A Phase 3, Double-Blinded, Multicenter, Randomized Study to Evaluate Safety and Efficacy of Twice Yearly Long-Acting Subcutaneous Lenacapavir, and Daily Oral Emtricitabine/Tenofovir Alafenamide for Pre-Exposure Prophylaxis in Adolescent Girls and Young Women at Risk of HIV Infection
Phase: PHASE3
Conditions: Pre-Exposure Prophylaxis of HIV Infection
Sponsor: Gilead Sciences

CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3, Double-Blinded, Multicenter, Randomized Study to 
Evaluate Safety and Efficacy of Twice Yearly Long-Acting 
Subcutaneous Lenacapavir, and Daily Oral 
Emtricitabine/Tenofovir Alafenamide for Pre-Exposure 
Prophylaxis in Adolescent Girls and Young Women at Risk of 
HIV Infection
Study Acronym: 
PURPOSE 1
Plain Language Short 
Title:
Pre-Exposure Prophylaxis Study of Lenacapavir and 
Emtricitabine/Tenofovir Alafenamide in Adolescent Girls and 
Young Women at Risk of HIV Infection
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
153858
Not Applicable
NCT04994509
Indication:
Pre-Exposure Prophylaxis of HIV Infection
Protocol ID:
GS-US-412-5624
Contact Information:
The medical monitor name and contact information will be 
provided on the Key Study Team Contact List.
Protocol Version/Date:
Amendment 4: 
10 October 2024
Amendment History:
Original: 
13 January 2021
Original Version 2:
10 March 2021
Amendment 1:
22 November 2021
Amendment 1.1:
06 December 2021
Amendment 2: 
02 February 2022
Amendment 3: 
17 October 2023
High-level summaries of the histories of amendments are 
provided in Appendix 8
GILEAU 

Country-Specific 
Requirements:
Country-specific requirements, as applicable, are listed in 
Appendix 7
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The information contained in this document, particularly unpublished data, is the property or 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 TABLES .........................................................................................................................................6
LIST OF IN-TEXT FIGURES........................................................................................................................................7
PROTOCOL SYNOPSIS................................................................................................................................................9
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................................25
1.
INTRODUCTION................................................................................................................................................30
1.1.
Background..............................................................................................................................................30
1.2.
Study Drugs.............................................................................................................................................31
1.2.1.
Tenofovir Alafenamide (TAF) ..............................................................................................31
1.2.2.
Emtricitabine (FTC; Emtriva) ...............................................................................................34
1.2.3.
Emtricitabine/Tenofovir Disoproxil Fumarate (F/TDF; Truvada)........................................35
1.2.4.
Lenacapavir ...........................................................................................................................35
1.2.5.
Nonclinical Studies in Pregnancy or Lactation .....................................................................72
1.2.6.
Human Studies in Pregnancy.................................................................................................73
1.2.7.
Human Studies in Lactation ..................................................................................................76
1.2.8.
Drug Interaction Potential for F/TAF, F/TDF, and LEN with Hormones.............................77
1.3.
Rationale for This Study..........................................................................................................................79
1.4.
Rationale for Dose Selection of Study Drugs..........................................................................................80
1.5.
Rationale for Oral Weekly Bridging of LEN for Missed SC Injection...................................................82
1.6.
Rationale For Allowing Pregnant Women to Remain on Study Drug ....................................................84
1.7.
Risk/Benefit Assessment for the Study ...................................................................................................85
1.7.1.
Pandemic Risk and Mitigation ..............................................................................................85
1.8.
Compliance..............................................................................................................................................85
2.
OBJECTIVES.......................................................................................................................................................86
2.1.
Incidence Phase Objectives .....................................................................................................................86
2.2.
Randomized Blinded Phase Objectives...................................................................................................86
3.
STUDY DESIGN.................................................................................................................................................88
3.1.
Incidence Phase Endpoint........................................................................................................................88
3.2.
Randomized Blinded Phase Endpoints....................................................................................................88
3.3.
Study Design ...........................................................................................................................................89
3.3.1.
Incidence Phase .....................................................................................................................90
3.3.2.
Randomized Blinded Phase...................................................................................................90
3.3.3.
Lenacapavir Open-Label Extension Phase............................................................................91
3.3.4.
Pharmacokinetic Tail Phase ..................................................................................................92
3.3.5.
Discontinuation Criteria ........................................................................................................93
3.4.
Study Drugs.............................................................................................................................................94
3.5.
Duration of Study Drug Administration..................................................................................................94
3.6.
End of Study............................................................................................................................................94
3.7.
Poststudy Care.........................................................................................................................................95
3.8.
Source Data .............................................................................................................................................95
3.9.
Biomarker Testing...................................................................................................................................95
3.9.1.
Biomarker Samples for 
Future Research................................................................95
4.
PARTICIPANT POPULATION..........................................................................................................................96
4.1.
Number of Participants and Participant Selection...................................................................................96
4.1.1.
Participant Replacement........................................................................................................96
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4.2.
Eligibility Criteria for the Incidence Phase .............................................................................................96
4.2.1.
Inclusion Criteria for the Incidence Phase.............................................................................96
4.2.2.
Exclusion Criteria for the Incidence Phase ...........................................................................97
4.3.
Eligibility Criteria for the Randomized Blinded Phase...........................................................................97
4.3.1.
Inclusion Criteria for the Randomized Blinded Phase ..........................................................97
4.3.2.
Exclusion Criteria for the Randomized Blinded Phase .........................................................97
5.
INVESTIGATIONAL MEDICINAL PRODUCTS.............................................................................................99
5.1.
Randomization, Blinding, and Treatment Codes Access ........................................................................99
5.1.1.
Randomization.......................................................................................................................99
5.1.2.
Blinding .................................................................................................................................99
5.1.3.
Planned Interim Unblinding ................................................................................................100
5.1.4.
Procedures for Breaking Treatment Codes..........................................................................100
5.2.
Description and Handling of Study Drugs ............................................................................................101
5.2.1.
Formulation .........................................................................................................................101
5.2.2.
Packaging and Labeling ......................................................................................................102
5.2.3.
Storage and Handling ..........................................................................................................103
5.3.
Dosage and Administration of Study Drugs..........................................................................................103
5.3.1.
Lenacapavir .........................................................................................................................103
5.3.2.
Emtricitabine/Tenofovir Alafenamide (F/TAF)..................................................................105
5.3.3.
Emtricitabine/Tenofovir Disoproxil Fumarate (F/TDF) .....................................................105
5.4.
Prior and Concomitant Medications......................................................................................................106
5.5.
Accountability for Investigational Medicinal Product ..........................................................................110
5.5.1.
Investigational Medicinal Product Return or Disposal .......................................................110
6.
STUDY PROCEDURES....................................................................................................................................111
6.1.
Participant Enrollment and Study Drug Assignment ............................................................................111
6.2.
Screening Assessments..........................................................................................................................111
6.2.1.
Incidence Phase Screening ..................................................................................................113
6.2.2.
Randomized Blinded Phase Screening................................................................................114
6.3.
Randomized Blinded Phase Assessments .............................................................................................116
6.3.1.
Day 1/Injection 1 Assessments............................................................................................116
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 .....................................................................................................................................118
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 ....................................................................................120
6.5.
Pharmacokinetic Tail Phase Assessments Day 1 and Weeks 13, 26, 39, 52, 65, and 78 (± 7 
days) ......................................................................................................................................................123
6.6.
Unscheduled Visits................................................................................................................................125
6.7.
Post-Study Drug Assessments...............................................................................................................125
6.7.1.
Early Study Drug Discontinuation Visit..............................................................................125
6.7.2.
30-Day Follow-Up Visit......................................................................................................127
6.7.3.
Post-HIV-Infection Follow-Up ...........................................................................................128
6.8.
Assessments for Study Drug Interruptions............................................................................................129
6.8.1.
Criteria for Restarting F/TDF (or Placebo) or F/TAF (or Placebo) After 
an Interruption.....................................................................................................................130
6.8.2.
Criteria for Administering SC LEN Outside of the Target Visit Window 
(26 weeks ± 7 days).............................................................................................................130
6.8.3.
Bridging With Oral LEN/Placebo .......................................................................................131
6.9.
Clinical Laboratory Assessments ..........................................................................................................132
6.9.1.
Urine Samples .....................................................................................................................132
6.9.2.
Blood Samples.....................................................................................................................133
6.10.
End of Study..........................................................................................................................................134

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6.11.
Poststudy Care.......................................................................................................................................134
6.12.
STI Testing ............................................................................................................................................134
6.13.
HIV-1 Infection .....................................................................................................................................134
6.13.1.
Suspected Acute HIV-1 Infection/Postexposure Prophylaxis.............................................137
6.14.
HIV Risk Reduction and Family Counseling........................................................................................138
6.15.
Adherence and Retention ......................................................................................................................138
6.16.
Participant-Reported Questionnaires.....................................................................................................138
6.17.
Pregnancy ..............................................................................................................................................139
6.18.
Social Harms Reporting ........................................................................................................................140
6.19.
Sample Storage......................................................................................................................................140
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT..............................................................................141
7.1.
Definitions of Adverse Events and Serious Adverse Events.................................................................141
7.1.1.
Adverse Events....................................................................................................................141
7.1.2.
Serious Adverse Events.......................................................................................................141
7.1.3.
Study Drugs and Gilead Concomitant Therapy Special Situations Reports .......................142
7.2.
Assessment of Adverse Events and Serious Adverse Events................................................................143
7.2.1.
Assessment of Causality for Study Drugs and Procedures .................................................143
7.2.2.
Assessment of Severity........................................................................................................144
7.3.
Investigator Reporting Requirements and Instructions .........................................................................144
7.3.1.
Requirements for Collection Prior to Study Drug Initiation ...............................................144
7.3.2.
Adverse Events....................................................................................................................144
7.3.3.
Serious Adverse Events.......................................................................................................144
7.3.4.
Study Drug Special Situations Reports ...............................................................................145
7.3.5.
Concomitant Therapy Reports.............................................................................................145
7.4.
Reporting Process for Serious Adverse Events and Special Situation Reports.....................................145
7.4.1.
Serious Adverse Event Reporting Process ..........................................................................145
7.4.2.
Special Situations Reporting Process ..................................................................................146
7.5.
Gilead Reporting Requirements ............................................................................................................149
7.6.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events.........................................................................................................................149
7.7.
Toxicity Management............................................................................................................................150
7.7.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event ................................................150
7.7.2.
Grade 3 Laboratory Abnormality or Clinical Event............................................................150
7.7.3.
Grade 4 Laboratory Abnormality or Clinical Event............................................................151
7.7.4.
Management of Changes in Estimated Glomerular Filtration Rate ....................................151
7.7.5.
Management of Adverse Events of Injection Site Reactions of Grade 3 or 
Higher or Persisting for More Than 26 Weeks ...................................................................151
8.
STATISTICAL CONSIDERATIONS...............................................................................................................152
8.1.
Analysis Objectives and Endpoints.......................................................................................................152
8.1.1.
Analysis Objectives.............................................................................................................152
8.1.2.
Primary Endpoint.................................................................................................................153
8.1.3.
Secondary Endpoints...........................................................................................................153
8.1.4.
8.2.
Planned Analyses...................................................................................................................................154
8.2.1.
Interim Analysis ..................................................................................................................154
8.2.2.
Primary Analysis .................................................................................................................155
8.2.3.
Final Analysis......................................................................................................................155
8.3.
Analysis Conventions............................................................................................................................155
8.3.1.
Analysis Sets .......................................................................................................................155
8.3.2.
Data Handling Conventions ................................................................................................155
8.4.
Demographic and Baseline Characteristics Analysis............................................................................156
8.5.
Efficacy Analysis...................................................................................................................................156
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8.5.1.
Primary Analysis .................................................................................................................156
8.5.2.
Secondary Analyses.............................................................................................................159
8.6.
Safety Analysis......................................................................................................................................160
8.6.1.
Extent of Exposure ..............................................................................................................160
8.6.2.
Adverse Events....................................................................................................................161
8.6.3.
Laboratory Evaluations .......................................................................................................161
8.6.4.
Renal Safety.........................................................................................................................161
8.6.5.
Other Safety Evaluations.....................................................................................................162
8.7.
Adjustments for Multiplicity .................................................................................................................162
8.7.1.
Multiple Alpha-Controlled Hypotheses - Two Experimental Arms ...................................162
8.7.2.
Multiple Analyses - Interim and Primary Efficacy Analyses..............................................163
8.8.
Pharmacokinetic Analysis .....................................................................................................................165
8.9.
Sample Size ...........................................................................................................................................165
8.10.
Data Monitoring Committee..................................................................................................................166
9.
RESPONSIBILITIES.........................................................................................................................................168
9.1.
Investigator Responsibilities .................................................................................................................168
9.1.1.
Good Clinical Practice.........................................................................................................168
9.1.2.
Financial Disclosure ............................................................................................................168
9.1.3.
Institutional Review Board/Independent Ethics Committee Review and 
Approval..............................................................................................................................168
9.1.4.
Informed Consent ................................................................................................................168
9.1.5.
Confidentiality.....................................................................................................................169
9.1.6.
Study Files and Retention of Records .................................................................................169
9.1.7.
Electronic Case Report Forms.............................................................................................171
9.1.8.
Investigator Inspections.......................................................................................................171
9.1.9.
Protocol Compliance ...........................................................................................................171
9.2.
Sponsor Responsibilities .......................................................................................................................171
9.2.1.
Protocol Modifications ........................................................................................................171
9.2.2.
Study Report and Publications ............................................................................................172
9.3.
Joint Investigator/Sponsor Responsibilities ..........................................................................................172
9.3.1.
Payment Reporting ..............................................................................................................172
9.3.2.
Access to Information for Monitoring.................................................................................172
9.3.3.
Access to Information for Auditing or Inspections .............................................................172
9.3.4.
Study Discontinuation .........................................................................................................172
10.
REFERENCES...................................................................................................................................................173
11.
APPENDICES....................................................................................................................................................182
LIST OF IN-TEXT TABLES
Table 1.
Comparison of LEN and GS-CA1...........................................................................................38
Table 2.
GS-US-200-4071: LEN Formulations and Doses Evaluated ..................................................40
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)..................41
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) ...................................................................................................................42
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) ...................................................................................................................44
Table 6.
GS-US-200-4538: Solution Formulations and Doses .............................................................46

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Table 7.
GS-US-200-4538: Summary Statistics of Plasma Pharmacokinetic Parameters LEN, 
309 mg/mL NaS (LEN PK Analysis Set)................................................................................48
Table 8.
GS-US-200-4538: Adverse Events Reported for at Least 4 Participants in Either 
Overall Treatment Group (Safety Analysis Set)......................................................................49
Table 9.
GS-US-200-5709: Summary Statistics of LEN Plasma Pharmacokinetic Parameters 
(Cohort 1) (LEN PK Analysis Set)..........................................................................................50
Table 10.
GS-US-200-5709: Summary Statistics of LEN Plasma Pharmacokinetic Parameters 
(Cohort 2) (LEN PK Analysis Set)..........................................................................................51
Table 11.
GS-US-200-5709: Summary Statistics of LEN Plasma Pharmacokinetic Parameters 
(Cohort 3) (LEN PK Analysis Set)..........................................................................................53
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) ..............................................................56
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)............................................................................................................57
Table 14.
GS-US-200-4333: Preliminary Plasma Pharmacokinetic Parameters of PIT (2 mg) 
Following Administration Alone or With LEN (N = 30-31)...................................................57
Table 15.
GS-US-200-4333: Preliminary Plasma Pharmacokinetic Parameters of ROS (5 mg) 
Following Administration Alone or with LEN (N = 30).........................................................58
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) ..........58
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) .....................................................................................................................59
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)................................................................64
Table 19.
GS-US-200-4334: Study Treatments.......................................................................................68
Table 20.
Oral LEN/Placebo Bridging and SC LEN/Placebo Restart Dosing Schedule.......................104
Table 21.
Missed Oral LEN/Placebo Dose Recommendations During Oral LEN/Placebo 
Weekly Bridging....................................................................................................................105
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 ........................................107
Table 23.
Antiretroviral Medications With Potential Drug-Drug Interactions With LEN....................109
LIST OF IN-TEXT FIGURES
Figure 1.
Similarity of LEN and GS-CA1 Chemical Structures.............................................................37
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).....................................................................................................................................41
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)........................43
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).............................................................44
Figure 5.
GS-US-200-4538: Mean (SD) Plasma Concentration-Versus Time (Part B) (LEN 
PK Analysis Set)......................................................................................................................47
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).....................................................52

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Figure 7.
GS-US-200-4072: Mean and 95% CI Change from Baseline in HIV-1 RNA 
(log10 copies/mL) (Full Analysis Set)......................................................................................61
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)...............................................................................................................................65
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................................81
Figure 10
Simulated Pharmacokinetic Profile of Oral Weekly Bridging of LEN (300 mg) (A) 
Prior to and (B) After Resuming SC Injection ........................................................................82
Figure 11.
Study Schema ..........................................................................................................................90
Figure 12.
Assessments to Determine Enrollment and Randomization Eligibility ................................112
Figure 13.
A High-Level Screening Schema and Contribution of Participants to the Estimation 
of the Background HIV-1 Incidence Rate .............................................................................158
Figure 14.
Overall Testing Procedure.....................................................................................................163
Figure 15.
Testing Procedure at the Interim Analysis.............................................................................164

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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 3, Double-Blinded, Multicenter, Randomized Study to 
Evaluate Safety and Efficacy of Twice Yearly Long-Acting 
Subcutaneous Lenacapavir, and Daily Oral 
Emtricitabine/Tenofovir Alafenamide for Pre-Exposure 
Prophylaxis in Adolescent Girls and Young Women at Risk of 
HIV Infection
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
153858
Not Applicable
NCT04994509
Study Centers Planned:
Approximately 25 centers in South Africa and Uganda
Objectives:
The primary objective of this study is to evaluate the efficacy of 
lenacapavir (LEN) and emtricitabine/tenofovir alafenamide 
(F/TAF) in preventing the risk of human immunodeficiency 
virus-1 (HIV-1) infection relative to the background HIV-1 
incidence rate.
The primary objective for the Incidence Phase of this study is to 
estimate the HIV-1 background incidence rate.
The primary objectives for the Randomized Blinded Phase of this 
study are as follows:
•
To evaluate the efficacy of LEN for HIV-1 pre-exposure 
prophylaxis (PrEP) in Adolescent Girls and Young Women 
(AGYW) at risk of HIV-1 infection
•
To evaluate the efficacy of F/TAF for HIV-1 PrEP in AGYW 
at risk of HIV-1 infection
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 AGYW at risk 
of HIV-1 infection
•
To evaluate the efficacy of LEN for HIV-1 PrEP in AGYW at 
risk of HIV-1 infection in participants adherent to LEN

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• 
To evaluate the efficacy ofF/TAF for HIV-1 PrEP in AGYW 
at risk of HIV-1 infection in paiiicipants adherent to FIT AF 
• 
To compare the efficacy of F/TAF with F/TDF for HIV-1 
PrEP in AGYW at risk of HIV-1 infection 
• 
To evaluate the safety and tolerability of LEN, F/TAF, and 
F/TDF for HIV-1 PrEP in AGYW at risk of HIV-1 infection 
• 
To evaluate the safety and tolerability of LEN and F/TAF for 
HIV-1 PrEP in AGYW 
16 to < 18 yeai·s of age who have sex 
with male paiiners and ai·e at risk for HIV-1 infection 
This is a Phase 3, double-blind, multisite, randomized study to 
compai·e HIV-1 incidence in each of the LEN and F/TAF study 
dmg groups with the nonrandomized contrnl 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 Phase, a LEN Open-label Extension (OLE) 
Phase, and a Phannacokinetic (PK) Tail Phase. 
The Incidence Phase will include initial assessments that will 
provide an estimate of the concmTent background HIV-1 
incidence rate (the counterfactual rate), using an HIV-1 recency 
assay. 
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Participants eligible for the Randomized Blinded Phase will be 
randomized, in a blinded fashion, in a 2:2:1 ratio to receive LEN, 
F/TAF, or F/TDF, respectively. Enrollment of adolescents 
(participants 16 and 17 years of age) will commence following the 
first external data monitoring committee (DMC) meeting, upon 
notification from Gilead Sciences (Gilead).
Number of Participants 
Planned:
Approximately 5010 participants will be randomized in the 
Randomized Blinded Phase.
Target Population:
Cisgender AGYW who have sex with male partners, at risk for 
HIV-1 infection ≥ 16 to ≤ 25 years of age.
Duration of Study Drug 
Administration:
Participants will be given study drugs (LEN, F/TAF, or F/TDF) 
for approximately 52 weeks in the Randomized Blinded Phase and 
LEN in the LEN OLE Phase every 26 weeks 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 daily oral F/TDF. 
Diagnosis and Main 
Eligibility Criteria:
Cisgender AGYW who have sex with male partners, at risk for 
HIV-1 infection, who meet the following criteria:
Incidence Phase (Cross-sectional Study)
•
Age ≥ 16 to ≤ 25 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 (has had ≥ 2 vaginal intercourse encounters 
within the last 3 months) with cisgender male individuals.
•
Prior use of HIV PrEP (including F/TDF) or HIV PEP 
(postexposure prophylaxis) in the past 12 weeks or any prior 
use of long-acting systemic PrEP (including cabotegravir or 
islatravir trials) 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).

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Randomized Blinded Phase
•
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).
•
Hepatitis B virus (HBV) negative or immune.
•
Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min at 
screening according to the Cockcroft-Gault formula for 
creatinine clearance (CLcr).
•
Body weight ≥ 35 kg.
•
Participants with severe hepatic impairment are not allowed.
•
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. NOTE: 
Receipt of routine COVID-19 vaccine is not exclusionary. 
Participation in the qualitative study (GS-US-528-6365) does 
not require sponsor approval.
Study Procedures/
Frequency:
Screening Visit
After providing written informed consent (or assent and/or 
parental/guardian consent as applicable for adolescent girls 
according to local regulations) for the Incidence Phase procedures, 
all eligible individuals will undergo:
•
Blood sample collection for local rapid fourth generation 
HIV-1/2 Ab/Ag testing, 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 sample for virology and 
safety testing.
•
Urine pregnancy test.
•
Participants will be assessed for serious adverse events 
(SAEs), adverse events (AEs), and any concomitant 
medications including prior receipt of a long-acting PrEP 
medication or HIV vaccine.
•
HIV risk reduction counseling, screening for intimate partner 
violence (with appropriate referral when applicable), and 
provision of condoms and lubricant.

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Any participant diagnosed with HIV will receive counseling, be 
referred for HIV-related care, and will be ineligible to screen for 
the Randomized Blinded Phase of the study. 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 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 (and/or assent with parental/guardian consent as 
applicable for adolescent girls according to local regulations) and 
will undergo additional screening procedures. After informed 
consent is provided, additional samples will be collected as 
follows:
•
Blood samples for: HBV and HCV testing, chemistry panel, 
including eGFR calculation, hematology panel, serum 
pregnancy test, and asymptomatic blood syphilis analysis per 
local testing protocol.
•
Urine will be collected for urinalysis, urine protein, and urine 
chemistry, asymptomatic STI testing (for Neisseria 
gonorrhoeae [GC], Chlamydia trachomatis [CT], and 
Trichomonas vaginalis [TV]).
•
Participants will be assessed for SAEs, AEs, and any 
concomitant medications. 
•
HIV risk reduction counseling, screening for intimate partner 
violence (with appropriate referral when applicable), and 
provision of condoms and lubricant. 
•
Individuals will complete a Sexual Risk and Behavior 
Questionnaire. 
•
Screening for intimate partner violence and appropriate 
referral when applicable.
Participants who have a negative local rapid fourth generation 
HIV-1/2 Ab/Ag test but are confirmed to have HIV by central 
testing during the Randomized Blinded Phase screening period 
will be referred for local HIV care and counseling as appropriate, 
thereby becoming ineligible for the Randomized Blinded Phase. 

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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 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 symptoms 
of acute HIV-1 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 2:2:1 (LEN:F/TAF:F/TDF) ratio to 1 of 
the following study drug groups:
•
LEN study drug group (N = 2004):
Subcutaneous (SC) LEN + placebo-to-match (PTM) oral 
F/TAF (n = 1336)
SC LEN + PTM oral F/TDF (n = 668)
•
F/TAF study drug group (N = 2004): 
Oral F/TAF + placebo SC LEN
•
F/TDF study drug group (N = 1002): 
Oral F/TDF + placebo SC LEN
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 (2 tablets). Two 
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/TAF (200/25 mg), 
PTM F/TAF, F/TDF (200/300 mg), or PTM F/TDF to 
self-administer once 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 dose.

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Participants will have study visits on 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, participants will have:
•
Urine sample collection for routine asymptomatic STI testing 
(GC, CT, and TV), urinalysis, urine proteins, urine chemistry, 
urine storage sample, urine pregnancy test.
•
Blood sample collection for chemistry, hematology, metabolic 
profile, 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 rapid 
HIV-1/2 test is positive), DBS storage sample, plasma storage 
sample for virology, safety, and/or PK testing, serum storage 
sample, serum pregnancy testing (in the event of a positive 
urine pregnancy test), local laboratory asymptomatic syphilis 
testing.
•
Participants will undergo a targeted physical exam, vital signs, 
height, weight and waist circumference. 
•
Sexual Risk and Behavior Questionnaire.
•
PrEP Impacts and Administration Preference Questionnaire – 
Day 1.
•
Numeric Pain Rating Scale – Injection Pain (must be 
completed postinjection). 
•
Review and record AEs including screening for any signs and 
symptoms of acute HIV-1 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 and provision of condoms and 
lubricant.
•
Screening for intimate partner violence (with appropriate 
referral when applicable). 
Any participant with signs or symptoms consistent with acute 
HIV-1 infection will undergo Day 1/Injection 1 procedures but 
will not receive study drug until HIV negative status is confirmed 

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by 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, participants will receive the 
following assessments and procedures: 
•
A local rapid fourth generation HIV-1/2 Ab/Ag test.
•
Central laboratory fourth generation HIV-1/2 Ab/Ag test.
•
Urine sample collection for urinalysis, urine proteins, urine 
chemistry, urine storage sample, and urine pregnancy test.
•
Blood sample collection for chemistry and hematology profile, 
eGFR calculation, HIV-1 RNA quantitative NAAT storage 
sample, DBS storage sample, plasma storage sample for 
virology, safety, and/or PK testing, serum storage sample, and 
serum pregnancy test (in the event of a positive urine 
pregnancy test).
•
Questionnaires:
Adherence to Oral Study Product Questionnaire: Weeks 4, 
8, 13, and every 13 weeks thereafter.
Sexual Risk and Behavior Questionnaire: 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 and every 26 weeks 
thereafter at injection visits.
Numeric Pain Rating Scale – Injection Pain (must be 
completed postinjection): Week 26/Injection 2 and every 
26 weeks thereafter at injection visits.
•
Participants will undergo a targeted physical exam, vital signs, 
height, weight and waist circumference. 
•
Review and record AEs including screening for any signs and 
symptoms of acute HIV-1 infection or STIs and changes in 
concomitant medications.
•
Counseling to encourage the importance of attending study 
visits in a timely fashion, daily adherence to study drug, and 
retention. 

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•
HIV risk reduction counseling and provision of condoms and 
lubricant. 
•
Screening for intimate partner violence (with appropriate 
referral when applicable). 
•
At Week 26/Injection 2, Week 52, and every 26 weeks 
thereafter, participants will also receive asymptomatic STI 
testing for GC, CT, TV (urine by central laboratory testing), 
asymptomatic syphilis testing (per local testing protocol), 
metabolic profile, HBV, and HCV testing.
Participants who become pregnant after randomization may 
remain on the study 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 
lactating information. 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/TAF or 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 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 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 LEN becomes available or 
the sponsor elects to discontinue the study, whichever occurs first, 
and will complete study visits as described below.
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 LEN 
injections at the LEN OLE Week 13 and 39 visits and every 
26 weeks thereafter; 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/TAF or F/TDF 
in the Randomized Blinded Phase will switch to SC LEN and have 
study visits at LEN OLE Weeks 4 and 8 (± 2 days), Week 13 
(± 7 days), and every 13 weeks (± 7 days). Subcutaneous LEN will 
be administered at the LEN OLE Day 1 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 continue in the LEN OLE Phase until LEN 
becomes available or the sponsor elects to discontinue the study, 
whichever occurs first. Upon completion of the LEN OLE Phase, 
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.
The following assessments will be performed at the LEN OLE 
Phase study visits: 
•
Urine collection for routine asymptomatic STI testing (GC, 
CT, and TV), urinalysis, urine pregnancy test. 

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•
Blood sample collection for chemistry (every 26 weeks) and 
hematology profile (every 26 weeks); eGFR calculation (every 
26 weeks); 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; HIV-1 RNA quantitative NAAT storage sample; 
plasma storage sample for virology, safety, and/or PK testing; 
serum storage sample; serum pregnancy test (in the event of a 
positive urine pregnancy test).
•
A DBS storage sample will be collected at the End of 
Randomized Blinded Phase visit/LEN OLE Day 1 visit only.
Participants will undergo a targeted physical exam, vital signs, 
height, and weight. 
•
Review and record AEs including screening for any signs and 
symptoms of acute HIV-1 infection or STIs. 
•
Review and record changes in concomitant medications.
•
Counseling to encourage the importance of attending study 
visits in a timely fashion, adherence to study drug injections, 
and retention. 
•
HIV risk reduction counseling and provision of condoms and 
lubricant. 
•
Screening for intimate partner violence (with appropriate 
referral when applicable). 
•
Questionnaires (until and including LEN OLE Week 52): 
Sexual Risk and Behavior 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 (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 services, 
which may include LEN or other available PrEP modalities as 
clinically indicated. If a participant chooses to end participation in 

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the OLE prior to conclusion of the OLE, the participant will 
complete an ESDD visit, be referred to locally available PrEP 
services as clinically indicated, and complete a 30-day follow-up 
visit.
Pharmacokinetic Tail Phase
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/TAF or 
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.
Participants who prematurely discontinue study drug in the 
Randomized Blinded Phase 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). The following assessments will 
be performed at the PK Tail Phase visits:
•
Urine sample collection for routine asymptomatic STI testing 
(GC, CT, and TV), urinalysis, urine proteins, urine chemistry, 
and urine pregnancy test.
•
Blood sample collection 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; plasma storage sample for 
virology, safety and/or PK testing; serum storage sample; 
serum pregnancy test (in the event of positive urine pregnancy 
test). 
•
Participants will undergo a targeted physical exam, vital signs, 
height, and weight. 
•
Review and record AEs including screening for any signs and 
symptoms of acute HIV-1 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. 

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•
HIV risk reduction counseling and provision of condoms and 
lubricant. 
•
Screening for intimate partner violence (with appropriate 
referral when applicable).
•
Questionnaires:
Sexual Risk and Behavior Questionnaire: 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.
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 visit) and oral LEN 
600 mg (2  300 mg tablets) administered on Day 1/Injection 1 
and Day 2. 
F/TAF fixed-dose combination (200 mg emtricitabine/25 mg 
tenofovir alafenamide), administered orally once daily with or 
without food.
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/TAF or 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.
PTM F/TAF, administered orally once daily.

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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:
Safety:
Incidence of treatment-emergent AEs (TEAEs) and 
treatment-emergent clinical laboratory abnormalities to evaluate 
safety and tolerability of LEN, F/TAF, and F/TDF for HIV 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, LEN plasma levels during pregnancy, 
postpartum and in infants, LEN levels in breast milk, drug-drug 
interactions between LEN and hormonal contraceptives.
Adherence:
On-time LEN injection administration.
Adherence to F/TAF or F/TDF assessed using intracellular 
TFV-DP levels in DBS.
Questionnaires:
The following self-reported data will be assessed by 
questionnaires:
1) Adherence
Sexual risk and behavior 
Numeric pain rating scale – injection pain
Experienced preference for PrEP medication 
Administration and dosing for PrEP medication
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 PY) in the LEN and F/TAF 
study drug groups 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 results using an incidence 
estimator similar to Kassanjee, et al {Kassanjee 2012}. The 
incidence rate ratio of the LEN or F/TAF study drug group to the 

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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 or 
F/TAF 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.
A secondary analysis of the primary endpoint will compare the 
HIV-1 incidence rate in the LEN and F/TAF study drug groups 
with a historical and other relevant external HIV-1 incidence rates 
(eg, ECHO and others as they become available).
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 5010 is considered for the study in AGYW. 
With 2004 participants in the LEN (1336 to receive LEN + PTM 
F/TAF and 668 to receive LEN + PTM F/TDF), 2004 in the 
F/TAF, and 1002 in the F/TDF study drug groups, the study will 
have > 95% power to show at least a 20% reduction compared 
with the background HIV-1 incidence rate.
The sample size estimates are based on the following assumptions:
•
Background HIV-1 incidence of 3.00/100 PY.
•
LEN incidence of 0.6/100PY, with an 80% risk reduction.
•
Mean duration of recent infection (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 year.
•
2:2:1 allocation for LEN: F/TAF: F/TDF; the allocation within 
the LEN study drug group is 2:1 for LEN + PTM F/TAF: 
LEN + PTM 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 further refined for the primary analysis. 
An external DMC will evaluate the safety 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. While enrollment will 

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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 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 
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
percentage of AUC extrapolated between AUClast and AUCinf
%CV
percentage coefficient of variation
3TC
lamivudine
Ab
antibody
AE
adverse event
Ag
antigen
AGYW
adolescent girls and young women
AIDS
acquired immunodeficiency syndrome
ALT
alanine aminotransferase
ANOVA
analysis of variance
APR
Antiviral Pregnancy Registry
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
bHIV
background HIV
BIC
bictegravir
BMD
bone mineral density
bNAb
broadly neutralizing antibody
BVY
bictegravir, emtricitabine, tenofovir alafenamide (B/F/TAF; Biktarvy®)
CD
clusters of differentiation
CDC
Centers for Disease Control and Prevention
CGM
cisgender male individuals
CGW
cisgender women
CI
confidence interval
CK
creatine kinase
CLcr
creatinine clearance
Cmax
maximum observed concentration of drug
COBI, C
cobicistat (Tybost®)
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization

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CSR
clinical study report
CT
Chlamydia trachomatis
Ctau
observed drug concentration at the end of the dosing interval
Ctrough
concentration at the end of the dosing interval
CWeek26
concentration at the end of the dosing interval at Week 26
CYP
cytochrome P450
DAIDS
Division of AIDS
DBS
dried blood spot
DDI
drug-drug interaction
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DRV
darunavir
DTG
dolutegravir
DVY
emtricitabine/tenofovir alafenamide (coformulated; Descovy®)
E/C/F/TAF
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (coformulated; Genvoya®)
EC
ethics committee
EC50
half-maximal effective concentration
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EFV
efavirenz
eGFR
estimated glomerular filtration rate
eGFRCG
estimated glomerular filtration rate calculated using the Cockcroft-Gault equation
ESDD
early study drug discontinuation
EU
European Union
EVG, E
elvitegravir (Vitekta®)
F/TAF
emtricitabine/tenofovir alafenamide (coformulated; Descovy®)
FAM
famotidine
FAS
Full Analysis Set
FDA
Food and Drug Administration
FDC
fixed-dose combination
FRR
false recency rate
FTC, F
emtricitabine
FTC/TDF
emtricitabine/tenofovir disoproxil fumarate (coformulated; Truvada®)
GC
Neisseria gonorrhoeae
GCP
Good Clinical Practice
GGT
gamma-glutamyltransferase
GFR
glomerular filtration rate
Gilead
Gilead Sciences/Gilead Sciences, Inc.
GMT
geometric mean trough

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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 lipoproteins
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HIV-1
human immunodeficiency virus type 1
HIV-2
human immunodeficiency virus type 2
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
IMPAACT
International Maternal Pediatric Adolescent AIDS Clinical Trials Network
IND
investigational new drug
INSTI
integrase strand-transfer inhibitor
IQ
inhibitory quotient
IQR
interquartile range
ISR
injection site reaction
IRB
institutional review board
IV
intravenous
IWRS
interactive web response system
IXRS
interactive voice/web response system
LDL
low-density lipoproteins
LEN
lenacapavir
LOCF
last observation carried forward
LPV
lopinavir
M = F
missing = failure
MACDP
Metropolitan Atlanta Congenital Defects Program
MDRI
mean duration of recent infection
MDZ
midazolam
MedDRA
Medical Dictionary for Regulatory Activities
MSM
men who have sex with men
MTCT
mother-to-child transmission
NAAT
nucleic acid amplification test
NGM
norgestimate

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NHP
nonhuman primate
NIH
National Institutes of Health
NOAEL
no observed adverse effect level
NOEL
no observed effect level
NRTI
nucleoside reverse transcriptase inhibitor
NVP
nevirapine
OATP
organic anion transporting polypeptide
OBR
optimized background regimen
OL
open-label
OLE
open-label extension
paEC95
protein-adjusted 95% effective concentration
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD
pharmacodynamic(s)
PEG
polyethylene glycol
PEP
postexposure prophylaxis
P-gp
P-glycoprotein
PI
principal investigator
PIT
pitavastatin
PK
pharmacokinetic(s)
PWH
people with HIV
POC
proof of concept
PopPK
population pharmacokinetic
PrEP
pre-exposure prophylaxis
PT
preferred term
PTM
placebo-to-match
PY
person-years
Q1
first quartile
Q3
third quartile
Q6M
every 6 months
RBP
randomized blinded phase
RIF
rifampin
RNA
ribonucleic acid
ROS
rosuvastatin
rSE
relative standard error
RT
reverse transcriptase
RTV
ritonavir
SAC
Safety Assessment Committee
SAE
serious adverse event
SAHCS
Southern African HIV Clinicians’ Society

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SC
subcutaneous
SD
standard deviation
SDV
source data verification
SHIV
simian/human 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
TBDR
Texas Birth Defects Registry
TDF
tenofovir disoproxil fumarate
TEAE
treatment-emergent adverse event
TFV
tenofovir
TFV-DP
tenofovir-diphosphate
TGW
transgender women
Tmax
time (observed time point) of Cmax
TN
treatment naive
TV
Trichomonas vaginalis
TVD
emtricitabine/tenofovir disoproxil fumarate (coformulated; Truvada®)
UGT
uridine diphosphate glucuronosyltransferase
UPCR
urine protein to creatinine ratio
US
United States
VL
viral load
WHO
World Health Organization

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1.
INTRODUCTION
1.1.
Background
Adolescent girls and young women (AGYW) in sub-Saharan Africa account for approximately 
25% of all new human immunodeficiency virus (HIV) infections globally, and nearly half of the 
approximately 38 million people living with HIV/AIDS are women {UNAIDS 2020}. Despite 
advances in treatment and prevention, HIV/AIDS remains one of the leading causes of death 
among girls worldwide; and in sub-Saharan Africa, it is one of the leading causes of death in 
women up to 60 years of age {World Health Organization (WHO) 2019}. Every week, 
approximately 5500 AGYW become infected with HIV {UNAIDS 2020}. In sub-Saharan 
Africa, 5 in 6 new infections among adolescents 15 to19 years of age, occur in girls. Violence or 
the fear of violence can stop AGYW from negotiating safer sex; accessing HIV, sexual, and 
reproductive health services; and disclosing their HIV status to partners, family members, and 
health providers {UNAIDS 2020}. More than one-third of women around the world have 
experienced physical and/or sexual violence at some time in their lives, and in some regions, 
women who experience violence are 1.5-times more likely to become infected with HIV 
{UNAIDS 2020}. Women may also be about 2-fold more susceptible biologically than men are 
to the acquisition of HIV during penile-vaginal sex {Patel 2014}. Further, previous evidence in 
sub-Saharan Africa showed that HIV infection increases risk of depression {Olley 2003, Olley 
2006, Simbayi 2007} and depression reduces treatment adherence and survival among 
individuals with HIV {Abas 2014, Nakimuli-Mpungu 2012, Rabkin 2008}. A recent study 
examining the association of depressive symptoms with HIV incidence among AGYW in 
South Africa found that the prevalence was almost twice that of a nationally representative 
survey of adults in South Africa {Goin 2019}.
Taken collectively, there is a clear and substantial unmet need for effective HIV prevention 
methods in AGYW. In 2012, the United States (US) Food and Drug Administration (FDA) 
approved Truvada® (emtricitabine and tenofovir disoproxil fumarate [F/TDF]) for pre-exposure 
prophylaxis (PrEP) in adults. Subsequently, F/TDF has been approved for PrEP in several 
sub-Saharan countries including South Africa in 2015 and Uganda in 2016 {Avert 2020}. 
In 2019, Descovy® (emtricitabine and tenofovir alafenamide [F/TAF]) was also approved for 
HIV PrEP in men who have sex with men (MSM) and transgender women (TGW), but its safety 
and efficacy have not been assessed for PrEP in women at risk for HIV acquisition through 
vaginal sex. In HIV endemic setting, high PrEP uptake would significantly reduce HIV 
incidence, and potentially contribute to population-wide HIV control {Grulich 2018, Sullivan 
2018}. Despite the approval of F/TDF for PrEP in all adults, uptake remains low in most of 
sub-Saharan Africa and a large proportion of those who initiated PrEP discontinued medication 
by Month 3 {Chakare 2020, Mugwanya 2019}. A recent study on PrEP persistence in Lesotho 
found that 78% of AGYW who initiated PrEP discontinued it after 1 month despite having a high 
perceived risk for HIV acquisition {Chakare 2020}. Similar discontinuation patterns have been 
observed in AGYW in South Africa, including female sex workers who have access to free PrEP 
services {Eakle 2017}. Reasons given for the high discontinuation rates include unpleasant 
encounters with health providers, medication side effects, medication pill size, a burdensome 
routine of taking daily PrEP, stigma, and lack of partner support.

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The suboptimal uptake of PrEP among AGYW highlights the need for additional PrEP options 
that address the key barriers to broader uptake. Two newer medications, F/TAF (daily oral 
tablets) and lenacapavir (LEN) (6 monthly subcutaneous injection) have the potential to provide 
much-needed new PrEP options for AGYW at risk of HIV-1 acquisition.
1.2.
Study Drugs
1.2.1.
Tenofovir Alafenamide (TAF)
1.2.1.1.
General Information
Tenofovir alafenamide (GS-7340, TAF, or L-Alanine, N-[(S)-[[(1R)-2-
(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]/phenoxyphosphinyl]-, 1-methylethyl ester) is an 
oral prodrug of tenofovir (TFV), a nucleotide analog that inhibits human immunodeficiency 
virus type 1 (HIV-1) reverse transcription. TFV is metabolized intracellularly to the active 
metabolite, tenofovir-diphosphate (TFV-DP), a competitive inhibitor of HIV-1 reverse 
transcriptase (RT) that terminates the elongation of the viral DNA chain. In the development of 
TAF, 3 forms of the drug substance have been used in various studies: GS-7340; GS-734002; 
and GS-734003. GS-734003, the salt form in Descovy, is considered comparable based on 
physical/chemical properties to GS-734002 that has been used in previous studies and several 
ongoing studies.
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.
1.2.1.2.
Nonclinical Studies of F/TAF for Pre-Exposure Prophylaxis
A series of nonhuman primate (NHP) studies have been conducted to evaluate the use of 
emtricitabine (Emtriva®; FTC) and TAF for PrEP and postexposure prophylaxis (PEP), or the 
use of elvitegravir (EVG), cobicistat (COBI), FTC, and TAF (E/C/F/TAF) for PEP. These 
nonclinical efficacy studies support the use of oral FTC and TAF for PrEP of HIV-1 infection 
through receptive vaginal intercourse.
1.2.1.2.1.
Vaginal Challenge NHP Studies
1.2.1.2.1.1.
Efficacy of Intermittent Prophylaxis with TAF and FTC Against Vaginal 
Simian/Human Immunodeficiency Virus (SHIV) Transmission
The Centers for Disease Control and Prevention (CDC) conducted a study to determine whether 
oral F/TAF can prevent vaginal SHIV infection in macaques {Massud 2019}. The study showed 
that F/TAF demonstrates efficacy in a vaginal challenge model in rhesus macaques. Further 
details are provided in the IB for F/TAF.

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1.2.1.3.
Preclinical Pharmacology and Toxicology
1.2.1.3.1.
Primary Pharmacodynamics
TAF is metabolized to TFV, which subsequently undergoes intracellular conversion to the 
disphosphorylated active metabolite, TFV-DP. The intracellular metabolism of TAF and TFV 
are consistent with the 600-fold enhancement in anti-HIV activity in cell culture of TAF over 
TFV. Metabolism of TAF was also studied in different human blood lymphocyte subpopulations, 
clusters of differentiation (CD4)-positive and CD8-positive T-cells, natural killer (NK) cells, 
B-cells, and macrophages/monocytes. Concentration of the active metabolite TFV-DP was 
substantial in all cell populations.
1.2.1.3.2.
Safety Pharmacodynamics
TAF monofumarate (GS-7430-02) has been evaluated to determine potential effects on the 
central nervous system (R990188), renal system (R990186), cardiovascular system (D2000006), 
and gastrointestinal system (R990187). Single doses did not induce pharmacologic effects on the 
central nervous system of the rat (1000 mg/kg), the renal system of the rat (1000 mg/kg), or the 
cardiovascular system of the dog (100 mg/kg). TAF monofumarate reversibly reduced distal 
transit and increased stomach weights at high doses (1000 mg/kg).
1.2.1.4.
Nonclinical Pharmacokinetics
Plasma pharmacokinetics (PK) of the intact prodrug, TAF, following oral administration of 
GS-7340-02 in dogs and monkeys demonstrated rapid absorption with peak plasma 
concentrations between 0.25 and 0.5 hours. Peak TFV plasma concentrations occurred following 
TAF absorption, with TFV Tmax values between 0.25 to 1.7 hours in rats, dogs, and monkeys. 
TFV plasma concentrations declined with a terminal half-life of 11.2 to 16.4 hours in rats 
(fasted), > 24 hours in dogs (fasted), and 8.1 to 12.5 hours in rhesus monkeys.
The tissue distribution and recovery of [14C]-radiolabeled GS-7340-02 was examined in beagle 
dogs. Radioactivity was detected in all tissues except brain. Tissue concentrations were the 
highest in kidney, PBMCs, liver, large intestine, and bile. Significant concentrations of 
TFV-related radioactive material were observed in lymph nodes suggesting that TAF may be 
selectively cleaved to TFV in the cells of the lymphoreticular system.
The primary route of elimination of TFV is renal excretion of unchanged drug based on 
intravenous (IV) studies of TFV. Biliary excretion of TFV in dogs, and fecal elimination of TFV 
in rats and dogs are negligible.
In human systems, TAF is metabolized by hydrolytic cleavage and, to a lesser extent, by 
cytochrome P450 (CYP)3A4 catalyzed oxidation (AD-120-2004). Because of the limited 
metabolism of TAF by CYP3A4, inhibition or induction of this enzyme should have little 
consequence on TAF exposure in vivo. TAF has limited potential to alter CYP enzyme activity 
through inhibition and does not inhibit uridine diphosphate glucuronosyltransferase (UGT)1A1 
function. These features combined with the relatively low plasma exposures of TAF in humans, 
suggest that the potential of TAF to cause or be affected by clinically relevant drug-drug 
interactions is very low.

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1.2.1.5.
Nonclinical Toxicology
TAF monofumarate (GS-7340-02) was evaluated in mice, rats, dogs, and monkeys for treatment 
periods up to 9 months. In chronic studies in rats, bone (atrophy of metaphyseal cancellous bone) 
and kidneys (karyomegaly) were the primary target organs after 26 weeks of treatment. In 
chronic exposure studies in beagle dogs the primary target organs were kidney and bone, and 
nonspecific mononuclear cell infiltrates were seen on histopathology in the lungs, spleen, and 
posterior uvea (eye) of animals in the 12-18 mg/kg group. There were no findings in the eyes of 
dogs treated with lower doses (2 mg/kg and 6 mg/kg), and it was concluded that the no observed 
adverse effect level (NOAEL) in beagle dogs was 2 mg/kg/day.
TAF monofumarate had no discernible electrocardiograph effect at the low dose of 2 mg/kg/day 
in dogs. There were no clear treatment-related effects observed in monkeys following 28 days of 
treatment, including no changes in mitochondrial function. TAF was not genotoxic in either 
in vitro or in vivo assays. In conjunction with the nonclinical data with TDF and the clinical 
experience with TDF and TAF, these toxicology studies support studies in humans of doses up to 
150 mg/day (120 mg free base; the highest anticipated human dose) for chronic treatment.
1.2.1.6.
Clinical Trials of Single Agent Tenofovir Alafenamide (TAF) or Fixed-Dose 
Combination Emtricitabine/Tenofovir Alafenamide (F/TAF)
Clinical trials entailing the use of TAF or F/TAF fixed-dose combination (FDC) are included in 
the F/TAF IB. Clinical trials of particular relevance to the present protocol are included below.
1.2.1.6.1.
Efficacy and Safety of F/TAF
F/TAF for PrEP of HIV Infection
GS-US-412-2055
Study GS-US-412-2055 is an ongoing Phase 3, randomized, double-blind study to evaluate the 
safety and efficacy of F/TAF once daily for PrEP in MSM and TGW who have sex with men and 
are at risk of HIV-1 infection.
A total of 5399 HIV-1 negative MSM and TGW (male at birth) adult participants were 
randomized to receive once daily F/TAF (N = 2700) or FTC/TDF (N = 2699).
After 8756 person-years (PY) of follow-up, 22 participants acquired HIV, with 7 infections on 
F/TAF (HIV incidence rate: 0.16/100 PY, 95% CI: 0.064, 0.330), and 15 infections on FTC/TDF 
(HIV incidence rate 0.34/100 PY, 95% exact CI: 0.191, 0.564). The incidence rate ratio 
(F/TAF over FTC/TDF) was 0.47 (95% CI: 0.19, 1.15; P = 0.003): the upper limit of the 95% CI 
was below the prespecified noninferiority margin of 1.62, confirming the noninferiority of 
F/TAF to F/TDF for HIV prevention.

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Of the 22 participants who were diagnosed with HIV, 5 (1 in F/TAF and 4 in FTC/TDF) were 
suspected to have HIV infection at baseline and 15 had low or undetectable dried blood spot 
(DBS) TFV-DP levels at diagnosis (5 in F/TAF and 10 in FTC/TDF). One F/TAF participant had 
a medium TFV-DP level (474 fmol/punch), and 1 FTC/TDF participant was missing a DBS; the 
imputed level (per prespecified criteria) was high (725 fmol/punch).
Of the 22 participants who acquired HIV, 19 participants met protocol-defined standards and had 
a satisfactory sample available for resistance testing. Four participants (all in the FTC/TDF 
group) had M184V/I mixtures, conferring resistance to FTC; each was suspected to have 
baseline HIV infection. No participant had resistance to TFV.
Statistically significant differences favored FTC/TAF over FTC/TDF at Week 48 for all 6 key 
predefined secondary safety endpoints. FTC/TAF was associated with increases in hip and spine 
bone mineral density (BMD) whereas FTC/TDF was associated with BMD decreases, indicating 
a more favorable bone safety profile of FTC/TAF than that of FTC/TDF. Changes in estimated 
glomerular filtration rate (eGFR) calculated using the Cockcroft-Gault equation and biomarkers 
of proximal tubular injury (urine beta-2-microglobulin and retinol binding protein to creatinine 
ratio) were more favorable in participants taking FTC/TAF compared with FTC/TDF. A lower 
proportion of participants had worsening urine protein to creatinine ratio (UPCR) and a higher 
proportion had improvements in UPCR in the FTC/TAF group compared with the FTC/TDF 
group. Adverse events (AEs) reported during this study were consistent with those reported in 
treatment studies of TAF versus TDF-containing regimens. 
1.2.2.
Emtricitabine (FTC; Emtriva)
Further information regarding FTC is available in the prescribing information, an overview is 
provided below.
1.2.2.1.
General Information
Emtricitabine (5-fluoro-1- [(2R, 5S)-2-(hydroxymethyl)- [1, 3]-oxathiolan-5-yl] cytosine, FTC) 
is an NRTI that has demonstrated potent and selective inhibition of the HIV. In HIV-infected 
adults, FTC is administered as a 200 mg once-daily dose concurrently with other antiretroviral 
(ARV) drugs. The 200 mg FTC capsule formulation was approved by the US FDA for marketing 
on 02 July 2003 and is available under the name Emtriva. In the European Union (EU), 
marketing authorization was granted for both the 200 mg Emtriva capsule formulation and a 
10 mg/mL Emtriva oral solution formulation on 24 October 2003, with indications for the 
treatment of HIV infection concurrently with other ARV agents in both adult and pediatric 
participants. In pediatric participants, the recommended dose of Emtriva is 6 mg/kg once daily 
up to a maximum of 200 mg once daily when administered using the capsule formulation (for 
children weighing > 33 kg), or up to a maximum of 240 mg when administered using the oral 
solution formulation.

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1.2.3.
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 prescribing information for F/TDF (Truvada).
1.2.4.
Lenacapavir
1.2.4.1.
General Information
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.
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 ARV treatment administered monthly or less frequently.
For further information on LEN, refer to the current IB for LEN.
1.2.4.2.
Preclinical Pharmacology and Toxicology
1.2.4.2.1.
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 CD4+ 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.

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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.
1.2.4.2.2.
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 subcutaneous (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, 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 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.

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1.2.4.3.
Efficacy of HIV Capsid Inhibitor in Nonhuman Primate PrEP Model
1.2.4.3.1.
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 model for SIV/SHIV transmission {Tsai 1995}. The model 
uses a repeat rectal challenge in rhesus macaques that has demonstrated prophylactic efficacy of 
TFV (TDF or TAF) ± 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). 
1.2.4.3.2.
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}.
1.2.4.3.3.
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
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F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
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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 
1.2.4.3.4.
Efficacy of GS-CA1 in Nonhuman Primate Vaginal 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.
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: 3-8) 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}.

F/TAF and LEN
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1.2.4.3.5.
Efficacy of GS-CA1 in Nonhuman Primate Rectal Challenge PrEP Study
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 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 to 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).
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). 
1.2.4.4.
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-412-5624 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 
[completed], 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 a completed Phase 2 study of LEN in 
combination with other ARV agents in ARV-naive PWH (GS-US-200-4334).
1.2.4.4.1.
Study GS-US-200-4071
GS-US-200-4071 is a completed Phase 1 study in healthy volunteers evaluating the safety, 
tolerability, and 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.

F/TAF and LEN
Protocol GS-US-412-5624
Final
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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).
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
a
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. 
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).

F/TAF and LEN
Protocol GS-US-412-5624
Final
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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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F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
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LEN PK parameters after 10 daily oral doses of LEN (50 mg/mL solution in capsule) are 
presented in Table 4. Consistent with its t1/2, following 10 days of multiple dosing, the mean 
LEN Cmax and AUC0-24h were at least 10-fold higher than those after a single dose (Table 3 and 
Table 4).
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)
Parameter
Cohort 1; 30 mg (N = 8)
Cohort 2; 100 mg (N = 8)
50 mg/mL solution in capsule
Cmax (ng/mL)
12.2 (17.1)
41.2 (53.8)
Tmax (h)a
3.50 (1.75, 10.0)
4.00 (4.00, 11.0)
AUC0-24h (h•ng/mL)
232 (17.9)
842 (56.5)
LEN = lenacapavir; Q1 = first quartile; Q3 = third quartile
a
Median (Q1, Q3).
Pharmacokinetic 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 administration of LEN oral tablets. Maximal concentrations (Cmax) of LEN were 
achieved approximately 4 to 8 hours postdose (Tmax), and LEN median t1/2 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).
LEN exposure and Tmax were comparable following administration of LEN 300-mg tablets under 
fasted conditions or with a high- or low-fat meal, thereby, supporting dosing of LEN tablets with 
or without food in future clinical studies (Table 5).

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
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CONFIDENTIAL
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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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F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 44
10 October 2024
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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F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
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10 October 2024
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 of 
40 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 events (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 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.

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
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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 
(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.
1.2.4.4.2.
Study GS-US-200-4538
GS-US-200-4538 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 6).
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.

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
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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 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.
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. 
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F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
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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)
Safety Results
Adverse events were reported for 69 of 80 participants (86.3%) who received one 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).

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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).
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.
1.2.4.4.3.
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)
LEN 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 is 23.9 ng/mL (20.4 ng/mL). From Days 0 
to 196, mean percentage coefficient of variation (%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)[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)
134000.5 (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)
LEN 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 inhibitory quotient (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 time to maximal concentration (Tmax) occurred approximately 70 days postdose. Mean 
LEN concentrations were consistently maintained above the efficacious target of IQ4 for the 
dosing interval. Mean concentration (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) 

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AUC0-196 days was 152,884.0 h•ng/mL (56.4%). LEN 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%). LEN 
exposures for the dosing interval as assessed by AUC0-196 days for Cohort 1 and AUC0-182 days 
for Cohort 2 was 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)
24.0 (24.0, 24.0)
4679.4 (4678.9, 4679.9)
Tlast (days)
1.0
195.0
AUC0-182 days (h•ng/mL)
148284.1 (56.6)
%CV = percentage coefficient of variation; LEN = lenacapavir; NaS = sodium salt; PK = pharmacokinetic(s); 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 31r. F'n 2131'1:~lmNl 
Cohiort 2 (N~14); Sknt>Ufht<I 
........... ., ..•.. ,. ..... ,. .............•..•.. ,. .............•..•. . •.. 104, 
-14 
14 
28 
42 
56 
70 
84 
98 
11 2 1 26 
40 1 54 116-8 
182 1 96 
Time (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.

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Preliminary Safety Results
In Cohort 1, a total of 31 participants received at least 1 dose of study drug. The median (first 
quartile [Q1], third quartile [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. 
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%). 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%). 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%) participants 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 

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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. 
1.2.4.4.4.
Study GS-US-200-4333
GS-US-200-4333 is a Phase 1 open-label, parallel design, single and multiple dose, multiple 
cohort study in healthy volunteers evaluating the drug-drug interaction (DDI) potential of LEN. 
Available preliminary data for LEN capsules administered in combination with known strong 
CYP3A/P-glycoprotein (P-gp) inhibitors, darunavir (DRV)/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. 
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. 
Safety data analysis is ongoing.
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.

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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. Safety data 
analysis is ongoing.
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. 

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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 
LEN. Agents were either co-dosed 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. Safety data analysis is ongoing.
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.

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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.
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.

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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.
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 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).
1.2.4.4.5.
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 ART naive or ART experienced but capsid inhibitor naive.

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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.
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
HIV-1 RNA levels 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.

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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)
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).
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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.
1.2.4.4.6.
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; 
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. 

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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.
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 at Week 26 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 at Week 52 were 77.8% (35 of 
45 participants) and 82.2% (37 of 45 participants), respectively.

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Preliminary Pharmacokinetic Results
LEN 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. 
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.

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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
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.
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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.
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 which 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.

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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.
1.2.4.4.7.
Study GS-US-200-4334
Study GS-US-200-4334 is an ongoing, 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 Biktarvy® (BVY; bictegravir, emtricitabine, tenofovir alafenamide 
[B/F/TAF]) 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 BVY 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 BVY group, as follows:
•
LEN total: 136 of 157 participants (86.6%).
•
SC LEN+ (emtricitabine/tenofovir alafenamide [DVY] → TAF): 47 of 52 participants 
(90.4%).
•
SC LEN + (DVY → bictegravir [BIC]): 45 of 53 participants (84.9%).
•
Oral LEN + DVY: 44 of 52 participants (84.6%).
•
BVY: 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 to 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 BVY group (24 of 25 participants) had been exposed to study drug for at 
least 54 weeks. Overall, subcutaneously 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 BVY (total of 
25 participants) groups had any AE by Week 54 (LEN total 87.9%, 138 participants; BVY 
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). 
•
BVY (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 BVY 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 BVY group 
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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).
•
BVY (25 participants): 16.0% (4 participants).
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).
•
BVY (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 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%]).

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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%]).
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.
1.2.5.
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.
1.2.5.1.
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 Investigator’s Brochure).
Tenofovir Alafenamide
Studies in animals have shown no evidence of teratogenicity or an effect on reproductive 
function. In offspring from rat and rabbit dams treated with TAF during pregnancy, there were 
no toxicologically significant effects on developmental endpoints (DESCOVY Investigator’s 
Brochure).
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.
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 

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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.
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 NOAEL for F0 maternal systemic 
toxicity, and the NOEL 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.
1.2.5.2.
Lactation
In animal studies, it has been shown that TFV is secreted into milk. 
1.2.6.
Human Studies in Pregnancy
1.2.6.1.
TDF Use During Pregnancy
The PK of TDF has been studied in pregnant women. In a retrospective 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•h/mL (the 
tenth 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 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.

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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 emtricitabine, 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 
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 
Republic of Uganda Ministry of Health {Ministry of Health (MOH) 2016}, the World Health 
Organization (WHO) {Leslie 2004}, and the US National Institutes of Health (NIH) {AIDSinfo 
2019}.
1.2.6.2.
TAF Use During Pregnancy
The PK of TAF has been studied in pregnant women. PK 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}. TAF levels were 
below the limit of quantification in all 15 cord blood samples tested. TAF 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 trial 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)+FTC/TAF, or DTG+FTC/TDF. Participants 
taking TAF-containing therapy had superior composite pregnancy outcomes: 24% of women 
taking DTG+FTC/TAF had an adverse pregnancy outcome compared with 33% of women taking 
DTG+FTC/TDF or EFV/FTC/TDF {Chinula 2020}.

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Furthermore, advantages of TAF over TDF demonstrated in HIV-1 treatment studies include less 
impact on 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 infants exposed to TDF during maternal ART has been shown {Siberry 
2015}, it is expected that this would be less likely to be the case for TAF-exposed infants 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 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 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 trials.
1.2.6.3.
FTC Use During Pregnancy
The PK data are available on the use of FTC during pregnancy. In the 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}.

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1.2.6.4.
Lenacapavir Use During Pregnancy
There are no human studies of LEN in pregnancy.
1.2.7.
Human Studies in Lactation
1.2.7.1.
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 
emtricitabine exposure to the fetus.
1.2.7.2.
TAF Use While Lactating
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 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}.

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1.2.7.3.
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.
1.2.7.4.
Lenacapavir Use While Lactating
It is not known if LEN is secreted in human breast milk.
1.2.8.
Drug Interaction Potential for F/TAF, F/TDF, and LEN with Hormones
1.2.8.1.
F/TAF and F/TDF
The potential for FTC, TAF, TDF, or TFV (major metabolite of TAF and TDF) to participate in 
drug-drug interactions has been comprehensively evaluated in vitro and in clinical studies during 
clinical development of these agents.
Emtricitabine (FTC) is primarily eliminated via renal excretion as unchanged drug and is not 
subject to enzyme or transporter-based drug-drug interactions. The primary metabolic route of 
TAF and TDF is hydrolase cleavage, a low-affinity and high-capacity system that is not likely to 
be impacted by commonly administered drugs. While TAF is a minor substrate of CYP3A in 
vitro, inhibition or induction of this pathway is not expected to affect its PK.
Both TAF and TDF, but not their major metabolite TFV, are substrates for intestinal efflux 
transporters P-gp and BCRP {DESCOVY 2020, Tong 2007, TRUVADA 2020}. However, the 
results of Phase 1 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. Of note, 
administration of strong P-gp inducers is permitted with F/TDF based on available data {Droste 
2005, TRUVADA 2020}.
While in vitro, TAF, but not TDF or TFV, weakly inhibited CYP3A, the results of the dedicated 
Phase 1 evaluation demonstrated lack of TAF effect on CYP3A activity using MDZ, 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.

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Commonly used hormonal contraceptives contain a combination of estrogens (eg, ethinyl 
estradiol) and progestins (eg, norethindrone, norgestimate [NGM], or levonorgestrel). 
Ethinylestradiol is metabolized via intestinal sulfation, and hepatic CYP3A-mediated 
hydroxylation and glucuronidation. Additionally, efflux transporters P-gp and BCRP may play a 
role in ethinyl estradiol disposition {Kearney 2009, Zhang 2007}. While metabolic pathways of 
progestins are not completely understood, CYP3A is at least partially responsible for oxidative 
metabolism of these agents {Zhang 2018}. Review of available literature suggested the clinically 
relevant drug interactions with hormones as victims of drug-drug interactions are primarily 
observed in the setting of strong CYP3A induction or inhibition. As perpetrators of drug-drug 
interactions, the effect of hormonal contraceptives is generally minor, with a few exceptions that 
involve drugs that undergo metabolism via CYP1A2 and UGT1A4 {Sun 2020}.
In agreement with these data, no alteration in the PK of F/TAF or F/TDF {DESCOVY 2020, 
Kearney 2009, TRUVADA 2020}, ethinyl estradiol/NGM (a representative oral contraceptive) 
or PD markers of efficacy (luteinizing hormone, follicle stimulation hormone, and progesterone) 
was noted on coadministration. Given overlapping metabolism pathways, these results are 
extrapolatable to other hormonal contraceptives {Sun 2020}.
The totality of these data support coadministration of F/TAF or F/TDF with hormonal 
contraceptives {DESCOVY 2020, TRUVADA 2020}.
1.2.8.2.
Lenacapavir
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.
While a dedicated Phase 1 evaluation between LEN and contraceptive hormones 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 database and 
other sources {Zhang 2018}. 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 ethinylestradiol {Calcagnile 2013, DIFLUCAN 2020, 
Townsend 2017, Weber 1996}, which did not warrant dose adjustment, and the use of combined 
oral contraceptives has been allowed in LEN treatment studies.
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.

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Amendment 4
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1.3.
Rationale for This Study
Daily F/TDF has been shown to be highly effective for PrEP and is recommended standard care 
for women at risk for HIV {Centers for Disease Control and Prevention 2018, 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}. Daily adherence is challenging for 
certain at-risk populations including AGYW in sub-Saharan Africa 15 to 25 years of age{Celum 
2019}. In 2018, approximately 84,000 people in East and Southern Africa took PrEP at least 
once, despite the region being home to the largest number of PWH and in which over 
730,000 persons acquired HIV in 2018 {UNAIDS 2019}.
The suboptimal uptake of PrEP among women leaves an unmet need for new PrEP options that 
can overcome the challenges that have been described for the current PrEP options. If found to 
be safe and efficacious, F/TAF and LEN could add important new options for PrEP for 
adolescent girls and women at risk of HIV acquisition, overcoming some of the challenges with 
current PrEP options.
F/TAF has been shown to have noninferior efficacy compared with F/TDF and to have more 
favorable effects on BMD and biomarkers of renal safety when used for PrEP by cisgender male 
individuals (CGM) and TGW who have sex with men {Mayer 2020}. However, its efficacy for 
HIV prevention in cisgender women (CGW) remains unknown. If found to be similarly 
efficacious in CGW, F/TAF would provide an additional PrEP option for transvaginal HIV 
acquisition, particularly for those with risk factors for, or preexisting, renal or bone disease. 
Additionally, the physical attributes of the F/TAF may address some of the acceptability 
concerns surrounding F/TDF, including the larger pill size and the association of taking F/TDF 
with having HIV in some countries {Van der Elst 2013}.
LEN has the potential to add an important additional option for PrEP in CGW at risk of HIV due 
to its PK profile that supports every 6-month (Q6M) subcutaneous injection administration. 
Because LEN does not rely on adherence to a daily oral regimen, LEN could overcome some of 
the barriers to PrEP in CGW, such as stigma and concerns regarding disclosure as well as the 
existing challenges to accessing health services in sub-Saharan Africa, all of which limit uptake 
of PrEP. Long-acting PrEP options such as LEN are expected to be a desirable alternative to 
daily oral F/TDF for current PrEP users who self-identify as wanting less frequent dosing 
{Minnis 2020, van der Straten 2018}. In a study on PrEP modality preferences, young women in 
South Africa and Kenya preferred injectables (64%) over tablets (21%) and rings (15%) {van der 
Straten 2018}. Young women in South Africa have also been found to prefer longer-duration 
injection instead of shorter duration injections or implants (1 year > 6 months > 2 months) 
{Minnis 2020}. Long-acting PrEP will therefore be an important option for AGYW 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, with the potential to increase the uptake of PrEP and to reduce 
new HIV infections on the population level {Coelho 2019}.

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Amendment 4
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1.4.
Rationale for Dose Selection of Study Drugs
The doses of F/TDF FDC (200 mg emtricitabine/300 mg tenofovir disoproxil fumarate) will be 
dispensed to the randomized participants with instructions to administer 1 tablet orally by mouth 
once daily for PrEP. This dose was evaluated in PrEP clinical trials and approved for PrEP in 
several sub-Saharan countries, including Uganda and South Africa.
The dose of F/TAF FDC (200 mg emtricitabine/25 mg tenofovir alafenamide) will be dispensed 
to the randomized participants with instructions to administer one tablet orally by mouth once 
daily for PrEP. This dose was evaluated in the DISCOVER Study and approved for PrEP in 
MSM and TGW in the US.
The rationale for dose selection for LEN in this study is supported by antiviral activity, PK 
and/or 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 
2 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 
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 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 Q6M SC dosing interval.
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 
(2  1.5 mL) administered on Day 1 along with oral tablet doses of LEN 600 mg (2  300 mg 
tablet) 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 

FfTAF and LEN 
Protocol GS-US-412-5624 
Gilead Sciences, Inc. 
Final 
Amendment4 
concentrations within a few days of dosing initiation with exposures maintained throughout the 
duration of the 6-month dosing interval (Figure 9). This is suppo1i ed by preliminaiy PK data 
available through 26 weeks postdose from Study GS-US-200-5709 (Cohort 2; see 
Section 1.2.4.4.3) where the proposed simplified regimen demonstrates good agreement between 
the observed and predicted/simulated data. 
Figure 9. 
A) 
B) 
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 
:::i'100 
E -
C) 
C -
• . ... . .... '" .. 
0 
C 
0 
......., _______________ 23.6 ng/ml (IQ6) 
0 
10 
L ·s;: 
cu 
a. 
(1J 
0 cu 
C 
Q) 
..J 
1-------..--...... ---------
1 
2 
3 
Study Day 
SC 900mg t 
PO600mg t t 
-
..J 
E -
C) 
C: -
z 
w 
..J 
100 
Line= Mean 
Area= 90% Cl 
6 
7 
8 
15.5 ng/ml (IQ4) 
; •••••••••••••••••••••• • • • • • • • • • • • •• • • • •• • • • • • • • • ·4-fold paEC95 (IQ4) 
10----------------
/ 
26 
52 
Day 1 : SC 927mg 
Study Week 
Day 1: PO 600mg 
+ 
+ 
Day 2: PO 600mg ______________ _ 
SC 927mg Q6MO 
paEC95 = protein-adjusted 95% effective concentration from MT-4 cells (3.87 ng/mL); IQ4 = inhibitory quotient of 4; 
IQ6 = inhibito1y quotient of 6; LEN = lenacapavir; CI = confidence interval; SC = subcutaneous; PO = oral 
CONFIDENTIAL 
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Amendment 4
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1.5.
Rationale for Oral Weekly Bridging of LEN 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/pharmacodynamics (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 : 90o/D Cl 
SC 
....,_ 
211 
NL_ ___ 
_,,,_ 
1'030011111 !M 
Line .. Geo. Mean 
ID 
Area • 90Yo Cl 
10 
SC 
2&D 
]& 
62 
"' 
study ~._'"" 
__ 
s_c_•_v_m
_;;_• ___ 

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Gilead Sciences, Inc.
Amendment 4
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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 IQ. 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.
Rationale For Allowing Pregnant Women to Remain on Study Drug
Substantial and urgent unmet need exists for HIV prevention options among pregnant and 
postpartum women. Pregnant and postpartum women are at increased risk of HIV acquisition, 
and incident HIV during pregnancy is associated with increased risk of vertical transmission, 
jeopardizing the health of both mother and fetus {Drake 2014, Graybill 2020, Thomson 2018}. 
Traditionally, pregnant and lactating women have been systematically excluded from clinical 
research of new HIV treatment and prevention options. This exclusion leads to significant delays 
in access to next-generation treatment and prevention options, potentially leading to worse health 
outcomes for pregnant and lactating women and their offspring. Furthermore, traditional 
mechanisms for postapproval assessment of safety during pregnancy such as the Antiviral 
Pregnancy Registry result in the collection of pregnancy safety data in a less scientifically 
rigorous and regulated manner, potentially exposing pregnant and lactating women and their 
offspring to increased risk. These challenges have led clinicians, ethicists and community 
advocates from the WHO, the IMPAACT, and the International AIDS Society and the Pregnancy 
and the HIV/AIDS Seeking Equitable Study (PHASES) Project to call for a paradigm shift from 
a policy of presumptive exclusion of pregnant and lactating women from HIV clinical trials to a 
policy of equitable inclusion {The PHASES Working Group 2020, World Health Organization 
(WHO) 2021}.
With respect to the present study, significant human data exist to support the safety of F/TDF 
and F/TAF in pregnant and lactating women, as outlined in Section 1.2. While LEN has not been 
studied during pregnancy and lactation in humans, preclinical in vitro and animal studies 
assessing genotoxicity, fertility, pregnancy, embryonal and fetal development, parturition, and 
postnatal development have not demonstrated harmful effects of LEN. Furthermore, the clinical 
development of LEN for HIV treatment has demonstrated an overall favorable safety profile of 
LEN. For these reasons, it is appropriate to allow women who become pregnant during the study 
to remain on study drug after discussion of potential risks and benefits and provision of 
additional informed consent.

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1.7.
Risk/Benefit Assessment for the Study
F/TDF PrEP has previously been demonstrated to have high efficacy and favorable tolerability in 
CGW in large randomized controlled trials and is thus expected to have good efficacy and safety 
in adherent participants in this study. F/TAF has been demonstrated to have high efficacy and a 
favorable safety profile for PrEP in MSM and TGW, findings that support potential safety and 
efficacy in CGW at risk for HIV acquisition through vaginal sex. While F/TAF has not been 
studied for PrEP in CGW, HIV treatment studies in this population have demonstrated high viral 
efficacy and a favorable safety profile, including in pregnant women with HIV on F/TAF based 
regimens {Chinula 2020}. 
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 the POC study with LEN in PWH 
has demonstrated high antiviral potency and a favorable safety profile. Moreover, ongoing HIV 
treatment studies will provide a significant database of efficacy and safety data prior to the 
initiation of LEN for PrEP clinical trials. Additionally, early results from NHP low-dose SHIV 
vaginal and rectal challenge models have demonstrated the ability of capsid inhibitors to prevent 
SHIV acquisition at clinically relevant exposures. 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 1.2.4.3). Among human studies, the Phase 1b study 
GS-US-200-4072 assessed the antiretroviral potency of LEN monotherapy in ART-naive PWH. 
Participants in Study 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 antiretroviral activity of LEN (see Section 1.2.4.4.5). In the Phase 2 Study 
GS-US-200-4334, ART-naive 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 1.2.4.4.7 and 
{Gupta 2021}). Similarly, the Phase 2/3 Study GS-US-200-4625 demonstrated good 
antiretroviral efficacy of LEN in participants who were HTE and had multidrug resistance 
(see Section 1.2.4.4.6 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.
1.7.1.
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.
1.8.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice, and all 
applicable regulatory requirements.

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2.
OBJECTIVES
The primary objective of this study is to evaluate the efficacy of LEN and F/TAF in preventing 
the risk of HIV-1 infection relative to the background HIV-1 incidence rate.
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 objectives for the Randomized Blinded Phase of this study are as follows:
•
To evaluate the efficacy of LEN for HIV-1 PrEP in AGYW at risk of HIV-1 infection.
•
To evaluate the efficacy of F/TAF for HIV-1 PrEP in AGYW at risk of 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 AGYW at risk of HIV-1 
infection.
•
To evaluate the efficacy of LEN for HIV-1 PrEP in AGYW at risk of HIV-1 infection in 
participants adherent to LEN.
•
To evaluate the efficacy of F/TAF for HIV-1 PrEP in AGYW at risk of HIV-1 infection 
in participants adherent to F/TAF.
•
To compare the efficacy of F/TAF with F/TDF for HIV-1 PrEP in AGYW at risk of 
HIV-1 infection.
•
To evaluate the safety and tolerability of LEN, F/TAF, and F/TDF for HIV-1 PrEP in 
AGYW at risk of HIV-1 infection.
•
To evaluate the safety and tolerability of LEN and F/TAF for HIV-1 PrEP in AGYW 
≥ 16 to < 18 years of age who have sex with male partners and are at risk for HIV-1 
infection.
CCI
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3_ 
STUDY DESIGN 
3.1. 
Incidence Phase Endpoint 
Final 
Amendment4 
The prirmuy endpoint for the Incidence Phase of this study is the diagnosis of recent HIV-I 
infection. 
The background HIV-I incidence per I 00 PY will be computed based on the recent infection 
testing algorithm using an HIV-I recency assay. 
3.2. 
Randomized Blinded Phase Endpoints 
The prirmuy endpoint for the Randomized Blinded Phase of this study for both prirmuy 
objectives is as follows: 
• 
Diagnosis of HIV-I infection. 
The secondaiy endpoints for the Randomized Blinded Phase of this study ai·e as follows: 
• 
Diagnosis of HIV-I among paiiicipants while adherent to study chug (as defined by medium 
and high TFV-DP concentrntion in DBS at the time of HIV-I diagnosis for the F/TAF and 
F/TDF study drng groups, and by LEN on-time administration in the past 26 weeks for the 
LEN study chug group). 
• 
OccmTence of treatment-emergent AEs (TEAEs) and treatment-emergent clinical laborato1y 
abnonnalities to evaluate safety and tolerability of LEN, F/TAF, and F/TDF for HIV-I PrEP. 
I 
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3.3.
Study Design
This is a Phase 3, double-blind, multisite, randomized study to compare HIV-1 incidence in each 
of the LEN and F/TAF study drug groups 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 PK Tail Phase. Participants eligible for the Randomized Blinded Phase will be randomized in a 
2:2:1 ratio to receive LEN, F/TAF, 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. 
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Figure 11.
Study Schema
F/TAF = emtricitabine/tenofovir alafenamide; F/TDF = emtricitabine/tenofovir disoproxil fumarate; LEN = lenacapavir; 
OLE = open-label extension; PK = pharmacokinetic; 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. In the case that the Randomized Blinded Phase is 
stopped early for an efficacy outcome, some participants may have less than 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/TAF or 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.
d
Week 4 and 8 visits are only required for participants who were randomized to oral F/TAF or F/TDF in the Randomized 
Blinded Phase.
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 an HIV-1 recency 
assay algorithm.
3.3.2.
Randomized Blinded Phase
All eligible participants will receive study drug and attend visits 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 remain at the study site for observation for at least 30 minutes 
after each SC injection dose. Two 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. 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. Subsequently, SC LEN or placebo SC LEN will be 
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of 
Study 

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administered every 26 weeks (± 7 days). Participants will also receive oral F/TAF (200/25 mg), 
PTM F/TAF, F/TDF (200/300 mg), or PTM F/TDF to self-administer daily starting on 
Day 1/Injection 1. 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/TAF or 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 (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 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 
first open-label LEN injections at the LEN OLE Day 1 visit).

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Participants randomized to F/TAF or F/TDF in the Randomized Blinded Phase will switch to SC 
LEN and have study visits at LEN OLE 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. 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.
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 OLE prior to conclusion 
of the OLE, the participant will complete an ESDD visit, be referred to locally available PrEP 
services as clinically indicated, and complete a 30-day follow-up visit.
3.3.4.
Pharmacokinetic Tail Phase
Participants who prematurely discontinue study drug in the Randomized Blinded Phase 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/TAF or 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 
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/TAF or 
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 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 

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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.
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 permanently 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.
•
Participant request to discontinue for any reason.
Study drug may be discontinued as applicable in the following instances:
•
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).
•
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).

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3.4.
Study Drugs
Approximately 5010 participants who meet all eligibility criteria will be randomized in a 
2:2:1 ratio (LEN:F/TAF:F/TDF) into 1 of the following study drug groups:
•
LEN study drug group (N = 2004):
SC LEN + PTM oral F/TAF (n = 1336); loading dose on Day 1/Injection 1 and Day 2 of 
Randomized Blinded Phase only: oral LEN 600 mg (2  300 mg tablets)
SC LEN + PTM oral F/TDF (n = 668); loading dose on Day 1/Injection 1 and Day 2 of 
Randomized Blinded Phase only: oral LEN 600 mg (2  300 mg tablets)
•
F/TAF study drug group (N = 2004):
Oral F/TAF + 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)
•
F/TDF study drug group (N = 1002): 
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 and continue 
study visits until LEN becomes available or the sponsor elects to discontinue the study, 
whichever occurs first, as described in Section 3.3.3.
Participants transitioning to the PK Tail Phase will receive F/TDF for up to 78 weeks as 
described in Section 3.3.4.
3.6.
End of Study
End of study is defined as the last participant’s last observation (last visit).

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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
3.9.1.
Biomarker Samples for 
Future Research
In addition to the study-specific informed consent to be signed by each participant in the study, 
participants will be required to document additional consent to allow the use of the remainder of 
their already collected blood and urine specimens for 
 future research, in accordance 
with applicable regulations.
The specimens collected for 
 future research may be used to advance development of the 
drug and/or increase our knowledge and understanding of the biology of prevention of HIV-1 
infection and related diseases. These specimens may also be used to study the association of 
biomarkers with biological pathways, treatment outcomes, including efficacy, AEs, and the 
processes of drug absorption and disposition. In addition, these specimens may be used to 
develop biomarker and/or diagnostic assays and establish the performance characteristics of 
these assays. The collection and analysis of 
 future research specimens may facilitate the 
design of new pharmaceutical agents and the development of diagnostic tests, which may allow 
for individualized drug therapy for patients in the future.
Blood and urine samples will be collected as described in Sections 6.9.1, 6.9.2, and Appendix 3.
The specimens for 
 future research will be destroyed no later than 15 years after the end 
of study or per country requirements.
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4.
PARTICIPANT POPULATION
4.1.
Number of Participants and Participant Selection
The study includes a cross-sectional study (Incidence Phase), a Randomized Blinded Phase, a 
LEN OLE Phase, and a PK Tail Phase.
The Incidence Phase of the study will remain open until the background HIV-1 incidence rate 
has been determined. Approximately 5010 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.
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 adolescent girls, 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 adolescent girls (in 
accordance with local laws and regulations).
2) Cisgender AGYW.
3) Age ≥ 16 to ≤ 25 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 initial screening and no prior HIV-1 testing within the last 
3 months.
5) Sexually active (has had ≥ 2 vaginal intercourse encounters within the last 3 months) with 
CGM.
6) Willing and able to comply with study procedures.

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4.2.2.
Exclusion Criteria for the Incidence Phase
1) 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).
2) Prior use of HIV PrEP (including F/TDF) or HIV PEP (postexposure prophylaxis) in the past 
12 weeks or any prior use of long-acting systemic PrEP (including cabotegravir or islatravir).
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) 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 randomized in 
the Randomized Blinded Phase.
1) Negative local rapid fourth generation HIV-1/2 Ab/Ag test, central fourth generation 
HIV-1/2 Ab/Ag, and HIV-1 RNA quantitative nucleic acid amplification testing (NAAT) 
(Appendix 6).
2) Estimated GFR ≥ 60 mL/min at screening according to the Cockcroft-Gault formula for CLcr 
{Cockcroft 1976}:
(140 − age in years) × (wt in kg)  [0.85 if female]  CLcr (mL/min)
72 × (serum creatinine in mg/dL)
3) Body weight ≥ 35 kg.
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. 
NOTE: Receipt of routine COVID-19 vaccine is not exclusionary. Participation in the 
qualitative study (GS-US-528-6365) does not require sponsor approval.
2) Known hypersensitivity to the study drug, the metabolites, or formulation excipient.

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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), 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 an 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.
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) Women who are pregnant or lactating prior to administration of the first study drug dose.
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
Study 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 
provided that all eligibility criteria have been confirmed.
5.1.1.
Randomization
Participants who meet all the Randomized Blinded Phase eligibility criteria will be randomized 
in a 2:2:1 ratio to active LEN, once daily oral F/TAF, 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 
a 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 IXRS for 
that participant. In case of technology failure, the investigator will contact the support line of the 
IXRS provider directly. After proper identification of user credentials, the support personnel will 
provide the treatment assignment to the investigator 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 assignment 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 
study drug discontinued and moved to 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, polyethylene glycol, 
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, polyethylene glycol, polyvinyl alcohol, talc and 
titanium dioxide, iron oxide red, iron oxide black, and iron oxide yellow.
5.2.1.2.
Emtricitabine/Tenofovir Alafenamide (F/TAF)
Emtricitabine 200 mg/tenofovir alafenamide 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 emtricitabine 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.
PTM F/TAF 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. PTM F/TAF tablets contain the 
following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose 
sodium, magnesium stearate, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and 
FD&C blue #2/indigo carmine aluminum lake.
5.2.1.3.
Emtricitabine/Tenofovir Disoproxil Fumarate (F/TDF)
Emtricitabine 200 mg/tenofovir disoproxil fumarate 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 emtricitabine 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.

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 102
10 October 2024
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.
5.2.2.
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, EU Guideline for Good Manufacturing 
Practice - Annex 13 (Investigational Medicinal Products), and/or other local regulations.
5.2.2.2.
Emtricitabine/Tenofovir Alafenamide (F/TAF)
F/TAF tablets and PTM F/TAF tablets are packaged in a white HDPE 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 FDA, EU Guideline for Good Manufacturing 
Practice - Annex 13 (Investigational Medicinal Products), and/or other local regulations.
5.2.2.3.
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 for Good Manufacturing 
Practice - Annex 13 (Investigational Medicinal Products), and/or other local regulations.

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 103
10 October 2024
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.
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 Alafenamide (F/TAF)
F/TAF tablets and PTM 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.
5.2.3.3.
Emtricitabine/Tenofovir Disoproxil Fumarate (F/TDF)
F/TDF tablets and PTM F/TDF tablets should be stored at a controlled room temperature of 
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.
5.3.
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

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
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10 October 2024
•
LEN OLE Phase
SC LEN 927 mg (2  1.5 mL injections) every 26 weeks 
Loading dose for participants randomized to F/TAF or 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.
5.3.1.2.
Dosage and Administration of Oral Weekly Bridging of LEN
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.

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 105
10 October 2024
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 (See Section 6.8.2)
LEN = lenacapavir
5.3.2.
Emtricitabine/Tenofovir Alafenamide (F/TAF)
F/TAF (200/25 mg) tablets and PTM F/TAF 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/TAF or PTM F/TAF each day.
5.3.3.
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.

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 106
10 October 2024
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 drugs on the study due to potential DDIs 
with LEN, F/TAF, or F/TDF. Antiretroviral medications with potential drug-drug interactions 
with LEN are listed in Table 23.
Data from clinical pharmacokinetic interaction studies of F/TAF and F/TDF have demonstrated 
that there is no reduction in the clinical efficacy of hormonal contraception. Based on in vitro 
and in vivo DDI liability assessment, a clinically significant DDI with LEN and hormonal 
contraceptives is not expected (see Section 1.2.8).

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 107
10 October 2024
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/TAF; F/TDF
-
-
Anticoagulants
Dabigatran etexilate: monitoring and/or 
dose reduction may be needed for certain 
populations per prescribing information
LEN
-
-
Anticonvulsants
-
-
Carbamazepine, oxcarbazepine, 
phenobarbital, phenytoin
F/TAF; LEN
Antimycobacterials
Clarithromycin: may increase 
concentration of TAF and/or TFV
F/TAF; F/TDF
Rifampin, rifabutin, rifapentine
F/TAF; LEN
Antifungals
Systemic itraconazole, ketoconazole, 
voriconazole: may increase concentration 
of TAF and/or TFV
F/TAF; F/TDF
-
-
Calcium channel 
blockers
Diltiazem, felodipine, verapamil: 
may increase concentration of 
TAF and/or TFV
F/TAF; 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/TAF; 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/TAF; F/TDF; 
LEN
Hepatitis C 
therapies
Ledipasvir/sofosbuvir: has been shown to 
increase TFV exposure
F/TAF; F/TDF
Boceprevir, telaprevir
F/TAF; F/TDF

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 108
10 October 2024
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/TAF; F/TDF
Systemic chemotherapeutic agents, systemic 
aminoglycoside antibiotics, amphotericin B, 
systemic cidofovir, cisplatin, foscarnet, 
IV pentamidine, or other agents with 
significant nephrotoxic potential
F/TAF; F/TDF
Other
-
-
Probenecid
F/TAF; F/TDF
Phosphodiesterase-5 
(PDE-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; F/TDF = emtricitabine/tenofovir disoproxil fumarate; HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A; IV = intravenous; 
LEN = lenacapavir; TFV = tenofovir

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
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10 October 2024
There are no substantial safety data regarding the concomitant administration of the coronavirus 
disease 2019 (COVID-19) vaccines and the study drugs. Participants are allowed to receive the 
COVID‑19 vaccine, and study visits should continue as planned if vaccination occurs while the 
participant is on the study. When possible, COVID-19 vaccines should not be administered 
within one week of study drug injections. 
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; ETV = etravirine; EVG = elvitegravir; FTC = emtricitabine; INSTI = integrase strand 
transfer inhibitor; LEN = lenacapavir; LPV = lopinavir; NNRTI = nonnucleoside reverse transcriptase inhibitor; 
NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; PEP = postexposure prophylaxis; RAL = raltegravir, 
RPV = rilpivirine; RTV = ritonavir; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate
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 antiretroviral medications, then the ARVs which reduce 
LEN concentrations (EFV, etravirine [ETV], nevirapine [NVP], lopinavir [LPV] with cobicistat, 
and DRV with ritonavir [RTV]) 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.

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 110
10 October 2024
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 an on-site monitoring visit.

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
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10 October 2024
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 noninjection 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.

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
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10 October 2024
Figure 12.
Assessments to Determine Enrollment and Randomization Eligibility
Ab = antibody; Ag = antigen; HIV = human immunodeficiency virus; HIV-1/2 = human immunodeficiency virus type 1/type2; 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.
lncideoce Phase Screening 
• Cl>tam informed ronsent 
• Coofirm initial eligibility: 
-
Geooer- arnd age oiteria 
-
Sexual behavior criteria 
-
Rior- HIV testing criteria 
• ObtaiJ11 demographic informatioo 
• PerfOl'"Jlll local rapid 4th 
generation HIV-1/2Ab/Ag test 
• Cdllect blood for lab analyses 
arnd ~torage safll)les 
Ra.pi d 
Randomized 
HIV O -
Phase'> 
Ra,pid 
Hl'r O I 
Obtairn Ranmmized Blinded 
AU eligih"lit.y 
criteria met. 
Central HIV 0 
Accepts 
Phase (RBP) "nf<nned consent r---i------=-
___ 
_, --
Complete REP assessments 
Declines 
Central HIVe, 
[see 6.2.2) 
Ce11tral HIV 0 
Central HIV O >------+- Refell'al to loca Ly 
available PrEP 
services 
-
Central HIV 0 
Referral to 
locally 
avail.able 
RrEP 
~rvices 
Central H VO ,_I------- Counseling and referral for HIV care 
Froceed to Day 1 
proatlires and 
randomizatioo 

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
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10 October 2024
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. 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). Rescreening will not be allowed. 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 initial 
screening:
•
Obtain written informed consent (or assent and/or parental/guardian consent as applicable 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 (including socioeconomic information), and medical 
history.
•
Query on sexual activity with CGM.
•
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 and provision of female and male 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 current 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 (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, reflexively 
confirmed by HIV-1/2 differentiation assay and HIV-1/2 RNA NAAT, if the fourth 
generation test and differentiation assay results are discrepant (refer to Appendix 6).
HIV-1 RNA quantitative NAAT.
HIV-1 recency assay (run as indicated based on HIV test results).
DBS storage sample.
Plasma storage sample for virology and safety testing.
CD4 cell count (run only if local 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 6.12) and study participation will 
conclude. If the local rapid fourth generation HIV-1/2 Ab/Ag test is negative, participants will be 
counseled on other HIV prevention options which may include proceeding to complete the 
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 the participants’ local rapid fourth generation HIV-1/2 Ab/Ag test is negative, urine pregnancy 
test is negative, and the Incidence Phase criteria are met, participants can be screened for the 
Randomized Blinded Phase if additional consent is obtained. Exclusionary screening laboratory 
assessments will not be repeated unless the protocol indicates retest is required or if assay failure 
is suspected. 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.
•
Urine collection (see Section 6.9.1) for:
Routine asymptomatic STI testing for GC, CT, and Trichomonas vaginalis (TV).
Urinalysis, urine proteins, urine chemistry.

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•
Blood collection (see Section 6.9.2) for:
Chemistry and hematology profile.
eGFR calculation.
HBV testing.
HCV testing.
Serum pregnancy testing.
Local laboratory asymptomatic syphilis testing.
•
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 condoms and lubricant (only if Incidence 
Phase screening occurs on a separate day).
•
Screening for intimate partner violence and appropriate referral when applicable.
•
Sexual Risk and Behavior Questionnaire.
Participants who 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 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.

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6.3.
Randomized Blinded Phase Assessments
6.3.1.
Day 1/Injection 1 Assessments
The following assessments are to be completed at the Day 1/Injection 1 visit. 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-1 infection.
•
Urine collection (see Section 6.9.1) for: 
Routine asymptomatic STI testing for GC, CT, and TV
Urinalysis, urine proteins, urine chemistry
Urine storage sample
Urine pregnancy test
•
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 6)
HIV-1 RNA quantitative NAAT
HIV-1 recency assay (run as indicated based on HIV test results)
CD4 cell count (run 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 
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.
•
Participants will be treated for STIs per local guidelines.

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•
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 and changes in concomitant medications.
•
Targeted (symptom directed) physical examination.
•
Vital signs, 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: 
Sexual Risk and Behavior Questionnaire. 
PrEP Impacts and Administration Preference Questionnaire – Day 1.
Numeric Pain Rating Scale – Injection Pain (must be completed postinjection).
•
Enrollment into the Randomized Blinded Phase and randomization in IWRS.
•
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) or F/TAF (or placebo)
One week (± 2 days) after each injection visit, participants will be contacted for a 
post-injection follow-up assessment and to confirm the participant has taken the Day 2 
dose.
•
Participants should be observed for approximately 30 minutes after each SC injection 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 and provision of male and female 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.
•
Family planning and contraception counseling, per local standard of care.
•
Screening for intimate partner violence and appropriate referral when applicable.

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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, 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-1 infection or STI.
•
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, CT, and TV (Week 26/Injection 2, Week 52, 
and every 26 weeks thereafter).
Urinalysis, urine proteins, urine chemistry.
Urine storage sample.
Urine pregnancy test.
•
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).

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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 6).
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.
Serum pregnancy testing (in the event of a positive urine pregnancy test).
Local laboratory asymptomatic syphilis testing (Week 26/Injection 2, Week 52, and 
every 26 weeks thereafter).
Note: For participants diagnosed with HIV after receiving study drug, refer to Section 6.13.
•
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.
Sexual Risk and Behavior Questionnaire: 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 and 
every 26 weeks thereafter at injection visits.
Numeric Pain Rating Scale – Injection Pain (must be completed postinjection): 
Week 26/Injection 2 and every 26 weeks thereafter at injection visits.
•
HIV risk reduction counseling and provision of male and female 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.

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•
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.
SC LEN/placebo administration at Weeks 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 SC injection dose. 
•
One week (± 2 days) after each injection, participants will be contacted for a post-injection 
follow-up assessment. 
•
Family planning and contraception counseling per local standard of care.
•
Screening for intimate partner violence and appropriate referral when applicable.
•
For mothers who reconsent to participate in the lactation and infant PK exploratory subset 
analysis, breast milk and infant plasma samples may be collected (in addition to the maternal 
plasma) at the next 2 protocol-scheduled visits postdelivery.
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 during 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 the 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-1 infection or STI.
•
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):
Routine asymptomatic STI testing for GC, CT, and TV (End of Randomized Blinded 
Phase visit/LEN OLE Day 1 and every 26 weeks thereafter).
Urinalysis.
Urine pregnancy test.
•
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).
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 6).
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.
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 26 weeks thereafter).
Note: For participants diagnosed with HIV after receiving study drug, refer to Section 6.13.
•
Participants will be treated for STIs per local guidelines.

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•
Questionnaires (until and including LEN OLE Week 52):
Sexual Risk and Behavior 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 Questionnaire: 13 weeks 
after each injection visit.
Experienced Preference for PrEP Medication Questionnaire: every injection visit.
Numeric Pain Rating Scale – Injection Pain (must be completed postinjection): every 
injection visit.
Adherence to Oral Study Product Questionnaire: End of Randomized Blinded Phase 
visit/LEN OLE Day 1 only.
•
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/TAF or F/TDF).
•
Drug dispensation.
LEN administration if participant agrees to take part in the LEN OLE Phase. Participants 
who were randomized to F/TAF or 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 LEN 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/TAF or 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 post-injection 
follow-up assessment. Any AEs reported by the participant will be recorded. 
•
HIV risk reduction counseling, including provision of 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.
•
Family planning and contraception counseling per local standard of care.

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•
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.
•
For mothers who reconsent to participate in the lactation and infant PK exploratory subset 
analysis, breast milk and infant plasma samples may be collected (in addition to the maternal 
plasma) at the next 2 protocol-scheduled visits postdelivery.
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). 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 the participant is < 20 years of age.
•
Review and record AEs per Section 7.3 and 7.3.2, including screening for any signs and 
symptoms of acute HIV-1 infection 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, CT, and TV (PK Tail Day 1 and every 26 
weeks thereafter).
Urinalysis, urine proteins, urine chemistry
Urine pregnancy test.
•
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.

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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 6).
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 test is positive, collect DBS.
Anytime plasma PK sample.
Plasma storage sample for virology, safety, and/or PK testing.
Serum storage sample.
Serum pregnancy testing (in the event of a positive urine pregnancy test).
Local laboratory asymptomatic syphilis testing (PK Tail Day 1 and every 26 weeks 
thereafter).
Note: For participants diagnosed with HIV after receiving study drug, refer to Section 6.13.
•
Questionnaires: 
Sexual Risk and Behavior Questionnaire: 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 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.

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•
HIV risk reduction counseling, including provision of male and female 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.
•
Family planning and contraception counseling per local standard of care.
•
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 rapid 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.

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The following assessments occur at the ESDD visit:
•
Targeted (symptom directed) physical examination, if clinically indicated, vital signs, and 
weight.
Waist circumference (only for Randomized Blinded Phase).
Height 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-1 infection or STIs, and changes in concomitant medications.
•
Urine sample collection (see Section 6.9.1) for:
Urinalysis, urine proteins, urine chemistry.
Urine pregnancy test.
•
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, 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 6).
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.
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).

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Experienced preference for PrEP Medication Questionnaire (if ESDD occurs during the 
LEN OLE Phase).
Sexual Risk and Behavior Questionnaire (at ESDD during any phase).
•
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 and provision of female and male condoms and lubricant. Participants will be 
educated on the signs and symptoms of acute HIV infection and will be instructed to call 
and/or present to the site for evaluation and HIV testing if they develop such symptoms. 
•
Family planning and contraception counseling per local standard of care.
•
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 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.
•
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, and 
weight.
Waist circumference (only for Randomized Blinded Phase).
Height if the 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-1 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, CT, and TV.
Urinalysis, urine proteins, urine chemistry.
Urine pregnancy test.
•
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 6).
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.
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.
•
Participants will be treated for STIs per local guidelines.
•
For participants not discontinuing due to HIV infection, provide HIV risk reduction 
counseling and provision of female and male condoms and lubricant. Participants will be 
educated on the signs and symptoms of acute HIV infection and will be instructed to call 
and/or present to the site for evaluation and HIV testing if they develop such symptoms.
•
Family planning and contraception counseling per local standard of care.
•
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 at 30 days (± 14 days) and 90 days (± 14 days) after confirmed HIV 
infection.

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6.7.3.1.
30-Day Post-HIV-Infection Follow-Up
The following assessments are to be completed at the 30-day follow-up visit:
•
Assessments in Section 6.7.2, except for the fourth generation HIV-1/2 Ab/Ag test, HIV-1 
RNA NAAT storage sample, and DBS.
•
CD4 cell count.
•
HIV resistance genotype (this will be performed only if genotype was not already collected at 
time of infection).
•
HIV-1 VL 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 VL 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 count and HIV-1 
VL data are not available, the participant will be requested to attend a site visit for laboratory and 
data collection.
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 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.
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).

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6.8.1.
Criteria for Restarting F/TDF (or Placebo) or F/TAF (or Placebo) After an 
Interruption
If a participant interrupts study drug 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, the diagnosis should be confirmed per 
Appendix 6 and the participant should be referred to care (Section 6.13).
Upon testing negative for the local rapid fourth generation HIV-1/2 Ab/Ag test, the 
participant may restart study drug dosing while pending the central laboratory HIV-1/2 
tests (Appendix 6), at the investigator’s discretion.
•
Blood sample collection for the following central laboratory analyses:
Central HIV-1/2 testing (Appendix 6).
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)
All study visits, including injection visits, should be conducted within the target visit window. In 
the event this is not possible for an injection visit, visits after the target dates may be completed 
with the guidance below. Study drug injections must not be given before the target visit window.
•
If the participant is past the target visit window (26 weeks + 7 days) but ≤ 28 weeks have 
elapsed since the last study drug injection, the scheduled administration of injection study 
drug may be given and future injection visits should be planned every 26 weeks thereafter.
•
If the participant is past the target visit window (26 weeks + 7 days) and > 28 weeks have 
elapsed since the last study drug injection, administration of injection study drug is allowed 
at the investigator’s discretion. Before treatment is resumed, the following procedures should 
be followed:
Local rapid fourth generation HIV-1/2 Ab/Ag.
○
If the result for the rapid testing is positive, diagnosis should be confirmed per 
Appendix 6 and participant should be referred to local HIV care (Section 6.13).

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Blood sample collection for the following central laboratory analyses:
○
Central HIV-1/2 testing (Appendix 6).
○
HIV-1 RNA quantitative NAAT and sample collection for possible genotypic 
resistance testing.
If rapid fourth generation HIV-1/2 Ab/Ag testing is negative, the participant may 
reinitiate study drug by administration of oral LEN/placebo (reloading dose: 2 pills on the 
first day and 2 on the next day) and injection LEN/placebo as described for 
Day 1/Injection 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 permitted with medical monitor approval. 
If oral LEN/placebo bridging is initiated during the Randomized Blinded Phase, the participant 
will receive blinded oral LEN or PTM oral LEN aligned with their original study drug 
assignment, taken once weekly. Participants will continue to take daily oral F/TDF or PTM 
F/TDF during LEN/placebo bridging (ie, participants will receive active study drug and placebo).
If oral LEN bridging is initiated during the LEN OLE Phase, the participant 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 are listed below:
•
The site will obtain permission from the medical monitor prior to initiating LEN/placebo 
bridging.
•
The participant will return to the site 26 weeks ± 7 days from the last SC LEN/placebo 
administration. Participants who are > 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.
•
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 postinjection 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.

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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. 
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) for central laboratory analyses.
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 collection for GC, CT, and TV.
•
Urine storage sample.
•
Urine pregnancy test (see Appendix 4).

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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 6).
•
Local fourth generation rapid HIV-1/2 Ab/Ag.
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 6).
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-glutamyltransferase (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 creatine phosphokinase (only at 
Randomized Blinded Phase).
•
Blood sample for syphilis analysis per local testing protocol.
•
Metabolic assessments: fasting (no food or drinks, except water, at least 8 hours prior to 
blood collection) lipid panel (total cholesterol, high-density lipoproteins, 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 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 an 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, which may be analyzed for TFV-DP and FTC-TP levels.

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•
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 as the last participant’s last observation (last visit).
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 testing 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 for GC, CT, and TV per laboratory testing.
•
Asymptomatic blood sample for syphilis analysis per local testing protocol.
In addition to scheduled asymptomatic testing for STIs, if participants report any sign or 
symptom of an STI or bacterial vaginosis, or are notified by a contact, they should be managed 
(diagnosed and treated) according to local clinical guidelines and practice.
6.13.
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 6, part a). Procedures for specific situations are noted below: 

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•
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 6, part a). A CD4 cell count will be run reflexively while central 
confirmatory testing is underway. 
•
HIV-1 recency assay will be performed as indicated based on the participant’s HIV testing 
results.
•
Any participant with a confirmed diagnosis of HIV will be counseled and referred for local 
HIV 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 6, 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-1 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 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. 

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•
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 care as appropriate.
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 6, 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 6). 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 a confirmed diagnosis of HIV will be counseled and referred for local 
HIV care as appropriate. 
Additional HIV Testing
At any point in the study, if the positive 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 
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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.
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 visit (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 
drugs 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.
•
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 and Family 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. Family planning and contraception counseling will be provided 
at each visit up to and including the 30-day follow-up visit.
6.15.
Adherence and Retention
The effectiveness of daily oral PrEP (F/TDF and F/TAF) is strictly correlated with adherence.
The study will provide adherence support/counseling to oral PrEP 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.
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 (must be completed postinjection): 
Day 1/Injection 1, Week 26/Injection 2, Week 52, and every 26 weeks thereafter at injection 
visits .
•
Sexual Risk and Behavior Questionnaire: Randomized Blinded Phase screening, 
Day 1/Injection 1, Week 13, and every 13 weeks thereafter.
•
Adherence to Oral Study Product Questionnaire: Weeks 4, 8, 13, and every 13 weeks 
thereafter. 
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.

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Numeric Pain Rating Scale – Injection Pain (must be completed postinjection): at every 
injection visit.
•
Sexual Risk and Behavior Questionnaire: End of Randomized Blinded Phase visit/LEN OLE 
Day 1, Week 13, and every 13 weeks thereafter.
•
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.
•
Sexual Risk and Behavior Questionnaire: PK Tail Day 1, Week 13, and every 13 weeks 
thereafter.
•
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.
•
Sexual Risk and Behavior Questionnaire: ESDD visit for any phase.
6.17.
Pregnancy
Participants who are planning on becoming pregnant may be randomized into the study but must 
have a negative pregnancy test at the Randomized Blinded Phase screening and 
Day 1/Injection 1. Prenatal care will be at the investigator's discretion per local standard of care 
and will not be provided as part 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 (Section 9.1.4). 
Participants who continue on study drug during pregnancy and lactation may also provide breast 
milk and infant blood samples for testing study drug levels after providing consent (Appendix 4).

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6.18.
Social Harms Reporting
It is possible that participants’ involvement in the study could become known to others, and that 
a social harm may result (ie, because participants could be perceived as having acquired HIV or 
at “high risk” for HIV infection). Social harms events are events that a participant reports as 
affecting them as a result of being involved in a research study, not the researcher’s opinion of 
how they perceive an event has affected a participant. For example, participants might be treated 
unfairly if it is known that they are participating in the study. Participants may also have 
problems being accepted by their families and/or communities.
The site staff will discuss social harms with participants via an interview, and the social harms 
may be reported according to local regulations and requirements.
In the event a participant reports a social harm, every effort will be made by study staff to 
provide appropriate care and counseling to the participant as necessary, and/or referral to 
appropriate resources for the safety of the participant.
6.19.
Sample Storage
The stored biological samples may be used by Gilead or its research partner for future testing to 
provide additional data to answer questions that relate to the main study. At the end of this study, 
these samples may be retained in storage by Gilead for a period up to 15 years. If participants 
provide additional specific consent for 
future research, blood and urine samples may be 
destroyed no later than 15 years after the end of study or per country requirements.
CCI-

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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). 
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.)

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•
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, mother-to-child transmission in women who become HIV-1 infected on study drug 
is to be considered medically important and therefore “serious.” 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 breastfeeding, 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.
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).

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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 infectious 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 ineffective treatment should not be considered as causally related in 
the context of AE reporting.
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).

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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 dug, 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 protocol-defined 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 to 
Gilead 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.
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.

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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.
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.

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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 posttreatment 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: Safety_FC@gilead.com 
or
Fax: 1-650-522-5477
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 Gilead 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: Safety_FC@gilead.com 
or
Fax: 1-650-522-5477
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 Gilead PS.

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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: Safety_FC@gilead.com 
or
Fax: 1-650-522-5477
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
Electronic Pregnancy Event Reporting Process 
Site personnel will record all pregnancy data on the applicable eCRFs and from there transmit 
the pregnancy information to Gilead PS within 24 hours of the investigator’s knowledge of the 
event from the time of study drug initiation throughout the duration of the study, including the 
protocol-required posttreatment follow-up period.
If for any reason it is not possible to record and report the pregnancy information electronically, 
record the pregnancy or pregnancy outcome on the paper Pregnancy or Pregnancy Outcome 
reporting form(s) and transmit within 24 hours to:
Gilead Patient Safety
Email: Safety_FC@gilead.com 
or
Fax: 1-650-522-5477
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 the 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, by completing the applicable eCRF forms 
within 24 hours of the investigator’s knowledge of the pregnancy outcome information. 
In addition, if the investigator learns of any pregnancy or pregnancy outcomes that occur after 
the protocol-defined follow-up period has concluded and the eCRF is no longer available for 
entry, 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: Safety_FC@gilead.com 
or
Fax: 1-650-522-5477
Refer to Appendix 4 for Pregnancy Precautions, and Definition of Females of Childbearing 
Potential, and Contraceptive Information.
AEs/SAEs observed in a neonate at the time of delivery will be reported via the Pregnancy 
Outcome eCRF (except for mother-to-child transmission). Events of mother-to-child 
transmission should be reported to Gilead PS via the electronic SAE reporting process described 
in Section 7.4.1.1.
AEs/SAEs observed in the infant that are unrelated to the delivery will be reported via the Infant 
Follow-up eCRF (except for mother-to-child transmission as stated above). 
7.4.2.4.
Reporting Breastfeeding Exposure When A Participant Breastfeeds during the 
Study
If a breastfeeding exposure occurs and the participant will continue to breastfeed while enrolled 
in the study, then a special situations report should be submitted within 24 hours of awareness of 
the event. A follow-up “breastfeeding exposure” special situations report will need to be 
submitted to capture the end of exposure to study drug via breast 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 a paper SAE report form if the event meets 
serious criteria. Events of mother-to-child transmission should be reported to Gilead PS via the 
electronic SAE reporting process described in Section 7.4.1.1.
Refer to Section 7.4.2 and the eCRF completion guidelines for instructions on submitting special 
situations reports 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 suspected unexpected 
serious adverse reaction (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, ECG, 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 
laboratory abnormality.

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7.7.
Toxicity Management
All clinical events and clinically significant laboratory toxicities that occur after administration 
of the first dose of study drug will be managed according to uniform guidelines detailed in 
Appendix 5 as outlined below:
•
During the Randomized Blinded Phase, all clinically significant Grade 3 and 4 laboratory 
abnormalities must be repeated within 3 calendar days to confirm toxicity grade. The medical 
monitor can approve an extension if logistical challenges exist regarding repeating laboratory 
tests within 3 days. Confirmation of toxicity grade is required prior to the next dose of study 
drug 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.
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.
Grade 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 investigational medicinal product.
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 clinical event or 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 clinical 
events or laboratory abnormalities considered unrelated to study drug may not require permanent 
discontinuation.

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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 clinical event or laboratory abnormality returns to 
baseline or is otherwise explained, whichever occurs first. A clinical event or clinically 
significant Grade 4 laboratory abnormality that is not confirmed by repeat testing should be 
managed according to the algorithm for the new toxicity grade.
Investigational medicinal product 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 injections site reactions (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 and F/TAF in preventing 
the risk of HIV-1 infection relative to the background HIV-1 incidence rate.
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 objectives for the Randomized Blinded Phase of this study are as follows:
•
To evaluate the efficacy of LEN for HIV-1 PrEP in AGYW at risk of HIV-1 infection.
•
To evaluate the efficacy of F/TAF for HIV-1 PrEP in AGYW at risk of 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 AGYW at risk of HIV-1 
infection.
•
To evaluate the efficacy of LEN for HIV-1 PrEP in AGYW at risk of HIV-1 infection in 
participants adherent to LEN.
•
To evaluate the efficacy of F/TAF for HIV-1 PrEP in AGYW at risk of HIV-1 infection in 
participants adherent to F/TAF.
•
To compare the efficacy of F/TAF with F/TDF for HIV-1 PrEP in AGYW at risk of HIV-1 
infection.
•
To evaluate the safety and tolerability of LEN, F/TAF, and F/TDF for HIV-1 PrEP in 
AGYW at risk of HIV-1 infection.
•
To evaluate the safety and tolerability of LEN and F/TAF for HIV-1 PrEP in AGYW ≥ 16 to 
< 18 years of age who have sex with male partners and are at risk for HIV-1 infection.
The exploratory objectives for the Randomized Blinded Phase of this study are as follows:
•
To assess the adherence rate to LEN as assessed by on-time LEN injection.
•
To assess LEN plasma levels.
•
To assess the adherence rate to F/TAF and F/TDF using intracellular TFV-DP levels in DBS.

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• 
To evaluate the acceptability and satisfaction of a Q6M LEN injection for HIV-1 PrEP in 
AGYW at risk of HIV-1 infection. 
• 
To assess study drng levels of interest in pregnant and postpartum women, in breast milk, 
and in infants. 
• 
To explore concentrations ofho1monal contraceptives in LEN paiiicipants. 
8.1.2. 
8.1.2.1. 
Primary Endpoint 
Incidence Phase Primaiy Endpoint 
The prima1y 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 an HIV-1 recency assay. 
8.1.2.2. 
Randomized Blinded Phase Primaiy Endpoint 
The prima1y 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 paiiicipants who acquired 
HIV-1 divided by the total of a) for paiiicipants 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 pa1iicipants diagnosed with 
HIV-1, sum of all duration time to confmned HIV-1 diagnoses. 
8.1.3. 
Secondary Endpoints 
The secondaiy endpoints for the Randomized Blinded Phase of this study ai·e as follows: 
• 
Diagnosis of HIV-1 among paii icipants while adherent to study diug 
• 
OccmTence ofTEAEs and treatment-emergent clinical laborato1y abnonnalities to evaluate 
safety and tolerability of LEN, F/TAF, and F/TDF for HIV-1 PrEP 
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•
Study drug concentrations in maternal plasma, breast milk, and infant plasma.
•
8.2.
Planned Analyses
8.2.1.
Interim Analysis
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. 
CCI
I 

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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 1 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 
when age is not collected.

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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-1 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 not be limited to race/ethnicity, age, sex at birth, 
alcohol and substance abuse.
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
The Randomized Blinded Phase of the study has 2 experimental study drug groups (LEN and 
F/TAF) and each is tested against the same background HIV-1 incidence to serve the 2 primary 
objectives of the study. Both experimental study drug arms are also tested against the active 
control arm (F/TDF). Including the 2 hypotheses based on the US FDA criteria for regulatory 
success, a total of 8 alpha controlled efficacy hypotheses are considered. Gatekeeping, alpha 
splitting and fallback procedures are used to control the overall Type I error; the details are listed 
in Section 8.7.1. Only the starting point for the series of 8 alpha controlled tests, the first 
hypothesis for the LEN arm, is listed under the Primary Analysis section (Section 8.5.1). The 
presentation of the 8 hypotheses in the following subsections does not diminish their role in 
supporting the primary and secondary efficacy objectives of the study.
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 (bHIV) represent the HIV incidence rate of the LEN study drug 
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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 𝐻01with 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 𝐻05 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 
method {Shao 2024} if the number of HIV-1 infections diagnosed 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.

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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 
The background incidence rate will be estimated by the formula:
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)
No 
HIV+ 
(N+) 
Incidence Phase 
Recency Test 
Conducted & Results 
Available 
Not Recent 
All Eligible Participants 
for HIV Testing 
(N) 
Test for HIV 
Recent 
(N..,J 
~ 0 = Nrec/ (N+,testf N+ ) - /JN+ 
N_ (fl - f]T) 
HIV-
(N_) 
Screen for Randomized 
Phase of the PrEP Study 

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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 𝜎2log(𝜆0) + 𝜎2log(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 and alpha splitting. In the equation below, F/TAF is being replaced with DVY and 
F/TDF is being replaced with emtricitabine/tenofovir disoproxil fumarate (coformulated; 
Truvada®) (TVD) for brevity and simplifying formulation of ratio in the listed null hypotheses:
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.
HIV-1 incidence rate for the F/TAF study drug group is significantly lower than the background 
incidence rate estimated in the Incidence Phase. 
•
𝐻03:𝐷𝑉𝑌/𝑏𝐻𝐼𝑉≥1.0 (superiority over background), which will be tested in a similar 
manner to the primary endpoint 
HIV-1 incidence rate of the F/TAF study drug group to the background HIV-1 is at least 20% 
lower in the F/TAF study drug group compared with the background incidence rate estimated in 
the Incidence Phase and the point estimate of F/TAF/background HIV ≤ 0.5.
•
𝐻04:𝐷𝑉𝑌/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 DVY/background HIV 
≤ 0.5.
HIV-1 incidence rate of the LEN study drug group is at least 0.8/100 PY higher than the F/TDF 
study drug group.
•
𝐻05:𝐿𝐸𝑁―  𝑇𝑉𝐷≥0.8/100𝑃𝑌 (comparable to F/TDF), which will be tested using a rate 
difference approach.
C) 
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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. 
•
𝐻06:𝐿𝐸𝑁/𝑇𝑉𝐷≥1.0 (superiority over F/TDF), which will be tested using a rate ratio 
approach.
HIV-1 incidence rate of the F/TAF study drug group is at least 0.8/100 PY higher than the 
F/TDF study drug group.
•
𝐻07:𝐷𝑉𝑌―  𝑇𝑉𝐷≥0.8/100𝑃𝑌 (comparable to F/TDF), which will be tested using a rate 
difference approach.
HIV-1 incidence rate of the F/TAF study drug group is significantly lower than the HIV-1 
incidence rate of the F/TDF study drug group. 
•
𝐻08:𝐷𝑉𝑌/𝑇𝑉𝐷≥1.0 (superiority over F/TDF), which will be tested using a rate ratio 
approach.
A secondary analysis of the primary endpoint will compare the HIV-1 incidence rate in the LEN 
and F/TAF study drug groups with a historical and other relevant external HIV-1 incidence rates 
(eg, ECHO and others as they become available).
The rate ratios of HIV-1 incidence between LEN and F/TDF and between F/TAF 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 may be used as sensitivity analyses for each of the experimental 
arms (LEN and F/TAF) to F/TDF.
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 group. 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 groups. 
For continuous safety data including laboratory data, a t-test or analysis of variance (ANOVA) 
model may be used to compare study drug groups. 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.

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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/TAF and 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 
(≥ 450 fmol/punch for the F/TAF study drug group and ≥ 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).
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 group. 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 5.
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 group. 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 the 3 study drug groups will be tested 
using an analysis of covariance (ANCOVA) model with study drug as fixed effect and baseline 
measure as a covariate.

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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 groups may be compared using ANCOVA model 
with study drug as fixed effect and baseline measure as a covariate.
8.7.
Adjustments for Multiplicity
Procedures to control the overall Type I error due to multiple efficacy analyses, one due to 
multiple primary hypotheses and the other due to one planned interim efficacy analysis, are 
described in this section. 
8.7.1.
Multiple Alpha-Controlled Hypotheses - Two Experimental Arms
Gatekeeping, alpha splitting, and fallback procedures will be utilized to control the overall alpha 
at 0.025. The following tests of hypotheses will be performed in sequence; see Figure 14 for 
details on the order and alpha splitting and fallback procedures. As before, F/TAF is being 
replaced with DVY and F/TDF is being replaced with TVD for brevity and simplifying 
formulation of ratio in the listed null hypotheses.
𝐻01:𝐿𝐸𝑁/𝑏𝐻𝐼𝑉≥1.0 (superiority over background)
12) 𝐻02:𝐿𝐸𝑁/𝑏𝐻𝐼𝑉≥0.8 (at least 20% reduction over background HIV-1)
13) 𝐻03:𝐷𝑉𝑌/𝑏𝐻𝐼𝑉≥1.0 (superiority over background)
14) 𝐻04:𝐷𝑉𝑌/𝑏𝐻𝐼𝑉≥0.8 (at least 20% reduction over background HIV-1)
15) 𝐻05:𝐿𝐸𝑁–𝑇𝑉𝐷≥0.8/100𝑃𝑌 (comparable to F/TDF)
16) 𝐻06:𝐿𝐸𝑁/𝑇𝑉𝐷≥1.0 (superiority over F/TDF)
17) 𝐻07:𝐷𝑉𝑌–𝑇𝑉𝐷≥0.8/100𝑃𝑌 (comparable to F/TDF)
18) 𝐻08:𝐷𝑉𝑌/𝑇𝑉𝐷≥1.0 (superiority over F/TDF)

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Figure 14. 
Overall Testing Procedure 
LEN vs bH IV 
Ho1: LEN / bHIV~ 1 
LEN / bHIV 0.5 & 
Ho2: LEN / bHIV ~ 0.8 
a = 0.025 (1st primary) 
I 
I 
0.4 
a=0.01 
LEN vs TVD 
Ho5: LEN - TVD 
0.8/ l00PY 
H06: LEN / TVD 
1 
a =0.015 
------0.6----
1 
(fallback) 
DVY vs b HIV 
Ho3: DVY / bHIV~ 1 
DVY I bHIV 
0.5 & 
Ho4: DVY I bHIV 
0.8 
(2nd primary) 
1 
DVY vs TVD 
Ho1: DVY - TVD 
0.8 / l00PY 
Hos: DVY / TVD~ 1 
bHIV = background HIV; DVY = emtricitabine/tenofovir alafenamide (cofo1mulated; Descovy®); LEN = lenacapavir; 
PY = person-year; TVD = emtricitabine/tenofovir disoproxil fumarate (cofo1mulated; Tmvada®) 
Note: Displayed alpha levels are the overall (controlled level) I-sided alpha (total alpha for both the interim and the primary 
analyses). Testing within each block is sequential. Transitional weights from one node to another indicate fraction oflocal 
significance level at the first node that is added to local significance level at the second node if the first node is rejected. 
The overall alpha split will be between H03 (a = 0.015) and H05 (a = 0.01). The fallback 
procedure will be implemented for H03 if H06 is rejected; that is, 0.01 will be added to 0.015 for 
a = 0.025 to test H03 and the subsequent hypotheses within that block. 
8.7.2. 
Multiple Analyses - Interim and Primary Efficacy Analyses 
One fo1mal evaluation of interim efficacy is planned. The overall I-sided Type I eITor rate of 
0.025 for the prima1y and key a-controlled secondaiy endpoints at both the interim and prima1y 
analyses will be controlled using a BonfeIToni method. An overall ai = 0.0026 will be used for 
the interim analysis and the remainder, a2 = 0.0224, will be used at the prima1y analysis. 
Figure 15 presents the testing procedure at the interim analysis. 
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Figure 15.
Testing Procedure at the Interim Analysis
bHIV = background HIV; DVY = emtricitabine/tenofovir alafenamide (coformulated; Descovy®); LEN = lenacapavir; 
PY = person-year; TVD = emtricitabine/tenofovir disoproxil fumarate (coformulated; Truvada®)
Note: Alpha levels are one-sided. Testing within each block is sequential. 
At the interim analysis, the Randomized Blinded Phase of the trial will stop early if superiority 
of LEN over bHIV, designated 𝐻02 with the point estimate of 𝐿𝐸𝑁/𝑏𝐻𝐼𝑉 ≤ 0.5, and over 
F/TDF, designated 𝐻06, both at 𝛼1 = 0.0026 are demonstrated. The interim analysis will serve as 
the primary analysis if the trial meets the stated criteria and stops early.
If the Randomized Blinded Phase continues to the primary analysis, the null hypotheses 𝐻01, 
𝐻02, …, 𝐻08 will be tested according to a procedure consistent with the overall testing procedure 
specified in Figure 14, using an overall 𝛼2 = 0.0224. 
Further details will be prespecified in the interim analysis plan and/or statistical analysis plan.
The use of an HIV-1 recency assay to estimate the bHIV in PrEP studies is a novel approach. 
The estimate of the bHIV is subject to many assay and operational issues. If the point estimate of 
the recency based counterfactual bHIV is less than 1.5/100 PY at the interim analysis, the 
estimate of bHIV incidence by the recency-assay based methodology will be deemed as not 
performing as expected. In this case, hypotheses H01 through H04 will be skipped at the interim 
analysis and recommendations to stop the randomized part of the study will be based on rejecting 
H06 at α1 = 0.0026. 
LEN vs bHIV 
Ho : L 
/ bHIV '.'.".: 1 
L 
/ bHIV 
0.5 & 
Ho2: LEN I bHIV '.'.".: 0.8 
a =0.0026 
LEN vs TVD 
Hos: LEN - TVD 2: 0.8/ l00PY 
Ho6: LEN / TVD 2: 1 
a = 0.0026 
DVYvs bHIV 
Hof DVY I bHIV 2: I 
DVY I bHIV 
0.5 & 
Ho4: DVY I bHIV 2: 0.8 
a = 0.0026 
DVYvsTVD 
Ho : DVY -TVD 2: 0.8 /l00PY 
Hos: DVY I TVD 2: 1 
a = 0.0026 

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The DMC will review, 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 and will make recommendations based on the boundaries specified below (see 
Section 8.10). 
8.8.
Pharmacokinetic Analysis
LEN plasma concentrations will be summarized by time point for SC and oral LEN. 
Additionally, population PK analysis of LEN is planned.
8.9.
Sample Size
A total sample size of 5010 is considered for the study in AGYW. More than 95% power is 
achieved with 2000 participants in the LEN study drug groups 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 rate of 3.00/100 PY.
•
LEN rate of 0.6/100PY, with an 80% risk reduction in HIV-1 compared with the 
nonrandomized control of background HIV-1 incidence.
•
Mean duration of recent infection (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 year.
•
2:2:1 allocation for LEN: F/TAF: F/TDF.
•
Alpha level of 0.025 (1-sided).
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 drops to 94%. These assay 
parameters are still under investigation and may be further refined for primary analysis. 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 or F/TAF over F/TDF), and the corresponding CI, will be 
estimated to characterize the comparative evaluation.

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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 600 participants before the safety review is conducted and, if determined by the 
DMC, the study is allowed to continue. Enrollment of adolescents (participants with 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. 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 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 H06 is rejected at the level α1 = 0.0026. However, if the point 
estimate of the recency based counterfactual bHIV is less than 1.5/100 PY, recommendations 
to stop the randomized part of the study will be based on rejecting H06 at α1 = 0.0026.
2) for futility, if F/TDF is found to be superior to both LEN and F/TAF or F/TAF is found to be 
superior to LEN at the level α1 = 0.0026. Additionally, as both LEN and F/TAF are under 
study, the trial continuation or early stopping for futility will be evaluated if either of the 
2 following situations occurs:
a) If F/TDF is found to be superior to F/TAF at level 𝛼1 = 0.0026, this would lead to 
stopping (and unblinding) the F/TAF arm. In this case, the blinded trial may continue 
with LEN and F/TDF arms.
b) If either F/TDF or F/TAF is found to be superior to LEN at level 1 = 0.0026, this would 
lead to stopping (and unblinding) the LEN arm. In this case, the study would be 
unblinded and may continue as an open-label study. 
The general approach for interim decisions and DMC recommendations is discussed in 
Section 8.7 (Adjustments for Multiplicity) and further details will be prespecified in the interim 
analysis plan and/or statistical analysis plan. 
The external 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 drug warrant 
the early termination of the study in the best interests of the participants, whether the study 
should continue as planned, or whether the study should continue with modifications. Should 
there be a substantial difference in HIV-1 incidence between those arms 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 regarding 
study design.

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The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct, interim data cut, scope of responsibilities, and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.

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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 ICF will inform participants about planned sample retention. In addition to the 
study-specific ICF to be signed by each participant taking part in the study, participants will be 
required to document agreement to provide additional samples or to allow the use of the 
remainder of their already collected specimens for 
 future research, in accordance with 
applicable regulations. The results of the tests done on the samples will not be given to the 
participant or the investigator. In addition to the study-specific ICF to be signed by each 
participant taking part in the study, participants who become pregnant after randomization may 
remain on the study after the reconsent process, as applicable according to local rules and 
regulation, where they will be informed of the benefits and risks of continuing receipt of study 
drug while pregnant and lactating and the collection of birth outcomes for the child.
9.1.5.
Confidentiality
The investigator must ensure that participants’ anonymity will be strictly maintained and that 
their identities are protected from unauthorized parties. Only an identification code and any other 
unique identifier(s) as allowed by local law (such as year of birth) will be recorded on any form 
or biological sample submitted to Gilead or the laboratory. Laboratory specimens must be 
labeled in such a way as to protect participant identity while allowing the results to be recorded 
to the proper participant. Refer to specific laboratory instructions. NOTE: The investigator must 
keep a screening log with details for all participants screened and enrolled in the study, in 
accordance with the site procedures and regulations. Participant data will be processed in 
accordance with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to the 
IB, this protocol, CRFs/eCRFs, study drug information, and any other study information, remain 
the sole and exclusive property of Gilead during the conduct of the study and thereafter. This 
information is not to be disclosed to any third party (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 further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise 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) participant clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRFs/eCRFs, and 
governmental approval with correspondence, the ICF(s), drug records, staff curriculum vitae and 
authorization forms, and other appropriate documents and correspondence.
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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
For each participant consented, an eCRF casebook will be completed by an authorized study 
staff member whose training for this function is completed in the EDC system. The eCRF 
casebook will only capture the data required per the protocol schedule of events and 
procedures. The Inclusion/Exclusion Criteria and Enrollment eCRFs should be completed only 
after all data related to eligibility have been received. Data entry should be performed in 
accordance with the eCRF completion guidelines provided by the sponsor. Subsequent to data 
entry, a study monitor will perform source data verification within the EDC system. 
System-generated or manual queries will be issued in the EDC system as data discrepancies are 
identified by the monitor and central monitoring team or Gilead staff 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. At a minimum, prior to any interim time points or database 
lock (as instructed by Gilead), the investigator will use his/her login credentials 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 regulatory 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 Tables
Appendix 4.
Information and Procedures for Pregnancy Events, Definition for Female of 
Childbearing Potential, and Contraceptive Information
Appendix 5.
Management of Clinical and Laboratory Adverse Events
Appendix 6.
HIV Testing Algorithms
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-Blinded, Multicenter, Randomized Study to Evaluate Safety and Efficacy of 
Twice Yearly Long-Acting Subcutaneous Lenacapavir, and Daily Oral Emtricitabine/Tenofovir 
Alafenamide for Pre-Exposure Prophylaxis in Adolescent Girls and Young Women at Risk of 
HIV Infection
GS-US-412-5624, Amendment 4, dated 10 October 2024
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval.
[See appended electronic signature]
Director, Clinical Development
Signature
[See appended electronic signature]
Date
INVESTIGATOR STATEMENT
I have read the protocol, including all appendices, and I agree that it contains all necessary 
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 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study.
Principal Investigator Name (Printed)
Signature
Date
Site Number
PPD

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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 drugs, the 
participant would not be able to stay on the study drug as planned per protocol.
Mitigation plan: Oral study drug supplies at noninjection 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 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 AEs 
(SAEs)/special situations (including pregnancy) 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, and family planning and contraception counseling. 
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 dried blood spot (DBS) collection. Participants will 
be asked to conduct self-HIV assessments and pregnancy testing, 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 (SDR) 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 participants remains unchanged.

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Appendix 3.
Study Procedures Tables
Procedures for Incidence Phase and Randomized Blinded Phase
Screening
Randomized Blinded Phase – Weeks (± 7 days; ± 2 days for 
Weeks 4 and 8)V
Study Procedure
Incidence 
Phase
Randomized 
Blinded 
Phase
Day 1
4
8
13
26
39
52
Post 
Week 52 
Every 
13 or 26 
Weeks
Oral Bridging 
Visitd
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)
Informed Consent (and 
assent for adolescents)e
X
X
Medical History
Xf
Xf
Demographics
X
Query on Sexual Activity 
With Cisgender Male 
Individuals
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 Exam
X
Targeted Physical Exam
Xg
X
X
X
X
X
X
Every 
13 weeks
X
X
X
X
Vital Signs and Weight, 
Height,h 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
Every 
26 weeks
Every 
26 weeks
X
X
Local Rapid Fourth 
Generation HIV-1/2 
Ab/Ag
X
X
X
X
X
X
X
X
Every 
13 weeks
X
X
X

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Screening
Randomized Blinded Phase – Weeks (± 7 days; ± 2 days for 
Weeks 4 and 8)V
Study Procedure
Incidence 
Phase
Randomized 
Blinded 
Phase
Day 1
4
8
13
26
39
52
Post 
Week 52 
Every 
13 or 26 
Weeks
Oral Bridging 
Visitd
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)
Central Fourth 
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 HIV-1 
Recency Assay
Xj
Xj
Blood Sample for DBS 
Assay
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
Estimated GFR
X
X
X
X
X
X
X
X
Every 
13 weeks
X
X
X
X

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Screening
Randomized Blinded Phase – Weeks (± 7 days; ± 2 days for 
Weeks 4 and 8)V
Study Procedure
Incidence 
Phase
Randomized 
Blinded 
Phase
Day 1
4
8
13
26
39
52
Post 
Week 52 
Every 
13 or 26 
Weeks
Oral Bridging 
Visitd
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)
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
X
Urine Pregnancy Testl
X
X
X
X
X
X
X
X
Every 
13 weeks
X
X
X
X
Serum Pregnancy Testl
X
Sexual Risk and 
Behavior 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 
(completed postinjection)
X
X
X
Every 
26 weeks 
(at 
injection 
visits)

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Screening
Randomized Blinded Phase – Weeks (± 7 days; ± 2 days for 
Weeks 4 and 8)V
Study Procedure
Incidence 
Phase
Randomized 
Blinded 
Phase
Day 1
4
8
13
26
39
52
Post 
Week 52 
Every 
13 or 26 
Weeks
Oral Bridging 
Visitd
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
X
X
Every 
26 weeks 
(at 13 
weeks 
after each 
injection 
visits)
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
X
X
X
X
X
X
X
X
Every 
13 weeks
X
X
X
X
Family Planning and 
Contraception 
Counseling
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/TAF, PTM F/TAF, 
F/TDF, or PTM F/TDF 
Dispensation and 
Accountabilityp
Xq
X
X
X
X
X
X
Every 
13 weeks
X
Xp

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Screening
Randomized Blinded Phase – Weeks (± 7 days; ± 2 days for 
Weeks 4 and 8)V
Study Procedure
Incidence 
Phase
Randomized 
Blinded 
Phase
Day 1
4
8
13
26
39
52
Post 
Week 52 
Every 
13 or 26 
Weeks
Oral Bridging 
Visitd
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)
Oral LEN or PTM LEN 
Dispensation and 
Accountability
Xr
Xp
X
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 and 
Appendix 6)
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/TAF = emtricitabine/tenofovir alafenamide; 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; IWRS = interactive web response system; LEN = lenacapavir; NAAT = nucleic acid amplification test; PrEP = pre-exposure prophylaxis; 
OLE = open-label extension; PK = pharmacokinetic(s); PTM = placebo-to-match; RNA = ribonucleic acid; 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 (± 14) days after discontinuation of the study drug for 
participants who complete an ESDD visit.

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 192
10 October 2024
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 RNA is ≥ 50 copies/mL at the 90-day post-HIV infection 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.
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 required if participant becomes pregnant.
f
Obtain the following information: date of last HIV test, prior PrEP use, and prior/current HIV vaccine at Incidence Phase screening; and a complete medical history 
including history of osteoporosis or fragility fracture and ongoing treatment for tuberculosis at Randomized Blinded Phase screening.
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, CT, and TV testing are to be performed by urine by central laboratory. Asymptomatic blood syphilis analysis per local testing protocol.
j
Run as indicated based on HIV test results.
k
Metabolic panel: Participants should be instructed to fast (no food or drinks, except water) at least 8 hours prior to blood collection.
l
Serum pregnancy test will be performed at Randomized Blinded Phase screening and subsequently in the event of a positive urine 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
Drug accountability will be performed by pill count for adherence.
q
Study drug dispensation only.
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.

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 193
10 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
Every 
26 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

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 194
10 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 Storage Sample 
for HIV-1 RNA by 
NAAT
X
X
X
X
X
X
X
X
X
X
X
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
Every 26 
weeks
X
X
X
Urinalysis
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
Sexual Risk and 
Behavior 
Questionnaire
X
X
X
X
X
X
Adherence to Oral 
Study Product 
Questionnaire
X
Experienced 
Preference for PrEP 
Medication 
Questionnaire
Every injection visit
X

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 195
10 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)
Numeric Pain Rating 
Scale - Injection Pain 
(completed 
postinjection)
Every injection visit
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
Family Planning and 
Contraception 
Counseling
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
Adherence Counseling
Xm
F/TAF, PTM F/TAF, 
F/TDF, or PTM F/TDF 
Accountabilitym
X
Oral LEN 
Dispensation and 
Accountability and 
Adherence Counseling
Xn,o
Xp
X

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 196
10 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)
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 6)
X
X
X
X
X
X
X
X
X
X
X
Xq
Xr
LEN Administrations
Every 26 weeks after the previous injectiont
X
Ab = antibody; Ag = antigen; CD4 = cluster determinant 4; CT = Chlamydia trachomatis; DBS = dried blood spot; ESDD = early study drug discontinuation; 
F/TAF = emtricitabine/tenofovir alafenamide; 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; NAAT = nucleic acid amplification test; OLE = open-label extension; PK = pharmacokinetic(s); PTM = placebo-to-match; QN = every N 
number of weeks; RNA = ribonucleic acid; 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 or F/TAF 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 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 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 of age, height is to be measured annually until they reach 20 years of age.

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 197
10 October 2024
h
GC, CT, and TV testing are to be performed by urine by central laboratory. Asymptomatic blood syphilis analysis per local testing protocol. 
i
Metabolic panel: Participants should be instructed to fast (no food or drinks, except water), at least 8 hours prior to blood collection.  
j
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 administered the Day 2 dose.
m
Drug accountability will be performed by pill count for adherence.
n
Only for participants randomized to F/TAF or F/TDF; oral LEN/PTM 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.
t
End of Randomized Blinded Phase visit coincides with the LEN OLE Day 1 visit. Participants who were randomized to F/TAF or 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.

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 198
10 October 2024
Procedures for PK Tail Phase
PK Tail Phase – Weeks (± 7 days)m
Study Procedure
Randomized Blinded 
Phase to
PK Tail Day 1
13
26
Post Week 26 
Every 13 or 26 
Weeks to Week 78
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
Every 13 weeks
X
X
X
X
Adverse Events
X
X
X
Every 13 weeks
X
X
X
Targeted Physical Exam
X
X
X
Every 13 weeks
X
X
X
Vital Signs, Weight, and Heightd
X
X
X
Every 13 weeks
X
X
X
Asymptomatic STI Testing for 
GC, CT, TV, and Syphilise
X
X
Every 26 weeks
X
X
Local Rapid Fourth Generation 
HIV-1/2 Ab/Ag
X
X
X
Every 13 weeks
X
X
Central Fourth 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
Xf
X
X
Every 13 weeks
X
X
Blood Sample for Metabolic 
Assessmentsg
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

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 199
10 October 2024
PK Tail Phase – Weeks (± 7 days)m
Study Procedure
Randomized Blinded 
Phase to
PK Tail Day 1
13
26
Post Week 26 
Every 13 or 26 
Weeks to Week 78
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)
Urinalysis, Urine Protein, Urine 
Chemistry
X
X
X
Every 13 weeks
X
X
X
Urine Pregnancy Testh
X
X
X
Every 13 weeks
X
X
X
Sexual Risk and Behavior 
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
Administration and Dosing 
Questionnaire for PrEP 
Medication
X
Intimate Partner Violence 
Screening
X
X
X
Every 13 weeks
X
X
X
Family Planning and 
Contraception Counseling
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 
Accountabilityi
X
X
X
Every 13 weeks
Xj
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 6)
X
X
X
Every 13 weeks
X
X
Xk
Xl
Ab = antibody; Ag = antigen; CD4 = cluster determinant 4; CT = Chlamydia trachomatis; DBS = dried blood spot; ESDD = early study drug discontinuation; 
F/TAF = emtricitabine/tenofovir alafenamide; 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; NAAT = nucleic acid amplification test; OLE = open-label extension; PK = pharmacokinetic(s); RNA = ribonucleic acid; STI = sexually 
transmitted infection; TV = Trichomonas vaginalis

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 200
10 October 2024
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 PK Tail 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 or completing the PK Tail Phase.
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 
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
For participants < 20 years of age, height is to be measured annually until they reach 20 years of age.
e
GC, CT, and TV testing are to be performed by urine by central laboratory. Asymptomatic blood syphilis analysis per local testing protocol. 
f
Only collect if the participant prematurely discontinues from the Randomized Blinded Phase.
g
Metabolic assessments: Participants should be instructed to fast (no food or drinks, except water) at least 8 hours prior to blood collection. 
h
Serum pregnancy test will be performed in the event of a positive urine pregnancy test.
i
Drug accountability will be performed by pill count for adherence.
j
No study drug will be dispensed.
k
HIV resistance genotype will be performed only if not already collected at time of infection.
l
CD4 cell count and HIV-1 RNA quantitative NAAT only.
m
All PK tail visits should be scheduled from PK Tail Day 1.

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 201
10 October 2024
CCI

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 202
10 October 2024
Appendix 4.
Information and Procedures for Pregnancy Events, Definition for 
Female of Childbearing Potential, and Contraceptive Information
Study Drug Effects on Pregnancy and Hormonal Contraception
Data from clinical pharmacokinetic interaction studies of F/TAF and 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 LEN and hormonal contraceptives is not expected; an oral contraception 
drug-drug interaction study was not done (see Section 1.2.8).
Nonclinical toxicity studies of F/TAF, 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) use by 
women in early pregnancy or their offspring. F/TAF for PrEP has not been studied in pregnant 
women; however, a randomized controlled trial of F/TAF plus dolutegravir for HIV treatment in 
pregnant women identified no safety concerns. No safety concerns have been identified among 
infants exposed to F/TDF during breastfeeding. Safety of breastfeeding while taking F/TAF has 
not been studied; however, a pharmacokinetic 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/TDF or F/TAF in utero is not yet known.
There are no clinical studies of LEN in pregnant women (Section 1.2.6.4). It is not known 
whether LEN is secreted in human breast milk (Section 1.2.7.4).
Please refer to the investigator’s brochures and Sections 1.2.6 and 1.2.7 of this protocol for 
additional information.
Procedures to be Followed in the Event of Pregnancy
Participants who are pregnant or suspect they are pregnant will be instructed to notify the 
investigator at any time during the study and within 700 days following the last dose of LEN or 
blinded LEN (if unblinding has not occurred). For every participant who becomes pregnant after 
randomization:
•
The pregnancy will be reported by eCRF and from there transmitted to Gilead Patient Safety 
within 24 hours of becoming aware of the pregnancy as described in Section 7.4.2.3. 
Instructions for reporting lactation are outlined in Section 7.4.2.4. See also Section 9.1.4 
regarding reconsent and remaining in the study.
•
Investigators will ensure that pregnant participants have been referred for antenatal care. 
Antenatal care is not provided as part of the study.
•
Investigators will discuss the risks and benefits of remaining on study drug with the 
participant. Participants who choose to remain on study drug may do so after providing 
informed consent.

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 203
10 October 2024
•
Participants will be asked to provide informed consent for the collection of breast milk and 
infant blood samples for PK analysis. Participants may opt out of providing these samples, 
which is not a requirement for continued participation in the study or continued receipt of 
study drug. 
•
Upon completion of the pregnancy, the investigators will document pregnancy outcomes 
including relevant dates, maternal history and complications, viability, delivery method and 
complications, congenital abnormalities, and overall infant health.
Procedures for women who consent to stay on study drug during pregnancy and lactation:
For participants who consent to provision of additional samples pertaining to pregnancy, 
lactation, and infant PK:
After provision of informed consent, participants who consent to stay on study drug during 
pregnancy and lactation may provide the following samples at each of the next 2 scheduled visits 
after delivery: 
•
20 mL of breast milk 
•
500 μL of infant plasma (1 mL of whole blood)
•
Infant DBS sample (150 μL of whole blood)
For cases where the first scheduled visit is within 10 days after delivery, these samples will be 
collected at the second and third visits postdelivery.
Participants who have a live birth during the study will be asked to report on the child's overall 
health at subsequent visits, including serious medical problems and previously unrecognized 
congenital abnormalities for 1 year or until participation in the study ends.

F/TAF and LEN
Protocol GS-US-412-5624
Final
Gilead Sciences, Inc.
Amendment 4
CONFIDENTIAL
Page 204
10 October 2024
Appendix 5.
Management of Clinical and Laboratory Adverse Events
Grade 1
Grade 4
Grade 3
Grade 2
May cont
ue 
d sing at th  
d scretion o  the 
i vestigat r
Repeat lab to 
onfirm oxicity 
rade
R peat lab t  
c nfirm toxic y 
g ade
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 
I 
I I 
11 
! 
! 
i 
i 
D 
D 
D-
l 
l 
l 
I 
I 
l 
I 
I 

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Appendix 6.
HIV Testing Algorithms
6a
Screening Visit 
Ab/Ag = antibody/antigen; ART = antiretroviral therapy; HIV-1/2 = human immunodeficiency virus type 1/2; NAAT = nucleic 
acid amplification test; RNA = ribonucleic acid
Screening Visit 
b/Ag ALGORI 
(CENTRA 
LLOAC 
ENTRAL) 
Screening Visit !------------+ ----------,------------1---t---:~~~~~~~~~~~~-l.._ ____ 
__, 
Rapid fourth 
generation HIV-
1/2 Ab/Ag test 
LOCAL 
TESTING 
Negative: Continue 
s-creening 
procedures 
Positive: perform HIV 
procedures as 
described in Section 6 
"HIV-1 lnfection" 1. Not 
eligible for Randomized 
Blinded Phase 
1. At the in\'estir,ator's discretion, positive rcpid 4th gener:1tion 
tests may be separa(efy- confirmed by loca,I testing in order to 
facilitate r3pid ART initiation 
2. 
For the screening and oay 1 \lisits only, centra) 4 ih r,-eneration 
HIV·l /2 Ab/ Ar, te-.:-t and HIV RNA quantitative NAAT tests are 
performed concurrently. Any HIV RNA detected is consid'e, ed a 
positive quantita.tive NAAT. 
Cent ral fourth gene@tion 
HIV-1/2 Ab/Ag test 
Positive: Not eligible 
for Randomized 
Blinded Phase. 
Negative 
HIV-1 RNA quantitative NAAT 
(viral load) ' 
eligible for the 
Randomized 
Blinded Phase 
Continue screening 
procedu res if el! HIV 
tests a re negative 

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6b
Day 1/Injection 1 Visit
Ab/Ag = antibody/antigen; ART = antiretroviral therapy; HIV-1/2 = human immunodeficiency virus type 1/2; NAAT = nucleic 
acid amplification test; RNA = ribonucleic acid
Day 1 Visit 
Day 1 Visit 
Rapid fourth 
generation HIV-
1/2 Ab/ Ag test 
LOCAL 
TESTING 
Negative: Continue 
Day 1 procedures' 
procedures as 
described in Section 6 
"HIV-! Infection"' 
1. 
tt is not necessary to await central HIV testing results prior to 
raindomi:z:al!ion 
2. 
A.II: the investigator's discretion, pmitive rapid 4th ga.eration 
t~"ts may be :s.a,puatelv confirmed by local t~"tin!!: in order to 
facilitate rapid ART initiation 
3. For the screening and Day 1 visits ooly, central 4o:1i generation 
HIV-1/2 Ab/ Ag test and HIV RNA quantitative NAATtests are 
periofmed concurrently. Any HIV RNA de.-.:ected is considered a 
positive qmntitative NAAT. 
/Ag ALGORITHM (CENTRAL 
Central fourth generation 
HIV-1/2 Ab/Ag test 
Positive: stop study 
drug. perform HIV 
care as described in 
Section 6 " HIV-1 
Infection" 
Positive: stop study drug. 
perform HIV care as 
described in Section 6 
" HIV-! Infection" 
VIRAL LOAD (CENTRALJ 
HIV RNA quantitative NAAT 
(vi ral load) ' 
Continue study 
procedures if Ab/Ag 
algorithm and viral 
load a re negative 

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Gilead Sciences, Inc.
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6c
Scheduled Visits After Day 1/Injection 1
Ab/Ag = antibody/antigen; ART = antiretroviral therapy; HIV-1/2 = human immunodeficiency virus type 1/2; NAAT = nucleic 
acid amplification test; RNA = ribonucleic acid
Scheduled Visits After Day 1 
Scheduled visit 
after Day 1 
Rapid fourth 
generation HIV-
1/2 Ab/Ag test 
LOCAL 
TESTI G 
Negative: Continue 
study procedures' 
Positive: do not give 
injection study drug. 
perform HIV procedures 
as described in Section 6 
"HIV-l lnfection" 2 
HIV :RNA quantitative 
fllAAT (reflexive) 
1. 
It is not necessary to .await central HIV testing results 
2. At t h@ · vo,;.tlgattor'< dl,crotlon, p<>•ltlv@ rapid fourth gon@ration t!>m 
m~ ba u p.r.tely confirmed by loail tuting in ord sr to ;,cir. i t 
ra ?id ART initiation 
3. 
HIV'-1 RNA quantitative NAAT will be performed reflexively if the 
c!ntral fourth ren!n tion HIV•1/2 Ab~ i.! o.!iliv! 
A / Ag ALGORITH 
Central fourth generation 
HIV-1/2 Ab/Ag test 
(CENTRAL) 
Positive: HIVl/ 2 
differentiation assay 3 
Negative: cont inue 
study procedures 
Positive: stop st!u dy 
drug. perform HIV 
procedures as 
described in Section 6 
"HIV-1 lnfectionn 
Negative: HIV RNA 
qualitative NAAT 
(reflexive) 
Positive: stop study drug. 
perform 1-llV procedures as 
described in Section 6 "HIV-
1 Infection" 

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Appendix 7.
Country-Specific Requirements
Not applicable.

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Appendix 8.
Amendment History
A high-level summary of amendment history is provided in tabular form in the subsection below, 
with changes listed in order of importance. 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 Amendment 3 to this amendment 
will be made available upon the publication of this protocol.
8.1
Amendment 4 (10 October 2024)
Rationale for Key Changes Included in Amendment 4
Affected Sections
Clarified that the duration of the Randomized Blinded Phase (RBP) will be 
approximately 52 weeks. This revision was made to acknowledge that the RBP 
duration could be shorter than 52 weeks if the RBP is stopped early by the study’s 
independent Data Monitoring Committee (DMC).
Synopsis, Section 3.3.2, 
Section 3.5
Revised lenacapavir (LEN) Open-label Extension (OLE) Phase language to 
extend subcutaneous (SC) LEN treatment until LEN becomes available 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 (coformulated; Truvada®) 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 (Study 
Schema), Section 3.3.3, 
Section 3.5, Section 6.4, 
Appendix 3 (Procedures for 
LEN OLE Phase table and 
footnotes), Appendix 3 
(Procedures for PK Tail 
Phase table and footnotes)
Revised Pharmacokinetic (PK) Tail Phase language to clarify that participants 
who complete or discontinue the LEN OLE Phase will not transition to the PK 
Tail Phase but will be transitioned to local HIV prevention services. With the 
safety and efficacy of LEN having been demonstrated in the primary analysis, it is 
appropriate for participants to transition to local prevention services after 
receiving LEN in the OLE Phase.
Synopsis, Figure 11 (Study 
Schema), Section 3.3.3, 
Section 3.3.4, Section 3.3.5
Revised frequency language for assessments of sexually transmitted infections to 
account for extended LEN OLE Phase and added the procedure to applicable 
Synopsis sections for accuracy. 
Synopsis, Section 6.4, 
Section 6.5, Appendix 3 
(Procedures for LEN OLE 
Phase), Appendix 3 
(Procedures for PK Tail 
Phase)
Reduced frequency of assessments for chemistry and hematology profile, 
metabolic assessments, estimated glomerular filtration rate, and hepatitis B and 
hepatitis C virus testing for the LEN OLE Phase and PK Tail Phase. A reduced 
frequency is appropriate since the safety of LEN was demonstrated in the RBP 
and because tenofovir-containing pre-exposure prophylaxis (PrEP) is not included 
in the LEN OLE Phase.  
Synopsis, Section 6.4, 
Section 6.5, Appendix 3 
(Procedures for LEN OLE 
Phase), Appendix 3 
(Procedures for PK Tail 
Phase)

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Rationale for Key Changes Included in Amendment 4
Affected Sections
Removed urine storage sample and waist circumference for all LEN OLE Phase 
visits and all PK Tail Phase visits. Removed urine protein and urine chemistry for 
the LEN OLE Phase. Additional urine assessments are not needed in the LEN 
OLE Phase since the safety of LEN has been established in the 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, Section 6.4, 
Section 6.5, Section 6.7.1, 
Appendix 3 (Procedures for 
LEN OLE Phase), 
Appendix 3 (Procedures for 
PK Tail Phase)
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, Sexual Risk and 
Behavior) 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.
Synopsis, Section 6.4, 
Section 6.5, Section 6.16, 
Appendix 3 (Procedures for 
LEN OLE Phase), 
Appendix 3 (Procedures for 
PK Tail Phase)
Revised LEN OLE Phase adherence counseling language for clarity.
Synopsis, Section 6.4
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 
emtricitabine/tenofovir disoproxil fumarate (F/TDF). Updated notation definitions 
of Figure 13 and background incidence rate formula. 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),
Updated references.
Synopsis, Section 8.5.1, 
Section 10
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.
Section 4.1
Removed requirement for medical monitor to approve administration of SC LEN 
outside the target window. This is considered appropriate considering the efficacy 
data and experience with LEN injections obtained during the RBP. 
Section 6.8.2
Removed drug-drug interaction (DDI) potential between F/TDF and 
anticonvulsants and between F/TDF and antimycobacterials from the list of 
Prohibited Medications. Added that concomitant use of dexamethasone may 
decrease LEN exposures, particularly with long-term use. 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.
Table 22
Revised the serious adverse event (SAE) reporting language to clarify recording 
and reporting requirements for initial and follow-up SAE data for electronic and 
paper case report forms.
Section 7.4.1.1
Added language regarding adverse event (AE)/SAE reporting for neonates/infants 
at the time of delivery, following delivery, and following lactation exposure. 
These revisions were made to provide clarity on the AE reporting procedures.
Section 7.4.2.3, 
Section 7.4.2.4

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Rationale for Key Changes Included in Amendment 4
Affected Sections
Revised language for the management of AEs of injection site reactions of Grade 
3 or higher. These revisions make discussions with the medical monitor regarding 
longer lasting or more severe injection site reactions at the discretion of the 
investigator. These revisions are supported by the experience and safety data 
collected during the RBP.
Section 7.7.5
For secondary analysis, updated the estimation methods for the rate ratios of HIV-
1 incidence between LEN and F/TDF and between emtricitabine/tenofovir 
alafenamide (F/TAF) and F/TDF and the associated CI if the number of infections 
is zero. This addition was first reflected in the statistical analysis plan and is 
necessary since the statistical methods listed in the prior protocol version do not 
work if the number of infections is zero.
Section 8.5.2
Removed repeated statement of success criteria of the US FDA 
Section 8.7.1
Added details of the interim analysis testing procedure. Added schematic figure of 
interim analysis testing procedure.
Section 8.7.2, Figure 15
Updated DMC criteria for rejection of hypothesis H02 and H06. These revisions to 
the DMC stopping criteria were required by the US FDA. 
Section 8.10
Changed protocol amendment signatory.
Appendix 1
Updated footnotes for LEN OLE Phase and PK Tail Phase Tables of Procedures 
as applicable.
Appendix 3 (Procedures for 
LEN OLE Phase), 
Appendix 3 (Procedures for 
PK Tail Phase)
Made minor changes to correct typographic errors and language and to provide 
clarifications.
Throughout, as needed
8.2
Amendment 3 (17 October 2023)
Rationale for Key Changes Included in Amendment 3
Affected Sections
Updated the efficacy, pharmacokinetic, and safety data of lenacapavir with the 
latest information from the ongoing studies (GS-US-200-5709, GS-US-200-4625, 
and GS-US-200-4334) to align with the current Investigator Brochure.
Sections 1.2.4.4.3, 1.2.4.4.6, 
and 1.2.4.4.7
Updated the language pertaining to the rationale of LEN dose selection to clarify 
that "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 Q6M SC dosing interval.”
Clarified that 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, which is supported by 
preliminary PK data available through 26 weeks postdose from 
Study GS-US-200-5709.
Section 1.4
Updated the rationale for Oral Weekly Bridging of LEN for missed 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

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Rationale for Key Changes Included in Amendment 3
Affected Sections
Additional information on the rationale for allowing women who become 
pregnant to remain on study drug has been added per the suggestion of research 
site Ethics Committees.
Section 1.6
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, 6.2.2, and 6.3
Text was revised to clarify that the study will only proceed to the LEN OLE Phase 
if LEN demonstrates acceptable safety and efficacy in the Randomized Blinded 
Phase.
Synopsis, Section 3.3.3
The Incidence Phase Exclusion Criteria pertaining to PrEP use in the past 12 
weeks was revised to include HIV postexposure prophylaxis (PEP), since PEP use 
in the period prior to randomization, like PrEP use, may interfere with accurate 
HIV incidence rate estimation.
Synopsis, Section 4.2.2
Text pertaining to unplanned participant unblinding was revised for consistency 
with the remainder of the protocol, and now indicates that any participant who is 
unblinded will move to the PK Tail Phase, which is necessary to provide PrEP 
coverage for the LEN PK tail period.
Section 5.1.4
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 bNAb use was deleted due to 
redundancy; this information is provided in the protocol eligibility criteria.
Section 5.4
Text pertaining to drug-drug interactions 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 (Table 23).
Section 5.4
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 bHIV 
incidence rate determination, and is an important allowance to minimize HIV 
acquisition risk during the screening period.
Section 6.2.1
Updated the text to clarify that the SC LEN/placebo administration at Weeks 
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
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
Text was updated to clarify that all study visits are to be scheduled relative to the 
previous injection visit date, except in instances of oral LEN/placebo bridging.
Section 6.4,
Study Procedure Table 
(Procedures for Incidence 
Phase and Randomized 

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Rationale for Key Changes Included in Amendment 3
Affected Sections
Blinded Phase [footnote v] 
and Procedures for LEN 
OLE Phase [footnote u]) 
Pharmacokinetic Tail Phase Assessments were updated to clarify that all study 
visits are to be scheduled relative to PK Tail Day 1.
Section 6.5
Text was added to clarify that glucose will be collected in a fasting state only on 
visits that metabolic assessments occur.
Section 6.9.2
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 make clear that participants 
who have a positive rapid HIV test should not receive injection study drug.
Section 6.13
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
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
Additional guidance was added to the adverse event reporting procedures to 
clarify the interpretation of DAIDS AE grading scale entries pertaining to ISRs.
Sections 7.2.2 and 7.7.1
Updated the language pertaining to injections 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, 
and 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.
Synopsis, Section 8.2.1.2
Updated to clarify the criteria for All Screened Set, which includes all participants 
who were screened for HIV-1 in the Incidence Phase and had nonmissing HIV-1 
diagnosis based on HIV test prior to first dose date.
Section 8.3.1.1
Updated the language for clarify that LEN plasma concentrations will be 
summarized by time point for SC and oral LEN. Additionally, Population PK 
analysis of LEN is planned.
Section 8.8
The relative standard error was corrected to 6.5% due to a typographical error.
Synopsis, Section 8.9

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Rationale for Key Changes Included in Amendment 3
Affected Sections
The title of the Study Procedures Table was revised for clarity and now notes that 
the table contains both Incidence Phase and Randomized Blinded Phase 
procedures.
Appendix 3 (Study 
Procedures Tables)
To align with Section 6.2.2, updated the routine asymptomatic sexually 
transmitted infection (STI) testing for Neisseria gonorrhoeae (GC), Chlamydia 
trachomatis (CT), Trichomonas vaginalis (TV), and Syphilis for Randomized 
Blinded Phase to reflect Week 26/Injection 2, Week 52, and every 26 weeks 
thereafter.
Appendix 3 (Study 
Procedures Tables)
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, Sections 6.1.1, 
6.2.1 and Appendix 3 
(Study Procedures Tables- 
Procedures for Incidence 
Phase and Randomized 
Blinded Phase [Footnote 
‘j’])
Recency assay language was removed from the chart, since it is not relevant to the 
determination of study eligibility.
Figure 12
The name of the rapid HIV test was corrected to reflect that it is an HIV-1/2 test. 
Reflexive RNA quantitative 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). References to performing 
HIV-1 RNA quantitative NAAT in Section 6.12 were removed in cases where 
such testing would be redundant with reflexive testing.
Appendix 6, Section 6.12
Updated the HIV testing algorithm footnotes to clarify that any HIV RNA 
detected is considered a positive quant NAAT'.
Appendix 6a (footnote 2) 
and 6b (footnote 3)
Added a new footnote ‘n’ to clarify that all PK tail visits should be scheduled 
from PK Tail Day 1.’
Appendix 3 (Study 
Procedures for PK Tail 
Phase)
Clarification was added in Schema that in case Randomized Blinded Phase is 
stopped early for an efficacy outcome, some participants may have less than 
52 weeks of follow-up.
Study Schema (footnote a)
Text was updated to align with the Gilead clinical trial agreement and publication 
policies.
Section 9.2.2 
Text was updated to align with the study procedures table that ‘RNA quantitative 
NAAT’ was added in place of ‘viral load.’
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 ‘m’)
Minor changes to correct typographic errors, language, and to provide 
clarifications.
Throughout, as needed

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Amendment 4
CONFIDENTIAL
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Prot GS-US-412-5624 amd-4
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Development
eSigned
11-Oct-2024
18:59:12
PPD