demonstrating that the LA ART arm has a significant unacceptable increase in AEs, 
consideration should be given to recommending modification of the study. Table 10.5-2 
below gives examples of extreme results that might lead to DSMB action at each 
scheduled review. 
 

 
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Table 10.5-2: Examples of Extreme Scenarios Based on the Proposed Timing of the 
Interim Review and 15% is the Maximum Acceptable Increase in AEs 
Interim 
Review # 
Anticipated 
Number of 
Participants in 
Each Group at or 
after Step 2, 
Week 48 
Number (%) with AEs 
Estimated 95% 
CI on the 
Difference (LA 
ART-SOC) 
LA ART Arm 
SOC Arm 
1 
50 
25 (50%) 
88 (16%) 
[16.8%, 51.2%] 
 
 
23 (46%) 
66 (12%) 
[17.7%, 50.5%] 
2 
100 
50 (50%) 
20 (20%) 
[17.5%, 42.5%] 
 
 
46 (46%) 
18 (18%) 
[15.7%, 40.3%] 
 
An additional interim review will be triggered if more than 60% of participants with Step 1 
HIV-1 VL evaluations used to determine Step 2 eligibility (or loss to follow up in Step 1) 
fail to enroll to Step 2 at any time or if an unexpectedly high proportion of participants 
with virologic failure (>35%) in Step 2 is observed in either arm (with at least 50 
participants with evaluable data). This virologic failure trigger is supported and based on 
data from the ACTG A5241 (OPTIONS) study with an overall failure rate of 24.7% for 
both arms combined. In our sample size calculation, we expect a virologic failure rate of  
25% in Arm B in Step 2. Observed rate greater than 35% will likely suggest a true 
virologic failure rate greater than the 25% expected.  
 
All interim reviews (planned or unplanned) will include by arm information on safety and 
the following information on study conduct: accrual, losses to follow-up, adherence to 
study visits, evaluations and study regimen, data completeness, and virtual/missed visit 
summary during the COVID-19 pandemic.  
 
Routine monitoring, which will be performed for the study leadership team, includes the 
following pooled over arms: accrual, study status, safety, data timeliness, quality and 
completeness, proportion of participant enrolling in Step 2, and virtual/missed visit 
summary during the COVID-19 pandemic.  
 
Interim accrual goals are as follows: 50 participants randomized in Step 2 by 12 months 
following Step 1 first enrollment. Not attaining these interim accrual goals may trigger an 
unplanned interim review. 
 
An endpoint adjudication committee consisting of one or more independent clinicians will 
review regimen and virologic failures. 
 

 
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10.6 
Analyses 
 
Full details of the proposed analyses for primary and secondary outcome measures will 
be described in the Primary Statistical Analysis Plan. For other outcome measures, full 
details of proposed analyses will be described in a separate statistical analysis plan.  
 
10.6.1 Primary Analyses 
 
Comparison of treatment arms will be made using the difference in the Kaplan-
Meier estimate for the week 48 cumulative probability of regimen failure. 
Specifically, Kaplan-Meier estimates of the 48-week cumulative probabilities of 
regimen failure and associated Greenwood variance will be calculated. A Z-test 
and corresponding two-sided confidence interval will then be constructed using 
the difference between the treatment arms and associated variance of the 
difference. The final confidence interval will be adjusted for Type I error spent at 
the interim efficacy analyses, to preserve an overall two-sided Type I error rate of 
0.05 for the trial. If the study is monitored per planned (2 interim reviews with 
O’Brien-Fleming spending function), at the end of Step 2, 95.4% CI will be used 
to examine the superiority of the LA ART arm. All participants who randomized to 
the treatment arms will be included in the analysis, regardless of status on the 
randomized treatment. Sensitivity analysis using a modified ITT population and 
an as-treated population will also be performed. The modified ITT population 
consists of all participants who were randomized to the treatment arms and 
received at least one dose of study treatment at/or after randomization.  
 
NOTE A: Due to the COVID-19 pandemic, participants enrolled in Step 2 prior to 
the COVID-19 pandemic at clinical research sites where a period of 
disruption is determined will be censored at the start of the disruption 
period. Additional supportive analyses may also be conducted to 
explore the impact of COVID-19 with guidance from FDA, statistical, or 
clinical research literature on approaches for analyzing clinical trial 
data impacted by COVID-19.  
 
NOTE B: Additional analysis will be carried out to explore the potential impact of 
relaxed transition criteria from Step 1 to Step 2 in Version 2. 
Participants enrolled under Versions 1 and 2 will be compared and 
primary outcome measures will be tabulated separately.  
 
For more details, please refer to the primary Statistical Analysis Plan.  
 
10.6.2 Secondary Analyses 
 
Cumulative probability of virologic failure and treatment-related failure by Step 2, 
week 48, will be estimated and compared using the same approach outlined for 
the primary comparison. 
 

 
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The proportion of participants with virologic non-success defined by FDA 
Snapshot algorithm at Step 2, week 48, will be summarized and compared 
between the two arms using a Fisher’s exact test.  
 
The proportions of participants with HIV-1 RNA <50 copies/mL and ≤200 
copies/mL at each study week on Step 1 will be estimated and plotted over time 
with 95% confidence intervals. Similar summaries will be produced for each 
study week on Step 2 by randomized treatment arms and comparison between 
the two arms at weeks 24 and 48 will use a Fisher’s exact test.  
 
The proportion of participants reporting AEs in Step 2 will be tabulated for each 
treatment arm. 
 
All reported AEs will be tabulated by steps and separately by randomized 
treatments for Step 2.  
 
Cumulative probability of discontinuation of randomized treatment will be 
estimated and compared using the same approach outlined for the primary 
comparison.  
 
Summary score of HIVTSQs will be summarized by study arm and compared 
using a Wilcoxon rank-sum test between arms. 
 
Adherence and behavioral measures will be summarized by scheduled study 
week and separately by randomized treatments for Step 2. Missed and delayed 
LA injection will be summarized by scheduled study week in those who initiated 
LA ART. 
 
The frequency of new HIV-1 drug resistance mutations at confirmation of 
virologic failure on Step 2 will be tabulated and compared using a Wilcoxon rank 
sum test between the two treatment arms. Factors associated with emerging 
drug resistance will be examined. 
 
All grade ISRs will be summarized and tabulated by schedule study weeks during 
Step 2. 
 
10.6.3 Other Analyses 
 
Cumulative probability of regimen failure and cumulative probability of virologic 
failure at Step 3, week 48, will be summarized with a two-sided 95% confidence 
interval for all participants who enrolled in Step 3 overall and by their Step 2 
randomized treatment. 
 
Virologic failure on LA ART in Steps 2 and 3, and as-treated analyses, will be 
summarized using cumulative incidence estimation, incorporating the competing 
event of treatment discontinuation.  

 
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The proportions of participants with HIV-1 RNA <50 copies/mL and ≤200 
copies/mL at each study week on Steps 3 and 4 will be estimated and plotted 
over time with 95% confidence intervals. 
 
All other outcome measures will be summarized and tabulated by schedule week 
and compared by treatment arm as applicable.  
 
If the sample size permits, analyses of primary, secondary, and other (e.g. self-
reported opinions about CEI withdrawal) outcome measures will also be carried 
out in the subset of young adults with HIV (18-24 years old) using the same 
aforementioned analytical approaches.   
 
11.0 
PHARMACOLOGY PLAN 
 
11.1 
Pharmacology Objectives 
 
11.1.1 
To examine the association of HIV treatment outcomes, including virologic 
failure, at Step 2 and Step 3 with corresponding CAB-LA and RPV-LA pre-dose 
trough concentrations.  
 
11.1.2 
To examine relationship between the hair concentrations of ARTs with self-
reported adherence measures.  
 
11.1.3 
To examine relationship between the DBS concentrations of ARTs with self-
reported adherence measures.  
 
11.2 
Pharmacology Study Design 
 
11.2.1 
Blood Samples 
• 
At Step 2 (for participants randomized to Arm A), pre-dose trough blood 
samples for quantification of CAB and RPV plasma concentrations will be 
obtained at Step 2 randomization and Step 2, weeks 4b, 8, 12, 16, 24, 32, 
36, 40, 48, and 52, visits for storage and future assay of CAB and RPV 
plasma concentrations to be performed in the participants who develop 
virologic failure. A pre-dose trough sample will also be obtained for storage 
and future assay of CAB and RPV plasma concentrations at study visits in 
which a participant has missed a prior scheduled study visit, at the time of 
study/treatment discontinuation, or at the time of confirmation of virologic 
failure.  
• 
At Step 3 (all participants), pre-dose trough blood samples for quantification 
of CAB and RPV plasma concentrations will be obtained at Step 3 
registration and Step 3, weeks 4b, 8, 12, 16, 24, 32, 36, 40, 48, and 52, 
visits for storage and future assay of CAB and RPV plasma concentrations 

 
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to be performed in the participants who develop virologic failure. A pre-dose 
trough sample will also be obtained for storage and future assay of CAB 
and RPV plasma concentrations at study visits in which a participant has 
missed a prior scheduled study visit, at the time of study/treatment 
discontinuation, or at the time of confirmation of virologic failure.   
• 
At Step 4 (all participants), pre-dose trough blood samples for quantification 
of CAB and RPV plasma concentrations will be obtained at Step 4 
registration. A pre-dose trough sample will also be obtained for storage and 
future assay of CAB and RPV plasma concentrations at the time of 
study/treatment discontinuation, or at the time of confirmation of virologic 
failure. 
 
11.2.2 
Hair Samples (all participants, optional) 
• 
At Step 1, hair samples for quantification of ART drug concentrations will be 
obtained at Entry and Step 1, week 12, and Step 1, week 24. 
• 
At Step 2, hair samples for quantification of ART drug concentrations will be 
obtained at Step 2 Randomization, Step 2, week 8; Step 2, week 24; Step 2, 
week 36; and Step 2, week 48. 
• 
At Step 3, hair samples for quantification of ART drug concentrations will be 
obtained at Step 3 Registration, Step 3, week 12; Step 3, week 24; Step 3, 
week 36; and Step 3, week 48. 
• 
Hair samples will also be obtained at confirmation of virologic failure, time of 
treatment discontinuation, and time of study discontinuation. 
 
11.2.3 
DBS Samples (for those on TAF/FTC or ABC/3TC) 
• 
At Step 1, DBS samples for quantification of ART drug concentrations will 
be obtained at Entry, Step 1, week 4, Step 1, week 12, and Step 1, week 
24. 
• 
At Step 2, DBS samples for quantification of ART drug concentrations will 
be obtained at Step 2 Randomization, Step 2, week 8; Step 2, week 24; 
Step 2, week 36; and Step 2, week 48, for those randomized to continuation 
of oral SOC. 
• 
DBS will also be obtained at confirmation of virologic failure, time of 
treatment discontinuation, and time of study discontinuation. 
 
11.3 
Primary and Secondary Data, Modeling, and Data Analysis 
 
CAB and RPV samples will be assayed at the University of Alabama Pharmacology 
Specialty Laboratory using methods approved by the DAIDS Clinical Pharmacology 
Quality Assurance program. ARV concentrations in hair samples will be analyzed in the 
UCSF Hair Analytical Laboratory. For both CAB-LA and LA-RPV formulations, the pre-
dose trough concentrations will be summarized by geometric means and interquartile 
ranges at each study visit. Concentrations of each drug may also be combined for 

 
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summary and comparison of variables of interest after steady-state concentrations are 
achieved. 
 
11.4 
Anticipated Outcomes 
 
We anticipate that participants who were previously non-adherent to ARV therapy and 
develop virologic failure during CAB-LA and RPV-LA will have lower pre-dose trough 
concentrations compared to historical data from persons with HIV without documented 
non-adherence who have also received CAB-LA and/or LA-RPV and have remained 
virologically suppressed.   
 
12.0 
DATA COLLECTION AND MONITORING  
 
12.1 
Reporting Protocol Deviations 
 
Refer to the MOPs for the definition of protocol deviation. The site principal investigator 
and personnel are responsible for identifying, and reporting deviations. Once protocol 
deviations are identified, corrective actions are to be developed by the site and 
implemented promptly. Protocol deviations must be sent to the IRB/EC per their 
guidelines. 
  
Protocol deviations as defined by the MOPS must be recorded on the study protocol 
deviation eCRF. Please see the MOPs for instructions on how to use the eCRF for 
reporting protocol deviations.  
 
12.2 
Records to Be Kept 
 
Electronic case report form screens (eCRFs) 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 randomization/registration. 
 
12.3 
Role of Data Management 
 
12.3.1 Instructions concerning entering study data on eCRFs will be provided by the 
ACTG DMC. Each CRS is responsible for keying the data in a timely fashion. 
 
12.3.2 It is the responsibility of the ACTG DMC to ensure the quality of computerized 
data for each ACTG study. This role extends from protocol development to 
generation of the final study databases. 
 
12.4 
Clinical Site Monitoring and Record Availability 
 
Monitoring visits may be conducted on-site or remotely. Remote visits may include 
remote source document verification using methods specified for this purpose by NIAID. 
Remote monitoring visits may be performed in place of, or in addition to, onsite visits to 

 
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ensure the safety of study participants and data integrity [45]. The site must make 
available study documents for site monitors to review utilizing a secure platform that is 
HIPAA and 21 CFR Part 11 compliant. The Data Management Center will configure 
Medidata Remote Source Review (RSR) and make it available to all sites. We 
encourage sites to use the DMC-provided Medidata RSR platform but other 
potential platform options include: Veeva SiteVault, site-controlled SharePoint or cloud-
based portal, and direct access to Electronic Medical Record (EMR). Other secure 
platforms that are 21 CFR Part 11 compliant may be utilized, as allowed by the DAIDS 
Office of Clinical Site Oversight (OCSO). 
 
13.0 
PARTICIPANTS 
 
13.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent documents (Informed Consent Form and 
Appendix II) and any subsequent modifications will be reviewed and approved by the 
IRB or ethics committee responsible for oversight of the study. A signed consent form 
will be obtained from the participant (or person with power of attorney for participants 
who cannot consent for themselves). 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 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, FDA, NIAID, 
OHRP, other local, US, or international regulatory entities, other government agencies 
as part of their duties, or the industry supporter(s) or designee. 
 
13.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, FDA, NIAID, OHRP, 
other government agencies as part of their duties to ensure that research participants 
are protected, or the industry supporter(s). 
 
14.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by ACTG policies. Any 
presentation, abstract, or manuscript will be made available for review by the industry 
supporter(s) prior to submission.  
 

 
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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 Centers for 
Disease Control and Prevention 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. 

 
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16.0 
REFERENCES 
 
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https://www.fda.gov/news-events/press-announcements/fda-approves-first-extended-
release-injectable-drug-regimen-adults-living-hiv 
22. Volpp KG, Gurmankin Levy A, Asch DA, et al. A randomized controlled trial of financial 
incentives for smoking cessation. Cancer Epidemiol Biomarkers Prev 2006;15:12-18. 
23. Volpp KG, John LK, Troxel AB, Norton L, Fassbender J, Loewenstein G. Financial 
incentive-based approaches for weight loss: a randomized trial. JAMA 2008;300:2631-7. 
24. Volpp KG, Loewenstein G, Troxel AB, et al. A test of financial incentives to improve 
warfarin adherence. BMC Health Serv Res. 2008;8:272. 
25. Marcus AC, Kaplan CP, Crane LA, et al. Reducing loss-to-follow-up among women with 
abnormal Pap smears. Results from a randomized trial testing an intensive follow-up 
protocol and economic incentives. Med Care 1998;36:397-410. 
26. Kirby KN, Petry NM. Heroin and cocaine abusers have higher discount rates for delayed 
rewards than alcoholics or non-drug-using controls. Addiction 2004;99:461-71. 
27. Kirby KC, Amass L, McLellan AT. Disseminating contingency management research to 
drug abuse practitioners. In: Motivating behavior change among illicit-drug abusers: 
Research on contingency management interventions. Higgins ST and Silverman K, 
Editors. Washington, DC:  American Psychological Association; 1999. p. 327-44. 
28. Petry NM, Weinstock J, Alessi SM, Lewis MW, Dieckhaus K. Group-based randomized trial of 
contingencies for health and abstinence in HIV patients. J Consult Clin Psychol 2010;78:89-97. 
29. Rigsby MO, Rosen MI, Beauvais JE, et al. Cue-dose training with monetary reinforcement: 
pilot study of an antiretroviral adherence intervention. J Gen Intern Med 2000;15:841-7. 
30. Rosen MI, Dieckhaus K, McMahon TJ, et al. Improved adherence with contingency 
management. AIDS Patient Care STDS 2007;21:30-40. 

 
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31. Moore BA, Rosen MI, Wang Y, et al. A Remotely-Delivered CBT and Contingency Management 
Therapy for Substance Using People with HIV. AIDS Behav 2015;19 Suppl 2:156-62. 
32. Farber S, Tate J, Frank C, et al. A study of financial incentives to reduce plasma HIV 
RNA among patients in care. AIDS Behav 2013;17:2293-300. 
33. Javanbakht M, Prosser P, Grimes T, Weinstein M, Farthing C. Efficacy of an individualized 
adherence support program with contingent reinforcement among nonadherent HIV-positive 
patients: results from a randomized trial. J Int Assoc Physicians AIDS Care (Chic) 2006;5:143-50. 
34. Sorensen JL, Haug NA, Delucchi KL, et al. Voucher reinforcement improves medication adherence 
in HIV-positive methadone patients: a randomized trial. Drug Alcohol Depend 2007;88:54-63. 
35. Galarraga O, Genberg BL, Martin RA, Barton Laws M, Wilson IB. Conditional economic 
incentives to improve HIV treatment adherence: literature review and theoretical considerations. 
AIDS Behav 2013;17:2283-92. 
36. El-Sadr WM, Donnell D, Beauchamp G, et al.; HPTN 065 Study Team. Financial incentives 
for linkage to care and viral suppression among HIV-positive patients: a randomized clinical 
trial (HPTN 065). JAMA Intern Med 2017;177:1083-92. 
37. Metsch LR, Feaster DJ, Gooden L, et al. Effect of patient navigation with or without financial 
incentives on viral suppression among hospitalized patients with HIV infection and 
substance use - a randomized clinical trial. JAMA 2016;316:156-70. 
38. Zullo AR, Caine K, Galarraga O. The dollars and sense of economic incentives to 
modify HIV-related behaviours. J Int AIDS Soc 2015;18:20724. 
39. Operario D, Kuo C, Sosa-Rubi SG, Galarraga O. Conditional economic incentives for 
reducing HIV risk behaviors: integration of psychology and behavioral economics. Health 
Psychol 2013;32:932-40. 
40. Metsch LR, Feaster DJ, Gooden L, et al. A Patient Navigation/Contingency 
Management RCT for Hospitalized HIV+ Substance Users. Conference on Retroviruses 
and Opportunistic Infections (CROI), February 22-25, 2016; Boston, Massachusetts. 
41. Gardner LI, Metsch LR, Anderson-Mahoney P, et al. Efficacy of a brief case management 
intervention to link recently diagnosed HIV-infected persons to care. AIDS 2005;19:423-31. 
42. Wilson IB, Lee Y, Michaud J, Fowler Jr, FJ, Rogers WH. Validation of a new three-item 
self-report measure for medication adherence. AIDS Behav 2016;20:2700-8. 
43. Thompson MA, Mugavero MJ, Amico KR, et al. Guidelines for improving entry into and 
retention in care and antiretroviral adherence for persons with HIV: evidence-based 
recommendations from an International Association of Physicians in AIDS Care panel. 
Ann Intern Med 2012;156:817-33. 
44. Tashima KT, Smeaton LM, Fichtenbaum CJ, et al.; A5241 Study Team. HIV salvage 
therapy does not require nucleoside reverse transcriptase inhibitors: a randomized, 
controlled trial. Ann Intern Med 2015;163:908-17. 
45. FDA Guidance on Conduct of Clinical Trials of Medical Products During the COVID-19 Public 
Health Emergency: Guidance for Industry, Investigators, and Institutional Review Boards, March 
2020. Updated on January 27, 2021. Available at: https://www.fda.gov/media/136238/download 
 
 
 

 
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APPENDIX I: INFORMED CONSENT FORM 
 
 
Sponsor / Study Title: 
  
NIAID/DAIDS / “A Phase III Study to Evaluate Long-Acting 
Antiretroviral Therapy in Non-adherent HIV-Infected 
Individuals (The LATITUDE Study)” 
 
Protocol Number: 
 
A5359 
 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
 
This form is for use in a research study that may involve participants who may or may not have 
the capacity to consent to take part in the study. When the participant cannot legally consent to 
take part, pronouns “you” and “your” should be read as referring to the participant rather than 
the person (legally authorized representative) who is signing this form for the participant. In 
cases where the participant’s representative gives consent, the participant should be informed 
about the study to the extent possible given his/her understanding. During the course of the 
study, if the participant regains the capacity to consent, informed consent will be obtained from 
the participant and the participant offered the ability to leave the study if desired. 
 
SUMMARY 
 
PURPOSE  
 
This is a research study and your participation in this study is voluntary. The purpose of this 
study is to test if injectable, long-acting, anti-HIV (human immunodeficiency virus) drugs that are 
given every month can be used safely and effectively in individuals who are infected with HIV 
and who have had problems taking daily medications in the past. The study will also look at how 
well these study drugs are tolerated. 
 
STUDY TREATMENT 
There will be study treatment provided and required in this study. The study drugs are oral 
cabotegravir, oral rilpivirine, long-acting injectable cabotegravir, and long-acting injectable 
rilpivirine. Oral rilpivirine is currently approved by the US Food and Drug Administration (FDA) 
for treating HIV/AIDS in treatment-naïve individuals who have never taken antiretroviral (ARV) 
drugs. Oral cabotegravir, long-acting cabotegravir, and long-acting rilpivirine are currently 
approved by the US FDA for treating HIV/AIDS in people who are well-controlled on their 
current treatment regimen and who have never changed their medications because they 
stopped working. 
 

 
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NUMBER OF PARTICIPANTS 
There will be a maximum of 640 participants in Step 1 to reach 320 participants in Step 2, which 
has two study treatment groups of 160 participants each. 
 
LENGTH OF STUDY  
The study will last between 6 months and 3 ½ years, depending on whether you successfully 
complete each step. There are four steps in the study (up to 24 weeks in Step 1 with about 7 
study visits, 52 weeks in Step 2 with about 14 study visits, 52 weeks in Step 3 with about 14 
study visits, and up to 52 weeks in Step 4 with about 2 study visits). 
 
REQUIRED ACTIVITIES 
 
 
Blood and urine collections 
• 
At most study visits, some blood will be collected from a vein in your arm.  
• 
At most study visits, you will be asked to provide a urine sample.  
  
Special procedures  
You will be asked to come to the clinic fasting (no food or drink except water, decaffeinated 
black coffee without sugar, and your prescription drugs for the 8 hours just before the study 
visit) for some study visits. If you did not fast before a required fasting study visit, you will be 
asked to come back to the clinic for another blood draw after you have fasted. 
 
RISKS 
Risks of participating in this study include side effects from the study drugs used in this study. 
 
BENEFITS  
You could possibly benefit from the study by having additional support to help you take your 
study treatment. 
 
OTHER CHOICES  
Instead of being in this study, you have the option of continuing with your current treatment or 
starting a new treatment under the care of your regular doctor or other health care provider. 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you are a person with HIV and 
you have had problems taking daily medications. This study is sponsored by the National 
Institutes of Health (NIH). The study doctor is in charge of this study at this study site. 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 and date this consent form. You will get a copy 
to keep. 
 
 

 
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WHY IS THIS STUDY BEING DONE? 
 
This study is being conducted to test if injectable, long-acting anti-HIV drugs that are given 
every month can be used safely and effectively in people with HIV and who have had problems 
taking daily medications in the past. This study is also being conducted to evaluate how well are 
these study drugs tolerated. 
 
The drugs being looked at in this study are oral cabotegravir, oral rilpivirine, long-acting 
injectable cabotegravir and long-acting injectable rilpivirine. A long-acting drug means it stays in 
the body much longer compared to the usual form of the drugs.  Oral rilpivirine is currently 
approved by the U.S. Food and Drug Administration (FDA) for treating HIV/AIDS in treatment-
naïve individuals who have never taken antiretroviral (ARV) drugs. Oral cabotegravir, long-
acting cabotegravir and long-acting rilpivirine are currently approved by the US FDA for treating 
HIV/AIDS in people who are well-controlled on their current treatment regimen and who have 
never changed their medications because they stopped working.  
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
If you agree to join this study, you will be asked to sign and date this consent form. After you 
have signed and dated the form, you will be asked some questions and will undergo some tests 
at the screening visit to see if it is safe for you to join the study.  
 
Study visits may be conducted remotely (for example, telephone, telehealth) if you are unable to 
attend a visit because of illness, inability to travel, concerns for potential exposure to COVID-19, 
or the clinic is temporarily unable to conduct non-essential visits in the clinic. 
 
Screening 
The screening visit will take about 1-2 hours. About 2 tablespoons of blood will be drawn. 
• 
You will be asked about your medical history including your HIV history.  
• 
You will be asked about any medicines you have taken in the last 12 months.  
• 
You will also be asked about any anti-HIV medications that you may have ever taken.   
• 
You will have a physical exam. The study staff will check your vital signs such as 
temperature, blood pressure, breathing, weight, and pulse.  
• 
You will have blood drawn for routine blood tests and HIV viral load (VL, the amount of virus 
in your blood sample) and CD4+ cell count (the number of white blood cells that fight 
infection). 
• 
You may have blood drawn for resistance testing (a test to see if the virus in your blood is 
likely to respond to study drugs).  
• 
You may have blood drawn to test for hepatitis B and C (viruses that can affect your liver).  
• 
You will have an electrocardiogram (ECG).  
• 
You will have urine collected for urinalysis. 
• 
You will be asked to complete a questionnaire that will ask questions about: mental health, 
smoking, alcohol and substance use. 

 
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• 
If you are a participant able to become pregnant, you will have a pregnancy test. Pregnant 
participants, or participants who want to become pregnant in the next 4 years, cannot enter 
the study.  
• 
An HIV test may be required to document your HIV status.  
• 
You will be asked to provide forms of additional contact including, but not limited to: mailing 
address, email address, home/cell phone, and additional emergency contacts (for example, 
someone from your family, a friend, or case manager). 
• 
You will be asked to sign a release of information to allow the study staff to consult with your 
HIV provider regarding your study participation.  
 
Information Collected at Screening 
There is some information that we collect on everyone who is screened for an ACTG (AIDS 
Clinical Trials Group) 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 also collect 
information on whether you use (or have used) IV drugs. 
  
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. 
 
Entry 
Within 60 days of your screening visit, you will come to the clinic for entry evaluations. This visit 
will last about 2 hours and you will need to be fasting. You will have about 4 tablespoons of 
blood drawn. You will also have some questionnaires given at entry. 
• 
You will have a physical exam and be asked about your medical history. 
• 
You will be asked about any medicine changes you have had since your screening visit. 
• 
You will have blood drawn for routine blood tests including liver function testing, CD4+, and 
HIV viral load.  
• 
You will have blood drawn for storage for future HIV-related ACTG approved research tests. 
• 
You will have urine collected for a drug screen, which will test for the presence of 
recreational drugs. The test results will be available to you, the study doctor, and may be 
available to your doctor. You may be referred for additional services based on the results of 
these tests.  
• 
You will have a blood draw for dried blood spots (drops of blood collected on a piece of 
paper) and will also have the option to provide about 100 strands of hair (obtained within 1 
cm of the scalp) collected to measure levels of anti-HIV medications. 
• 
If you are a participant able to become pregnant, a pregnancy test will be done before you 
begin your study medications. 
• 
You will be asked to come to the clinic fasting (no food or drink except water, decaffeinated 
black coffee without sugar, and your prescription drugs for the 8 hours just before the visit) 
for lipid testing. If you did not fast before a required fasting visit, you will be asked to come 
back to the clinic for another blood draw after you have fasted. 
• 
You will be asked to complete a questionnaire that will ask questions about: mental health, 
domestic violence, healthcare utilization and medication adherence. 

 
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If you qualify to participate in this study, you will initially be prescribed an oral anti-HIV regimen 
that your study doctor will recommend based on your previous drug regimens and the results of 
your HIV resistance tests. Your anti-HIV drugs will be provided to you at this study visit. If your 
study drugs start making you sick or stop working for you, your study doctor can switch you to 
another regimen.  
 
Post-Entry Step 1 
During Step 1, the study doctor will consult with your HIV provider to determine which anti-HIV 
medications will be safe and most likely to decrease your HIV VL. The study will provide these 
anti-HIV medications to you at no charge unless it is decided that you should stay on 
medication provided by your local provider. This step will last approximately 24 weeks. 
During this step, you will be closely monitored to see if the study drugs that you were started on 
are working and you will be asked to return to clinic at Step 1, weeks 2, 4, 8, 12, 16, 20, and 24, 
depending on your viral load results. Study visits will last about 1 hour. You will have about 3-4 
tablespoons of blood drawn. At most of the study visits: 
• 
You will have a physical exam and be asked about any medications that you may be taking.  
• 
You will be given questionnaires to complete, which may include questions about how you 
take your medications, health and behavior questions, and about your smoking, alcohol and 
drug use habits and demographics. You may also have pill counts where you will be asked 
to bring back all left over pills and pill bottles so that we can see how well you are taking the 
study drugs. 
• 
You will have blood collected for routine blood tests, HIV viral load, CD4+ and CD8+, and 
study drug levels (including plasma and dried blood spots). You will not have blood taken at 
Step 1, week 2. 
• 
If you are a participant who can become pregnant and/or if you think you might be pregnant, 
you will be asked to provide a blood or urine specimen for pregnancy testing. If you are 
taking dolutegravir, you will be asked to provide a specimen for pregnancy testing at every 
visit. 
• 
You will be asked to give urine specimens for recreational drug testing and to monitor for 
possible drug effects on your kidney function. The drug testing results will not be given to 
you or the study clinic providers.  
• 
Blood may be drawn and stored for future HIV-related ACTG approved research tests.  
• 
You will have the option to provide about 100 strands of hair (obtained within 1 cm of the 
scalp) collected to measure levels of anti-HIV medications. This test will be an optional 
procedure. 
 
Conditional Economic Incentives (CEI) 
Because taking your pills every day is an important part of making sure the study treatment 
works, you will receive additional financial incentives (also known as conditional economic 
incentives or CEI) if you achieve some specific “milestones” related to the results of your study 
treatment during this first part of the study, according to the following plan: 
• 
$75 if you complete a study visit at Step 1, week 2. 
• 
$75 if you have a ten-fold decrease (for example from 1000 copies to 100 copies) in your 
HIV VL at Step 1, week 4, and a 100-fold (for example from 10,000 copies to 100 copies) 

 
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decrease in your HIV VL at Step 1, week 8, visit compared to your VL at the beginning of the 
study entry OR if your HIV VL is equal to or less than 200 copies at weeks 4 or 8. 
• 
$600 if your HIV VL is equal to or less than 200 copies at week 4; $525 if your HIV VL 
is equal to or less than 200 copies at week 8; $450 if your HIV VL is equal to or less than 
200 copies at Step 1, week 12; $300 if your HIV VL is equal to or less than 200 copies at 
Step 1, week 16; and $150 if your HIV VL is equal to or less than 200 copies at Step 1, 
week 20. Your total amount of incentive will not be reduced if you achieve an HIV VL equal 
to or less than 200 early during Step 1. 
• 
A completion of a Step 1 virtual visit during the COVID-19 pandemic restrictions will also 
meet criteria for disbursement of the incentives. 
 
If you do not achieve the milestones, you will not receive the additional conditional economic 
incentives (but you will receive the usual compensation given for attending your study visit). You 
will, however, be allowed to continue on the study and you may be eligible for the next available 
economic incentive. For example, you may not qualify for an incentive at Step 1, week 4, but 
you could still receive it at Step 1, weeks 8, 12, 16, and/or 20, based on these milestones. The 
CEI will stop at Step 1, week 20. 
 
The CEIs in this study are intended to enhance your possibility of reaching an undetectable HIV 
VL by the end of Step 1. This is important because you can only be eligible for randomization 
(assigned by chance as if by the toss of a coin) in Step 2 if your HIV VL is equal to or less than 
200 copies, in order for you to be a candidate to receive long-acting therapy. CEIs have shown 
to be most helpful for short periods of time; in most studies, the effect of using them stops after 
an individual stops receiving them. Therefore, we only plan to provide CEIs during Step 1, for up 
to 20 weeks. After week 20 in Step 1, all CEIs will be discontinued for all participants. 
 
After the CEIs are discontinued, you may feel disappointed about not receiving them. This is 
expected and should improve overtime. Keep in mind that you will still receive the usual 
compensation for your participation in the study, as it is customary in the studies performed by 
the AIDS Clinical Trials Group. The study personnel will be able to answer any questions you 
may have about the CEIs. As mentioned, the CEIs are only intended to be a temporary 
intervention as part of a research study. 
 
Please indicate and initial below to ensure that you understand that:  
a) The CEIs will only be implemented during Step 1 and; 
b) All CEIs will be discontinued for all participants once they are eligible for Step 2. 
 
________ Study Participant’s initials 
 
Step 2 
To be eligible to move on to Step 2, your HIV VL will need to be equal to or less than 200 copies 
at or after the Step 1, week 4, study visit. If your HIV VL is greater than 200 copies but less than 
400 copies, you will need to come in for a retest within 2 weeks. If your HIV VL is less than or 
equal to 200 copies by Step 1, week 20, or at your retest, you will be randomized (assigned by 
chance as if by the toss of a coin) to one of two study groups in the next phase of the study, 

 
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known as Step 2 randomization study visit. Your chance of being assigned to one of the study 
groups is one out of two (50%). You will be told which study group you are in. The study groups 
are as follows:  
 
Study Group A – Switch your anti-HIV regimen to an initial short course of daily oral 
cabotegravir and rilpivirine tablets for 4 weeks, followed by long-acting injectable 
cabotegravir + long-acting injectable rilpivirine administered to you every 4 weeks. You and 
your study doctor may decide to skip the short course of daily oral cabotegravir and 
rilpivirine and directly start the injectable regimen at the start of Step 2.  
 
Study Group B – Continue on your current regimen. 
 
If you are assigned to Study Group A, your anti-HIV regimen will be switched to a combination 
of oral cabotegravir + oral rilpivirine for 1 month. After 1 month on the new oral study drug, you 
will return to the clinic to have your safety labs checked to make sure that it will be safe for you 
to receive the study drug as a long-acting injectable. If your lab results confirm that it is safe for 
you to receive an injection, you will be asked to come to the clinic within 1 week to receive your 
first injection of long-acting anti-HIV medications. You and your study doctor may decide to skip 
the short course of daily oral cabotegravir and rilpivirine and directly start the injectable regimen 
at the start of Step 2. 
 
At that study visit, you will receive 2 injections: a loading dose of 3 mL (less than a teaspoon) of 
long- acting cabotegravir plus a loading dose of 3 mL of long-acting rilpivirine, both in the gluteal 
muscle (in the buttocks). You will need to return to clinic within 4 weeks (28 days) for an 
additional dose of long-acting anti-HIV study drugs. In all of the following study visits, you will 
receive 2 injections which will include 2 mL of long-acting cabotegravir plus 2 mL of long-acting 
rilpivirine, both in the gluteal muscle. You will be asked to return to the clinic every 4 weeks for 
injections and study procedures. on Step 2, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 
and 52. If more than 8 weeks pass between your injections you will need to receive another 
loading dose of 3 mL of long- acting cabotegravir plus a loading dose of 3 mL of long-acting 
rilpivirine, both in the gluteal muscle. 
 
If you are assigned to Study Group B, you will continue your current anti-HIV regimen. You will 
be asked to return to the clinic for a study visit on Step 2, weeks 4, 8, 16, 24, 36, 48, and 52. 
Study visits will last about 1 hour.  
 
During most of these study visits in Step 2 (regardless of which study group you are randomized 
to), you will have about 3-4 tablespoons of blood drawn. In addition: 
 
• 
You will have a physical exam, including an evaluation of the site where you are receiving 
the injection (Study Group A only). 
• 
You will have an ECG at Step 2, Randomization, and Step 2, week 48. 
• 
You will be asked about any side effects and about any medications that you may be taking.  

 
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• 
You will be given questionnaires to complete, which may include questions about how you 
take your medications, pill counts, mental health and behavior questions, domestic violence, 
stigma, self-efficacy, treatment satisfaction, demographics and about your smoking, alcohol 
and drug use habits.  
• 
You will have blood collected for routine blood tests, HIV viral load, CD4+ and CD8+, and 
study drug levels. You may also have and HIV resistance test (HIV genotype).  
• 
You will have the option to provide about 100 strands of hair (obtained within 1 cm of the 
scalp) collected to measure levels of anti-HIV medications. This test will be an optional 
procedure. 
• 
You may be asked to give urine specimens for drug toxicology and to monitor for possible 
drug effects on your kidney function. Neither you nor your clinic provider will receive the 
results of the drug tests. 
• 
If you are a participant who is capable of becoming pregnant, you will be asked to give urine 
specimens for a pregnancy test at various times during the study. You must have a negative 
pregnancy test result before receiving the first injection. If you are taking dolutegravir, you 
will be asked to provide a specimen for pregnancy testing at every visit. Otherwise in Study 
Group B, you will be asked to provide a specimen for a pregnancy test only if you or your 
study doctor thinks you could be pregnant.   
• 
Blood may be drawn and stored for future HIV-related ACTG approved research tests.  
• 
At Step 2 randomization and Step 2, week 48, you will be asked to come to the clinic fasting 
(no food or drink except water, decaffeinated black coffee without sugar, and your 
prescription drugs for the 8 hours just before the visit) for lipid testing. If you did not fast 
before a required fasting visit, you will be asked to come back to the clinic for another blood 
draw after you have fasted. 
 
Step 3 
To be eligible to move on to Step 3, your HIV VL will need to be equal to or less than 200 copies 
at the Step 2, week 48, visit. If your HIV VL is greater than 200 copies but less than 400 copies, 
you will need to come in for a retest within 2 weeks. If your HIV VL is less than or equal to 200 
copies by Step 2, week 52, you may enter into Step 3.  
 
In Step 3, all participants will receive the long-acting injectable study drugs. If you had 
previously been receiving the long-acting injectables, you will continue to do so and come to the 
clinic every 4 weeks during this Step through week 52. If you have never received long-acting 
study drugs, your anti-HIV regimen will be switched to a combination of oral cabotegravir + oral 
rilpivirine for 1 month. After 1 month on the new oral study drug, you will return to the clinic to 
have your safety labs checked to make sure that it will be safe for you to receive the study drug 
as a long-acting injectable. If your lab results confirm that it is safe for you to receive an 
injection, you will be asked to come to the clinic within 1 week to receive your first injection of 
long-acting anti-HIV study drugs. You will need to return to clinic within 4 weeks (28 days) for an 
additional dose of long-acting anti-HIV study drugs. You and your study doctor may decide to 
skip the short course of daily oral cabotegravir and rilpivirine and directly start the injectable 
regimen at the start of Step 3. All participants in Step 3 will come to the clinic every 4 weeks for 
injections and study procedures on Step 3, Registration and on Step 3, weeks 4, 8, 12, 16, 20,  

 
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24, 28, 32, 36, 40, 44, 48, and 52. Study visits will last about 1 hour. In Step 3, you will have 
about 1-2 tablespoons of blood drawn. At most study visits: 
 
• 
You will have a physical exam including an evaluation of the site where you are receiving 
the injection. 
• 
You will have an ECG at Step 3, Registration, and Step 3, week 48.  
• 
You will be asked about any side effects and any medications that you may be taking.  
• 
You will be given questionnaires to complete, which may include questions about smoking, 
mental health, self-efficacy, stigma, domestic violence, treatment satisfaction, alcohol and 
drug use, and health care utilization.  
• 
You will have blood collected for routine blood tests, HIV viral load, CD4+ and CD8+, and for 
drug concentrations. You may also have an HIV resistance testing (HIV genotype). 
• 
You will have an evaluation of the site where you are receiving the injections. 
• 
You will have the option to provide about 100 strands of hair (obtained within 1 cm of the 
scalp) collected to measure levels of anti-HIV medications. This test will be an optional 
procedure. 
• 
You may be asked to give urine specimens for drug toxicology and to monitor for possible 
drug effects on your kidney function. Neither you nor your clinic provider will receive the 
results of the drug tests. 
• 
If you are a participant who is capable of becoming pregnant, you will be asked to give a 
urine for a pregnancy test. You must have a negative pregnancy test result before receiving 
the first injection. If you are taking dolutegravir, you will be asked to provide a specimen for 
pregnancy testing at every visit. 
• 
Blood may be drawn and stored for future HIV-related ACTG approved research tests.  
• 
At week 52, you will be asked to come to the clinic fasting (no food or drink except water, 
decaffeinated black coffee without sugar, and your prescription drugs for the 8 hours just 
before the visit) for lipid testing. If you did not fast before a required fasting visit, you will be 
asked to come back to the clinic for another blood draw after you have fasted. 
 
If you are a participant who is able to become pregnant, a pregnancy test will be done at various 
visits in Steps 1, 2 and 3, if pregnancy is suspected, to make sure that you are not pregnant. 
Pregnancy testing must be performed before each injection. You will need to inform the study 
staff know if you change your birth control method or if you suspect you might be pregnant. 
 
Step 4 
If you received at least one dose of long-acting injectable study drug during the study, you will 
need to be observed on oral HIV medications for 52 weeks after your last dose of injectable 
therapy. You will complete the study visits for the step you are in (either Step 2 or Step 3) and 
then enter Step 4 to complete 52 weeks total on oral HIV study drugs. Please note that after 
completing Step 3, long-acting injectable medication will not be provided by the study, and will 
only be available to participants if it is available through your doctor’s office. If you decide to 
continue this treatment, you may not need to enter Step 4. 
 
In Step 4 of the study, you will obtain HIV pill medications from your doctor. You will come for 
study visits every 6 months for 1 year. You will have labs drawn and complete questionnaires at 

 
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those study visits. Study visits will last about 1 hour. You will have about 1-2 tablespoons of 
blood drawn. At most visits: 
 
• 
You will have a physical exam. At Step 4, Registration, you will have an evaluation of the 
site where you receive your final injection. 
• 
You will be asked about any side effects and any medications that you may be taking.  
• 
You will be given questionnaires to complete, which may include questions related to your 
mental health, self-efficacy, treatment satisfaction, smoking, substance use, and how you 
take your medications.  
• 
You will have blood collected for routine blood tests, HIV viral load, CD4+, CD8+ and drug 
concentrations.  
• 
You may be asked to give urine specimens and to monitor for possible drug effects on your 
kidney function. You may also have an HIV resistance testing (HIV genotype). 
• 
If you are a participant who is capable of becoming pregnant and you think you may be 
pregnant, you will be asked to give a urine sample for a pregnancy test. If you are taking 
dolutegravir, you will be asked to provide a specimen for pregnancy testing at every visit. 
• 
At Step 4 registration and week 52 you will be asked to come to the clinic fasting (no food or 
drink except water, decaffeinated black coffee without sugar, and your prescription drugs for 
the 8 hours just before the visit) for lipid testing. If you did not fast before a required fasting 
visit, you will be asked to come back to the clinic for another blood draw after you have 
fasted. 
• 
Blood may be drawn and stored for future HIV-related ACTG approved research tests. 
 
Virologic Failure Confirmation Study Visit 
If your HIV VL has not decreased enough or your HIV VL increases at or after entry into Step 2, 
you will return for an additional visit and have a second HIV VL test between 7 - 21 days of the 
previous HIV VL testing. At this study visit: 
 
• 
You will have blood drawn for HIV VL, CD4+ and CD8+ and drug concentrations. You may 
also have a blood draw for HIV resistance testing (HIV genotype)  
• 
You will have a blood draw for dried blood spots (if this happens during Steps 1 or 2) and 
will also have the option to provide about 100 strands of hair (obtained within 1 cm of the 
scalp) collected to measure levels of anti-HIV drugs (if this happens during Steps 1 through 
3).  
• 
You will be given a questionnaire to complete, which will include questions about how you 
take your medications. 
 
Your study doctor may keep you on your current study drugs, or you may be switched to 
another study drug regimen selected by your study doctor. If you are switched to a different 
study drug regimen not provided by the study, you will need to obtain that regimen from your 
study doctor. You will continue to come in for your regular study visits as described above until 
the end of the study.  
 

 
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Premature Discontinuation of Study Therapy Visit 
If you stop taking the study drugs before the end of the study or if you had virologic failure, you 
will be asked to return to the clinic for additional evaluations. This visit will last about 1 hour. You 
will have about 3 tablespoons of blood drawn. You also will be asked to continue to be part of 
the study and attend study visits even though you are no longer taking the study drugs. 
 
• 
You will have a physical exam. The clinic staff will check your vital signs such as 
temperature, blood pressure, breathing, and pulse. You may have an evaluation of your 
injection site if you were receiving injections.  
• 
You will be asked about the reasons why you discontinued the study drugs, about side 
effects and about any medicine changes you have had since screening. 
• 
You will have blood drawn for routine blood tests, HIV viral load, CD4+ and CD8+, drug 
levels, and HIV genotype (if clinically indicated). You will also have a lipid profile if you are in 
Step 4. 
• 
You will have a blood draw for dried blood spots (Step 2 only) and will also have the option 
to provide about 100 strands of hair (obtained within 1 cm of the scalp) collected to measure 
levels of anti-HIV medications.  
• 
You will be given questionnaires to complete, which may include questions about how you 
take your medications, pill counts, health and behavior questions, and about your smoking, 
alcohol and drug use habits. 
• 
You may be asked to give urine specimens.  
• 
If you are a participant who is capable of becoming pregnant, you will be asked to give a 
urine for a pregnancy test. 
• 
Blood may be drawn and stored for future HIV-related ACTG approved research tests. 
 
Final Study Visit 
When you complete the study or if you leave the study early, you will be asked to come in to the 
clinic for final study evaluations. This study visit will last about 1 hour. You will have about 4 
tablespoons of blood drawn.  
 
• 
You will have a physical exam. The study staff will check your vital signs such as 
temperature, blood pressure, breathing, and pulse. You may have an evaluation of your 
injection site if you were receiving injections.  
• 
You will be asked about any medicine changes you have had since your last visit. 
• 
You will have blood drawn for routine blood tests which may include HIV viral load, CD4+ 
and CD8+, drug levels. You may have an HIV genotype drawn if clinically indicated. You will 
also have a lipid profile if you are in Step 4. 
• 
You will have blood drawn and stored for future HIV-related ACTG approved research tests.  
• 
You will have a blood draw for dried blood spots (Step 2 only) and will also have the option 
to provide about 100 strands of hair (obtained within 1 cm of the scalp) collected to measure 
levels of anti-HIV medications. 
• 
You will be given questionnaires to complete, which may include questions about how you 
take your medications, pill counts, health and behavior questions, and about your smoking, 
alcohol and drug use habits. 
• 
You may be asked to give urine specimens.  

 
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• 
If you are a participant who is capable of becoming pregnant, you will be asked to give a 
urine for a pregnancy test. 
 
You will be given the results of the pregnancy (if done), CD4+ and CD8+ cell counts, viral load, 
routine blood tests, glucose, cholesterol, triglycerides, hepatitis B and C. 
 
OPTIONAL TESTS 
 
Hair Collection 
You have the option to provide about 100 strands of hair (obtained within 1 cm of the scalp) 
collected to measure levels of anti-HIV medications. Hair collection is not a requirement to 
participate in the study and you may withdraw your approval for hair collection, at any time.  
 
Please indicate and initial below whether you approve the collection of your hair. 
 
________ YES, I approve the collection of my hair                      
 
 
________ NO, I do not approve the collection of my hair 
 
Other Information 
Your research site will collect your contact information including your address in order to keep in 
touch with you. In addition, in order to get a better understanding of the impact of your 
surrounding environment on your health, we are asking that we collect ONLY the first 3 digits of 
your zip code for a future analysis. Collection of this information is not a requirement to 
participate in the study.  
 
Please indicate and initial below whether you approve the collection of the first 3 digits of your 
zip code.  
 
________ YES, I approve the collection of the first 3 digits of my zip code.                     
 
________ NO, I do not approve the collection of the first 3 digits of my zip code. 
 
 

 
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CAN I CHOOSE THE TYPES OF RESEARCH THAT MY SAMPLES AND INFORMATION 
ARE USED FOR? 
 
Some of your blood will be stored and used for study-required pharmacologic, metabolic, 
immunologic, and virologic testing. Hair and dried blood spots will be stored for current and 
future research. 
 
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. 
 
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 the “CONSENT FOR USE OF SAMPLES IN OTHER STUDIES” for use of your 
samples in other studies. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
A maximum of 640 people will take part in this study 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study between 24 weeks and 180 weeks depending on if you successfully 
complete each step of the study, and if the long-acting study drug is not available at the end of 
Step 3.  
 
 
WHY WOULD THE STUDY 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 by the ACTG, the US Food and Drug Administration 
(FDA), the Office for Human Research Protections (OHRP), National Institutes of Health 
(NIH), other government agencies, the drug companies supporting this study, or the site’s 
Institutional Review Board (IRB). (An IRB is a committee that watches over the safety and 
rights of research participants.) 
• 
A Data Safety Monitoring Board (DSMB) recommends that the study be stopped early (a 
DSMB is an outside group of experts who monitor the study). 
• 
You are not able to attend the study visits as required by the study. 
• 
You become imprisoned or involuntarily incarcerated in a medical facility and miss too many 
study visits and/or are unable to take your study drugs.  
• 
Request of your regular doctor if s/he thinks the study is no longer in your best interest. 

 
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• 
If the study doctor feels that you may not be able to complete all of the necessary steps of 
the study or if continuing on the study may be harmful to you. 
 
The study doctor may also need to take you off the study drug(s) without your permission if: 
 
• 
Continuing the study drug(s) may be harmful to you 
• 
You need a treatment that you may not take while on the study 
• 
You are not able to take the study drug(s) as required by the study 
• 
You become pregnant or are breast-feeding. 
 
If you must stop taking the study drug(s) before the study is over, the study doctor may ask you 
to continue to be part of the study and return for some study visits and procedures. 
 
 
IF I HAVE TO PERMANENTLY STOP TAKING STUDY-PROVIDED DRUGS OR ONCE I 
LEAVE THE STUDY, HOW WOULD THESE MEDICATIONS BE PROVIDED? 
 
During the study: 
 
If you must permanently stop taking study-provided drugs before your study participation is 
over, the study staff will discuss other options that may be of benefit to you. 
 
After the study: 
 
After the completion of the study, it is important that you continue treatment for your HIV 
infection. The study staff will discuss with you what your best options are for continuing 
treatment. This may be long-acting injectable drugs, if they are available or oral anti-HIV 
therapy. This will be determined in conjunction with your study and regular doctors.  
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
The drugs used in this study may have side effects, some of which are listed below. Please note 
that these lists do not include all the side effects seen with these study drugs. These lists 
include the more serious or common side effects with a known or possible relationship. If you 
have questions concerning the additional study drug side effects, please ask the medical staff at 
your site. 
 
There is a risk of serious and/or life-threatening side effects when non-study medications are 
taken with the study drugs. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study and also before starting any new 
medications while on the study. Also, you must tell the study doctor or study nurse before 
enrolling in any other clinical trials while on this study. 
 

 
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Risks of the Questionnaires 
You may feel embarrassed or uncomfortable answering the questions in the questionnaires, 
which will ask mental health questions related to depression, anxiety, suicidal thoughts, as well 
as substance use and alcohol use. 
 
If you are having suicidal thoughts call the study doctor at the telephone number listed on the 
first page of this form. If you feel in crisis, you can call 911 and/or a Nationwide Suicide Hotline 
that is answered 24 hours a day with a skilled, trained counselor. One example is the National 
Suicide Prevention Lifeline at 1-800-273-TALK (8255). 
 
If your answers reveal that you are having suicidal thoughts you will be seen by a study doctor 
before you leave the clinic and you may be referred for psychiatric care. If your answers reveal 
a substance use problem to study staff, you may be referred for drug abuse treatment if you 
agree with being referred. 
 
Risks of Drawing Blood 
Taking blood may cause discomfort, bleeding, and bruising where the blood is drawn. 
Occasionally, there is swelling in the area where the needle enters the body and there is a small 
risk of infection. There is also a risk of lightheadedness, fainting, and blood clots. 
 
Risks of Hair Collection 
For participants who consent to the hair collection, we will collect about 100 strands of your hair. 
To do this, we will obtain a hair sample from the back of your head and cut close to the scalp 
with scissors. A noticeable place on the scalp where hair was cut may be visible. Cutting hair 
will not cause any pain. We will try to cut hair from underneath hair on top of it to hide where the 
hair was cut from. 
 
Risks of Fasting 
Some individuals find fasting to be bothersome. It may make some individuals feel anxious, 
irritable, light-headed, weak, or hungry. Participants who are required to take their morning 
medications with food should wait until after the study visit has been completed to take their 
medications. 
 
Risks of Standard of Care Medications 
NOTE: For more information about the side effects and risks of the drugs prescribed to you, ask 
your study doctor or pharmacist for the package insert.  
 
Risks of Combination Antiretroviral Therapy 
Immune Reconstitution Inflammatory Syndrome (IRIS): In some people with advanced HIV 
infection, signs and symptoms of inflammation from other infections may occur soon after anti-
HIV treatment is started.   
 
Some people may develop resistance to the anti-HIV medications. This is more likely to happen 
if you do not take your medications regularly, but it can also happen if you do. We do not know if 
the risk of resistance is higher in people who take injectable anti-HIV medications compared to  

 
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oral medications. We also do not know if not being able to obtain a resistance test prior to 
starting this treatment increases the risk of resistance. 
 
The use of potent anti-HIV drug combinations may be associated with an abnormal placement 
of body fat and wasting. Some of the body changes include: 
• 
Increase in fat around the waist and stomach area 
• 
Increase in fat on the back of the neck 
• 
Thinning of the face, legs, and arms 
• 
Breast enlargement 
 
Risks with the Use of Nucleoside Analogues: Emtricitabine (FTC, Emtriva™), Tenofovir 
alafenamide fumarate (TAF, a component of Genvoya™, Odefsey™ and Descovy™), Abacavir 
(ABC, Ziagen™), Lamivudine (3TC, Epivir™), Abacavir+Lamivudine (ABC/3TC, Epzicom™ and 
a component of Triumeq™) 
 
Lactic acidosis (elevated lactic acid levels in the blood) and severe hepatomegaly (enlarged 
liver) with steatosis (fatty liver) that may result in liver failure, other complications or death have 
been reported with the use of antiretroviral nucleoside analogues alone or in combination. The 
liver complications and death have been seen more often in individuals assigned female sex 
at birthon these drug regimens. Some nonspecific symptoms that might indicate lactic acidosis 
include: unexplained weight loss, stomach discomfort, nausea, vomiting, fatigue (feeling tired), 
cramps, muscle pain, weakness, dizziness, and shortness of breath. 
 
In addition, the following side effects have been associated with the use of Nucleoside 
Analogues:  
• 
Upset stomach, vomiting, gas, loose or watery stools  
• 
Generalized weakness 
• 
Vague overall feeling of discomfort 
• 
Decrease in appetite  
• 
Hypersensitivity reaction (overreaction of the immune system) 
• 
Depression 
• 
Headache 
• 
Abdominal pain  
• 
Worsening or new kidney damage or failure   
• 
Inflammation or swelling and possible damage to the pancreas and liver 
• 
Shortness of breath  
• 
Rash, itching, which sometimes can be a sign of an allergic reaction 
• 
Muscle pain and muscle weakness 
• 
Numbness, tingling, and pain in the hands or feet  
• 
Bronchitis 
• 
Pain (not specific) 
• 
Allergic reaction: symptoms may include fever, rash, upset stomach, vomiting, loose or 
watery stools, abdominal pain, achiness, shortness of breath, a general feeling of illness or 
potentially serious swelling of the face, lips, and/or tongue 

 
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• 
Bone pain and bone changes such as thinning and softening which may increase the risk of 
breakage 
• 
Headache 
• 
Dizziness 
• 
Tiredness 
• 
Inability to sleep, unusual dreams 
• 
Increased cough 
• 
Runny nose  
• 
Abnormal liver function tests, which could mean liver damage 
• 
Increases in pancreatic enzyme (substances in the blood), which could mean a problem with 
the pancreas  
• 
Increased triglycerides  
• 
Increased creatine phosphokinase (CPK), which could mean muscle damage 
• 
Low cells counts such as anemia, low white count and/or low platelets 
 
NOTE: If you have hepatitis B, you are not eligible for the study. Before starting abacavir, your 
study doctor should test you to determine if you are at risk of developing a severe allergy to 
abacavir.  
 
Risks with the Use of Protease Inhibitors: Darunavir (DRV, Prezista™) and Cobicistat (COBI, 
PrezcobixTM) 
The use of protease inhibitors may be associated with the following:  
• 
Increases in the amount of triglycerides and/or cholesterol in the blood 
• 
Development of diabetes or the worsening of high blood sugar 
• 
There have been reports of increased bleeding in  people with HIV with hemophilia who 
were treated with protease inhibitors. It is not known if protease inhibitors were the cause of 
these bleeding episodes. 
 
The risks of DRV or DRV/COBI include: 
• 
Severe liver problems, which may be life-threatening. People who have increased liver 
function tests before starting DRV and people with liver diseases such as hepatitis B or C 
have an increased risk of worsening liver disease. If you are developing liver problems, you 
may have one or more of the following symptoms: 
o Yellowing of the skin or of the whites of your eyes 
o Dark urine 
o Pain on the right side of your stomach 
o Loss of appetite 
o Upset stomach or vomiting 
o Pale colored stools 
• 
Itchy skin 
• 
Rash, which may be severe or life-threatening. Contact your study doctor if you develop a 
rash. If you develop any skin changes with the following symptoms, stop using the 
DRV/COBI combination and contact your study doctor right away: 
o Fever 

 
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o Tiredness 
o Muscle or joint pain 
o Blisters 
o Mouth sores 
o Red or inflamed eyes 
• 
Changes in blood test results that may show problems with the liver, kidneys and cholesterol 
levels 
• 
Inflammation of the pancreas. When the pancreas becomes inflamed, it can cause pain in 
the stomach, nausea, vomiting 
• 
Joint stiffness and bone pains may occur, rarely death of bone tissue and collapse of the 
bone may occur 
 
Additional side effects include: 
• 
Diarrhea 
• 
Nausea 
• 
Stomach pain 
• 
Vomiting 
• 
Headache 
 
Before starting DRV, you should inform your study doctor if you are allergic to sulfa medicines. 
 
DRV/COBI (Prezcobix®) when taken with some other drugs, like tenofovir, can cause new or 
worsening kidney problems, which can lead to kidney failure. 
 
NOTE: Your study doctor can provide more complete information about the side effects of 
protease inhibitors. Before starting darunavir (DRV, Prezista™ and a component of 
Prezcobix™), you should inform your study doctor if you are allergic to sulfa drugs. 
 
Risks with Use of Integrase Inhibitors: Dolutegravir (DTG, Tivicay™ and a component of 
Triumeq™) and Elvitegravir/Cobicistat (EVG/COBI, a component of Stribild™ and Genvoya™)  
 
The following side effects have been associated with the use of Integrase Inhibitors:  
• 
Upset stomach 
• 
Headache 
• 
Tiredness  
• 
Weakness 
• 
Trouble sleeping 
• 
Vertigo (feeling dizzy and off balance) 
• 
Rash, which may be severe 
• 
Feeling anxious 
• 
Depression, suicidal thoughts and actions 
• 
Paranoia (an abnormal sense of fear) 
• 
Low blood platelet count 
• 
Muscle pain, tenderness, or weakness, which can be serious and lead to kidney damage 

 
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• 
Abnormal liver function tests 
• 
Changes in body fat 
• 
Abnormal heart rhythm if receiving certain antiarrhythmics such as dofetilide. 
• 
Participants with underlying hepatitis B or C may be at increased risk for worsening or 
development of transaminase elevations with use of dolutegravir. 
• 
Cancers have been seen in people who took raltegravir with other HIV drugs. The types of 
cancers seen are typical for people with very sick immune systems. It is unknown if the 
cancers were related to raltegravir use.  
• 
Contact your study doctor right away if you develop a rash while taking dolutegravir, 
especially if it is associated with any of the following symptoms: 
o Fever;  
o Blisters or sores in your mouth;  
o Blisters or peeling skin; 
o Redness or swelling of your eyes; 
o Swelling of your mouth, face, lips, or tongue;  
o Trouble breathing 
• 
Contact your study doctor right away if you have any of the following symptoms that could 
be signs of liver problems: 
o Yellowing of your skin or whites of your eyes (jaundice);  
o Dark or tea-colored urine;  
o Pale-colored bowel movements;  
o Nausea or vomiting;  
o Loss of appetite;  
o Pain, aching, or tenderness on your right side below your ribs 
 
Risks with Use of Rilpivirine (RPV, Edurant™ and a component of Complera™ and Odefsey™) 
and RPV Long-Acting injections 
More than 500 people have received RPV LA injections in clinical trials, and this study drug was 
approved by the Food and Drug Administration on January 21, 2021, for use in people with HIV 
who are well-controlled (consistently less than 50 copies/mL) on a stable oral anti-HIV regimen, 
who have never changed anti-HIV medications because they stopped working, and who do not 
have a history of resistance to CAB or RPV. The following side effects have been seen with 
rilpivirine in people with HIV in clinical trials. Note that oral rilpivirine (Edurant) is an approved 
drug that may be prescribed by your regular doctor.  
 
The following serious side effects have been associated with the use of rilpivirine: 
• 
Depression or mood changes. Be sure to contact your study doctor immediately if you are 
feeling sad or hopeless, feeling anxious or restless, or having thoughts of hurting yourself 
(suicide) or have tried to hurt yourself. 
• 
Rash, which may be severe or life-threatening. Contact your study doctor if you develop a 
rash or other skin changes, especially if either is associated with any of the following: 
o Fever 
o Blistering on the skin or ulcers in the mouth 
o Eye redness or swelling of the face, moth, or other parts of the body 

 
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• 
Liver problems can happen. People who have abnormal liver tests before starting rilpivirine 
and people with liver diseases like hepatitis B or C have an increased risk of worsening liver 
disease. If you are developing problems, you may have one or more of the following 
symptoms: 
o Yellowing of the skin or of the whites of your eyes 
o Dark urine 
o Pain on the right side of your stomach 
o Loss of appetite 
o Upset stomach or vomiting 
o Pale colored stools 
o Itchy skin 
 
• 
Additional side effects include: 
o Headache 
o Trouble sleeping 
o Abdominal pain 
o Fatigue (feeling tired) 
 
NOTE: Some people taking rilpivirine have had liver problems. People with a history of hepatitis 
B virus (HBV) or hepatitis C virus (HCV) infection or who have elevated results on liver function 
tests may have an increased risk of developing new or worsening liver problems while taking 
rilpivirine.  
 
In healthy participants, there was no clinically relevant effect on QTc interval (one of the 
measurements of the electrical activity of the heart as recorded on the electrocardiogram [ECG], 
and related to heart rate) at a dose of RPV 25 mg once daily. A modest increase in the QTc 
interval (change in electrical activity) has been observed with RPV at a dose of 75 mg once 
daily or higher (for example, higher than used in this study). In participants with HIV treated with 
RPV once daily, the change in electrical activity was similar with RPV as in the control group in 
the phase IIb study after 240 weeks as well as in the phase III study after 96 weeks There is a 
very small chance this change in electrical activity may lead to more serious heart problems 
such as abnormal heart rhythms (arrhythmias) and very rarely this could lead to sudden death. 
These risks may be higher when RPV is combined with certain other drugs with a known risk for 
such abnormal heart rhythms. However, to date, no such heart rhythm irregularities or sudden 
deaths have been observed in clinical studies with RPV. Your study doctor will check for these 
drugs prior to starting the study. 
 
Cabotegravir (CAB) Tablets and CAB Long-Acting Injections 
As of December 2017, an estimated 2169 people (including people with HIV, people who do not 
have HIV and who are taking PrEP, and people who do not have HIV and are not taking PrEP) 
have received CAB in studies sponsored by ViiV Healthcare. These included blinded studies 
(where people did not know what treatment they were receiving). In these studies, 1269 of the 
estimated 2169 people took the long acting (LA) formulation. Both the CAB tablets and CAB 
injections were approved by the Food and Drug Administration on January 21, 2021, for use in 
people with HIV who are well-controlled (consistently less than 50 copies/mL) on a stable oral 

 
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anti-HIV regimen, who have never changed anti-HIV medications because they stopped 
working, and who do not have a history of resistance to CAB or RPV. 
 
The following serious effects may occur with the use of CAB: 
• 
Hypersensitivity reactions. This is a type of allergic reaction that may start as a rash. If you 
develop a rash while taking CAB, contact your study doctor right away, especially if you also 
have: 
o Blisters or peeling skin 
o Fever 
o General ill feeling 
o Extreme tiredness 
o Muscle or joint pain 
o Blisters or sores in your mouth 
o Redness of the eyes 
o Swelling around your eyes, face, mouth, lips, or tongue 
o Trouble breathing 
• 
Liver problems. Contact your study doctor right away if you have any of the following 
possible symptoms of a liver problem: 
o Yellowing of your skin or of the whites of your eyes (jaundice) 
o Dark or tea-colored urine 
o Pale colored stools 
o Nausea (feeling sick to your stomach) or vomiting 
o Loss of appetite 
o Pain, aching, or tenderness on your right side, below your ribs 
• 
Depression, suicide attempts, or suicide, especially in people with pre-existing history of 
depression or other mental health problems. If your mental health problems worsen or if you 
develop suicidal thoughts, call your study doctor right away. 
• 
Seizures/convulsions: If you have a history of seizures at any point in your life, please let 
your study doctor know. 
 
Additional side effects include: 
• 
Headache 
• 
Upper respiratory tract infection. Symptoms may include 
o Sore throat 
o Cough 
o Runny nose 
o Fever 
o Trouble breathing 
• 
Fever 
• 
Fatigue (feeling tired) 
• 
Nausea 
• 
Diarrhea 
• 
Lack of energy or weakness 
• 
Abdominal pain and discomfort 
• 
Back pain 

 
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• 
Trouble sleeping 
• 
Abnormal dreams 
• 
Dizziness 
• 
Joint aches and pains 
• 
Muscle pain and/or breakdown of muscles 
• 
Abnormal liver blood tests 
• 
Increase in the level of enzymes produced in the muscles (creatine phosphokinase) 
 
General Side Effects of Injections Long-Acting Medications 
The injections you receive in this study are long acting, meaning they stay in your body for a 
long time. Following an injection of CAB-LA or RPV-LA, the study drugs stay in your body for 
months. In some people, low levels of CAB and RPV may be present in your body for more than 
a year. If you develop a side effect to CAB-LA or RPV-LA after the injection there will be no way 
to remove the study drug from your body. You may be taking these study drugs as tablets first, 
which stay in the body for a shorter amount of time. This will help the study staff understand if 
you would have problems with the study drugs when received as an injection. 
 
If you develop a symptom from these study drugs, every effort to treat the symptoms will be 
made. The amount of study drug will decrease overtime and will eventually disappear.  
 
During the time that study drug is leaving your body, your HIV virus could develop resistance 
(stop working) to these study drugs, even if it is many weeks or months since you last took the 
study drug. When discontinuing long-acting HIV treatment, it will be very important to start 
taking other HIV drugs, as recommended by your study or regular doctor, to help prevent your 
HIV from developing resistance to HIV drugs. 
 
Injection Site Reactions: 
Side effects at the location where you received injections (termed Injection Site Reactions) been 
seen with both CAB-LA and RPV-LA. Common side effects could include: 
• 
Pain or redness, swelling, itching, bruising, lumps, and irritation where you receive the 
injection(s). Most reactions resolve in a week or less.  
• 
The injections that you receive will be given to you in the muscles of your buttocks (gluteal 
muscle).  
 
Other Possible Injection Complications:  
The injections will be given in the muscles of your buttocks (“bottom” or “cheeks”). It is possible 
that the person giving you your injection could accidentally give the injection too deeply or not 
deeply enough, missing the muscle and entering your skin, blood stream or a nerve. The risks 
of injecting a long-acting drug outside of the muscle are not well understood, but could include 
having drug levels that are either too low or too high. The risk of having levels that are too low is 
that the study drug may not work against your HIV virus. The risks of having high levels of CAB 
in your body are not well known. The risk of having high levels of RPV in your body are not well 
known, but one possible risk could include a change in your heart beat, which in severe cases 
can be life-threatening. In rare cases, symptoms such as feeling lightheaded, numbness or 
tingling, difficulty breathing, chest or stomach discomfort, sweating, nausea, and/or feeling 

 
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anxious have occurred after an injection with RPV-LA. In these cases, high blood levels of RPV 
have been observed, which may be due to an accidental injection of part of the drug into a blood 
vessel instead of the muscle. Not all people in whom an accidental injection in a blood vessel 
was suspected reported such symptoms. Most of the symptoms resolved within minutes. Your 
study doctor may need to administer treatment to help resolve these symptoms. Every 
precaution will be taken to ensure that the correct size needle and injection technique is used to 
reduce these risks. You will also be monitored for safety events during the study. If your study 
doctor is concerned that the injection was not given correctly, he or she may ask you to stay in 
the clinic up to 2 hours after the injection to monitor how you are doing and may order tests to 
monitor your safety. If you are concerned about this risk, speak to your study doctor. 
 
After receiving RPV-LA injectable, the study drug may be found in the body for longer than a 
year (longer than 12 months). This means you also may have study drug in your body for longer 
than a year after the last injection. No safety issues are expected with this. We don’t know when 
all of the study drug will completely leave your body. We do know that levels of the study drug in 
your body slowly decrease over time and we know that some people still have low levels of 
study drug in their body a year or longer after receiving the last injection. You have to keep 
taking the study treatment to avoid that the virus becomes resistant to RPV due to low RPV 
plasma concentrations, and other types of HIV medications would have to be used to treat your 
HIV infection. 
 
Receiving injections can cause some people to feel lightheaded or feel like they might pass out. 
Fainting can also occur. This reaction, called a “vasovagal reaction”, has been reported with 
other injectable medicines, and resolves quickly. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
You should not take part in this study if you are pregnant or intend to become pregnant in the 
next 4 years. Mothers should not breastfeed a baby while on this study. The drugs used in this 
study may be unsafe for unborn babies. If you are having sex that could lead to pregnancy, you 
must agree not to become pregnant. If you are a participant who can get pregnant, you must 
talk to your study doctor about birth control and use it all of the time. You must continue to use 
birth control until 30 days after stopping your oral anti-HIV study drugs and 52 weeks after 
stopping your injectable anti-HIV study drugs (for example, 52 weeks after receiving the last 
dose of injectable anti-HIV study drug).  
 
You must choose one of the birth control methods listed below: 
• 
Contraceptive subdermal implant 
• 
Intrauterine device or intrauterine system 
• 
Combined estrogen and progestogen oral contraceptive 
• 
Injectable progestogen  
• 
Contraceptive vaginal ring  
• 
Percutaneous contraceptive patches  
 

 
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If you can become pregnant, you must have a pregnancy test before you enter this study. The 
test must show that you are not pregnant. If you think you may be pregnant at any time during 
the study, tell your study staff right away. If you become pregnant while on study, the study staff 
will talk to you about your choices.    
 
If you become pregnant at any time during the study, tell your study staff right away. You may 
need to change your study treatment, but continue your study visits. If you choose to continue 
on in the study you will need to sign and date the pregnancy informed consent attached to this 
main consent. Pregnancies will be reported to the antiretroviral pregnancy registry at 
http://www.apregistry.com. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you take part in this study, there may be a direct benefit to you, but no guarantee can be 
made. It is also possible that you may receive no benefit from being in this study. Information 
learned from this study may help others who have HIV. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study you have the choice of: 
• 
Treatment with other prescription drugs available to you 
• 
Treatment with experimental drugs, if you qualify  
• 
No treatment 
 
On January 21, 2021, oral CAB used in combination with oral RPV for 1 month followed by 
monthly injectable CAB and RPV were approved by the US Food and Drug Administration for 
use in people with HIV who are well-controlled (consistently less than 50 copies/mL) on an oral 
anti-HIV regimen, and who have never changed anti-HIV medications because they stopped 
working. On March 24, 2022, the oral CAB and oral RPV 1-month lead-in was made 
optional. 
 
Please talk to your study doctor about these and other choices available to you. Your study 
doctor will explain the risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
We will do everything we can to protect your privacy. Some of the questionnaires you will 
complete while in this study reveal very personal information about your mental health and 
substance use.  Study staff will do all they can to keep your information private, but if you want 
referral for treatment or study staff feel referral to other providers for treatment of these 
conditions is necessary, some of the information may need to be shared with these other 
providers. In addition to the efforts of the study staff to help keep your personal information 

 
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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.  
 
People who may review your records include the ACTG, Office for Human Research Protections 
(OHRP) or other local, US, and international regulatory entities as part of their duties, Food and 
Drug Administration (FDA), (insert name of site) institutional review board (IRB) (a committee 
that protects the rights and safety of participants in research), National Institutes of Health 
(NIH), study staff, study monitors, drug companies supporting this study, and their designees. 
Having a 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 
including a clinical provider if indicated. 
 
A description of this clinical trial will be available on https://ClinicalTrials.gov, as required by US 
Law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site 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. The anti-HIV study drugs (oral and injectable) will be provided to 
you by the study. 
 
 
WILL I RECEIVE ANY PAYMENT? 
 
You will be compensated for taking part in this study. You will be compensated (insert amount of 
site specific visit compensation) for attending each one of your study visits. During the induction 
phase (first 20 weeks) you will be compensated additionally if you achieve certain VL 
“milestones” as follows: 
 
Compensation 
 
Step 1, Week 
Milestone 
Incentive 
2 
Completed visit (in person or virtual during the 
COVID-19 pandemic restrictions) 
$75.00 
4 
If you have a ten-fold decrease (for example from 
1000 copies to 100 copies) in your HIV VL from 
entry visit or HIV VL less than or equal to 200 
$75.00 

 
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Step 1, Week 
Milestone 
Incentive 
copies/mL or completed a virtual visit during the 
COVID-19 pandemic restrictions 
8 (if needed) 
If you have a 100-fold decrease in your HIV-1 VL 
from entry visit (for example from 10,000 copies to 
100 copies) or HIV-1 VL less than or equal to 200 
copies/mL or completed virtual visit during the 
COVID-19 pandemic restrictions 
$75.00 
12 (if needed) 
HIV-1 RNA less than or equal to 200 copies/mL or 
completed virtual visit during the COVID-19 
pandemic restrictions 
$150.00* 
16 (if needed) 
HIV-1 RNA less than or equal to 200 copies/mL or 
completed virtual visit during the COVID-19 
pandemic restrictions 
$150.00* 
20 (if needed) 
or  
Confirmation Viral load 
after week 20 (but prior 
to week 24) 
HIV-1 RNA less than or equal to 200 copies/mL  
$150.00 
Additional Continuity 
Visits during the COVID-
19 pandemic (only 
applicable if in person 
visits are not permitted 
by your research site) 
HIV-1 RNA less than or equal to 200 copies/mL or 
completed virtual visit  
$150.00 
 
* NOTE: If you are virally suppressed (less than or equal to 200 copies/mL) at week 4, 8, 12 or 
week 16, you will be eligible for randomization into Step 2 and will not continue further visits in 
Step 1. You will additionally receive the CEI that would have been distributed at the later Step 1 
visits. For example, if your HIV VL is less than or equal to 200 copies/mL at Step 1, week 12, 
the CEI for week 12+16+20 ($450) will be disbursed at that time and you will proceed to Step 2 
randomization; or if you meet the HIV VL criteria at Step 1, week 16, the CEI for week 16+20 
($300) will be disbursed at that time and you will proceed to Step 2 randomization. 
 
If you do not achieve the milestones, you will not receive conditional economic incentives (you 
will still receive the usual compensation given for attending your study visit) but you will be 
allowed to continue on the study and you may be eligible for the next financial compensation 
(for example, you may not qualify to compensation at Step 1, week 4, but you could still receive 
conditional economic incentives at Step 1, weeks 8, 12, 16, and/or 20, based on these 
milestones). The conditional economic incentives will stop once you achieved HIV VL equal to 
or less than 200 copies/mL. 
 
The total financial reimbursement (compensation for completing all study visits and conditional 
economic incentives for reaching all “milestones” during the first 20 weeks) of the study is (insert 
sum of site specific visit compensations + $675). 

 
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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. The cost for this treatment will be charged to you or your insurance company. 
 
[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. 
• 
There is no program for compensation through the US National Institutes of 
Health, but 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.  
OR 
• 
There is no program for compensation either through this institution or the US 
National Institutes of Health.] 
  
You will not be giving up any of your legal rights by signing and dating 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 
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. 
 
 
WHOM TO CONTACT ABOUT THIS STUDY 
 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns or complaints about the study, please contact the study doctor at the 
telephone number listed on the first page of this consent document. If you seek emergency 
care, or hospitalization is required, alert the treating physician that you are participating in this 
research study.  
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research participants. If you have any questions about your rights as a research 
participant, and/or concerns or complaints regarding this research study, contact: 
 
• 
By mail: 
Study Subject Adviser 

 
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Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
• 
Or call toll free:    877-992-4724 
• 
Or by email:          adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: 
Pro00041207. 

 
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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 and date 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 SIGNATURE FOR PARTICIPANTS WHO CANNOT READ   
The study subject has indicated that he/she is unable to read.  The consent document has been 
read to the subject by a member of the study staff, discussed with the subject by a member of 
the study staff, and the subject has been given an opportunity to ask questions of the study 
staff.    
 
 
 
____________________________ 
__________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 
 
 
 

 
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ATTACHMENT 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. Your samples will never be used for commercial profit. 
 
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 study 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 
 

 
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OR 
____ (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 another study that collects samples for genetic testing. If you live in the US, this 
study is called ACTG A5128, Plan for Obtaining Informed Consent to Use Stored Human 
Biological Materials (HBM) for Currently Unspecified 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 and date a separate consent form. 
 
 

 
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APPENDIX II: INFORMED CONSENT FOR PARTICIPANTS WHO BECOME PREGNANT 
WHILE ON STUDY 
 
INTRODUCTION 
 
Because you are now pregnant, you are being asked if you want to continue taking part in this 
research study. This study was designed so that participants who were pregnant could not join 
the study. However, because you were already in the study when you became pregnant, you 
will be allowed to stay in the study and come for the same study visits whether or not you 
continue study treatment during your pregnancy.  
 
This is a consent form. It gives you more information about how continuing on this study may 
affect your pregnancy and your baby. The research staff will talk with you about this information. 
You may also talk with your own doctor about what is best for you and your baby, if you should 
remain on study-provided anti-HIV drugs, or choose other anti-HIV drugs. If you agree to stay in 
this study, you will be asked to sign and date this consent form. You will get a copy to keep. You 
are free to ask questions of the study staff at any time. 
 
 
WHAT DO I HAVE TO DO IF I STAY IN THIS STUDY? 
 
If you stay in this study, you will continue to be followed as described above. You may choose to 
stay on the anti-HIV study drugs provided through the study, or you may receive a different anti-
HIV regimen from your own doctor. You will continue to come for regularly scheduled study 
visits, however, you will not be required to fast for any visits.  
 
If you become and remain pregnant during Step 1, you will be followed on study until Step 1, 
week 24, but will not be eligible to enroll into Step 2.  
 
If you become pregnant during Step 2 Study Group A or Step 3 and already received at least 
one dose of RPV-LA + CAB-LA injection, you will be able to continue study treatment if you 
choose after discussing with your study doctor. If you decide to continue, you will be permitted 
to move onto the next study step upon completion of your current step. 
 
If you are in Step 2 Study Group A or Step 3 and become pregnant while receiving oral CAB + 
RPV but have not received yet any CAB-LA/RPV-LA injection, you will discontinue study 
treatment and will need a new regimen. You can remain on study but will not enroll into the next 
study step. 
 
If you become pregnant while in Step 2 Study Group B, you can remain on study until Step 2, 
week 52, but will complete the study at that time. You will not be eligible to start Step 3 if you 
are pregnant at the time of your Step 3 registration visit.  
 
This study will not provide care related to your pregnancy, the delivery of your baby, or the care of 
your baby. You must arrange care for yourself and your baby outside of this study. The study staff 
would like to obtain information from you about the outcome of the pregnancy (even if it is after 

 
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your participation in the study ends). If you are taking anti-HIV drugs when you become pregnant, 
your pregnancy will be reported to an international database that collects information about 
pregnancies in people taking anti-HIV drugs. This report will not use your name or other 
information that could be used to identify you. 
 
Study visits may be conducted remotely (for example, telephone, telehealth) if you are unable to 
attend a visit because of illness, inability to travel, concerns for potential exposure to COVID-19, 
or the clinic is temporarily unable to conduct non-essential visits in the clinic. 
 
Stored whole blood and plasma will not be collected for participants who become and remain 
pregnant during the study. 
 
 
WHAT ARE THE RISKS RELATED TO STAYING IN THE STUDY? 
 
Now that you are pregnant, there are some possible risks you should know. These possible 
risks to you and your baby are in addition to the risks that are described above. 
 
Risks to You if You Stay on Anti-HIV Drugs 
All HIV treatment guidelines recommend that pregnant individuals with HIV should take HIV 
drugs during pregnancy for their own health and to prevent perinatal transmission of HIV.  
Different side effects or more severe side effects may occur in pregnant individuals taking anti-
HIV drugs. This may make it more difficult for the drugs to work on the HIV in your blood. The 
amount of anti-HIV drugs in the blood may change during pregnancy. This means that the 
amounts of anti-HIV drugs in your blood may decrease and not work as well or cause the HIV to 
become resistant to the drugs. It will be important to follow up closely with your doctor to ensure 
your virus is still under control.  
 
You and your study doctor will decide whether you will stay on your study treatment or whether 
you will change to a different drug provided by the study doctor.  
 
We do not know if the use of injectable cabotegravir (CAB) or injectable rilpivirine (RPV) will 
increase the risk of birth defects, stillbirth, or miscarriage. In one study evaluating CAB in 
pregnant rats and their newborn pups, there was a higher rate of pups that died at the time of 
delivery or shortly after delivery in the rats that received a 1000 milligram per kilogram dose of 
CAB compared to pregnant rats who did not receive CAB. This finding did not occur in pregnant 
rats who received two lower doses (0.5 and 5 milligrams per kilogram) of CAB. The blood levels 
of CAB given in this study are expected to be lower than the blood levels in pregnant rats where 
this finding was observed. In another study, CAB was administered orally to pregnant rabbits at 
0, 30, 500, or 2000 mg/kg/day from Gestation Days 7 to 19. No drug-related fetal toxicities were 
observed. The significance of this finding on human pregnancies is not known. Birth defects 
have not been observed in animal studies with CAB, to date. 
  
Based on reports to a registry collecting outcomes of 390 participants of child-bearing 
potential exposed to oral (pill-version) RPV during the first trimester of pregnancy, and over 
170 during second/third trimester of pregnancy, the rate of birth defects was lower than 

 
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compared to the expected rate of birth defects in the US (1.3% versus 2.27%).  
 
Breastfeeding 
It is unknown whether the study drug passes through breast-milk and may cause harm to your 
infant. You must not breast-feed if you are in this study. 
 
 
ARE THERE BENEFITS TO STAYING IN THIS STUDY? 
 
Use of combination anti-HIV drugs during pregnancy significantly decreases the chance that the 
baby will get HIV during pregnancy. However, you can also continue to receive anti-HIV drugs 
from your provider. If you continue to take part in this study, no guarantee can be made of a 
benefit to you or your baby. It is possible that you and your baby will receive no benefit from 
continuing in this study. Information learned from this study may help others who have HIV.  
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES STAYING ON STUDY DRUGS? 
 
Instead of staying on the study drugs you have the choice of: 
 
• 
Treatment with prescription medicines available to you 
• 
Treatment with experimental drugs being studied for use during pregnancy, if you qualify  
• 
No treatment 
 
Please talk to your study doctor about these and other choices available to you.  Your study 
doctor will explain the risks and benefits of these choices.   
 
 
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 received 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.   
 
People who may review your records include the ACTG, FDA, (insert name of site) IRB, OHRP, 
National Institutes of Health (NIH), study staff, study monitors, drug companies supporting this 
study and their designees, and other local, US, and international regulatory entities. Having a 
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. 

 
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WHAT ARE THE COSTS TO ME? 
 
In addition to any costs that are described above, this study will not cover any cost related to 
your pregnancy, delivery of your baby, or care of your baby.    
 
 
WILL I RECEIVE ANY PAYMENT? 
 
If you continue your study visits, you will continue to be compensated for study visits as outlined 
above.  
 
 
WHAT HAPPENS IF MY BABY OR I AM INJURED? 
 
If your baby or you are injured as a result of being in this study, you will both be given 
immediate treatment for your injuries. The cost for this treatment will be charged to you or your 
insurance company.  
 
[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. 
• 
There is no program for compensation through the US National Institutes of 
Health, but 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.  
OR 
• 
There is no program for compensation either through this institution or the US 
National Institutes of Health.] 
 
You will not be giving up any of your legal rights by signing and dating this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Continuing to take part in this study after you become pregnant (and at any time) is completely 
voluntary. You may choose not to continue in this study or leave this study at any time. Your 
decision will not have any impact on your participation in other studies conducted by NIH and 
will not result in any penalty or loss of benefits to which you are otherwise entitled. You will be 
treated the same no matter what you decide. 
 
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. 
 
 
 

 
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SIGNATURE PAGE 
 
If you have read this consent form (or had it explained to you), all of your questions have been 
answered, and you agree to take part in this pregnancy follow up, please sign and date 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 SIGNATURE FOR PARTICIPANTS WHO CANNOT READ   
The study participant has indicated that he/she is unable to read.  The consent document has 
been read to the participant by a member of the study staff, discussed with the participant by a 
member of the study staff, and the participant has been given an opportunity to ask questions of 
the study staff.  
 
 
 
____________________________ 
__________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate)