A Phase 3, Double-Blind, Multicenter, Randomized Study to Evaluate the Efficacy and Safety of Subcutaneous Twice Yearly Long-Acting Lenacapavir for HIV Pre-Exposure Prophylaxis in Cisgender Men, Transgender Women, Transgender Men, and Gender Nonbinary People ≥ 16 Years of Age Who Have Sex With Male Partners and Are at Risk for HIV Infection
Phase: PHASE3
Conditions: Pre-Exposure Prophylaxis of HIV Infection
Sponsor: Gilead Sciences

CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3, Double-Blind, Multicenter, Randomized Study to 
Evaluate the Efficacy and Safety of Subcutaneous Twice Yearly 
Long-Acting Lenacapavir for HIV Pre-Exposure Prophylaxis in 
Cisgender Men, Transgender Women, Transgender Men, and 
Gender Nonbinary People ≥ 16 Years of Age who Have Sex with 
Male Partners and are at Risk for HIV Infection 
Study Acronym: 
PURPOSE 2
Plain Language Short 
Title:
Pre-Exposure Prophylaxis Study of Lenacapavir in Cisgender Men, 
Transgender Women, Transgender Men, and Gender Nonbinary 
People at Risk for HIV Infection
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
153858
Not Applicable
NCT04925752
Population Diagnosis 
or Condition:
Pre-Exposure Prophylaxis of HIV Infection
Protocol ID:
GS-US-528-9023
Contact Information:
The medical monitor name and contact information will be 
provided on the Key Study Team Contact List.
Protocol Version/Date:
Amendment 4: 
21 October 2024
Amendment History::
Original: 
01 March 2021
Original Version 2:
10 March 2021
Amendment 1:
08 June 2021
Amendment 2: 
31 January 2022
Amendment 3: 
25 October 2023
High-level summaries of the histories of amendments are provided 
in Appendix 8.
Country-specific 
Requirements:
Country-specific requirements, as applicable, are listed in 
Appendix 7. 
GILEAU 

This study will be conducted under United States Food and Drug Administration investigational 
new drug (IND) regulations (21 Code of Federal Regulations Part 312).
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
institutional review board or independent ethics committee. The information is only to be used 
by you in connection with authorized clinical studies of the investigational drug described in 
the protocol. You will not disclose any of the information to others without written 
authorization from Gilead Sciences, Inc., except to the extent necessary to obtain informed 
consent from those persons to whom the drug may be administered.

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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................................3
LIST OF IN-TEXT TABLE ...........................................................................................................................................7
LIST OF IN-TEXT FIGURES........................................................................................................................................8
PROTOCOL SYNOPSIS................................................................................................................................................9
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................................27
1.
INTRODUCTION................................................................................................................................................32
1.1.
Background..............................................................................................................................................32
1.2.
Study Drugs.............................................................................................................................................33
1.2.1.
Emtricitabine/Tenofovir Disoproxil Fumarate (F/TDF; Truvada)........................................33
1.2.2.
Emtricitabine/Tenofovir Alafenamide (F/TAF; Descovy)....................................................33
1.2.3.
Lenacapavir ...........................................................................................................................33
1.2.4.
Nonclinical Studies in Pregnancy or Lactation .....................................................................70
1.2.5.
Human Studies in Pregnancy.................................................................................................71
1.2.6.
Human Studies in Lactation ..................................................................................................73
1.2.7.
Drug-Interaction Potential for F/TDF and LEN with Hormones ..........................................74
1.3.
Rationale for This Study..........................................................................................................................76
1.4.
Rationale for Dose Selection of Study Drugs..........................................................................................77
1.5.
Rationale for Oral Weekly Bridging of Lenacapavir for Missed SC Injection.......................................80
1.6.
Risk/Benefit Assessment for the Study ...................................................................................................82
1.6.1.
Pandemic Risk and Mitigation ..............................................................................................83
1.7.
Compliance..............................................................................................................................................83
2.
OBJECTIVES.......................................................................................................................................................84
2.1.
Incidence Phase Objectives .....................................................................................................................84
2.2.
Randomized Blinded Phase Objectives...................................................................................................84
3.
STUDY DESIGN.................................................................................................................................................86
3.1.
Incidence Phase Endpoints......................................................................................................................86
3.2.
Randomized Blinded Phase Endpoints....................................................................................................86
3.3.
Study Design ...........................................................................................................................................87
3.3.1.
Incidence Phase .....................................................................................................................88
3.3.2.
Randomized Blinded Phase...................................................................................................88
3.3.3.
Lenacapavir Open-Label Extension Phase............................................................................88
3.3.4.
Pharmacokinetic Tail Phase ..................................................................................................89
3.3.5.
Discontinuation Criteria ........................................................................................................90
3.4.
Study Drugs.............................................................................................................................................91
3.5.
Duration of Study Drug Administration..................................................................................................91
3.6.
End of Study............................................................................................................................................92
3.7.
Poststudy Care.........................................................................................................................................92
3.8.
Source Data .............................................................................................................................................92
3.9.
Biomarker Testing...................................................................................................................................92
4.
PARTICIPANT POPULATION..........................................................................................................................93
4.1.
Number of Participants and Participant Selection...................................................................................93
4.1.1.
Participant Replacement........................................................................................................93
4.2.
Eligibility Criteria for the Incidence Phase .............................................................................................94
4.2.1.
Inclusion Criteria for the Incidence Phase.............................................................................94
4.2.2.
Exclusion Criteria for the Incidence Phase ...........................................................................94
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4.3.
Eligibility Criteria for the Randomized Blinded Phase...........................................................................95
4.3.1.
Inclusion Criteria for the Randomized Blinded Phase ..........................................................95
4.3.2.
Exclusion Criteria for the Randomized Blinded Phase .........................................................95
5.
INVESTIGATIONAL MEDICINAL PRODUCTS.............................................................................................97
5.1.
Randomization, Blinding, and Treatment Codes Access ........................................................................97
5.1.1.
Randomization.......................................................................................................................97
5.1.2.
Blinding .................................................................................................................................97
5.1.3.
Planned Interim Unblinding ..................................................................................................98
5.1.4.
Procedures for Breaking Treatment Codes............................................................................98
5.2.
Description and Handling of Study Drugs ..............................................................................................99
5.2.1.
Formulation ...........................................................................................................................99
5.2.2.
Packaging and Labeling ......................................................................................................100
5.2.3.
Storage and Handling ..........................................................................................................100
5.3.
Dosage and Administration of Study Drugs..........................................................................................101
5.3.1.
Lenacapavir .........................................................................................................................101
5.3.2.
Emtricitabine/Tenofovir Disoproxil Fumarate (F/TDF) .....................................................103
5.3.3.
Emtricitabine/Tenofovir Alafenamide (F/TAF)..................................................................103
5.4.
Prior and Concomitant Medications......................................................................................................103
5.5.
Accountability for Investigational Medicinal Product ..........................................................................107
5.5.1.
Investigational Medicinal Product Return or Disposal .......................................................107
6.
STUDY PROCEDURES....................................................................................................................................108
6.1.
Participant Enrollment and Study Drug Assignment ............................................................................108
6.2.
Screening Assessments..........................................................................................................................108
6.2.1.
Incidence Phase Screening ..................................................................................................110
6.2.2.
Randomized Blinded Phase Screening................................................................................111
6.3.
Randomized Blinded Phase Assessments .............................................................................................113
6.3.1.
Day 1/Injection 1 .................................................................................................................113
6.3.2.
Weeks 4 and 8 (± 2 days) and Weeks 13, 26/Injection 2, 39, 52, and 
Every 13 Weeks (± 7 days) Until the End of Randomized Blinded Phase 
Visit .....................................................................................................................................115
6.4.
LEN Open-Label Extension Phase Assessments Day 1, Weeks 4 and 8 (± 2 days), and Weeks 
13, 26, 39, 52, and every 13 weeks thereafter .......................................................................................118
6.5.
Pharmacokinetic Tail Phase Assessments Day 1 and Weeks 13, 26, 39, 52, 65, and 78 (± 7 
days) ......................................................................................................................................................121
6.6.
Unscheduled Visits................................................................................................................................123
6.7.
Post-Study Drug Assessments...............................................................................................................123
6.7.1.
Early Study Drug Discontinuation Visit..............................................................................123
6.7.2.
30-Day Follow-Up Visit......................................................................................................125
6.7.3.
Post-HIV-Infection Follow-Up ...........................................................................................127
6.8.
Assessments for Study Drug Interruptions............................................................................................128
6.8.1.
Criteria for Restarting F/TDF or F/TDF Placebo After an Interruption..............................128
6.8.2.
Criteria for Administering SC LEN Outside of the Target Visit Window 
(26 weeks ± 7 days).............................................................................................................128
6.8.3.
Bridging With Oral LEN/Placebo .......................................................................................129
6.9.
Clinical Laboratory Assessments ..........................................................................................................131
6.9.1.
Urine Samples .....................................................................................................................131
6.9.2.
Blood Samples.....................................................................................................................131
6.10.
End of Study..........................................................................................................................................132
6.11.
Poststudy Care.......................................................................................................................................133
6.12.
STI Testing ............................................................................................................................................133
6.13.
Diagnosis of HIV-1 Infection................................................................................................................133
6.13.1.
Suspected Acute HIV-1 Infection/Postexposure Prophylaxis.............................................136

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6.14.
HIV Risk Reduction Counseling...........................................................................................................137
6.15.
Adherence and Retention ......................................................................................................................137
6.16.
Participant-Reported Questionnaires.....................................................................................................137
6.17.
Pregnancy ..............................................................................................................................................139
6.18.
Social Harms Reporting ........................................................................................................................139
6.19.
Sample Storage......................................................................................................................................139
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT..............................................................................140
7.1.
Definitions of Adverse Events and Serious Adverse Events.................................................................140
7.1.1.
Adverse Events....................................................................................................................140
7.1.2.
Serious Adverse Events.......................................................................................................141
7.1.3.
Study Drugs and Gilead Concomitant Therapy Special Situations Reports .......................141
7.2.
Assessment of Adverse Events and Serious Adverse Events................................................................142
7.2.1.
Assessment of Causality for Study Drugs and Procedures .................................................142
7.2.2.
Assessment of Severity........................................................................................................143
7.3.
Investigator Reporting Requirements and Instructions .........................................................................143
7.3.1.
Requirements for Collection Prior to Study Drug Initiation ...............................................143
7.3.2.
Adverse Events....................................................................................................................143
7.3.3.
Serious Adverse Events.......................................................................................................143
7.3.4.
Study Drug Special Situations Reports ...............................................................................144
7.3.5.
Concomitant Therapy Reports.............................................................................................144
7.4.
Reporting Process for Serious Adverse Events and Special Situation Reports.....................................144
7.4.1.
Serious Adverse Event Reporting Process ..........................................................................144
7.4.2.
Special Situations Reporting Process ..................................................................................145
7.5.
Gilead Reporting Requirements ............................................................................................................148
7.6.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events.........................................................................................................................148
7.7.
Toxicity Management............................................................................................................................149
7.7.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event ................................................149
7.7.2.
Grades 3 Laboratory Abnormality or Clinical Event ..........................................................149
7.7.3.
Grade 4 Laboratory Abnormality or Clinical Event............................................................149
7.7.4.
Management of Changes in Estimated Glomerular Filtration Rate ....................................150
7.7.5.
Management of Adverse Events of Injection Site Reactions of Grade 3 or 
Higher or Persisting for More Than 26 Weeks ...................................................................150
8.
STATISTICAL CONSIDERATIONS...............................................................................................................151
8.1.
Analysis Objectives and Endpoints.......................................................................................................151
8.1.1.
Analysis Objectives.............................................................................................................151
8.1.2.
Primary Endpoint.................................................................................................................152
8.1.3.
Secondary Endpoints...........................................................................................................152
8.2.
Planned Analyses...................................................................................................................................153
8.2.1.
Interim Analyses..................................................................................................................153
8.2.2.
Primary Analysis .................................................................................................................154
8.2.3.
Final Analysis......................................................................................................................154
8.3.
Analysis Conventions............................................................................................................................154
8.3.1.
Analysis Sets .......................................................................................................................154
8.3.2.
Data Handling Conventions ................................................................................................154
8.4.
Demographic and Baseline Characteristics Analysis............................................................................155
8.5.
Efficacy Analysis...................................................................................................................................155
8.5.1.
Primary Analysis .................................................................................................................155
8.5.2.
Secondary Analyses.............................................................................................................157
8.6.
Safety Analysis......................................................................................................................................158
8.6.1.
Extent of Exposure ..............................................................................................................158
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8.6.2.
Adverse Events....................................................................................................................159
8.6.3.
Laboratory Evaluations .......................................................................................................159
8.6.4.
Renal Safety.........................................................................................................................159
8.6.5.
Other Safety Evaluations.....................................................................................................159
8.7.
Adjustments for Multiplicity .................................................................................................................160
8.8.
Pharmacokinetic Analysis .....................................................................................................................160
8.9.
Sample Size ...........................................................................................................................................160
8.10.
Data Monitoring Committee..................................................................................................................161
9.
RESPONSIBILITIES.........................................................................................................................................163
9.1.
Investigator Responsibilities .................................................................................................................163
9.1.1.
Good Clinical Practice.........................................................................................................163
9.1.2.
Financial Disclosure ............................................................................................................163
9.1.3.
Institutional Review Board/Independent Ethics Committee Review and 
Approval..............................................................................................................................163
9.1.4.
Informed Consent ................................................................................................................163
9.1.5.
Confidentiality.....................................................................................................................164
9.1.6.
Study Files and Retention of Records .................................................................................164
9.1.7.
Electronic Case Report Forms.............................................................................................166
9.1.8.
Investigator Inspections.......................................................................................................166
9.1.9.
Protocol Compliance ...........................................................................................................166
9.2.
Sponsor Responsibilities .......................................................................................................................166
9.2.1.
Protocol Modifications ........................................................................................................166
9.2.2.
Study Report and Publications ............................................................................................167
9.3.
Joint Investigator/Sponsor Responsibilities ..........................................................................................167
9.3.1.
Payment Reporting ..............................................................................................................167
9.3.2.
Access to Information for Monitoring.................................................................................167
9.3.3.
Access to Information for Auditing or Inspections .............................................................167
9.3.4.
Study Discontinuation .........................................................................................................167
10.
REFERENCES...................................................................................................................................................168
11.
APPENDICES....................................................................................................................................................177
Appendix 1.
Investigator Signature Page...................................................................................................178
Appendix 2.
Pandemic Risk Assessment and Mitigation Plan ..................................................................179
Appendix 3.
Study Procedures Table.........................................................................................................182
Appendix 4.
Management of Clinical and Laboratory Adverse Events.....................................................195
Appendix 5.
HIV Testing Algorithms........................................................................................................196
Appendix 6.
Randomized Blinded Phase Pregnancy Precautions, Definition Childbearing 
Potential for Participants Assigned Female at Birth, and Contraceptive 
Requirements.........................................................................................................................199
Appendix 7.
Country-Specific Requirements ............................................................................................203
Appendix 8.
Amendment History ..............................................................................................................207

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LIST OF IN-TEXT TABLE
Table 1.
Comparison of LEN and GS-CA1...........................................................................................37
Table 2.
GS-US-200-4071: LEN Formulations and Doses Evaluated ..................................................39
Table 3.
GS-US-200-4071: Plasma Pharmacokinetic Parameters of LEN Following Single-
Dose Oral Administration of 50 mg/mL Solution in Capsule (N = 8 per Cohort)..................40
Table 4.
GS-US-200-4071: Plasma Pharmacokinetic Parameters of LEN Following Multiple-
Dose Oral Administration of 30 mg and 100 mg Solution in Capsule (50 mg/mL) 
(N = 8 per Cohort) ...................................................................................................................41
Table 5.
GS-US-200-4071: Plasma Pharmacokinetic Parameters Following Single-Dose Oral 
Administration of LEN Tablets, Fasted, or Following a High- or Low-Fat Meal 
(N = 8 per Cohort) ...................................................................................................................43
Table 6.
GS-US-200-4538: Solution Formulations and Doses .............................................................45
Table 7.
GS-US-200-4538: Summary Statistics of Plasma Pharmacokinetic Parameters LEN, 
309 mg/mL NaS (LEN PK Analysis Set)................................................................................46
Table 8.
GS-US-200-4538: Adverse Events Reported for at Least 4 Participants in Either 
Overall Treatment Group (Safety Analysis Set)......................................................................48
Table 9.
GS-US-200-5709: Summary Statistics of LEN Plasma Pharmacokinetic Parameters 
(Cohort 1) (LEN PK Analysis Set)..........................................................................................49
Table 10.
GS-US-200-5709: Summary Statistics of LEN Plasma Pharmacokinetic Parameters 
(Cohort 2) (LEN PK Analysis Set)..........................................................................................50
Table 11.
GS-US-200-5709: Summary Statistics of LEN Plasma Pharmacokinetic Parameters 
(Cohort 3) (LEN PK Analysis Set)..........................................................................................52
Table 12.
GS-US-200-4333: Preliminary Plasma Pharmacokinetic Parameters of LEN 300 mg 
Oral Capsule Following Administration Alone or with DRV/COBI (800/150 mg 
QD) or COBI (150 mg QD) (N = 29-30 per Cohort) ..............................................................54
Table 13.
GS-US-200-4333: Preliminary Plasma Pharmacokinetic Parameters of LEN 300 mg 
Tablet Following Administration Alone or with RIF (600 mg QD) or FAM (40 mg) 
(N = 25-27 per cohort).............................................................................................................55
Table 14.
GS-US-200-4333: Preliminary Plasma Pharmacokinetic Parameters of PIT (2 mg) 
Following Administration Alone or With LEN (N = 30-31)...................................................56
Table 15.
GS-US-200-4333: Preliminary Plasma Pharmacokinetic Parameters of ROS (5 mg) 
Following Administration Alone or With LEN (N = 30)........................................................56
Table 16.
GS-US-200-4333: Preliminary Plasma Pharmacokinetic Parameters of TAF (25 mg) 
and its Metabolite, TFV, Following Administration Alone or With LEN (N = 28-30) ..........57
Table 17.
GS-US-200-4333: Preliminary Plasma Pharmacokinetic Parameters of MDZ 
(2.5 mg) and its Metabolite, 1-OH-MDZ, Following Administration Alone or with 
LEN (N = 30-31) .....................................................................................................................57
Table 18.
GS-US-200-4625: Plasma Pharmacokinetic Parameters of LEN Following Oral 600 
mg Daily Dosing (Days 1 and 2) and 300 mg (Day 8), With SC LEN Injection 
Every 26 Weeks Starting From Day 15 (Day 1 SC)................................................................63
Table 19.
GS-US-200-4334: Study Treatments.......................................................................................66
Table 20.
Oral LEN/Placebo Bridging and SC LEN/Placebo Restart Dosing Schedule.......................102
Table 21.
Missed Oral LEN/Placebo Dose Recommendations During Oral LEN/Placebo 
Weekly Bridging....................................................................................................................103
Table 22.
Prior and Concomitant Medications that are Prohibited or To Be Used with Caution 
due to the Potential for Drug-Drug Interaction with Study Drugs ........................................104
Table 23.
Antiretroviral Medications With Potential Drug-Drug Interactions With LEN....................106

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LIST OF IN-TEXT FIGURES
Figure 1.
Similarity of LEN and GS-CA1 Chemical Structures.............................................................36
Figure 2.
GS-US-200-4071: Mean (SD) LEN Plasma Concentration-Time Profiles Following 
Single-Dose Administration of Oral LEN Solution in Capsule (50 mg/mL; N = 8 per 
Cohort).....................................................................................................................................40
Figure 3.
GS-US-200-4071: Mean (SD) LEN Plasma Concentration-Time Profiles Following 
Single-Dose Fasted Administration of Oral LEN Tablets (N = 8 per Cohort)........................42
Figure 4.
GS-US-200-4071: Mean (SD) LEN Plasma Concentration-Time Profiles Following 
Single-Dose Administration of Oral LEN 300 mg Tablets, Administered Fasted or 
with a High-Fat or Low-Fat Meal (N = 8 per Cohort).............................................................43
Figure 5.
GS-US-200-4538: Mean (SD) Plasma Concentration Versus Time (Part B) (LEN 
PK Analysis Set)......................................................................................................................46
Figure 6.
GS-US-200-5709: Comparison of Mean (90% CI)a LEN Plasma Concentration-time 
Profiles Between Cohorts 1 and 2 (LEN PK Analysis Set).....................................................51
Figure 7.
GS-US-200-4072: Mean and 95% CI Change from Baseline in HIV-1 RNA 
(log10 copies/mL) (Full Analysis Set)......................................................................................59
Figure 8.
GS-US-200-4625: Mean (SD) LEN Plasma Concentration-time Profiles 
(Semilogarithmic Scale) Following Oral 600 mg Daily Dosing (Days 1 and 2) and 
300 mg (Day 8), With SC LEN Injection Every 26 Weeks Starting From Day 15 
(Day 1 SC)...............................................................................................................................63
Figure 9.
Simulated Plasma Profile of LEN Following the Proposed SC LEN Regimen 
Administered Every 26 Weeks With an Oral PK Load on Days 1 and 2................................79
Figure 10.
Simulated Pharmacokinetic Profile of Oral Weekly Bridging of LEN (300 mg) (A) 
Prior to and (B) After Resuming SC Injection ........................................................................80
Figure 11.
Study Schema ..........................................................................................................................87
Figure 12.
Assessments to Determine Enrollment and Randomization Eligibility ................................109
Figure 13.
A High-Level Screening Schema and Contribution of Participants to the Estimation 
of the Background HIV-1 Incidence Rate .............................................................................156

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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title:
A Phase 3, Double-Blind, Multicenter, Randomized Study to 
Evaluate the Efficacy and Safety of Subcutaneous Twice Yearly 
Long-Acting Lenacapavir for HIV Pre-Exposure Prophylaxis in 
Cisgender Men, Transgender Women, Transgender Men, and Gender 
Nonbinary People ≥ 16 Years of Age who Have Sex With Male 
Partners and are at Risk for HIV Infection
Study Acronym:
PURPOSE 2
Plain Language 
Short Title:
Pre-Exposure Prophylaxis Study of Lenacapavir in Cisgender Men, 
Transgender Women, Transgender Men, and Gender Nonbinary 
People at Risk for HIV Infection
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
153858
Not Applicable
NCT04925752
Study Sites Planned:
Approximately 110 sites globally
Objectives:
The primary objective of this study is to evaluate the efficacy of 
lenacapavir (LEN) in preventing the risk of HIV-1 infection relative 
to the background HIV-1 incidence rate. Participants are cisgender 
men (CGM), transgender women (TGW), transgender men (TGM), 
and gender nonbinary people (GNB).
The primary objective for the Incidence Phase of this study is to 
estimate the HIV-1 background incidence rate.
The primary objective for the Randomized Blinded Phase of this 
study is as follows:
•
To evaluate the efficacy of LEN for HIV-1 pre-exposure 
prophylaxis (PrEP) in participants ≥ 16 years of age who have 
condomless receptive anal sex with partners assigned male at 
birth and are at risk for HIV-1 infection

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The secondary objectives for the Randomized Blinded Phase of this 
study are as follows:
•
To compare the efficacy of LEN with emtricitabine/tenofovir 
disoproxil fumarate (F/TDF) for HIV-1 PrEP in participants 
≥ 16 years of age who have condomless receptive anal sex with 
partners assigned male at birth and are at risk for HIV-1 infection
•
To evaluate the efficacy of LEN for HIV-1 PrEP in participants at 
risk of HIV-1 infection in participants adherent to LEN
•
To evaluate the safety and tolerability of LEN and F/TDF for 
HIV-1 PrEP in participants ≥ 16 years of age who have 
condomless receptive anal sex with partners assigned male at 
birth and are at risk for HIV-1 infection
•
To evaluate the safety and tolerability of LEN for HIV-1 PrEP in 
adolescent participants ≥ 16 to < 18 years of age who have 
condomless receptive anal sex with partners assigned male at 
birth and are at risk for HIV-1 infection
Study Design:
This is a Phase 3, double-blind, multi-site, randomized study to 
compare HIV-1 incidence in the LEN study drug group with the 
nonrandomized control of background HIV-1 incidence, defined as 
the estimated HIV-1 incidence without PrEP in the population 
studied. F/TDF will serve as the internal active control. This study 
includes a cross-sectional study (Incidence Phase), a Randomized 
Blinded Phase, a LEN Open-label Extension (OLE) Phase, and a 
Pharmacokinetic (PK) Tail Phase. Participants eligible for the 
Randomized Blinded Phase will be randomized in a 2:1 ratio to 
receive LEN or F/TDF, respectively. 
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Enrollment of adolescents (participants 16 and 17 years of age) will 
commence following the first data monitoring committee (DMC) 
review of the unblinded safety data and recommendation to continue 
the study. Gilead Sciences (Gilead) will notify sites when they may 
begin enrollment of adolescents.
Number of 
Participants 
Planned:
Approximately 3000 participants will be randomized in the 
Randomized Blinded Phase.
Target Population:
CGM, TGW, TGM, and GNB ≥ 16 years of age who have 
condomless receptive anal sex with partners assigned male at birth 
and are at risk for HIV infection.
Duration of Study 
Drug 
Administration:
Participants enrolled in the Randomized Blinded Phase will receive 
study drug for approximately 52 weeks. Participants transitioning to 
the LEN OLE Phase will receive SC LEN injections every 26 weeks 
(± 7 days) until either LEN becomes available or the sponsor elects to 
discontinue the study, whichever occurs first. Participants eligible for 
the PK Tail Phase will receive up to 78 weeks of once daily oral 
F/TDF.
Diagnosis and Main 
Eligibility Criteria:
Incidence Phase Key Criteria:
•
CGM, TGW, TGM, and GNB who have condomless receptive 
anal sex with partners assigned male at birth and are at risk for 
HIV-1 infection.
•
Age ≥ 16 years at screening. Enrollment of adolescents 
(participants 16 and 17 years of age) will commence following 
the first DMC review of the unblinded safety data and 
recommendation to continue the study. Gilead will notify sites 
when they may begin enrollment of adolescents.
•
HIV-1 status unknown at screening and no prior HIV-1 testing 
within the last 3 months
•
Sexually active with ≥ 1 partner assigned male at birth 
(condomless receptive anal sex) in the last 12 months and 1 of the 
following:
Condomless receptive anal sex with ≥ 2 partners in the last 
12 weeks
History of syphilis, rectal gonorrhea, or rectal chlamydia in 
the last 24 weeks
Self-reported use of stimulants with sex in the last 12 weeks

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•
Willing and able to comply with study procedures
•
Prior use of HIV PrEP (including F/TDF or F/TAF) or HIV 
postexposure prophylaxis (PEP) in the past 12 weeks or any prior 
use of long-acting systemic PrEP (including cabotegravir or 
islatravir) is not allowed
•
Participants who previously received an HIV vaccine or HIV 
broadly neutralizing antibody (bNAb) are not eligible. Individuals 
may be eligible if they participated in an HIV vaccine or bNAb 
study but have documentation that they did not receive active 
product (eg, placebo recipients).
Randomized Blinded Phase Key Criteria:
•
Negative local rapid fourth generation HIV-1/2 antibody 
(Ab)/antigen (Ag), central fourth generation HIV-1/2 Ab/Ag, and 
HIV-1 RNA quantitative nucleic acid amplification testing 
(NAAT)
•
Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min at 
screening according to the Cockcroft-Gault formula for creatinine 
clearance 
•
Body weight ≥ 35 kg
•
Participants of childbearing potential who engage in frontal 
(vaginal) intercourse must not intend to become pregnant during 
the study and must agree to utilize protocol-specified method(s) 
of contraception
•
Participation in any other clinical trial (including observational 
and COVID-19 vaccine trials) without prior approval from the 
sponsor is prohibited while participating in this trial. An 
exception is made for participation in the sponsor-approved 
ancillary qualitative participant interview study, which is allowed 
and does not require medical monitor approval.
•
Hepatitis B virus (HBV) negative or immune 
•
Participants with severe hepatic impairment are not allowed

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Study Procedures/
Frequency:
Screening Visit 
After providing written informed consent (or assent and/or 
parental/guardian consent as appropriate) for the Incidence Phase 
procedures, participants will be screened to determine eligibility for 
participation in the study, including the following assessments:
•
Blood collection for local rapid fourth generation HIV-1/2 Ab/Ag 
test, confirmatory central HIV-1/2 testing, HIV-1 RNA 
quantitative NAAT, HIV-1 recency assay (run as indicated based 
on HIV test results), cluster determinant (CD) 4 cell count (only if 
local rapid HIV-1/2 test is positive), DBS storage sample, and 
plasma storage samples for virology, safety, and/or PK testing
•
Record serious adverse events (SAEs) and adverse events (AEs) 
related to protocol-mandated procedures
•
Obtain medical history, including prior receipt of a long-acting 
PrEP medication or HIV vaccine
•
Urine pregnancy test for participants assigned female at birth who 
are of childbearing potential
•
HIV risk reduction counseling including provision of external 
(penile) and internal (vaginal) condoms and lubricant
If the local rapid fourth generation HIV-1/2 Ab/Ag test is positive, 
participants will undergo confirmatory testing and counseling as 
appropriate, and study participation will conclude. At the 
investigator’s discretion, a positive local rapid fourth generation 
HIV-1/2 Ab/Ag test may be separately confirmed by following local 
testing guidelines in order to facilitate rapid antiretroviral therapy 
(ART) initiation. 
Participants who have a negative local rapid fourth generation 
HIV-1/2 Ab/Ag test and urine pregnancy test (for participants 
assigned female at birth who are of childbearing potential) and meet 
the Incidence Phase eligibility criteria will be offered participation in 
the Randomized Blinded Phase, and if interested, will complete a 
separate written informed consent (or assent with parental/guardian 
consent as applicable). After informed consent is provided, the 
following assessments will be performed:
•
Blood collection for HBV and hepatitis C virus (HCV) testing, 
chemistry and hematology profile, eGFR calculation, serum 
pregnancy test for participants assigned female at birth who are of 
childbearing potential, and local laboratory asymptomatic syphilis 
testing 

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•
Urine collection for urinalysis, urine protein, urine chemistry, and 
routine asymptomatic sexually transmitted infection (STI) testing 
for Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) 
(for participants assigned female at birth, central laboratory urine 
Trichomonas vaginalis [TV] testing may be performed at the 
investigator’s discretion)
•
Record SAEs and AEs related to protocol-mandated procedures
•
Obtain medical history and any prior medications
•
Complete physical examination including vital signs, weight, 
height, and waist circumference 
•
Pharyngeal and rectal swab collection for asymptomatic GC and 
CT testing per central laboratory testing. Swabs may be 
self-collected by the participant at the discretion of the 
investigator.
•
HIV risk reduction counseling including provision of external 
(penile) and internal (vaginal) condoms and lubricant 
•
Screening for intimate partner violence and appropriate referral 
when applicable
•
Integrated Sexual Behaviors and Alcohol and Substance Use 
Questionnaire 
Any participant diagnosed with HIV will receive counseling, be 
referred for local HIV-related care, and study participation will 
conclude.
Eligible HIV-negative participants will return to the study site within 
30 days of the screening visit for Day 1/Injection 1 assessments.
Randomized Blinded Phase
On Day 1/Injection 1, after confirmation that all HIV-1/2 tests from 
the Randomized Blinded Phase screening were negative, a local rapid 
fourth generation HIV-1/2 Ag/Ab test will be performed to confirm 
negativity, and participants will be screened for signs and symptoms 
of acute HIV infection. 
If rapid HIV-1/2 testing and acute HIV symptom screening are 
negative and all other eligibility criteria are fulfilled, participants will 
be randomized in a 2:1 (LEN:F/TDF) ratio to 1 of the following study 
drug groups:
•
LEN study drug group: subcutaneous (SC) 
LEN + placebo-to-match (PTM) F/TDF (N = 2000)
•
F/TDF study drug group: F/TDF + placebo SC LEN (N = 1000)

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On Day 1/Injection 1, SC LEN 927 mg or placebo SC LEN will be 
administered at the study site with a PK loading dose of oral LEN 
600 mg (2  300 mg tablets) or PTM oral LEN tablets (2 tablets). In 
addition, 2 oral LEN tablets or PTM LEN tablets will be provided to 
participants to self-administer on Day 2. If a participant misses the 
Day 2 dose, the dose should be administered immediately upon 
realizing the dose was missed. Subsequently, SC LEN or placebo SC 
LEN will be administered at the study site every 26 weeks (± 7 days). 
Participants will also receive oral F/TDF (200/300 mg) or PTM 
F/TDF to self-administer daily starting on Day 1/Injection 1. The site 
staff will contact the participant 1 week (± 2 days) after injection to 
assess for any injection site reactions (ISRs) and to confirm the 
participant has administered the Day 2 dose. At each injection visit, 
participants will be observed for approximately 30 minutes after each 
SC injection administration.
Participants will attend study visits on Day 1/Injection 1, Weeks 4 
and 8 (± 2 days), Week 13 (± 7 days), and every 13 weeks (± 7 days) 
thereafter until all enrolled participants have completed at least 52 
weeks of follow-up in the study and the primary analysis is 
completed. This will indicate the end of the Randomized Blinded 
Phase.
On Day 1/Injection 1, the following assessments will be performed:
•
Urine collection for routine asymptomatic STI testing for GC and 
CT (for participants assigned female at birth, central laboratory 
urine TV testing may be performed at the investigator’s 
discretion); urinalysis, urine proteins, and urine chemistry; urine 
storage sample; and urine pregnancy test for participants assigned 
female at birth who are of childbearing potential
•
Blood collection for chemistry, hematology, and metabolic 
assessments; eGFR calculation; local rapid fourth generation 
HIV-1/2 Ab/Ag test; central HIV-1/2 testing; HIV-1 RNA 
quantitative NAAT; HIV-1 recency assay (run as indicated based 
on HIV test results); CD4 cell count (only if local HIV-1/2 test is 
positive); DBS storage sample; plasma and serum storage samples 
for virology, safety, and/or PK testing; serum pregnancy testing 
(in the event of a positive urine pregnancy test), local laboratory 
asymptomatic syphilis testing
•
Targeted (symptom-directed) physical examination
•
Vital signs, height, weight, and waist circumference 

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•
Pharyngeal and rectal swab collection for asymptomatic GC and 
CT testing per central laboratory testing. Swabs may be 
self-collected by the participant at the discretion of the 
investigator. 
•
Questionnaires:
Integrated Sexual Behaviors and Alcohol and Substance Use
PrEP Impacts and Administration Preference Questionnaire - 
Day 1
Numeric Pain Rating Scale – Injection Pain Questionnaire 
(must be completed postinjection)
•
Review and record AEs, including screening for any signs and 
symptoms of acute HIV infection or STIs, and changes in 
concomitant medications
•
Adherence counseling to encourage the importance of attending 
study visits in a timely fashion, daily adherence to study drug, and 
study retention 
•
HIV risk reduction counseling including provision of external 
(penile) and internal (vaginal) condoms and lubricant 
•
Screening for intimate partner violence and appropriate referral 
when applicable 
Any participant with signs or symptoms consistent with acute HIV 
infection will undergo Day 1/Injection 1 procedures but will not 
receive study drug until HIV negative status is confirmed by a central 
laboratory fourth generation HIV-1/2 Ab/Ag test and HIV-1 RNA 
quantitative NAAT. 
At Weeks 4 and 8 (± 2 days), Week 13 (± 7 days), and every 
13 weeks (± 7 days) thereafter in the Randomized Blinded Phase, the 
following assessments will be performed: 
•
Urine collection for asymptomatic STI testing for GC and CT (for 
participants assigned female at birth, central laboratory urine TV 
testing may be performed at the investigator’s discretion); 
urinalysis, urine proteins, and urine chemistry; urine storage 
sample; and urine pregnancy test for participants assigned female 
at birth who are of childbearing potential

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•
Blood collection for chemistry and hematology profile; metabolic 
assessments and HBV and HCV testing (Week 26/Injection 2, 
Week 52, and every 26 weeks thereafter); eGFR calculation; local 
rapid fourth generation HIV-1/2 Ab/Ag test; central HIV-1/2 
testing; HIV-1 RNA quantitative NAAT storage sample; DBS 
storage sample; plasma and serum storage samples for virology, 
safety, and/or PK testing; serum pregnancy test (in the event of a 
positive urine pregnancy test), local laboratory asymptomatic 
syphilis testing (Week 13 and every 13 weeks thereafter)
•
One week (± 2 days) after each injection, participants will be 
contacted for a postinjection follow-up assessment.
•
Questionnaires:
Adherence to Oral Study Product Questionnaire: Weeks 4, 
8, 13, and every 13 weeks thereafter
Integrated Sexual Behaviors and Alcohol and Substance 
Use: Week 13 and every 13 weeks thereafter
Administration and Dosing Questionnaire for PrEP 
Medication: Weeks 13, 39, and 13 weeks after each 
injection visit thereafter
PrEP Impacts and Administration Preference 
Questionnaire: Week 26/Injection 2, Week 52, and every 
26 weeks thereafter at injection visits
Numeric Pain Rating Scale – Injection Pain Questionnaire 
(must be completed postinjection): Week 26/Injection 2, 
Week 52, and every 26 weeks thereafter at injection visits
•
Targeted (symptom-directed) physical examination
•
Vital signs, height, weight, and waist circumference 
•
Pharyngeal and rectal swab collection for asymptomatic GC and 
CT testing per central laboratory testing (Week 13 and every 
13 weeks thereafter). Swabs may be self-collected by the 
participant at the discretion of the investigator. 
•
Review and record AEs, including screening for any signs and 
symptoms of acute HIV infection or STIs, and changes in 
concomitant medications
•
Adherence counseling to encourage the importance of attending 
study visits in a timely fashion, daily adherence to study drug, and 
study retention 

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•
HIV risk reduction counseling including provision of external 
(penile) and internal (vaginal) condoms and lubricant
•
Screening for intimate partner violence and appropriate referral 
when applicable
Participants assigned female at birth who are of childbearing potential 
are required to use effective contraception for the duration of the 
study. Any participant who becomes pregnant after randomization 
may remain in the study and continue to receive study drug after a 
reconsent process in which they will be informed of the benefits and 
risks of continuing receipt of study drug and the collection of birth 
outcomes for the child and lactation information. Participants who are 
taking testosterone and become pregnant during the study must 
discontinue testosterone if continuing the pregnancy and wish to 
continue on study drug. The outcome of the pregnancy should be 
reported to Gilead Patient Safety throughout the study, including the 
protocol-defined follow-up period.
Participants randomized to LEN who decline to participate in the 
LEN OLE Phase will transition to the PK Tail Phase at this visit 
(ie, End of Randomized Blinded Phase visit will coincide with PK 
Tail Day 1 visit).
Participants randomized to F/TDF who decline to participate in the 
LEN OLE Phase will complete the early study drug discontinuation 
(ESDD) visit at this visit, be transitioned to local HIV prevention 
services, and be required to return for a 30-day follow-up visit.
Participants who prematurely discontinue blinded study drug during 
the Randomized Blinded Phase will transition to the PK Tail Phase. If 
a participant chooses not to enter the PK Tail Phase (after discussion 
of benefits/risk with the investigator), the participant will complete an 
ESDD visit and a 30-day follow-up visit.
Lenacapavir Open-Label Extension Phase
Following completion of the primary analysis, if LEN demonstrates 
acceptable safety and efficacy in the Randomized Blinded Phase, the 
study will proceed to the LEN OLE Phase. All participants who still 
remain on randomized blinded study drug at the time of the End of 
Randomized Blinded Phase visit will have the option to transition to 
the LEN OLE Phase at this visit (ie, End of Randomized Blinded 
Phase visit will coincide with LEN OLE Day 1 visit).

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Participants will receive SC LEN injections every 26 weeks 
(± 7 days) in the LEN OLE Phase until either LEN becomes available 
or the sponsor elects to discontinue the study, whichever occurs first. 
LEN OLE Day 1 will coincide with the end of the Randomized 
Blinded Phase. Participants randomized to LEN in the Randomized 
Blinded Phase who choose to participate in the LEN OLE Phase will 
receive SC LEN every 26 weeks (± 7 days) and have study visits 
every 13 weeks (± 7 days). The SC LEN injection visits in the LEN 
OLE Phase will be determined by the previous LEN injection 
(ie, participants whose last LEN injection was 13 weeks before LEN 
OLE Day 1 will receive their first open-label LEN injections at the 
LEN OLE Week 13 visit; participants whose last LEN injection was 
26 weeks before LEN OLE Day 1 will receive their LEN injections at 
the LEN OLE Day 1 and Week 26 visits) and every 26 weeks 
thereafter.
Participants randomized to F/TDF in the Randomized Blinded Phase 
will switch to SC LEN and have study visits at LEN OLE Day 1, 
Weeks 4 and 8 (± 2 days), Week 13 (± 7 days), and every 13 weeks 
(± 7 days) thereafter. Subcutaneous LEN will be administered at the 
LEN OLE Day 1, Week 26, and every 26 weeks thereafter. These 
participants will also receive a loading dose of oral LEN on LEN 
OLE Days 1 and 2, as described in the Randomized Blinded Phase. If 
a participant misses the Day 2 dose, the dose should be administered 
immediately upon realizing the dose was missed. The site staff will 
contact the participant 1 week (± 2 days) after injection to assess for 
any ISRs and to confirm the participant has administered the Day 2 
dose. Participants will complete the LEN OLE Phase once LEN 
becomes available or the sponsor elects to discontinue the study, 
whichever occurs first. 
Upon completion of the LEN OLE Phase or discontinuation of the 
study, participants will transition to locally available PrEP, which 
may include lenacapavir or other available PrEP modalities as 
clinically indicated. If a participant chooses to end participation in the 
LEN OLE Phase prior to conclusion, then the participant will 
complete an ESDD visit, be referred to locally available PrEP 
services as clinically indicated, and will complete a 30-day follow-up 
visit. 
The following assessments will be performed at the LEN OLE Phase 
study visits: 
•
Urine collection for routine asymptomatic STI testing for GC and 
CT (for participants assigned female at birth, central laboratory 
urine TV testing may be performed at the investigator’s 

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discretion) (End of Randomized Blinded Phase visit/LEN OLE 
Day 1, and every 13 weeks thereafter); urinalysis; urine storage 
sample (End of Randomized Blinded Phase visit/LEN OLE Day 1 
only); and urine pregnancy test for participants assigned female at 
birth who are of childbearing potential
•
Blood sample collection for chemistry (every 26 weeks) and 
hematology profile (every 26 weeks); metabolic assessments and 
HBV and HCV testing (End of Randomized Blinded Phase 
visit/LEN OLE Day 1 and every 52 weeks thereafter); eGFR 
calculation (End of Randomized Blinded Phase visit/LEN OLE 
Day 1 and every 26 weeks thereafter); local rapid fourth 
generation HIV-1/2 Ab/Ag test; central HIV-1/2 testing; HIV-1/2 
RNA qualitative NAAT storage sample; DBS storage sample 
(End of Randomized Blinded Phase visit/LEN OLE Day 1 only); 
Anytime plasma PK sample; plasma and serum storage samples 
for virology, safety, and/or PK testing; serum pregnancy test (in 
the event of a positive urine pregnancy test); local laboratory 
asymptomatic syphilis testing (End of Randomized Blinded Phase 
visit/LEN OLE Day 1, Week 13, and every 13 weeks thereafter)
•
Targeted (symptom-directed) physical examination
•
Vital signs, height, and weight 
•
Pharyngeal and rectal swab collection for asymptomatic GC and 
CT testing per central laboratory testing (End of Randomized 
Blinded Phase visit/LEN OLE Day 1, Week 13, and every 
13 weeks thereafter). Swabs may be self-collected by the 
participant at the discretion of the investigator. 
•
Review and record AEs, including screening for any signs and 
symptoms of acute HIV infection or STIs and changes in 
concomitant medications
•
Adherence counseling to encourage the importance of attending 
study visits in a timely fashion, adherence to study drug 
injections, and retention 
•
HIV risk reduction counseling including provision of external 
(penile) and internal (vaginal) condoms and lubricant 
•
Screening for intimate partner violence and appropriate referral 
when applicable 
•
One week (± 2 days) after each injection participants will be 
contacted for a postinjection follow-up assessment.
•
Questionnaires (until and including LEN OLE Week 52): 

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Integrated Sexual Behaviors and Alcohol and Substance Use 
Questionnaire: End of Randomized Blinded Phase visit/LEN 
OLE Day 1, Week 13, and every 13 weeks thereafter 
Administration and Dosing Questionnaire for PrEP 
Medication: 13 weeks after each injection visit
Experienced Preference for PrEP Medication Questionnaire: 
every injection visit 
Numeric Pain Rating Scale – Injection Pain Questionnaire 
(must be completed postinjection): every injection visit
Adherence to Oral Study Product Questionnaire: End of 
Randomized Blinded Phase visit/LEN OLE Day 1 only
Upon completion of the LEN OLE or discontinuation of the study, 
participants will transition to locally available PrEP, which may 
include lenacapavir or other available PrEP modalities as clinically 
indicated. If a participant chooses to end participation in the LEN 
OLE Phase prior to conclusion, then the participant will complete an 
ESDD visit, be referred to locally available PrEP services as 
clinically indicated, and will complete a 30-day follow-up visit.
Pharmacokinetic Tail Phase
Participants who prematurely discontinue study drug in the 
Randomized Blinded Phase will transition to the PK Tail Phase to 
receive OL oral F/TDF once daily for up to 78 weeks to cover the PK 
tail and complete visits every 13 weeks (± 7 days).
Upon unblinding, participants who were randomized to LEN in the 
Randomized Blinded Phase who decline to participate in the LEN 
OLE Phase will transition to the PK Tail Phase. 
Upon unblinding, participants who were randomized to F/TDF in the 
Randomized Blinded Phase who decline to participate in the LEN 
OLE Phase will complete the ESDD visit, transition to local HIV 
prevention services, and return for a 30-day follow-up visit.
See Appendix 7 for US-specific text.
The following assessments will be performed at the PK Tail Phase 
study visits:
•
Urine collection for routine asymptomatic STI testing for GC and 
CT (for participants assigned female at birth, central laboratory 
urine TV testing may be performed at the investigator’s 

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discretion); urinalysis, urine proteins, and urine chemistry; and 
urine pregnancy test for participants assigned female at birth who 
are of childbearing potential
•
Blood collection for chemistry and hematology profile; metabolic 
assessments and HBV and HCV testing (PK Tail Day 1 and every 
52 weeks thereafter); eGFR calculation; local rapid fourth 
generation HIV-1/2 Ab/Ag test; central HIV-1/2 testing; HIV-1 
RNA quantitative NAAT storage sample; DBS storage sample 
(PK Tail Day 1 for participants who prematurely discontinue 
study drug during the Randomized Blinded Phase, Week 13, and 
every 13 weeks thereafter); anytime plasma PK sample; plasma 
and serum storage samples for virology, safety, and/or PK testing; 
serum pregnancy test (in the event of positive urine pregnancy 
test); local laboratory asymptomatic syphilis testing
•
Targeted (symptom-directed) physical examination
•
Vital signs, height, and weight 
•
Pharyngeal and rectal swab collection for asymptomatic GC and 
CT testing per central laboratory testing. Swabs may be 
self-collected by the participant at the discretion of the 
investigator. 
•
Review and record AEs, including screening for any signs and 
symptoms of acute HIV infection or STIs and changes in 
concomitant medications
•
Adherence counseling to encourage the importance of attending 
study visits in a timely fashion, daily adherence to study drug, and 
retention 
•
HIV risk reduction counseling including provision of external 
(penile) and internal (vaginal) condoms and lubricant 
•
Screening for intimate partner violence and appropriate referral 
when applicable

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•
Questionnaires: 
Integrated sexual behaviors and alcohol and substance use: 
PK Tail Day 1, Week 13, and every 13 weeks thereafter 
PrEP Impacts and Administration Preference Questionnaire: 
PK Tail Day 1 for participants who transition from the 
Randomized Blinded Phase
Administration and Dosing Questionnaire for PrEP 
Medication: PK Tail Day 1 
Adherence to Oral Study Product Questionnaire: PK Tail Day 
1 for participants who transition from the Randomized 
Blinded Phase, Week 13, and every 13 weeks thereafter 
Participants who permanently discontinue study drug during the PK 
Tail Phase will complete an ESDD visit and a 30-day follow-up visit.
See Appendix 7 for US-specific text
Test Product, Dose, 
and Mode of 
Administration:
Randomized Blinded Phase
SC LEN 927 mg injection, 309 mg/mL (2  1.5 mL) administered 
every 26 weeks starting on Day 1/Injection 1 and oral LEN 600 mg 
(2  300 mg tablets) administered on Day 1/Injection 1 and Day 2.
Lenacapavir Open-Label Extension Phase
SC LEN 927 mg injection, 309 mg/mL (2 ´ 1.5 mL) administered 
every 26 weeks. Participants randomized to F/TDF in the 
Randomized Blinded Phase will also be administered oral LEN 600 
mg (2 ´ 300 mg tablets) on LEN OLE Days 1 and 2.
Reference Therapy, 
Dose, and Mode of 
Administration:
Randomized Blinded Phase
F/TDF fixed-dose combination (200 mg emtricitabine/300 mg 
tenofovir disoproxil fumarate), administered orally once daily with or 
without food.
PTM F/TDF, administered orally once daily
Placebo for SC LEN injection (2  1.5 mL) administered every 
26 weeks and PTM oral LEN (2 tablets) administered on 
Day 1/Injection 1 and Day 2.
Pharmacokinetic Tail Phase
F/TDF, administered orally once daily
Criteria for 
Evaluation:

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Safety:
Occurrence of treatment-emergent AEs and treatment-emergent 
clinical laboratory abnormalities to evaluate safety and tolerability of 
LEN and F/TDF for HIV-1 PrEP.
Efficacy:
Diagnosis of HIV-1 infection is the primary endpoint for the 
Randomized Blinded Phase for both primary objectives of this study.
Pharmacokinetics:
LEN plasma levels
Adherence:
1) On-time LEN injection administration
2) Adherence to F/TDF assessed using intracellular TFV-DP levels 
in DBS
Questionnaires:
The following self-reported data will be assessed by questionnaires:
1) Adherence
2) Integrated sexual behaviors and alcohol and substance use
3) Numeric pain rating scale – injection pain
4) Administration and dosing for PrEP medication
5) PrEP impacts and administration preference 
Statistical Methods:
The primary objective of the study will be achieved by showing that 
the HIV-1 incidence (per 100 person-years [PY]) in the LEN study 
drug group during the study is significantly lower than the 
background incidence rate with 1-sided alpha of 0.025. The 
background incidence rate will be calculated from the Incidence 
Phase based on the HIV-1 recency assay result using an HIV-1 
incidence formula similar to Kassanjee, et al {Kassanjee 2012}. The 
incidence rate ratio of the LEN study drug group to the background, 
the associated 95% CI, and p-value will be calculated using the delta 
method {Gao 2021} or a likelihood-based method {Shao 2024} if the 
number of HIV-1 infections in the LEN group is zero. The primary 
analysis will be conducted when all enrolled participants have 
completed a minimum of 52 weeks (1 year) of follow-up in the study 
or prematurely discontinued from the study (whichever occurs first) 
after randomization.
Key (α-controlled) secondary analyses will be 1) to assess whether 
the HIV-1 incidence rate ratio of the LEN study drug group is at least 
20% lower than the background incidence rate and the point estimate 
of LEN/background HIV ≤ 0.5, 2) to assess whether the HIV-1 
incidence in the LEN study drug group is at most 0.8 per 100 PY 
higher than the HIV-1 incidence in the F/TDF study drug group, and 
3) to assess whether the HIV-1 incidence in the LEN study drug 
group is significantly lower than the HIV-1 incidence in the F/TDF 
study drug group. The overall type 1 error rate for these analyses will 

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be controlled at α = 0.025 (1-sided) by following a fixed-sequence 
gatekeeping approach in the sequential order listed in Section 8.7.
A secondary analysis of the HIV-1 incidence rate will be the 
comparison with one-half of the lower bound of the 95% CI of the 
nonrandomized control background HIV-1 incidence rate reported as 
3.49 (3.05, 3.92) {Mera 2020}. This analysis will estimate the HIV-1 
incidence and its 95% CI for the LEN study drug group based on the 
Full Analysis Set and will conclude significance for the secondary 
analysis if the upper bound of the 95% CI is lower than 1.525 (half of 
3.05). The concurrent background HIV-1 incidence rates will also be 
estimated by other methods. These will include prerandomization 
methods such as recent epidemiologic data, and postrandomization 
methods such as correlation of rectal gonorrhea rates with HIV-1 
incidence.
Descriptive statistics will summarize baseline characteristics, 
exposure to study drug, follow-up time, and all safety measures in the 
entire population and specifically in adolescents.
A total sample size of 3000 is considered. With 2000 participants in 
the LEN study drug group, the study will have > 95% power to show 
at least a 20% reduction compared with the background HIV-1 
incidence rate.
The sample size estimate is based on the following assumptions and 
considerations:
•
Background HIV-1 incidence of 3.00/100 PY
•
LEN incidence of 0.6/100 PY, with an 80% risk reduction in 
HIV-1 compared with the nonrandomized control of background 
HIV-1 incidence
•
Mean duration of recent infections (MDRI) of 173 days, with 
relative standard error (rSE) of 6.5%
•
False recency rate (FRR) of 1.5%, with rSE of 70%
•
Average follow-up of 1.5 years in the study
•
2:1 allocation for LEN:F/TDF
•
Alpha level of 0.025 (1-sided)
The MDRI and FRR are based on the Sedia Lag assay {Kassanjee 
2016}. These assay parameters are still under investigation and may 
be fine-tuned further.
An external DMC (data monitoring committee) will evaluate the 
safety and efficacy of LEN in this population. The first data review 
meeting of the DMC will be convened when the first 300 participants 
have completed their Week 8 visit to evaluate the safety of LEN. 

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While enrollment will not be paused during this safety review, 
enrollment will not exceed beyond 600 participants before the safety 
review is conducted and, if determined by the DMC, the study is 
allowed to continue. Enrollment of adolescents (participants 16 and 
17 years of age) will commence following the first DMC review of 
the unblinded safety data and recommendation to continue the study. 
Gilead will notify sites when they may begin enrollment of 
adolescents. Data monitoring committee safety review meetings will 
occur approximately annually thereafter during the Randomized 
Blinded Phase of the study. The DMC will formally evaluate efficacy 
data, only once, after 50% of participants enrolled have completed at 
least 52 weeks of follow-up in the study or prematurely discontinued 
from the study. The DMC may recommend stopping the study early if 
the prespecified evaluation criteria are met. If the Randomized 
Blinded Phase is stopped early due to an efficacy outcome, the 
interim analysis will serve as the primary analysis. The DMC will 
have access to treatment codes for all their reviews.
This study will be conducted in accordance with the guidelines of Good Clinical Practice, 
including archiving of essential documents.

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
%AUCexp
%CV
percentage of AUC extrapolated between AUClast and AUCinf
percentage coefficient of variation
3TC
lamivudine
Ab
antibody
AE
adverse event
Ag
antigen
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AIDS
acquired immunodeficiency syndrome
ART
antiretroviral therapy
ARV
antiretroviral
AST
aspartate aminotransferase
ATV
atazanavir
AUC
area under the concentration versus time curve
AUClast
area under the concentration versus time curve from time zero to the last quantifiable 
concentration
AUCinf
area under the concentration versus time curve extrapolated to infinite time, calculated 
as AUClast + (Clast/z)
AUCx-xx
partial area under the concentration versus time curve from time “x” to time “xx”
BCRP
breast cancer resistance protein
B/F/TAF
bictegravir/emtricitabine/tenofovir alafenamide (coformulated; Biktarvy®)
BL
baseline
BLQ
below the limit of quantitation
bNAb
broadly neutralizing antibody
CA
capsid protein
CBC
complete blood count
CC50
half maximal cytotoxic concentration
CD4
cluster determinant 4
CDC
Centers for Disease Control and Prevention
CGM
cisgender men
CI
confidence interval
CK
creatine kinase
CLcr
creatinine clearance
Cmax
maximum observed concentration of drug
Cmin
minimum observed concentration of drug
COBI, C, co
cobicistat (Tybost®)
COC
combination oral contraceptives

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CRF
case report form
CRO
contract research organization
CSR
clinical study report
CT
Chlamydia trachomatis
Ctrough
concentration at the end of the dosing interval
CWeek26
concentration at the end of the dosing interval at Week 26
CYP
cytochrome P450 enzyme
DAIDS
Division of AIDS
DBS
dried blood spot
DDI
drug-drug interaction
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DRV
darunavir
DVY
emtricitabine/tenofovir alafenamide (coformulated; Descovy®)
E2
17β-estradiol
EC
ethics committee
EC50
half-maximal effective concentration
ECG
electrocardiogram
EE
ethinylestradiol
eCRF
electronic case report form
EDC
electronic data capture
EFV
efavirenz
eGFR
estimated glomerular filtration rate
ESDD
early study drug discontinuation
ETV
etravirine
EU
European Union
F
relative bioavailability
F/TAF
emtricitabine/tenofovir alafenamide (coformulated; Descovy®)
FA
free acid
FAS
Full Analysis Set
FAM
famotidine
FDA
Food and Drug Administration
FDC
fixed-dose combination
FRR
false recency rate
FTC
emtricitabine
FTC/TDF
emtricitabine/tenofovir disoproxil fumarate (coformulated; Truvada®)
GAHT
gender-affirming hormone therapy
GC
Neisseria gonorrhoeae
GCP
Good Clinical Practice
GFR
glomerular filtration rate

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GGT
gamma glutamyltransferase
Gilead
Gilead Sciences/Gilead Sciences, Inc.
GNB
gender nonbinary people
HbA1c
hemoglobin A1c
HbcAb
hepatitis B core antibody
HbsAb
hepatitis B surface antibody
HbsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HDL
high-density lipoprotein
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HIV-1
human immunodeficiency virus type 1
HIV-2
human immunodeficiency virus type 2
HMG-CoA
3-hydroxy-3-methylglutaryl-coenzyme A
HTE
heavily treatment-experienced
IB
investigator’s brochure
ICF
informed consent form
ICH
International Council for Harmonisation (of Technical Requirements for 
Pharmaceuticals for Human Use)
IEC
independent ethics committee
IND
investigational new drug
ISR
injection site reaction
IQ
inhibitory quotient
IQR
interquartile range
IQ4
inhibitory quotient of 4
IQ6
inhibitory quotient of 6
IRB
institutional review board
IV
intravenous
IWRS
interactive web response system
LDH
lactate dehydrogenase
LDL
low-density lipoprotein
LEN
lenacapavir
LLOQ
lower limit of quantitation
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MDRI
mean duration of recent infections
MDZ
midazolam
MSM
men who have sex with men
MTCT
mother-to-child transmission

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NAAT
nucleic acid amplification test
NaS
LEN injection
NaSP
LEN injection with poloxamer
ND
not determined
NHP
nonhuman primate
NOAEL
no observed adverse effect level
NOEL
no observed effect level
NVP
nevirapine
OATP
organic anion transporting polypeptide
OBR
optimized background regimen
OL
open-label
OLE
open-label extension
paEC95
protein-adjusted 95% effective concentration 
PEG
polyethylene glycol
PEP
postexposure prophylaxis
P-gp
P-glycoprotein
PI
principal investigator
PIT
pitavastatin
PK
pharmacokinetic(s)
PWH
people with HIV
PO
oral
POC
proof of concept
PopPK
population pharmacokinetic
PR (interval)
electrocardiographic interval occurring between the onset of the P wave and the QRS 
complex representing time for atrial and ventricular depolarization, respectively
PrEP
pre-exposure prophylaxis
PS
Patient Safety
PT
preferred term
PTM
placebo-to-match
PY
person-years
Q1
first quartile
Q3
third quartile
Q6MO
every 6 months
QRS
electrocardiographic deflection between the beginning of the Q wave and termination 
of the S wave, representing time for ventricular depolarization
QT (interval)
electrocardiographic interval between the beginning of the Q wave and termination of 
the T wave, representing the time for both ventricular depolarization and 
repolarization to occur
QTcF
QT interval corrected for heart rate using the Fridericia formulation
RTV
RBP
ritonavir
randomized blinded phase

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RIF
rifampin
RNA
ribonucleic acid
ROS
rosuvastatin
rSE
relative standard error
SAE
serious adverse event
SAHCS
Southern African HIV Clinicians’ Society
SARS-COV-2
severe acute respiratory syndrome coronavirus 2
SC
subcutaneous
SD
standard deviation
SDV
source data verification
SHIV
simian human immunodeficiency virus
SIV
simian immunodeficiency virus
SOC
system organ class
SOP
standard operating procedure
SSRs
special situation reports
STI
sexually-transmitted infection
SUSAR
suspected unexpected serious adverse reaction
t1/2
estimate of the terminal elimination half-life of the drug, calculated by dividing the 
natural log of 2 by the terminal elimination rate constant (z)
TAF
tenofovir alafenamide (Vemlidy®)
TDF
tenofovir disoproxil fumarate (Viread®)
TEAE
treatment-emergent adverse event
TFV
tenofovir
TFV-DP
tenofovir diphosphate
TGM
transgender men
TGW
transgender women
Tmax
time (observed time point) of Cmax
TN
treatment naive
TPV
tipranavir
TV
Trichomonas Vaginalis
TVD
emtricitabine/tenofovir disoproxil fumarate (coformulated; Truvada®)
UNAIDS
Joint United Nations Programme on HIV/AIDS
UWDIS
University of Washington Drug Interaction Solutions
US
United States
VL
viral load
VORI
voriconazole
WHO
World Health Organization

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1.
INTRODUCTION
1.1.
Background
The Joint United Nations Programme on HIV/AIDS (UNAIDS) estimates that there were 
1.7 million new human immunodeficiency virus type 1 (HIV-1) infections in 2019, despite 
efforts to improve human immunodeficiency virus (HIV) testing, linkage to treatment, and 
prevention {UNAIDS 2020}. From 2008 through 2018, the rates of new HIV-1 infections in the 
United States (US) were consistently stable in the population as a whole, and stabilized at high 
rates in men who have sex with men (MSM) after more than a decade of increases {Centers for 
Disease Control and Prevention 2017}. However, notable disparities exist in the impact of the 
HIV epidemic on racial and ethnic minorities in the US, with Black and Hispanic/LatinX MSM 
being disproportionally affected {Hess 2017}. In 2018, Black Americans accounted for 13% of 
the US population but 42% of new HIV diagnoses {Becasen 2019}. Epidemiologic studies have 
estimated that 1 in 6 MSM, including 1 in 2 Black, 1 in 5 Latino, and 1 in 11 White MSM, will 
be diagnosed with HIV in their lifetime. The HIV epidemic has also disproportionally affected 
transgender women (TGW); in the US, an estimated 42% of TGW are living with HIV, with 
evidence of intersectional compounding of disproportionate risk, as the majority of TGW living 
with HIV are Black (62%) or Latina (35%) compared with less than 17% in White TGW 
{Centers for Disease Control and Prevention (CDC) 2021, Clark 2017}. Transgender men 
(TGM) and gender nonbinary people (GNB) are an understudied population and there are limited 
HIV incidence data; however, recent studies suggest ongoing HIV risk due to low HIV testing. 
In Brazil and Peru, the HIV epidemic also disproportionately affects MSM and TGW {Chow 
2016, Saffier 2017}. In South Africa, there is a generalized HIV epidemic, with growing 
recognition of disproportionately higher HIV incidence in MSM and TGW {Sandfort 2021, 
Sullivan 2020}. There remains an important unmet medical need globally for improved 
approaches to HIV prevention, including new options for HIV pre-exposure prophylaxis (PrEP). 
There are now 2 highly safe and efficacious options for HIV PrEP in MSM and TGW, Descovy® 
(DVY) and Truvada® (TVD), approved in 2019 and 2012, respectively. In locations where 
uptake of PrEP is high, there has been a significant population-level reduction in HIV incidence, 
demonstrating the potential for PrEP to contribute to population-wide HIV control {Grulich 
2018, Sullivan 2018}. However, for many individuals at risk for HIV, the uptake of daily oral 
PrEP has been a challenge. In the US, it is estimated that 1.1 million persons are at risk for HIV, 
yet only 240,000 are on DVY or TVD, and another > 400,000 started but have stopped daily oral 
PrEP. The underutilization of PrEP is particularly striking in populations that are 
disproportionately affected by HIV incidence, particularly in Black TGW {Klein 2019}. Several 
reasons likely contribute to the suboptimal uptake of PrEP, including lack of health system 
accessibility, medical mistrust due to experiences of homophobia, transphobia, and stigma, lack 
of willingness to take daily oral PrEP, concerns about side effects, and low self-perception of 
risk {Centers for Disease Control and Prevention (CDC) 2017, Wood 2019}. Among TGW, 
additional concerns about drug interactions with gender-affirming hormones have been identified 
as a significant barrier to PrEP uptake, despite increasing PrEP awareness {Poteat 2019}. Similar 
challenges have been identified as barriers to PrEP adherence and persistence in those who begin 

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daily oral PrEP, including stigma, an unacceptable dosing regimen, side effects, and low-risk 
perception. Even among TGW with health insurance and access to health care, significant 
disparities exist in daily oral PrEP uptake compared with cisgender MSM {Liu 2018}. Among 
TGM and transmasculine individuals in the US in a 2019 survey, 25% met eligibility criteria for 
PrEP, and yet only 11% had been prescribed PrEP {Golub 2019, Reisner 2019}. Recent data 
from gay-identified TGM who have sex with cisgender male partners revealed a higher 
eligibility for PrEP (55%) and yet only 22% of this sample were currently using PrEP.
Taken together, persistent disparities exist in ongoing HIV incidence in Black, 
Hispanic/LatinX MSM and TGW populations, with the greatest disparities in Black TGW in the 
US, and with continued low uptake of PrEP in these disproportionately affected populations 
globally. These barriers clearly highlight the need for additional PrEP options that may address 
disparities to PrEP uptake. LEN (6-monthly subcutaneous [SC] injections) have the potential to 
provide an additional option for populations at risk of HIV acquisition. LEN can help address 
substantial existing PrEP barriers including 1) requirement for daily adherence, 2) stigma and 
concerns about disclosure and discrimination or other social harms, 3) oral medication-associated 
adverse events (AEs) including gastrointestinal tolerability, and 4) challenges with access to 
health care providers in overburdened health systems or in geographical PrEP deserts. Thus, 
LEN has the potential to increase the uptake of, adherence to, and thereby the scalability of PrEP 
in those populations most disproportionately affected by HIV-1 which will contribute to the 
overarching goal of ending the HIV-1 epidemic. 
1.2.
Study Drugs
1.2.1.
Emtricitabine/Tenofovir Disoproxil Fumarate (F/TDF; Truvada) 
Truvada has been approved in 52 countries for PrEP in combination with safer sex practices in 
adults and in 34 countries for PrEP in combination with safer sex practices in adolescents. 
Further information is available in the local prescribing information for F/TDF (Truvada).
1.2.2.
Emtricitabine/Tenofovir Alafenamide (F/TAF; Descovy)
See Appendix 7 for US-specific text.
1.2.3.
Lenacapavir
1.2.3.1.
General Information
Lenacapavir (LEN) is a novel, first-in-class, multistage, selective inhibitor of HIV-1 capsid 
function being developed for the treatment of HIV-1 infection. LEN inhibits HIV at multiple 
points in the viral lifecycle, including interfering with capsid-mediated nuclear uptake of 
preintegration complexes and impairing virion production and proper capsid core formation. 
Virus produced in the presence of LEN display aberrantly shaped capsids. These malformed 
virus particles can still infect a new target cell but cannot replicate as they are unable to support 
reverse transcription without a properly formed capsid core.

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LEN is characterized by potent antiviral activity, a novel resistance profile, low human 
clearance, and low aqueous solubility. These combined characteristics allow LEN to be well 
suited for an extended-release parenteral formulation that can potentially be used as a novel 
long-acting antiretroviral (ARV) treatment administered monthly or less frequently.
For further information on LEN, refer to the current investigator’s brochure (IB) for LEN.
1.2.3.2.
Preclinical Pharmacology and Toxicology 
1.2.3.2.1.
Preclinical Pharmacology
LEN is a novel, potent, and highly selective multistage inhibitor of HIV-1 replication in the 
MT-4 T-cell line, in primary human cluster determinant (CD)4 positive T-lymphocytes, and in 
monocyte-derived macrophages, with half-maximal effective concentration (EC50) and 
selectivity index (half-maximal cytotoxic concentration [CC50]/EC50) values ranging from 
0.030 to 0.19 nM and 140,000 to > 1,670,000, respectively. LEN exhibits consistent antiviral 
activity against multiple HIV-1 clinical isolates with EC50 values ranging from 0.02 to 0.16 nM. 
LEN also shows potent antiviral activity against HIV-2 isolates but was at least 15-fold less 
active relative to HIV-1. The antiviral activity of LEN is affected by the level of infection in a 
manner similar to other ARVs but was still 5- to > 100-fold more potent relative to other ARVs 
at the highest multiplicity of infection tested.
LEN acts by inhibiting the proper functioning of HIV-1 capsid. LEN binds with high affinity and 
specificity to recombinant HIV-1 capsid protein and is a potent inhibitor of both early- and 
late-stage capsid-mediated processes essential for HIV-1 replication. LEN interferes with 
late-stage virus production and capsid core formation events and with an early-stage process 
occurring after reverse transcription but before the integration of viral DNA. LEN interferes with 
HIV-1 nuclear entry as measured by the accumulation of integration products and abortive 
2-LTR-containing circles, both of which form exclusively in the nucleus. The LEN binding site 
is highly conserved and is shared by host proteins implicated in HIV-1 nuclear entry.
Resistance studies indicated that LEN will be clinically active against HIV-1 variants with 
reduced susceptibility to other ARV classes. LEN shows synergistic antiviral activity and no 
antagonism in combination with agents from other ARV classes. LEN shows low cytotoxicity in 
primary human hepatocytes and in several nontarget human cell lines of different tissue origin 
(CC50 values > 44 to 50 μM). Resistance selection assays suggest that the target clinical plasma 
exposure for LEN (plasma concentrations > 16 nM, corresponding to an inhibitory quotient [IQ] 
of > 4) is expected to provide sufficient barrier to drug resistance development relative to other 
ARVs presently used in the clinic.
1.2.3.2.2.
Preclinical Toxicology
LEN was considered not genotoxic in either in vitro or in vivo assays. The potential for LEN to 
be phototoxic is low. The lack of systemic toxicity after LEN oral and SC administration is not 
unexpected based on the specific viral target. Expected local injection site reactions (ISRs) 
(granulomatous inflammation) were observed histologically after SC administration in rats, dogs, 

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and rabbits. The chronic granulomatous inflammation reaction at the injection site in rats and 
dogs is a foreign body response to the LEN SC depot and is an expected host response. 
Granulomatous inflammation has been observed after SC and intramuscular implantation of 
bioactive material, including those for HIV treatment {Anderson 1997, Shah 2017, Van't 
Klooster 2010}.
No adverse effects occurred in a male and female fertility study in rats that evaluated potential 
effects in the reproductive process resulting from SC administration of a long-acting LEN 
formulation. Endpoints included evaluation of estrous cycling, tubal transport, implantation, 
development of the preimplantation stages of the embryo in the female, and functional 
reproductive effects (alterations in libido and epididymal sperm maturation) in the male.
Embryo-fetal toxicity studies were conducted with LEN in rats via oral administration and in 
rabbits via intravenous (IV) administration. No adverse effects occurred upon external, visceral, 
and skeletal examination.
LEN was well tolerated after 6 months of exposure in rats when administered as a single 
100-mg/kg SC dose via polyethylene glycol (PEG) 300/ethanol/water solutions. No systemic 
toxicity was observed. LEN-related nonadverse edema, macroscopic thickening and/or tan 
discoloration, and correlative granulomatous inflammation were present at the SC injection site. 
LEN was also well tolerated after 9 months of exposure in dogs when administered as monthly 
SC doses of 20 or 40 mg/kg via PEG 300/ethanol/water solutions. No systemic toxicity was 
observed. LEN-related nonadverse edema and erythema and correlative microscopic 
observations of necrosis, granulomatous inflammation, mixed cell inflammation, and/or 
hemorrhage were present at the SC injection sites of animals administered LEN. Adverse SC 
injection site necrosis was noted in animals administered 20 mg/kg/dose with sodium hydroxide 
or 40 mg/kg/dose without sodium hydroxide in the vehicle.
1.2.3.3.
Efficacy of HIV Capsid Inhibitor in Nonhuman Primate PrEP Model
1.2.3.3.1.
Nonhuman Primate Proof of Concept for PrEP Efficacy
Proof-of-concept (POC) data to support evaluation of ARV drugs for HIV-1 prophylaxis were 
provided by the nonhuman primate (NHP) model for simian immunodeficiency virus 
(SIV)/simian human immunodeficiency virus (SHIV) transmission {Tsai 1995}. The model uses 
a repeat rectal challenge in rhesus macaques that has demonstrated prophylactic efficacy of 
tenofovir (TFV) (tenofovir disoproxil fumarate [TDF] or tenofovir alafenamide [TAF]) 
± emtricitabine (FTC), and has been further validated with correlative positive data from the 
highly-adherent participants in PrEP clinical studies receiving daily PrEP regimens (eg, iPrEx, 
IPERGAY, and DISCOVER). 

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1.2.3.3.2.
HIV Capsid Inhibitor Lenacapavir
Lenacapavir (LEN, formerly GS-6207) is the first clinically validated HIV capsid inhibitor with 
a unique, multistage mechanism of action {Link 2020}. Lenacapavir binds at a highly conserved 
interface between capsid protein (CA) monomers, thereby disrupting multiple late-stage and 
early-stage CA-mediated processes essential during viral replication. A long-acting formulation 
of LEN has demonstrated potent antiviral activity (up to 2.3 log10 decline in HIV-1 RNA after 
9 days of monotherapy) and a potential for twice-yearly SC dosing in a Phase 1b study 
(GS-US-200-4072){Link 2020}. Additionally, LEN has demonstrated potent antiviral activity in 
a Phase 2/3 study (GS-US-200-4625) in heavily treatment-experienced (HTE) people with 
HIV (PWH) failing their current regimen {Segal-Maurer 2021}.
1.2.3.3.3.
GS-CA1, A Close Analog of Lenacapavir 
GS-CA1, a close analog of LEN, is an HIV-1 capsid inhibitor with high antiviral efficacy and 
long-acting potential as an injectable drug (Figure 1, Table 1). GS-CA1 was used for NHP 
studies as the compound has demonstrated similar inhibition of HIV and SHIV replication in 
vitro {Yant 2019}.
Figure 1.
Similarity of LEN and GS-CA1 Chemical Structures
GS-6207 = Lenacapavir (LEN)
GS-6207
GS-CA1
H 
N , _ 
o~\\ 
0 

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Table 1.
Comparison of LEN and GS-CA1
Parameter
Analysis
LEN
GS-CA1
EC50, MT-4, HIV-1IIIb (nM)
0.100
0.240
Human paEC95, MT-4, HIV-1IIIb (nM)
4.02
8.26
EC50, human PBMCs, HIV-1, n=23 (nM)
0.050
0.130
EC50, rhesus PBMCs, SHIV-SF162P3 
(nM)
0.569
0.748
In Vitro 
Antiviral 
Activity
Rhesus-paEC95, rhPBMCs, 
SHIV-SF162P3 (nM)
ND
31.5
Compound 
MoA
Inhibits early or late stages of HIV 
replication
both
both
In Vitro 
Cytotoxicity
CC50, Primary Human CD4+ T Cells 
(μM)
> 50
> 50
Predicted 
Hepatic 
Clearance (3H)
Rat/dog/rhesus/
cyno/human (L/h/kg)
0.02/0.06/0.16/
0.05/0.01
0.06/0.15/0.07/
0.04/0.02
In Vivo 
Clearance
Rat/dog/rhesus/cyno (L/h/kg)
0.06/0.11/0.26/0.24
0.08/0.33/0.30/0.21
CC50 = half-maximal cytotoxic concentration; CD = cluster determinant; EC50 = half-maximal effective concentration; 
LEN = lenacapavir; MoA = mechanism of action; ND = not determined; paEC95 = protein-adjusted 95% effective concentration; 
PBMC = peripheral blood mononuclear cell; rh = rhesus; SHIV = simian human immunodeficiency virus 
1.2.3.3.4.
Efficacy of GS-CA1 in Nonhuman Primate Rectal Challenge PrEP Study
An NHP study was designed to determine the prophylactic efficacy of the capsid inhibitor 
GS-CA1, an analog of LEN with potent activity against both HIV and SIV capsids, in the 
preclinical macaque model of HIV/AIDS prevention.
Male and female treatment-naive rhesus macaques (n = 24) were given a single injection of 
GS-CA1 at 2 dose levels, 150 mg/kg and 300 mg/kg (n = 8 for each dose level), followed by 
repeat, escalating-dose weekly intrarectal challenges with SHIV. An SC injection of vehicle 
control, GS-CA1 (150 mg/kg), or GS-CA1 (300 mg/kg) was given to 8 macaques per group, 
1 week before virus exposure and followed by up to 15 weekly SHIV162p3 rectal challenges 
escalating from 10 (n = 8) to 33 (n = 2) to 100 (n = 5) median tissue culture infectious dose. 
During the study, 100% (8/8) of placebo-control animals became SHIV RNA positive after a 
median of 6.5 (range: 1-14) challenges. In contrast, all GS-CA1–dosed animals (150 mg/kg 
group) remained negative through Week 10 (9 challenges), with 6 of 8 becoming SHIV positive 
between Weeks 11 and 16. Similarly, all GS-CA1–dosed animals (300 mg/kg group) remained 
negative through Week 16 (15 challenges), with 3 of 8 becoming SHIV positive after Week 16. 
Cox regression analysis translated into 86% and 96% per-exposure risk reduction for the low and 
high dose groups, respectively, and both were highly significant (p = 0.0061 and p = 0.0002, 
respectively).

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Notably, infections were detected in the GS-CA1–dosed groups only after the drug exposures 
began to fall below the protein-adjusted 95% effective concentration (paEC95) (IQ = 1) when the 
GS-CA1 concentrations had fallen to 31.5 nM (Table 1). 
1.2.3.3.5.
Efficacy of GS-CA1 in Nonhuman Primate Vaginal Challenge PrEP Study
Female treatment-naive rhesus macaques (n = 24) were given a single injection of GS CA1 at 
2 dose levels, 150 mg/kg and 300 mg/kg (n = 8 for each dose level), followed by repeat weekly 
vaginal challenges with SHIV. An SC injection of vehicle control, GS-CA1 (150 mg/kg), or 
GS-CA1 (300 mg/kg) was given to 8 macaques per group, 1 week before virus exposure and 
followed by up to 10 weekly SHIV162p3 challenges.
During the study 100% (8/8) of placebo control animals became SHIV RNA positive after a 
median of 4 (range 3 to 8) challenges. The GS-CA1–dosed animals (150 mg/kg group) remained 
negative through Week 9 (8 challenges), with 6 of 8 becoming SHIV positive between Weeks 10 
and 18. The GS-CA1–dosed animals (300 mg/kg group) remained negative through Week 20 
(10 challenges) {Bekerman 2021}.
1.2.3.4.
Clinical Studies of Lenacapavir 
A summary of the relevant available data from studies not yet included in the IB at the time of 
the development of the GS-US-528-9023 protocol is presented. These data are from 4 Phase 1 
clinical studies in healthy volunteers (GS-US-200-4071, GS-US-200-4538, GS-US-200-5709 
and GS-US-200-4333), a Phase 1b study in PWH (GS-US-200-4072), an ongoing Phase 2/3 
study of LEN together with an optimized background regimen (OBR) in HTE PWH with 
multidrug resistant infection (GS-US-200-4625), and an ongoing Phase 2 study of LEN in 
combination with other ARV agents in ARV-naive PWH (GS-US-200-4334).
1.2.3.4.1.
Study GS-US-200-4071
GS-US-200-4071 is a completed Phase 1 study in healthy volunteers evaluating the safety, 
tolerability, and pharmacokinetics (PK) of single and multiple ascending doses of oral LEN as an 
oral liquid (solution)-filled capsule (50 or 100 mg/mL) or tablet (50 or 300 mg). 
Pharmacokinetic Results
The PK results presented here are from a database finalization date of 04 February 2020. As of 
this date, a total of 50 unique participants have received LEN or placebo capsules and 56 unique 
participants have received LEN or placebo tablets. Single- and multiple-dose PK data from the 
50-mg/mL solution-filled capsule and single-dose PK data from the tablets are presented below.
This study was originally designed as a single ascending dose/multiple ascending dose 
evaluation of solution in capsule formulations, with 10 days of washout between the single-dose 
and multiple-dose periods (Part A; Cohorts 1 and 2). Following receipt of PK data from these 
2 cohorts suggesting the t1/2 was longer than predicted from nonclinical studies, the study design 
was altered to single ascending dose (Parts B to D).

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Within each cohort in Parts A to C, participants were randomized to receive LEN (N = 8) or 
placebo (N = 2); all treatments were administered under fasted conditions. In Cohorts 1, 2, and 5, 
capsules containing 50 mg/mL solution were evaluated at doses of 30, 100, and 300 mg, 
respectively. Following development of a tablet formulation, 50- and 300-mg tablets were 
evaluated at doses of 300, 900, 1800, and 50 mg in Cohorts 7, 8, 9, and 10, respectively. In 
Part D, 2 cohorts received OL 300-mg LEN tablets (N = 8) given with a high-fat, high-calorie 
meal (Cohort 12) or with a low-fat, low-calorie meal (Cohort 13). A brief description of these 
cohorts is presented in Table 2.
Table 2.
GS-US-200-4071: LEN Formulations and Doses Evaluated
Formulation Description
Cohort
Dose (Number of capsules, fasting 
status)
Single-dose solution in capsule
50 mg/mL
Cohort 1
Cohort 2
Cohort 5
30 mg (1 capsule, fasted)
100 mg (3 capsules, fasted)
300 mg (8 capsules, fasted)
Multiple-dose (10 days, once-daily administration) solution in capsule
50 mg/mL
Cohort 1
Cohort 2
30 mg (1 capsule, fasted)
100 mg (3 capsules, fasted)
Single-dose tablet
50 mg
Cohort 10
50 mg (1 tablet, fasted)
300 mg
Cohort 7
Cohort 8
Cohort 9
Cohort 12
Cohort 13
300 mg (1 tablet, fasted)
900 mg (3 tablets, fasted)
1800 mg (6 tablets, fasted)
300 mg (1 tablet, high fat)a
300 mg (1 tablet, low fat)a
LEN = lenacapavir
High-fat meal included high calorie count (~1000 kcal, ~50% fat); low-fat meal included low calorie count (~400 kcal, 
~25% fat).
LEN concentration-time profiles and PK parameters after administration of single oral doses of 
LEN oral solution (50 mg/mL) in capsules are presented in Figure 2 and Table 3, respectively. 
Maximum plasma concentrations of LEN (Cmax) occurred between 7 and 29 hours (median Tmax), 
and the median t1/2 of LEN was approximately 13 days. Within each increase in dose, the 
increase in LEN exposure was less than dose proportional, suggesting that it exhibits solubility 
limited absorption (Table 3).

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Figure 2.
GS-US-200-4071: Mean (SD) LEN Plasma Concentration-Time Profiles 
Following Single-Dose Administration of Oral LEN Solution in Capsule 
(50 mg/mL; N = 8 per Cohort)
BLQ = below the limit of quantitation; LEN = lenacapavir; LLOQ = lower limit of quantitation
Treatments: A: LEN 30 mg (50-mg/mL solution-filled capsule); B: LEN 100 mg (50-mg/mL solution-filled capsule); 
E: LEN 300 mg (50-mg/mL solution-filled capsule) 
Values BLQ were treated as 0 for predose and one-half the LLOQ for postdose summaries.
Lower limit of quantitation is defined as 0.5 ng/mL for LEN.
Postdose concentration values ≤ LLOQ are not presented on the figure.
Figure was set to include all lower bar and mean/median values > 0 on the Y-axis.
Table 3.
GS-US-200-4071: Plasma Pharmacokinetic Parameters of LEN 
Following Single-Dose Oral Administration of 50 mg/mL Solution in 
Capsule (N = 8 per Cohort)
Parameter
Cohort 1; 30 mg 
(N = 8)
Cohort 2; 100 mg
(N = 8)
Cohort 5; 300 mg
(N = 8)
Cmax (ng/mL)
1.16 (23.9)
2.70 (55.4)
4.75 (52.4)
Tmax (h)a
29.0 (4.00, 108.00)
26.0 (4.00, 96.0)
7.00 (4.00, 28.00)
AUClast (h*ng/mL)b
145 (30.1)
318 (46.0)
2230 (52.9)
AUCinf (h*ng/mL)
ND
ND
2300 (51.3)
AUCexp (%)
ND
ND
3.76 (59.7)
AUC0-24h (h*ng/mL)
16.8 (26.9)
34.4 (47.4)
ND
Tlast (h)a
168 (168, 168)
168 (168, 168)
1540 (1340, 1850)
t1/2 (h)a [days]b
ND
ND
318 (293, 346) [13.3]
LEN = lenacapavir; ND = not determined; Q1 = first quartile; Q3 = third quartile
a
Median (Q1, Q3).
b
Median t1/2 is presented in days to 3 significant digits.
Pharmacokinetic parameters are presented as mean and percentage coefficient of variation (%CV) and shown to 3 significant 
digits.
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Lenacapavir 
Protocol GS-US-528-9023 
Gilead Sciences, Inc. 
FINAL 
Amendment4 
LEN PK parameters after 10 daily oral doses of LEN (50 mg/mL solution in capsule) are 
presented in Table 4. Consistent with its t112, following 10 days of multiple dosing, the mean 
LEN Cmax and AUC0.24h were at least IO-fold higher than those after a single dose (Table 3 and 
Table 4). 
Table 4. 
Parameter 
Cmax (ng/mL) 
Tmax (h)• 
AUC0.24h (h*ng/mL) 
GS-US-200-4071: Plasma Pharmacokinetic Parameters of LEN 
Following Multiple-Dose Oral Administration of 30 mg and 100 mg 
Solution in Capsule (50 mg/mL) (N = 8 per Cohort) 
Cohort 1; 30 mg (N = 8) 
Coho1·t 2; 100 mg (N = 8) 
50 mg/mL solution in capsule 
12.2 (17.1) 
41.2 (53.8) 
3.50 (1.75, 10.0) 
4.00 (4.00, 11.0) 
232 (17.9) 
842 (56.5) 
LEN = lenacapavit·; Ql = first quartile; Q3 = third quartile 
a 
Median (Ql, Q3). 
Pha1macokinetic parameters are presented as mean and percentage coefficient of variation (%CV) and shown to 3 significant 
digits. 
LEN concentration-time profiles and PK parameters after administration of single doses of LEN 
oral tablets administered either under fasted conditions or with a high-fat or low-fat meal are 
presented in Figure 3, Figure 4, and Table 5. As observed with the oral solution in capsule, LEN 
exposures increased in a less than dose-proportional manner over the range of 50 to 1800 mg 
following administrntion of LEN oral tablets. Maximal concentrntions (Cmax) of LEN were 
achieved approximately 4 to 8 hours postdose (Tmax), and LEN median t112 ranged from 10 to 
13 days (Table 5). In comparison with the oral solution in capsule, LEN 300-mg tablet AUCinf 
was approximately 3.5-fold higher than that observed following a 300-mg dose of 50 mg/mL 
solution in capsule (Table 3 and Table 5). 
CONFIDENTIAL 
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Lenacapavir
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Figure 3.
GS-US-200-4071: Mean (SD) LEN Plasma Concentration-Time 
Profiles Following Single-Dose Fasted Administration of Oral LEN 
Tablets (N = 8 per Cohort)
BLQ = below the limit of quantitation; LEN = lenacapavir; LLOQ = lower limit of quantitation
Treatments: F: LEN 300 mg (1  300-mg tablet); G: LEN 900 mg (3  300-mg tablets); H: LEN 1800 mg (6  300-mg tablets); 
I: LEN 50 mg (1  50-mg tablet)
Values BLQ were treated as 0 for predose and one-half the LLOQ for postdose summaries.
Lower limit of quantitation is defined as 0.5 ng/mL for LEN.
Postdose concentration values ≤ LLOQ are not presented on the figure.
Figure was set to include all lower bar and mean/median values > 0 on the Y-axis.
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Lenacapavir
Protocol GS-US-528-9023
FINAL
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
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Figure 4.
GS-US-200-4071: Mean (SD) LEN Plasma Concentration-Time 
Profiles Following Single-Dose Administration of Oral LEN 300 mg 
Tablets, Administered Fasted or with a High-Fat or Low-Fat Meal 
(N = 8 per Cohort)
BLQ = below the limit of quantitation; LEN = lenacapavir; LLOQ = lower limit of quantitation
Treatments: F: LEN 300 mg (1  300-mg tablet) (fasted); J: LEN 300 mg (1  300-mg tablet) with high-fat, high-calorie meal; 
K: LEN 300 mg (1  300-mg tablet) with light meal 
Values BLQ were treated as 0 for predose and one-half the LLOQ for postdose summaries.
Lower limit of quantitation is defined as 0.5 ng/mL for LEN.
Postdose concentration values ≤ LLOQ are not presented on the figure.
Figure was set to include all lower bar and mean/median values > 0 on the Y-axis.
Table 5.
GS-US-200-4071: Plasma Pharmacokinetic Parameters Following 
Single-Dose Oral Administration of LEN Tablets, Fasted, or 
Following a High- or Low-Fat Meal (N = 8 per Cohort)
Parameter
50 mg
(1  50-mg 
tablet)
(N = 8)
300 mg
(1  300-mg 
tablet)
(N = 8)
900 mg
(3  300-mg 
tablets)
(N = 8)
1800 mg
(6  300-mg 
tablets)
(N = 8)
300 mg + 
High-Fat 
Meal
(N = 8)
300 mg 
+ Low-Fat 
Meal
(N = 8)
AUCinf 
(h*ng/mL)
2650 (61.0)
7690 (57.8)
9790 (45.5)
14,100 (37.5)
8060 (39.8)
7290 (49.6)
Cmax (ng/mL)
8.24 (48.3)
33.7 (96.3)
43.9 (73.3)
53.8 (48.0)
35.0 (33.0)
32.6 (62.4)
Tmax (h)a
4.00
(4.00, 5.00)
4.00
(4.00, 6.00)
4.00
(3.00, 16.0)
8.00
(6.00, 8.00)
5.00
(4.00, 6.00)
6.00
(4.00, 8.00)
t1/2 (h)a 
[days]b
299 (270, 415) 
[12.5]
243 (204, 281) 
[10.1]
289 (255, 327) 
[12.0]
311 (262, 362) 
[13.0]
267 (244, 357) 
[11.1]
287 
(255, 322) 
[12.0]
LEN = lenacapavir; Q1 = first quartile; Q3 = third quartile
a
Median (Q1, Q3).
b
Median t1/2 is presented in days to 3 significant figures.
Pharmacokinetic parameters are presented as mean and percentage coefficient of variation (%CV) and shown to 3 significant 
digits. 
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Safety Results
Final safety results are available from a database finalization date of 04 February 2020 for the 
study. A total of 106 participants were randomized or enrolled into the study. Of the 
106 participants, 40 participants received LEN as capsules (50 mg/mL solution-filled capsules or 
100 mg/mL solution-filled capsules), 10 participants received placebo as solution-filled capsules, 
48 participants received LEN as tablets (50 mg or 300 mg), and 8 participants received placebo 
as tablets.
LEN was generally safe and well tolerated across all treatment groups. A total of 40 participants 
received LEN capsules, and 48 participants received LEN tablets, and 18 participants received 
placebo (capsules or tablets). The median duration of follow-up was 85 days for participants who 
received LEN or placebo as capsules and 64 days for participants who received LEN or placebo 
as tablets.
Adverse events were reported for 12 of 40 participants (30.0%) who received LEN capsules, 
14 of 48 participants (29.2%) who received LEN tablets, 5 of 18 participants (27.8%) who 
received placebo (capsules or tablets). For participants who received LEN either as capsules or 
tablets, the most commonly reported AE was headache (2 of 40 participants [5.0%] who received 
LEN capsules, 4 of 48 participants [8.3%] who received LEN tablets, and 1 of 18 participants 
[5.6%] who received placebo [capsules or tablets]). For participants who received placebo, the 
most commonly reported AE was back pain (2 of 18 participants [11.1%]).
Overall, Grade 1 AEs were reported for 12 of 40 participants (30.0%) who received LEN 
capsules, 14 of 48 participants (29.2%) who received LEN tablets, and 4 of 18 participants 
(22.2%) who received placebo (capsules or tablets). One participant who received placebo 
tablets, had Grade 2 AEs (limb abscess and staphylococcal infection). Overall, 4 participants 
(10.0%), who received LEN capsules, had AEs considered related to study drug. All 
treatment-related AEs were Grade 1 in severity and the only treatment-related AE occurring in 
more than 1 participant was headache (2 participants). No Grade 3 or 4 AEs, deaths, serious 
adverse event (SAEs), pregnancy, or AEs leading to permanent discontinuation of study drug 
were reported in any treatment group.
There were no clinically relevant changes from predose in median values for hematology or 
clinical chemistry (including metabolic parameters) across study parts. One participant who 
received LEN capsule (Cohort 4, 75 mg) had Grade 2 alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST) elevations on Day 29 (without graded laboratory abnormalities 
in other liver function tests) which were reported as a Grade 1 AE of hepatic enzyme increased 
and was considered related to study drug. The AE resolved by Day 57 at which time both ALT 
and AST values returned to predose values. There were no Grade 3 or 4 liver function test 
abnormalities or other hepatic AEs in the study.
The maximum abnormality grade for most of the participants was Grade 1 or Grade 2. Grade 3 
laboratory abnormalities reported for more than 1 participant were occult urine blood 
(3 participants who received LEN capsules, 7 participants who received LEN tablets and 
2 participants who received placebo as capsules) and elevated fasting low-density lipoprotein 

Lenacapavir
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(LDL) (2 participants who received LEN capsules and 2 participants who received placebo as 
tablets). Grade 4 laboratory abnormalities were reported for 1 participant who received LEN 
capsule (increase in triacylglycerol lipase) and 1 participant who received LEN tablet (increase 
in creatine kinase [CK]); both Grade 4 laboratory abnormalities were isolated events that 
returned to normal by the end of the study.
No notable changes from predose in vital signs (systolic blood pressure, diastolic blood pressure, 
pulse, temperature, and respiration rate) were observed in the study. No clinically significant 
electrocardiogram (ECG) abnormalities were reported during the study.
1.2.3.4.2.
Study GS-US-200-4538
GS-US-200-4538 (completed) was a blinded, Phase 1 study in healthy volunteers evaluating the 
safety, tolerability, and PK of single-ascending SC doses of LEN solution formulations. 
100 unique participants received single doses of either SC LEN formulations or placebo 
(4:1 ratio) (Table 8).
Table 6.
GS-US-200-4538: Solution Formulations and Doses
Formulation
Dose of LEN (volume injected)
300 mg/mL, free acid
(300 mg/mL FA)
300 mg (1 × 1 mL)
309 mg (1  1 mL)
927 mg (3  1 mL)
309 mg/mL, LEN injection
(309 mg/mL NaS)
927 mg (2  1.5 mL)
309 mg (1  2 mL)
155 mg/mL, LEN injection
(155 mg/mL NaS)
927 mg (3  2 mL)
300 mg/mL, LEN injection with poloxamer
(300 mg/mL NaSP)
900 mg (3  1 mL)
75 mg (1 × 1 mL)
75 mg/mL, LEN injection with poloxamer
(75 mg/mL NaSP)
225 mg (2 × 1.5 mL)
50 mg/mL, LEN injection with poloxamer
(50 mg/mL NaSP)
50 mg (1 × 1 mL)
FA = free acid; LEN = lenacapavir; NaS = LEN injection; NaSP = LEN injection with poloxamer 
Pharmacokinetic samples were collected for up to 449 days; safety and PK analyses are ongoing. 
Data from select formulations are presented below. 
Pharmacokinetic Results
Data following administration of single doses of SC LEN injection, 309 mg/mL (the SC LEN 
formulation intended to be used in the PrEP study) are presented below (Figure 5 and Table 7). 
Based on the PK data, a slow initial release of LEN was observed; however, concentrations 
exceeding an inhibitory quotient of 4 (IQ4; 4-fold higher than the paEC95 from MT-4 cells; 
3.87 ng/mL) were observed for at least 26 weeks following a single 927-mg dose (Figure 5 and 
Table 7). Similar PK profiles were observed following SC administration of a 927-mg dose 
administered as either 3 × 1.0 mL or 2 × 1.5 mL SC injections.

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Figure 5.
GS-US-200-4538: Mean (SD) Plasma Concentration Versus Time 
(Part B) (LEN PK Analysis Set)
BLQ = below the limit of quantitation; LEN = lenacapavir; LLOQ = lower limit of quantitation; PK = pharmacokinetic(s); 
SD = standard deviation
Values BLQ were treated as 0 for predose and one-half the LLOQ for postdose summaries. LLOQ was defined as 0.5 ng/mL for 
LEN. 
Postdose concentration values ≤ LLOQ are not presented on the figure. 
Figures on the linear scale in which lower bars were negative were truncated to 0 on the Y-axis. 
Table 7.
GS-US-200-4538: Summary Statistics of Plasma Pharmacokinetic 
Parameters LEN, 309 mg/mL NaS (LEN PK Analysis Set)
Parameter (Unit)
Cohort 5 (309 mg, 
309 mg/mL 1  1 mL)
Cohort 6 (927 mg, 
309 mg/mL 3  1 mL)
Cohort 7 (927 mg, 
309 mg/mL 2  1.5 mL)
AUC6month (h*ng/mL)
44,083.9 (33.2)
183,820.6 (39.3)
165,735.5 (27.6)
AUClast (h*ng/mL)
63,414.1 (28.6)
186,428.8 (52.9)
196,592.6 (49.2)
AUCinf (h*ng/mL)
66,173.0 (27.6)
226,534.1 (32)
232,382.4 (28.7)
AUCexp (%)
4.4 (43.8)
2.1 (112.5)
4.0 (44.5)
Cmax (ng/mL)
17.7 (50.3)
67.0 (54.8)
61.2 (43.5)
Tmax (h)
2352.22 
(1405.14, 3336.09)a
1848.00 
(1680.00, 2016.00)a
2016.94 
(1680.00, 2629.08)a
Tlast (h)
10,716.63 
(10,202.20, 10,910.43)a
9407.78 
(6431.48, 9432.14)a
10,756.65 
(9183.46, 10,756.97)a
t1/2 (h)
1859.94 
(1665.30, 2386.67)a
1277.39 
(1184.33, 1334.53)a
1939.25 
(1486.68, 2354.08)a
%CV = percentage coefficient of variation; LEN = lenacapavir; NaS = LEN injection; PK = pharmacokinetic; Q1 = first quartile; 
Q3 = third quartile
PK parameters are reported as mean (CV%)
a
Median (Q1, Q3)
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Amendment 4
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Safety Results
Adverse events were reported for 69 of 80 participants (86.3%) who received 1 of the SC LEN 
formulations (155 mg/mL NaS injection or 309 mg/mL [NaS] or 300 mg/mL with poloxamer 
[NaSP] or 50 mg/mL [NaSP] or 75 mg/mL [NaSP]), and 17 of 20 participants (85.0%) who 
received placebo (Table 8). No deaths or Grade 4 AEs were reported.
The most frequently reported AEs in all LEN cohorts were injection site induration 
(n = 52, 65.0%), injection site pain (n = 41, 51.3%), and injection site erythema (n = 37, 46.3%). 
Two participants (2.5%) who received LEN had Grade 3 AEs: 1 with tibia fracture and the other 
with limb abscess (the participant with the limb abscess also had Grade 2 AEs of cellulitis, 
localized infection, gastroenteritis, and headache). None of the SAEs were attributed to study 
drug.
Overall, 22 participants (27.5%) who received LEN and 6 participants (30.0%) who received 
placebo had maximum Grade 3 laboratory abnormalities. Grade 3 laboratory abnormalities 
reported for more than 1 participant in either overall treatment group were occult blood in urine 
(11 participants [13.8%] who received LEN and 4 participants [20.0%] who received placebo; all 
were due to menses or considered not clinically significant by the investigator); LDL cholesterol 
and fasting LDL cholesterol (each in 6 participants [7.5%] who received LEN and 1 participant 
[5.0%] who received placebo; all 7 participants had Grade 1 or 2 LDL abnormalities at predose); 
CK (2 participants [2.5%] who received LEN and 2 participants [10.0%] who received placebo; 
these were either abnormal predose and/or due to exercise); and lymphocytes (2 participants 
[2.5%] who received LEN; 1 participant had a viral infection at the time and the other participant 
was asymptomatic).
Isolated Grade 4 laboratory abnormalities were reported for 2 participants (2.5%) who received 
LEN (exercise-related increased CK in 1 participant, and increases in fasting triglycerides in 
another) and 1 participant (5.0%) who received placebo (increases in AST, CK, and lipase, with 
alternative etiologies).

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Table 8.
GS-US-200-4538: Adverse Events Reported for at Least 4 Participants 
in Either Overall Treatment Group (Safety Analysis Set)
Preferred Term
Overall
LEN
(All Cohorts)
(N = 80)
Overall
Placebo
(All Cohorts)
(N = 20)
Number (%) of Participants with Any 
Treatment-Emergent Adverse Event
69 (86.3%)
17 (85.0%)
Injection site induration
52 (65.0%)
6 (30.0%)
Injection site pain
41 (51.3%)
5 (25.0%)
Injection site erythema
37 (46.3%)
0
Injection site swelling
27 (33.8%)
2 (10.0%)
Headache
20 (25.0%)
5 (25.0%)
Injection site bruising
14 (17.5%)
8 (40.0%)
Injection site nodule
10 (12.5%)
0
Upper respiratory tract infection
6 (7.5%)
3 (15.0%)
Oropharyngeal pain
6 (7.5%)
1 (5.0%)
Back pain
4 (5.0%)
0
AE = adverse event; LEN = lenacapavir; MedDRA = Medical Dictionary for Regulatory Activities; PT = preferred term
Adverse events were coded according to MedDRA Version 23.1.
Treatment-emergent events began on or after the study drug start date, or led to premature study drug discontinuation.
Multiple AEs were counted only once per participant for each PT.
PTs were presented by descending order of total frequencies.
No notable changes from predose in vital signs (systolic blood pressure, diastolic blood pressure, 
pulse, temperature, and respiration rate) have been observed in the study. No clinically 
significant ECG abnormalities have been reported during the study.
1.2.3.4.3.
Study GS-US-200-5709
GS-US-200-5709 is a Phase 1, open-label, multiple-cohort study in healthy participants assessing 
the safety, tolerability, and PK of multiple-dose oral (tablet) and SC (309 mg/mL NaS) LEN.
In Cohorts 1 and 2 of this study, safety and PK of potential clinical regimens were evaluated.
Cohort 3 of this study characterized the safety and PK of LEN administered at clinically relevant 
therapeutic and supratherapeutic exposures; this regimen included oral LEN 600 mg 
administered twice daily for 11 days, with the last dose given in the morning on the 11th day. 

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Preliminary Pharmacokinetic Results
Cohort 1 (Phase 2/3 Regimen)
Lenacapavir plasma PK parameters and concentration-time profiles based on interim analysis up 
to Day 197 are presented in Table 9 and Figure 6.
Following oral LEN administration, mean concentration and its lower bound 90% CI were 
consistently maintained above IQ4 (15.5 ng/mL) from 2 hours postdose on Day 2 to Day 197. 
Following SC administration on Day 15, median Tmax occurred approximately 85 days postdose. 
Mean concentration (lower 90% CI) at Day 197 was 23.9 ng/mL (20.4 ng/mL). From 
Days 0 to 196, mean (%CV) AUC0-196 days was 134,000.5 h*ng/mL (55.9%).
Table 9.
GS-US-200-5709: Summary Statistics of LEN Plasma 
Pharmacokinetic Parameters (Cohort 1) (LEN PK Analysis Set)
Cohort 1
PK Parameter
Mean (%CV)
Day 1a
(N = 31)
Day 2a
(N = 31)
Day 8a
(N = 31)
Day 15-Day 197a
(N = 30)
Cmax (ng/mL)
22.0 (45.5)
40.4 (43.4)
39.3 (44.7)
58.7 (58.1)
Tmax (h)b [days]
4.00 (4.00, 
6.00) [0.17]
6.00 (4.00, 
8.00) [0.25]
6.00 (4.00, 
8.00) [0.25]
2028.0 (1682.5, 2688.2) 
[84.5]
Clast (ng/mL)
11.8 (57.2)
19.1 (40.0)
19.9 (40.4)
29.8 (67.6)
Tlast (h)b [days]
24.0 (24.0, 
24.0) [1.0]
144.0 (144.0, 
144.0) [6.0]
168.0 (168.0, 
168.0) [7.0]
4319.5 (2689.0, 4365.8) 
[180.0]
AUC0-196 days (h•ng/mL)
134,000.5 (55.9)
%CV = percentage coefficient of variation; LEN = lenacapavir; NaS = sodium salt; PK = pharmacokinetics; Q1 = first quartile; 
Q3 = third quartile; SC = subcutaneous
a
600 mg oral LEN (2  300 mg tablets) on Day 1 and Day 2, followed by 300 mg oral LEN (1  300 mg tablet) on Day 8, 
and 927 mg SC LEN (2  1.5 mL, 309 mg/mL NaS) on Day 15.
b
Median (Q1, Q3).
Cohort 2 (Simplified Regimen)
Lenacapavir plasma PK parameters and concentration-time profiles based on interim analysis up 
to Day 197 are presented in Table 10 and Figure 6.
Mean concentration and its lower bound 90% CI exceeded IQ1 (paEC95 from MT-4 cells; 
3.87 ng/mL) within 4 hours of dosing on Day 1 and were maintained above IQ1 through Day 2. 
Following 600 mg oral dose on Day 2, mean concentration and its lower bound 90% CI 
exceeded IQ4 (15.5 ng/mL) within 2 hours. Following SC administration on Day 1, median Tmax 
occurred approximately 70 days postdose. Mean LEN concentrations were consistently 
maintained above the efficacious target of IQ4 for the dosing interval. Mean concentrations 
(lower 90% CI) at Days 183 and 197 were 19.0 ng/mL (14.0 ng/mL) and 16.1 ng/mL 
(11.5 ng/mL), respectively. From Days 0 to 196, mean (%CV) AUC0-196 days was 

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152,884.0 h*ng/mL (56.4%). Lenacapavir Cmax and AUC0-196 days were within ± 8% and ± 15%, 
respectively, when compared with Cohort 1 exposures. From Days 0 to 182 (26 weeks postdose), 
mean (%CV) AUC0-182 days was 148,284.1 h*ng/mL (56.6%). Lenacapavir exposures for the 
dosing interval as assessed by AUC0-196 days for Cohort 1 and AUC0-182 days for Cohort 2 were 
within ± 11%.
Table 10.
GS-US-200-5709: Summary Statistics of LEN Plasma 
Pharmacokinetic Parameters (Cohort 2) (LEN PK Analysis Set)
Cohort 2
PK Parameter
Mean (%CV)
Day 1a
(N = 14)
Day 2-Day 197a
(N = 14)
Cmax (ng/mL)
20.1 (34.5)
67.1 (47.2)
Tmax (h)b
6.00 (4.00, 8.00)
1653.9 (985.0, 1991.2)
Tmax (days)
0.25
68.9
Clast (ng/mL)
14.4 (36.9)
21.4 (93.1)
Tlast (h)b
24.0 (24.0, 24.0)
4679.4 (4678.9, 4679.9)
Tlast (days)
1.0
195.0
AUC0-182 days (h•ng/mL)
148,284.1 (56.6)
%CV = percentage coefficient of variation; LEN = lenacapavir; NaS = sodium salt; PK = pharmacokinetics; Q1 = first quartile; 
Q3 = third quartile; SC = subcutaneous
a
927 mg SC LEN (2  1.5 mL, 309 mg/mL NaS) + 600 mg oral LEN (2  300 mg tablets) on Day 1 followed by 600 mg oral 
LEN (2  300 mg tablets) on Day 2.
b
Median (Q1, Q3).

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Figure 6.
GS-US-200-5709: Comparison of Mean (90% CI)a LEN Plasma 
Concentration-time Profiles Between Cohorts 1 and 2 (LEN PK 
Analysis Set)
CI = confidence interval; IQ4 = inhibitory quotient of 4; LEN = lenacapavir; PK = pharmacokinetic(s); SC = subcutaneous
Cohort 1 (Phase 2/3 regimen) was oral LEN 600 mg on Days 1 and 2, oral LEN 300 mg on Day 8, and SC LEN 927 mg on 
Day 15.
Cohort 2 (simplified regimen) was SC LEN 927 mg and oral LEN 600 mg on Day 1 and oral LEN 600 mg on Day 2.
a
Blue and pink shaded areas represent 90% CI band for the mean profile for Cohort 1 and Cohort 2, respectively; Horizontal 
dotted line shows IQ4 of 15.5 ng/mL. 
On X-axis, values −14 to 0 represent 14-day oral lead-in period for Cohort 1.
Cohort 3
Final PK data from Cohort 3 after administration of oral LEN 600 mg twice daily (Days 1 
through 10), followed by an oral LEN 600 mg dose in the morning on Day 11, are presented in 
Table 11. Intensive PK sampling (from 0 to 12 hours) was conducted on Days 1, 2, and 11 with 
sparse sampling on Days 3, 4, 8, 9, and 10. As shown, LEN exhibited significant accumulation 
over the course of 11 days of dosing, which is consistent with its long t1/2. Overall, Cmax observed 
in Cohort 3 was approximately 10-fold above the anticipated Cmax in the Phase 3 PrEP study.
100 
10 
C<1hort 1 IN 31 t. F'h 213 l'i"'>llmNI 
Cohort 2 CN~141; Slmpilflll<I 
avtmom 
• • • • • • • • • • • • • • • • • • • • • • • ,. • .. • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • 104, 
-14 
14 
28 
42 
56 
70 
84 
98 
112 
126 14,0 
154 '16-8 
182 
198 
i im,e (days) 

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Table 11.
GS-US-200-5709: Summary Statistics of LEN Plasma 
Pharmacokinetic Parameters (Cohort 3) (LEN PK Analysis Set)
LEN
600 mg oral LEN (2  300 mg tablets; AM dose) and
600 mg oral LEN (2  300 mg tablets; PM dose)
600 mg 
oral LEN 
(2  300 mg 
tablets; 
AM dose)
PK Parameter
Mean (%CV)
Day 1
(N = 15)
Day 2
(N = 15)
Day 3
(N = 15)
Day 4
(N = 15)
Day 8
(N = 15)
Day 9
(N = 15)
Day 10
(N = 15)
Day 11
(N = 15)
AUC0-12h 
(h•ng/mL)
135.4 (30.7)
894.4 
(47.2)
NC
NC
NC
NC
NC
9706.9 
(28.2)
Cmax (ng/mL)
19.0
(24.0)
96.4 
(49.5)
NC
NC
NC
NC
NC
1012.1 
(26.2)
Tmax (h)a
5.00
(4.00, 5.00)
8.00
(5.00, 
11.97)
NC
NC
NC
NC
NC
4.00 (4.00, 
5.00)
Clast (ng/mL)
11.1 (39.9)
88.4
(45.2)
241.6 
(41.2)
376.9 
(31.7)
604.8
(32.6)
680.5
(28.2)
751.9
(25.7)
787.7 (31.3)
Tlast (h)a
11.97
(11.97, 11.97)
11.97
(11.97, 
11.97)
11.97
(11.97, 
11.97)
11.97
(11.97, 
11.97)
11.97
(11.97, 
11.97)
11.97
(11.97, 
11.97)
11.97
(11.97, 
11.97)
11.97
(11.97, 
11.97)
C0 (ng/mL)
BLQ
(BLQ)
42.0
(47.2)
152.6 
(49.7)
342.4 
(39.6)
558.5
(36.8)
699.9
(33.2)
693.1
(35.0)
788.8
(32.1)
BLQ = below the limit of quantitation; %CV = percentage coefficient of variation; LEN = lenacapavir; LLOQ = lower limit of 
quantitation; NC = not calculated due to insufficient PK sampling; PK = pharmacokinetics; Q1 = first quartile; Q3 = third quartile
a
Median (Q1, Q3).
C0 represents concentration at time 0 hours.
Values BLQ were treated as 0 for predose and one-half the LLOQ for postdose summaries.
LLOQ was defined as 0.5 ng/mL for LEN.
Preliminary Safety Results
In Cohort 1, a total of 31 participants received at least 1 dose of study drug. The median 
(Q1, Q3) duration of follow-up was 264 (145, 372) days. No deaths, pregnancies, or SAEs were 
reported. Adverse events were reported for 27 of 31 participants (87.1%). Adverse events 
considered related to study drug were reported for 22 participants (71.0%). The most commonly 
reported AEs in Cohort 1 were injection site induration (16 of 31 participants, 51.6%), injection 
site pain (12 of 31 participants, 38.7%), and injection site erythema (10 of 31 participants, 
32.3%). All the AEs were Grade 1 or 2 in severity. No Grade 3 or 4 AEs were reported. One of 
31 participants (3.2%) prematurely discontinued study due to an AE (SARS-CoV-2 test 
positive). Graded laboratory abnormalities were reported for 23 of 31 participants (74.2%). The 
maximum abnormality grade for most of the participants was Grade 1 or 2. Five participants had 
Grade 3 laboratory abnormalities (increased creatine kinase, increased creatinine, increased 
fasting triglycerides, and glycosuria) and 1 participant had a Grade 4 laboratory abnormality 
(increased fasting triglycerides). None of the graded laboratory abnormalities were reported as 
AEs. 

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In Cohort 2, a total of 14 participants received at least 1 dose of study drug. The median 
(Q1, Q3) duration of follow-up was 136 (136, 150) days. No deaths, pregnancies, SAEs, AEs for 
confirmed or suspected COVID-19, or AEs leading to permanent discontinuation of study or 
study drug were reported. Adverse events were reported for all participants (14 of 
14 participants, 100.0%). The most commonly reported AEs were injection site induration (14 of 
14 participants, 100%), injection site erythema (5 of 14 participants, 35.7%), and injection site 
pain (4 of 14 participants, 28.6%). All AEs were Grade 1 or 2 in severity. No Grade 3 or 4 AEs 
were reported. Treatment-related AEs were reported for all participants (100.0%). All ISRs were 
considered related to study drug and accounted for all the treatment-related AEs. Graded 
laboratory abnormalities were reported for 7 of 14 participants (50.0%). The maximum 
abnormality grade for most of the participants was Grade 1 or 2. Three of 14 participants 
(21.4%) had Grade 3 laboratory abnormalities (increased creatine kinase, increased fasting LDL, 
fasting hypercholesterolemia, and increased fasting triglycerides) and no participants had 
Grade 4 laboratory abnormalities. None of the graded laboratory abnormalities were reported as 
AEs. 
No participant in Cohort 1 or 2 had notable changes in vital signs (systolic blood pressure, 
diastolic blood pressure, pulse, and temperature) or clinically significant ECG abnormalities. 
In Cohort 3, a total of 15 participants received at least 1 dose of study drug. The median 
(Q1, Q3) duration of follow-up was 71 (71, 71) days. No Grade 3 or 4 AEs, deaths, SAEs, 
treatment-related AEs, AEs for confirmed or suspected COVID-19, or AEs leading to permanent 
discontinuation of study or study drug were reported. The only AE reported was dyspepsia 
(6.7%, 1 of 15 participants). This AE was Grade 1 and not treatment related. Graded laboratory 
abnormalities were reported for 11 of 15 participants (73.3%). The maximum abnormality grade 
for the majority of participants was Grade 1 or 2, and there were no Grade 4 laboratory 
abnormalities. One participant had Grade 3 increased fasting triglycerides. None of the graded 
laboratory abnormalities were reported as AEs. No notable changes from predose values in vital 
signs (systolic blood pressure, diastolic blood pressure, pulse, and temperature) were observed 
during the study. No clinically significant ECG abnormalities were reported. Minimal changes 
were observed in baseline values for time-matched change from baseline in PR interval, QRS 
interval, QT interval, QTcF interval, and heart rate. These were not considered clinically 
relevant. 
1.2.3.4.4.
Study GS-US-200-4333
GS-US-200-4333 was a Phase 1 open-label, parallel design, single and multiple dose, multiple 
cohort study in healthy volunteers to evaluate the drug-drug interaction (DDI) potential of LEN. 
Available preliminary data for LEN capsules administered in combination with known strong 
cytochrome P450 enzyme (CYP)3A/P-glycoprotein (P-gp) inhibitors, darunavir 
(DRV)/cobicistat (COBI) and COBI, or LEN tablets administered in combination with a strong 
CYP3A/UGT/P-gp inducer, rifampin (RIF), an acid reducing agent, famotidine (FAM), and 
organic anion transporting polypeptide (OATP), breast cancer resistance protein (BCRP), P-gp 
or CYP3A substrates, pitavastatin (PIT), rosuvastatin (ROS), TAF, and midazolam (MDZ), 
respectively are presented below. 

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Cohort 1 served as a reference arm for Cohorts 2 and 3; participants received a single dose of 
LEN 300 mg alone (N = 30). Participants in Cohorts 2 and 3 received up to 90 days of COBI 
150 mg once daily, or DRV/COBI 800/150 mg once daily, respectively, with a single dose of 
LEN 300 mg coadministered in the morning on Day 11 (N = 29 per cohort). All doses were 
administered in the morning under fed conditions. PK samples were obtained up to Day 63 
(Cohort 1) and up to Day 35 (Cohorts 2 and 3) to characterize the PK of LEN in each treatment..
Preliminary PK data are presented below (Table 12). The median times at which maximum 
plasma concentrations of LEN were achieved ranged from 6 to 8 hours postdose (Tmax), and the 
median t1/2 of LEN administered alone was 12.3 days, and ranged from 16.8 to 18.8 days 
following administration with DRV/COBI or COBI. Coadministration of DRV/COBI or COBI 
with LEN resulted in an approximate 2-fold increase in Cmax and AUCinf. This 2-fold increase in 
LEN exposure was not deemed clinically relevant based on safety data from ongoing Phase 1 
studies at or above exposures anticipated to be achieved following administration of LEN with 
strong CYP3A/P-gp inhibitors. Accordingly, the use of strong CYP3A and P-gp inhibitors is 
permitted with LEN.
Table 12.
GS-US-200-4333: Preliminary Plasma Pharmacokinetic Parameters 
of LEN 300 mg Oral Capsule Following Administration Alone or with 
DRV/COBI (800/150 mg QD) or COBI (150 mg QD) (N = 29-30 per 
Cohort)
Parameter
LEN Alone 300 mg
(N = 30)
LEN 300 mg + COBI 
(N = 29)
LEN 300 mg + DRV/COBI
(N = 29)
Cmax (ng/mL)
30.6 (74.4)
57.8 (53.6)
61.5 (43.4)
AUClast (h•ng/mL)
10,400 (77.7)
16,100 (61.3)
14,200 (47.3)
AUCinf (h•ng/mL)
10,700 (76.8)
22,700 (62.5)
19,500 (48.7)
Tmax (hours)
8.00 (6.00, 48.0)
8.00 (6.00, 48.0)
6.00 (6.00, 8.00)
t1/2 (days) 
12.3 (9.97, 15.9)
18.8 (15.9, 24.2)
16.8 (14.5, 19.3)
%CV = percentage coefficient of variation; COBI = cobicistat; DRV = darunavir; LEN = lenacapavir; Q1 = first quartile; 
Q3 = third quartile; QD = once daily
Pharmacokinetic parameters are presented as mean (%CV) except Tmax, t1/2, and Tlast, which are presented as median (Q1, Q3), 
and shown to 3 significant digits 
Cohort 4 served as a reference arm for Cohorts 8 and 10; in Cohort 4, participants received a 
single dose of LEN 300 mg tablet alone (N = 27). Participants in Cohort 8 received 25 days of 
RIF (600 mg once daily), with LEN administered on Day 14, and participants in Cohort 10 
received a single dose of FAM (40 mg) 2 hours prior to LEN on Day 1 (N = 25 per cohort). All 
LEN doses were administered in the morning under fasted conditions. Pharmacokinetic samples 
were obtained up to Day 23 post-LEN dose (Cohorts 4 and 10) and up to Day 12 postdose 
(Cohort 8) to characterize the PK of LEN in each treatment..

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The median t1/2 of LEN administered alone was 13.4 days (Table 13). Following 
coadministration with RIF, LEN Cmax and AUCinf were approximately 2.5-fold and 5-fold lower, 
respectively, with a corresponding ~5-fold decrease in t1/2. These data support the existing 
recommendations to disallow the use of strong CYP3A4/UGT1A1/P-gp inducers with LEN. 
Following coadministration with FAM, no change in LEN exposure or t1/2 was observed; 
accordingly, administration of FAM and other acid reducing agents with LEN is therefore 
permitted. 
Table 13.
GS-US-200-4333: Preliminary Plasma Pharmacokinetic Parameters 
of LEN 300 mg Tablet Following Administration Alone or with RIF 
(600 mg QD) or FAM (40 mg) (N = 25-27 per cohort)
Parameter
LEN Alone 300 mg
(N = 27)
LEN 300 mg +RIF
(N = 25)
LEN 300 mg +FAM
(N = 25)
Cmax (ng/mL)
20.4 (102)
8.17 (59.6)
18.6 (60.2)
AUClast (h•ng/mL)
3880 (65.3)a
745 (48.1)b
4610 (58.3)
AUCinf (h•ng/mL)
5430 (58.0)a
786 (47.7)
6360 (52.9)
%AUCexp
30.0 (24.6)
5.20 (50.7)
28.5 (24.7)
Tmax (hours)
4.00 (4.00, 6.00)
24.0 (24.0, 48.0)
10.0 (4.00, 48.0)
t1/2 (hours)[days] 
321 (261, 374) [13.4]a
63.8 (59.5, 71.1) [2.66]b
270.0 (250, 331) [11.3]
Tlast (days) 
23.0 (23.0, 23.0)
12.0 (12.0, 12.0)
23.0 (23.0, 23.0)
%CV = percentage coefficient of variation; FAM = famotidine; LEN = lenacapavir; RIF = rifampin; Q1 = first quartile; 
Q3 = third quartile; QD = once daily
a
N = 25
b
N = 24 
Pharmacokinetic parameters are presented as mean (%CV) except Tmax, t1/2, and Tlast, which are presented as median (Q1, Q3), 
and shown to 3 significant digits.
In Cohort 11, participants received PIT, ROS, TAF, and MDZ alone, or coadministered with oral 
GS-LEN. Agents were either coadministered with oral LEN to evaluate the worst-case 
(coadministration; PIT, ROS, TAF, and MDZ), or up to 3 days after the last dose of LEN 
(PIT, MDZ) to evaluate the systemic drug interaction liability of LEN. Mean concentrations of 
LEN were at, or above clinically relevant Cmax concentrations (> 100 ng/mL) throughout the 
drug interaction evaluation (data not shown). Preliminary PK data are presented in Table 14, 
Table 15, Table 16, and Table 17..

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Table 14.
GS-US-200-4333: Preliminary Plasma Pharmacokinetic Parameters 
of PIT (2 mg) Following Administration Alone or With LEN 
(N = 30-31)
Parameter
PIT Alone
(N = 31)
PIT+ LEN 
(Day 15; 
Coadministration)
(N = 30)
PIT + LEN 
(Day 27; 3 Days Post LEN 
Dose)
(N = 30)
Cmax (ng/mL)
31.4 (52.8)
31.0 (48.1)
26.8 (50.5)
AUClast (h•ng/mL)
85.7 (44.9)a
96.8 (47.8)
76.2 (37.7)b
AUCinf (h•ng/mL)
90.9 (43.7)a
102 (46.9)
81.5 (36.1)b
Tmax (hours)
1.00 (1.00, 1.00)
1.00 (1.00, 2.00)
1.00 (1.00, 2.00)
t1/2 (hours)
11.7 (8.56, 13.5)a
10.9 (7.41, 14.7)
14.1 (10.2, 16.5)b
Tlast (hours) 
36.0 (24.0, 48.0)
36.0 (24.0, 48.0)
36.0 (24.0, 48.0)
%CV = percentage coefficient of variation; LEN = lenacapavir; PIT = pitavastatin; Q1 = first quartile; Q3 = third quartile
a
N = 25
b
N =24 
Pharmacokinetic parameters are presented as mean (%CV) except Tmax, t1/2, and Tlast, which are presented as median (Q1, Q3), 
and shown to 3 significant digits.
Table 15.
GS-US-200-4333: Preliminary Plasma Pharmacokinetic Parameters 
of ROS (5 mg) Following Administration Alone or With LEN (N = 30)
Parameter
ROS Alone
(N = 33)
ROS+ LEN 
(Day 18; Coadministration)
(N = 30)
Cmax (ng/mL)
1.06 (39.5)
1.87 (65.8)
AUClast (h•ng/mL)
10.8 (34.2)a
14.2 (48.1)b
AUCinf (h•ng/mL)
12.3 (33.9)a
16.1 (43.8)b
Tmax (hours)
5.00 (5.00, 5.00)
4.00 (2.00, 4.00)
t1/2 (hours)
13.1 (9.13, 17.8)a
17.3 (13.9, 20.8)b
Tlast (hours) 
36.0 (24.0, 48.0)
48.0 (36.0, 48.0)
%CV = percentage coefficient of variation; LEN = lenacapavir; ROS = rosuvastatin; Q1 = first quartile; Q3 = third quartile
a
N = 25
b
N = 24 
Pharmacokinetic parameters are presented as mean (%CV) except Tmax, t1/2, and Tlast, which are presented as median (Q1, Q3), 
and shown to 3 significant digits.

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Table 16.
GS-US-200-4333: Preliminary Plasma Pharmacokinetic Parameters 
of TAF (25 mg) and its Metabolite, TFV, Following Administration 
Alone or With LEN (N = 28-30)
Parameter
TAF Alone
(N = 30)
TAF+ LEN 
(Day 21; Coadministration)
(N = 30)
TAF
Cmax (ng/mL)
248 (52.5)
322 (52.6)
AUClast (h•ng/mL)
256 (54.3)
328 (35.3)
AUCinf (h•ng/mL)
262 (54.4)a
361 (27.8)b
Tmax (hours)
1.00 (0.50, 1.13)
1.00 (0.50, 1.50)
t1/2 (hours)
0.38 (0.34, 0.42)a
0.41 (0.35, 0.43)b
TFV
Cmax (ng/mL)
6.29 (30)
7.97 (34.2)
AUClast (h•ng/mL)
171 (26.3)
259 (22.2)c
AUCinf (h•ng/mL)
206 (25.9)
322 (21)
%CV = percentage coefficient of variation; LEN = lenacapavir; TAF = tenofovir alafenamide; TFV = tenofovir; 
Q1 = first quartile; Q3 = third quartile
a
N = 25
b
N =24
Pharmacokinetic parameters are presented as mean (%CV) except Tmax, and t1/2, which are presented as median (Q1, Q3), and 
shown to 3 significant digits.
Table 17.
GS-US-200-4333: Preliminary Plasma Pharmacokinetic Parameters 
of MDZ (2.5 mg) and its Metabolite, 1-OH-MDZ, Following 
Administration Alone or with LEN (N = 30-31)
Parameter
MDZ Alone
(N = 31)
MDZ+ LEN 
(Day 24; Coadministration)
(N = 30)
MDZ + LEN 
(Day 25; 1 Day Post LEN Dose)
(N = 30)
MDZ
Cmax (ng/mL)
9.46 (29.1)
17.7 (22.7)
19.7 (23.8)
AUClast (h•ng/mL)
50.5 (35.1)
129 (24.9)
171 (27.7)
AUCinf (h•ng/mL)
52.9 (36.3)
170 (30.6)
208 (34.5)
Tmax (hours)
2.00 (1.00, 2.00)
2.00 (1.25, 4.00)
2.00 (1.00, 2.00)
t1/2 (hours)
5.18 (3.96, 7.2)
7.05 (6.06, 9.05)
9.38 (7.04, 11.4)
1-OH-MDZ
Cmax (ng/mL)
2.64 (44.4)
1.39 (34.9)
1.33 (36.5)
AUClast (h•ng/mL)
13.1 (39.2)
8.12 (28.6)
9.7 (35.9)
AUCinf (h•ng/mL)
13.9 (38.9)
9.56 (30)
11.5 (43)
%CV = percentage coefficient of variation; LEN = lenacapavir; MDZ = midazolam; Q1 = first quartile; Q3 = third quartile
Pharmacokinetic parameters are presented as mean (%CV) except Tmax, and t1/2, which are presented as median (Q1, Q3), and 
shown to 3 significant digits.
I 
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PIT AUC and Cmax were not affected following administration with LEN, suggesting LEN does 
not inhibit OATP transporters (Table 14). ROS AUC and Cmax were approximately 1.3 to 
1.6-fold higher following coadministration with LEN (Table 15), suggesting LEN weakly 
inhibits BCRP transporters. TAF and TFV AUC and Cmax were 1.2- to 1.6- fold higher following 
coadministration with LEN (Table 16), suggesting LEN is a weak inhibitor of P-gp transporters. 
MDZ AUC and Cmax were approximately 2- to 4- fold higher, and 1-OH-MDZ AUC and Cmax 
were correspondingly lower following coadministration with LEN (Table 17), suggesting LEN is 
a moderate inhibitor of CYP3A. Coadministration of a single dose of LEN with strong 
UGT1A1/CYP3A4/P-gp inhibitor (ATV+COBI) resulted in increases in LEN AUCinf of 306%. 
The larger effect observed with ATV+COBI relative to COBI alone suggests that UGT1A1 is an 
elimination pathway for LEN. Strong and moderate inducers of CYP3A4/P-gp decreased LEN 
exposures by 84% and 56% (RIF and efavirenz [EFV], respectively) and may result in loss of 
virologic response; therefore, concomitant use of strong and moderate inducers of CYP3A4/P-gp 
with LEN should be avoided (Please refer to Section 5.4 for prior and concomitant medications 
that are prohibited).
No SAEs, Grade 4 AEs, or deaths were reported during the study. A total of 8 participants had 
AEs that led to premature discontinuation of study drug, of which only 1 was considered related 
to LEN treatment (transaminases increased). Across all cohorts, most AEs reported were Grade 1 
or Grade 2 in severity. Grade 3 AEs and Grade 3 laboratory abnormalities were reported most 
frequently after treatment with ATV+COBI and ATV+COBI with LEN; most of these findings 
were associated with transient elevations in total bilirubin concentrations that were expected with 
ATV+COBI treatment. No other clinically relevant changes for clinical laboratory evaluations or 
vital signs were observed, and no clinically significant ECG abnormalities were reported. 
1.2.3.4.5.
Study GS-US-200-4072
GS-US-200-4072 is a completed, Phase 1b, randomized, double-blinded, placebo-controlled, 
multicohort, dose-ranging study evaluating the safety, tolerability, PK, and short-term antiviral 
activity of monotherapy with SC doses of a LEN free-acid suspension (100 mg/mL) in PWH 
who were either ARV therapy (ART) naive or ART experienced but capsid inhibitor naive.
This study enrolled 5 cohorts to receive LEN (20, 50, 150, 450, and 750 mg) or placebo. Within 
each cohort (n = 8), participants were randomized in a 3:1 ratio to receive active LEN (n = 6) or 
placebo (n = 2). A single dose of LEN or placebo was administered as SC injection(s) on Day 1.
Disposition and Baseline Characteristics
Of the 41 randomized participants, 29 participants received a single dose of LEN (6 participants 
each in the LEN 20, 50, 150, and 450 mg groups and 5 participants in the LEN 750 mg group), 
and 10 participants received a single dose of placebo. Two randomized participants did not 
receive study drug due to withdrawal of consent. Of the 39 randomized participants who 
received study drug, 38 participants completed the study, and 1 participant (LEN 450 mg group) 
prematurely discontinued the study due to being lost to follow-up.

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The median study duration (number of days between Day 1 and the last study date) was 226 days 
and ranged from 169 to 233 days across the 5 LEN cohorts.
The majority of participants were male (89.7%, 35 participants), White (53.8%, 21 participants), 
and not Hispanic or Latino (84.6%, 33 participants). The median age was 33 years (range: 19 to 
65 years). The median (first quartile [Q1], third quartile [Q3]) baseline HIV-1 RNA was 
4.53 (4.30, 4.74) log10 copies/mL, and the median (Q1, Q3) CD4 cell count was 463 
(359, 614) cells/μL. The majority of participants were ART naive (82.1%).
Virologic Efficacy Results
Levels of HIV-1 RNA decreased following initiation of study drug (Figure 7). The mean (SD) 
maximum HIV-1 RNA reductions from baseline through Day 10 were 1.35 (0.318), 1.79 (0.476), 
1.76 (0.203), 2.20 (0.468), and 2.26 (0.662) log10 copies/mL at doses of LEN 20, 50, 150, 450, 
and 750 mg, respectively. All participants who received ≥ 50 mg LEN had a > 1 log10 copies/mL 
reduction in their HIV-1 RNA through Day 10. Overall, antiviral activity was comparable across 
the dose range of 50 to 750 mg but lower at the 20 mg dose.
Figure 7.
GS-US-200-4072: Mean and 95% CI Change from Baseline in 
HIV-1 RNA (log10 copies/mL) (Full Analysis Set)
BL = baseline; CI = confidence interval; HIV-1 = human immunodeficiency virus type 1; GS-6207 = lenacapavir (LEN)
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Pharmacokinetic Results
The median Tmax of LEN ranged between approximately 6 and 21 days postdose across treatment 
groups. The median t1/2 values of LEN ranged between approximately 36 and 45 days and were 
comparable across the doses evaluated. 
Following single-dose administration of LEN 20, 50, 150, 450, and 750 mg, mean LEN plasma 
concentrations on Day 10 were 2.6, 4.4, 12.9, 38.2, and 79.2 ng/mL, respectively. These values 
correspond to approximately 0.7-, 1.1-, 3.3-, 9.9-, and 20.5-fold higher, respectively, than the 
protein-adjusted 95% effective concentration for wild-type HIV-1 (3.87 ng/mL) in MT-4 cells.
Safety Results
Up to Day 10, AEs were reported for 21 of 29 participants (72.4%) who received LEN across the 
LEN treatment groups and 4 of 10 participants (40.0%) who received placebo. There were no 
notable differences in the number of participants who had AEs up to Day 10 across the 
increasing doses of LEN for doses > 20 mg. For participants who received LEN, the most 
commonly reported AEs were injection site pain (55.2%, 16 participants), injection site erythema 
(34.5%, 10 participants), and injection site induration (24.1%, 7 participants). The only AEs 
reported for > 1 participant in the placebo group were injection site pain (30.0%, 3 participants) 
and headache (20.0%, 2 participants).
No deaths, Grade 4 AEs, or AEs leading to study drug discontinuation were reported. 
One participant experienced a Grade 3 SAE of atrial fibrillation, which occurred following 
methamphetamine use and was not considered related to study drug by the investigator. After the 
data cut, the same participant with a history of hypertension, hyperlipidemia, and tobacco abuse 
experienced Grade 4 SAEs of coronary artery disease and acute myocardial infarction, Grade 3 
AE of unstable angina and angina pectoris, and Grade 3 SAE of noncardiac chest pain. All AEs 
and SAEs were considered not related to study drug by the investigator. Another participant 
experienced a Grade 2 SAE of small intestinal obstruction which was considered not related to 
study drug by the investigator. 
A total of 5 participants (17.2%) who received LEN and 3 participants (30.0%) who received 
placebo had a Grade 3 or Grade 4 laboratory abnormality reported. The only Grade 3 
or 4 abnormalities reported for more than 1 participant in the LEN group were transient CK 
elevations (n = 2 participants), attributed to recent strenuous exercise. No Grade 3 or 4 laboratory 
abnormality was reported for more than 1 participant in the placebo group during the study. 
1.2.3.4.6.
Study GS-US-200-4625 
Study GS-US-200-4625 is a Phase 2/3, placebo-controlled, multicenter study of LEN together 
with an OBR in HTE PWH with multidrug resistant infection.
Participants in Cohort 1 were randomized to receive either oral LEN or placebo, while also 
continuing their failing regimen during a 14-day Functional Monotherapy Period. After this 
period, participants who received oral LEN switched to SC LEN (972 mg; 309 mg/mL; 

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2  1.5 mL) and OBR, and participants who had received placebo then received oral LEN and 
OBR for 14 days prior to switching to SC LEN (972 mg; 309 mg/mL; 2  1.5 mL) and OBR. 
Participants in Cohort 2 received oral LEN and OBR for 14 days before switching to SC LEN 
and OBR. Cohort 2 includes participants that did not meet the criteria for randomization in 
Cohort 1 or who joined the study after Cohort 1 was fully enrolled.
Disposition and Baseline Characteristics
Overall in Cohorts 1 and 2, 72 participants were enrolled in the study and were included in the 
Safety Analysis Set (Cohort 1: LEN, 24 participants; placebo, 12 participants; Cohort 2: 
LEN + OBR, 36 participants). All 72 participants completed the Functional Monotherapy 
(Cohort 1, 36 participants) or Oral Lead-in Period (Cohort 2, 36 participants), and all received 
Day 1 SC LEN.
Of the 72 participants who received Day 1 SC LEN, 32 participants (all from Cohort 2) are 
continuing study drug in the Main Phase, and 37 participants completed study drug in the Main 
Phase (Week 52). Three participants discontinued study drug during the Main Phase. Reasons for 
premature discontinuation were lost to follow-up, investigator’s discretion, and death 
(1 participant each, 1.4%). One participant who decided not to receive SC LEN at Week 52 and 
not to continue the study completed the study at the Week 52 visit. Thirty-six participants 
entered into the Extension Phase (Cohort 1: 34 participants; Cohort 2: 2 participants). Of the 
36 participants who entered the Extension Phase, 34 participants are continuing study drug. 
Two participants discontinued study drug during the Extension Phase. Reasons for premature 
discontinuation were AE and lost to follow-up (1 participant each, 2.8%).
In Cohort 1, demographic and baseline characteristics were generally similar between the LEN 
and placebo groups. The majority of participants were male (72.2%; 26 of 36 participants), 
White (45.7%, 16 participants) or Black (45.7%, 16 participants), and not Hispanic or Latino 
(71.4%, 25 participants). Median age was 54 years (range: 24 to 71 years). Baseline disease 
characteristics were consistent with the profile of the HTE population, with a median (range) 
number of prior ARV medications of 9 (2, 24), and 75% of participants with CD4 cell count 
< 200 cells/μL (a hallmark of severe immune suppression and the criterion to diagnose AIDS). 
Differences were seen between the LEN and placebo groups in HIV-1 RNA (log10 copies/mL), 
HIV-1 RNA categories, and CD4 cell counts and CD4 percentage.
In Cohort 2, the majority of participants were male (77.8%; 28 of 36 participants), 
White (36.1%, 13 participants) or Asian (33.3%, 12 participants), and not Hispanic or 
Latino (86.1%, 31 participants). Median age was 49 years (range: 23 to 78 years). The baseline 
disease characteristics, prior ARVs, failing regimens, OBR regimen, and resistance 
characteristics for Cohort 2 were consistent with the profile of the HTE population. 

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Primary Virologic Efficacy Results
A significantly greater percentage of participants receiving LEN had a reduction in HIV-1 RNA 
of ≥ 0.5 log10 copies/mL from baseline at the end of the Functional Monotherapy Period than 
those receiving placebo (87.5% vs 16.7%; P < 0.0001). To address the imbalance in baseline 
HIV-1 RNA between the LEN and placebo groups, a post hoc analysis of the primary efficacy 
endpoint with adjustment for baseline HIV-1 RNA using rank analysis of covariance was 
conducted. Results from this post hoc analysis confirmed that the difference between the groups 
remained statistically significant: 87.5% versus 16.7%; P = 0.0003. To address the imbalance in 
baseline CD4 cell count between the LEN and placebo groups, post hoc analyses of the primary 
efficacy endpoint were conducted in participants with comparable or clinically relevant CD4 cell 
counts. These analyses showed that the difference between groups remained statistically 
significant for the comparison between participants in the LEN group with a low baseline 
CD4 cell count (median: 98.5 cells/μL; n = 12) and participants in the placebo group (median: 
84.5 cells/μL; n = 12) (P = 0.0008) and between participants in the LEN and placebo groups with 
a baseline CD4 cell count < 200 cells/μL (P < 0.0001).
Secondary Efficacy Endpoints
At Week 26, the percentages of participants in Cohorts 1 and 2 with HIV-1 RNA < 50 and 
< 200 copies/mL using the US FDA-defined snapshot algorithm were 80.6% (58 of 
72 participants) and 87.5% (63 of 72 participants), respectively.
At Week 52, the percentages of participants in Cohorts 1 and 2 with HIV-1 RNA < 50 and 
< 200 copies/mL using the US FDA-defined snapshot algorithm were 77.8% (35 of 
45 participants) and 82.2% (37 of 45 participants), respectively.
Preliminary Pharmacokinetic Results
Lenacapavir plasma PK parameters and concentration-time profiles based on interim analysis at 
Week 52 are presented in Table 18 and Figure 8. The key findings were: 
•
Mean LEN concentrations and the lower bound 90% CI reached IQ4 (15.5 ng/mL) in 
approximately 1 hour postdose on Day 1 with majority of the participants (> 80%) achieving 
concentrations above IQ4 at 4 hours postdose on Day 1 and continued to be above IQ4 
through the end of dosing intervals at Week 26 and Week 52. 
•
For the Oral Lead-in Period, mean (%CV) predose concentrations, and the lower bound 
90% CI, on Day 2 (55.0 ng/mL [116%]; lower 90% CI = 42.3 ng/mL), on Day 8 (61.0 ng/mL 
[70.9%]; lower 90% CI = 52.5 ng/mL), and Day 1 SC (50.5 ng/mL [66.1%]; lower 90% 
CI = 44.0 ng/mL) exceeded IQ4.
•
For the maintenance period, mean (%CV) predose concentrations, and the lower bound 
90% CI, at Week 26 (35.9 ng/mL [57.1%]; lower 90% CI = 31.8 ng/mL) and at Week 52 
(40.8 ng/mL [51.0%]; lower 90% CI = 35.0 ng/mL) exceeded IQ4.
•
Ctrough at Week 52 was 1.14-fold higher compared with Week 26 indicating minimal 
accumulation over the dosing period of 52 weeks.

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Table 18.
GS-US-200-4625: Plasma Pharmacokinetic Parameters of LEN 
Following Oral 600 mg Daily Dosing (Days 1 and 2) and 300 mg 
(Day 8), With SC LEN Injection Every 26 Weeks Starting From 
Day 15 (Day 1 SC)
PK Parameter 
Mean (%CV)
Day 2a
(N = 70)
Day 8a
(N = 72)
Day 1 SC
(N = 72)
Week 26
(N = 69)
Week 52
(N = 37)
Ctrough (ng/mL)
55.0 (116)
61.0 (70.9)
50.5 (66.1)
35.9 (57.1)
40.8 (51.0)
Lower 90% CI of Ctrough (ng/mL)
42.3
52.5
44.0
31.8
35.0
%CV = percentage coefficient of variance; LEN = lenacapavir; SC = subcutaneous 
a
For Cohort 1B, Days 16 and 22 reflect Days 2 and 8 respectively, relative to the start of oral LEN.
Figure 8.
GS-US-200-4625: Mean (SD) LEN Plasma Concentration-time 
Profiles (Semilogarithmic Scale) Following Oral 600 mg Daily Dosing 
(Days 1 and 2) and 300 mg (Day 8), With SC LEN Injection Every 
26 Weeks Starting From Day 15 (Day 1 SC)
IQ = inhibitory quotient; LEN = lenacapavir; SC = subcutaneous; SD = standard deviation 
On the X-axis, −2 to 0 represents 2-Week Oral Lead-in Period
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Preliminary Safety Results
Functional Monotherapy Period
During the Functional Monotherapy Period, the percentages of participants who experienced 
AEs were: LEN 37.5% (9 of 24 participants); placebo 25.0% (3 of 12 participants). Nausea was 
the only AE reported in > 1 participant (LEN 12.5%, 3 participants).
The only AE considered related to study drugs that was reported in > 1 participant was nausea 
(8.3%, 2 participants; LEN group).
No deaths, SAEs, AEs leading to discontinuation of study drug, or Grade 3 or higher AEs, were 
reported in either the LEN or placebo group.
All LEN Analysis
The percentage of participants who received LEN in Cohorts 1 and 2 and experienced AEs was 
93.1% (67 of 72 participants). The 3 most commonly reported AEs were injection site pain 
(37.5%, 27 of 72 participants), injection site swelling (33.3%, 24 participants), and injection site 
erythema (27.8%, 20 participants). Some ISRs were attributed to enfuvirtide.
The majority of AEs were Grade 1 or 2 in severity. Grade 3 or higher AEs were reported for 
16 participants (22.2%). Grade 3 or higher AEs that were reported for ≥ 2 participants were 
injection site erythema (5.6%, 4 participants), injection site edema, injection site pain, and 
injection site swelling (2.8%, 2 participants each). Four participants experienced Grade 3 or 
higher AEs that were considered related to study drug: rash and abdominal abscess, injection site 
swelling and injection site erythema, injection site pain, and immune reconstitution inflammatory 
syndrome (1 participant each). The AE of abdominal abscess was an abscess at the injection site 
due to secondary infection most likely because the participant scratched the injection site.
Overall, 66.7% (48 of 72 participants) experienced treatment-related AEs. The most commonly 
reported treatment-related AEs were injection site pain and injection site swelling 
(30.6%, 22 participants), injection site erythema (25.0%, 18 participants), and injection site 
nodule (23.6%, 17 participants). 
Serious adverse events were reported for 11.1% (8 of 72 participants). The only SAE that was 
reported for more than 1 participant was COVID-19. None of these events led to discontinuation 
of study drug. No SAEs were considered related to study drug. One SAE of cancer resulted in 
death, which was also reported as an AE leading to premature discontinuation from the study. 
This participant in Cohort 2 died on Study Day 90, and the cause of death was reported as 
cancer. The event was previously reported in the Week 26 analysis and was considered not 
related to study drug.
While no participant discontinued study drug due to AE at the Week 26 analysis, 1 participant 
(1.4%) in Cohort 1 experienced a Grade 1 AE of injection site nodule during the Extension 
Phase, leading to premature discontinuation from the study after receiving the Week 52 SC LEN 
injection. The event was considered related to study drug.

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Overall, 45 participants (62.5%) experienced a study drug-related ISR. All were Grade 1 or 2 
with the exception of 2 participants (2.8%) who experienced a Grade 3 ISR that resolved after a 
few days. No Grade 3 or 4 ISRs were reported beyond Week 26. The median (Q1, Q3) total 
duration of any study drug-related ISR was 8 (3, 67) days. The most frequently reported study 
drug-related ISRs (reported in ≥ 10% of participants overall) and duration in median (Q1, Q3) 
days were as follows:
•
Injection site swelling (30.6%, 22 participants), 12 (6, 30) days
•
Injection site pain (30.6%, 22 participants), 3 (2, 7) days
•
Injection site nodule (23.6%, 17 participants), 180 (111, 330) days
•
Injection site erythema (25%, 18 participants), 6 (3, 8) days
•
Injection site induration (15.3%, 11 participants), 118 (15, 182) days
A numerically lower percentage of participants had ISRs after the second LEN injection 
compared with the first injection.
Overall, 17 participants experienced study drug-related injection site nodule, and 11 participants 
experienced study drug-related injection site induration. All events were Grade 1 or 2. Outcomes 
of injection site nodule and induration events reported due to Day 1 SC injection were as 
follows:
•
Nodules: Ongoing (9/23 [39.1%]); Resolved (14/23 [60.9%])
•
Indurations: Ongoing (1/8 [12.5%]); Resolved (7/8 [87.5%])
The median (Q1, Q3) duration of resolved injection site nodule and injection site induration due 
to Day 1 SC injection was 107 (70, 227) days and 43 (15, 196) days, respectively.
Outcomes of injection site nodule and induration events reported due to the second LEN 
injection at Week 26 were as follows:
•
Nodules: Ongoing (12/14 [85.7%]); Resolved (2/14 [14.3%])
•
Indurations: Ongoing (3/7 [42.9%]); Resolved (4/7 [57.1%])
The median (Q1, Q3) duration of resolved injection site nodule and injection site induration due 
to the second LEN injection at Week 26 was 92 (3, 180) days and 38 (9, 123) days, respectively.
1.2.3.4.7.
Study GS-US-200-4334
Study GS-US-200-4334 is a Phase 2, randomized, open-label, active-controlled, multicenter 
study evaluating the safety and efficacy of LEN in combination with other ARV agents in ARV-
naive PWH. Participants were randomized in a 2:2:2:1 ratio to 1 of 4 treatment groups 
(Table 19).

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Table 19.
GS-US-200-4334: Study Treatments
Treatment 
Group
Time Period
Study Treatments
Induction 
(Day 1 through Week 27)
Oral LEN 600 mg (2  300 mg tablet) on Days 1 and 2; 
300 mg (1  300 mg tablet) on Day 8
Oral daily F/TAF (200/25 mg) from Day 1 onwards for a 
total of 28 weeksa
SC LEN 927 mg (3 mL of 309 mg/mL) on Day 15
1
Maintenance 
(Week 28 through Week 80)
SC LEN 927 mg (3 mL of 309 mg/mL) at Week 28 and 
every 26 weeks thereafter
Oral daily TAF (25 mg)
Induction 
(Day 1 through Week 27)
Oral LEN 600 mg (2  300 mg tablet) on Days 1 and 2; 
300 mg (1  300 mg tablet) on Day 8
Oral daily F/TAF (200/25 mg) from Day 1 onwards for a 
total of 28 weeksb
SC LEN 927 mg (3 mL of 309 mg/mL) on Day 15
2
Maintenance 
(Week 28 through Week 80)
SC LEN 927 mg (3 mL of 309 mg/mL) at Week 28 and 
every 26 weeks thereafter
Oral daily BIC (75 mg)
3
Day 1 through Week 80
Oral LEN 600 mg (2  300 mg tablet) on Days 1 and 2; 
50 mg (1  50 mg tablet) daily from Day 1 onwards
Oral daily F/TAF (200/25 mg)
4
Day 1 through Week 80
Oral daily B/F/TAF (50/200/25 mg)
BIC, B = bictegravir; F = emtricitabine; LEN = lenacapavir; SC = subcutaneous; TAF = tenofovir alafenamide
a
Treatment Group 1 participants with < 50 copies/mL of HIV-1 RNA at Week 16 and Week 22 stopped F/TAF at Week 28 
and initiated oral daily TAF.
b
Treatment Group 2 participants with < 50 copies/mL of HIV-1 RNA at Week 16 and Week 22 stopped F/TAF at Week 28 
and initiated oral daily BIC.
Participants are treated for at least 80 weeks. Participants in Treatment Group 4 will complete the 
study at Week 80.
Disposition and Baseline Characteristics
Of the 249 participants screened, 183 were randomized, and 182 received at least 1 dose of study 
drug. Of these 182 participants, 22 participants (12.1%) prematurely discontinued the study drug 
during the Main Phase (ie, data collected on or before Week 80): 17 of 105 participants (16.2%) 
in the SC LEN total group, 4 of 52 participants (7.7%) in the oral LEN group, and 1 of 
25 participants (4.0%) in the bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF; 
coformulated; Biktarvy®) group. The reasons for premature study drug discontinuation in the SC 
LEN total group were participant decision and lost to follow-up (each 4 participants [3.8%]), 
investigator’s discretion, lack of efficacy, and AE (each 3 participants [2.9%]). The reasons for 
premature study drug discontinuation in the oral LEN group were lost to follow-up 
(3 participants [5.8%]) and participant decision (1 participant [1.9%]) and in the B/F/TAF group 
it was participant decision (1 participant [4.0%]).

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As of the Week 54 data cut date, 8 participants entered into the Extension Phase (SC LEN total 
group, 5 participants; oral LEN group, 3 participants) and were continuing study drug. 
Demographic and baseline characteristics were similar across the treatment groups. Most 
participants were male (93.4%), cisgender (92.3%), and gay (69.8%). Median age was 29 years 
(range: 19 to 72 years). Race was balanced between Black versus non-Black (52.2% vs 47.8%, 
respectively), as was ethnicity between Hispanic or Latino versus not Hispanic or 
Latino (45.1% vs 54.9%, respectively). Baseline disease characteristics were similar across the 
treatment groups. Overall, the median (Q1, Q3) baseline HIV-1 RNA value was 
4.37 (3.86, 4.74) log10 copies/mL, and the median (Q1, Q3) baseline CD4 cell count was 
437 (332, 599) cells/μL.
Among the 182 participants, most had HIV-1 RNA ≤ 100,000 copies/mL (85.2%, 
155 participants) and a CD4 cell count range of ≥ 350 to < 500 cells/μL (31.9%, 58 participants) 
or ≥ 500 cells/μL (37.4%, 68 participants).
Virologic Efficacy Results
The primary efficacy endpoint was HIV-1 RNA < 50 copies/mL at Week 54 using the 
US FDA-Defined Snapshot Algorithm. The primary analysis at Week 54 demonstrated similar 
results in each treatment group, with no significant difference between each of the 
LEN-containing groups and the B/F/TAF group, as follows:
•
LEN total: 136 of 157 participants (86.6%)
•
SC LEN + (DVY → TAF): 47 of 52 participants (90.4%)
•
SC LEN + (DVY → BIC): 45 of 53 participants (84.9%)
•
Oral LEN + DVY: 44 of 52 participants (84.6%)
•
B/F/TAF: 23 of 25 participants (92.0%)
Preliminary Pharmacokinetic Results
Based on the interim analysis, for both the SC LEN treatment groups (SC LEN + [F/TAF → 
TAF] and SC LEN + [F/TAF → BIC]), mean LEN concentrations and the lower bound 90% CI 
were consistently maintained above IQ4 (15.5 ng/mL) from Day 2 onwards to Week 54. For SC 
LEN, mean predose concentrations at Week 54 for Treatment Groups 1 and 2 were 1.22-fold and 
1.15-fold higher, respectively, compared with Week 28, indicating minimal accumulation over 
the dosing period of 54 weeks. 
For oral LEN 50 mg once daily (oral LEN + F/TAF treatment group), mean LEN single anytime 
concentrations and the lower bound 90% CI reached IQ4 (15.5 ng/mL) by Day 2 and were 
maintained at Weeks 28 and 54 for this interim analysis. For oral LEN, accumulation was not 
apparent after Week 4, indicating steady state is achieved by Week 4. Mean predose 
concentration at Week 54 was consistent with that at Week 28.

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Preliminary Safety Results
By Week 54, 89.2% of participants in the LEN total group (140 of 157 participants) and 
96.0% of those in the B/F/TAF group (24 of 25 participants) had been exposed to study drug for 
at least 54 weeks. Overall, SC and orally administered LEN were generally safe and well 
tolerated. No deaths were reported by Week 54. Serious AEs were reported for 6.4% (10 of 
157 participants) in the LEN total group. None of the SAEs were reported for > 1 participant, 
and all were considered not related to the study drugs.
Adverse Events
Similar percentages of participants in the LEN total (total of 157 participants) and B/F/TAF 
(total of 25 participants) groups had any AE by Week 54 (LEN total 87.9%, 138 participants; 
B/F/TAF 84.0%, 21 participants). The most commonly reported AEs were as follows:
•
LEN total (157 participants), excluding ISRs: headache and nausea (each 13.4%, 
21 participants), COVID-19 (9.6%, 15 participants), and syphilis and lymphadenopathy 
(each 8.9%, 14 participants)
•
SC LEN total (105 participants), only ISRs: injection site erythema (31.4%, 33 participants), 
injection site swelling (27.6%, 29 participants), and injection site pain (23.8%, 
25 participants)
•
Oral LEN + DVY (52 participants): headache (13.5%, 7 participants), nausea and 
lymphadenopathy (each 11.5%, 6 participants), and COVID-19, syphilis, diarrhea, and 
influenza (each 9.6%, 5 participants)
•
B/F/TAF (25 participants): syphilis and arthralgia (each 16.0%, 4 participants) and headache, 
COVID-19, back pain, weight increased, upper respiratory tract infection, and insomnia 
(each 12.0%, 3 participants)
The majority of the AEs reported in the 4 treatment groups were Grade 1 or 2 in severity. The 
percentage of participants with AEs of Grade 3 or higher was 8.3% (13 of 157 participants) in 
the LEN total group and 8.0% (2 of 25 participants) in the B/F/TAF group. No AEs of Grade 3 
or higher were reported for > 1 participant in any treatment group. Since the Week 28 analysis, 
2 additional AEs of Grade 3 or higher were reported in the LEN total group (SC LEN + [DVY 
→ TAF] group: 1 participant; SC LEN + [DVY → BIC] group: 1 participant]) and 1 additional 
AE of Grade 3 or higher was reported in the B/F/TAF group (1 participant).
The percentages of participants with treatment-related AEs were as follows:
•
LEN total (157 participants): 43.9% (69 participants)
•
SC LEN total (105 participants): 58.1% (61 participants)
•
Oral LEN + DVY (52 participants): 15.4% (8 participants)
•
B/F/TAF (25 participants): 16.0% (4 participants)

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The higher frequency of treatment-related AEs in the SC LEN total group was mainly because of 
ISRs, as reflected in the most common AEs considered related to study drugs:
•
LEN total group (157 participants), excluding ISRs: nausea (5.1%, 8 participants), diarrhea 
and headache (each 2.5%, 4 participants), and fatigue (1.9%, 3 participants)
•
SC LEN total group (105 participants), only ISRs: injection site erythema (26.7%, 
28 participants), injection site swelling (22.9%, 24 participants), injection site pain (19.0%, 
20 participants)
•
Oral LEN + DVY (52 participants): nausea and diarrhea (each 3.8%, 2 participants), fatigue, 
headache, dyspepsia, flatulence, vomiting, weight increased, influenza, overdose, and hot 
flush (each 1.9%, 1 participant)
•
B/F/TAF (25 participants): dyspepsia, salivary hypersecretion, insomnia, and weight 
increased (4.0%, 1 participant)
Overall, 57 of 103 participants (55.3%) who received SC LEN had a study drug-related ISR; all 
were Grade 1 or Grade 2, except for 1 participant with a Grade 3 injection site nodule. The most 
frequently reported ISRs (≥ 15% in the SC LEN total group) and their duration in median 
(Q1, Q3) days were as follows:
•
Injection site erythema (27.2%, 28 participants), 5 (2, 11) days
•
Injection site swelling (23.3%, 24 participants), 11 (6, 29) days
•
Injection site pain (19.4%, 20 participants), 4 (1, 9) days
Overall, 15 of 103 participants had an AE of injection site nodule and 13 of 103 participants had 
an AE of injection site induration. All were Grade 1 or Grade 2, except for 1 participant with a 
Grade 3 injection site nodule. Outcomes of injection site induration and nodule events after the 
first (Day 15) SC LEN injection were as follows:
•
Nodules: Ongoing (1 of 13 [7.7%]); Resolved (12 of 13 [92.3%])
•
Indurations: Ongoing (6 of 9 [66.7%]); Resolved (3 of 9 [33.3%])
The median (Q1, Q3) duration of resolved injection site nodule and injection site induration was 
278 (136, 366) days and 202 (101, 213) days, respectively.
Outcomes of injection site induration and nodule events after the second (Week 28) SC LEN 
injection were as follows:
•
Nodules: Ongoing (5 of 8 [62.5%]); Resolved (3 of 8 [37.5%])
•
Indurations: Ongoing (3 of 6 [50.0%]); Resolved (3 of 6 [50.0%])

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The median (Q1, Q3) duration of resolved injection site nodule and injection site induration was 
152 (123, 240) days and 145 (4, 258) days, respectively.
1.2.4.
Nonclinical Studies in Pregnancy or Lactation
This study may enroll participants assigned female at birth with reproductive potential and as 
such, available preclinical and clinical pregnancy and lactation studies are summarized below.
1.2.4.1.
Pregnancy
Emtricitabine
Reproductive studies were conducted in rats, mice, and rabbits. Animal studies (performed at 
60- to 120-fold human exposure) did not indicate harmful effects of FTC with respect to fertility, 
pregnancy, fetal parameters, parturition, or postnatal development. FTC is not considered to be 
genotoxic (DESCOVY IB).
Tenofovir Disoproxil Fumarate
Reproductive studies were conducted in rats and rabbits. Animal studies do not indicate direct or 
indirect harmful effects of TDF with respect to pregnancy, fetal development, parturition, or 
postnatal development. There were no effects on mating or fertility parameters {BIKTARVY 
2021}.
Tenofovir Alafenamide
See Appendix 7 for US-specific text.
Lenacapavir
Animal studies do not indicate direct or indirect harmful effects of LEN on fertility, pregnancy, 
embryonal and fetal development, parturition, or postnatal development. Animal study 
TX-200-2043 was conducted to determine the potential adverse effects on male and female 
fertility. Lenacapavir was administered at doses of 0 (77% PEG 200, 10% ethanol, and 
13% sterile water for injection), 20, or 100 mg/kg once via SC injection to male and female 
Crl:CD (SD) rats (N = 25/sex/group) via 200 mg/mL LEN (0.5, 0.1, and 0.5 mL/kg, 
respectively). Assessment of toxicity was based on mortality, clinical signs, body weights, body 
weight gains, food consumption, estrous cycles, reproductive performance, intrauterine survival, 
gross necropsy findings, sperm parameters, and organ weights. A dose level of 100 mg/kg, the 
highest dose level evaluated, was considered to be the no observed effect level (NOEL) for male 
and female systemic toxicity, male and female reproductive toxicity, and embryonic toxicity of 
LEN. At the NOEL (100 mg/kg), the Cmax and AUC0-1008h values were 577 ng/mL and 
441,000 h•ng/mL, respectively, for males and the Cmax and AUC0-672h values were 597 ng/mL 
and 192,000 h•ng/mL, respectively, for females.

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Animal study TX-200-2049 was conducted to determine the potential adverse effects of maternal 
LEN exposure from implantation to weaning on pregnancy, parturition, and lactation of the 
maternal (F0) animals and on the growth, viability, and development of the F1 neonates. A single 
SC dose of LEN was administered to assumed pregnant rats on Gestation Day 6 at dose levels of 
30 and 300 mg/kg. Dams were exposed to LEN for the duration of gestation and to Lactation 
Day 10. No LEN-related systemic effects were noted at any dose level in the F0 or F1 generation; 
nonadverse local ISRs were observed in the F0 LEN-dosed dams. Therefore, a dose level of 
300 mg/kg, the highest level tested, was considered to be the no observed adverse effect level 
(NOAEL) for F0 maternal systemic toxicity, and the NOAEL for F1 developmental/neonatal, F1 
parental systemic, F1 reproductive toxicity, and F2 embryo intrauterine survival of LEN when 
administered SC as a single dose to Sprague-Dawley rats on Gestation Day 6. This dose level 
corresponds to F0 maternal AUC0–192h and Cmax values of 54,800 h•ng/mL and 412 ng/mL, 
respectively.
1.2.4.2.
Lactation
In animal studies, it has been shown that TFV is secreted into milk.
1.2.5.
Human Studies in Pregnancy
1.2.5.1.
TDF Use During Pregnancy
The PK of TDF has been studied in pregnant women. In a retrospective population 
pharmacokinetic (PopPK) study of 46 pregnant women and 156 nonpregnant women who were 
receiving combination regimens that included TDF, pregnant women had a 39% higher apparent 
clearance of TFV compared with nonpregnant women {Benaboud 2012}. In the P1026s study of 
37 pregnant women who received TDF-based combination therapy at 30 to 36 weeks’ gestation 
and 6 to 12 weeks postpartum, the percentage of women with TFV AUC exceeding the target of 
1.99 μg•hour/mL (the 10th percentile in nonpregnant adults) was lower in the third trimester than 
postpartum. Trough levels and AUCs were roughly 20% lower during the third trimester 
compared with postpartum. The median weight of the women below the target exposure 
(97.9 kg) was significantly higher than the median weight of the women who met the target 
exposure (74.2 kg) {Best 2015a}. In a study of women who did not have HIV and who were 
using TDF as part of PrEP, intracellular concentrations of tenofovir diphosphate (TFV-DP) in 
pregnant women were about 70% of those in nonpregnant women, even after adjusting for 
adherence {Pyra 2018}. These changes are not believed to be large enough to warrant dose 
adjustment of TDF during pregnancy.
Several studies have assessed outcomes in pregnant women receiving TDF or F/TDF for PrEP, 
demonstrating a favorable safety profile. In a study of 431 pregnancies that occurred during an 
HIV PrEP trial in which women who did not have HIV infection were randomized to receive 
placebo, TDF, or TDF plus FTC, there was no difference in risk of congenital anomalies between 
the TDF-containing arms and placebo arms {Mugo 2014}. A systematic review and 
meta-analysis evaluated the evidence for use of oral PrEP containing TDF as an additional HIV 
prevention strategy in populations at substantial risk for HIV. Eighteen studies were included, 
comprising data from 39 articles and 6 conference abstracts through April 2015. Across 

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populations and PrEP regimens, PrEP significantly reduced the risk of HIV acquisition compared 
with placebo. Additionally, oral PrEP containing TDF was not associated with increased 
pregnancy-related AEs or hormonal contraception effectiveness {Fonner 2016}.
TDF has been studied for HIV treatment during pregnancy and is currently included in first-line 
regimens for pregnant women in combination with FTC or lamivudine (3TC) in guidelines from 
the Republic of South Africa Department of National Health {Moorhouse 2018}, the World 
Health Organization (WHO) {Leslie 2004}, and the US National Institutes of Health (NIH) 
{AIDSinfo 2019}.
1.2.5.2.
TAF Use During Pregnancy
See Appendix 7 for US-specific text.
1.2.5.3.
FTC Use During Pregnancy
The PK data are available on the use of FTC during pregnancy. In the International Maternal 
Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1026s study, FTC exposure 
was modestly lower during the third trimester (geometric mean 8.0 μg•h/mL; 90% CI: 7.1–8.9) 
than during the postpartum period (9.7 μg•h/mL; 90% CI: 8.6–10.9). Fifty-eight percent of 
pregnant women (15 of 26 women) versus 95% of postpartum women (21 of 22 women) met the 
AUC target (≤ 30% reduction from typical exposure for nonpregnant historical controls). Trough 
FTC levels were also lower during pregnancy (C24 geometric mean trough [GMT] concentration 
58 ng/mL; 90% CI: 37–63) than during the postpartum period (C24 GMT 85 ng/mL; 90% CI: 
70-100) {Benaboud 2012}. Similar differences in PK parameters of FTC were found among 
women during pregnancy or after delivery in the PACTG 394 study and in a European study 
from the PANNA network {Best 2015a, Colbers 2013}. The increase in FTC clearance during 
pregnancy correlated with the normal pregnancy-related increase in GFR {Pyra 2018}. These 
changes are not believed to be large enough to warrant dose adjustment of FTC during 
pregnancy.
FTC has been studied for HIV treatment during pregnancy and it or the closely-related drug 3TC 
are currently included in first-line regimens for pregnant women in guidelines from the Republic 
of South Africa Department of National Health {Moorhouse 2018}, the Republic of Uganda 
Ministry of Health {Ministry of Health (MOH) 2016}, the WHO {Leslie 2004}, and the US NIH 
{AIDSinfo 2019}.
1.2.5.4.
Lenacapavir Use During Pregnancy
There are no human studies of LEN in pregnancy. The partner study, GS-US-412-5624, 
evaluating the safety and efficacy of LEN in cisgender adolescent girls and young women, will 
evaluate LEN in pregnancy, including collection of pregnancy outcomes.

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1.2.6.
Human Studies in Lactation
1.2.6.1.
TDF Use While Lactating 
In a study of 50 lactating women without HIV infection who received F/TDF for PrEP (under 
directly observed therapy for 10 days), median peak and trough time-averaged TFV breast milk 
concentrations were similar at 3.2 ng/mL (interquartile range [IQR] 2.3–4.7) and 3.3 ng/mL 
(IQR 2.3–4.4), respectively. The infant plasma TFV concentration was unquantifiable 
(< 0.31 ng/mL) in 94% of infants (46 of 49 infants); in the 3 infants with detectable TFV, the 
level was 0.9 ng/mL in 2 infants and 17.4 ng/mL in 1 infant. Based on this study’s results, the 
median TFV dose ingested through breast milk was estimated to be 0.47 μg/kg, or < 0.01% of 
the proposed daily 6 mg/kg pediatric TDF dose {Mugwanya 2016}. In a study of 
59 breastfeeding women who received TDF/3TC/EFV in Uganda and Nigeria, no infant had 
detectable TFV in plasma {Waitt 2018}.
The inclusion of women who are lactating is consistent with the WHO guidelines concerning the 
benefits of breastfeeding and the recommendation that there does not appear to be a 
safety-related rationale for disallowing or discontinuing F/TDF for PrEP during lactation for 
HIV-negative women who are at continuing risk of HIV acquisition {World Health Organisation 
(WHO) Department of HIV/AIDS 2017}. This rationale is again further supported by the 
2018 Southern African HIV Clinicians’ Society (SAHCS) guidelines {Moorhouse 2018}. The 
WHO guidelines {World Health Organisation (WHO) Department of HIV/AIDS 2017} conclude 
that in settings with high risk of HIV acquisition and accompanying increased risk of 
mother-to-child transmission (MTCT), the advantages of using F/TDF for PrEP outweigh any 
potential risks, including any risks of fetal and infant exposure to TDF in PrEP regimens. This 
opinion is further supported by the 2018 SAHCS guidelines {Moorhouse 2018}. In these 
guidelines, SAHCS, in alignment with the WHO recommendations, advises that woman be 
maintained on F/TDF for PrEP throughout pregnancy and that the benefits of continuing F/TDF 
for PrEP throughout pregnancy in order to avoid seroconversion in the pregnant woman, with 
consequent significant risk of MTCT, are considered to far outweigh any potential risk of TFV or 
FTC exposure to the fetus.
1.2.6.2.
TAF Use While Lactating
See Appendix 7 for US-specific text.
1.2.6.3.
FTC Use While Lactating
Samples of breast milk obtained from 5 women living with HIV-1 show that FTC is secreted in 
human milk at estimated neonatal concentrations 3- to 12-times higher than the FTC half-
maximal inhibitory concentration, but 3- to 12-times lower than the Cmin achieved from oral 
administration of FTC. Breastfeeding infants whose mothers are being treated with FTC may be 
at risk for developing viral resistance to FTC in the setting of HIV infection {Benaboud 2011}. 
Other FTC-associated risks in infants breastfed by mothers being treated with FTC are unknown.

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1.2.6.4.
Lenacapavir Use While Lactating
It is not known if LEN is secreted in human breast milk.
1.2.7.
Drug-Interaction Potential for F/TDF and LEN with Hormones
1.2.7.1.
F/TDF and F/TAF
Emtricitabine (FTC) is primarily eliminated via renal excretion as unchanged drug and is not 
subject to enzyme or transporter-based DDIs. The primary metabolic route of TDF is hydrolase 
cleavage, a low-affinity and high-capacity system that is not likely to be impacted by commonly 
administered drugs. TDF, but not its major metabolite tenofovir (TFV), is a substrate for 
intestinal efflux transporters P-gp and BCRP {DESCOVY 2020, Tong 2007, TRUVADA 2020}. 
In clinical studies, F/TDF was not identified as a victim or perpetrator of clinically relevant 
enzyme or transporter-mediated DDIs {TRUVADA 2020}.
In agreement with these data, a dedicated Phase 1 evaluation between F/TDF and ethinylestradiol 
(EE)/norgestimate (a representative combination oral contraceptives [COC]) showed lack of 
clinically relevant changes in PK of either agent or pharmacodynamic markers of efficacy 
(luteinizing hormone, follicle-stimulating hormone, and progestin); thereby supporting the use of 
F/TDF with estrogen and progestin containing hormonal contraceptives. No meaningful 
differences in intracellular TFV-diphosphate or FTC-triphosphate were observed in TGW taking 
high-dose hormone therapy in the DISCOVER trial, suggesting that F/TDF is a safe and 
effective option for PrEP in TGW on gender-affirming hormone therapy (GAHT). A study with 
daily observed therapy of F/TDF in both TGW and TGM confirmed that there was no impact of 
GAHT on TFV-diphosphate in dried blood spots (DBS), nor was there any impact of F/TDF on 
estradiol or testosterone levels in either TGW or TGM {Grant 2020}. 
See Appendix 7 for US-specific text.
1.2.7.2.
LEN
The potential of LEN as a perpetrator of DDIs has been comprehensively evaluated in vitro and 
in the Phase 1 clinical program. LEN was identified as a moderate inhibitor of CYP3A and a 
weak inhibitor of P-gp using sensitive probe substrates MDZ and TAF, respectively, whereas in 
vitro data indicate it is not an inhibitor of UGT1A1. Based on these data, administration of 
CYP3A, UGT1A1, and P-gp substrates was permitted in LEN clinical development program. In 
vivo, P-gp plays a role limiting LEN oral absorption. LEN metabolism is primarily mediated by 
glucuronidation via UGT1A1 with CYP3A playing a minor role.
The general approach to GAHT therapy entails a combination of an estrogen (eg 17β-estradiol 
[E2]) with an androgen blocker (eg spironolactone, finasteride or dutasteride) and in some cases 
a progestogen {Deutsch 2016, Hembree 2017, Khan 2019, Unger 2016}. While a dedicated 
Phase 1 evaluation between LEN and GAHT has not been performed, Gilead has conducted a 
thorough literature review of inhibitory CYP3A-mediated drug interactions using the University 
of Washington Drug Interaction Solutions (UWDIS) database and other sources {Zhang 2018}. 

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The search revealed that the vast majority of hormone DDI studies have been performed with 
COC rather than GAHT. However, because of the overlap in the disposition pathways of EE and 
E2 (intestinal sulfation, hepatic CYP3A-mediated hydroxylation and conjugation with glucuronic 
acid), data from these studies can be extrapolated to E2.
Collectively, these studies showed that moderate CYP3A inhibitors (eg, isavuconazole, 
netupitant, fluconazole or grapefruit juice) caused only small (approximately 10% to < 40%) 
increases in the exposure (expressed as AUC) of EE, {Calcagnile 2013, DIFLUCAN 2020, 
Townsend 2017, Weber 1996} which did not warrant dose adjustment, and the use of COC has 
been allowed in LEN treatment studies. Similar or smaller increases were observed for oral E2 
administered with the moderate CYP3A inhibitors erythromycin (E2 valerate) and grapefruit 
juice {Blode 2012, Schubert 1994}. While clinical DDI data for parenterally administered 
hormones in combination with CYP3A inhibitors are scarce, considering lack of intestinal 
contribution, no or only small changes in hormone levels are expected {Winkler 2015}. As 
perpetrators of DDIs, the effect of hormonal contraceptives is generally minor, with a few 
exceptions that involve drugs that undergo metabolism via CYP1A2 and UGT1A4 enzymes 
{Sun 2020}. Based on the totality of these data, a clinically relevant alteration in the PK of 
contraceptive hormones or LEN upon coadministration is not expected. 
Similar to the estrogen hormones, anti-androgens and progestogens are extensively metabolized 
in the liver with CYP3A playing a role in the metabolism of dutasteride, finasteride and 
progestogens. While no to minimal clinical DDI data are available in the public domain, 
administration of these agents with moderate and strong CYP3A inhibitors is allowed regardless 
of potentially increased exposures per their respective prescribing information {AVODART 
2020, PROSCAR 2013, PROVERA 2007}. Taken together, LEN can be safely coadministered 
with estrogen-based GAHT and androgen blockers in TGW on GAHT.
For TGM, exogenous testosterone is the mainstay of GAHT {Deutsch 2016, Unger 2016}. 
Long-acting injectable ester prodrugs of testosterone are typically used, in addition to topical 
formulations. Testosterone is metabolized to various 17-keto steroids through 2 different 
pathways {AndroGel 2020, Delatestryl 2016, Depo -Testosterone 2018}. The major active 
metabolites of testosterone are E2 and dihydrotestosterone, and about 90% of the dose is 
excreted renally as glucuronides and sulfates. Although testosterone is a CYP3A substrate, a 
search for clinical DDI studies in the UWDIS database did not return any results, neither for 
testosterone itself nor its marketed esters. The respective prescribing information does not 
contain restrictions with regard to coadministration of CYP inhibitors {AndroGel 2020, 
Delatestryl 2016, Depo -Testosterone 2018} and no interactions with LEN are anticipated. LEN 
can be safely coadministered with testosterone-based GAHT. 
During this study, all participants on GAHT should be monitored according to clinical practice 
guidelines, including the evaluation of hormone levels as indicated.

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1.3.
Rationale for This Study
Both daily oral F/TDF and F/TAF have been shown to be highly effective for PrEP, and F/TDF 
is recommended per World Health Organization (WHO) guidelines as part of HIV prevention 
standard of care for individuals at risk for HIV {Center for Disease Control and Prevention 2019, 
World Health Organization (WHO) 2015}. However, the requirement of high adherence to a 
daily regimen has limited the potential population-level impact on reducing HIV incidence. The 
efficacy of PrEP is highly dependent on adherence. In studies that failed to demonstrate efficacy, 
lower adherence was clearly implicated {Marrazzo 2015, Van Damme 2012}. 
According to Gilead estimates, there were approximately 140,000 individuals on TVD for PrEP 
and 95,000 on DVY for PrEP in the US as of July 2020, with an estimated 400,000 individuals 
who have initiated and discontinued use. This uptake of PrEP represents a small fraction of the 
1.1 million people estimated by the US Centers for Disease Control and Prevention (CDC) to 
have an indication for PrEP {Sullivan 2018}. With a novel mechanism of action and a PK profile 
that can support every 6-month administration, LEN can address this significant unmet medical 
need to prevent HIV infection without relying on adherence to a daily oral regimen and by 
reducing stigma and concerns regarding disclosure, which limit uptake of PrEP. The availability 
of a long-acting SC option could significantly increase the number of people on PrEP and 
increase persistence and continued engagement on PrEP.
Long-acting PrEP options are expected to be a desired alternative to daily oral F/TDF or F/TAF 
for current PrEP users who self-identify as wanting less frequent dosing. In addition, long-acting 
PrEP will be an important option for a sizable population at high risk of HIV infection who have 
stopped taking or have never taken daily oral PrEP because of the requirement for daily pill 
taking. Most importantly, long-acting PrEP may increase the uptake of PrEP in the proportion of 
individuals who are at risk for HIV but who have never considered PrEP, which is particularly 
important for those disproportionately affected by HIV incidence. Developing long-acting PrEP 
options will be critical in both improving quality of life of PrEP users as well as providing 
protection against HIV infection in a broader set of individuals who could benefit from PrEP and 
has the potential to accelerate reduction in new HIV infections at a population level. This may be 
particularly important where use of daily oral PrEP options poses a challenge for a key portion of 
populations at disproportionate risk such as Black and Hispanic/LatinX individuals, TGW, 
particular Black and Hispanic/LatinX TGW, adolescents and young people, others belonging to 
socially marginalized groups in developed countries and in more general populations in the 
developing world {Coelho 2019}.
This study will aim to demonstrate the efficacy of LEN, particularly in these populations that are 
disproportionately affected by HIV incidence and with low uptake of current PrEP options, and 
who have been historically underrepresented in HIV clinical trials. Specifically, the study has set 
overall goals for the enrollment of 50% Black MSM in the US and 20% TGW study wide, to 
ensure the meaningful enrollment of historically underrepresented, disproportionately affected 
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Early clinical data from the LEN for treatment program show that LEN demonstrates potent 
antiviral activity in PWH and sustained exposure supporting twice-yearly dosing. Data from the 
low-dose NHP rectal challenge model demonstrate that animals are protected from HIV-1 
infection after a single dose of GS-CA1, a long-acting capsid inhibitor followed by multiple 
SHIV exposures. Taken together, these data suggest that LEN has the potential to provide 
substantial improvement over currently available PrEP therapies and to meet a high unmet need 
for alternative PrEP options by eliminating the need for daily adherence.
1.4.
Rationale for Dose Selection of Study Drugs
F/TDF fixed dose combination (FDC) (200 mg FTC/300 mg TDF) will be dispensed to the 
randomized participants with instructions to administer 1 tablet orally by mouth once daily for 
PrEP. This dose of F/TDF was the dose evaluated in PrEP clinical trials and approved for PrEP. 
See Appendix 7 for US-specific text.
The rationale for dose selection for LEN in this study is supported by antiviral activity, PK and 
safety data from the ongoing Phase 1b POC study (GS-US-200-4072) in TN and 
treatment-experienced (but capsid inhibitor-naive) PWH, as well as PK and safety data from the 
two Phase 1 studies in healthy volunteers (Study GS-US-200-4538 and Study GS-US-200-4071). 
In the Phase 1b POC study (GS-US-200-4072), potent antiviral activity of LEN has been 
demonstrated; the mean maximum HIV-1 RNA decline over 10-day monotherapy after single SC 
doses of 50 to 450 mg was 1.8 to 2.2 log10 copies/mL. All treated participants achieved at least 
1 log10 copies/mL decline in their HIV-1 RNA at Day 10. Antiviral activity on Day 10 was 
comparable across a dose range of single doses of 50 to 450 mg. At these doses, mean (%CV) 
LEN concentrations on Day 10 were 1.1- to 9.9-fold higher (eg, IQ 1.1 – 9.9) than the paEC95 for 
wild type HIV-1 (paEC95 = 3.87 ng/mL in MT-4 cells).
The LEN formulations and doses to be evaluated in this PrEP study are informed by PK and/or 
safety data from Phase 1 Studies GS-US-200-4071, GS-US-200-4538, and GS-US-200-5709 in 
healthy volunteers, as well as available safety data from the ongoing clinical studies in HTE and 
TN PWH (GS-US-200-4625 and GS-US-200-4334). In the absence of an established efficacy 
benchmark in the prevention setting, the current study will target systemic LEN exposures 
consistent with those of HIV-1 treatment, as per the recommendations of the US Food and Drug 
Administration (FDA) Guidance for Developing Systemic Drug Products for Pre-Exposure 
Prophylaxis {U. S. Department of Health & Human Services (DHHS) 2019}. To that end, the 
target LEN concentrations in the PrEP study are aligned with those of the ongoing Phase 2 and 3 
clinical studies in PWH (GS-US-200-4625 and GS-US-200-4334). As with the ongoing Phase 2 
and 3 studies in PWH, the proposed regimen targets an exposure whereby the lower bound of the 
90% CI of mean LEN concentration is 4-fold higher than the paEC95 (ie, IQ4) within a few days 
of dosing initiation through the end of the SC dosing interval (once every 6 months).
Currently, a SC LEN regimen (927 mg or 2  1.5 mL at 309 mg/mL, administered every 
26 weeks) preceded by a 14-day oral lead-in is being evaluated in ongoing clinical studies in 
HTE and TN PWH (GS-US-200-4625 and GS-US-200-4334). As clinical data of LEN to date do 
not raise concern for acute safety issues, where an oral lead-in would be beneficial, a simplified 
LEN regimen is being proposed for this study: 927 mg SC LEN injection, 309 mg/mL 

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(2  1.5 mL) administered on Day 1 along with oral tablet doses of LEN 600 mg (2  300 mg) 
administered on Day 1 and Day 2. This will be followed by SC doses of LEN 927 mg 
administered every 26 weeks. The proposed simplified regimen is predicted to achieve target 
concentrations within a few days of dosing initiation with exposures maintained throughout the 
duration of the 6-month dosing interval (Figure 9). This is supported by preliminary PK data 
available through 26 weeks postdose from Study GS-US-200-5709 (Cohort 2; see 
Section 1.2.3.4.3) where the proposed simplified regimen demonstrates good agreement between 
the observed and predicted/simulated data.

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Figure 9. 
Simulated Plasma Profile of LEN Following the Proposed SC LEN 
Regimen Administered Every 26 Weeks With an Oral PK Load on 
Days 1 and 2 
A) 
J 100 
E 
._ 
C) 
.s 
.. , .. ...... .. ,. . 
u 
C 
0 
- ------------ 23.6 ng/ml (IQ6) 
u 
10 
... 
> 
CG 
Q. 
CG u 
CG 
C 
1--"""T""---.----,.--~-""T"""-"""T"----, 
1 
2 
SC 900mg t 
PO600mg t t 
B) 
-
..J 
E 
C> 
C: -
z 
w 
..J 
100 
3 
Study Day 
Line= Mean 
Area= 90% Cl 
6 
7 
8 
15.5 ng/mL (IQ4) 
~-••••••••••••••••••• • • • • • • • • • • • • • • • • • • • • • • • • • • • • ·4-fold paEC95 (IQ4) 
10-------~--------. 
I 
26 
52 
Day 1 : SC 927mg 
Study Week 
Day 1: PO 600mg 
t 
t 
Day 2: PO G00mg ____________ _ 
SC 927mg QGMO 
CI = confidence interval; IQ4 = inhibitory quotient of 4; IQ6 = inhibitory quotient of 6; LEN = lenacapavir; 
paEC95 = protein-adjusted 95% effective concentration from MT-4 cells (3.87 ng/mL); PO = oral; Q6MO = eve1y 6 months; 
SC = subcutaneous 
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1.5.
Rationale for Oral Weekly Bridging of Lenacapavir for Missed SC Injection
Oral bridging of LEN is supported by antiviral activity, PK, and safety data from a Phase 1b 
proof-of-concept study (GS-US-200-4072) and 2 ongoing Phase 2 and 2/3 studies 
(GS-US-200-4334 and GS-US-200-4625), as well as PK and safety data from 2 Phase 1 studies 
in healthy volunteers (GS-US-200-4071 and GS-US-200-4333). Phenotypic analyses and PK/PD 
modeling indicate that a LEN plasma concentration of ≥ 15.5 ng/mL, corresponding to IQ4 or 
higher, would provide near maximal antiviral activity (GS-US-200-4072). 
The oral bridging dose of LEN is 300 mg administered once weekly starting 26 to 28 weeks after 
the last LEN SC injection. This oral weekly LEN bridging dose, even when started as late as 
28 weeks after the last LEN SC injection, is predicted to immediately maintain the lower bound 
of the 90% CI of arithmetic mean for LEN Ctrough above IQ4 (ie, even before reaching steady 
state) (Figure 10A). As long as the oral weekly LEN bridging is initiated between 26 to 28 weeks 
after the last SC LEN injection, the PK profile upon resuming SC injection is predicted to be 
comparable with that of the prior SC dose and within the target range regardless of when SC 
injection is resumed (Figure 10B).
LEN has been administered orally at doses up to 1800 mg (Study GS-US-200-4071). Safety data 
from all completed and ongoing clinical studies indicate that LEN is generally safe and well 
tolerated at the intended exposures.
Figure 10.
Simulated Pharmacokinetic Profile of Oral Weekly Bridging of LEN 
(300 mg) (A) Prior to and (B) After Resuming SC Injection
EC95 = 95% effective concentration; IQ = inhibitory quotient; LEN = lenacapavir; PO = oral; SC = subcutaneous; QW = once 
weekly 
The solid line and the shaded region correspond to the geometric mean and 90% CI, respectively. Inhibitory quotient is calculated 
as trough concentration/in vitro protein-adjusted EC95 (paEC95) against wild-type virus. Horizontal dashed lines correspond to 
target IQ values of 4 based on phenotypic analyses and pharmacokinetic/pharmacodynamic modeling.
line • Geo. Mean 
Area : 90-/D Cl 
SC 
II 18 
31 
P0300mg 
Line • Geo. Mean 
ID Area • 90'/o Cl 
10 
SC 
.... 
J6 
711 
5nldy ~L•----=•:.:c:.:•:.:v:...m
:.:•::.... __ _, 

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Preliminary Oral Bridging PK Data Available From Phase 2/3 Studies GS-US-200-4625 
and GS-US-200-4334
Bridging with oral LEN was used in HIV treatment Studies GS-US-200-4625 and 
GS-US-200-4334 during a period of time when injection LEN was unavailable due to a clinical 
hold implemented as a result of container vial incompatibility.
In Study GS-US-200-4625, of 72 participants who were enrolled and received SC LEN, 
57 participants received oral bridging during the clinical hold and were included in the Oral 
Bridging Analysis Set. All 57 participants completed the Week 26 visit (ie, 26 weeks after the 
first dose of SC LEN) before initiating oral bridging. A total of 13, 29, and 15 participants started 
oral bridging after Week 26 SC, Week 52 SC, and Week 78 SC, respectively. Three participants 
discontinued the study drug during oral bridging (1 due to death and 2 due to participant 
decision). A total of 54 participants resumed SC LEN after the Oral Bridging Period and are 
continuing the study drug at the date of the data cut.
Mean LEN concentration and the lower bound of the 90% CI were maintained above the efficacy 
target of IQ4 (15.5 ng/mL) from the first oral LEN bridging visit through the SC LEN 
resumption visit.
For the Oral Bridging Period, mean (%CV) predose concentration and the lower bound 90% CI 
at oral bridging Day 1 (46.1 ng/mL [56.3%]; lower 90% CI = 40.3 ng/mL), at oral bridging 
Week 10 (76.2 ng/mL [59.6%]; lower 90% CI = 66.1 ng/mL), at oral bridging Week 20 
(74.8 ng/mL [116.1%]; lower 90% CI = 50.4 ng/mL), at oral bridging Week 30 (41.7 ng/mL 
[45.7%]; lower 90% CI = 29.9 ng/mL) exceeded IQ4. At the SC resumption visit, mean (%CV) 
predose concentration and the lower bound 90% CI (74.4 ng/mL [105.1%]; 
lower 90% CI = 56.2 ng/mL) also exceeded IQ4.
In Study GS-US-200-4334, 121 participants received oral bridging (SC LEN total group: 
82 participants) or continued oral therapy (oral LEN group: 39 participants), 4 participants 
(3.3%; SC LEN total group: 2 participants; oral LEN group: 2 participants) prematurely 
discontinued study drug during the Oral Bridging Period (all due to participant decision). As of 
the oral bridging analysis data cutoff date, 117 participants (96.7%) were continuing study drug 
with SC LEN resumed (SC LEN total group: 80 [97.6%] participants) or continued oral therapy 
(oral LEN group: 37 [94.9%] participants).
In Study GS-US-200-4334, for Treatment Group 1 (SC LEN + [F/TAF → TAF]), mean (%CV) 
concentrations on Day 1 (28.8 ng/mL [47.7%]; lower bound 90% CI: 25.2 ng/mL), Week 10 
(50.9 ng/mL [67.0%]; lower bound 90% CI: 41.1 ng/mL), and Week 20 (53.1 ng/mL [84.5%]; 
lower bound 90% CI: 39.6 ng/mL) exceeded IQ4. At Week 30, the mean (%CV) concentration 
was 43.7 ng/mL (74.7%), but a lower bound 90% CI was not reported due to a sample size of 
< 5. At the SC LEN resumption visit, the mean (%CV) concentration was 49.4 ng/mL (84.6%), 
with a lower bound 90% CI of 38.6 ng/mL.

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For Treatment Group 2 (SC LEN + [F/TAF → BIC]), mean (%CV) concentrations on Day 1 
(26.7 ng/mL [47.3%]; lower bound 90% CI: 23.0 ng/mL), Week 10 (59.3 ng/mL [73.6%]; lower 
bound 90% CI: 46.4 ng/mL), and Week 20 (51.9 ng/mL [70.2%]; lower bound 90% CI: 
40.2 ng/mL) exceeded IQ4. At Week 30, the mean (%CV) concentration was 56.5 ng/mL 
(62.5%), but a lower bound 90% CI was not reported due to a sample size of < 5. At the SC LEN 
resumption visit, the mean (%CV) concentration was 52.2 ng/mL (66.6%), with a lower bound 
90% CI of 42.7 ng/mL. 
For Treatment Groups 1 and 2 combined (SC LEN total), mean (%CV) concentrations on Day 1 
(27.8 ng/mL [47.4%]; lower bound 90% CI: 25.3 ng/mL), Week 10 (54.9 ng/mL [70.8%]; lower 
bound 90% CI: 47.1 ng/mL), Week 20 (52.5 ng/mL [77.7%]; lower bound 90% CI: 43.7 ng/mL), 
and Week 30 (50.1 ng/mL [62.3%]; lower bound 90% CI: 24.4 ng/mL) exceeded IQ4. At the SC 
LEN resumption visit, the mean (%CV) concentration was 50.7 ng/mL (75.7%), with a lower 
bound 90% CI of 43.6 ng/mL.
1.6.
Risk/Benefit Assessment for the Study
F/TDF PrEP has previously been demonstrated to have high efficacy and favorable tolerability in 
cisgender men (CGM) and TGW in large randomized controlled trials, and thus F/TDF is 
expected to have good efficacy and safety in adherent participants in this study. While LEN has 
not been studied for PrEP in CGM, TGW, TGM, or GNB people, HIV treatment studies have 
demonstrated high antiviral potency and a favorable safety profile. 
See Appendix 7 for US-specific text.
A Phase 2 study of the efficacy of LEN for PrEP has not been conducted because such a study 
could not be adequately powered to assess efficacy. However, data from studies of LEN for HIV 
treatment and from nonhuman primate studies indicate a sufficient probability of efficacy to 
justify a Phase 3 study. Studies of GS-CA1, a close analog of LEN with activity against HIV and 
SIV, has shown good protective efficacy against SHIV transmission from both rectal and vaginal 
challenge routes (see Section 1.2.3.3). Among human studies, the Phase 1b study 
GS-US-200-4072 assessed the ARV potency of LEN monotherapy in ART-naïve PWH. 
Participants in GS-US-200-4072 who received a single SC LEN dose of 450 mg or 750 mg had 
mean reductions in HIV-1 RNA greater than 2 log10 copies/mL by Day 10, demonstrating potent 
ARV activity of LEN (see Section 1.2.3.4.5). In the Phase 2 study GS-US-200-4334, ART-naïve 
PWH received LEN as part of a complete HIV-1 treatment regimen. Greater than 90% of 
participants receiving LEN had HIV-1 RNA < 50 copies/mL at Week 28, demonstrating the 
efficacy of LEN in the treatment of HIV (see Section 1.2.3.4.7 and {Gupta 2021}). Similarly, the 
Phase 2/3 study GS-US-200-4625 demonstrated good ARV efficacy of LEN in participants who 
were HTE and had multidrug resistance (see Section 1.2.3.4.6 and {Molina 2021}. Together, 
these preclinical and clinical data establish a sufficient likelihood of preventative efficacy to 
justify this Phase 3 study of the safety and efficacy of LEN for PrEP in CGM, TGW, TGM, and 
GNB.

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1.6.1.
Pandemic Risk and Mitigation 
An infectious disease pandemic or other force majeure events may pose additional risks to study 
drug availability, study visit schedule, and adherence to protocol-specified safety monitoring or 
laboratory assessments. Refer to Appendix 2 for further details on the risks and risk mitigation 
strategy. 
1.7.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.

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2.
OBJECTIVES
The primary objective of this study is to evaluate the efficacy of LEN in preventing the risk of 
HIV-1 infection relative to the background HIV-1 incidence rate. Participants are CGM, TGW, 
TGM, and GNB.
2.1.
Incidence Phase Objectives
The primary objective for the Incidence Phase of this study is to estimate the HIV-1 background 
incidence rate.
2.2.
Randomized Blinded Phase Objectives
The primary objective for the Randomized Blinded Phase of this study is as follows:
•
To evaluate the efficacy of LEN for HIV-1 PrEP in participants ≥ 16 years of age who have 
condomless receptive anal sex with partners assigned male at birth and are at risk for HIV-1 
infection
The secondary objectives for the Randomized Blinded Phase of this study are as follows:
•
To compare the efficacy of LEN with F/TDF for HIV-1 PrEP in participants ≥ 16 years of 
age who have condomless receptive anal sex with partners assigned male at birth and are at 
risk for HIV-1 infection
•
To evaluate the efficacy of LEN for HIV-1 PrEP in participants at risk of HIV-1 infection in 
participants adherent to LEN
•
To evaluate the safety and tolerability of LEN and F/TDF for HIV-1 PrEP in participants 
≥ 16 years of age who have condomless receptive anal sex with partners assigned male at 
birth and are at risk for HIV-1 infection
•
To evaluate the safety and tolerability of LEN for HIV-1 PrEP in adolescent participants 
≥ 16 to < 18 years of age who have condomless receptive anal sex with partners assigned 
male at birth and are at risk for HIV-1 infection
CCI

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CCI

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3.
STUDY DESIGN
3.1.
Incidence Phase Endpoints
The primary endpoint for the Incidence Phase of this study is the diagnosis of recent HIV-1 
infection. 
The background HIV-1 incidence per 100 person-years (PY) will be computed based on the 
recency assay algorithm.
3.2.
Randomized Blinded Phase Endpoints
The primary endpoint for the Randomized Blinded Phase of this study is as follows:
•
Diagnosis of HIV-1 infection
The secondary endpoints for the Randomized Blinded Phase of this study are as follows:
•
Diagnosis of HIV-1 among participants while adherent to study drug (as defined by medium 
and high TFV-DP concentrations in DBS at the time of HIV-1 diagnosis for the F/TDF study 
drug group, and by LEN on time administration in the past 26 weeks for the LEN study drug 
group)
•
Occurrence of treatment-emergent AEs (TEAEs) and treatment-emergent clinical laboratory 
abnormalities to evaluate safety and tolerability of LEN and F/TDF for HIV-1 PrEP
CCI

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3.3.
Study Design
This is a Phase 3, double-blind, multi-site, randomized study to compare HIV-1 incidence in the 
LEN study drug group with the nonrandomized control of background HIV-1 incidence, defined 
as the estimated HIV-1 incidence without PrEP in the population studied. F/TDF will serve as 
the internal active control. This includes a cross-sectional study (Incidence Phase), a 
Randomized Blinded Phase, a LEN Open-label Extension (OLE) Phase, and a PK Tail Phase. 
Participants eligible for the Randomized Blinded Phase will be randomized in a 2:1 ratio to 
receive LEN or F/TDF, respectively. 
Enrollment of adolescents (participants 16 and 17 years of age) will commence following the 
first data monitoring committee (DMC) review of the unblinded safety data and recommendation 
to continue the study. Gilead will notify sites when they may begin enrollment of adolescents.
An overview of the study design is described below and shown in Figure 11.
Figure 11.
Study Schema
F/TDF = emtricitabine/tenofovir disoproxil fumarate; LEN = lenacapavir; OLE = open-label extension; PK = pharmacokinetic; 
PTM = placebo to match; SC = subcutaneous; Wk = week
a
Participants will continue in the Randomized Blinded Phase until all enrolled participants have completed at least 52 weeks 
of follow-up in the study and Gilead completes the primary analysis. If the Randomized Blinded Phase is stopped early for 
an efficacy outcome, some participants may have < 52 weeks of follow-up.
b
In the OLE Phase, LEN will be administered every 26 weeks until either SC LEN becomes available or the sponsor elects to 
discontinue the study, whichever occurs first. For participants on LEN in the Randomized Blinded Phase, the timing of the 
first OLE LEN injection will be dependent on the last LEN injection in the Randomized Blinded Phase. For participants on 
F/TDF in the Randomized Blinded Phase, the first OLE LEN injection will be on LEN OLE Day 1.
c
Participants who prematurely discontinue study drug during the Randomized Blinded Phase or those randomized to LEN in 
the Randomized Blinded Phase who decline to participate in the LEN OLE Phase upon unblinding, will transition to the PK 
Tail Phase. In PK Tail Phase, US participants to receive F/TDF or F/TAF up to 78 weeks. See Appendix 7 for US-specific 
text.
d
Week 4 and 8 visits are only required for participants who were randomized to oral F/TDF in the Randomized Blinded 
Phase.
Screening 
:5: 30 days 
Screening 
Visit 
Day I 
Randomized Blinded Phase• 
At least 52 weeks 
LEN+ F/TDF PTM; 
n = 2000 
F/TDF + LEN Placebo; 
n = 1000 
\Vk34, 8, 13, 
26, and 39 
Wk 52 Every 
Primary 13 Wk! 
Endp<,int 
LE Open-Label Extension Phase 
52 ~
~ 
r-----------------------, 
, 
PK Tail Phase!<.. 
, 
30-Day 
Follow-Up 
I 
-~~ 
L 
~---F/TDF up to 78 weeks ___ J ----------- ---- ---------- ---
End of 
Random:iz.ed 
Blinded 
Phase/LEN OLE 
Day I Visit 
LEN 
Wb 4, S, 13, and 
e\re:ry 13 weeks 
End of Study 

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3.3.1.
Incidence Phase
The Incidence Phase will include initial assessments that will provide an estimate of the 
concurrent background HIV-1 incidence rate (the counterfactual rate), using a recency assay 
algorithm. 
3.3.2.
Randomized Blinded Phase
All eligible participants will receive study drug and be followed for approximately 52 weeks. On 
Day 1/Injection 1, SC LEN 927 mg or placebo will be administered at the study site with a PK 
loading dose of oral LEN 600 mg (2  300 mg tablets) or placebo-to-match (PTM) oral LEN 
(2 tablets). Participants should be observed for approximately 30 minutes after each SC injection 
dose. In addition, 2 oral LEN tablets or PTM LEN tablets will be provided to participants to 
self-administer on Day 2. If a participant misses the Day 2 dose, the dose should be administered 
immediately upon realizing the dose was missed. Subsequently, SC LEN or placebo SC LEN 
will be administered every 26 weeks (± 7 days). Participants will also receive oral F/TDF 
(200/300 mg), or PTM F/TDF to self-administer daily starting on Day 1/Injection 1. The site 
staff will contact the participant 1 week (± 2 days) after injection to assess for any ISRs and to 
confirm the participant has administered the Day 2 dose. Participants will attend study visits at 
Day 1/Injection 1, Weeks 4 and 8 (± 2 days), Week 13 (± 7 days), and every 13 weeks (± 7 days) 
thereafter until all enrolled participants have completed at least 52 weeks of follow-up in the 
study and Gilead completes the primary analysis. This will indicate the end of the Randomized 
Blinded Phase.
Participants randomized to LEN who decline to participate in the LEN OLE Phase will transition 
to the PK Tail Phase at this visit (ie, End of Randomized Blinded Phase visit will coincide with 
PK Tail Day 1 visit). Participants randomized to F/TDF who decline to participate in the LEN 
OLE Phase will complete the ESDD visit at this visit, be transitioned to local HIV prevention 
services, and be required to return for a 30-day follow-up visit (Section 6.7.2). 
Participants who prematurely discontinue blinded study drug during the Randomized Blinded 
Phase will transition to the PK Tail Phase. If a participant chooses not to enter the PK Tail Phase 
(after discussion of benefits/risk with the investigator), the participant will complete an ESDD 
visit and a 30-day follow-up visit.
3.3.3.
Lenacapavir Open-Label Extension Phase
Following the completion of the primary analysis, if LEN demonstrates acceptable safety and 
efficacy in the Randomized Blinded Phase, the study will proceed to the LEN OLE Phase. All 
participants will return to the study site upon notification by Gilead. All participants who still 
remain on randomized blinded study drug at the time of the End of Randomized Blinded Phase 
visit will have the option to transition to the LEN OLE Phase at this visit (ie, End of Randomized 
Blinded Phase visit will coincide with LEN OLE Day 1 visit). 
Participants will receive SC LEN injections every 26 weeks (± 7 days), until either LEN 
becomes available or the sponsor elects to discontinue the study, whichever occurs first.

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LEN OLE Day 1 will coincide with the end of the Randomized Blinded Phase. Participants 
randomized to LEN in the Randomized Blinded Phase who choose to participate in the LEN 
OLE Phase will receive SC LEN every 26 weeks (± 7 days) and have study visits every 13 weeks 
(± 7 days). The SC LEN injection visits in the LEN OLE Phase will be determined by the 
previous LEN injection (ie, participants whose last LEN injection was 13 weeks before LEN 
OLE Day 1 will receive their first open-label LEN injections at the LEN OLE Week 13 visit; 
participants whose last LEN injection was 26 weeks before LEN OLE Day 1 will receive their 
first open-label LEN injections at the LEN OLE Day 1 visit).
Participants randomized to F/TDF in the Randomized Blinded Phase will switch to SC LEN and 
have study visits at LEN OLE Day 1, Weeks 4 and 8 (± 2 days), Week 13 (± 7 days), and every 
13 weeks (± 7 days) thereafter. Subcutaneous LEN will be administered at the LEN OLE Day 1, 
Week 26, and every 26 weeks thereafter. These participants will also receive a loading dose of 
oral LEN on LEN OLE Days 1 and 2, as described in the Randomized Blinded Phase. If a 
participant misses the Day 2 dose, the dose should be administered immediately upon realizing 
the dose was missed. Participants should be observed for approximately 30 minutes after each 
SC injection dose. The study site staff will contact the participant 1 week (± 2 days) after 
injection to assess for any ISRs and to confirm the participant has administered the Day 2 dose. 
Participants will complete the LEN OLE Phase once LEN becomes available or the sponsor 
elects to discontinue the study, whichever occurs first.
Upon completion of the LEN OLE Phase or discontinuation of the study, participants will 
transition to locally available PrEP, which may include lenacapavir or other available PrEP 
modalities as clinically indicated. If a participant chooses to end participation in the LEN OLE 
Phase prior to conclusion, then the participant will complete an ESDD visit, be referred to locally 
available PrEP services as clinically indicated, and will complete a 30-day follow-up visit.
3.3.4.
Pharmacokinetic Tail Phase 
Participants who prematurely discontinue study drug in the RBP will receive OL oral F/TDF 
once daily for up to 78 weeks to cover the PK Tail Phase and complete study visits every 
13 weeks (± 7 days).
These participants will complete the PK Tail Day 1 visit 26 weeks (± 7 days) after their last SC 
LEN injection. Upon completion of the PK Tail Week 78 visit, participants will be transitioned 
to local HIV prevention services, and return for a 30-day follow-up visit; at this point, 
participation in the study ends.
Upon unblinding, participants who were randomized to LEN in the Randomized Blinded Phase 
who decline to participate in the LEN OLE Phase will transition to the PK Tail Phase. 
Upon unblinding, participants who were randomized to F/TDF in the Randomized Blinded Phase 
who decline to participate in the LEN OLE Phase will complete the ESDD visit, transition to 
local HIV prevention services, and return for a 30-day follow-up visit.
Participants can also transition to the PK Tail Phase if study drug is prematurely discontinued in 
the Randomized Blinded Phase. Upon unblinding, participants from the Randomized Blinded 

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Phase who were randomized to LEN will continue the PK Tail Phase for 78 weeks. Upon 
unblinding, participants from the Randomized Blinded Phase who were randomized to F/TDF 
will complete the ESDD visit, transition to local HIV prevention services, and return for a 30-
day follow-up visit.
Participants who permanently discontinue study drug during the PK Tail Phase will complete an 
ESDD visit (Section 6.7.1) and a 30-day follow-up visit. 
Participants who began receiving OL F/TDF due to unavailability of SC LEN/placebo may 
rejoin the RBP of the study if approved by the medical monitor. In these cases, as soon as SC 
LEN/placebo is available, the participant should be contacted and notified to return to the site 
and complete the injection visit that was missed due to SC LEN/placebo unavailability. For 
instance, if a participant could not receive SC LEN/placebo at Week 26 and began OL F/TDF, 
the participant would return to the site as soon as SC LEN/placebo administration is feasible and 
resume the study at the Week 26/Injection 2 visit.
See Appendix 7 for US-specific text.
3.3.5.
Discontinuation Criteria
If a participant discontinues study drug for any reason other than acquiring HIV, every attempt 
should be made to keep the participant in the study. Participants who prematurely discontinue 
study drug in the Randomized Blinded Phase will transition to the PK Tail Phase. If a participant 
chooses not to enter the PK Tail Phase (after discussion of benefits/risks with the investigator), 
the participant will complete an ESDD visit (Section 6.7.1) and a 30-day follow-up visit 
(Section 6.7.2) and be withdrawn from the study. The ESDD visit occurs once in the study when 
the participant permanently discontinues dosing with any assigned study drug prior to 
completing the study (regardless of study phase) for any reason other than acquiring HIV. 
A participant who is diagnosed with HIV during the study will discontinue study drug and will 
be required to return to the study site for follow-up at 30 days (± 14 days) and 90 days 
(± 14 days) after confirmation of HIV infection (Section 6.7.3). Participants whose HIV-1 RNA 
is ≥ 50 copies/mL at the 90-day post-HIV follow-up visit will continue to have follow-up visits 
every 3 months until HIV-1 RNA is < 50 copies/mL at which point their participation will 
conclude. Participants will be followed up for a maximum of 1 year from the date they were 
diagnosed with HIV infection. The procedures performed at the 90-day post-HIV follow-up visit 
should be carried forward for these visits thereafter.
Study drug will be discontinued as applicable in the following instances:
•
HIV infection is diagnosed 
•
Unacceptable toxicity, or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedures or is considered to not be in the participant’s 
best interest

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•
Participant request to discontinue for any reason 
•
Study drug may be discontinued as applicable in the following instances:
A) Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. Following resolution of intercurrent illness, the 
participant may resume study dosing at the discretion of the investigator (see Section 6.8.1 
for criteria for restarting study drug after an interruption)
B) Participant nonadherence to study drug or injection visits
•
At the discretion of the investigator 
•
Discontinuation of the study at the request of Gilead, a regulatory agency, or an institutional 
review board (IRB) or independent ethics committee (IEC).
3.4.
Study Drugs
Approximately 3000 participants who meet all eligibility criteria will be randomized in a 
2:1 ratio into 1 of the following study drug groups:
•
LEN study drug group: LEN + PTM F/TDF (N = 2000)
SC LEN + PTM oral F/TDF; loading dose on Day 1/Injection 1 and Day 2 of 
Randomized Blinded Phase only: oral LEN 600 mg (2  300 mg tablets)
•
F/TDF study drug group: F/TDF + placebo LEN (N = 1000) 
Oral F/TDF + placebo SC LEN; loading dose on Day 1/Injection 1 and Day 2 of 
Randomized Blinded Phase only: PTM oral LEN (2 tablets)
Loading dose on first day of SC LEN injection in LEN OLE Phase and following day: 
oral LEN 600 mg (2  300 mg tablets)
3.5.
Duration of Study Drug Administration
Participants enrolled in the Randomized Blinded Phase will receive study drug for approximately 
52 weeks as described in Section 3.3.2.
Participants transitioning to the LEN OLE Phase will receive SC LEN injections every 26 weeks 
until either LEN becomes available or the sponsor elects to discontinue the study, whichever 
occurs first as described in Section 3.3.3. 
Participants eligible for the PK Tail Phase will receive oral F/TDF once daily for up to 78 weeks 
as described in Section 3.3.4. 
See Appendix 7 for US-specific text.

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3.6.
End of Study
End of study is defined as the last participant’s last observation (last visit).
3.7.
Poststudy Care 
Participants randomized in the study who have completed or terminated participation in the study 
will be transitioned to local HIV prevention services.
Participants who are diagnosed with HIV during the study will be referred to locally available 
HIV treatment and care services upon confirmation of HIV infection and be encouraged to 
immediately begin an HIV-1 treatment regimen (Section 6.13).
3.8.
Source Data
The source data for this study will be obtained from electronic data capture (EDC), interactive 
web response system (IWRS), central laboratory, local laboratory, specialty laboratory, and 
questionnaires.
3.9.
Biomarker Testing 
CCI

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4.
PARTICIPANT POPULATION
Inclusion of participants disproportionally affected by HIV and historically underrepresented in 
HIV clinical studies, particularly Black and Hispanic/LatinX MSM and transgender people, is an 
important goal of this study. Furthermore, the novel counterfactual background HIV incidence 
design of this study necessitates recruitment and enrollment of participants in populations with 
high background HIV incidence (eg, at least 3 per 100 PY). In order to ensure the study achieves 
the goals of recruiting priority populations disproportionately affected by HIV and historically 
underrepresented in HIV clinical studies, specific enrollment goals have been established. In the 
US, where Black MSM are disproportionally affected by HIV, the study will strive to enroll at 
least 50% Black MSM, consistent with normative guidance for the goals of enrollment of Black 
MSM {Watson 2014}. Globally, the study will strive to enroll 20% TGW study wide. The study 
team will collaborate with individual sites to develop site-specific recruitment plans to ensure the 
inclusion of priority populations. During the enrollment period, the study team will monitor the 
race, ethnicity, and gender of participants and provide ongoing guidance, feedback, and support 
to ensure that individual sites and the study overall achieves its goals for the recruitment of 
priority populations.
4.1.
Number of Participants and Participant Selection 
The study includes a cross-sectional study (Incidence Phase), Randomized Blinded Phase, LEN 
OLE Phase, and PK Tail Phase. 
The Incidence Phase of the study will remain open until the background HIV-1 incidence rate 
has been determined. Approximately 3000 participants will be randomized in the Randomized 
Blinded Phase to receive study drug. Participants must meet all eligibility criteria to be eligible 
for participation in the Incidence Phase and the Randomized Blinded Phase. The collection of 
race, ethnicity, gender, and age data allows for the analysis and reporting of safety and efficacy 
data by demographic subgroups as required by certain health authorities.
4.1.1.
Participant Replacement
Participants who discontinue before the end of study will not be replaced.

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4.2.
Eligibility Criteria for the Incidence Phase 
4.2.1.
Inclusion Criteria for the Incidence Phase 
1) The ability to comprehend and provide a signed written informed consent, which must be 
obtained prior to initiation of study procedures. For adolescents, the ability to comprehend 
and provide a signed assent form, which must be obtained prior to initiation of study 
procedures. A parent/guardian may provide informed consent for adolescents (in accordance 
with local laws and regulations).
2) CGM, TGW, TGM, and GNB who have condomless receptive anal sex with partners 
assigned male at birth and are at risk for HIV-1 infection.
3) Age ≥ 16 years at screening. Enrollment of adolescents (participants 16 and 17 years of age) 
will commence following the first DMC review of the unblinded safety data and 
recommendation to continue the study. Gilead will notify sites when they may begin 
enrollment of adolescents.
4) HIV-1 status unknown at screening and no prior HIV-1 testing within the last 3 months
5) Sexually active with ≥ 1 partner assigned male at birth (condomless receptive anal sex) in the 
last 12 months and 1 of the following:
a) Condomless receptive anal sex with ≥ 2 partners in the last 12 weeks
b) History of syphilis, rectal gonorrhea, or rectal chlamydia in the last 24 weeks
c) Self-reported use of stimulants with sex in the last 12 weeks
6) Willing and able to comply with study procedures 
4.2.2.
Exclusion Criteria for the Incidence Phase 
1) Prior use of HIV PrEP (including F/TDF or F/TAF) or HIV postexposure prophylaxis (PEP) 
in the past 12 weeks or any prior use of long-acting systemic PrEP (including cabotegravir or 
islatravir)
2) Participants who previously received an HIV vaccine or HIV broadly neutralizing antibody 
(bNAb) are not eligible. Individuals may be eligible if they participated in an HIV vaccine or 
bNAb study but have documentation that they did not receive active product (eg, placebo 
recipients).

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4.3.
Eligibility Criteria for the Randomized Blinded Phase
4.3.1.
Inclusion Criteria for the Randomized Blinded Phase
Participants who have a negative fourth generation HIV-1/2 antibody (Ab)/antigen (Ag) test and 
meet the criteria from the Incidence Phase can be screened for the Randomized Blinded Phase if 
additional consent is obtained. Participants who meet the following criteria will be included in 
the Randomized Blinded Phase.
1) Negative local rapid fourth generation HIV-1/2 Ab/Ag, central fourth generation 
HIV-1/2 Ab/Ag, and HIV-1 RNA quantitative nucleic acid amplification testing (NAAT) 
(Appendix 5)
2) Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min at screening according to the 
Cockcroft-Gault formula for creatinine clearance (CLcr) {Cockcroft 1976}:
(140 − age in years)  (weight in kg)  [0.85 if female] = CLcr (mL/min)
72  (serum creatinine in mg/dL)
3) Body weight ≥ 35 kg
4) Participants of childbearing potential who engage in frontal (vaginal) intercourse must not 
intend to become pregnant during the study and must agree to utilize protocol-specified 
method(s) of contraception as described in Appendix 6.
4.3.2.
Exclusion Criteria for the Randomized Blinded Phase
Participants who meet any of the following exclusion criteria are not eligible to be randomized in 
the Randomized Blinded Phase of this study. 
1) Participation in any other clinical trial (including observational and COVID-19 vaccine 
trials) without prior approval from the sponsor is prohibited while participating in this trial. 
An exception is made for participation in the sponsor-approved ancillary qualitative 
participant interview study, which is allowed and does not require medical monitor approval. 
2) Known hypersensitivity to the study drug, the metabolites, or formulation excipient
3) Acute viral hepatitis A, B, or C or evidence of chronic hepatitis B or C infection 
a) If a participant has a negative hepatitis B surface antigen (HBsAg), negative hepatitis B 
surface antibody (HBsAb), and positive hepatitis B core antibody (HBcAb), hepatitis B 
virus (HBV) DNA testing will be completed. If the HBV DNA result is positive, the 
participant is a screen failure. Participants found to be susceptible to HBV infection will 
be offered HBV vaccination.
b) If the hepatitis C virus (HCV) Ab result is positive, then HCV RNA will be evaluated. 
Participants found to be positive for HCV at screening must not have active infection or 
must have completed treatment and achieved a sustained virologic response. 

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4) Severe hepatic impairment or a history of or current clinical decompensated liver cirrhosis 
(eg, ascites, encephalopathy, variceal bleeding)
5) Have a suspected or known active, serious infection(s) (eg, active tuberculosis, etc)
6) Need for continued use of any contraindicated concomitant medications
7) Have a history of osteoporosis or bone fragility fractures
8) Current alcohol or substance abuse judged by the investigator to be problematic such that it 
potentially interferes with participant study adherence
9) Grade 3 or Grade 4 proteinuria or glycosuria at screening that is unexplained or not clinically 
manageable
10) Participants assigned female at birth of childbearing potential who are pregnant or lactating 
at screening or on Day 1. Participants must have a negative pregnancy test at screening and 
on Day 1 (see “Definition of Childbearing Potential” in Appendix 6).
11) Any other clinical condition, laboratory abnormalities, or psychosocial condition or prior 
therapy that, in the opinion of the Investigator, would make the participant unsuitable for the 
study or unable to comply with dosing requirements

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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding, and Treatment Codes Access
Participants will be assigned a screening number using IWRS on the day of the Incidence Phase 
screening visit. Participants who consent and are eligible for the Randomized Blinded Phase will 
keep their screening number assigned from the Incidence Phase. Upon confirmation that all 
screening procedures have been completed and eligibility criteria have been met, the investigator 
or designee will enroll and randomize the participant into the study using IWRS to receive study 
drug (Randomized Blinded Phase only). Once a participant number has been assigned, it will not 
be reassigned to another participant.
Randomization in IWRS may occur approximately 3 days prior to the Day 1/Injection 1 visit.
5.1.1.
Randomization
Participants who meet all Randomized Blinded Phase eligibility criteria will be randomized in a 
2:1 ratio to either active LEN or once daily oral F/TDF starting on Day 1/Injection 1 using 
IWRS. There is no stratification for randomization. The randomization list will be generated by 
the IWRS provider.
5.1.2.
Blinding
During the Randomized Blinded Phase, participants and all personnel directly involved in the 
conduct of the study will be blinded to study drug assignment. Specified personnel may be 
unblinded based on their study role. Study drug will be dispensed by the unblinded study 
pharmacist, or designee, in a blinded fashion to the participants. The PK File Administrator, or 
designee, in Bioanalytical Operations and/or Clinical Data Management who facilitates the data 
transfer of PK files between Gilead and vendors will remain unblinded. Individuals in Clinical 
Packaging and Labeling or Clinical Supply Management who have an Unblinded Inventory 
Manager role in the IWRS for purposes of study drug inventory management will remain 
unblinded. Individuals in Patient Safety (PS) responsible for safety signal detection, 
investigational new drug (IND) safety reporting, and/or expedited reporting of suspected 
unexpected serious adverse reactions (SUSARs) may be unblinded to individual case data and/or 
group-level summaries. Individuals in Clinical Pharmacology may be unblinded for the purpose 
of PopPK/pharmacodynamic analysis. External (ie, contract research organizations [CROs]) 
biostatisticians and programmers will be unblinded to produce outputs supporting data review by 
an independent DMC or IND safety reporting. External dried blood spot and pharmacology 
bioanalytical vendors may be unblinded for the purposes of identifying participants for whom 
study drug concentrations are to be analyzed. Regulatory Quality and Compliance personnel in 
Research and Development may also be unblinded for purposes of supporting Quality Assurance 
activities and/or regulatory agency inspections. If the DMC recommends early study termination, 
including stopping enrollment for efficacy, an Oversight Committee may be unblinded for a 
thorough evaluation of the recommendation. None of the unblinded staff at the investigational 
site, vendors or Gilead will be involved in daily activities related to capturing and processing 
clinical data. 

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During the Randomized Blinded Phase, the site pharmacist, investigational site staff preparing 
and administering the study drugs, and study monitors responsible for study drug accountability 
will be unblinded while Gilead staff, any other investigational site personnel, and study 
participants will remain blinded. A limited number of Gilead or CRO Clinical Operations 
personnel may potentially receive unblinding information as part of a sponsor oversight role. To 
mitigate the risks of inadvertently releasing the treatment information, Gilead staff will only be 
provided with the unblinded information when there is a need to access such information. Should 
Gilead staff receive unblinding information, they will maintain the confidentiality of the 
unblinded information and will not communicate the information to blinded sites or participants 
as specified in Gilead standard operating procedures (SOPs). 
Detailed instructions and additional procedures for maintaining the blinding of SC LEN and 
placebo SC LEN are outlined in the study Pharmacy Manual, which will be provided to each site.
5.1.3.
Planned Interim Unblinding 
Additionally, to assess the safety and/or efficacy of LEN for planning and development of this 
compound, a Gilead unblinded internal DMC, independent of the blinded study team, may be 
assembled. This committee, if assembled, will consist of at least 1 representative from Clinical 
Research, Biostatistics, and PS, and may include other personnel as necessary. The Gilead 
medical monitor, other Clinical Research, Biostatistics or PS staff directly interacting with the 
study sites or data processing or analysis will not be participating in the internal monitoring 
committee and will not be unblinded to the participant study drug assignment.
The scope of responsibilities, access to data as well as level of unblinding, membership, conduct, 
and meeting schedule of the internal unblinded team will be documented in the planned 
unblinding committee charter as specified in Gilead SOPs.
5.1.4.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the participant, the investigator may obtain study drug assignment directly from the IWRS for 
that participant. In case of technology failure, the principal investigator (PI) will contact the 
support line of the IWRS provider directly. After proper identification of user credentials, the 
support personnel will provide the treatment assignment to the PI and the participant will 
discontinue study drug but may continue participation in the study. Gilead recommends but does 
not require that the investigator contact the Gilead medical monitor before breaking the blind. 
Study drug assignment should remain blinded unless that knowledge is necessary to determine 
participant emergency medical care. The rationale for unblinding must be clearly explained in 
source documentation along with the date on which the study drug assignment was obtained. The 
investigator is requested to contact the Gilead medical monitor promptly in case of any study 
drug unblinding.
Blinding of study drug is critical to the integrity of this clinical study. Therefore, if a 
participant’s study drug assignment is disclosed to the investigator, the participant will have 
blinded study drug discontinued and proceed to the PK Tail Phase. All participants will be 
followed until study completion unless consent to do so is specifically withdrawn by the 
participant.

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5.2.
Description and Handling of Study Drugs 
5.2.1.
Formulation
5.2.1.1.
Lenacapavir
LEN injection, 309 mg/mL, is a clear, yellow to brown solution for SC injection. In addition to 
the active ingredient, LEN injection, 309 mg/mL, contains the following inactive ingredients: 
PEG 300 and water for injection.
Placebo for LEN injection is a clear, colorless solution for SC injection. Placebo for LEN 
injection contains the following inactive ingredient: PEG 400.
LEN tablets, 300 mg, are capsule-shaped, film-coated beige tablets, debossed with “GSI” on 
one side of the tablet and “62L” on the other side of the tablet. Each tablet core contains the 
equivalent of 300 mg LEN in the form of LEN sodium. In addition to the active ingredient, LEN 
tablets, 300 mg, contain the following inactive ingredients: microcrystalline cellulose, mannitol, 
poloxamer 407, copovidone, croscarmellose sodium, magnesium stearate, PEG, polyvinyl 
alcohol, talc, titanium dioxide, iron oxide red, iron oxide black, and iron oxide yellow.
PTM LEN tablets, 300 mg, are capsule-shaped, film-coated beige tablets, debossed with “GSI” 
on one side of the tablet and “62L” on the other side of the tablet. PTM LEN tablets, 300 mg, 
contain the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, 
croscarmellose sodium, magnesium stearate, PEG, polyvinyl alcohol, talc and titanium dioxide, 
iron oxide red, iron oxide black, and iron oxide yellow.
5.2.1.2.
Emtricitabine/Tenofovir Disoproxil Fumarate (F/TDF)
F/TDF 200/300 mg tablets are blue, capsule-shaped, film-coated tablets debossed with 
“GILEAD” on one side of the tablets and “701” on the other side of the tablet. Each tablet core 
contains 200 mg of FTC and 300 mg of TDF. In addition to the active ingredients, the F/TDF 
tablets contain the following inactive ingredients: microcrystalline cellulose, pregelatinized 
starch, croscarmellose sodium, lactose monohydrate, magnesium stearate, hypromellose, 
titanium dioxide, triacetin, and FD&C blue #2/indigo carmine aluminum lake.
PTM F/TDF tablets are blue, capsule-shaped, film-coated tablets debossed with “GILEAD” on 
one side of the tablets and “701” on the other side of the tablet. PTM F/TDF tablets contain the 
following inactive ingredients: denatonium benzoate, lactose monohydrate, pregelatinized starch, 
croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, triacetin, and 
FD&C blue #2/indigo carmine aluminum lake.
5.2.1.3.
Emtricitabine/Tenofovir Alafenamide (F/TAF)
See Appendix 7 for US-specific text.

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5.2.2.
Packaging and Labeling
5.2.2.1.
Lenacapavir
LEN injection, 309 mg/mL, and placebo for LEN injection are supplied as a sterile solution 
packaged in a single-use, clear vial fitted with a rubber stopper and an aluminum flip-off seal.
LEN tablets, 300 mg, and PTM LEN tablets, 300 mg, are packaged in white, high-density 
polyethylene (HDPE) bottles. Each bottle contains 4 tablets, silica gel desiccant and polyester 
packing material. Each bottle is enclosed with a white, continuous thread, child-resistant 
polypropylene screw cap fitted with an induction-sealed, and aluminum-faced liner.
Study drugs to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the US FDA, European Union (EU) Guideline to 
Good Manufacturing Practice - Annex 13 (Investigational Medicinal Products), and/or other 
local regulations.
5.2.2.2.
Emtricitabine/Tenofovir Disoproxil Fumarate (F/TDF)
F/TDF tablets and PTM F/TDF tablets are packaged in a white HDPE bottle. Each bottle 
contains 30 tablets and silica gel desiccant. Each bottle is enclosed with a white, continuous 
thread, child-resistant polypropylene screw cap fitted with an induction-sealed and 
aluminum-faced liner.
Study drugs to be distributed to centers in the US, and other participating countries shall be 
labeled to meet applicable requirements of the US FDA, EU Guideline to Good Manufacturing 
Practice – Annex 13 (Investigational Medicinal Products), and/or other local regulations.
5.2.2.3.
Emtricitabine/Tenofovir Alafenamide (F/TAF)
See Appendix 7 for US-specific text.
5.2.3.
Storage and Handling
Until dispensed to the participants, all study drugs should be stored in a securely locked area, 
accessible only to authorized site personnel.
To ensure the stability and proper identification, study drug(s) should not be stored in a container 
other than the container in which they were supplied.
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure when handling.

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5.2.3.1.
Lenacapavir
LEN injection, 309 mg/mL and placebo for LEN injection should be stored below 30°C (86°F), 
protected from light. Storage conditions are specified on the label.
LEN tablets, 300 mg, and PTM LEN tablets, 300 mg, should be stored below 30°C (86°F). 
Storage conditions are specified on the label.
5.2.3.2.
Emtricitabine/Tenofovir Disoproxil Fumarate (F/TDF)
F/TDF tablets and PTM F/TDF tablets must be stored at a controlled room temperature below 
25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Storage 
conditions are specified on the label.
5.2.3.3.
Emtricitabine/Tenofovir Alafenamide (F/TAF)
See Appendix 7 for US-specific text.
5.3.
Dosage and Administration of Study Drugs
5.3.1.
Lenacapavir 
5.3.1.1.
Dosage and Administration of Subcutaneous Lenacapavir 
LEN will be administered without regard to food during the Randomized Blinded Phase and the 
LEN OLE Phase as follows: 
•
Randomized Blinded Phase
SC LEN 927 mg (2  1.5 mL injections) or placebo SC LEN (2  1.5 mL injections) 
every 26 weeks starting on Day 1/Injection 1
Loading dose: oral LEN 600 mg (2  300 mg tablets) or PTM oral LEN (2 tablets) once 
daily on Day 1/Injection 1 and Day 2
•
LEN OLE Phase
SC LEN 927 mg (2  1.5 mL injections) every 26 weeks 
Loading dose for participants randomized to F/TDF: oral LEN 600 mg (2  300 mg 
tablets) once daily on Days 1 and 2
See Section 5.3.1.2 if SC LEN/placebo cannot be administered within the injection visit window.

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5.3.1.2.
Dosage and Administration of Oral Weekly Bridging of Lenacapavir
If SC LEN/placebo cannot be administered within the injection visit window due to extenuating 
circumstances and the investigator deems it clinically appropriate to continue LEN/placebo, 
bridging with oral LEN/placebo may be permitted with medical monitor approval. Information 
on assessments during oral weekly LEN/placebo bridging is found in Section 6.8.3. 
Dosing for bridging with oral LEN/placebo will differ depending on the time elapsed since the 
last SC LEN/placebo injection. See Table 20 for details.
•
If 25 to 28 weeks have elapsed since the last SC LEN/placebo injection, LEN/placebo 
reloading is not required prior to starting oral weekly LEN/placebo bridging.
•
If > 28 weeks have elapsed since the last SC LEN/placebo injection, LEN/placebo reloading 
will be required prior to starting oral weekly LEN/placebo bridging. 
Table 20.
Oral LEN/Placebo Bridging and SC LEN/Placebo Restart Dosing 
Schedule
Day of Oral 
Bridging
No Reloading
25 to 28 Weeks Since Last Injection
Reloading
> 28 Weeks Since Last Injection
Day 1
Oral LEN 300 mg (1  300 mg tablet)
or PTM oral LEN (1 tablet)
Oral LEN 600 mg (2  300 mg tablets)
or PTM oral LEN (2 tablets)
Day 2
NA
Oral LEN 600 mg (2  300 mg tablets)
or PTM oral LEN (2 tablets)
Day 8 and weekly 
until 
SC LEN/placebo 
resumed
Oral LEN 300 mg (1  300 mg tablet)
or PTM oral LEN (1 tablet)
Oral LEN 300 mg (1  300 mg tablet)
or PTM oral LEN (1 tablet)
LEN = lenacapavir; NA = not applicable; PTM = placebo-to-match; SC = subcutaneous
If a participant misses an oral LEN/placebo dose during weekly bridging, recommendations for 
restarting are summarized in Table 21.

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Table 21.
Missed Oral LEN/Placebo Dose Recommendations During Oral 
LEN/Placebo Weekly Bridging
Number of Days Since Missed Weekly Oral 
300 mg LEN/Placebo Dose
Recommendation
1 to 6 days
(1 missed weekly dose)
Take 300 mg (1 tablet) LEN/placebo orally as soon as 
possible. Then resume weekly dosing by taking 300 mg 
(1 tablet) LEN/placebo orally on the next scheduled weekly 
dosing day and weekly thereafter.
7 to 14 days
(1-2 missed weekly doses)
Take 600 mg (2 tablets) LEN/placebo orally as soon as 
possible. Then resume weekly dosing by taking 300 mg 
(1 tablet) LEN/placebo orally on the next scheduled weekly 
dosing day and weekly thereafter. If participant remembers on 
the scheduled weekly dosing day, take a total of 600 mg 
(2 tablets) LEN/placebo (never take greater than 600 mg on a 
single day).
More than 14 days
(3 or more missed weekly doses)
Consult with medical monitor
LEN = lenacapavir
5.3.2.
Emtricitabine/Tenofovir Disoproxil Fumarate (F/TDF)
F/TDF (200/300 mg) tablets and PTM F/TDF tablets will be provided by Gilead. Study drug will 
be dispensed to participants at the Day 1/Injection 1 visit. Participants will be instructed to take 
their first dose of study drug following completion of the study procedures at the 
Day 1/Injection 1 visit. If study drug was not taken in the clinic following the completion of 
Day 1/Injection 1 study procedures, initiation of the study drug must take place within 24 hours 
after the Day 1/Injection 1 visit and after the investigator has confirmed eligibility with the 
participant.
Participants will continue to take their daily dose of F/TDF or PTM F/TDF each day.
5.3.3.
Emtricitabine/Tenofovir Alafenamide (F/TAF)
See Appendix 7 for US-specific text.
5.4.
Prior and Concomitant Medications
Medications and use of herbal/natural supplements listed in Table 22 are excluded or should be 
used with caution while participants are taking study drug on the study due to potential DDIs 
with LEN or F/TDF. Antiretroviral medications with potential drug-drug interactions with LEN 
are listed in Table 23.
See Appendix 7 for US-specific text.
Bidirectional adverse interactions with GAHT with exogenous hormones are not expected 
(see Section 1.2.7).

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Table 22.
Prior and Concomitant Medications that are Prohibited or To Be Used with Caution due to the Potential 
for Drug-Drug Interaction with Study Drugs
Use Discouraged and To Be Used with Caution
Prohibited Medications
Medication Class
Medication(s)
Drug-Drug 
Interaction 
Potential
 Medication(s)
Drug-Drug 
Interaction 
Potential
Antiarrhythmics
Amiodarone, quinidine: May increase 
concentration of TAF and/or TFV
F/TDFa
-
-
Anticoagulants
Dabigatran etexilate: monitoring and/or dose 
reduction may be needed for certain 
populations per prescribing information
LEN
-
-
Anticonvulsants
-
-
Carbamazepine, oxcarbazepine, phenobarbital, 
phenytoin
LEN
Antimycobacterials
Clarithromycin: may increase concentration 
of TAF and/or TFV
F/TDF
Rifampin, rifabutin, rifapentine
LEN
Antifungals
Systemic itraconazole, ketoconazole, 
voriconazole: may increase concentration of 
TAF and/or TFV
F/TDF
-
-
Calcium channel 
blockers
Diltiazem, felodipine, verapamil: 
may increase concentration of 
TAF and/or TFV
F/TDF
-
-
Digoxin
Concomitant use may result in an increased 
or decreased digoxin concentration; use with 
caution and with appropriate monitoring of 
serum digoxin concentrations
F/TDF; LEN
-
-
Ergot derivatives
-
-
Ergotamine, ergonovine, dihydroergotamine, 
methylergonovine, ergometrine
LEN
Herbal/Natural 
Supplements
-
-
St. John’s Wort, Echinacea, Milk thistle (eg, 
silymarin), Chinese herb sho-saiko-to (or 
Xiao-Shai-Hu-Tang)
F/TDF; LEN
Hepatitis C therapies
Ledipasvir/sofosbuvir: has been shown to 
increase TFV exposure
F/TDF
Boceprevir, telaprevir
F/TDF

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Use Discouraged and To Be Used with Caution
Prohibited Medications
Medication Class
Medication(s)
Drug-Drug 
Interaction 
Potential
 Medication(s)
Drug-Drug 
Interaction 
Potential
HMG-CoA 
Reductase Inhibitors
Concentrations of statins may increase with 
LEN. Start with the lowest dose and titrate to 
clinical response. For each of the following 
statins, the maximum allowed dose is:
Simvastatin: 10 mg
Lovastatin: 20 mg
Atorvastatin: 40 mg
Careful monitoring for signs and symptoms 
of muscle weakness or myopathy, including 
rhabdomyolysis
LEN
-
-
Nephrotoxic 
medications
High-dose or multiple nonsteroidal anti-
inflammatory drug (NSAIDs)
F/TDF
Systemic chemotherapeutic agents, systemic 
aminoglycoside antibiotics, amphotericin B, 
systemic cidofovir, cisplatin, foscarnet, 
IV pentamidine, or, other agents with 
significant nephrotoxic potential
F/TDF
Other
-
-
probenecid
F/TDF
Phosphodiesterase-5 
Inhibitors
Concentrations of PDE-5 inhibitors may 
increase with LEN. Sildenafil, vardenafil, 
tadalafil: It is recommended that a single dose 
of sildenafil no more than 25 mg in 48 hours, 
vardenafil no more than 2.5 mg in 72 hours, 
or tadalafil no more than 10 mg in 72 hours 
be coadministered.
LEN
-
-
Sedatives/Hypnotics
midazolam, triazolam concentrations may 
increase with LEN
LEN
-
-
Systemic 
Corticosteroids
Concomitant use may increase corticosteroid 
exposure. Limit use to 7 days or less. 
Concomitant use of dexamethasone may 
decrease LEN exposures, particularly with 
long-term use. 
LEN
Use of all agents for greater than 7 days
LEN
F/TAF = emtricitabine/tenofovir alafenamide (coformulated; Descovy®); F/TDF = emtricitabine/tenofovir disoproxil fumarate; HMG-CoA = 3-hydroxy-3-methylglutaryl-
coenzyme A; LEN= Lenacapavir; PK = pharmacokinetic(s); TAF = tenofovir alafenamide; TFV = tenofovir; US = United States
a
F/TAF may be used in the US during PK Tail Phase. See Appendix 7 for US-specific text.

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Should participants have a need to initiate treatment with any prohibited concomitant 
medication, the Gilead medical monitor must be consulted, and approval granted prior to 
initiation of the new medication. In instances where a prohibited medication is initiated prior to 
discussion with the sponsor, the investigator must notify Gilead as soon as he/she is aware of the 
use of the prohibited medication.
Table 23.
Antiretroviral Medications With Potential Drug-Drug Interactions 
With LEN
Drug
Interaction Potential
Use for HIV Treatmenta
Use for PEPa
INSTI (BIC, CAB, DTG, 
EVG, RAL)
No clinically relevant 
interactions with LEN
Acceptable
Acceptable
NRTI (3TC, FTC, TAF, 
TDF)
No clinically relevant 
interactions with LEN
Acceptable
Acceptable
NNRTI (DOR, EFV, 
ETV, NVP, RPV) 
EFV, ETV, and NVP may 
reduce LEN levels
Acceptableb
Do not use
ATV with RTV or 
cobicistat
ATV significantly 
increases LEN levels
Do not use
Do not use
LPV with RTV or 
cobicistat
No clinically relevant 
interactions with LEN
Acceptableb
Acceptable
DRV with RTV
No clinically relevant 
interactions with LEN
Acceptableb
Acceptable
DRV with cobicistat
No clinically relevant 
interactions with LEN
Acceptable
Acceptable
3TC = lamivudine; ATV = atazanavir; BIC = bictegravir; CAB = cabotegravir; DOR = doravirine; DRV = darunavir; 
DTG = dolutegravir; EFV = efavirenz; EVG = elvitegravir; ETV = etravirine; FTC = emtricitabine; INSTI = integrase strand 
transfer inhibitor; LPV = lopinavir; NRTI = nucleoside reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse 
transcriptase inhibitor; NVP = nevirapine; PEP = postexposure prophylaxis; PI = protease inhibitor; RAL = raltegravir, 
RPV = rilpivirine; RTV = ritonavir; TDF = tenofovir disoproxil fumarate; TAF = tenofovir alafenamide
a
Refer to applicable guidelines for information on suitable regimens for HIV treatment and PEP.
b
Reduction in LEN levels are acceptable because LEN is not considered an active agent for HIV treatment regimens in this 
study.
If a participant is nonadherent to oral study drug or nonadherent with injection site visits, and 
experiences an event requiring PEP with ARV medications, then the ARVs which reduce LEN 
concentrations (EFV, ETV, NVP, LPV with cobicistat, and DRV with ritonavir) are not 
recommended if the participant plans to continue in the study on study drug after the 28-day 
course of PEP (Section 6.13.1). If a person acquires HIV in the study, it is not recommended that 
the participant initiate an ART regimen containing ATV/cobicistat (or ATV/ritonavir) as 
coadministration could significantly elevate LEN levels.

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5.5.
Accountability for Investigational Medicinal Product 
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug kits. This includes acknowledgment of receipt of each shipment of study drug kits (quantity 
and condition). All used and unused study drug kits dispensed to participants must be returned to 
the site.
Each study site must keep accountability records that capture:
•
The date received and quantity of study drug kits 
•
The date, participant number, and the study drug kit number dispensed
•
The date, quantity of used and unused study drug kits returned, along with the initials of the 
person recording the information
5.5.1.
Investigational Medicinal Product Return or Disposal
Gilead recommends that used and unused study drug supplies be destroyed at the site. If the site 
has an appropriate SOP for drug destruction as determined by Gilead, the site may destroy used 
(empty or partially empty) and unused study drug supplies in accordance with that site’s 
approved SOP. A copy of the site’s approved SOP will be obtained for electronic trial master 
file. If study drug is destroyed at the site, the investigator must maintain accurate records for all 
study drugs destroyed. Records must show the identification and quantity of each unit destroyed, 
the method of destruction, and the person who disposed of the study drug. Upon study 
completion, copies of the study drug accountability records must be filed at the site. Another 
copy will be returned to Gilead. 
If the site does not have an appropriate SOP for drug destruction, used and unused study drug 
supplies are to be sent to the designated disposal facility for destruction. The study monitor will 
provide instructions for return.
The study monitor will review study drug supplies and associated records at periodic intervals.
For both disposal options listed above, the study monitor must first perform drug accountability 
during a monitoring visit.

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6.
STUDY PROCEDURES
The study procedures to be conducted for each participant enrolled in the study are presented in 
tabular form in Appendix 3 and described in the text that follows. 
During emergency circumstances, such as an infectious disease pandemic and other force 
majeure events, refer to Appendix 2 for further details on the risks and risk mitigation strategy.
In exceptional circumstances (ie, if a participant is not able to come to the study site for an 
unavoidable reason), the investigator can conduct an off-site visit for non-injection visits only, 
after written approval from Gilead. The investigator must document any deviation from the 
protocol procedures and notify Gilead or the CRO.
From the time of obtaining informed consent through the first administration of study drug in the 
Randomized Blinded Phase, record all SAEs, as well as any AEs related to protocol-mandated 
procedures on the AE electronic case report form (eCRF). All other untoward medical 
occurrences observed during the screening period, including exacerbation or changes in medical 
history, are to be considered medical history. See Section 7, Adverse Events and Toxicity 
Management, for additional details.
6.1.
Participant Enrollment and Study Drug Assignment
Entry into screening does not guarantee enrollment of the study. In order to manage the total 
study enrollment, Gilead, at its sole discretion, may suspend screening and/or enrollment at any 
site or study wide at any time. 
6.2.
Screening Assessments
Assessments to determine eligibility to enroll into the study and be randomized for study drug 
are depicted in Figure 12 and described in Sections 6.2.1 and 6.2.2. Enrollment of adolescents 
(participants 16 and 17 years of age) will commence following the first DMC review of the 
unblinded safety data and recommendation to continue the study. Gilead will notify sites when 
they may begin enrollment of adolescents.

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Figure 12.
Assessments to Determine Enrollment and Randomization Eligibility
Ab = antibody; AG = antigen, PrEP = pre-exposure prophylaxis, RBP = Randomized Blinded Phase
a
Local HIV confirmation may be performed in addition to central laboratory confirmation at the investigator’s discretion.
b
A participant with a negative rapid HIV-1/2 Ab/Ag test who is not offered the randomization due to investigator’s discretion will be recorded as a screen completer. 
Participants with a positive rapid HIV-1/2 Ab/Ag test and a negative central HIV-1/2 Ab/Ag test will not be randomized into the study.
Incidence Phase Screening 
• Obtain informed consent 
• Confinn initial eligibility: 
-
Gender and age criteria 
-
Sexual behavior criteria 
-
Prior HIV testing criteria 
• Obtain demographic information 
• Perform local rapid 4th 
generation HIV-1 Ab/Ag test 
• Collect blood for lab analyses 
and storage samples 
Rapid 
--+ Randomized 
HIV O 
Pha~ 
Rapid 
Hlva () 
Obtain Randomized Blinded 
All eligibility 
criteria met, 
Central HIV 0 
Ace 
ts J- Phase (RBP) informed consent f-f-1-.illil 
ep 
• Complete RBP assessments 
Declines 
Central HIVO 
(see 6.2.2) 
Referral to 
locally 
available 
PrEP 
services 
Central HIV 0 
Central HIV 0 
Referral to locally 
available PrEP 
services 
Central HIV O ~ ------- Counseling and referral for HIV care 
Proceed to Day 1 
procedures and 
randomization 

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6.2.1.
Incidence Phase Screening 
Participants will be screened within 30 days of Day 1/Injection 1 to determine eligibility for 
participation in the study. Rescreening will not be allowed. In the event of a laboratory specimen 
technical failure requiring recollection, an extension of up to 7 days may be granted after medical 
monitor approval. Screening window extensions may be allowed with medical monitor approval 
in cases of study drug unavailability, as noted in Section 6.2.2. Exclusionary screening 
laboratory assessments will not be repeated for eligibility determination purposes unless assay 
failure is suspected. The following will be performed and documented at screening:
•
Obtain written informed consent (and assent for participants < 18 years of age, in accordance 
with local laws and regulations) for the Incidence Phase assessments. A parent/guardian may 
provide informed consent for adolescents (in accordance with local laws and regulations). 
The investigator or person designated by the investigator will provide ample time to the 
participant to review the informed consent form (ICF) and allow the participant the 
opportunity to ask questions about the study.
•
Obtain screening number from IWRS
•
Obtain demographic information and medical history
•
Query on sexual activity with partners assigned male at birth, including receptive anal sex
•
Collect date and result (documented, if available) from the last HIV-1 test performed prior to 
the screening visit
•
Query prior receipt of a long-acting PrEP medication or HIV vaccine
•
Obtain history regarding prior PrEP use
•
HIV risk reduction counseling including provision of both external (penile) and internal 
(vaginal) condoms and lubricant. Participants will be educated on the signs and symptoms of 
acute HIV-1 infection and will be instructed to call and/or present to the site immediately for 
evaluation and HIV-1 testing if they develop such symptoms. 
•
Participation in any prior or concurrent HIV vaccine or other PrEP study
•
Record any SAEs and all AEs related to protocol-mandated procedures occurring after 
signing of the ICF 
•
Urine pregnancy test for participants assigned female at birth who are of childbearing 
potential (see Appendix 6) (if positive, participants will not be eligible to enter the 
Randomized Blinded Phase)

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•
Blood collection (see Section 6.9.2) for: 
Local rapid fourth generation HIV-1/2 Ab/Ag test
Central HIV-1/2 testing, including a fourth generation HIV-1/2 Ab/Ag test if positive, 
reflexively confirmed by HIV-1/2 differentiation assay and HIV-1/2 RNA qualitative 
NAAT, if the fourth generation test and differentiation assay results are discrepant (refer 
to Appendix 5). 
HIV-1 RNA quantitative NAAT
Recency assay (run as indicated based on HIV test results)
DBS storage sample
Plasma storage samples for virology, safety, and/or PK testing
CD4 cell count (only if local rapid HIV-1/2 test is positive)
If the local rapid fourth generation HIV-1/2 Ab/Ag test is positive, participants will undergo 
confirmatory testing and counseling as appropriate (refer to Section 6.13), and study 
participation will conclude. If the local rapid fourth generation HIV-1/2 Ab/Ag test is negative, 
participants will proceed to complete Randomized Blinded Phase screening assessments if 
additional consent is obtained. At the investigator’s discretion, a positive local rapid fourth 
generation HIV-1/2 Ab/Ag test may be separately confirmed by following local testing 
guidelines in order to facilitate rapid ART initiation. 
After completion of Incidence Phase screening procedures, participants may be started on 
nonstudy oral PrEP at the investigator’s discretion. If nonstudy oral PrEP is initiated during the 
screening window, the last dose should be taken the day prior to Day 1/Injection 1.
6.2.2.
Randomized Blinded Phase Screening 
If a participant’s local rapid fourth generation HIV-1/2 Ab/Ag test is negative, pregnancy test is 
negative (in participants assigned female at birth who are of childbearing potential), and the 
Incidence Phase criteria are met, participants can be screened for the Randomized Blinded Phase 
if additional consent is obtained. The following will be performed:
•
Offer the Randomized Blinded Phase ICF. If participant accepts, obtain written informed 
consent (and assent for participants < 18 years of age, in accordance with local laws and 
regulations) pertaining to Randomized Blinded Phase assessments. A parent/guardian may 
provide informed consent for adolescents (in accordance with local laws and regulations). 
The investigator or person designated by the investigator will provide ample time to the 
participant to review the ICF and allow the participant the opportunity to ask questions about 
the study. 

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•
Urine collection (see Section 6.9.1) for:
Routine asymptomatic sexually transmitted infection (STI) testing for Neisseria 
gonorrhoeae (GC) and Chlamydia trachomatis (CT); for participants assigned female at 
birth, central laboratory urine Trichomonas vaginalis (TV) testing may be performed at 
the investigator’s discretion
Urinalysis, urine proteins, urine chemistry
•
Blood collection (see Section 6.9.2) for:
Chemistry and hematology profile
eGFR calculation
HBV testing
HCV testing
Serum pregnancy test for participants assigned female at birth who are of childbearing 
potential (see Appendix 6)
Local laboratory asymptomatic syphilis testing
•
Pharyngeal and rectal swab collection for asymptomatic GC and CT testing per central 
laboratory testing. Swabs may be self-collected by the participant at the discretion of the 
investigator.
•
Obtain medical history and prior medications used by the participant in the 30 days prior to 
the screening visit
•
Complete physical examination including, vital signs (blood pressure, pulse, respiration rate, 
and temperature), weight, height, and waist circumference
•
Record any SAEs and all AEs related to protocol-mandated procedures occurring after 
signing of the ICF
•
HIV risk reduction counseling and provision of both external (penile) and internal (vaginal) 
condoms and lubricant (only if Incidence Phase screening occurs on a separate day) 
•
Screening for intimate partner violence and appropriate referral when applicable
•
Integrated sexual behaviors and alcohol and substance use (see Appendix 7 for US-specific 
text)
Participants who completed the Incidence Phase assessments and were unable to complete the 
screening process due to unavailability of study drug or related materials may undergo 
Randomized Blinded Phase screening assessments with medical monitor approval. In the event 
that some or all Randomized Blinded Phase screening assessments were previously completed 

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and the participant remained eligible after those completed assessments, all Randomized Blinded 
Phase screening assessments will be repeated, except for questionnaires. Additionally, a local 
rapid fourth generation HIV-1/2 Ab/Ag test, a central fourth generation HIV-1/2 Ab/Ag test, and 
an HIV-1 RNA quantitative NAAT must be repeated and resulted as negative prior to 
randomization. In this scenario, participants must be randomized within 30 days of the initiation 
of repeated Randomized Blinded Phase screening assessments if confirmed to be eligible.
6.3.
Randomized Blinded Phase Assessments
6.3.1.
Day 1/Injection 1 
The following assessments are to be completed at the Day 1/Injection 1 visit (Appendix 3). The 
investigator must have confirmed eligibility in the Randomized Blinded Phase before proceeding 
with the Day 1/Injection 1 visit. Participants must complete all study procedures before being 
administered study drug, including having a negative local rapid fourth generation HIV-1/2 
Ab/Ag test and a negative screen for signs and symptoms of acute HIV infection. 
•
Urine collection (see Section 6.9.1) for:
Routine asymptomatic STI testing for GC and CT; for participants assigned female at 
birth, central laboratory urine TV testing may be performed at the investigator’s 
discretion
Urinalysis, urine proteins, urine chemistry
Urine storage sample
Urine pregnancy test for participants assigned female at birth who are of childbearing 
potential (see Appendix 6)
•
Blood collection (see Section 6.9.2) for:
Chemistry, hematology, and metabolic assessments
eGFR calculation
Local rapid fourth generation HIV-1/2 Ab/Ag test
Central HIV-1/2 testing, including a fourth generation HIV-1/2 Ab/Ag test, reflexively 
confirmed by HIV-1/2 differentiation assay and HIV-1/2 RNA qualitative NAAT, if the 
fourth generation test and differentiation assay results are discrepant (refer to 
Appendix 5)
HIV-1 RNA quantitative NAAT
Recency assay (run as indicated based on HIV test results)

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CD4 cell count (only if local HIV-1/2 test is positive)
DBS storage sample
Plasma storage sample for virology, safety, and/or PK testing
Serum storage sample for virology, safety, and/or PK testing
Serum pregnancy testing (in the event of a positive urine pregnancy test)
Local laboratory asymptomatic syphilis testing
Note: For participants diagnosed with HIV after receiving study drug, refer to Section 6.13
•
Pharyngeal and rectal swab collection for asymptomatic GC and CT testing per central 
laboratory testing. Swabs may be self-collected by the participant at the discretion of the 
investigator.
Participants will be treated for STIs per local guidelines
•
Review and record AEs per Sections 7.3 and 7.3.2, including screening for any signs or 
symptoms of acute HIV infection or STIs 
•
Review and record changes in concomitant medications
•
Targeted (symptom directed) physical examination
•
Vital signs, and height, weight and waist circumference (if the Day 1/Injection 1 visit is 
> 7 days after the screening visit)
Height is to be measured once on Day 1/Injection 1 if the participant is ≥ 20 years of age 
and annually if < 20 years of age until the age of 20 years.
•
Questionnaires 
Integrated sexual behaviors and alcohol and substance use (see Appendix 7 for 
US-specific text)
PrEP Impacts and Administration Preference Questionnaire - Day 1
Numeric Pain Rating Scale – Injection Pain Questionnaire (must be completed 
postinjection)
•
Enrollment into the Randomized Blinded Phase and randomization in IWRS

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•
Drug dispensation 
SC LEN/placebo administration and observed first administration of oral LEN/placebo 
300 mg tablets (2) Day 1/Injection 1 and observed first dose administration of oral F/TDF 
(or placebo) 
Participants should be observed for approximately 30 minutes after each SC injection 
dose 
•
One week (± 2 days) after each injection visit, participants will be contacted for a 
postinjection follow-up assessment and to confirm the participant has taken the Day 2 dose
•
Adherence counseling to encourage the importance of attending study visits in a timely 
fashion, daily adherence to study drug, and study retention
•
HIV risk reduction counseling including provision of both external (penile) and internal 
(vaginal) condoms and lubricant. Participants will be educated on the signs and symptoms of 
acute HIV-1 infection and will be instructed to call and/or present to the site immediately for 
evaluation and HIV-1 testing if they develop such symptoms. 
•
Screening for intimate partner violence and appropriate referral when applicable
6.3.2.
Weeks 4 and 8 (± 2 days) and Weeks 13, 26/Injection 2, 39, 52, and Every 
13 Weeks (± 7 days) Until the End of Randomized Blinded Phase Visit
The following assessments will occur at Randomized Blinded Phase visits (Appendix 3). 
Participants who are diagnosed with HIV during the Randomized Blinded Phase will discontinue 
study drug prior to the End of Randomized Blinded Phase visit and have samples collected 
(Section 6.13), and will be required to return to the study site for a post-HIV-infection follow-up 
visit (Section 6.7.3). 
All study visits are to be scheduled relative to the previous injection visit date, except in 
instances of oral LEN/placebo bridging (Section 6.8.3). 
•
Targeted (symptom directed) physical examination if clinically indicated
•
Vital signs, weight, height, and waist circumference
Height is to be measured annually if participant is < 20 years of age 
•
Review and record AEs per Sections 7.3 and 7.3.2, including screening for any signs and 
symptoms of acute HIV infection or STIs 
•
Review and record changes in concomitant medications

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•
Urine sample collection for the following laboratory analyses will be performed at every visit 
unless otherwise specified (see Section 6.9.1) for:
•
Routine asymptomatic STI testing for GC and CT; for participants assigned female at birth, 
central laboratory urine TV testing may be performed at the investigator’s discretion 
(Week 13 and every 13 weeks thereafter)
Urinalysis, urine proteins, urine chemistry
Urine storage sample
Urine pregnancy test for participants assigned female at birth who are of childbearing 
potential (see Appendix 6)
•
Blood sample collection for the following laboratory analyses will be performed at every 
visit unless specified (see Section 6.9.2):
Chemistry and hematology profile
Metabolic assessments (Week 26/Injection 2, Week 52, and every 26 weeks thereafter)
eGFR calculation
HBV and HCV testing (Week 26/Injection 2, Week 52, and every 26 weeks thereafter)
Local rapid fourth generation HIV-1/2 Ab/Ag test
Central HIV-1/2 testing, including a fourth generation HIV-1/2 Ab/Ag test, reflexively 
confirmed by HIV-1/2 differentiation assay and HIV-1/2 RNA qualitative NAAT, if the 
fourth generation test and differentiation assay results are discrepant (refer to 
Appendix 5)
HIV-1 RNA quantitative NAAT storage sample
DBS storage sample
Anytime plasma PK sample
Plasma storage sample for virology, safety, and/or PK testing
Serum storage sample for virology, safety, and/or PK testing
Serum pregnancy testing (in the event of a positive urine pregnancy test)
Local laboratory asymptomatic syphilis testing (Week 13, and every 13 weeks thereafter)

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Note: For participants diagnosed with HIV after receiving study drug, refer to Section 6.13
•
Pharyngeal and rectal swab collection for asymptomatic GC and CT testing per central 
laboratory testing (Week 13 and every 13 weeks thereafter). Swabs may be self-collected by 
the participant at the discretion of the investigator.
Participants will be treated for STIs per local guidelines
•
Questionnaires:
Adherence to Oral Study Product Questionnaire: Weeks 4, 8, and 13, and every 13 weeks 
thereafter
Integrated sexual behaviors and alcohol and substance use: Week 13 and every 13 weeks 
thereafter (see Appendix 7 for US-specific text)
Administration and Dosing Questionnaire for PrEP Medication: Weeks 13, 39, and 
13 weeks after each injection visit thereafter
PrEP Impacts and Administration Preference Questionnaire: Week 26/Injection 2, 
Week 52, and every 26 weeks thereafter at injection visits
Numeric Pain Rating Scale – Injection Pain Questionnaire (must be completed 
postinjection): Week 26/Injection 2, Week 52, and every 26 weeks thereafter at injection 
visits
•
HIV risk reduction counseling, including provision of both external (penile) and internal 
(vaginal) condoms and lubricant. Participants will be educated on the signs and symptoms of 
acute HIV-1 infection, and will be instructed to call and/or present to the site for evaluation 
and HIV-1 testing, if they develop such symptoms 
•
Adherence counseling to encourage the importance of attending study visits in a timely 
fashion, daily adherence to study drug, and study retention
•
Collect and review used and unused study drug for accountability and calculate adherence 
•
Study drug dispensation 
LEN/placebo administration at Week 26/Injection 2, Week 52, and every 26 weeks 
(± 7 days) thereafter. All SC injections will be administered 26 weeks (± 7 days) from the 
last SC injection.
Participants should be observed for approximately 30 minutes after each LEN injection 
•
One week (± 2 days) after each injection, participants will be contacted for a postinjection 
follow-up assessment 
•
Screening for intimate partner violence and appropriate referral when applicable

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6.4.
LEN Open-Label Extension Phase Assessments Day 1, Weeks 4 and 8 
(± 2 days), and Weeks 13, 26, 39, 52, and every 13 weeks thereafter
The following assessments will occur at LEN OLE Phase study visits unless otherwise specified 
(Appendix 3). 
All study visits are to be scheduled relative to the previous injection visit date, except in 
instances of oral LEN/placebo bridging (Section 6.8.3).
Note: the End of Randomized Blinded Phase visit coincides with LEN OLE Day 1. Refer to 
Section 3.3.3 for further details.
•
Targeted (symptom directed) physical examination, if clinically indicated 
•
Vital signs and weight 
Height is to be measured annually if participant is < 20 years of age 
•
Review and record AEs as per Sections 7.3 and 7.3.2, including any signs and symptoms of 
acute HIV infection or STIs
•
Review and record changes in concomitant medications
•
Urine sample collection for the following laboratory analyses will be performed at every visit 
unless otherwise specified (see Section 6.9.1):
Routine asymptomatic STI testing for GC and CT; for participants assigned female at 
birth, central laboratory urine TV testing may be performed at the investigator’s 
discretion (End of Randomized Blinded Phase visit/LEN OLE Day 1 and every 13 weeks 
thereafter)
Urinalysis 
Urine pregnancy test for participants assigned female at birth who are of childbearing 
potential (see Appendix 6)
•
Blood sample collection for the following laboratory analyses will be performed at every 
visit unless otherwise specified (see Section 6.9.2):
Chemistry and hematology profile (End of Randomized Blinded Phase visit/LEN OLE 
Day 1, and every 26 weeks thereafter)
Metabolic assessments (End of Randomized Blinded Phase visit/LEN OLE Day 1 and 
every 52 weeks thereafter)
eGFR calculation (End of Randomized Blinded Phase visit/LEN OLE Day 1, and every 
26 weeks thereafter)

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HBV and HCV testing (End of Randomized Blinded Phase visit/LEN OLE Day 1 and 
every 52 weeks thereafter)
Local rapid fourth generation HIV-1/2 Ab/Ag test
Central HIV-1/2 testing, including a fourth generation HIV-1/2 Ab/Ag test, reflexively 
confirmed by HIV-1/2 differentiation assay and HIV-1/2 RNA qualitative NAAT, if the 
fourth generation test and differentiation assay results are discrepant (refer to 
Appendix 5)
HIV-1 RNA quantitative NAAT storage sample
DBS storage sample (End of Randomized Blinded Phase visit/LEN OLE Day 1 only)
Anytime plasma PK sample
Plasma storage sample for virology, safety, and/or PK testing
Serum storage sample for virology, safety, and/or PK testing
Serum pregnancy testing (in the event of a positive urine pregnancy test)
Local laboratory asymptomatic syphilis testing (End of Randomized Blinded Phase 
visit/LEN OLE Day 1 and every 13 weeks thereafter)
Note: For participants diagnosed with HIV after receiving study drug, refer to Section 6.13).
•
Questionnaires (until and including LEN OLE Week 52): 
Integrated sexual behaviors and alcohol and substance use: End of Randomized Blinded 
Phase visit/LEN OLE Day 1, Week 13, and every 13 weeks thereafter (see Appendix 7 
for US-specific text)
Administration and Dosing Questionnaire for PrEP Medication questionnaire: 13 weeks 
after each injection visit
Experienced Preference for PrEP Medication Questionnaire: every injection visit
Numeric Pain Rating Scale – Injection Pain Questionnaire (must be completed 
postinjection): every injection visit
Adherence to Oral Study Product Questionnaire: End of Randomized Blinded Phase 
visit/LEN OLE Day 1 only

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•
Pharyngeal and rectal swab collection for asymptomatic GC and CT testing per central 
laboratory testing (End of Randomized Blinded Phase visit/LEN OLE Day 1, Week 13, and 
every 13 weeks thereafter). Swabs may be self-collected by the participant at the discretion 
of the investigator.
Participants will be treated for STIs per local guidelines
•
Collect and review used and unused study drug for accountability and calculate adherence 
(End of Randomized Blinded Phase/LEN OLE Day 1 only and Week 4 for participants 
randomized to F/TDF)
•
Drug dispensation
LEN administration if participant agrees to take part in the LEN OLE Phase. Participants 
who were randomized to F/TDF will receive their first LEN injection at End of 
Randomized Blinded Phase/LEN OLE Day 1 and every 26 weeks (± 7 days) thereafter 
until LEN becomes available or the sponsor elects to discontinue the study, whichever 
occurs first. Participants who were randomized to LEN will receive their first OLE 
injection 26 weeks (± 7 days) after their last injection in the Randomized Blinded Phase. 
All SC injections will be administered 26 weeks (± 7 days) from the last SC injection.
Participants should be observed for approximately 30 minutes after each SC injection 
dose.
Dispensation of oral LEN and adherence counseling (only for participants randomized to 
F/TDF to receive loading dose of oral LEN) should be completed.
•
One week (± 2 days) after each injection participants will be contacted for a postinjection 
follow-up assessment 
•
HIV risk reduction counseling, including provision of both external (penile) and internal 
(vaginal) condoms and lubricant. Participants will be educated on the signs and symptoms of 
acute HIV-1 infection and will be instructed to call and/or present to the site for evaluation 
and HIV-1 testing, if they develop such symptoms. 
•
Counseling to encourage the importance of attending study visits in a timely fashion, 
adherence to study drug injections, and study retention
•
Screening for intimate partner violence and appropriate referral when applicable

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6.5.
Pharmacokinetic Tail Phase Assessments Day 1 and Weeks 13, 26, 39, 52, 65, 
and 78 (± 7 days)
The following assessments will occur at PK Tail Phase visits unless otherwise specified 
(Appendix 3). Refer to Section 3.3.4 for further detail. All study visits are to be scheduled 
relative to PK Tail Day 1:
•
Targeted (symptom directed) physical examination, if clinically indicated.
•
Vital signs and weight 
Height is to be measured annually if participant is < 20 years of age 
•
Review and record AEs per Sections 7.3 and 7.3.2, including screening for any signs and 
symptoms of acute HIV infections or STIs, and changes in concomitant medications
•
Urine sample collection for the following laboratory analyses will be performed at every visit 
unless otherwise specified (see Section 6.9.1)
Routine asymptomatic STI testing for GC and CT; for participants assigned female at 
birth, central laboratory urine TV testing may be performed at the investigator’s 
discretion
Urinalysis, urine proteins, urine chemistry
Urine pregnancy test for participants assigned female at birth who are of childbearing 
potential (see Appendix 6)
•
Blood sample collection for the following laboratory analyses will be performed at every 
visit unless otherwise specified (see Section 6.9.2):
Chemistry and hematology profile (PK Tail Day 1 and every 26 weeks thereafter)
Metabolic assessments (PK Tail Day 1 and every 52 weeks thereafter)
eGFR calculation (PK Tail Day 1 and every 26 weeks thereafter).
HBV and HCV testing (PK Tail Day 1 and every 52 weeks thereafter)
Local rapid fourth generation HIV-1/2 Ab/Ag test
Central HIV-1/2 testing, including a fourth generation HIV-1/2 Ab/Ag test, reflexively 
confirmed by HIV-1/2 differentiation assay and HIV-1/2 RNA qualitative NAAT, if the 
fourth generation test and differentiation assay results are discrepant (refer to 
Appendix 5)

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HIV-1 RNA quantitative NAAT storage sample
DBS storage sample (PK Tail Day 1 for participants who prematurely discontinue study 
drug during the Randomized Blinded Phase, Week 13, and every 13 weeks thereafter)
■
If PK Tail Day 1 local rapid is positive, collect DBS
Anytime plasma PK sample
Plasma storage sample for virology, safety, and/or PK testing
Serum storage sample for virology, safety, and/or PK testing
Serum pregnancy testing (in the event of a positive urine pregnancy test)
Local laboratory asymptomatic syphilis testing (PK Tail Day 1 and every 13 weeks 
thereafter).
Note: For participants diagnosed with HIV after receiving study drug, refer to Section 6.13)
•
Questionnaires: 
Integrated sexual behaviors and alcohol and substance use: PK Tail Day 1, Week 13, and 
every 13 weeks thereafter (see Appendix 7 for US-specific text)
PrEP Impacts and Administration Preference Questionnaire: PK Tail Day 1 for 
participants who transition from the Randomized Blinded Phase
Administration and Dosing Questionnaire for PrEP Medication: PK Tail Day 1 
Adherence to Oral Study Product Questionnaire: PK Tail Day 1 for participants who 
transition from the Randomized Blinded Phase, Week 13, and every 13 weeks thereafter 
•
Pharyngeal and rectal swab collection for asymptomatic GC and CT testing per central 
laboratory testing. Swabs may be self-collected by the participant at the discretion of the 
investigator.
•
Participants will be treated for STIs per local guidelines
•
Collect and review used and unused study drug for accountability and calculate adherence 
•
Study drug dispensation 
•
Observed first-dose administration of oral OL F/TDF (see Appendix 7 for US-specific text)

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•
HIV risk reduction counseling, including provision of both external (penile) and internal 
(vaginal) condoms and lubricant. Participants will be educated on the signs and symptoms of 
acute HIV-1 infection and will be instructed to call and/or present to the site for evaluation 
and HIV-1 testing, if they develop such symptoms
•
Adherence counseling to encourage the importance of attending study visits in a timely 
fashion, daily adherence to study drug, and study retention
•
Screening for intimate partner violence and appropriate referral when applicable
6.6.
Unscheduled Visits
Additional unscheduled assessments may be performed at the discretion of the investigator 
(eg, for evaluation of AEs and/or laboratory abnormalities, including any signs and symptoms 
for STIs). Participants who have HIV testing performed during an unscheduled visit will have a 
local rapid fourth generation HIV-1/2 Ab/Ag test and DBS performed. If the HIV-1/2 Ab/Ag test 
is positive, participants will be followed as described in Section 6.13.
6.7.
Post-Study Drug Assessments
6.7.1.
Early Study Drug Discontinuation Visit
This study has multiple phases and study drug refers to any and all drugs provided to the 
participant while participating in the study. An early study drug discontinuation visit will occur 
once in the study when the participant permanently discontinues dosing with any assigned study 
drug prior to completing the study (regardless of study phase) for any reason other than acquiring 
HIV. Participants will be asked to return to the clinic for an ESDD visit within 72 hours of 
stopping study drug in the Randomized Blinded Phase or PK Tail Phase, or within 72 hours of 
informing the investigator they no longer wish to receive SC LEN injections in the LEN OLE 
Phase. 
At the ESDD visit, any assessment showing abnormal results that the investigator determines to 
have a possible or probable causal relationship with the study drug, will be repeated weekly 
(or as often as deemed prudent by the investigator) until the abnormality is resolved, returns to 
baseline, or is otherwise explained.
The following assessments occur at the ESDD visit:
•
Targeted (symptom directed) physical examination, if clinically indicated; vital signs, 
weight, and waist circumference (only for Randomized Blinded Phase)
Height if participant is < 20 years of age 
•
Review and record AEs as per Sections 7.3 and 7.3.2, including screening for any signs and 
symptoms of acute HIV infection or STIs, and changes in concomitant medications

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•
Urine sample collection (see Section 6.9.1)
Urinalysis, urine proteins, urine chemistry
Urine pregnancy test for participants assigned female at birth who are of childbearing 
potential (see Appendix 6)
•
Blood sample collection (see Section 6.9.2) for:
Chemistry and hematology profile
eGFR calculation
Local rapid fourth generation HIV-1/2 Ab/Ag test
Central HIV-1/2 testing including a fourth generation HIV-1/2 Ab/Ag test if positive, 
reflexively confirmed by HIV-1/2 differentiation assay and HIV-1/2 RNA qualitative 
NAAT, if the fourth generation test and differentiation assay results are discrepant 
(refer to Appendix 5)
HIV-1 RNA quantitative NAAT storage sample
DBS storage sample (only for Randomized Blinded Phase and PK Tail Phase)
Anytime plasma PK sample
Plasma storage sample for virology, safety, and/or PK testing
Serum storage sample for virology, safety, and/or PK testing
Serum pregnancy testing (in the event of a positive urine pregnancy test)
Note: For participants diagnosed with HIV after receiving study drug, refer to Section 6.13)
•
Questionnaires:
Adherence to Oral Study Product Questionnaire (if ESDD occurs during the Randomized 
Blinded Phase or PK Tail Phase)
PrEP Impacts and Administration Preference Questionnaire (if ESDD occurs during the 
Randomized Blinded Phase) 
Experienced Preference for PrEP Medication Questionnaire (if ESDD occurs during the 
LEN OLE Phase)
Integrated sexual behaviors and alcohol and substance use (at ESDD during any phase) 
(see Appendix 7 for US-specific text)

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•
Collect and review used and unused study drug for accountability and calculate adherence 
according to Appendix 3
•
For participants not discontinuing due to HIV infection, provide HIV risk reduction 
counseling, including provision of both external (penile) and internal (vaginal) condoms and 
lubricant. Participants will be educated on the signs and symptoms of acute HIV-1 infection 
and will be instructed to call and/or present to the site for evaluation and HIV-1 testing if 
they develop such symptoms 
•
Screening for intimate partner violence and appropriate referral when applicable
If participant is unwilling to return to the clinic for an ESDD visit, every effort will be made by 
the site staff to contact the participant to assess the current risk behavior, provide guidance and 
counseling, and understand the reason for discontinuing study drug.
6.7.2.
30-Day Follow-Up Visit
Participants who have received at least one dose of study drug may be required to complete a 
follow-up visit 30 days (± 14 days) after:
•
Discontinuation of the study drug for participants who complete an ESDD visit
•
Completing the PK Tail Phase
If the participant does not wish to proceed to the PK Tail Phase during the Randomized Blinded 
Phase or LEN OLE Phase, the participant will be required to return to the study site for the 
30-day follow-up visit. 
At the 30-day follow-up visit, any assessment showing abnormal results that the investigator 
determines to have a possible or probable causal relationship with the study drug will be repeated 
weekly (or as often as deemed prudent by the investigator) until the abnormality is resolved, 
returns to baseline, or is otherwise explained.
The following assessments are to be completed at the 30-day follow-up visit:
•
Targeted (symptom directed) physical examination if clinically indicated; vital signs, weight, 
height and waist circumference (only for Randomized Blinded Phase)
Height if the participant is < 20 years of age 
•
Review and record AEs as per Sections 7.3 and 7.3.2, including screening for any signs and 
symptoms of acute HIV infection or STIs, and changes in concomitant medications

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•
Urine sample collection (see Section 6.9.1) for:
Routine asymptomatic STI testing for GC and CT; for participants assigned female at 
birth, central laboratory urine TV testing may be performed at the investigator’s 
discretion
Urinalysis, urine proteins, urine chemistry
Urine pregnancy test for participants assigned female at birth who are of childbearing 
potential (see Appendix 6)
•
Blood sample collection (see Section 6.9.2) for:
Chemistry and hematology profile
eGFR calculation
Local rapid fourth generation HIV-1/2 Ab/Ag test
Central HIV-1/2 testing including a fourth generation HIV-1/2 Ab/Ag test if positive, 
reflexively confirmed by HIV-1/2 differentiation assay and HIV-1/2 RNA qualitative 
NAAT, if the fourth generation test and differentiation assay results are discrepant (refer 
to Appendix 5)
Local laboratory asymptomatic syphilis testing
HIV-1 RNA quantitative NAAT storage sample
DBS storage sample (only for Randomized Blinded Phase and PK Tail Phase)
Anytime plasma PK sample
Plasma storage sample for virology, safety, and/or PK testing
Serum storage sample for virology, safety, and/or PK testing
Serum pregnancy testing (in the event of a positive urine pregnancy test)
CD4 cell count, HIV-1 RNA quantitative NAAT, and HIV resistance genotype (for 
participants diagnosed with HIV after receiving study drug, refer to Section 6.13)
•
Pharyngeal and rectal swab collection for asymptomatic GC and CT testing per central 
laboratory testing. Swabs may be self-collected by the participant at the discretion of the 
investigator.
•
Participants will be treated for STIs per local guidelines

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•
For participants not discontinuing due to HIV infection, provide HIV risk reduction 
counseling, including provision of both external (penile) and internal (vaginal) condoms and 
lubricant. Participants will be educated on the signs and symptoms of acute HIV-1 infection 
and will be instructed to call and/or present to the site for evaluation and HIV-1 testing if 
they develop such symptoms.
•
Screening for intimate partner violence and appropriate referral when applicable
6.7.3.
Post-HIV-Infection Follow-Up
All participants diagnosed with HIV after receiving study drug will be required to complete a 
follow-up assessment 30 days (± 14 days) and 90 days (± 14 days) after confirmed HIV 
infection.
6.7.3.1.
30-Day Post-HIV-Infection Follow-Up 
The following assessments are to be completed at the 30-day post-HIV-infection follow-up visit:
•
Assessments in Section 6.7.2, except for the fourth generation HIV-1/2 Ab/Ag test, HIV-1 
RNA quantitative NAAT storage sample and DBS
•
CD4 cell count
•
HIV resistance genotype (run only if genotype was not already collected at time of infection)
•
HIV-1 by HIV-1 RNA quantitative NAAT
•
Review and record AEs per Sections 7.3 and 7.3.2, including screening for any signs and 
symptoms of STIs, and changes in concomitant medications
•
Status of HIV counseling and support received
6.7.3.2.
90-Day Post-HIV-Infection Follow-Up
The site staff will contact the participant to obtain the following information at 90 days 
(± 14 days) after confirmed HIV infection:
•
CD4 cell count
•
HIV-1 by HIV-1 RNA quantitative NAAT
•
Concomitant medications (including HIV treatments) and relevant information
If the participant does not have the above information, the site staff will ask the participant for 
permission to contact the participant’s doctor for the information. If CD4 cell counts and HIV-1 
VL data are not available, the participant will be requested to attend a site visit for laboratory and 
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Participants whose HIV-1 RNA is ≥ 50 copies/mL at the 90-day post-HIV follow-up visit will 
continue to have follow-up visits every 3 months until HIV-1 RNA is < 50 copies/mL at which 
point their participation will conclude. Participants will be followed up for a maximum of 1 year 
from the date of they were diagnosed with HIV infection. The procedures performed at the 
90-day post-HIV follow-up visit should be carried forward for these visits thereafter.
6.8.
Assessments for Study Drug Interruptions
If a participant discontinues study drug dosing (see Section 6.7.1) for any reason other than 
acquiring HIV, every attempt should be made to keep the participant in the study and continue to 
perform the required study-related follow-up and procedures. The participant will be requested to 
return for an ESDD visit. If it is not possible or acceptable to the participant, (after discussion of 
benefits/risks with the investigator) to keep the participant in the study, the participant will be 
withdrawn from the study and be required to return to the study site for a 30-day follow-up visit 
(Section 6.7.2). 
6.8.1.
Criteria for Restarting F/TDF or F/TDF Placebo After an Interruption
If a participant interrupts F/TDF or F/TDF placebo dosing for more than 7 consecutive days, the 
participant should have samples collected for the following HIV tests prior to restarting study 
dosing:
•
Local rapid fourth generation HIV-1/2 Ab/Ag
If the result for the rapid testing is positive, diagnosis should be confirmed per 
Appendix 5 and participant should be referred to local HIV care (Section 6.13) 
Upon testing negative for the rapid HIV-1/2 test, the participant may restart study drug 
dosing while pending the central laboratory HIV-1/2 tests, at the investigator’s discretion 
(Appendix 5).
•
Blood sample collection for the following central laboratory analyses:
Central HIV-1/2 testing (Appendix 5)
HIV-1 RNA quantitative NAAT and sample collection for possible genotypic resistance 
testing
6.8.2.
Criteria for Administering SC LEN Outside of the Target Visit Window 
(26 weeks ± 7 days)
Each study visit, including the injection visit, should be conducted within the target visit 
window. In the event this is not possible, visits outside of the target dates may be completed with 
the guidance below. Study drug injections must not be given before the target visit window.

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• 
If the paiiicipant is past the target visit window (26 weeks + 7 days) and > 28 weeks have 
elapsed since the last study drng injection, administration of injection study chug is allowed 
at the investigator's discretion. Prior to resuming treatment, the following procedures should 
be followed: 
-
Local rapid fomih generation HIV-1/2 Ab/Ag 
If the result for the rapid testing is positive, diagnosis should be confnmed per 
Appendix 5 and paiiicipant should be refened to local HIV cai·e (Section 6.13). 
-
Blood sample collection for the following centrnl laborato1y analyses: 
Central HIV-1/2 testing (Appendix 5) 
HIV-I RNA quantitative NAA T and sample collection for possible genotypic 
resistance testing 
-
If rapid fomih generation HIV-1/2 Ab/ Ag testing is negative, the paiiicipant may 
reinitiate study drng by administration of oral LEN/placebo (reloading dose) and 
injection LEN/placebo as described for Day 1 procedures (Sections 5.3.1 and 6.3.1), 
while central HIV-1/2 testing is pending, at the investigator's discretion. 
6.8.3. 
Bridging With Oral LEN/Placebo 
If SC LEN/placebo cannot be administered within the injection visit window due to extenuating 
circumstances and the investigator deems it clinically appropriate to continue LEN/placebo, 
bridging with oral LEN/placebo may be pe1mitted with medical monitor approval. 
If oral LEN/placebo bridging is initiated during the Randoinized Blinded Phase, the participant 
will receive blinded oral LEN or PTM oral LEN aligned with their original study chug 
assignment, taken once weekly. Paiiicipants will continue to take daily oral F/TDF or PTM 
F/TDF during LEN/placebo bridging (ie, pa1iicipants will receive active study drng and placebo). 
If oral LEN bridging is initiated during the LEN OLE Phase, the pa1iicipant will receive 
open-label oral LEN to be taken once weekly. 
The procedures for initiating oral LEN/placebo bridging and resuming SC LEN/placebo 
injections ai·e listed below: 
• 
The site will obtain pe1mission from the medical monitor prior to initiating LEN/placebo 
bridging. 
• 
The paiiicipant will retmn to the site 26 weeks ± 7 days from the last SC LEN/placebo 
administration. Paiiicipants who ai·e > 28 weeks from the last SC LEN/placebo injection 
require additional oral doses for loading as described in Section 5.3.1.2 and Table 20. 
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The scheduled visit assessments (see Sections 6.3.2 or 6.4) will be performed, with the 
exception of SC LEN/placebo administration and 1-week post-injection follow-up. No 
questionnaires will be required for the bridging initiation visit.
•
Only the number of bottles needed for the LEN/placebo bridging period will be dispensed to 
participants. Up to 4 bottles (16 tablets) of LEN/placebo may be dispensed to bridge to the 
next scheduled every-13-week visit.
•
If the participant requires LEN/placebo bridging beyond 12 doses, the site will contact the 
medical monitor to approve continued bridging. The participant will then return to the site for 
the scheduled every-13-week visit and complete all associated assessments, except for the 
questionnaires. The site should schedule this visit to occur before or on the day that the 
participant is due for their 13th oral LEN/placebo dose. At this visit, the site may dispense up 
to an additional 3 bottles (12 tablets) of LEN/placebo.
•
The participant will take the first dose of oral LEN/placebo at the site (bridging Day 1) and 
continue taking LEN/placebo 300 mg (1 tablet) orally once per week (eg, bridging Days 8, 
15, 22, etc). See Section 5.3.1.2 for dosing details including additional loading doses for 
participants who are > 28 weeks from the last SC LEN/placebo injection (Table 20) and for 
guidance on missed oral LEN/placebo bridging doses (Table 21).
•
During oral LEN/placebo bridging, the site will contact the participant weekly to confirm 
dosing of oral LEN/placebo (by telehealth, phone, and if required on-site visit, off-site visit, 
or other means).
•
The participant will resume SC LEN/placebo injections as soon as possible; this does not 
need to occur on a scheduled visit date. Once it becomes possible to administer SC 
LEN/placebo, the participant will return to the site and complete the injection visit that was 
originally missed. For instance, if a participant began oral LEN/placebo bridging because 
they could not receive SC LEN/placebo injection at Week 26, the participant would return to 
the site as soon as SC LEN/placebo administration is feasible and resume the study at the 
Week 26/Injection 2 visit.
•
When resuming SC LEN/placebo, the SC LEN/placebo injection can be given any time 
within 7 days of the last oral LEN/placebo dose. 

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6.9.
Clinical Laboratory Assessments
Blood and urine samples will be collected throughout the study as outlined below and in 
Appendix 3. 
6.9.1.
Urine Samples
•
Urine sample for urinalysis, urine proteins, and urine chemistry (uric acid, phosphate, and 
creatinine) 
Participants who test positive for Grade 3 or Grade 4 proteinuria or glycosuria that is 
unexplained or not clinically manageable will be withdrawn from the study
•
Urine storage sample (samples collected at RBP)
•
Urine collection for GC and CT testing 
•
For participants assigned female at birth, central laboratory urine TV testing may be 
performed at the investigator’s discretion
•
Urine pregnancy test for participants assigned female at birth who are of childbearing 
potential (See Appendix 6) 
6.9.2.
Blood Samples
•
Central HIV-1/2 testing, including a fourth generation HIV-1/2 Ab/Ag test, reflexively 
confirmed by HIV-1/2 differentiation assay and HIV-1/2 RNA qualitative NAAT, if the 
fourth generation test and differentiation assay results are discrepant (Appendix 5)
•
Local rapid fourth generation rapid HIV-1/2 Ab/Ag test 
If the result for rapid testing is positive, refer to Section 6.13.
•
HIV-1 RNA quantitative NAAT at Incidence Phase screening and on Day 1/Injection 1 of the 
Randomized Blinded Phase (Appendix 5)
If a participant is confirmed to have acquired HIV, refer to Section 6.13.
•
Hematology profile: complete blood count (CBC) with differential and platelet count
•
Chemistry profile: alkaline phosphatase, AST, ALT, gamma-glutamyl transferase (GGT), 
total bilirubin, direct and indirect bilirubin, total protein, albumin, lactate dehydrogenase 
(LDH), bicarbonate, blood urea nitrogen, calcium, chloride, creatinine, glucose, phosphorus, 
magnesium, potassium, sodium, uric acid, lipase, and creatinine phosphokinase (only at 
RBP).
•
Blood sample for syphilis analysis per local testing protocol 

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Metabolic assessments: Fasting (no food or drinks, except water, at least 8 hours prior to 
blood collection) lipid panel (total cholesterol, high-density lipoprotein [HDL], direct LDL, 
and triglycerides) and hemoglobin A1c (HbA1c). Glucose (part of the chemistry profile) will 
be collected in a fasting state on visits when metabolic assessments are performed. If the 
participant has not fasted prior to the visit, the visit may proceed but the participant should 
return within 72 hours in a fasted state to draw blood for the metabolic assessments. 
•
Estimated GFR according to the Cockcroft-Gault formula for CLcr
•
Hepatitis B testing (HBsAg, HBsAb, HBcAb):
If a participant has a negative HBsAg, negative HBsAb, and positive HBcAb, HBV DNA 
testing will be completed. If the HBV DNA result is positive, the participant is a screen 
failure. 
Participants found to be susceptible to HBV infection will be offered HBV vaccination.
•
Hepatitis C testing 
If the HCV Ab result is positive at screening, then HCV RNA will be completed. For 
other visits aside from screening, HCV RNA will not be performed if HCV Ab is positive 
and HCV RNA is negative at screening. 
•
Blood sample for DBS storage 
•
CD4 cell count 
•
HIV resistance genotype 
•
HIV-1 recency assay 
•
Blood storage sample for HIV-1 RNA quantitative NAAT 
•
Anytime plasma PK sample for LEN 
•
Plasma storage sample for virology, safety, and/or PK testing 
•
Serum storage sample
•
Serum pregnancy test if urine pregnancy test is positive
6.10.
End of Study
End of study is defined the last participant’s last observation (last visit). 

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6.11.
Poststudy Care
Participants randomized in the study who have completed or terminated participation in the study 
will be transitioned to local HIV prevention services.
Participants who are diagnosed with HIV during the study will be referred to locally available 
HIV treatment and care services upon confirmation of HIV infection (Section 6.13). 
6.12.
STI Testing
Scheduled asymptomatic screening for STIs will occur regularly throughout the study for 
participants enrolled in the Randomized Blinded, LEN OLE, and PK Tail Phases, and will 
include: 
•
Asymptomatic urine sample, pharyngeal and rectal swab collection for GC and CT testing 
per central laboratory testing. Swabs may be self-collected by the participant at the discretion 
of the investigator.
•
For participants assigned female at birth, central laboratory asymptomatic urine TV testing 
may be performed at the investigator’s discretion
•
Asymptomatic blood syphilis analysis as per local testing protocol
In addition to scheduled asymptomatic screening for STIs, if participants report any sign or 
symptom of an STI, they should be managed (diagnosed and treated) according to local clinical 
guidelines and practice.
6.13.
Diagnosis of HIV-1 Infection
HIV Diagnoses Identified at Screening
At screening, participants will have HIV-1/2 testing samples collected as specified in 
Section 6.2.1, and eligibility will be determined as noted in Figure 12 and in the HIV testing 
algorithm (Appendix 5, part a). Procedures for specific situations are noted below:
•
Participants with any positive HIV-1/2 test at screening (local rapid fourth generation 
HIV-1/2 Ab/Ag, central laboratory fourth generation HIV-1/2 Ab/Ag, or HIV-1 RNA 
quantitative NAAT) are not eligible for randomization.
•
If the local rapid fourth generation HIV-1/2 Ab/Ag test is positive at screening, the 
participant will not proceed with Randomized Blinded Phase screening procedures, and the 
central laboratory will reflexively run confirmatory testing (per the central HIV-1/2 testing 
algorithm in Appendix 5, part a). A CD4 cell count will be run reflexively while central 
confirmatory testing is underway.
•
HIV recency assay will be performed as indicated based on the participant’s HIV testing 
results.

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•
Any participant with a confirmed diagnosis of HIV will be counseled and referred for local 
HIV-related care as appropriate, and study participation will conclude.
•
Any participant with a positive HIV test who is subsequently determined to be HIV negative 
(ie, false positives) will be ineligible for randomization. Participants will be counseled on the 
meaning of their test results and will be referred to locally available HIV prevention services 
HIV Diagnoses Identified at Day 1/Injection 1
At Day 1/Injection 1, all participants will have HIV-1/2 testing samples collected as specified in 
Section 6.3.1, and results will be managed as outlined in Appendix 5, part b. Procedures for 
specific situations are noted below:
•
If the local rapid fourth generation HIV-1/2 Ab/Ag test is negative and all other eligibility 
criteria are satisfied, the participant may proceed to randomization and receipt of study drug.
•
If the local rapid fourth generation HIV-1/2 Ab/Ag test is positive, the participant will not 
proceed to randomization or receive study drug, and the central laboratory will reflexively 
run confirmatory testing and a CD4 cell count. 
•
HIV recency assay will be performed as indicated based on the participant’s HIV testing 
results.
•
Participants with a positive local rapid fourth generation HIV-1/2 Ab/Ag test on 
Day 1/Injection 1 who test negative by the central HIV-1/2 testing algorithm (ie, false 
positive rapid test) remain ineligible for randomization. Participants will be counseled on the 
meaning of their test results and will be referred to locally available HIV prevention services. 
•
Participants with a negative local rapid fourth generation HIV-1/2 Ab/Ag test on 
Day 1/Injection 1 who test positive by the central HIV-1/2 testing algorithm (ie, false 
negative rapid test) will return to the site as soon as possible to have samples collected for a 
CD4 cell count and HIV resistance genotype. 
•
Participants with a positive HIV-1 RNA quantitative NAAT who test negative by local rapid 
fourth generation HIV-1/2 Ab/Ag test and central HIV-1/2 testing algorithm will undergo 
repeat testing (local rapid HIV-1/2 Ab/Ag, central HIV-1/2 Ab/Ag, and HIV-1 RNA 
quantitative NAAT). If repeat testing is completely negative, the participant may continue 
study drug and study procedures after approval by the medical monitor.
•
Any participant with a confirmed diagnosis of HIV will be counseled and referred for local 
HIV-related care as appropriate. 

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HIV Diagnoses Identified Beyond Day 1/Injection 1
For the Randomized Blinded Phase, LEN OLE Phase, and PK Tail Phase, participants will have 
HIV-1/2 testing samples collected as specified in the Sections 6.3.2, 6.4, and 6.5, respectively, 
and results will be managed as outlined in Appendix 5, part c. Procedures for specific situations 
are noted below:
•
Participants with a positive local rapid fourth generation HIV-1/2 Ab/Ag test will undergo 
reflexive confirmatory testing by the central HIV-1/2 testing algorithm (Appendix 5). If HIV 
diagnosis is confirmed by the central HIV-1/2 testing algorithm, the participant will return to 
the site as soon as possible to have samples collected for CD4 cell count, and HIV resistance 
genotype. At the investigator’s discretion, CD4 cell count, and resistance genotype may be 
sent at the same visit where the positive local rapid fourth generation HIV-1/2 Ab/Ag test 
occurs, while central laboratory confirmation is pending. Injection study drug will not be 
administered to participants with a positive local rapid fourth generation HIV-1/2 Ab/Ag test 
unless central HIV-1/2 testing confirms HIV-negative status (see below).
•
Participants with a positive local rapid fourth generation HIV-1/2 Ab/Ag test who test 
negative by the central HIV-1/2 testing algorithm including HIV-1 RNA quantitative NAAT 
(ie, false positive rapid test) may continue study drug, receive study drug injections if due, 
and continue study procedures after confirmation from the medical monitor.
•
Participants with a negative local rapid HIV-1/2 Ab/Ag who test positive by the central 
HIV-1/2 testing algorithm (ie, false negative rapid test) will return to the site as soon as 
possible to have samples collected for CD4 cell count and HIV resistance genotype.
•
Any participant with confirmed diagnosis of HIV will be counseled and referred for local 
HIV-related care as appropriate. 
Additional HIV Testing
At any point in the study, if the local rapid fourth generation HIV-1/2 Ab/Ag is positive, the 
investigator may, at their discretion, perform additional local testing in order to expedite 
diagnosis and initiation of ART. At any point in the study, if HIV testing results are inconclusive 
or discrepant, additional testing may be performed after discussion with the medical monitor. 
Additionally, retrospective testing of stored specimens may be conducted to confirm the date of 
HIV acquisition. 
If the participant’s HIV-1 VL at diagnosis is > 200 copies/mL at any time after the study drug 
dosing, a stored plasma sample will be sent for HIV resistance genotype testing.

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HIV Follow-up and ART Initiation
Rapid ART initiation should be considered for any participant diagnosed with HIV. In cases 
where HIV diagnosis is not yet confirmed or HIV testing results are discrepant, decisions 
regarding discontinuation of oral study drug and initiation of ART will be made by the 
investigator in consultation with the medical monitor. Initiation of ART while awaiting 
confirmation of HIV-1 diagnosis is allowed, and in the event that a participant initiates ART and 
is ultimately determined to be HIV-negative, study drug may be resumed after approval by the 
medical monitor.
All participants diagnosed with HIV after receiving study drug will undergo additional study 
follow-up as described in Section 6.7.3.
Participants will be interviewed to understand the details of their seroconversion, including 
elicitation of signs and symptoms of acute HIV-1 infection, self-report of study drug 
adherence/injection visit adherence, and any other relevant clinical historical and/or behavioral 
information via the HIV infection/seroconversion interview. They will receive counseling 
(including the benefit of rapid start of an ARV treatment regimen) and be referred to receive 
local HIV-related care to initiate HIV-1 treatment as appropriate. Participants will be required to 
return to the study site for post-HIV-infection follow-up visits (Section 6.7.3).
6.13.1.
Suspected Acute HIV-1 Infection/Postexposure Prophylaxis
Investigators may at their discretion provide PEP in accordance with local medical practice 
and/or guidelines when a participant is suspected of having an acute HIV-1 infection or high-risk 
exposure under the following circumstances:
•
In the Randomized Blinded Phase: if a participant has been nonadherent to the oral study 
drug or has been nonadherent to per-protocol LEN injection administration and has had a 
high-risk exposure event, the investigator may discontinue the participant from the study 
drugs and provide a 3-drug regimen for PEP. Further details on recommendations for prior 
and concomitant medications with LEN are included in Section 5.4.
•
In the LEN OLE Phase, if a participant has missed a scheduled LEN injection and 
subsequently had a high-risk exposure event, the investigator may provide a 3-drug regimen 
for PEP.
•
In the PK Tail Phase, if the participant has been nonadherent to F/TDF and has had a 
high-risk exposure event, the investigator may restart the participant on F/TDF and add a 
third agent to comprise PEP treatment (see Appendix 7 for US-specific text).
•
Guidance on PEP drugs suitable for coadministration with LEN can be found in Table 23.
Participants who undertake PEP treatment may resume with oral study drug after meeting the 
criteria for restarting study drug after interruption (Section 6.8.1) after 28 days of PEP.

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6.14.
HIV Risk Reduction Counseling
HIV risk reduction counseling will be provided at each study visit, in accordance with local 
standard of care, and will include messaging about consistent condom use. External (penile) and 
internal (vaginal) condoms and lubricant will be offered to all participants at each study visit 
consistent with local standards.
6.15.
Adherence and Retention
The effectiveness of daily oral PrEP (F/TDF) is strictly correlated with adherence.
The study will provide adherence support/counseling to oral F/TDF or PTM at Day 1/Injection 1 
and at all dispensing visits for all participants. Participants will also be counseled to adhere to the 
injection schedule for LEN or LEN placebo. 
See Appendix 7 for US-specific text.
6.16.
Participant-Reported Questionnaires
The questionnaires may include questions on the participant’s sexual behavior, HIV risk 
perception, and participation in the study. The questions may also include questions on mental 
health, and alcohol and drug use.
Randomized Blinded Phase Questionnaires
•
PrEP Impacts and Administration Preference Questionnaire: Day 1/Injection 1, 
Week 26/Injection 2, Week 52, and every 26 weeks thereafter at injection visits 
•
Administration and Dosing Questionnaire for PrEP Medication: Weeks 13, 39, and 13 weeks 
after each injection visit thereafter
•
Numeric Pain Rating Scale – Injection Pain Questionnaire (must be completed postinjection) 
Day 1/Injection 1, Week 26/Injection 2, Week 52, and every 26 weeks thereafter at injection 
visits 
•
Integrated sexual behaviors and alcohol and substance use: Randomized Blinded Phase 
screening, Day 1/Injection 1, Week 13, and every 13 weeks thereafter (see Appendix 7 for 
US-specific text)
•
Adherence to Oral Study Product Questionnaire: Weeks 4, 8, 13, and every 13 weeks 
thereafter 

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LEN OLE Phase Questionnaires (until and including LEN OLE Week 52)
•
Experienced Preference for PrEP Medication Questionnaire: every injection visit 
•
Administration and Dosing Questionnaire for PrEP Medication: 13 weeks after each injection 
visit
•
Numeric Pain Rating Scale – Injection Pain Questionnaire (must be completed postinjection): 
at every injection visit 
•
Integrated sexual behaviors and alcohol and substance use: End of Randomized Blinded 
Phase visit/LEN OLE Day 1, Week 13, and every 13 weeks thereafter (see Appendix 7 for 
US-specific text)
•
Adherence to Oral Study Product Questionnaire: End of Randomized Blinded Phase 
visit/LEN OLE Day 1 only
PK Tail Phase Questionnaires
•
PrEP Impacts and Administration Preference Questionnaire: PK Tail Day 1 for participants 
who transition from the Randomized Blinded Phase
•
Administration and Dosing Questionnaire for PrEP Medication: PK Tail Day 1
•
Integrated sexual behaviors and alcohol and substance use: PK Tail Day 1, Week 13, and 
every 13 weeks thereafter (see Appendix 7 for US-specific text)
•
Adherence to Oral Study Product Questionnaire: PK Tail Day 1 for participants who 
transition from the Randomized Blinded Phase, Week 13, and every 13 weeks thereafter
ESDD Visit Questionnaires
•
PrEP Impacts and Administration Preference Questionnaire: Randomized Blinded Phase 
ESDD visit
•
Experienced Preference for PrEP Medication Questionnaire: LEN OLE Phase ESDD visit
•
Adherence to Oral Study Product Questionnaire: Randomized Blinded Phase or PK Tail 
Phase ESDD visit
•
Integrated sexual behaviors and alcohol and substance use: ESDD visit for any phase (see 
Appendix 7 for US-specific text)

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Pregnancy 
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Paiiicipants who were assigned female at birth and ai·e of reproductive potential must have a 
negative pregnancy test at the Randomized Blinded Phase screening and Day I/Injection 1 and 
agree to utilize protocol-specified method(s) of contraception as described in Appendix 6. 
Paiiicipants assigned female at biiih who ai·e of childbearing potential ai·e requii·ed to use 
effective contraception for the duration of the study. Any paiiicipant who becomes pregnant after 
randomization may remain in the study and continue to receive study chug after a reconsent 
process in which they will be infonned of the benefits and risks of continuing receipt of study 
chug and the collection ofbiiih outcomes for the child and lactation info1mation (Section 9.1.4). 
Paiiicipants who are taking testosterone and become pregnant during the study must discontinue 
testosterone if continuing the pregnancy and wish to continue on study chug. Prenatal care will 
be at the investigator's discretion per local standai·d of cai·e and will not be provided as paii of the 
study. Pregnant paiiicipants who continue on study ch11g will also be info1med that plasma PK 
sainples that ai·e being collected may be tested for LEN. 
6.18. 
Social Harms Reporting 
It is possible that paiiicipants' involvement in the study could become known to others, and that 
a social hann may result (ie, because pai·ticipants could be perceived as having acquii·ed HIV or 
at "high risk" for HIV infection). Social haims events ai·e events that a paiiicipant repo1is as 
affecting them as a result of being involved in a reseai·ch study, not the reseai·cher's opinion of 
how they perceive an event has affected a paiiicipant. For example, pa1iicipants might be treated 
unfaii·ly if it is known that they are paiiicipating in the study. Participants may also have 
problems being accepted by their families and/or communities. 
The site staff will discuss social haims with paiiicipants via an interview, and the social hanns 
may be repo1ied according to local regulations and requii·ements. 
In the event a paiiicipant repo1is a social haim, eve1y effo1i will be made by study staff to 
provide appropriate cai·e and counseling to the paiiicipant as necessaiy, and/or refe1Tal to 
appropriate resources for the safety of the participant. 
6.19. 
Sample Storage 
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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events and Serious Adverse Events
7.1.1.
Adverse Events
An AE is any untoward medical occurrence in a clinical study participant administered a study 
drug, which does not necessarily have a causal relationship with the treatment. An AE can 
therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated 
with the use of a study drug, whether or not the AE is considered related to the study drug. 
Adverse events may also include pretreatment or posttreatment complications that occur as a 
result of protocol-specified procedures or special situations (Section 7.1.3). 
An AE does not include the following:
•
Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an AE and must be reported
•
Preexisting diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen
•
Situations where an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions)
•
Overdose without clinical sequelae (Section 7.1.3)
•
Any medical condition or clinically significant laboratory abnormality with an onset date 
before the ICF is signed and not related to a protocol-associated procedure is not an AE but 
rather considered to be preexisting and should be documented as medical history.
Preexisting events that increase in severity or change in nature after study drug initiation or 
during or as a consequence of participation in the clinical study will also be considered AEs.
7.1.1.1.
Protocol-Specific Adverse Event Reporting Exemptions
Incidence of HIV-1 infection is an outcome of this study and therefore should not be reported as 
an AE (Section 6.13 for reporting of HIV infection).

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7.1.2.
Serious Adverse Events
An SAE is defined as an event that, at any dose, results in the following:
•
Death
•
A life-threatening situation (Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the participant was at risk of death at the time of the event; it does 
not refer to an event that hypothetically might have caused death if it were more severe.)
•
In-patient hospitalization or prolongation of existing hospitalization
•
Persistent or significant disability/incapacity
•
A congenital anomaly/birth defect
•
A medically important event or reaction: Such events 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 constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. 
7.1.2.1.
Protocol-Specific Serious Adverse Event Definitions
In this study, vertical transmission in participants who become infected with HIV on study drug 
is to be considered medically important and therefore “serious.” Vertical transmission of HIV 
infection can occur during gestation, delivery, or breastfeeding. Instructions for reporting SAEs 
are described in Section 7.4.1.
7.1.3.
Study Drugs and Gilead Concomitant Therapy Special Situations Reports
Special situation reports (SSRs) include all reports of medication error, abuse, misuse, overdose, 
occupational exposure, drug interactions, exposure via chestfeeding, unexpected benefit, 
transmission of infectious agents via the product, counterfeit of falsified medicine, and 
pregnancy regardless of an associated AE. 
Medication error is any unintentional error in the prescribing, dispensing, preparation for 
administration or administration of a study drug while the medication is in the control of a health 
care professional, patient, or consumer. Medication errors may be classified as a medication error 
without an AE, which includes situations of missed dose, medication error with an AE, 
intercepted medication error, or potential medication error.
Abuse is defined as persistent or sporadic intentional excessive use of a study drug by a 
participant.

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Misuse is defined as any intentional and inappropriate use of a study drug that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a study 
drug given per administration or cumulatively which is above the maximum recommended dose 
as per protocol or in the product labeling (as it applies to the daily dose of the participant in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the participant has taken the excess dose(s). Overdose cannot be established 
when the participant cannot account for the discrepancy, except in cases in which the 
investigator has reason to suspect that the participant has taken the additional dose(s).
Occupational exposure is defined as exposure to a study drug as a result of one’s professional or 
nonprofessional occupation.
Drug interaction is defined as any drug/drug, drug/food, or drug/device interaction.
Unexpected benefit is defined as an unintended therapeutic effect where the results are judged to 
be desirable and beneficial. 
Transmission of infectious agents is defined as any suspected transmission of an infected agent 
through a Gilead study drug.
Counterfeit or falsified medicine: Any study drug with a false representation of (a) its identity, 
(b) its source, or (c) its history.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to study 
drug using clinical judgment and the following considerations:
•
No: Evidence exists that the AE has an etiology other than the study drug. For SAEs, an 
alternative causality must be provided (eg, preexisting condition, underlying disease, 
intercurrent illness, concomitant medication).
•
Yes: There is reasonable possibility that the AE may have been caused by the study drug.
A “reasonable possibility” of a causal relationship means that there is evidence, fact and/or other 
rationale to suggest a causal relationship, rather than a relationship that cannot be ruled out.
It should be emphasized that lack of efficacy of study drug should not be considered as causally 
related in the context of AE reporting. 

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The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:
•
No: Evidence exists that the AE has an etiology other than the study procedure.
•
Yes: The AE occurred as a result of protocol procedures (eg, venipuncture).
7.2.2.
Assessment of Severity 
The severity of AEs will be graded using the Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events, Version 2.1 For each episode, the highest grade 
attained should be reported as defined in the Toxicity Grading Scale.
The DAIDS scale is available at the following location: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf
Grade 1 and Grade 2 study drug injection site pain or tenderness will be interpreted as referring 
to any study drug injection site rather than referring just to “limb” as stated in the grading scale. 
Injection site nodule and injection site induration measured at < 2.5 cm should be recorded as 
Grade 1 despite the DAIDS “induration and swelling” cutoff of 2.5 cm as the lower limit for 
Grade 1.
7.3.
Investigator Reporting Requirements and Instructions 
7.3.1.
Requirements for Collection Prior to Study Drug Initiation
After informed consent, but prior to initiation of study medication, the following types of events 
must be reported on the applicable eCRFs: all SAEs and any AEs related to protocol-mandated 
procedures.
7.3.2.
Adverse Events
Following initiation of study drug, collect all AEs, regardless of cause or relationship throughout 
the duration of the study, including the protocol-specified follow-up period, and report them on 
the eCRFs as instructed.
All AEs should be followed until resolution or until the AE is stable, if possible. Gilead may 
request that certain AEs be followed beyond the protocol-defined follow-up period.
7.3.3.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occur after the participant first consents to 
participate in the study (ie, signing the ICF) and throughout the duration of the study, including 
the protocol-defined follow-up period, must be reported on the applicable eCRFs and PS as 
instructed below in this section. This also includes any SAEs resulting from protocol-associated 
procedures performed after the ICF is signed.
Any SAEs and deaths that occur within the protocol-defined follow-up period, regardless of 
causality, should also be reported. 

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Investigators are not obligated to actively seek SAEs after the protocol-defined follow-up period; 
however, if the investigator learns of any SAEs that occur after the protocol-defined follow-up 
period has concluded and the event is deemed relevant to the use of study drug, the investigator 
should promptly document and report the event to Gilead PS.
Instructions for reporting SAEs are described in Section 7.4.1.
7.3.4.
Study Drug Special Situations Reports
All study drug SSRs that occur from study drug initiation and throughout the duration of the 
study, including the protocol-defined follow-up period, must be reported to Gilead PS 
(Section 7.4.2). Adverse events and SAEs resulting from SSRs must be reported in accordance to 
the AE and SAE reporting guidance (Section 7.3).
7.3.5.
Concomitant Therapy Reports
7.3.5.1.
Gilead Concomitant Therapy Special Situations Report
Special situation reports involving a Gilead concomitant therapy (not considered study drug), 
that occurs after the participant first consents to participate in the study (ie, signing the ICF) and 
throughout the duration of the study, including the protocol-defined follow-up period, must be 
reported to Gilead PS utilizing the paper SSR (Section 7.4.2.2).
7.3.5.2.
Non-Gilead Concomitant Therapy Report
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the SSR form; however, for special situations that result in AEs due to a non-Gilead concomitant 
medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
All clinical sequelae in relation to these SSRs will be reported as AEs or SAEs at the same time 
using the AE eCRF and/or the SAE report form. Details of the symptoms and signs, clinical 
management, and outcome will be reported, when available.
7.4.
Reporting Process for Serious Adverse Events and Special Situation Reports
7.4.1.
Serious Adverse Event Reporting Process
For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be transmitted by email or fax when requested and applicable. 
Transmission of such documents should occur without personal participant identification, 
maintaining the traceability of a document to the participant identifiers.
Additional information may be requested to ensure the timely completion of accurate safety 
reports.

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Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the participant’s eCRF and the SAE narrative section of the Safety Report 
Form eCRF.
7.4.1.1.
Electronic Serious Adverse Event Reporting Process 
Site personnel will record all initial or follow-up SAE data (including updates to the reported 
event term[s]) on the applicable eCRFs within 24 hours of the investigator’s knowledge of the 
initial event/update in order for the SAE information to be transmitted timely to PS. Serious 
adverse event information must be reported from the time of the ICF signature throughout the 
duration of the study, including the protocol-required follow-up period. 
If for any reason it is not possible to record and transmit the SAE information electronically, site 
personnel must record the SAE on the paper Initial or Follow-up SAE Report Form and transmit 
by emailing or faxing the report within 24 hours of the investigator´s knowledge of the initial 
event/update using the contact information below:
Gilead Patient Safety
Email: 
 
or
Fax: 
If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary. If the database is not locked, any SAE reported via paper must be 
transcribed as soon as possible on the applicable eCRFs and transmitted to PS.
7.4.2.
Special Situations Reporting Process 
7.4.2.1.
Electronic Special Situations Reporting Process for Study Drug 
Site personnel will record all SSR data on the applicable eCRFs and from there transmit the SSR 
information to Gilead PS from study drug initiation throughout the duration of the study, 
including the protocol-defined follow-up period. 
If for any reason it is not possible to record the SSR information electronically, record the SSR 
on the paper special situation reporting form and transmit to:
Gilead Patient Safety
Email: 
 
or
Fax: 
PPD
PPD
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If an SSR has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary. If the database is not locked, any SSR reported via paper must be 
transcribed as soon as possible on the applicable eCRFs and transmitted to PS.
See Section 7.4.2.2 for instructions on reporting special situations with Gilead concomitant 
medications. 
7.4.2.2.
Reporting Process for Gilead Concomitant Medications
Special situations that involve Gilead concomitant medications that are not considered study 
drug must be reported within 24 hours of the investigator’s knowledge of the event to Gilead PS 
utilizing the paper special situations report form to:
Gilead Patient Safety
Email: 
 
or
Fax: 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the SSR form; however, special situations that result in AEs due to a non-Gilead concomitant 
medication, must be reported as an AE.
7.4.2.3.
Pregnancy Reporting Process
The investigator should report any pregnancies in study participants of reproductive potential 
that are identified after initiation of study drug and throughout the study, including the protocol-
defined follow-up period, to Gilead PS using both the eCRF pregnancy form and the paper the 
pregnancy report form within 24 hours of becoming aware of the pregnancy. Contact details for 
transmitting the pregnancy report form are as follows:
Gilead Patient Safety
Email: 
 
or
Fax: 
The pregnancy itself is not considered an AE, nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
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All other premature terminations of pregnancy (eg, a spontaneous abortion, an induced 
therapeutic abortion due to complications or other medical reasons) must be reported within 
24 hours as an SAE, as described in Section 7.4.1. The underlying medical reason for this 
procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Section 7.4.1. Furthermore, any SAE occurring as an adverse pregnancy outcome after study 
must be reported to the Gilead PS.
The participant should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome of the pregnancy should be reported to Gilead PS throughout the study, 
including the protocol-defined follow-up period, using both the eCRF pregnancy form and the 
paper pregnancy outcome report form. In addition, if the investigator learns of any pregnancy or 
pregnancy outcomes that occur after the protocol-defined follow-up period has concluded but 
within 700 days following the last dose of LEN or blinded LEN (if unblinding has not occurred), 
the investigator should promptly document and report the pregnancy outcome directly to Gilead 
PS using the paper pregnancy outcome form. Gilead PS contact information is as follows: 
Gilead Patient Safety
Email: 
 
or
Fax: 
Refer to Appendix 6 for Randomized Blinded Phase Pregnancy Precautions, Definition 
Childbearing Potential for Participants Assigned Female at Birth, and Contraceptive 
Requirements
AEs/SAEs observed in a neonate at the time of delivery will be reported via the paper Pregnancy 
Outcome Report form and to Gilead PS via the paper Clinical Study Infant/Child Report form 
(except vertical transmission). Events of vertical transmission should be reported to Gilead PS 
via the electronic SAE reporting process described in section 7.4.1.1.
Subsequent to delivery if there are any identified AEs/SAEs observed they will be reported via 
the paper Clinical Study Infant/Child Report form to Gilead PS (except vertical transmission as 
stated above).
7.4.2.4.
Reporting Lactation Exposure When a Participant Chestfeeds During the Study
If a lactation exposure occurs and the participant will continue to chestfeed while enrolled in the 
study, then an SSR should be submitted within 24 hours of awareness of the event. A follow-up 
“lactation exposure” SSR will need to be submitted to capture the end of exposure to study drug 
via milk. 
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If an AE/SAE occurs in the infant following lactation exposure, the electronic SSR should be 
utilized to report the event in addition to submitting the paper Clinical Study Infant/Child Report 
form (except for vertical transmission) to Gilead PS. Events of vertical transmission should be 
reported to Gilead PS via the electronic SAE reporting process described in 7.4.1.1. 
Refer to Section 7.4.2 and the eCRF completion guidelines for instructions on submitting SSRs 
involving study drug.
7.5.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, which may be in the form of line listings, 
serious adverse drug reactions, or SUSARs. In accordance with the EU Clinical Trials Directive 
(2001/20/EC), Gilead or a specified designee will notify worldwide regulatory agencies and the 
relevant IEC in concerned Member States of applicable SUSARs as outlined in current 
regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the IB or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study drug. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.6.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not to be recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, urinalysis) that require 
medical or surgical intervention or lead to study drug interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
Severity should be recorded and graded according to the DAIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events, Version 2.1. For AEs associated with laboratory 
abnormalities, the event should be graded on the basis of the clinical severity in the context of 
the underlying conditions; this may or may not be in agreement with the grading of the 
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7.7.
Toxicity Management 
All clinical and clinically significant laboratory toxicities will be managed according to uniform 
guidelines detailed in Appendix 4 as outlined below:
•
All clinically significant Grade 3 and 4 laboratory abnormalities should be repeated within 
3 calendar days to confirm toxicity grade. Confirmation of toxicity grade is required prior to 
the next dose of investigational medicinal product for any Grade 3 and 4 laboratory 
abnormality that in the opinion of the investigator is clinically significant and may pose a risk 
to the participant’s safety.
•
Clinical events and clinically significant laboratory abnormalities will be graded according to 
the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Version 2.1 (refer to Section 7.2.2).
Any questions regarding toxicity management should be directed to the medical monitor.
7.7.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue study drug at the discretion of the investigator. Grade 1 and Grade 2 injection site pain 
or tenderness will be interpreted as referring to the injection site rather than the limb as stated in 
the DAIDS grading scale. Injection site nodule and injection site induration measured at 
< 2.5 cm should be recorded as Grade 1 despite DAIDS “induration and swelling” cutoff of 
2.5 cm as the lower limit for Grade 1.
7.7.2.
Grades 3 Laboratory Abnormality or Clinical Event
For Grade 3 clinically significant laboratory abnormality or clinical event, study drug may be 
continued if the event is considered to be unrelated to study drug.
For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by repeat 
testing, that is considered to be related to study drug, study drug should be withheld until the 
toxicity returns to ≤ Grade 2.
If a laboratory abnormality recurs to ≥ Grade 3 following re-challenge with study drug and is 
considered related to study drug, then study drug should be permanently discontinued, and the 
participant managed according to local practice. Recurrence of laboratory abnormalities 
considered unrelated to study drug may not require permanent discontinuation.
7.7.3.
Grade 4 Laboratory Abnormality or Clinical Event
For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality confirmed 
by repeat testing that is considered related to study drug, study drug should be permanently 
discontinued, and the participant managed according to local practice. The participant should be 
followed as clinically indicated until the laboratory abnormality returns to baseline or is 
otherwise explained, whichever occurs first. A clinically significant Grade 4 laboratory 
abnormality that is not confirmed by repeat testing should be managed according to the 
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Study drug may be continued without dose interruption for a clinically nonsignificant Grade 3 or 
4 laboratory abnormality (eg, CK elevation after strenuous exercise, or triglyceride elevation that 
is nonfasting or that can be medically managed) or a Grade 3 or 4 clinical event considered 
unrelated to study drug.
7.7.4.
Management of Changes in Estimated Glomerular Filtration Rate
Estimated GFR, according to the Cockcroft-Gault formula, will be followed postbaseline during 
the study. All participants with eGFR < 60 mL/min must have serum creatinine and participant’s 
weight measured again within 3 calendar days of receipt of results. If a participant has confirmed 
eGFR < 60 mL/min, the investigator should notify the medical monitor, evaluate potential 
causes, re-assess the potential risks and benefits of continued treatment in the study and consider 
consultation with a qualified nephrologist.
7.7.5.
Management of Adverse Events of Injection Site Reactions of Grade 3 or 
Higher or Persisting for More Than 26 Weeks
In clinical studies of SC LEN, Grade 3 or higher AEs of ISRs were uncommon. Some 
participants experienced AEs of injection site nodule and induration, which decreased in size 
over 6 months or longer. Investigators will contact the medical monitor to discuss the evaluation 
and management of long-lasting or severe (Grade 3 or higher) ISRs if the ISR is determined to 
be of clinical concern by the investigator. Photographic documentation of ISRs that meet the 
above criteria is recommended but not mandatory. If obtained, documentation of ISR evaluation 
findings, including photographs, may be shared with the sponsor and study team.

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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective of this study is to evaluate the efficacy of LEN in preventing the risk of 
HIV-1 infection relative to the background HIV-1 incidence rate. Participants are CGM, TGW, 
TGM, and GNB.
8.1.1.1.
Incidence Phase Objectives
The primary objective for the Incidence Phase of this study is to estimate the HIV-1 background 
incidence rate.
8.1.1.2.
Randomized Blinded Phase Objectives
The primary objective for the Randomized Blinded Phase of this study is as follows:
•
To evaluate the efficacy of LEN for HIV-1 PrEP in participants ≥ 16 years of age who have 
condomless receptive anal sex partners assigned male at birth and are at risk for HIV-1 
infection
The secondary objectives for the Randomized Blinded Phase of this study are as follows:
•
To compare the efficacy of LEN with F/TDF for HIV-1 PrEP in participants ≥ 16 years of 
age who have condomless receptive anal sex with partners assigned male at birth and are at 
risk for HIV-1 infection
•
To evaluate the efficacy of LEN for HIV-1 PrEP in participants at risk of HIV-1 infection in 
participants adherent to LEN
•
To evaluate the safety and tolerability of LEN and F/TDF for HIV-1 PrEP in participants 
≥ 16 years of age who have condomless receptive anal sex with partners assigned male at 
birth and are at risk for HIV-1 infection
•
To evaluate the safety and tolerability of LEN for HIV-1 PrEP in adolescent participants 
≥ 16 to < 18 years of age who have condomless receptive anal sex with partners assigned 
male at birth and are at risk for HIV-1 infection
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8.1.2.
Primary Endpoint
8.1.2.1.
Incidence Phase Primary Endpoint
The primary endpoint for the Incidence Phase of this study is the diagnosis of recent HIV-1 
infection. 
The background HIV-1 incidence per 100 PY will be computed based on the recent infection 
testing algorithm using a recency assay.
8.1.2.2.
Randomized Blinded Phase Primary Endpoint
The primary efficacy endpoint for the Randomized Blinded Phase will be the diagnosis of HIV-1 
infection.
The HIV-1 incidence per 100 PY will be computed as the number of participants who acquired 
HIV-1 divided by the total of a) for participants not diagnosed with HIV-1, sum of all duration of 
follow-up time in years (where a year is 365.25 days) and b) for participants diagnosed with 
HIV-1, sum of all duration of time to confirmed HIV-1 diagnosis.
8.1.3.
Secondary Endpoints
The secondary endpoints for the Randomized Blinded Phase of this study are as follows:
•
Diagnosis of HIV-1 among participants while adherent to study drug
•
Occurrence of TEAEs and treatment-emergent clinical laboratory abnormalities to evaluate 
safety and tolerability of LEN and F/TDF for HIV-1 PrEP
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8.2.
Planned Analyses
8.2.1.
Interim Analyses
A DMC will periodically evaluate participants’ safety and conduct one interim efficacy 
evaluation. The DMC will have access to treatment codes for all their reviews and evaluations 
(unblinded).
8.2.1.1.
Interim Analyses of Safety Data
The first meeting of the DMC will be when the first 300 participants have completed their 
Week 8 visit to evaluate the safety of LEN. While enrollment will not be paused during this 
safety review, enrollment will not exceed 600 participants before the safety review is conducted 
and, if determined by the DMC, the study will be allowed to continue. Enrollment of adolescents 
(participants 16 and 17 years of age) will commence following the first DMC review of the 
safety data and recommendation to continue the study. DMC review meetings of safety data will 
occur approximately annually thereafter during the Randomized Blinded Phase of the study.
8.2.1.2.
Interim Analyses of Efficacy Data
The DMC will formally evaluate efficacy data, only once for efficacy and futility, after 50% of 
participants enrolled have completed at least 52 weeks of follow-up in the study or prematurely 
discontinued from the study. The DMC may recommend stopping the study early if the 
prespecified evaluation criteria are met. If the Randomized Blinded Phase is stopped early due to 
an efficacy outcome, the interim analysis will serve as the primary analysis. The general 
approach for interim decisions and DMC recommendations are discussed in Section 8.7 
(Adjustments for Multiplicity) and further details will be prespecified in the interim analysis plan 
and/or statistical analysis plan. 
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8.2.2.
Primary Analysis 
The primary analysis will be conducted when all enrolled participants have completed a 
minimum of 52 weeks (1 year) of follow-up in the study or prematurely discontinued from the 
study (whichever occurs first) after randomization. 
8.2.3.
Final Analysis
The final analysis will be performed after all participants have completed the Randomized 
Blinded, LEN OLE, and PK Tail Phases of the study, outstanding data queries have been 
resolved or adjudicated as unresolvable, and the data have been cleaned and finalized. The 
HIV-1 incidence rate during the LEN OLE Phase will be conducted in the final analysis.
8.3.
Analysis Conventions
8.3.1.
Analysis Sets
8.3.1.1.
Efficacy
The primary analysis sets for efficacy analysis are the All Screened Set (Incidence Phase) and 
the FAS (Randomized Blinded Phase). The All Screened Set includes all participants who were 
screened for HIV-1 in the Incidence Phase and had nonmissing HIV-1 diagnosis based on HIV 
test at Incidence Screening. Any additional participants who took at least 1 dose of any study 
drug (but missing central laboratory HIV tests at Incidence Screening) should be included in the 
All Screened Set and considered as HIV-1 negative. The FAS will include all randomized 
participants who received at least 1 dose of study drug and have not been diagnosed with HIV-1 
by Day 1. Participants will be grouped according to the randomly assigned study drug. 
Sensitivity analyses may be performed to assess the impact of those with no postbaseline HIV-1 
test on the interpretation of the study results.
8.3.1.2.
Safety
The primary analysis set for safety analyses is the Safety Analysis Set which will include all 
randomized participants who received at least one dose of study drug. Participants will be 
grouped according to the study drug they receive.
8.3.1.3.
Pharmacokinetics
The DBS Analysis Set will include all participants who have at least 1 reported TFV-DP 
concentration. The LEN PK Analysis Set will include all participants who have at least 
1 reported LEN concentration.
8.3.2.
Data Handling Conventions
In general, age at first dose of study drug, relative to date of birth, will be considered for 
analysis. As only year of birth will be collected “01 July” will be used for calculations of age 
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For calculation of HIV-1 incidence, HIV-1 negative participants ongoing in the study at the time 
of the primary analysis will be censored at the date of their last HIV test.
In general, analysis of safety measures will be based on observed data. Although last observation 
carried forward (LOCF) or other imputation for safety measures may be considered for 
sensitivity analyses, there are no preplanned imputations rules for analysis of safety data. Details 
on imputation of numerical values reported as beyond the limit of quantitation will be provided 
in the statistical analysis plan.
8.4.
Demographic and Baseline Characteristics Analysis
Demographic and baseline measurements will be summarized using standard descriptive 
methods.
Demographic summaries will include, but would not be limited to, race/ethnicity, age, sex at 
birth, sexual orientation, gender identification, alcohol and substance use.
Baseline characteristics data will include, but would not be limited to, a summary of body weight 
(kg), height (cm), body mass index (kg/m2), and waist circumference (cm).
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary endpoint will be analyzed using a method appropriate for a single Poisson rate 
based on the FAS. The primary objective of the study will be achieved by showing that the 
HIV-1 incidence rate for the LEN study drug group is significantly lower than the background 
incidence rate estimated in the Incidence Phase with 1-sided alpha of 0.025. 
Null hypothesis H01:LEN/bHIV ≥1.0 (superiority over background)
Here LEN and background HIV represent the HIV incidence rate of the LEN study drug group 
and the background, respectively.
Additionally, the primary success criteria for the US FDA regulatory review is defined as the 
HIV-1 incidence rate ratio of at least 20% lower in the LEN study drug group compared with the 
background incidence rate estimated in the Incidence Phase, formulated as the key 
alpha-controlled 𝐻02 in the next section (gated on rejection of 𝐻01 with overall 1-sided alpha of 
0.025) with the point estimate of LEN/bHIV ≤ 0.5 and comparability of LEN to F/TDF, 
formulated as the key alpha-controlled 𝐻03 in the next section. 
The background incidence will be estimated based on the HIV-1 recency assay results of those 
who were not on PrEP when screened in the Incidence Phase, using an HIV-1 incidence formula 
similar to {Kassanjee 2012}, adjusting for participants with HIV-1 who may not have recency 
assay results. 
The incidence rate ratio of the LEN study drug group to the background, the associated 95% CI, 
and the p-value will be estimated using the delta method {Gao 2021} or a likelihood-based 

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method{Shao 2024} if the number of HIV-1 infections in the LEN group is zero. The incidence 
rate difference of LEN from F/TDF, the associated 95% CI and the P value will be calculated 
based on a hybrid approach{Li 2011}.
The primary analysis will be conducted when all enrolled participants have completed a 
minimum of 52 weeks (1 year) of follow-up in the study or prematurely discontinued from the 
study (whichever occurs first) after randomization.
Figure 13.
A High-Level Screening Schema and Contribution of Participants to 
the Estimation of the Background HIV-1 Incidence Rate 
HIV = human immunodeficiency virus; PrEP = pre-exposure prophylaxis
The following are the notations:
N: Total number of participants screened
N―: number of participants who test negative
N+: number of participants who test positive
N+,test: number of positive participants who have recency outcomes available 
𝑁𝑟𝑒𝑐: number of recent infections as classified by the Recent Infection Testing Algorithm 
No 
HIV+ 
(N+) 
Incidence Phase 
Not Recent 
All Eligible Participants 
for HIV Testing 
(N) 
Test for HIV 
Recent 
(N,.J 
HIV-
(N_) 
Screen for Randomized 
Phase of the PrEP Study 

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Then the background incidence rate will be estimated by the formula:
λ0 = Nrec/(N+,test/N+) ― βN+
N―(Ω ― βT)
𝑇: cutoff time (eg, 2 years) for the definition of true recent infections
Ω: Mean duration of recent infections (MDRI) 
𝛽: False recency rate (FRR)
The standard error of λ0 in the log scale σlog(λ0) will be estimated by the delta method {Gao
2021}, considering the variance of Ω, β, and the observed counts of N―, N+,test, Nrec.
The HIV-1 incidence rate λ1 in the study will be estimated by the number of HIV-1 infections 
divided by the total follow-up time for each arm. The standard error of the incidence estimate λ1 
in the log scale σlog(λ0) will be the inverse of the number of infections, based on the Poisson
assumptions. The difference in log scale will be estimated by log λ1 ― log λ0 , with the 
standard error being σ2
log(λ0) + σ2
log(λ1). The confidence interval of the incidence ratio λ1/
λ0 will be obtained by exponentiating the confidence interval of log(λ1) ― log(λ0).
8.5.2.
Secondary Analyses
The key α-controlled secondary analyses in the study include the following tests of null 
hypotheses. In the equation below, F/TDF is being replaced with TVD for brevity and 
simplifying formulation of ratio in the listed null hypotheses:
1) HIV-1 incidence rate of the LEN study drug group to the background HIV-1 is at least
20% lower in the LEN study drug group compared with the background incidence rate
estimated in the Incidence Phase and the point estimate of LEN/background HIV ≤ 0.5.
•
𝐻02:𝐿𝐸𝑁/𝑏𝐻𝐼𝑉≥0.8 (at least 20% reduction over background HIV-1), which
will be tested in a similar manner to the primary endpoint and the point estimate
of LEN/background HIV ≤ 0.5.
2) HIV-1 incidence rate of the LEN study drug group is at most 0.8/100 PY higher than the
F/TDF study drug group
•
𝐻03:𝐿𝐸𝑁― 𝑇𝑉𝐷≥0.8/100𝑃𝑌 (comparable to F/TDF), which will be tested
using a rate difference approach.
3) HIV-1 incidence rate of the LEN study drug group is significantly lower than the HIV-1
incidence rate of the F/TDF study drug group
v/ 
( J 
( J 

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•
𝐻04:𝐿𝐸𝑁/𝑇𝑉𝐷≥1.0 (superiority over F/TDF), which will be tested using a rate 
ratio approach.
A secondary analysis of the primary endpoint will be the comparison of the HIV-1 incidence rate 
in the LEN study drug group with a predefined bound of 1.525 per 100 PY. This bound 
represents 50% of the lower 95% confidence bounds of the nonrandomized control of 
background HIV-1 incidence rate reported as 3.49 (3.05, 3.92) {Mera 2020}.
The background HIV-1 incidence rate may also be estimated using prerandomization methods 
such as recent epidemiologic data and/or the screening HIV-1 positivity rate, and 
postrandomization, such as correlation of rectal gonorrhea incidence rate with HIV-1 incidence 
rate in each study group or other methods as they become validated. 
The rate ratio of HIV-1 incidence between LEN and F/TDF and the associated CI will be 
estimated using a generalized model associated with a Poisson distribution and logarithmic link 
with the study drug group being the main effect, or an exact conditional Poisson model if the 
number of infections is zero in any of the experimental groups. Proportional hazard models, 
comparing LEN vs F/TDF, may be used as sensitivity analyses for H04.
8.6.
Safety Analysis
All treatment-emergent safety data collected on or after the date that study drug was first 
dispensed up to the end of the statistical analysis plan-defined follow-up period will be 
summarized by study drug arm. Data for the prestudy drug initiation and poststudy drug 
initiation follow-up time will be included in data listings. 
In general, and unless specified otherwise, for categorical safety data including incidence of AEs 
or categorical laboratory data, a Fishers exact test may be used to compare study drug arms. For 
continuous safety data including laboratory data, a t-test or analysis of variance (ANOVA) model 
may be used to compare study drug arms. Some details are noted below, and full details will be 
provided in the statistical analysis plan (to be finalized before database lock for the primary 
analysis).
8.6.1.
Extent of Exposure
A participant’s extent of exposure to study drug data will be generated from the study drug 
administration data. Exposure data will be summarized by study drug group. 
Duration of exposure to study drug will be expressed as the number of weeks between the 
first and last dose of the study drug exposure, inclusive, regardless of temporary interruptions in 
study drug administration. Dosing information for individual participants will be listed.
A participant is defined as adherent to F/TDF during an HIV-1 testing interval (time period 
between determining HIV-1 status through study testing) if TFV-DP in DBS is adequate 
(≥ 350 fmol/punch for the F/TDF study drug group). A participant is defined as adherent to LEN 
if they have received a per-protocol administration of LEN within the last 26 weeks (± 14 days).

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8.6.2.
Adverse Events
Clinical and laboratory AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). System organ class (SOC), high-level group term, high-level term, 
preferred term (PT), and lower-level term will be attached to the clinical database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
AE will be defined as any AE that begins on or after the date of first dose of study drug up to the 
end of the statistical analysis plan-defined follow-up period.
Summaries (number and percentage of participants) of TEAEs (by SOC and PT) will be 
provided by study drug arm. Additional summaries will include summaries for AEs by grade, 
investigator’s assessment of relationship to study drug, and effect on study drug dosing.
8.6.3.
Laboratory Evaluations
Selected laboratory data will be summarized using only observed data. Data and change from 
baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using the grading scheme in Appendix 4.
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
one toxicity grade from baseline at any time postbaseline up to the end of the statistical analysis 
plan-defined follow-up period, will be summarized by study drug arm. If baseline data are 
missing, then any graded abnormality (ie, at least a Grade 1) will be considered treatment 
emergent. The maximum toxicity grade observed for participants will be summarized by 
laboratory parameter. 
Laboratory abnormalities that occur before the first dose of study drug or after the end of the 
statistical analysis plan-defined follow-up period will be included in a data listing.
8.6.4.
Renal Safety
The change from baseline in serum creatinine at Week 52 will be summarized using descriptive 
statistics. The difference in change from baseline between 2 study drug arms will be tested using 
analysis of covariance (ANCOVA) model with study drug as fixed effect and baseline measure 
as a covariate.
8.6.5.
Other Safety Evaluations
Weight (kg) and waist circumference (cm) will be summarized by visit and change (and/or 
percent change) from baseline in study drug arms may be compared using ANCOVA model with 
study drug as fixed effect and baseline measure as a covariate.

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8.7.
Adjustments for Multiplicity
One formal evaluation of interim efficacy is planned. The overall 1-sided Type I error rate of 
0.025 for the primary and key α-controlled secondary endpoints at both the interim and primary 
analyses will be controlled using a Bonferroni type spending function accompanying a 
gatekeeping testing strategy. The overall alpha of 0.025 will be split between the interim analysis 
(α1 = 0.0026) and the primary analysis (α2 = 0.0224). At both the interim and primary analyses, 
the 1-sided Type I error rate will be controlled using a fixed-sequence gatekeeping testing 
strategy (ie, tested sequentially in the order given below).
1) H01:LEN/bHIV ≥1.0 (superiority over background)
2) H02:LEN/bHIV ≥0.8 (at least 20% reduction over background HIV-1)
3) H03:LEN–TVD ≥0.8/100PY (comparable to F/TDF)
4) 𝐻04:𝐿𝐸𝑁/𝑇𝑉𝐷≥1.0 (superiority over F/TDF)
In the above mathematical formulas, TVD stands for the incidence rate of the F/TDF arm.
The DMC may recommend to stop the randomized part of the study early:
1) For efficacy, if the hypothesis H02 is rejected at the level α1 = 0.0026 with the point 
estimate for the LEN/bHIV ≤ 0.5 and H04 is rejected at the level α1 = 0.0026. 
2) For futility, if F/TDF is found to be superior to LEN at the level α1 = 0.0026. 
The use of a recency assay to estimate the background HIV incidence in PrEP studies is a novel 
approach. The estimate of the background HIV is subject to many assay and operational issues. 
If the point estimate of the recency based counterfactual background HIV is less than 1.5/100 PY 
at the interim analysis, the estimate of background HIV incidence by the recency-assay based 
methodology will be deemed as not performing as expected. In this case, hypotheses H01 and H02 
will be skipped at the interim analysis and recommendations to stop the randomized part of the 
study will be based on rejecting H04 at α1 = 0.0026.
8.8.
Pharmacokinetic Analysis
LEN plasma concentrations will be summarized by timepoint for SC and oral LEN. Additionally, 
the PopPK analysis of LEN is planned. 
8.9.
Sample Size
A total sample size of 3000 is considered for the study in CGM, TGW, TGM, and GNB. More 
than 95% power is achieved with 2000 participants in the LEN study drug group to show at least 
a 20% reduction compared with the background incidence rate (powered for both H01 and H02). 
In this sample size analysis, the following assumptions are made:
•
Background HIV-1 incidence of 3.00/100 PY

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•
LEN incidence of 0.6/100 PY, with an 80% risk reduction in HIV-1 compared with the 
nonrandomized control of background HIV-1 incidence
•
Mean duration of recent infections (MDRI) of 173 days, with relative standard error (rSE) of 
6.5%
•
False recency rate (FRR) of 1.5%, with rSE of 70%
•
Average follow-up of 1.5 years in the study
•
2:1 allocation for LEN: F/TDF
•
Alpha level of 0.025 (1-sided) 
The background HIV-1 incidence rate assumption is a conservative estimate based on 
epidemiologic data {Mera 2019}. The LEN incidence rate corresponds to an 80% risk reduction 
and is consistent with the incidence rates observed in a large randomized controlled trial of 
long-acting cabotegravir for PrEP conducted in a similar study population {Landovitz 2021}.
The MDRI and FRR are based on the Sedia LAg assay {Kassanjee 2016}, assuming T = 2 years 
and virologic cutoff of 75 copies/mL. Here T is the cutoff for the time period defined in 
Section 8.5.1. Under the assumption of T = 1 year, the power remains at > 95%. These assay 
parameters are still under investigation and may be fine-tuned further. The power calculation is 
based on the formula in Gao, et al (2021) using the test statistics for rate ratio {Gao 2021}.
The statistical power to compare the randomized study drug groups is not assessed. The ratio of 
incidence rates (LEN over F/TDF) and the corresponding 95% CI will be estimated to 
characterize the comparative evaluation.
8.10.
Data Monitoring Committee
An external DMC will primarily evaluate the safety of LEN in this population. The first meeting 
of the DMC will be when the first 300 participants have completed their Week 8 visit to evaluate 
the safety of LEN. While enrollment will not be paused during this safety review, enrollment 
will not exceed beyond 600 participants before the safety review is conducted and, if determined 
by the DMC, the study is allowed to continue. Enrollment of adolescents (participants 16 and 
17 years of age) will commence following the first DMC review of the safety data and 
recommendation to continue the study. Gilead will notify sites when they may begin enrollment 
of adolescents. DMC safety review meetings will occur approximately annually thereafter during 
the Randomized Blinded Phase of the study. 
The DMC will formally evaluate efficacy data, only once for efficacy and futility, after 50% of 
participants enrolled have completed at least 52 weeks of follow-up in the study or prematurely 
discontinued from the study. The DMC may recommend stopping the study early if the 
prespecified evaluation criteria are met. The general approach for interim decisions and DMC 
recommendations are discussed in Section 8.7 (Adjustments for Multiplicity) and further details 
will be prespecified in the interim analysis plan and/or statistical analysis plan.

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The external independent multidisciplinaiy DMC will review the progress of the study and 
provide recommendations to Gilead whether the nature, frequency, and severity of adverse 
effects associated with study drng wan ant the early tennination of the study in the best interests 
of the paiiicipants, whether the study should continue as planned, or whether the study should 
continue with modifications. Should there be a substantial difference in HIV-I incidence 
between the 2 study aims emergent during study follow-up, the DMC is empowered to 
recommend changes to the study protocol or procedures, as such a difference may fall within 
their purview to make recommendations based on concerns related to participant safety. The 
DMC may also provide recommendations as needed regai·ding study design. 
The DMC's specific activities will be defined by a mutually agreed chaiier, which will define the 
DMC's membership, conduct, interim data cut, scope ofresponsibilities, and meeting schedule. 
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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with International Council 
for Harmonisation (of Technical Requirements for Pharmaceuticals for Human Use) (ICH) 
E6(R2) addendum to its guideline for GCP and applicable laws and regulations.
9.1.2.
Financial Disclosure
The investigator and subinvestigators will provide prompt and accurate documentation of their 
financial interest or arrangements with Gilead or proprietary interests in the study drug during 
the course of a clinical study. This documentation must be provided prior to the investigator’s 
(and any subinvestigator’s) participation in the study. The investigator and subinvestigator agree 
to notify Gilead of any change in reportable interests during the study and for 1 year following 
completion of the study. Study completion is defined as the date when the last participant 
completes the protocol-defined activities.
9.1.3.
Institutional Review Board/Independent Ethics Committee Review and 
Approval
The investigator (or Gilead as appropriate according to local regulations) will submit this 
protocol, ICF, and any accompanying material to be provided to the participant (such as 
advertisements, participant information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study participant activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the participant after initial IRB/IEC approval, with the exception of those necessary 
to reduce immediate risk to study participants.
9.1.4.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study before undertaking any study-related procedures. The investigator 
must use the most current IRB- or IEC-approved ICF for documenting written informed consent. 
Each ICF (or assent as applicable) will be appropriately signed and dated by the participant or 
the participant’s legally authorized representative, the person conducting the consent discussion, 
and an impartial witness if required by IRB or IEC or local requirements.

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The results of the tests done on the samples will not be given to the 
pati 1c1pant or t e mvestigator. In addition to the study-specific ICF to be signed by each 
pati icipant taking patt in the study, pati icipants assigned female at bi1ih who are of reproductive 
potential who become pregnant after randomization may remain on the study after the reconsent 
process, as applicable according to local mles and regulation, where they will be info1med of the 
benefits and risks of continuing receipt of study diug while pregnant and lactating and the 
collection of birth outcomes for the child. Patticipants who at·e taking testosterone and become 
pregnant during the study must discontinue testosterone due to teratogenic potential if continuing 
the pregnancy and wish to continue on study diug. 
9.1.5. 
Confidentiality 
The investigator must ensure that pati icipants' anonymity will be strictly maintained and that 
their identities at·e protected from unauthorized patties. Only an identification code and any other 
unique identifier(s) as allowed by local law (such as year of bi1ih) will be recorded on any fo1m 
or biological sample submitted to Gilead or the laborato1y . Laborato1y specimens must be 
labeled in such a way as to protect pati icipant identity while allowing the results to be recorded 
to the proper pa1ticipant. Refer to specific laborato1y instructions. NOTE: The investigator must 
keep a screening log with details for all pati icipants screened and emolled in the study, in 
accordance with the site procedures and regulations. Pati icipant data will be processed in 
accordance with all applicable regulations. 
The investigator agrees that all info1mation received from Gilead, including but not limited to the 
IB, this protocol, case repo1i fonns (CRFs)/eCRFs, study diug info1mation, and any other study 
info1mation, remain the sole and exclusive prope1ty of Gilead during the conduct of the study 
and thereafter. This info1mation is not to be disclosed to any third pa1ty (except employees or 
agents directly involved in the conduct of the study or as required by law) without prior written 
consent from Gilead. The investigator fmi her agrees to take all reasonable precautions to prevent 
the disclosure by any employee or agent of the study site to any third patty or othe1w ise into the 
public domain. 
9.1.6. 
Study Files and Retention of Records 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following 2 categories: (1) investigator's study file and 
(2) patiicipant clinical source documents. 
The investigator's study file will contain the protocol/amendments, CRFs/eCRFs, governmental 
approval with con espondence, the ICF(s), di11g records, staff cmTiculum vitae and authorization 
fo1ms, and other appropriate documents and con espondence. 
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The required source data should include sequential notes containing at least the following 
information for each participant:
•
Participant identification
•
Documentation that participant meets eligibility criteria, ie, medical history, physical 
examination, and confirmation of diagnosis (to support inclusion and exclusion criteria)
•
Documentation of the reason(s) a consented participant is not enrolled
•
Participation in study (including study number)
•
Study discussed and date of informed consent
•
Dates of all visits
•
Documentation that protocol-specific procedures were performed
•
Results of efficacy parameters, as required by the protocol
•
Start and end date (including dose regimen) of study drug, including dates of dispensing and 
return
•
Record of all AEs and other safety parameters (start and end date; causality and severity) and 
documentation that adequate medical care has been provided for any AE
•
Concomitant medication (start and end date; dose if relevant; dose changes)
•
Date of study completion and reason for early discontinuation, if it occurs
All clinical study documents must be retained by the investigator for at least 2 years or according 
to local laws, whichever is longer, after the last approval of a marketing application in an ICH 
region (ie, US, Europe, or Japan) and until there are no pending or planned marketing 
applications in an ICH region; or, if no application is filed or if the application is not approved 
for such indication, for 2 years after the investigation is discontinued and regulatory authorities 
have been notified. Investigators may be required to retain documents longer if specified by 
regulatory requirements, by local regulations, or by an agreement with Gilead. The investigator 
must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
participant, appropriate copies should be made for storage away from the site.

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9.1.7.
Electronic Case Report Forms
An eCRF casebook will be completed by an authorized study personnel member whose training 
for this function is completed in the EDC system unless otherwise directed. The eCRF casebook 
will only capture the data required per the protocol schedule of events and procedures, unless 
collected by a nonelectronic data capture vendor system (eg, central laboratory). The 
Inclusion/Exclusion Criteria and Enrollment eCRFs should be completed only after all data 
related to eligibility are available. Data entry should be performed in accordance with the case 
report form Completion Guidelines provided by the sponsor. Subsequent to data entry, a study 
monitor may perform source data verification (SDV). System-generated or manual queries will 
be issued in the EDC system as data discrepancies are identified by the study monitor or Gilead 
personnel who routinely review the data for completeness, correctness, and consistency. The site 
investigator, site coordinator, or other designee is responsible for responding to the queries in a 
timely manner, within the system, either by confirming the data as correct or updating the 
original entry, and providing the reason for the update (eg, data entry error). Original entries as 
well as any changes to data fields will be stored in the audit trail of the system. Regular oversight 
by the principal investigator of the data entered into the EDC system is expected to occur on an 
ongoing basis throughout the study to ensure quality and completeness. At a minimum, before 
any interim, final, or other time points (as instructed by Gilead), the investigator will apply 
his/her electronic signature to confirm that the forms have been reviewed and that the entries 
accurately reflect the information in the source documents. At the conclusion of the study, Gilead 
will provide the site investigator with a read-only archive copy of the data entered by that site. 
This archive must be stored in accordance with the records retention requirements outlined in 
Section 9.1.6.
9.1.8.
Investigator Inspections
The investigator will make available all source documents and other records for this study to 
Gilead’s appointed study monitors, to IRBs/IECs, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study participants, 
may be made only by Gilead. The investigator must submit all protocol modifications to the IRB 
or IEC in accordance with local requirements and receive documented IRB or IEC approval 
before modifications can be implemented.

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9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the agency(ies) when applicable 
and in accordance with local regulatory requirements. Gilead will ensure that the report meets 
the standards set out in the ICH Guideline for Structure and Content of Clinical Study Reports 
(ICH E3). Note that an abbreviated report may be prepared in certain cases. For studies with sites 
in countries following the EU Regulation No. 536/2014, a CSR will be submitted within 1 year 
(6 months for pediatric studies, in accordance with Regulation [EC] No. 1901/2006) after the 
global end of study (as defined in Section 3.6).
Investigators in this study may communicate, orally present, or publish study data in scientific 
journals or other scholarly media in accordance with the Gilead clinical trial agreement.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol (eg, attendance at investigator meetings). If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to federal and state agencies any 
expenses paid or reimbursed for such services, including any clinical study payments, meal, 
travel expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any participant records 
needed to verify the entries in the CRF/eCRF. The investigator agrees to cooperate with the 
monitor to ensure that any problems detected through any type of monitoring (central, on-site) 
are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both Gilead and the investigator reserve the right to terminate the study at any time. Should this 
be necessary, both parties will arrange discontinuation procedures and notify the participants, 
appropriate regulatory authority, IRBs, and IECs. In terminating the study, Gilead and the 
investigator will ensure that adequate consideration is given to the protection of the participants 
interests.

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10.
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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Pandemic Risk Assessment and Mitigation Plan
Appendix 3.
Study Procedures Table
Appendix 4.
Management of Clinical and Laboratory Adverse Events
Appendix 5.
HIV Testing Algorithms
Appendix 6.
Randomized Blinded Phase Pregnancy Precautions, Definition Childbearing 
Potential for Participants Assigned Female at Birth, and Contraceptive 
Requirements
Appendix 7.
Country-Specific Requirements
Appendix 8.
Amendment History

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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGMENT 
A Phase 3, Double-Blind, Multicenter, Randomized Study to Evaluate the Efficacy and Safety of 
Subcutaneous Twice Yearly Long-Acting Lenacapavir for HIV Pre-Exposure Prophylaxis in 
Cisgender Men, Transgender Women, Transgender Men, and Gender Nonbinaiy People 
16 Years of Age who Have Sex with Male Paitners and ai·e at Risk for HIV Infection 
GS-US-528-9023, Amendment 4, 21 October 2024 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
PD 
[See appended electronic signature} 
Name (Printed) 
Signature 
PD 
[See appended electronic signature} 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessa1y 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
infonnation provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they ai·e fully info1med about the diugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 178 
21 October 2024 

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Appendix 2.
Pandemic Risk Assessment and Mitigation Plan
During emergency circumstances, such as an ongoing infectious disease pandemic, and other 
force majeure events, potential risks associated with participants being unable to attend study 
visits have been identified for this study. For infectious disease pandemics, sites will utilize 
regional or local guidelines to manage the clinic and participants.
These risks can be summarized as follows:
1) Study drug supplies to participants and sites:
a) Participants may be unable to return to the site for a number of visits to get the study 
drug, or the site may be unable to accept any participant visits. Without study drug, the 
participant would not be able to stay on the study drug as planned per protocol.
Mitigation plan: Oral study drug supplies at non-injection scheduled visits may be 
provided to the participant from the site without a clinic visit, once it is confirmed that 
the participant may safely continue on study drug as determined by the principal 
investigator (PI) or qualified designee. However, study drug injections of lenacapavir 
(LEN)/placebo must occur at the study site. For any missed injection visits the site must 
remind the participant of the potential risks. A virtual study visit, via phone or video 
conferencing, must be performed prior to remote oral study drug resupply. Prior to the 
virtual visit, the PI or qualified designee should contact the participant to obtain verbal 
consent from the participant to ship and perform the home rapid HIV test or arrange for 
the participant to attend a local laboratory/facility for HIV testing. Participants should be 
given clear instructions on how to perform the HIV test. The date and time that consent 
was obtained must be documented in the participant’s medical records. The PI or 
qualified designee will then perform the virtual visit, including review of the HIV test 
result, within the protocol target visit window dates whenever possible. The calls should 
be documented in the source documents at the site and relevant information entered in 
EDC. At the earliest opportunity, the site will schedule in-person participant visits and 
return to the protocol’s regular schedule of assessments. A qualified courier may be 
utilized to ship the study drug from sites to study participants if permitted by local ethics 
committee (EC)/institutional review boards (IRB)/regulatory authority, as applicable and 
with sponsor's approval.
b) Shipments of study drug and study drug supplies could be delayed because of 
transportation issues. Without study drug, participant would not be able to stay on the 
study drug as planned per protocol.
Mitigation plan: The sites' study drug inventory and study drug supplies should be closely 
monitored. Site staff should notify the sponsor or delegate if they foresee shortage in 
study drug inventory or if there is any interruption in local shipping service. The sponsor 
will continue to monitor inventory at the study drug depot and study sites. Manual 
shipments will be triggered as necessary.

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2) Participant’s safety monitoring and follow-up:
a) Participants may be unable or unwilling to come to the study site for their scheduled 
study visits as required per protocol.
Mitigation plan: For participants who may be unable or unwilling to visit the study site 
for their scheduled study visits as required per protocol, the PI or qualified designee will 
conduct a virtual study visit, via phone or video conferencing, to assess the participant 
within target visit window date whenever possible. During the virtual study visit, the 
following information at minimum will be reviewed:
i)
Confirm if participant has experienced any adverse events (AEs)/serious adverse 
events (SAEs)/special situations and follow-up on any unresolved AEs/SAEs.
ii) Review current list of concomitant medications and document any new concomitant 
medications.
iii) If applicable, confirm participants’ oral study drug supply is sufficient to last until the 
next planned visit date. If oral study drug resupply is needed it will be provided as 
described above in (1).
iv) If feasible, participant will be provided with adherence, retention, HIV risk 
assessment and reduction. Participant will be reminded to maintain current dosing and 
to keep all dispensed study drug kits for return at the next on-site visit.
b) Participants may be unable or unwilling to travel to the site for planned assessments 
(eg, safety blood draws); hence samples may not be sent for central laboratory analyses.
Mitigation plan: The following planned assessments during specified study visits will 
continue to be performed: HIV and DBS collection. Participants will be asked to conduct 
self-HIV assessments using home testing kits, if there is no option to perform these tests 
by study staff during a home/alternate location visit. Self-administered test results will be 
transmitted to site via photo or verbally. For visits which require a blood sample for DBS 
collection, study staff to arrange with participant to collect blood sample via 
home/alternate location visit. Local laboratories may be utilized as appropriate to monitor 
participant safety until the participant can return to the site for their regular follow-up per 
protocol. Any laboratory assessments conducted at a local laboratory due to the pandemic 
will be documented accordingly.
c) Participants may be unable or unwilling to attend the study visit to sign an updated 
informed consent form (ICF) version.
Mitigation plan: The site staff will follow their approved consent process and remain in 
compliance with local EC/IRB and national laws and regulations. Remote consent will be 
allowed if has been approved by the local EC/IRB. The consent process will be 
documented and confirmed by normal consent procedure at the earliest opportunity.

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3) Protocol and monitoring compliance:
a) Protocol deviations may occur, in case scheduled visits cannot occur as planned per 
protocol.
Mitigation plan: If it is not possible to complete a required procedure, an unscheduled 
visit should be conducted as soon as possible when conditions allow. The situation should 
be recorded and explained as a protocol deviation. Any missed participant visits or 
deviation to the protocol due to the pandemic must be reported in the electronic case 
report form (eCRF) and described in the clinical study report. Any virtual study visits that 
are conducted in lieu of clinic visits due to the pandemic will be documented as a 
protocol deviation related to the pandemic.
b) Monitors may be unable to carry out source data review or source data verification 
(SDV), or study drug accountability or assess protocol and Good Clinical Practice (GCP) 
compliance. This may lead to delays in SDV, an increase in protocol deviations, or under 
reporting of AEs.
Mitigation plan: The study monitor is to remain in close communication with the site to 
ensure data entry and query resolution. Remote SDV may be arranged if allowed. The 
study monitor is to reference the study monitoring plan for guidance on how to conduct a 
remote monitoring visit. The study staff is to save and document all relevant 
communication in the study files. The status of sites that cannot accept monitoring visits 
and/or participants on site, must be tracked centrally and updated on a regular basis.
4) Missing data and data integrity:
a) There may be an increased amount of missing data due to participants missing 
visits/assessments. This could have an impact on the analysis and the interpretation of 
clinical trial data. 
Mitigation plan: Implications of a pandemic on methodological aspects for the study will 
be thoroughly assessed and documented, and relevant actions will be taken as appropriate 
(ie, modification of the statistical analysis plan) and in compliance with regulatory 
authorities’ guidance. Overall, the clinical study report will describe the impact of the 
pandemic on the interpretability of study data.
Risks will be assessed continuously, and temporary measures will be implemented to mitigate 
these risks as part of a mitigation plan, as described above. These measures will be 
communicated to the relevant stakeholders as appropriate and are intended to provide alternate 
methods that will ensure the evaluation and assessment of the safety of participants who are 
enrolled in this study. 
Since these potential risks are considered mitigated with the implementation of these measures, 
the expected benefit-risk assessment of study drug(s) in study participant remains unchanged. 

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Appendix 3.
Study Procedures Table
Procedures for Incidence Phase and Randomized Blinded Phase
Study Procedure
Screening
Randomized Blinded Phase – Weeks (± 7 Days; ± 2 days for 
Week 4 and 8)v
ESDDa
30-Day 
Follow-upb
(± 14 days)
30-Day 
Post-HIV 
Infection 
Follow-up 
(± 14 days)
90-Day 
Post-HIV 
Infection 
Follow-upc
(± 14 days)
Incidence 
Phase
Randomized 
Blinded 
Phase
Day 
1
4
8
13
26
39
52
Post Week 52 
Every 13 or 26 
Weeks
Oral 
Bridging 
Visitd
Informed Consent (and 
assent for adolescents)e
X
X
Medical History
Xe
Xf
Demographics
X
Query on sexual 
activity with partners 
assigned male at birth, 
including receptive anal 
sex
X
Concomitant 
Medications
X
X
X
X
X
X
X
X
Every 13 weeks
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
Every 13 weeks
X
X
X
X
Complete Physical 
Examination
X
Targeted Physical 
Examination
Xg
X
X
X
X
X
X
Every 13 weeks
X
X
X
X
Vital Signs and Weight, 
Heighth, and Waist 
Circumference
X
Xg
X
X
X
X
X
X
Every 13 weeks
X
X
X
X
Asymptomatic STI 
Testing for GC, CT, 
TV, and syphilisi
X
X
X
X
X
X
Every 13 weeks
Every 
13 weeks
X
X

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Study Procedure
Screening
Randomized Blinded Phase – Weeks (± 7 Days; ± 2 days for 
Week 4 and 8)v
ESDDa
30-Day 
Follow-upb
(± 14 days)
30-Day 
Post-HIV 
Infection 
Follow-up 
(± 14 days)
90-Day 
Post-HIV 
Infection 
Follow-upc
(± 14 days)
Incidence 
Phase
Randomized 
Blinded 
Phase
Day 
1
4
8
13
26
39
52
Post Week 52 
Every 13 or 26 
Weeks
Oral 
Bridging 
Visitd
Local Rapid 4th 
Generation HIV-1/2 
Ab/Ag
X
X
X
X
X
X
X
X
Every 13 weeks
X
X
X
Central 4th Generation 
HIV-1/2 Ab/Ag
X
X
X
X
X
X
X
X
Every 13 weeks
X
X
X
HIV-1 RNA 
quantitative NAAT
X
X
Hepatitis B Testing 
(HBsAg/HBsAb/
HBcAb)
X
X
X
Every 26 weeks
Every 
26 weeks
Hepatitis C Testing 
(HCV Ab)
X
X
X
Every 26 weeks
Every 
26 weeks
Blood Sample for 
Chemistry/ 
Hematology
X
X
X
X
X
X
X
X
Every 13 weeks
X
X
X
X
Blood storage sample 
for HIV-1 RNA 
NAAT
X
X
X
X
X
X
Every 13 weeks
X
X
X
Blood sample for 
recency assay
Xj
Xj
Blood Sample for DBS
X
X
X
X
X
X
X
X
Every 13 weeks
X
X
X
Blood Sample for 
Metabolic 
Assessmentsk
X
X
X
Every 26 weeks
Every 
26 weeks
Anytime Plasma PK 
sample
X
X
X
X
X
X
Every 13 weeks
X
X
X
X
Plasma Storage Sample
X
X
X
X
X
X
X
X
Every 13 weeks
X
X
X
X
Serum Storage Sample
X
X
X
X
X
X
X
Every 13 weeks
X
X
X
X

Lenacapavir
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FINAL
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 184
21 October 2024
Study Procedure
Screening
Randomized Blinded Phase – Weeks (± 7 Days; ± 2 days for 
Week 4 and 8)v
ESDDa
30-Day 
Follow-upb
(± 14 days)
30-Day 
Post-HIV 
Infection 
Follow-up 
(± 14 days)
90-Day 
Post-HIV 
Infection 
Follow-upc
(± 14 days)
Incidence 
Phase
Randomized 
Blinded 
Phase
Day 
1
4
8
13
26
39
52
Post Week 52 
Every 13 or 26 
Weeks
Oral 
Bridging 
Visitd
Estimated GFR
X
X
X
X
X
X
X
X
Every 13 weeks
X
X
X
X
Urinalysis, Urine 
Protein, Urine 
Chemistry
X
X
X
X
X
X
X
X
Every 13 weeks
X
X
X
X
Urine Storage Sample
X
X
X
X
X
X
X
Every 13 weeks
X
Urine Pregnancy Testl
X
X
X
X
X
X
X
X
Every 13 weeks
X
X
X
X
Serum Pregnancy Testl
X
Integrated Sexual 
Behaviors and Alcohol 
and Substance Use 
Questionnaire
X
X
X
X
X
X
Every 13 weeks
X
Adherence to Oral 
Study Product 
Questionnaire
X
X
X
X
X
X
Every 13 weeks
X
PrEP Impacts and 
Administration 
Preference 
Questionnaire (Day 1)
X
PrEP Impacts and 
Administration 
Preference 
Questionnaire 
X
X
Every 26 weeks
(at injection 
visits)
X
Numeric Pain Rating 
Scale - Injection Pain 
Questionnaire-
X
X
X
Every 26 weeks 
(at injection 
visits)

Lenacapavir
Protocol GS-US-528-9023
FINAL
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 185
21 October 2024
Study Procedure
Screening
Randomized Blinded Phase – Weeks (± 7 Days; ± 2 days for 
Week 4 and 8)v
ESDDa
30-Day 
Follow-upb
(± 14 days)
30-Day 
Post-HIV 
Infection 
Follow-up 
(± 14 days)
90-Day 
Post-HIV 
Infection 
Follow-upc
(± 14 days)
Incidence 
Phase
Randomized 
Blinded 
Phase
Day 
1
4
8
13
26
39
52
Post Week 52 
Every 13 or 26 
Weeks
Oral 
Bridging 
Visitd
Administration and 
Dosing Questionnaire 
for PrEP Medication
X
X
Every 26 weeks 
(at 13 weeks after 
each injection 
visit)
Participants 
contacted 1 week 
(± 2 days) after each 
injection visit for 
postinjection 
follow-up 
assessment
Xm
X
X
Every 26 weeks
Randomization and 
enrollmentn in IWRS
X
Intimate partner 
violence screening, 
when applicable
X
X
X
X
X
X
X
X
Every 13 weeks
X
X
X
X
HIV Risk Reduction 
Counseling
X
Xo
X
X
X
X
X
X
X
Every 13 weeks
X
X
X
Adherence Counseling
X
X
X
X
X
X
X
Every 13 weeks
X
F/TDF or PTM F/TDF 
Dispensation and 
Accountabilityq
Xp
X
X
X
X
X
X
Every 13 weeks
X
Xq
Oral LEN or PTM 
LEN Dispensation and 
Accountability
Xr
Xq
X

Lenacapavir
Protocol GS-US-528-9023
FINAL
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 186
21 October 2024
Study Procedure
Screening
Randomized Blinded Phase – Weeks (± 7 Days; ± 2 days for 
Week 4 and 8)v
ESDDa
30-Day 
Follow-upb
(± 14 days)
30-Day 
Post-HIV 
Infection 
Follow-up 
(± 14 days)
90-Day 
Post-HIV 
Infection 
Follow-upc
(± 14 days)
Incidence 
Phase
Randomized 
Blinded 
Phase
Day 
1
4
8
13
26
39
52
Post Week 52 
Every 13 or 26 
Weeks
Oral 
Bridging 
Visitd
CD4 cell count 
(Screening if local rapid 
HIV-1/2 test is positive 
and for participants 
diagnosed with HIV 
after receiving study 
drug, refer to 
Section 6.13)
X
X
X
X
X
X
X
X
Every 13 weeks
X
X
X
X
X
HIV-1 RNA 
quantitative NAAT and 
HIV resistance 
genotype (for 
participants diagnosed 
with HIV after 
receiving study drug, 
refer to Section 6.13)
X
X
X
X
X
X
X
Every 13 weeks
X
X
X
Xs
Xt
SC LEN/Placebo for 
SC LEN 
administrationu
X
X
X
Every 26 weeks
Ab = antibody; Ag = antigen; CD4 = cluster determinant 4; CT= Chlamydia trachomatis; DBS = dried blood spot; ESDD = early study drug discontinuation; 
F/TDF = emtricitabine/tenofovir disoproxil fumarate; GC = Neisseria gonorrhea; GFR = glomerular filtration rate; HbA1c = hemoglobin A1c; HBcAb = hepatitis B core antibody; 
HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HIV-1 = human immunodeficiency 
virus type 1; IWRS = interactive web response system; LEN = lenacapavir; NAAT = nucleic acid amplification test; OLE = open-label extension; PK = pharmacokinetic; 
PrEP = pre-exposure prophylaxis; PTM = placebo-to-match; SC = subcutaneous; STI = sexually-transmitted infection; TV = Trichomonas vaginalis
a
Early study drug discontinuation visit occurs once in the study when the participant permanently discontinues dosing with any assigned study drug prior to completing the 
study (regardless of study phase) for any reason other than acquiring HIV. The participant will be asked to return to the clinic for an ESDD visit within 72 hours of stopping 
study drug in the Randomized Blinded Phase.
b
Participants who have received at least 1 dose of study drug will be required to complete a follow-up visit 30 days (± 14) days after discontinuation of the study drug for 
participants who complete an ESDD visit.
c
Participants will only be requested to return to the clinic for a post-HIV-infection follow-up visit 90 (± 14) days after the HIV diagnosis visit if the required information is not 
available from participant’s HIV physician. Participants whose HIV-1 RNA is ≥ 50 copies/mL at the 90-day Post-HIV infection follow-up visit will continue to have 

Lenacapavir
Protocol GS-US-528-9023
FINAL
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 187
21 October 2024
follow-up visits every 3 months until HIV-1 RNA < 50 copies/mL, at which point their participation will conclude. Participants will be followed up for a maximum of 1 year 
from the date of they were diagnosed with HIV infection.
d
Only applicable to participants who require oral weekly bridging if an SC LEN injection cannot be administered for any reason within the protocol visit window.
e
Informed consent/assent are 2 separate ICFs specific to Incidence Phase and Randomized Blinded Phase. Reconsent is required if participant becomes pregnant.
f
Obtain the following information: date of last HIV-1 test, a prior PrEP use and HIV vaccine history, history of osteoporosis or fragility fracture and ongoing treatment for 
tuberculosis, in the Incidence Phase and a complete medical history at the Randomized Blinded Phase.
g
To be performed if Day 1/Injection 1 visit is > 7 days after screening visit.
h
Height collected at screening and Day 1/Injection 1 of Randomized Blinded Phase only for participants ≥ 20 years of age. For participants < 20 years of age, height is to be 
measured annually until they reach 20 years of age.
i
GC and CT testing are to be performed by urine, pharyngeal, and rectal swabs by central laboratory. Swabs may be self-collected by the participant at the discretion of the 
investigator. Asymptomatic blood syphilis analysis per local testing protocol. For participants assigned female at birth, central laboratory urine TV testing may be performed 
at the investigator’s discretion.
j
Run as indicated based on HIV test results.
k
Metabolic Assessments: Participants should be instructed to fast (no food or drinks, except water) at least 8 hours prior to blood collection.
l
For participants assigned female at birth who are of childbearing potential only. After screening visit, positive urine pregnancy tests will be confirmed with a serum pregnancy 
test.
m
The site staff will also confirm the participant has administered the Day 2 dose.
n
Enrollment into the Randomized Blinded Phase.
o
Only if Incidence Phase screening occurs on a separate day.
p
Study drug dispensation only.
q
Drug accountability will be performed by pill count for adherence.
r
Oral LEN/PTM is to be dosed on Day 1/Injection 1 and Day 2.
s
Genotype will be performed only if not already collected at time of infection.
t
HIV-1 RNA quantitative NAAT only.
u
LEN injections are to be given every 26 weeks (± 7 days) after the previous one.
v
All study visits are to be scheduled relative to the previous injection visit date, except in instances of oral LEN/placebo bridging.

Lenacapavir
Protocol GS-US-528-9023
FINAL
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
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21 October 2024
Procedures for LEN OLE Phase
LEN OLE Phase – Weeks (± 7 days; ± 2 days for Weeks 4 and 8)u
Post Week 52
Study Procedure
End of 
Randomized 
Blinded 
Phase 
Visit/LEN 
OLE Day 1
4d
8d
13
26
39
52e
Q13
Q26
Q52
Oral 
Bridging 
Visitf
ESDDa
30-Day 
Follow-upb
(± 14 days)
30-Day
Post-HIV 
Infection 
Follow-up 
(± 14 days)
90-Day
Post-HIV 
Infection 
Follow-upc
(± 14 days)
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
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
Vital Signs, Weight, 
and Heightg
X
X
X
X
X
X
X
X
X
X
X
X
Asymptomatic STI 
Testing for GC, CT, 
TV, and Syphilish
X
X
X
X
X
X
Every 
13 weeks
X
X
Local Rapid Fourth 
Generation HIV-1/2 
Ab/Ag
X
X
X
X
X
X
X
X
X
X
X
Central Fourth 
Generation HIV-1/2 
Ab/Ag
X
X
X
X
X
X
X
X
X
X
X
Hepatitis B Testing 
(HBsAg/HBsAb/
HBcAb)
X
X
X
Every 52 
weeks
Hepatitis C Testing 
(HCV Ab)
X
X
X
Every 
52 weeks
Blood Sample for 
Chemistry/Hematology
X
X
X
X
Every 26 
weeks 
X
X
X
Blood Storage Sample 
for HIV-1 RNA by 
NAAT
X
X
X
X
X
X
X
X
X
X
X

Lenacapavir
Protocol GS-US-528-9023
FINAL
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 189
21 October 2024
LEN OLE Phase – Weeks (± 7 days; ± 2 days for Weeks 4 and 8)u
Post Week 52
Study Procedure
End of 
Randomized 
Blinded 
Phase 
Visit/LEN 
OLE Day 1
4d
8d
13
26
39
52e
Q13
Q26
Q52
Oral 
Bridging 
Visitf
ESDDa
30-Day 
Follow-upb
(± 14 days)
30-Day
Post-HIV 
Infection 
Follow-up 
(± 14 days)
90-Day
Post-HIV 
Infection 
Follow-upc
(± 14 days)
Blood Sample for DBS
X
Blood Sample for 
Metabolic 
Assessmentsi
X
X
X
Every 
52 weeks
Anytime Plasma PK 
Sample
X
X
X
X
X
X
X
X
X
X
X
X
Plasma Storage 
Sample
X
X
X
X
X
X
X
X
X
X
X
X
Serum Storage Sample
X
X
X
X
X
X
X
X
X
X
X
X
Estimated GFR
X
X
X
X
Every 26 
weeks
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
Urine Pregnancy Testj
X
X
X
X
X
X
X
X
X
X
X
X
Integrated Sexual 
Behaviors and Alcohol 
and Substance Use 
Questionnaire
X
X
X
X
X
X
Adherence to Oral 
Study Product 
Questionnaire
X
Experienced 
Preference for PrEP 
Medication 
Questionnaire
Every injection visit
X
Numeric Pain Rating 
Scale - Injection Pain 
(completed 
postinjection)
Every injection visit

Lenacapavir
Protocol GS-US-528-9023
FINAL
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 190
21 October 2024
LEN OLE Phase – Weeks (± 7 days; ± 2 days for Weeks 4 and 8)u
Post Week 52
Study Procedure
End of 
Randomized 
Blinded 
Phase 
Visit/LEN 
OLE Day 1
4d
8d
13
26
39
52e
Q13
Q26
Q52
Oral 
Bridging 
Visitf
ESDDa
30-Day 
Follow-upb
(± 14 days)
30-Day
Post-HIV 
Infection 
Follow-up 
(± 14 days)
90-Day
Post-HIV 
Infection 
Follow-upc
(± 14 days)
Administration and 
Dosing Questionnaire 
for PrEP Medication
13 weeks after each injection visitk
Participants contacted 
1 week (± 2 days) after 
each injection visit for 
postinjection follow-up 
assessmentl
Every injection visit
X
Intimate partner 
violence screening
X
X
X
X
X
X
X
X
X
X
X
X
HIV Risk Reduction 
Counseling
X
X
X
X
X
X
X
X
X
X
X
F/TDF or PTM F/TDF 
Accountabilitym
X
Oral LEN 
Dispensation and 
Accountability and 
Adherence Counseling
Xn,o
Xp
X
CD4 cell count, HIV-1 
RNA quantitative 
NAAT, and HIV 
resistance genotype 
(for participants 
diagnosed with HIV 
only, refer to 
Section 6.13 and 
Appendix 5)
X
X
X
X
X
X
X
X
X
X
X
Xq
Xr
LEN administrations
Every 26 weeks after the previous injectiont
X

Lenacapavir
Protocol GS-US-528-9023
FINAL
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 191
21 October 2024
Ab = antibody; Ag = antigen; CD4 = cluster determinant 4; CT = Chlamydia trachomatis; DBS = dried blood spot; ESDD = early study drug discontinuation; 
F/TDF = emtricitabine/tenofovir disoproxil fumarate; GC = Neisseria gonorrhea; GFR = glomerular filtration rate; HbA1c = hemoglobin A1c; HBcAb = hepatitis B core antibody; 
HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HIV-1 = human immunodeficiency 
virus type 1; LEN = lenacapavir; NAAT = nucleic acid amplification test; OLE = open-label extension; PK = pharmacokinetic(s); PrEP = pre-exposure prophylaxis; 
PTM = placebo-to-match; QN = every N number of weeks; SC = subcutaneous; STI = sexually transmitted infection; TV = Trichomonas vaginalis
a
Early study drug discontinuation visit occurs once in the study when the participant permanently discontinues dosing with any assigned study drug prior to completing the 
study (regardless of study phase) for any reason other than acquiring HIV. The participant will be asked to return to the clinic within 72-hours of informing the investigator 
they no longer wish to receive SC LEN injections in the LEN OLE Phase. 
b
Participants who have received at least 1 dose of study drug will be required to complete a follow-up visit 30 days (± 14 days) after discontinuation of the study drug for 
participants who complete an ESDD visit.
c
Participants will only be requested to return to the clinic for a post-HIV infection follow-up visit 90 (± 14) days after the HIV diagnosis visit if the required information is not 
available from participant’s HIV physician. Participants whose HIV-1 RNA is ≥ 50 copies/mL at the 90-day post-HIV follow-up visit will continue to have follow-up visits 
every 3 months until HIV-1 RNA < 50 copies/mL, at which point their participation will conclude. Participants will be followed up for a maximum of 1 year from the date 
they were diagnosed with HIV infection.
d
Only participants randomized to oral F/TDF (in the Randomized Blinded Phase) who switch to SC LEN will have visits at LEN OLE Weeks 4 and 8.
e
The first SC LEN administration in the LEN OLE Phase will be determined by the previous LEN injection and should be dosed within 26 weeks (± 7 days) of the last 
administered dose of SC LEN (ie, participants whose last LEN injection was 13 weeks before LEN OLE Day 1 will receive their first open-label LEN injections at the LEN 
OLE Week 13 and every 26 weeks thereafter; participants whose last LEN injection was 26 weeks before LEN OLE Day 1 will receive their first open-label LEN injections at 
the LEN OLE Day 1 and every 26 weeks thereafter).
f
Only applicable to participants who require oral weekly bridging if an SC LEN injection cannot be administered for any reason within the protocol visit window.
g
For participants < 20 years old, height is to be measured annually until they reach 20 years of age.
h
GC and CT testing are to be performed by urine, pharyngeal, and rectal swabs by central laboratory. Swabs may be self-collected by the participant at the discretion of the 
investigator. Asymptomatic blood syphilis analysis as per local testing protocol. For participants assigned female at birth, central laboratory urine TV testing may be 
performed at the investigator’s discretion. 
i
Metabolic panel: Participants should be instructed to fast (no food or drinks, except water), at least 8 hours prior to blood collection.
j
For participants assigned female at birth who are of childbearing potential only. Serum pregnancy test will be performed in the event of a positive urine pregnancy test. 
k
Participants will either have the questionnaire at Week 13 and Week 39 or at Week 26 and Week 52, depending on when they receive their SC LEN injections.
l
For the LEN OLE Day 1 follow-up, the site staff will also confirm the participant has been administered the Day 2 dose.
m
Drug accountability will be performed by pill count for adherence. 
n
Only for participants randomized to F/TDF; oral LEN is to be dosed on LEN OLE Days 1 and 2.
o
Study drug dispensation only. 
p
No study drug will be dispensed. Drug accountability will be performed by pill count for adherence.
q
HIV resistance genotype will be performed only if not already collected at time of infection. 
r
CD4 cell count and HIV-1 RNA quantitative NAAT only. 
s
LEN injections are to be given every 26 weeks (± 7 days) after the previous one until either LEN becomes available or the sponsor elects to discontinue the study, whichever 
occurs first.
t
End of Randomized Blinded Phase visit coincides with the LEN OLE Day 1 visit. Participants who were randomized to F/TDF and are entering into the LEN OLE Phase will 
receive their first LEN injection at this visit. Participants who were randomized to LEN and are continuing in the LEN OLE Phase will receive their first LEN OLE injection 
26 weeks (± 7 days) after their last injection in the Randomized Blinded Phase.
u
All study visits are to be scheduled relative to the previous injection visit date, except in instances of oral LEN/placebo bridging. 

Lenacapavir
Protocol GS-US-528-9023
FINAL
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 192
21 October 2024
Procedures for PK Tail Phase
Study Procedure
PK Tail Phase – Weeks (± 7 days)a
Randomized 
Blinded Phase 
to PK Tail 
Day 1
13
26
Post Week 26 Every 
13 or 26 Weeks to 
Week 78
ESDDb
30-Day 
Follow-upc
(± 14 days)
30-Day 
Post-HIV 
Infection 
Follow-up
(± 14 days)
90-Day 
Post-HIV 
Infection 
Follow-upd
(± 14 days)
Concomitant Medications
X
X
X
Every 13 weeks
X
X
X
X
Adverse Events
X
X
X
Every 13 weeks
X
X
X
Targeted Physical Examination
X
X
X
Every 13 weeks
X
X
X
Vital Signs, Weight, and Heighte 
X
X
X
Every 13 weeks
X
X
X
Asymptomatic STI testing for GC, CT, TV, and syphilisf
X
X
X
Every 13 weeks
X
X
Local Rapid 4th Generation HIV-1/2 Ab/Ag
X
X
X
Every 13 weeks
X
X
Central 4th Generation HIV-1/2 Ab/Ag
X
X
X
Every 13 weeks
X
X
Hepatitis B Testing (HBsAg/HBsAb/
HBcAb)
X
Every 52 weeks
Hepatitis C Testing (HCV Ab)
X
Every 52 weeks
Blood Sample for Chemistry/Hematology
X
X
Every 26 weeks
X
X
X
Blood storage sample for HIV-1 RNA NAAT
X
X
X
Every 13 weeks
X
X
Blood Sample for DBS
Xg
X
X
Every 13 weeks
X
X
Blood Sample for Metabolic Assessmentsh
X
Every 52 weeks
Anytime Plasma PK sample
X
X
X
Every 13 weeks
X
X
X
Plasma Storage Sample
X
X
X
Every 13 weeks
X
X
X
Serum Storage Sample
X
X
X
Every 13 weeks
X
X
X
Estimated GFR
X
X
Every 26 weeks
X
X
X
Urinalysis, Urine Protein, Urine Chemistry
X
X
X
Every 13 weeks
X
X
X
Urine Pregnancy Testi
X
X
X
Every 13 weeks
X
X
X
Integrated Sexual Behaviors and Alcohol and 
Substance Use Questionnaire
X
X
X
Every 13 weeks
X
Adherence to Oral Study Product Questionnaire
X
X
X
Every 13 weeks
X
PrEP Impacts and Administration Preference 
Questionnaire
X

Lenacapavir
Protocol GS-US-528-9023
FINAL
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 193
21 October 2024
Study Procedure
PK Tail Phase – Weeks (± 7 days)a
Randomized 
Blinded Phase 
to PK Tail 
Day 1
13
26
Post Week 26 Every 
13 or 26 Weeks to 
Week 78
ESDDb
30-Day 
Follow-upc
(± 14 days)
30-Day 
Post-HIV 
Infection 
Follow-up
(± 14 days)
90-Day 
Post-HIV 
Infection 
Follow-upd
(± 14 days)
Administration and Dosing Questionnaire for PrEP 
Medication
X
Intimate partner violence screening, when 
applicable
X
X
X
Every 13 weeks
X
X
X
HIV Risk Reduction Counseling
X
X
X
Every 13 weeks
X
X
Adherence Counseling
X
X
X
Every 13 weeks
F/TDF Dispensation and Accountabilityj
X
X
X
Every 13 weeks
Xk
CD4 cell count, HIV-1 RNA quantitative 
NAAT, and HIV resistance genotype (for 
participants diagnosed with HIV only, refer to 
Section 6.13 and Appendix 5)
X
X
X
Every 13 weeks
X
X
Xl
Xm
Ab = antibody; Ag = antigen; CD4 = cluster determinant 4; CT = Chlamydia trachomatis; DBS = dried blood spot; ESDD = early study drug discontinuation; 
F/TDF = emtricitabine/tenofovir disoproxil fumarate; GC = Neisseria gonorrhoeae; GFR = glomerular filtration rate; HbA1c = hemoglobin A1c; HBcAb = hepatitis B core 
antibody; HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; LEN = lenacapavir; 
NAAT = nucleic acid amplification test; OLE = open-label extension; PK = pharmacokinetic(s); SC = subcutaneous; STI = sexually transmitted infection; TV = Trichomonas 
vaginalis; US = United States
a
All PK tail visits should be scheduled from PK Tail Day 1. 
b
Early study drug discontinuation visit occurs once in the study when the participant permanently discontinues dosing with any assigned study drug prior to completing the 
study (regardless of study phase) for any reason other than acquiring HIV. The participant will be asked to return to the clinic for an ESDD visit within 72 hours of stopping 
study drug in the PK Tail Phase.
c
Participants who have received at least 1 dose of study drug will be required to complete a follow-up visit 30 days (± 14 days) after discontinuation of the study drug for 
participants who complete an ESDD visit or completing the PK Tail Phase.
d
Participants will only be requested to return to the clinic for a post-HIV-infection follow-up visit 90 (± 14) days after the HIV diagnosis visit if the required information is not 
available from participant’s HIV physician. Participants whose HIV-1 RNA is ≥ 50 copies/mL at the 90-Day Post-HIV Follow-Up visit will continue to have follow-up visits 
every 3 months until HIV-1 RNA < 50 copies/mL, at which point their participation will conclude. Participants will be followed up for a maximum of 1 year from the date of 
they were diagnosed with HIV infection.
e
For participants < 20 years of age, height is to be measured annually until they reach 20 years of age.
f
GC and CT testing are to be performed by urine, pharyngeal, and rectal swabs by central laboratory. Swabs may be self-collected by the participant at the discretion of the 
investigator. Asymptomatic blood syphilis analysis per local testing protocol. For participants assigned female at birth, central laboratory urine TV testing may be performed 
at the investigator’s discretion.
g
Only collect if the participant prematurely discontinues from the Randomized Blinded Phase.
h
Metabolic Assessment: Participants should be instructed to fast (no food or drinks, except water) at least 8 hours prior to blood collection.
i
For participants assigned female at birth who are of childbearing potential only. Serum pregnancy test will be performed in the event of a positive urine pregnancy test.

Lenacapavir
Protocol GS-US-528-9023
FINAL
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 194
21 October 2024
j
Drug accountability will be performed by pill count for adherence. (See Appendix 7 for US-specific text.)
k
No study drug will be dispensed. 
l
HIV resistance genotype will be performed only if not already collected at time of infection. 
m
CD4 cell count and HIV-1 RNA quantitative NAAT only.

Lenacapavir
Protocol GS-US-528-9023
FINAL
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 195
21 October 2024
Appendix 4.
Management of Clinical and Laboratory Adverse Events
Grade 1
Grade 4
Grade 3
Grade 2
May continue 
d sing at the 
d scretion of the 
i vestigator
Repeat lab to 
 xicity 
grade
Repeat lab to 
confirm toxicity 
g
If confirmed and possibly and/or probably related to 
investigational medicinal products:
1.
Withhold investigational medicinal products until Grade 2
2.
Restart all investigational medicinal products at full dose
If confirmed and unrelated to 
investigational medicinal products, 
dosing may continue at the 
discretion of the investigator
If confirmed and 
possibly or probably 
related to 
investigational 
medicinal products,
discontinue 
investigational 
medicinal products
dosing permanently 
and follow at periodic 
intervals at least 
weekly until a return 
to baseline or is 
otherwise explained
If Grade 3 or 4 recurrence that is confirmed and possibly or 
probably related to investigational medicinal products, 
discontinue all investigational medicinal products dosing 
permanently
If Grade 3 or 4 recurrence that is considered unrelated to 
investigational medicinal products, continue all investigational 
medicinal products at the same dose at the discretion of the 
investigator
I 
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Appendix 5.
HIV Testing Algorithms 
5a Screening Visit 
Screening Visit 
Screening Visit 
Rapid 4th 
generation HIV-
1/2 Ab/Ag test 
OCAL 
ESTIN 
Negative: continue 
screening 
procedures 
Positive: perform HIV 
procedures as 
described in Section 6 
"HIV-1 lnfection"1. Not 
eligible for Randomized 
Blinded Phase 
1. At the investigator's discretion, positive rapid 4th generation 
tests may be separately confirmed by local testing in order to 
facilitate rapid ART initiation 
2. 
For the screening and Day 1 visits only, central 41h generation 
HIV-1/2 Ab/Ag test and HIV-1 RNA quantitative NAAT tests are 
performed concurrently. Any HIV-1 RNA detected is considered 
a positive quantitative NAAT. 
b/Ag ALG 
'VI {CENTRA 
Central 4th generation 
HIV-1/2 Ab/Ag test 
Positive: not eligible for 
Randomized Blinded 
Phase. HIV-1/2 
differentiation assay 
{reflexive) 
Positive: perform HIV care 
as described in Section 6 
"HIV-1 Infection" 
Positive: perform HIV care 
as described in Section 6 
"HIV-1 Infection" 
Negative 
Negative: HIV-1 RNA 
qualitative NAAT 
{reflexive) 
Negative 
AL LOAD (CENTRA J 
HIV-1 RNA quantitative NAAT 
{viral load) 2 
Continue screening 
procedures if~ HIV 
tests are negative 

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5b Day 1/Injection 1 Visit
Day 1 Visit 
Day 1 Visit 
Rapid 4th 
generation HIV-
1/2 Ab/Ag test 
LOCAL 
TESTING 
Negative: continue 
Day 1 procedures1 
Positive: perform HIV 
procedures as 
described in Section 6 
"HIV-1 lnfection"2 
1. It is not necessary to await central HIV testing results prior to 
randomization 
2. At the investigator's discretion, positive rapid 4th generation tests 
may be separately confirmed by local testing in order to facilitate 
rapid ART initiation 
3. 
For the screening and Day 1 visits only, central 4th generation HIV-
1/2 Ab/Ag test and HIV RNA quantitative NAAT tests are 
performed concurrently. Any HIV-1 RNA detected is considered a 
positive quantitative NAAT. 
Ab/Ag ALGORITHM (CENTRAL} 
Central 4th generation 
HIV-1/ 2 Ab/Ag test 
differentiation assay 
(reflexive) 
Positive: stop study drug. 
perform HIV care as 
described in Section 6 
"HIV-1 Infection" 
perform HIV care as 
described in Section 6 
"HIV-1 Infection" 
Negative: HIV RNA 
qualitative NAAT 
(reflexive) 
VIRAL LOAD (CENTRAL) 
HIV RNA quantitative NAAT 
(viral load) 3 
Continue study 
procedures if Ab/Ag 
algorithm and viral 
load are negative 

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5c Scheduled Visits After Day 1/Injection 1
Scheduled Visits After Day 1 
Scheduled visit 
after Day 1 
Rapid 4th 
generation HIV-
1/2 Ab/Ag test 
LOCAl 
TESTING 
Negative: continue 
study procedures1 
Positive: do not give 
injection study drug. 
Perform HIV procedures 
as described in Section 6 
"H IV-1 lnfection" 2 
HIV-1 RNA quantitative 
NAAT (reflexive) 
1. 
It is not necessary to await central HIV testing results 
2. 
At the investigator's discretion, positive rapid 4th generation tests 
may be separately confirmed by local testing in order to facilitate 
rapid ART initiation 
3. 
HIV-1 RNA quantitative NAAT will be performed reflexively if the 
central 4th generation HIV-1/2 Ab/Ag is positive 
Ab/Ag ALGORITHM (CENTRAL) 
Central 4th generation 
HIV-1/2 Ab/Ag test 
Positive: stop study drug. 
Perform HIV procedures 
as described in Section 6 
" HIV-1 Infection" 
Negative: continue 
study procedures 
Negative: HIV RNA 
qualitative NAAT 
(reflexive) 
Positive: stop study drug. 
perform HIV procedures 
as described in Section 6 
Negative: continue 
study procedures 
" HIV-1 Infection" 

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Appendix 6.
Randomized Blinded Phase Pregnancy Precautions, Definition 
Childbearing Potential for Participants Assigned Female at Birth, and 
Contraceptive Requirements
1) Definitions
a) Definition of Childbearing Potential
For the purposes of this study, a participant assigned female at birth, including transgender men, 
gender nonbinary people, and individuals taking testosterone and not experiencing regular 
menses are considered of childbearing potential following the initiation of puberty (Tanner 
stage 2) until becoming postmenopausal unless the participant is permanently sterile or has 
medically documented ovarian failure.
Participants assigned female at birth are considered to be in a postmenopausal state when they 
are ≥ 54 years of age with cessation of previously occurring menses for ≥ 12 months without an 
alternative cause. 
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a participant assigned female at birth of any age.
b) Definition of Fertility in Participants assigned Male at Birth
For the purposes of this study, a participant assigned male at birth is considered fertile after the 
initiation of puberty unless the participant is permanently sterile by bilateral orchidectomy or 
medical documentation.
2) Contraception Requirements for Participants Assigned Female at Birth
a) Study Drug Effects on Pregnancy and Hormonal Contraception
Data from clinical pharmacokinetic interaction studies of emtricitabine/tenofovir disoproxil 
fumarate (F/TDF) have demonstrated that there is no reduction in the clinical efficacy of 
hormonal contraception. Based on in vitro and in vivo drug-drug interaction liability assessment, 
a clinically significant drug-drug interaction with lenacapavir (LEN) and hormonal 
contraceptives is not expected; an oral contraception drug-drug interaction study was not done 
(see Section 1.2.7).
Nonclinical toxicity studies of F/TDF and LEN have demonstrated no adverse effect on fertility 
or embryo-fetal development.
No safety concerns have been associated with F/TDF for pre-exposure prophylaxis (PrEP) in 
early pregnancy or their offspring. No safety concerns have been identified among infants 
exposed to F/TDF during lactation. The long-term safety of infants exposed to F/TDF in utero is 
not yet known.
There are no clinical studies of LEN in pregnancy (Section 1.2.5.4). It is not known whether 
LEN is secreted in human milk (Section 1.2.6.4).

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Please refer to the latest version of the investigator’s brochures, and Sections 1.2.5 and 1.2.6 for 
additional information.
b) Contraception Requirements for Participants Assigned Female at Birth of Childbearing 
Potential
The inclusion of participants assigned female at birth of childbearing potential requires using at 
least an acceptable effective contraceptive measure. Pregnancy tests will be performed as defined 
by the study procedures in Appendix 3. They must have a negative serum pregnancy test at 
Randomized Blinded Phase screening and a negative pregnancy test at the Day 1/Injection 1 
Randomized Blinded Phase visit prior to the dose of study drug. At any time pregnancy is 
suspected, a pregnancy test must be performed to rule out pregnancy. This is also applicable for 
participants assigned female at birth of childbearing potential with infrequent or irregular 
periods. 
Duration of contraception for participants assigned female at birth of childbearing potential 
enrolled in this clinical trial should start from the screening visit until 700 days after the last dose 
of LEN.
Participants assigned female at birth of childbearing potential must agree to one of the following 
contraceptive methods:
•
Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the participant’s preferred and usual 
lifestyle.
Or
Consistent and correct use of 1 of the following methods of birth control listed below: 
•
Hormonal and nonhormonal intrauterine device
•
Bilateral tubal occlusion (upon medical assessment of surgical success)
•
Vasectomy in the partner assigned male at birth (upon medical assessment of surgical 
success)
Or

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Participants assigned female at birth of childbearing potential who initiate use of a hormonal 
contraceptive > 7 days after onset of menses as one of their birth control methods should use 
additional back-up contraception or avoid sexual intercourse for 7 days. Hormonally-based 
contraceptives and barrier methods permitted for use in this protocol are as follows:
•
Hormonal methods 
Oral contraceptives (either combined or progesterone only)
Injectable progesterone
Subdermal contraceptive implant
Transdermal contraceptive patch
Contraceptive vaginal ring
•
Barrier methods 
External (penile) condom (with or without spermicide)
Internal (vaginal) condom (with or without spermicide)
Diaphragm with spermicide
Cervical cap with spermicide
Sponge with spermicide
Inclusion of methods of contraception in this list of permitted methods does not imply that the 
method is approved in any country or region. Methods should only be used if locally approved. 
Participants assigned female at birth must also refrain from egg donation and in vitro fertilization 
during treatment and until the end of contraception requirement.
3) Contraception Requirements for Participants Assigned Male at Birth
No contraception measures are needed.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method. An internal (vaginal) condom and an external (penile) condom 
should not be used together.

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5) Procedures to be Followed in the Event of Pregnancy
Participants assigned female at birth will be instructed to notify the investigator if they become 
pregnant or suspect they are pregnant at any time from start of the study until 700 days from last 
dose of LEN. Instructions for reporting pregnancy and pregnancy outcome are outlined in 
Section 7.4.2.3. See also Section 9.1.4 regarding reconsent and remaining in the study.
See Appendix 7 for US-specific text.

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Appendix 7.
Country-Specific Requirements
1) Additional Country-Specific Requirements for the US
Country-specific Requirements
Affected Sections
Included a background subsection for emtricitabine/tenofovir alafenamide (F/TAF; 
Descovy). F/TAF is approved for pre-exposure prophylaxis (PrEP) in the 
United States (US), Canada, Australia, and Taiwan.
For further information on F/TAF, including findings of nonclinical studies of F/TAF for 
PrEP, refer to the current investigator’s brochure (IB) for F/TAF.
Section 1.2.2
Included summary of nonclinical studies in pregnancy for tenofovir alafenamide (TAF) 
stating that animal studies do not indicate direct or indirect harmful effects of TAF with 
respect to pregnancy, embryonal and fetal development, parturition, or postnatal 
development. Tenofovir alafenamide is not considered to be genotoxic. In offspring from 
rat and rabbit dams treated with TAF during pregnancy, there were no toxicologically 
significant effects on developmental endpoints (DESCOVY IB).
Section 1.2.4.1
Included summary of TAF use during human pregnancy stating that the 
pharmacokinetics (PK) of TAF has been studied in pregnant women. Pharmacokinetics 
in pregnant women was reported in 31 women taking TAF 25 mg without any 
pharmacoenhancer and in 27 women taking TAF 10 mg boosted with cobicistat 150 mg 
{Best 2015a, Best 2015b, Chinula 2020}. This study evaluated plasma TAF exposures 
with and without boosting in pregnant and postpartum women relative to those in 
nonpregnant adults. No significant differences in PK were seen between pregnant and 
postpartum women taking boosted TAF. Among women taking unboosted TAF, 
exposures were lower during pregnancy than postpartum, but this was driven by higher 
exposures postpartum. Despite the differences observed, exposures in both regimens 
were within the range of those typically observed in nonpregnant adults {Momper 
2018}. Tenofovir alafenamide levels were below the limit of quantification in all 15 cord 
blood samples tested. Tenofovir alafenamide was safe and well tolerated by mothers and 
babies in this small sample.
Recent results from the International Maternal Pediatric Adolescent AIDS Clinical Trials 
Network (IMPAACT) 2010 study have added to the available pregnancy data for TAF. 
IMPAACT investigators randomized 643 women with HIV to begin HIV treatment 14 to 
28 weeks into their pregnancies with efavirenz/emtricitabine/tenofovir disoproxil 
fumarate (EFV/FTC/TDF; Atripla®), dolutegravir (DTG) + F/TAF, or DTG+F/TDF. 
Participants taking TAF-containing therapy had superior composite pregnancy 
outcomes: 24% of women taking DTG+F/TAF had an adverse pregnancy outcome 
compared with 33% of women taking DTG+F/TDF or EFV/FTC/TDF {Chinula 2020}.
Furthermore, advantages of TAF over TDF demonstrated in HIV-1 treatment studies 
include less impact on bone mineral density (BMD). It has been shown that growing 
children treated for HIV-1 infection with a TAF-based regimen have minimal changes in 
BMD height-age Z-scores which offers advantage over TDF-based regimens {Gaur 
2016}. The expectation is that this could be extrapolated to the fetus in utero, thus 
conferring this advantage for safe use of F/TAF for PrEP during pregnancy. Also, as loss 
of BMD in newborns exposed to TDF in utero during maternal antiretroviral therapy 
(ART) has been shown {Siberry 2015}, it is expected that this would be less likely to be 
the case for TAF-exposed newborns during pregnancy based on the evidence for the 
bone safety benefit of TAF versus TDF in growing children.
The antiretroviral pregnancy registry (APR) is a voluntary prospective, 
exposure-registration, observational study designed to collect and evaluate data on the 
outcomes of pregnancy exposures to antiretroviral (ARV) products. The APR collects 
provider-reported birth outcomes of women taking ART and compares the prevalence of 
birth defects with birth defects rates reported by 2 large registries, the US Centers for 
Section 1.2.5.2

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Disease Control and Prevention’s (CDC’s) birth defects surveillance system 
(Metropolitan Atlanta Congenital Defects Program [MACDP]) and the Texas Birth 
Defects Registry (TBDR). The 31 July 2021 APR report included 606 pregnancies with 
TAF exposure, with a birth defect rate that was not statistically different from the 
MACDP or the TBDR.
While current guidelines do not recommend routine initiation of TAF during pregnancy 
due to limited data {Panel on Treatment of Pregnant Women with HIV Infection and 
Prevention of Perinatal Transmission 2020}, the currently available data on TAF use in 
pregnancy have not revealed safety concerns and support its continued study in clinical 
studies. 
Included summary of TAF use while lactating stating that there are little data on the 
secretion of TAF into breast milk, although the 90% lower circulating levels of TFV 
associated with TAF 25 mg administration compared with TDF 300 mg administration 
make it likely that breast milk and fetal exposures would be significantly lower than 
those observed with TDF administration. This is supported by data from a study of TAF 
and TDF used for hepatitis B treatment in pregnant women. In this study, 26 pregnant 
women received TAF for hepatitis B virus (HBV), and TAF concentrations were below 
the limit of quantification (0.5 ng/mL) in cord blood or breast milk samples from all 
women {Bojun 2020}.
Section 1.2.6.2
Included summary of drug-interaction potential for F/TAF with hormones stating that 
TAF along with TDF, but not their major metabolite TFV, are substrates for intestinal 
efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) 
{DESCOVY 2020, Tong 2007, TRUVADA 2020}. However, the results of Phase 1 
drug-drug interactions (DDI) evaluations revealed that a clinically relevant alteration in 
systemic exposure of TAF is limited to strong induction of intestinal P-gp by rifampin 
{Custodio 2017}. As such, the use of strong P-gp inducers with F/TAF is not 
recommended.
While in vitro, TAF, but not TDF or TFV, weakly inhibited cytochrome P450 enzyme 
(CYP)3A, the results of the dedicated Phase 1 evaluation demonstrated lack of TAF 
effect on CYP3A activity using midazolam, a sensitive CYP3A probe {DESCOVY 
2020}. These data confirm that F/TAF and F/TDF may be administered with CYP3A 
substrates. Collectively, these studies demonstrated that F/TAF and F/TDF have a low 
propensity to act as victims or perpetrators of clinically significant drug interactions, 
including with estrogens, testosterone, and nonhormonal gender-affirming hormone 
therapy (GAHT).
In agreement with these data, dedicated Phase 1 evaluations between TDF, F/TAF, and 
estrogen containing contraceptives showed no clinically relevant changes in PK 
parameters of either ARV agent or estradiol, thereby supporting the use of F/TDF and 
F/TAF with estrogen containing medications. No meaningful differences in intracellular 
TFV diphosphate or FTC-triphosphate were observed in transgender women (TGW) 
taking high-dose hormone therapy concomitantly with F/TDF and F/TAF in the 
DISCOVER trial, suggesting that F/TDF and F/TAF are safe and effective options for 
PrEP in TGW on GAHT. A study with daily observed therapy of F/TDF in both TGW 
and transgender men (TGM) confirmed that there was no impact of GAHT on 
TFV-diphosphate in dried blood spots (DBS), nor was there any impact of F/TDF on 
estradiol or testosterone levels in either TGW or TGM {Grant 2020}. The metabolic 
profiles of F/TDF and F/TAF also make clinically significant interactions with 
testosterone or nonhormonal gender-affirming therapy unlikely (Section 1.2.7.2). In 
summary, the available data suggest that estrogen-containing contraceptives, 
estrogen-containing GAHT, testosterone, and nonhormonal gender-affirming therapy can 
be used concomitantly with F/TDF and F/TAF.
Section 1.2.7.1

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Included rationale for dose selection F/TAF FDC (200 mg FTC/25 mg TAF) stating it 
will be dispensed to participants in the PK Tail Phase, as applicable, with instructions to 
administer 1 tablet orally by mouth once daily for PrEP. This dose was evaluated in the 
DISCOVER study and approved for PrEP in men who have sex with men (MSM) and 
TGW in the US.
Section 1.4
Risk/Benefit assessment data were updated to state that F/TAF has been demonstrated to 
have high efficacy and a favorable safety profile for PrEP in MSM and TGW.
Section 1.6
Included that participants in the US can receive either F/TDF or F/TAF in the PK tail 
phase for up to 78 weeks.
Participants may switch between F/TDF and F/TAF during the PK Tail Phase if 
determined to be necessary by the investigator.
Furthermore, participants who began receiving open-label (OL) F/TDF or F/TAF due to 
unavailability of SC LEN/placebo may rejoin the Randomized Blinded Phase of the 
study if approved by the medical monitor. In these cases, as soon as SC LEN/placebo is 
available, the participant should be contacted and notified to return to the site and 
complete the injection visit that was missed due to SC LEN/placebo unavailability. For 
instance, if a participant could not receive SC LEN/placebo at Week 26 and began OL 
F/TDF or F/TAF, the participant would return to the site as soon as SC LEN/placebo 
administration is feasible and resume the study at the Week 26/Injection 2 visit.
Figure 11, 
Sections 3.3, 3.3.4, 
3.5, 6.5, Appendix 3
Included information pertaining to F/TAF formulation, packaging and labeling, storage 
and handling, and dosage and administration as below. 
F/TAF 200/25 mg tablets are blue, rectangular-shaped, film-coated tablets, debossed 
with “GSI” on one side of the tablets and “225” on the other side of the tablet. Each 
tablet core contains 200 mg of FTC and 25 mg of TAF. In addition to the active 
ingredients, the F/TAF tablets contain the following inactive ingredients: 
microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyethylene 
glycol, polyvinyl alcohol, talc, titanium dioxide, and FD&C blue #2/indigo carmine 
aluminum lake.
F/TAF tablets are packaged in a white high-density polyethylene bottle. Each bottle 
contains 30 tablets, silica gel desiccant, and polyester packing material. Each bottle is 
enclosed with a white, continuous thread, child-resistant polypropylene screw cap fitted 
with an induction-sealed and aluminum faced liner.
Study drugs to be distributed to centers in the US and other participating countries shall 
be labeled to meet applicable requirements of the US Food and Drug Administration, 
International Council for Harmonisation (ICH), and/or other local regulations.
F/TAF tablets must be stored at a controlled room temperature below 25 °C (77 °F); 
excursions are permitted between 15 °C and 30 °C (59 °F and 86 °F). Storage conditions 
are specified on the label.
F/TAF (200/25 mg) tablets will be provided by Gilead. The decision to administer 
F/TAF during the PK Tail Phase is at the discretion of the investigator. Study drug will 
be dispensed to participants on PK Tail Day 1. Participants will be instructed to take 
their first dose of study drug following completion of the study procedures at the PK Tail 
Day 1 visit. If study drug was not taken in the clinic following the completion of PK Tail 
Day 1 study procedures, initiation of the study drug must take place within 24 hours after 
the PK Tail Day 1 visit and after the investigator has confirmed eligibility with the 
participant.
Participants will continue to take their daily dose of F/TAF each day.
Sections 5.2.1.3, 
5.2.2.3, 5.2.3.3, 5.3.3
Prior and concomitant medications were updated to clarify that medications and use of 
herbal/natural supplements listed in Table 22 that are excluded or should be used with 
caution while participants are taking study drug on the study due to potential DDIs with 
F/TDF also apply F/TAF. 
Section 5.4, Table 22

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Clarified that if in the PK Tail Phase the participant has been nonadherent to F/TDF or 
F/TAF and has had a high risk exposure event, the investigator may restart the 
participant on F/TDF or F/TAF and add a third agent to comprise postexposure 
prophylaxis treatment.
Section 6.13.1
Included clarification that oral PrEP can include F/TDF or F/TAF. 
Section 6.15
Text was updated to include F/TAF information with respect to the effects of study drug 
on pregnancy and hormonal contraception to state that data from clinical PK interaction 
studies of F/TAF have demonstrated that there is no reduction in the clinical efficacy of 
hormonal contraception. Based on in vitro and in vivo drug-drug interaction liability 
assessment, a clinically significant drug-drug interaction with LEN and hormonal 
contraceptives is not expected; an oral contraception drug-drug interaction study was not 
done. That nonclinical toxicity studies of F/TAF have demonstrated no adverse effect on 
fertility or embryo-fetal development. F/TAF for PrEP has not been studied in pregnant 
women; however, a randomized controlled study of F/TAF plus DTG for HIV treatment 
in pregnant women identified no safety concerns. Safety of lactation while taking F/TAF 
has not been studied; however, a PK study reported that breast milk TAF levels were 
below the limit of quantification in all women studied. The long-term safety of infants 
exposed to F/TAF in utero is not yet known.
Appendix 6

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Appendix 8.
Amendment History
A high-level summary of amendment history is provided in tabular form in the subsection below. 
Minor changes such as the correction of typographic errors, grammar, or formatting are not 
detailed.
Separate summary of change documents for earlier amendments are available upon request.
A separate tracked change (red-lined) document comparing the previous version of the protocol 
to this amendment will be made available upon the publication of this protocol.
1) Amendment 4 (21 October 2024)
Rationale for Key Changes Included in Amendment 4
Affected Sections
Clarified that duration of Randomized Blinded Phase (RBP) will be 
approximately 52 weeks. This revision acknowledges that RBP would be 
shorter than 2 weeks if RBP is stopped early by the study’s independent 
Data Monitoring Committee (DMC).
Synopsis, Sections 3.3.2 and 3.5
Revised LEN OLE Phase language to extend SC LEN treatment every 26 
weeks until LEN becomes available in their location or the sponsor elects to 
discontinue the study, whichever occurs first. This revision was made 
following the finding of superior efficacy of LEN over 
emtricitabine/tenofovir disoproxil fumarate (F/TDF; Truvada®; TVD) at the 
study’s primary analysis. This extension of the OLE will allow study 
participants to continue receiving the superior intervention (LEN) until it 
becomes available in their country. While unlikely to occur, the sponsor 
retains the right to stop the study if circumstances require. 
Synopsis, Figure 11, Sections 3.3.3, 
and 6.4
Appendix 3
Dosing time point for first dose of SC LEN updated.
Synopsis, Figure 11, Section 3.3, 
Appendix 3
The study schema and footnotes were updated to align with the changes in 
the LEN OLE Phase and PK Tail Phase.
Figure 11
Updated language related to use of LEN during pregnancy.
Section 1.2.54
Revised PK Tail Phase language to clarify that participants who prematurely 
discontinue study drug in the RBP will transition to the PK Tail Phase and 
that participants who complete the LEN OLE Phase or discontinue from the 
study will be transitioned to local HIV prevention services.
Synopsis, Figure 11, Sections 3.3.4 
and 3.3.5, Appendix 3
Clarified that participants eligible for the PK Tail Phase will receive oral 
F/TDF once daily for up to 78 weeks.
Section 3.3.4
Updated language pertaining to participant randomized to F/TDF in the RBP 
and switched to LEN.
Section 3.3.3, Figure 11
Removed drug-drug interaction (DDI) potential between F/TDF and 
anticonvulsants as well as antimycobacterials from list of Prohibited 
Medications.
Added that “concomitant use of dexamethasone may decrease LEN 
exposures, particularly with long-term use.”
Table 22

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Rationale for Key Changes Included in Amendment 4
Affected Sections
The DDI language regarding F/TDF was erroneous in the prior version and 
corrected here. The language regarding dexamethasone reflects the currently 
available data on this DDI, as described in the Investigator’s Brochure.
Revised frequency language for sexually-transmitted infection (STI) 
assessments and questionnaires.
Synopsis, Sections , 6.4 and 6.5, 
Appendix 3
Reduced frequency of assessments for chemistry and hematology profile, 
metabolic assessments, estimated glomerular filtration rate (eGFR), and 
hepatitis B and hepatitis C virus testing for the LEN OLE Phase and PK Tail 
Phase. A reduced frequency is appropriate since no safety signals with LEN 
were identified in the RBP and the updated schedule of assessments will 
reduce burden on participants.
Synopsis, Sections 6.4 and 6.5, 
Appendix 3
Removed urine protein and urine chemistry for all LEN OLE Phase visits. 
Additional urine assessments are not needed in the LEN OLE Phase since 
participants are not receiving tenofovir-containing PrEP. Removed urine 
storage sample for all LEN OLE Phase visits and PK Tail Phase visits. 
Synopsis, Sections 6.4, 6.5, 6.7.1, and 
6.9.1, Appendix 3
Clarified that waist circumference will only be collected at RBP. Adequate 
waist circumference data were collected in the RBP, making additional data 
collection unnecessary in the LEN OLE Phase and PK Tail Phase.  
Synopsis, Sections 6.4, 6.5, 6.7.1 and 
6.7.2, Appendix 3
Added text for creatinine phosphokinase collected only at RBP. No safety 
signals were detected in the Randomized Blinded Phase for creatine 
phosphokinase and reduced specimen collection is appropriate for OLE in 
order to reduce burden on participants.
Section 6.9.2
Updated eGFR assessment to be conducted every 2 weeks to match blood 
chemistry for the LEN OLE Phase and PK Tail Phase. Monitoring of eGFR 
every 13 weeks is unnecessary in the LEN OLE Phase as participants are not 
receiving tenofovir-containing PrEP.
Synopsis, Sections 6.4 and 6.5, 
Appendix 3
Updated text pertaining to HIV-1 infection questionnaire eCRF.
Section 6.13
Updated participant-reported questionnaires for the LEN OLE Phase 
(Experienced Preference for PrEP Medication, Administration and Dosing 
Questionnaire for PrEP Medication, Numeric Pain Rating Scale, Integrated 
Sexual Risk and Behaviors and Alcohol and Substance Use, Adherence to 
Oral Study Product Questionnaire) to be stopped at 52 weeks and eliminated 
the administration of the Experienced Preference for PrEP Medication 
questionnaire from the PK Tail Phase. Adequate data on these topics will 
have been collected by Week 52 of the LEN OLE Phase, making additional 
collection unnecessary. This will reduce the burden on sites and participants 
in the later stages of the LEN OLE Phase. Footnote k was added to the 
procedures for the LEN OLE Phase Table to provide additional guidance to 
sites as to when the Administration and Dosing Questionnaire for PrEP 
Medication should be administered.
Synopsis, Sections 6.4, 6.5 and 6.16, 
Appendix 3
Added language regarding adverse events/serious adverse events 
(AEs/SAEs) reporting for neonates/infants for at the time of delivery, 
following delivery, and following lactation exposure. This change was made 
to provide clearer reporting guidance to sites and ensure timely and accurate 
reporting of any adverse events in neonates and infants.
Sections 7.4.2

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Revised LEN OLE Phase adherence counseling language to clarify that since 
all participants will receive LEN injections in the OLE phase, therefore daily 
adherence to an oral study drug is not required.
Synopsis, Section 6.4
Removed text stating that the End of LEN OLE Phase visit coincided with 
PK Tail Day 1 as the LEN OLE Phase was extended until LEN becomes 
available or the sponsor elects to discontinue the study and eligibility 
requirements for the PK Tail Phase were updated.
Section 6.5
Guidance for administering LEN injections when > 28 weeks have elapsed 
since the last injection was updated to remove the requirement that medical 
monitor approval is required. This was changed to allow investigators to use 
their clinical discretion and minimize delays in restarting participants on 
LEN. This is considered appropriate considering the efficacy data and 
experience with LEN injections obtained during the RBP.
Section 6.8.2
Language on reporting vertical HIV transmission as serious adverse events 
was added to provide clearer guidance to sites and ensure that these events 
are properly reported, if they were to occur.
Section 7.1.2.1
Added text describing “reasonable possibility” of a causal relationship 
between study drugs and adverse events. This update provides more 
guidance to investigators on the reporting of adverse events and causality to 
the sponsor. The added text aligns with the International Conference for 
Harmonisation (ICH) guidelines on Clinical Safety Data Management E2A.
Section 7.2.1
Updated management of injection site reactions (ISRs). Clarified that 
investigators will contact the study medical monitor to discuss the evaluation 
and management of long-lasting or severe (Grade 3 or higher) ISRs if they 
are determined to be of clinical concern. This change has been made to the 
protocol to allow the investigators to use their clinical judgement regarding 
the discussion of ISRs with the medical monitor and to decrease burden on 
sites so that they do not need to report ISRs that are not of clinical concern.
Section 7.7.5
For primary analysis, updated details of the primary success criteria. 
Updated the estimation methods for the incidence rate ratio of the LEN study 
drug group to the background and the incidence rate ratio difference of LEN 
from F/TDF to account for the possibility that the number of HIV-1 
infections in the LEN group is zero. Updated notation definitions of Figure 
13 to provide more clarity and remove notations that are not relevant. The 
updates to the success criteria were required by the United States Food and 
Drug Administration (US FDA).
Synopsis, Section 8.5.1, Figure 13 
(footnotes)
Deleted text related to incidence and weight management.
Section 8.6.1
Updated participant selection language to clarify that the collection of race, 
ethnicity, gender, and age data allows for the analysis and reporting of safety 
and efficacy data by demographic subgroups as required by certain health 
authorities, which is essential for the analysis of the study data.
Section 4.1
Revised the SAE reporting language per latest template to clarify recording 
and reporting requirements for SAEs. Gilead protocol template language was 
updated to clarify reporting requirements generally and to note that there is 
now a Follow-up SAE report form (in addition to the Initial SAE report 
form).
Section 7.4.1.1

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Clarified that the HIV-1 incidence rate of the LEN study drug group is at 
most 0.8/100 PY higher than the F/TDF study drug group. This change was 
made to correct a typographical error.
Synopsis, Section 8.5.2
For secondary analysis, updated the estimation methods for the rate ratios of 
HIV-1 incidence between LEN and F/TDF and between F/TAF and F/TDF 
and the associated CI if the number of infections is zero. This provides more 
details on the analysis methods to be used, in alignment with the Statistical 
Analysis Plan.
Section 8.5.2
Clarified that duration of exposure will be expressed as the number of weeks 
between the first and last dose of the study drug exposure, inclusive. Given 
the long acting nature of LEN, any exposure time after SC LEN dosing is 
considered part of the exposure time.
Section 8.6.1
Removed language related to HIV-1 incidence rate calculation based on 
weights adjusted for case-cohort sampling to align with the current 
Statistical Analysis Plan.
Section 8.6.1
Updated DMC criteria for rejection of hypothesis H02 and H04. The interim 
stopping criteria was changed after discussions with the FDA, which 
requires additionally LEN superiority versus F/TDF.
Section 8.7
Updated name of Study Director.
Appendix 1
Blood sample collection for DBS was removed at the 30-day follow-up visit 
in the LEN OLE Phase, to correct an error in the prior protocol version. DBS 
samples are used to measure adherence to F/TDF. Since participants in the 
LEN OLE Phase are not on F/TDF, collection of blood sample for DBS is 
unnecessary.
Appendix 3
Urinalyses was removed from the 30-Day Post-HIV Infection Follow-up 
visit of the LEN OLE Phase as it was listed for that visit in error.
Appendix 3
Updated footnotes for LEN OLE and PK Tail study procedures tables, as 
applicable. These corrections were made to provide additional clarifications 
and to align with changes made to the LEN OLE Phase and PK Tail Phase.
Appendix 3
The column “LEN OLE to PK Tail Day 1” was removed from the 
procedures for PK Tail Phase table to reflect changes to the PK Tail Phase 
described in Section 3.5.4. This was removed because participants are now 
able to stay in LEN OLE Phase until LEN becomes available or the sponsor 
elects to discontinue the study, whichever occurs first.
Appendix 3
Minor changes to correct typographic errors, language, and to provide 
clarifications.
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Country-specific requirements for the United States were added to the 
protocol.
Synopsis; Sections 1.2.2, 1.2.4.1, 
1.2.5.2, 1.2.6.2, 1.2.7.1, 1.4, 1.6, 
3.3, 3.3.4, 3.5, 5.2.1.3, 5.2.2.3, 
5.2.3.3, 5.3.3, 5.4, 6.2.2, 6.3.1, 
6.3.2, 6.4, 6.5, 6.7.1, 6.13.1, 6.15, 
6.16, Figure 11; Table 22; 
Appendices 3, 6, and 7
Country-specific requirements for Mexico were added to the protocol.
Study Procedures Table
Updated the lenacapavir (LEN) clinical history with the latest information 
from ongoing studies.
Sections 1.2.3.4.2, 1.2.3.4.3, 
1.2.3.4.4, 1.2.3.4.6, and 1.2.3.4.7
Updated the rationale for Oral Weekly Bridging of LEN for missed 
subcutaneous (SC) injection with the preliminary Oral Bridging PK data 
available from Phase 2/3 Studies GS-US-200-4625 and GS-US-200-4334.
Section 1.5
Postinjection observation text was revised to clarify that observation for 
approximately 30 minutes pertains to all study drug injection visits.
Synopsis, Sections 3.3.2, 3.3.3, 
6.3.1, 6.3.2, and 6.4
Text was revised to clarify that the study will only proceed to the LEN 
Open-Label Extension (OLE) Phase if LEN demonstrates acceptable safety 
and efficacy in the Randomized Blinded Phase.
Synopsis, Section 3.3.3
The Incidence Phase exclusion criterion pertaining to pre-exposure 
prophylaxis (PrEP) use in the past 12 weeks was revised to include HIV 
postexposure prophylaxis (PEP) because PEP use in the period prior to 
randomization, like PrEP use, may interfere with accurate HIV incidence 
rate estimation.
Synopsis, Section 4.2.2
Updated the nomenclature of the Sexual Risk and Behavior Questionnaire to 
“Integrated sexual behaviors and alcohol and substance use.”
Synopsis, Sections 6.2.2, 6.3.1, 
6.3.2, 6.4, 6.5, 6.7.1, and 6.16
Clarified that only participants in the open label extension phase will 
perform ‘Experienced Preference for PrEP Medication’ questionnaire.
Synopsis, Sections 3.2, 6.5, 8.1.4, 
and Appendix 3 (Study Procedure 
Table [Procedures for PK Tail 
Phase])
Tablet storage conditions were revised for clarity to indicate that tablets 
must be stored at a controlled room temperature below 25 °C.
Section 5.2.3.2
Text pertaining to PEP, HIV vaccine, and HIV broadly neutralizing antibody 
use was deleted due to redundancy; this information is provided in the 
protocol eligibility criteria.
Section 5.4
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Text pertaining to drug-drug interactions (DDI) was updated for consistency 
with the IB, based on the available DDI data, and our current understanding 
of LEN disposition. Specifically, removed rosuvastatin 10 mg and 
pravastatin 40 mg from the “Use Discouraged and To Be Used with 
Caution” list.
Clarified that there is no clinically relevant interactions between LEN and 
lopinavir (LPV) with ritonavir (RTV) or cobicistat and darunavir (DRV) 
with RTV, also clarified that the use of these drug(s) is acceptable for PEP.
Section 5.4, Tables 22 and 23
A provision allowing noninjection visits to be performed at an off-site 
location in exceptional circumstances was added. This provision will 
improve the ability to perform rigorous participant follow-up.
Section 6
Protocol language was revised for clarity to explicitly state that PrEP use 
between the Incidence Phase and Randomization is allowable. The use of 
PrEP after Incidence Phase HIV testing has been completed has no impact 
on HIV incidence rate determination, and is an important allowance to 
minimize HIV acquisition risk during the screening period.
Section 6.2.1
Recency assay text was updated to reflect that the assay will be run as 
indicated based on HIV testing results (ie when HIV testing indicates HIV 
infection).
Synopsis, Section 6.2.1, 6.3.1, and 
Appendix 3 (Study Procedure 
Table [Procedures for Incidence 
Phase and Randomized Blinded 
Phase; Footnote ‘j’])
Updated the text to clarify that the SC LEN/placebo administration at 
Week 26/Injection 2, Week 52, and every 26 weeks (± 7 days) are always 
administered 26 weeks (± 7 days) from the prior SC injection.
Sections 6.3.2 and 6.4
Text pertaining to urine storage sample visits was updated to include Oral 
Bridging visit in addition to End of Randomized Blinded Phase visit and 
LEN OLE Day 1 visit to align with the study procedures table.
Sections 6.4 and 6.5
Text was added to clarify that glucose will be collected in a fasting state 
only on visits when metabolic assessments are performed.
Section 6.9.2
The name of the rapid HIV test was corrected to reflect that it is an HIV-1/2 
test. Reflexive RNA quantitative nucleic acid amplification test (NAAT) 
was added for positive rapid HIV-1/2 Ab/Ag tests and central laboratory 
HIV-1/2 Ab/Ag tests occurring after Day 1; this provision was added to 
accelerate the interpretation of discordant HIV tests results (eg, suspected 
false positive rapid HIV-1/2 tests). 
Section 6.13, Appendix 5; 
Appendix 3 - Procedures for 
Incidence Phase and Randomized 
Blinded Phase (Footnote ‘t’), 
Procedures for LEN OLE Phase 
(Footnote ‘r’), Procedure for PK 
Tail Phase (Footnote ‘r’)
Text describing additional HIV testing and ART initiation was reorganized 
for clarity. The revised text allows the investigator to perform additional 
local testing if the participant has a positive local rapid HIV test; this 
provision may allow ART to be initiated more quickly in the case of HIV 
acquisition, which is in the interest of participant wellbeing
Section 6.13
The text pertaining to the performing of recency assays was consolidated 
into separate bullets and revised to clarify that recency assays will be 
performed based on laboratory testing indicative of HIV infection.
Section 6.13
Post-Day-1 HIV diagnosis procedures were revised to clarify that 
participants who have a positive rapid HIV test should not receive injection 
study drug.
Section 6.13

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A provision was added to indicate that participants with a positive rapid HIV 
test after Day 1 may receive injection study drug if central HIV testing, 
including an HIV-1 RNA quantitative NAAT, is negative, ie, in the case of a 
false positive local rapid HIV test.
Section 6.13
Recency assay language was removed from the chart and HIV diagnoses at 
screening since it is not relevant to the determination of study eligibility.
Figure 12
Clarification added to HIV testing strategy and injection restrictions.
Section 6.13
Additional guidance was added to the adverse event reporting procedures to 
clarify the interpretation of Division of AIDS adverse event grading scale 
entries pertaining to injection site reactions.
Sections 7.2.2 and 7.7.1
Updated the language pertaining to injection site reactions (ISRs) of Grade 3 
or higher or persisting for more than 26 weeks to clarify that the investigator 
must contact and discuss the appropriate next steps with the medical 
monitor, that ISRs will be followed until resolution or study completion, and 
that documentation of any ISR evaluation, including photographic 
documentation, may be shared with the sponsor and study team.
Section 7.7.5
Updated to clarify the language pertaining to the primary and secondary 
endpoints; the endpoints were not changed; however the language was 
revised for clarity to distinguish between endpoints (observed at the 
individual participant level) and how each will be estimated and reported at 
the study population level.
Sections 3, 8.1.2.1, 8.1.2.2, 8.1.3
The Interim Analyses of Efficacy Data section was edited for clarity to 
indicate that the interim efficacy analysis will serve as the study’s primary 
analysis in the event that the Randomized Blinded Phase is stopped early 
due to an efficacy outcome.
Section 8.2.1.2
Updated to clarify the criteria for All Screened Set.
Section 8.3.1.1
Updated the language to clarify that LEN plasma concentrations will be 
summarized by timepoint for SC and oral LEN. Additionally, population PK 
analysis of LEN is planned.
Section 8.8
Text was updated to align with the Gilead clinical trial agreement and 
publication policies.
Section 9.2.2
Updated the number of sites.
Synopsis 
The relative standard error was corrected to 6.5 due to a typographical error.
Synopsis, Section 8.9
Timing of visits for each study phase clarified
Appendix 3 (Study Procedures 
Tables)
Clarified timing of routine asymptomatic sexually transmitted infection 
testing is only every 26 weeks for Oral Bridging Visit.
Appendix 3 (Study Procedure 
Tables [Procedures for Incidence 
Phase and Randomized Blinded 
Phase])
Minor changes to correct typographic errors, language, and to provide 
clarifications.
Throughout, as needed

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