A Phase 2 Randomized, Open-Label, Active-Controlled Study Evaluating the Safety and Efficacy of an Oral Weekly Regimen of Islatravir in Combination With Lenacapavir in Virologically Suppressed People With HIV
Phase: PHASE2
Conditions: HIV-1 Infection
Sponsor: Gilead Sciences

 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Study Title: 
A Phase 2 Randomized, Open-Label, Active Controlled Study 
Evaluating the Safety and Efficacy of an Oral Weekly Regimen 
of Islatravir in Combination with Lenacapavir in Virologically 
Suppressed People with HIV 
 
 
Sponsor: 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
USA 
 
 
IND Number: 
138311 
EU CT Number: 
Not Applicable 
ClinicalTrials.gov 
Identifier: 
NCT05052996 
 
 
Indication: 
HIV-1 Infection 
 
 
Protocol ID: 
GS-US-563-6041 
 
 
Contact Information: 
The medical monitor name and contact information will be 
provided on the Key Study Team Contact List. 
 
 
Protocol Version/Date: 
Amendment 6 
02 December 2025 
 
 
Amendment History: 
Original: 
09 June 2021 
Amendment 1 
07 September 2021 
Amendment 2 
20 July 2022 
Amendment 3 
26 October 2022 
Amendment 4 
21 February 2024 
Amendment 5 
19 November 2024 
A high-level summary of the changes in each amendment is 
provided in Appendix 6. 
 
 
Country-Specific 
Requirements: 
Country-specific requirements, as applicable, are listed in 
Appendix 5. 
 
This study will be conducted under United States Food and Drug Administration investigational 
new drug application regulations (21 Code of Federal Regulations Part 312). 
 
This study will be conducted in compliance with this protocol and in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki, and that are consistent with 
(r) GILEAU 

Islatravir + Lenacapavir 
 
Protocol GS-US-563-6041 
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Gilead Sciences, Inc.  
Amendment 6 
CONFIDENTIAL 
Page 2 
02 December 2025 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) and applicable 
regulatory requirements. 
 
 
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The information contained in this document, particularly unpublished data, is the property or 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. 
 

Islatravir + Lenacapavir 
 
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Amendment 6 
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TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................................. 3 
LIST OF IN-TEXT TABLES ........................................................................................................................................ 6 
LIST OF IN-TEXT FIGURES ...................................................................................................................................... 7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................................. 8 
PROTOCOL SYNOPSIS ............................................................................................................................................ 11 
STUDY SCHEMA ...................................................................................................................................................... 17 
STUDY PROCEDURES TABLE ............................................................................................................................... 18 
1. 
INTRODUCTION .............................................................................................................................................. 26 
1.1. 
Background ............................................................................................................................................ 26 
1.2. 
Background on Study Interventions ....................................................................................................... 26 
1.2.1. 
Information About Islatravir ................................................................................................ 26 
1.2.2. 
Information About Lenacapavir ........................................................................................... 27 
1.2.3. 
Clinical Studies of Coadministered ISL and LEN and ISL/LEN Fixed-
dose Combination................................................................................................................. 40 
1.2.4. 
Information About B/F/TAF ................................................................................................ 41 
1.3. 
Rationale for This Study ........................................................................................................................ 41 
1.4. 
Rationale for Dose Selection of Islatravir .............................................................................................. 42 
1.5. 
Rationale for Dose Selection of Lenacapavir ......................................................................................... 47 
1.6. 
Risk/Benefit Assessment for the Study .................................................................................................. 47 
1.7. 
Compliance ............................................................................................................................................ 50 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................................................... 51 
3. 
STUDY DESIGN ................................................................................................................................................ 52 
3.1. 
Study Design Overview ......................................................................................................................... 52 
3.2. 
Study Treatments ................................................................................................................................... 53 
3.3. 
Duration of Treatment ............................................................................................................................ 53 
3.4. 
Discontinuation Criteria ......................................................................................................................... 53 
3.4.1. 
Early Discontinuation from Study Treatment ...................................................................... 53 
3.4.2. 
Early Discontinuation from the Study .................................................................................. 54 
3.4.3. 
Lost to Follow-up ................................................................................................................. 54 
3.5. 
Definitions for Time of Primary Endpoint and End of Study ................................................................ 54 
3.5.1. 
Primary Endpoint ................................................................................................................. 54 
3.5.2. 
End of Study ......................................................................................................................... 54 
3.6. 
Poststudy Care ........................................................................................................................................ 54 
3.7. 
Source Data ............................................................................................................................................ 54 
4. 
PARTICIPANT POPULATION ......................................................................................................................... 55 
4.1. 
Number of Participants and Participant Selection .................................................................................. 55 
4.1.1. 
Participant Replacement ....................................................................................................... 55 
4.2. 
Inclusion Criteria (Applicable to Both Cohorts, Unless Specified Otherwise) ...................................... 55 
4.3. 
Exclusion Criteria (Applicable to Both Cohorts, Unless Specified Otherwise) ..................................... 55 
5. 
STUDY DRUGS ................................................................................................................................................. 58 
5.1. 
Randomization, Blinding, and Treatment Codes Access ....................................................................... 58 
5.1.1. 
Randomization ..................................................................................................................... 58 
5.1.2. 
Blinding ................................................................................................................................ 58 
5.2. 
Description and Handling of Islatravir ................................................................................................... 58 

Islatravir + Lenacapavir 
 
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5.2.1. 
Formulation .......................................................................................................................... 58 
5.2.2. 
Packaging and Labeling ....................................................................................................... 59 
5.2.3. 
Storage and Handling ........................................................................................................... 59 
5.3. 
Description and Handling of Lenacapavir .............................................................................................. 59 
5.3.1. 
Formulation .......................................................................................................................... 59 
5.3.2. 
Packaging and Labeling ....................................................................................................... 60 
5.3.3. 
Storage and Handling ........................................................................................................... 60 
5.4. 
Description and Handling of B/F/TAF ................................................................................................... 60 
5.4.1. 
Formulation .......................................................................................................................... 60 
5.4.2. 
Packaging and Labeling ....................................................................................................... 60 
5.4.3. 
Storage and Handling ........................................................................................................... 61 
5.5. 
Description and Handling of ISL/LEN 
 .......................................................................................... 61 
5.5.1. 
Formulation .......................................................................................................................... 61 
5.5.2. 
Packaging and Labeling ....................................................................................................... 61 
5.5.3. 
Storage and Handling ........................................................................................................... 61 
5.6. 
Dosage and Administration of Islatravir and Lenacapavir ..................................................................... 61 
5.7. 
Dosage and Administration of B/F/TAF ................................................................................................ 65 
5.8. 
Prior and Concomitant Medications ....................................................................................................... 65 
5.9. 
Accountability for Study Drugs ............................................................................................................. 67 
5.9.1. 
Study Drug Return or Disposal ............................................................................................ 67 
6. 
STUDY PROCEDURES .................................................................................................................................... 68 
6.1. 
Informed Consent ................................................................................................................................... 68 
6.2. 
Screening, Participant Enrollment, and Treatment Assignment ............................................................. 68 
6.3. 
Instructions for Study Procedures .......................................................................................................... 69 
6.3.1. 
Adverse Events ..................................................................................................................... 69 
6.3.2. 
Concomitant Medications ..................................................................................................... 69 
6.3.3. 
Electrocardiograms ............................................................................................................... 69 
6.3.4. 
Medical History and Demographic Information................................................................... 69 
6.3.5. 
Physical Examination ........................................................................................................... 69 
6.3.6. 
Clinical Laboratory Assessments ......................................................................................... 70 
6.3.7. 
Pharmacokinetics Assessments ............................................................................................ 71 
6.3.8. 
Clinical Virology Analyses .................................................................................................. 71 
6.3.9. 
Patient-Reported Outcomes .................................................................................................. 73 
6.4. 
Assessments for Early Discontinuation from Study Treatment or from the Study ................................ 74 
6.4.1. 
Assessments for Early Discontinuation from Study Treatment ............................................ 74 
6.4.2. 
Assessments for End of Study .............................................................................................. 74 
6.5. 
Poststudy Care ........................................................................................................................................ 75 
6.6. 
Sample Storage....................................................................................................................................... 75 
7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ............................................................................... 76 
7.1. 
Definitions of Adverse Events and Serious Adverse Events .................................................................. 76 
7.1.1. 
Adverse Events ..................................................................................................................... 76 
7.1.2. 
Serious Adverse Events ........................................................................................................ 76 
7.1.3. 
Adverse Events of Special Interest ....................................................................................... 77 
7.1.4. 
Study Drugs and Gilead Concomitant Medications Special Situations 
Reports ................................................................................................................................. 77 
7.2. 
Assessment of Adverse Events and Serious Adverse Events ................................................................. 78 
7.2.1. 
Assessment of Causality for Study Drugs and Procedures ................................................... 78 
7.2.2. 
Assessment of Severity ........................................................................................................ 79 
7.3. 
Investigator Reporting Requirements and Instructions .......................................................................... 79 
7.3.1. 
Requirements for Collection Before Study Drug Initiation .................................................. 79 
7.3.2. 
Adverse Events ..................................................................................................................... 79 
7.3.3. 
Serious Adverse Events ........................................................................................................ 79 
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Amendment 6 
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7.3.4. 
Adverse Events of Special Interest ....................................................................................... 80 
7.3.5. 
Study Drug Special Situations Reports ................................................................................ 80 
7.3.6. 
Concomitant Medications Reports ....................................................................................... 80 
7.4. 
Reporting Process for Serious Adverse Events, Adverse Events of Special Interest, and 
Special Situations Reports ...................................................................................................................... 80 
7.4.1. 
Serious Adverse Event Reporting Process ........................................................................... 80 
7.4.2. 
Adverse Events of Special Interest Reporting Process ......................................................... 81 
7.4.3. 
Special Situations Reporting Process ................................................................................... 81 
7.5. 
Gilead Reporting Requirements ............................................................................................................. 82 
7.6. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events .......................................................................................................................... 83 
7.7. 
Toxicity Management ............................................................................................................................ 83 
8. 
STATISTICAL CONSIDERATIONS ................................................................................................................ 85 
8.1. 
Analysis Objectives and Endpoints ........................................................................................................ 85 
8.2. 
Planned Analyses ................................................................................................................................... 85 
8.2.1. 
Interim Analysis ................................................................................................................... 85 
8.2.2. 
Primary Analysis .................................................................................................................. 86 
8.2.3. 
Final Analysis ....................................................................................................................... 86 
8.3. 
Analysis Conventions ............................................................................................................................. 86 
8.3.1. 
Analysis Sets ........................................................................................................................ 86 
8.3.2. 
Data Handling Conventions ................................................................................................. 87 
8.4. 
Demographic and Baseline Characteristics Analysis ............................................................................. 87 
8.5. 
Efficacy Analysis ................................................................................................................................... 88 
8.5.1. 
Primary Analysis .................................................................................................................. 88 
8.5.2. 
Secondary Analyses ............................................................................................................. 88 
8.5.3. 
All ISL+LEN Analysis ......................................................................................................... 88 
8.6. 
Safety Analysis....................................................................................................................................... 89 
8.6.1. 
Extent of Exposure ............................................................................................................... 89 
8.6.2. 
Adverse Events ..................................................................................................................... 89 
8.6.3. 
Laboratory Evaluations ........................................................................................................ 90 
8.6.4. 
Other Safety Evaluations ...................................................................................................... 90 
8.7. 
Adjustments for Multiplicity .................................................................................................................. 90 
8.8. 
Pharmacokinetic Analysis ...................................................................................................................... 90 
8.9. 
Sample Size ............................................................................................................................................ 90 
8.10. 
Data Monitoring Committee .................................................................................................................. 91 
9. 
RESPONSIBILITIES.......................................................................................................................................... 92 
9.1. 
Investigator Responsibilities .................................................................................................................. 92 
9.1.1. 
Good Clinical Practice.......................................................................................................... 92 
9.1.2. 
Financial Disclosure ............................................................................................................. 92 
9.1.3. 
Institutional Review Board/Independent Ethics Committee Review and 
Approval............................................................................................................................... 92 
9.1.4. 
Informed Consent ................................................................................................................. 92 
9.1.5. 
Confidentiality ...................................................................................................................... 93 
9.1.6. 
Study Files and Retention of Records .................................................................................. 93 
9.1.7. 
Case Report Forms ............................................................................................................... 95 
9.1.8. 
Investigator Inspections ........................................................................................................ 95 
9.1.9. 
Protocol Compliance ............................................................................................................ 95 
9.2. 
Sponsor Responsibilities ........................................................................................................................ 95 
9.2.1. 
Protocol Modifications ......................................................................................................... 95 
9.2.2. 
Study Reports and Publications ............................................................................................ 96 
9.3. 
Joint Investigator/Sponsor Responsibilities ........................................................................................... 96 
9.3.1. 
Payment Reporting ............................................................................................................... 96 

Islatravir + Lenacapavir 
 
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9.3.2. 
Access to Information for Monitoring .................................................................................. 96 
9.3.3. 
Access to Information for Auditing or Inspections .............................................................. 96 
9.3.4. 
Study Discontinuation .......................................................................................................... 96 
9.3.5. 
Data Protection ..................................................................................................................... 97 
10. REFERENCES ................................................................................................................................................... 98 
11. APPENDICES .................................................................................................................................................... 99 
 
Appendix 1. 
Investigator Signature Page .................................................................................................. 100 
Appendix 2. 
Pandemic Risk Assessment and Mitigation Plan .................................................................. 101 
Appendix 3. 
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements................................................................................................. 104 
Appendix 4. 
Management of Clinical and Laboratory Adverse Events .................................................... 107 
Appendix 5. 
Country-Specific Requirements ........................................................................................... 108 
Appendix 6. 
Amendment History ............................................................................................................. 109 
 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Study Procedures for Cohort 1 ............................................................................................... 18 
Table 2. 
Study Procedures for Cohort 2 ............................................................................................... 21 
Table 3. 
GS-US-563-6148: Summary Statistics and Statistical Comparisons of ISL and LEN 
PK Parameters ........................................................................................................................ 28 
Table 4. 
GS-US-200-4333: Preliminary Plasma PK Parameters of LEN 300 mg Oral Capsule 
Following Administration Alone or with DRV/COBI (800/150 mg QD) or COBI 
(150 mg QD) .......................................................................................................................... 29 
Table 5. 
GS-US-200-4333: Preliminary Plasma PK Parameters of LEN 300 mg Oral Tablet 
Following Administration Alone or with VORI (400/200 mg BID) ...................................... 30 
Table 6. 
GS-US-200-4333: Preliminary Plasma PK Parameters of LEN 300 mg Oral Tablet 
Following Administration Alone or with ATV/COBI (300/150 mg QD) .............................. 30 
Table 7. 
GS-US-200-4333: Preliminary Plasma PK Parameters of LEN 300 mg Tablet 
Following Administration Alone or with RIF (600 mg QD), EFV (600 mg QD), or 
FAM (40 mg).......................................................................................................................... 31 
Table 8. 
GS-US-200-4333: Preliminary Plasma PK Parameters of PIT (2 mg) Following 
Administration Alone or with LEN ........................................................................................ 32 
Table 9. 
GS-US-200-4333: Preliminary Plasma PK Parameters of ROS (5 mg) Following 
Administration Alone or with LEN ........................................................................................ 32 
Table 10. 
GS-US-200-4333: Preliminary Plasma PK Parameters of TAF (25 mg) and its 
Metabolite, TFV, Following Administration Alone or with LEN .......................................... 33 
Table 11. 
GS-US-200-4333: Preliminary Plasma PK Parameters of MDZ (2.5 mg) and its 
Metabolite, 1-OH-MDZ, Following Administration Alone or with LEN .............................. 33 
Table 12. 
GS-US-200-4330: Treatment-Emergent Adverse Events by Preferred Term (Safety 
Analysis Set)........................................................................................................................... 35 
Table 13. 
GS-US-200-4330: Summary Statistics and Statistical Comparison of Plasma PK 
Parameters (LEN PK Analysis Sets) ...................................................................................... 36 
Table 14. 
GS-US-200-4334: Study Treatments ...................................................................................... 37 
Table 15. 
GS-US-200-4334: Treatment-Related, Treatment-Emergent Adverse Events in > 
5% of Participants Overall Receiving SC LEN by Preferred Term ........................................ 38 
Table 16. 
GS-US-200-4625: Treatment-Related, Treatment-Emergent Adverse Events in 
> 5% of Participants Overall by Preferred Term .................................................................... 40 

Islatravir + Lenacapavir 
 
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Gilead Sciences, Inc.  
Amendment 6 
CONFIDENTIAL 
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02 December 2025 
Table 17. 
Week 48 Predicted Mean Absolute Lymphocyte Cell Count and Predicted Change 
From Baseline Ratio Following Once Weekly Dosing, Islatravir Versus Control, 
Virologically Suppressed Population ..................................................................................... 45 
Table 18. 
Week 48 Predicted Mean Absolute Lymphocyte Cell Count and Predicted Change 
From Baseline Ratio Following Once Weekly Dosing, Islatravir Versus Control, 
Treatment-Naive Population................................................................................................... 45 
Table 19. 
Week 48 Predicted Mean CD4+ T-Cell Count and Predicted Change From Baseline 
Ratio Following Once Weekly Dosing, Islatravir Versus Control, Virologically 
Suppressed Population............................................................................................................ 46 
Table 20. 
Week 48 Predicted Mean CD4+ T-Cell Count and Predicted Change From Baseline 
Ratio Following Once Weekly Dosing, Islatravir Versus Control, Treatment-Naive 
Population ............................................................................................................................... 46 
Table 21. 
Cohort 2: Treatment Group 3 Dosing Schedule ..................................................................... 62 
Table 22. 
Cohort 2: Missed Dose Recommendations for ISL and LEN ................................................. 63 
Table 23. 
Cohort 2: Missed Dose Recommendations for ISL/LEN 
 .............................................. 64 
Table 24. 
Examples of Prior and Concomitant Medications That are to be Used With Caution 
or That Are Prohibited due to the Potential for PK DDI With Islatravir or 
Lenacapavira ........................................................................................................................... 66 
Table 25. 
Laboratory Assessments ......................................................................................................... 70 
Table 26. 
PK Substudy Sample Collection Time Points ........................................................................ 71 
 
 
LIST OF IN-TEXT FIGURES 
Figure 1. 
Study Schema for Cohort 1 and Cohort 2 ............................................................................... 17 
Figure 2. 
ISL-TP Concentrations, Achieved with an ISL 20 mg Once-Weekly Regimen, 
Provide Coverage for Both Wild-type and M184V Mutant Virus.......................................... 42 
Figure 3. 
Simulations of ISL-TP Time Series Following Multiple QD and QW ISL Dosing ............... 44 
Figure 4. 
Target Exposures are Rapidly Achieved and Maintained with An Oral LEN 
Once-Weekly Regimen .......................................................................................................... 47 
Figure 5. 
Virologic Rebound Schema .................................................................................................... 73 
 
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Amendment 6 
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02 December 2025 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
3TC 
lamivudine 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ART 
antiretroviral therapy 
ARV 
antiretroviral 
ATV 
atazanavir 
AUC 
area under the concentration versus time curve 
AUCinf 
area under the concentration versus time curve extrapolated to infinite time, calculated 
as AUClast + (Clast/z) 
AUClast 
area under the concentration versus time curve from time zero to the last quantifiable 
concentration 
AUCtau 
area under the concentration versus time curve over the dosing interval 
BCRP 
breast cancer resistance protein 
B/F/TAF 
bictegravir/emtricitabine/tenofovir alafenamide (coformulated; Biktarvy®) 
BLQ 
below the limit of quantification 
BMI 
body mass index 
CD4 
clusters of differentiation 4 
CD8 
clusters of differentiation 8 
CI 
confidence interval 
CLcr 
creatinine clearance 
CL/F 
apparent oral clearance 
Cmax 
maximum observed concentration of drug 
COBI 
cobicistat (Tybost®) 
CSR 
clinical study report 
Ctau 
observed drug concentration at the end of the dosing interval 
CYP 
cytochrome P450 enzyme 
DAIDS 
Division of AIDS 
dCK 
deoxycytidine kinase 
DDI 
drug-drug interaction 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
DRV 
darunavir 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EFV 
efavirenz 
EQ-5D-5L 
EuroQoL 5 dimension 5 level 
ESDD 
early study drug discontinuation 
EU 
European Union 

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Amendment 6 
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FAM 
famotidine 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
 
 
FTC 
emtricitabine 
Gilead 
Gilead Sciences, Inc. 
GLSM 
geometric least-squares mean 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDPE 
high-density polyethylene 
HIV 
human immunodeficiency virus 
HIV-1 
human immunodeficiency virus type 1 
HIVDQoL 
HIV Dependent Quality of Life 
HIVTSQ12 
HIV Treatment Satisfaction Questionnaires 12 
HIVTSQc12 
HIV Treatment Satisfaction Questionnaire change version 
HIVTSQs12 
HIV Treatment Satisfaction Questionnaire 12 status version 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation (of Technical Requirements for 
Pharmaceuticals for Human Use) 
IND 
investigational new drug 
IQ 
inhibitory quotient 
IRT 
interactive response technology 
ISL 
islatravir 
ISL-TP 
triphosphate form of islatravir 
LEN 
lenacapavir 
LLOQ 
lower limit of quantification 
M = F 
missing = failure 
MDZ 
midazolam 
MSD 
Merck Sharp & Dohme LLC 
NNRTI 
nonnucleoside reverse transcriptase inhibitor 
NRTI 
nucleoside reverse transcriptase inhibitor 
OATP 
organic anion transporting polypeptide 
OBR 
optimized background regimen 
P-gp 
P-glycoprotein 
PIT 
pitavastatin 
PK 
pharmacokinetic(s) 
PP-R 
The Patient Perspective of Regimen  
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PP-RC 
The Patient Perspective of Regimen Change 
PrEP 
pre-exposure prophylaxis 
PRO 
patient-reported outcome 
PWH 
people with HIV 
Q1 
first quartile 
Q3 
third quartile 
QD 
once daily 
QM 
once monthly 
QW 
once weekly 
rBA 
relative bioavailability 
RIF 
rifampin 
RNA 
ribonucleic acid 
ROS 
rosuvastatin 
SAC 
Safety Assessment Committee 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SSR 
special situation report 
TAF 
tenofovir alafenamide (Vemlidy®) 
Tmax 
time (observed time point) of Cmax 
UGT1A1 
uridine diphosphate glucuronosyltransferase 1A1 
ULN 
upper limit of normal 
US 
United States 
VL 
viral load 
VORI 
voriconazole 
WT 
wild type 
 

Islatravir + Lenacapavir 
 
Protocol GS-US-563-6041 
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Gilead Sciences, Inc.  
Amendment 6 
CONFIDENTIAL 
Page 11 
02 December 2025 
PROTOCOL SYNOPSIS 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
 
 
Study Title: A Phase 2 Randomized, Open-Label, Active Controlled Study Evaluating the 
Safety and Efficacy of an Oral Weekly Regimen of Islatravir in Combination with 
Lenacapavir in Virologically Suppressed People with HIV 
Regulatory Agency Identifier Number(s): 
IND Number: 138311 
EU CT Number: Not Applicable 
ClinicalTrials.gov Identifier: NCT05052996 
Study Centers Planned: 
Approximately 45 centers in the United States (US) 
Objectives and Endpoints: 
Primary Objective 
Primary Endpoint 
• 
To evaluate the efficacy of oral weekly islatravir 
(ISL, MK-8591) in combination with lenacapavir 
(LEN, GS-6207) in virologically suppressed 
people with HIV (PWH) at Week 24 
• 
The proportion of participants with HIV-1 RNA 
≥ 50 copies/mL at Week 24 as determined by the 
US Food and Drug Administration 
(FDA)-defined snapshot algorithm 
Secondary Objectives 
Secondary Endpoints 
• 
To evaluate the efficacy of oral weekly ISL in 
combination with LEN in virologically 
suppressed PWH at Weeks 12, 24, and 48 
• 
The proportion of participants with HIV-1 RNA 
≥ 50 copies/mL at Weeks 12 and 48 as 
determined by the US FDA-defined snapshot 
algorithm 
• 
The proportions of participants with HIV-1 RNA 
< 50 copies/mL at Weeks 12, 24, and 48 as 
determined by the US FDA-defined snapshot 
algorithm 
• 
The change from baseline in CD4+ T-cell count 
at Weeks 12, 24, and 48 
• 
To evaluate the safety and tolerability of oral 
weekly ISL in combination with LEN 
• 
The incidence of treatment-emergent adverse 
events (AEs) leading to study drug 
discontinuation 
• 
To evaluate the pharmacokinetics (PK) of ISL 
and LEN administered as an oral weekly 
combination regimen 
• 
ISL and LEN PK parameters (Cmax, Tmax, Ctau, 
AUCtau, and t1/2, as applicable) 

Islatravir + Lenacapavir 
 
Protocol GS-US-563-6041 
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Gilead Sciences, Inc.  
Amendment 6 
CONFIDENTIAL 
Page 12 
02 December 2025 
 
Study Design: 
A schematic diagram of the study is provided in Figure 1. 
This is a Phase 2, randomized, open-label, active-controlled, multicenter study to evaluate the 
safety, efficacy, and PK of ISL+LEN. 
Cohort 1: 
Virologically suppressed PWH who meet all eligibility criteria will be randomized in a 
2:1 ratio to 1 of 2 treatment groups. Enrollment and dosing in Cohort 1 were stopped 
prematurely by the sponsor. 
Treatment Group 1 (n = 50 planned) 
Oral ISL 40 mg and LEN 600 mg loading on Days 1 and 2 
Oral weekly ISL 20 mg administered with LEN 300 mg (ISL+LEN) 
Treatment Group 2 (n = 25 planned) 
Oral daily bictegravir/emtricitabine/tenofovir alafenamide (1  50/200/25 mg tablet) 
(B/F/TAF). 
Participants in Cohort 1 will receive randomized study drugs for 48 weeks. Prior to the 
sponsor discontinuation of Cohort 1, it was planned that following completion of the Week 48 
visit, participants receiving ISL+LEN in Treatment Group 1 were to continue ISL+LEN and 
attend visits every 12 weeks. Participants in Treatment Group 2 were to switch from B/F/TAF 
to the ISL+LEN regimen (starting with the loading doses over 2 days) and continue the study. 
Participants in Treatment Group 2 who did not switch from B/F/TAF to ISL+LEN at Week 48 
were to be discontinued from the study. 
After Week 48, participants taking ISL+LEN were to attend visits every 12 weeks until the 
product became accessible to participants commercially or Gilead Sciences, Inc. (Gilead) 
elected to discontinue the study. 
 
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Islatravir + Lenacapavir 
 
Protocol GS-US-563-6041 
Final 
Gilead Sciences, Inc.  
Amendment 6 
CONFIDENTIAL 
Page 13 
02 December 2025 
Cohort 2: 
Virologically suppressed PWH who meet all eligibility criteria will be randomized in a 
1:1 ratio to 1 of 2 treatment groups: 
Treatment Group 3 (n = 50 planned) 
Day 1: LEN oral 
  
 and ISL 
  
 
Day 2: LEN oral 
  
 
Day 8 and weekly thereafter (ie, every 7 days): LEN oral 
  
) and ISL 
  
 or ISL
 tablet (when 
available)  
Treatment Group 4 (n = 50 planned) 
Oral daily B/F/TAF (1  50/200/25 mg tablet) 
Randomization will be stratified by CD4+ T-cell count (350 to 499 [inclusive] 
cells/mm3 or ≥ 500 cells/mm3) at screening. 
Participants in Cohort 2 will receive study drugs for at least 48 weeks during the Randomized 
Phase. At the Week 48 visit, all participants will be given an option to participate in an 
Extension Phase to receive ISL+LEN or ISL/LEN 
 tablet (when available). Participants in 
Treatment Group 3 may continue to receive ISL+LEN, while participants in Treatment 
Group 4 may switch from B/F/TAF to ISL+LEN, starting with the loading doses of LEN over 
2 days. During the Extension Phase, participants who are receiving ISL+LEN will switch to 
ISL/LEN
 when it becomes available and begin taking ISL/LEN
 starting at their 
next scheduled dose. Participants who do not wish to participate in the Extension Phase will be 
discontinued from the study. Participants in the Extension Phase will attend visits every 
12 weeks until Week 144; visits will occur every 24 weeks after Week 144 until ISL/LEN 
 becomes available to participants or Gilead elects to discontinue the study, whichever 
occurs first. 
Number of Participants Planned: 
Cohort 1: Approximately 75 virologically suppressed PWH will be enrolled in this cohort. 
Fifty participants may be enrolled in Treatment Group 1 and 25 participants may be enrolled 
in Treatment Group 2. Cohort 1 enrollment was stopped prior to reaching the target. 
Cohort 2: Approximately 100 virologically suppressed PWH will be enrolled in this cohort. 
Fifty participants may be enrolled in each of Treatment Groups 3 and 4. 
Target Population: Virologically suppressed PWH ≥ 18 years of age. 
Duration of Treatment: Duration of treatment in the Randomized Phase is 48 weeks. 
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Islatravir + Lenacapavir 
 
Protocol GS-US-563-6041 
Final 
Gilead Sciences, Inc.  
Amendment 6 
CONFIDENTIAL 
Page 14 
02 December 2025 
Diagnosis and Main Eligibility Criteria: Virologically suppressed PWH who meet the 
following criteria: 
• Aged ≥ 18 years at screening 
• Plasma HIV-1 RNA < 50 copies/mL for ≥ 24 weeks before and at screening 
• Received B/F/TAF for ≥ 24 weeks prior to screening 
• No nonnucleoside reverse transcriptase inhibitor (NNRTI) or nucleos(t)ide reverse 
transcriptase inhibitor (NRTI) resistance, including M184V/I (Cohort 2) 
• CD4+ T-cells ≥ 200 cells/mm3 (Cohort 1) 
• CD4+ T-cells ≥ 350 cells/mm3 (Cohort 2) 
Study Procedures/Frequency: 
Cohort 1: 
The schedule of study procedures is presented in Table 1. 
After screening, participants will have onsite visits on Day 1; at Weeks 4, 8, and 12; and then 
every 12 weeks thereafter. Participants in the PK substudy will have an additional onsite visit 
on Day 2. Participants in Treatment Group 1 will have telephone visits on Day 2 and at 
Week 2. 
Cohort 2: 
The schedule of study procedures is presented in Table 2. 
After screening, participants will have onsite visits on Day 1; at Weeks 4, 8, and 12; and then 
every 6 weeks thereafter through Week 48 of the Randomized Phase. Participants in the PK 
substudy will have an additional onsite visit on Day 2 of the Randomized Phase. Participants 
in Treatment Group 3 and 4 will have a telephone visit at Day 2 and Week 2 of the 
Randomized Phase. 
Participants in the Extension Phase will have onsite visits every 12 weeks through Week 144 
and every 24 weeks thereafter. Participants in Treatment Group 4 who switch to ISL+LEN or 
ISL/LEN
 (when available) in the Extension Phase will receive telephone calls to confirm 
adherence to the second day of the LEN loading dose and the second ISL+LEN or ISL/LEN 
(when available) weekly dose.  
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Islatravir + Lenacapavir 
 
Protocol GS-US-563-6041 
Final 
Gilead Sciences, Inc.  
Amendment 6 
CONFIDENTIAL 
Page 15 
02 December 2025 
Test Product, Dose, and Mode of Administration: 
Cohort 1: 
Treatment Group 1: 
Oral ISL 40 mg (2  20 mg capsules) and oral LEN 600 mg (2  300 mg tablets) administered 
on the first and second days of the ISL+LEN regimen without regard to food. 
Oral ISL 20 mg (1  20 mg capsule) and oral LEN 300 mg (1  300 mg tablet) administered 
on Day 8 of the ISL+LEN regimen and every week (7 days) thereafter (ie, on the same day of 
the week) without regard to food. 
Cohort 2: 
For Treatment Group 3 (and any Treatment Group 4 participant electing to start ISL+LEN in 
the Extension Phase), oral ISL and oral LEN are to be taken without regard to food and, where 
indicated, taken together. From Day 8 onward, ISL and LEN should be taken weekly on the 
same day of the week. 
During the Extension Phase, participants who are receiving ISL+LEN will switch to the 
ISL/LEN 
tablet (when available) administered orally on the same schedule, taken weekly 
on the same day of the week, without regard to food. 
  
LENa 
ISLa 
Day 1 
Day 2 
No ISL 
Day 8 (and weekly thereafter) 
 
; ISL = islatravir; LEN = lenacapavir 
a 
Including participants in Treatment Group 4 who continue in the Extension Phase. 
Reference Therapy, Dose, and Mode of Administration: 
Treatment Groups 2 and 4: Oral daily B/F/TAF (1  50/200/25 mg tablet) administered 
without regard to food. 
Statistical Methods: The primary efficacy endpoint is the proportion of participants with 
HIV-1 RNA ≥ 50 copies/mL at Week 24 as determined by the US FDA-defined snapshot 
algorithm. The 95% CI of the difference in the proportion of participants with HIV-1 RNA 
≥ 50 copies/mL at Week 24 between the ISL+LEN group and the B/F/TAF group within each 
cohort will be constructed based on an unconditional exact method using 2 inverted 1-sided 
tests. 
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Islatravir + Lenacapavir 
 
Protocol GS-US-563-6041 
Final 
Gilead Sciences, Inc.  
Amendment 6 
CONFIDENTIAL 
Page 16 
02 December 2025 
The same methods used to analyze the primary efficacy endpoint, as determined by the 
US FDA-defined snapshot algorithm, will be used to assess the proportion of participants with 
HIV1 RNA ≥ 50 copies/mL at Weeks 12 and 48 and the proportion of participants with HIV-1 
RNA <50 copies/mL at Weeks 12, 24, and 48. 
Changes from baseline in CD4+ T-cell count at Weeks 12, 24, and 48 will be summarized by 
treatment group within each cohort using descriptive statistics. The differences in changes 
from baseline in CD4+ T-cell count between the ISL+LEN group and the B/F/TAF group 
within each cohort and the associated 95% CIs will be constructed using analysis of 
covariance (ANCOVA) models, including baseline CD4+ T-cell count as a covariate and 
treatment (ISL+LEN vs B/F/TAF) as a fixed-effect in the models. 
Incidence of treatment-emergent AEs, AEs leading to discontinuation of study drugs, and 
treatment-emergent laboratory abnormalities will be summarized using descriptive statistics by 
treatment group within each cohort. 
For the general PK analyses, the PK of ISL and LEN may be evaluated using descriptive 
statistics or population analysis approaches. For the intensive PK substudy, plasma 
concentrations of ISL and LEN will be summarized by nominal sampling time. 
Pharmacokinetic parameters (Cmax, Tmax, Ctau, AUCtau, and t1/2, as appropriate) will be listed 
and summarized using descriptive statistics. 
 
 

Islatravir + Lenacapavir 
Protocol GS-US-563-6041 
Gilead Sciences, Inc. 
Figure 1. 
Cohort 1 
Screening 
Cohort 2 
Screening 
I 
Day l 
STUDY SCHEMA 
Study Schema for Cohort 1 and Cohort 2 
I 
Week24 
l O Endpoint 
I 
Visits every 12 weeks 
Week48 
I 
Extension Phase 
Day l Day 2 
Day 8 Week 24 
Week 48 
Week 144 
Final 
Amendment 6 
l O Endpoint 
Visits eveiy 12 weeks 
Visits eve1y 24 weeks 
1 ° = prima1y; B/F/T AF = bictegravir/emtricitabine/tenofovir alafenamide ( cofonuulated; Biktarvy®); 
ISL = islatravir; LEN = lenacapavir; QD = once daily; QW = once weekly 
The randomized treatment period is at least 48 weeks. At the Week 48 visit, all pa1t icipants will be given the option to take 
ISL+LEN or ISL/LEN-
in an Extension Phase until ISL/LE~ 
becomes available or until Gilead elects to discontinue 
the study, whichever occtu·s first. 
a 
At the Week 48 visit, all participants will be given the option to take ISL+LEN in an Extension Phase until ISIA,EN-
becomes available or until Gilead elects to discontinue the study, whichever occurs first. 
CONFIDENTIAL 
Page 17 
02 December 2025 

Islatravir + Lenacapavir 
 
 
Protocol GS-US-563-6041 
 
Final 
Gilead Sciences, Inc.  
 
Amendment 6 
CONFIDENTIAL 
Page 18 
02 December 2025 
STUDY PROCEDURES TABLE 
Table 1. 
Study Procedures for Cohort 1 
Enrollment and dosing in Cohort 1 were stopped prematurely by the sponsor in December 2021. 
Visit Window 
(Days) 
Screeninga 
Day 
1b 
Day 
2c 
Week 
2d 
Week 
4 
Week 
8 
Week 
12 
Week 
24 
Week 
36 
Week 
48e 
Week 
60 
Week 
72 
Week 84 
and every 
12 weeks 
thereafter 
ESDDf 
30- and 
60-Day 
Follow-upg 
Within 35 days 
prior to Day 1 
 
 
± 1 
day 
± 7 days 
± 14 days 
 
± 2 days 
Written informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PRO 
questionnaire 
administrationh 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
Obtain 
demographic 
information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsi 
(including weight) 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examinationj 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Symptom-directed 
physical 
examination 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
12-lead ECG 
(supine) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Islatravir + Lenacapavir 
 
 
Protocol GS-US-563-6041 
 
Final 
Gilead Sciences, Inc.  
 
Amendment 6 
CONFIDENTIAL 
Page 19 
02 December 2025 
Visit Window 
(Days) 
Screeninga 
Day 
1b 
Day 
2c 
Week 
2d 
Week 
4 
Week 
8 
Week 
12 
Week 
24 
Week 
36 
Week 
48e 
Week 
60 
Week 
72 
Week 84 
and every 
12 weeks 
thereafter 
ESDDf 
30- and 
60-Day 
Follow-upg 
Within 35 days 
prior to Day 1 
 
 
± 1 
day 
± 7 days 
± 14 days 
 
± 2 days 
Hematology, 
chemistry, 
urinalysis and 
urine chemistry, 
CD4+ T-cell 
countk 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy 
testl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSHm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
testl 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBV, HCV testsn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma HIV-1 
RNA 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma storage 
sampleo 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Whole blood 
storage samplep 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
PK plasma 
collectionq 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Randomizations 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oral ISL+LEN 
dispensation 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
B/F/TAF 
dispensation 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Telephone visit 
 
 
Xc 
Xd 
 
 
 
 
 
Xe 
 
 
 
 
 
Study drug 
accountability 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
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Islatravir + Lenacapavir 
 
 
Protocol GS-US-563-6041 
 
Final 
Gilead Sciences, Inc.  
 
Amendment 6 
CONFIDENTIAL 
Page 20 
02 December 2025 
AE = adverse event; ALT = alanine aminotransferase; ART = antiretroviral therapy; ARV = antiretroviral; AST = aspartate aminotransferase; 
B/F/TAF = bictegravir/emtricitabine/tenofovir alafenamide; CD4 = clusters of differentiation 4; CPK = creatine phosphokinase; ECG = electrocardiogram; EQ-5D-5L = 5-level 
EuroQoL (5 dimensions); ESDD = early study drug discontinuation; FSH = follicle-stimulating hormone; HBV = hepatitis B virus; HBcAb = hepatitis B core antibody; 
HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIVDQoL = HIV Dependent Quality of Life; HIVTSQ12 = HIV Treatment Satisfaction Questionnaire 12; 
HIVTSQs12 = HIV Treatment Satisfaction Questionnaire 12 status version; HIVTSQc12 = HIV Treatment Satisfaction Questionnaire change version ICF = informed consent 
form; ISL = islatravir; LEN = lenacapavir; PK = pharmacokinetic(s); PRO = patient-reported outcome 
a 
Screening evaluations must be completed within 35 days prior to Day 1. Conditions for participant rescreening are outlined in Section 6.2. 
b 
Day 1 tests and procedures must be completed prior to administration of the dose of study drugs. Participants must begin dosing on the same day as Day 1. 
c 
Participants in the PK substudy will come to the site for a study visit on Day 2 and will take their dose of study drugs at the site. All other participants in Treatment Group 1 
will receive a telephone call to confirm adherence to the Day 2 ISL+LEN dose. 
d 
Participants in Treatment Group 1 will have a telephone visit at Week 2 to assess AEs and concomitant medications, and to confirm adherence to weekly ISL+LEN dosing. 
e 
Participants in Treatment Group 2 who switch to ISL+LEN at Week 48 will receive telephone calls to confirm adherence to the second day of the ISL+LEN loading dose and 
the first ISL+LEN weekly dose. 
f 
Visit should occur within 3 days (+1 day) of permanently discontinuing study drugs. Participant should be counseled regarding the importance of resuming a complete ARV 
therapy in accordance with standard-of-care and referred to an appropriate HIV treatment facility. 
g 
Participants who received ISL+LEN and discontinue study drugs are required to return to the clinic for follow-up visits 30 and 60 days after the last ISL+LEN dose. 
Participants who received only B/F/TAF (ie, did not switch to ISL+LEN) and discontinue study drugs will be required to return to the clinic for a follow-up visit 30 days after 
the last on-study B/F/TAF dose. Details are provided in Section 6.4. 
h 
Before completion of other study procedures, participants in both treatment groups will complete the following questionnaires at the specified visits (if available): HIVDQoL 
at Day 1, Weeks 24 and 48; HIVTSQs12 at Day 1, Weeks 4, 24, and 48; HIVTSQc12 at Week 48; EQ-5D-5L at Day 1, Weeks 4, 24, and 48. The Patient Perspective of 
Regimen and the Patient Perspective of Regimen Change will be completed by participants in Treatment Group 1 at Weeks 24, 48, and 72, and by participants in Treatment 
Group 2 at Week 72 only. 
i 
Vital signs include blood pressure, pulse, temperature, and weight. 
j 
Complete physical examination is required at the screening, Day 1, and ESDD visits. 
k 
Analyses to be performed by the central laboratory. Analytes are presented in Table 25. 
l 
Women will have a serum test at screening. Urine pregnancy test will only be done for women of childbearing potential. If any pregnancy test is positive, study drugs should 
be immediately discontinued, and participant should come to the site for serum pregnancy test. 
m 
FSH test is required for women who are < 54 years old and have stopped menstruating for ≥ 12 months but do not have documentation of ovarian hormonal failure. 
n 
HBcAb, HBsAg, HBV DNA, HCV RNA. 
o 
For additional safety and virology testing (HIV-1 genotype and phenotype). 
p 
To test for archived resistance. Sampling will occur at the Day 1, Week 24, and Week 48 visits, and every 24 weeks thereafter. 
q 
PK collection: For Treatment Group 1, single anytime plasma PK sampling for ISL and LEN will occur at each onsite visit through Week 48. The date and time of the 
previous dose of ISL+LEN will be recorded. 
r 
PK substudy: For Treatment Group 1, approximately 10 participants on Days 1 and 2, and at Week 12 on scheduled dosing days, with the dose taken at the site during the 
study visit. See Table 26 for PK substudy details. 
s 
Participants will be randomized to 1 of the 2 treatment groups on Day 1 after the ICF has been signed, all screening and eligibility tests and assessments have been performed, 
and study eligibility has been confirmed. 

Islatravir + Lenacapavir 
 
 
Protocol GS-US-563-6041 
 
Final 
Gilead Sciences, Inc.  
 
Amendment 6 
CONFIDENTIAL 
Page 21 
02 December 2025 
Table 2. 
Study Procedures for Cohort 2 
Study 
Procedures 
Screeninga 
Randomized Phase 
Extension Phase 
ESDDf 
Post-Study Drug Follow-up 
Day 
1b 
Day 
2c 
Week 
Week 
 
 
2d 
4, 8 
12 
18 
24 
30, 
36, 42 
48e 
Week 60 and 
every 
12 weeks Until 
Week 144 
Week 168 
and every 
24 weeks 
thereafter 
Within 
3 Days of 
Last 
Dose 
30-Day 
Follow-upg 
60-Day 
Follow-upg 
100-Day 
and 
200-Day 
Follow-uph 
Visit Window 
(Days) 
Within 
35 Days 
Prior to 
Day 1 
 
 
± 1 
day 
± 7 days 
± 14 days 
+ 1 day 
± 7 days 
Written informed 
consent 
X 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
Obtain 
demographic 
information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HIVDQoLi 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
HIVTSQs12i 
 
X 
 
  
X i 
 
 
X 
 
X 
 
 
 
 
 
 
HIVTSQc12i 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
EQ-5D-5Li 
 
X 
 
 
X i 
 
 
X 
 
X 
 
 
 
 
 
 
HIV Patient 
Perspective of 
Regimen 
(PP-R) j 
 
X 
 
 
X 
X 
 
X 
X j 
X 
X 
 
 
 
 
 
HIV Patient 
Perspective of 
Regimen Change 
(PP-RC) k 
 
 
 
 
X 
X 
 
X 
Xk 
X 
X 
 
 
 
 
 
Vital signsl 
(including weight) 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

Islatravir + Lenacapavir 
 
 
Protocol GS-US-563-6041 
 
Final 
Gilead Sciences, Inc.  
 
Amendment 6 
CONFIDENTIAL 
Page 22 
02 December 2025 
Study 
Procedures 
Screeninga 
Randomized Phase 
Extension Phase 
ESDDf 
Post-Study Drug Follow-up 
Day 
1b 
Day 
2c 
Week 
Week 
 
 
2d 
4, 8 
12 
18 
24 
30, 
36, 42 
48e 
Week 60 and 
every 
12 weeks Until 
Week 144 
Week 168 
and every 
24 weeks 
thereafter 
Within 
3 Days of 
Last 
Dose 
30-Day 
Follow-upg 
60-Day 
Follow-upg 
100-Day 
and 
200-Day 
Follow-uph 
Visit Window 
(Days) 
Within 
35 Days 
Prior to 
Day 1 
 
 
± 1 
day 
± 7 days 
± 14 days 
+ 1 day 
± 7 days 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examinationm 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Symptom-directed 
physical 
examination 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
12-lead ECG 
(supine) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, 
chemistry, 
urinalysis and 
urine chemistry, 
CD4+ T-cell 
count/TBNK 
paneln 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy 
testo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSHp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
testo 
 
X 
 
 
 
X 
 
X 
Week 
36 
only 
X 
X 
X 
X 
 
 
 
HBV, HCV testsq 
X 
 
 
 
 
 
 
 
 
X 
Xq 
Xq 
 
 
 
 
Plasma HIV-1 
RNAs 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Plasma storage 
sampler 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

Islatravir + Lenacapavir 
 
 
Protocol GS-US-563-6041 
 
Final 
Gilead Sciences, Inc.  
 
Amendment 6 
CONFIDENTIAL 
Page 23 
02 December 2025 
Study 
Procedures 
Screeninga 
Randomized Phase 
Extension Phase 
ESDDf 
Post-Study Drug Follow-up 
Day 
1b 
Day 
2c 
Week 
Week 
 
 
2d 
4, 8 
12 
18 
24 
30, 
36, 42 
48e 
Week 60 and 
every 
12 weeks Until 
Week 144 
Week 168 
and every 
24 weeks 
thereafter 
Within 
3 Days of 
Last 
Dose 
30-Day 
Follow-upg 
60-Day 
Follow-upg 
100-Day 
and 
200-Day 
Follow-uph 
Visit Window 
(Days) 
Within 
35 Days 
Prior to 
Day 1 
 
 
± 1 
day 
± 7 days 
± 14 days 
+ 1 day 
± 7 days 
HIV-1 proviral 
genotypes 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood 
storage samplet 
 
X 
 
 
 
 
 
X 
 
X 
Xt 
X 
 
 
 
 
PK plasma 
collectionu 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Randomizationw 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oral ISL+LEN 
dispensation 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Xx 
Xx 
 
 
 
 
B/F/TAF 
dispensation 
(Treatment Group 
4)y 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Telephone visit 
 
 
Xc 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug 
accountability 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
AE = adverse event; ALT = alanine aminotransferase; ART = antiretroviral therapy; ARV = antiretroviral; AST = aspartate aminotransferase; 
B/F/TAF = bictegravir/emtricitabine/tenofovir alafenamide; CD4 = clusters of differentiation 4; CPK = creatine phosphokinase; ECG = electrocardiogram; EQ-5D-5L = 5-level 
EuroQoL (5 dimensions); ESDD = early study drug discontinuation; 
; FSH = follicle-stimulating hormone; HBV = hepatitis B virus; HBcAb = 
hepatitis B core antibody; HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIVDQoL = HIV Dependent Quality of Life; 
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Islatravir + Lenacapavir 
 
 
Protocol GS-US-563-6041 
 
Final 
Gilead Sciences, Inc.  
 
Amendment 6 
CONFIDENTIAL 
Page 24 
02 December 2025 
HIVTSQs12 = HIV Treatment Satisfaction Questionnaire 12 status version; HIVTSQc12 = HIV Treatment Satisfaction Questionnaire change version; ICF = informed consent 
form; ISL = islatravir; LEN = lenacapavir; PK = pharmacokinetic(s); PP-R = Patient Perspective of Regimen; PP-RC = Patient Perspective of Regimen Change; PRO = patient-
reported outcome; TBNK = T, B, and natural killer cells 
a 
Screening evaluations must be completed within 35 days prior to Day 1. Conditions for participant rescreening are outlined in Section 6.2. Participants in Treatment Group 3 
must stop their B/F/TAF treatment on Day −1. 
b 
Day 1 tests and procedures must be completed prior to administration of the dose of study drugs. Participants in Treatment Group 3 must begin dosing on Day 1 and will take 
their dose of study drug on site. 
c 
Participants in the PK substudy will come to the site for a study visit on Day 2 and will take their dose of study drug at the site. All other participants in Treatment Group 3 
will receive a telephone call to confirm adherence to the Day 2 LEN dose. 
d 
Participants in Treatment Groups 3 and 4 will have a telephone visit at Week 2 to assess AEs and concomitant medications and, for Treatment Group 3 only, to confirm 
adherence to weekly ISL+LEN dosing. 
e 
At the Week 48 visit, all participants will be given the option to take ISL+LEN or ISL/LEN 
 (when available) in an Extension Phase until ISL/LEN 
becomes 
available or until Gilead elects to discontinue the study, whichever occurs first. Participants in Cohort 2 who complete the study through the Week 48 visit and do not wish to 
participate in the Extension Phase will be required to return to the clinic after the Week 48 visit for a 30-day follow-up visit, and participants in Treatment Group 3 will also 
return for a 60-day follow-up visit. Then the participants will be considered to have completed the study. Participants in Treatment Group 4 who switch to ISL+LEN or 
ISL/LEN 
 (when available) in the Extension Phase will receive telephone calls to confirm adherence to the second day of the LEN loading dose and the second ISL+LEN 
or ISL/LEN 
 (when available) weekly dose. 
f 
Visit should occur within 3 days (+1 day) of permanently discontinuing study drugs. Participant should be counseled regarding the importance of resuming a complete ARV 
therapy in accordance with standard-of-care and referred to an appropriate HIV treatment facility. 
g 
Participants who received ISL+LEN or ISL/LEN 
and discontinue study drugs are required to return to the clinic for follow-up visits 30 and 60 days after the last 
ISL+LEN or ISL/LEN 
 dose. Participants who received only B/F/TAF (ie, did not switch to ISL+LEN or ISL/LEN 
) and discontinue study drugs will be required to 
return to the clinic for a follow-up visit 30 days after the last on-study B/F/TAF dose. Details are provided in Section 6.4. 
h 
Participants in Treatment Group 3 or any Cohort 2 participant in the Extension Phase who were discontinued on ISL+LEN due to decrease in CD4 or lymphocytes. Day 200 
follow-up visit to be completed only as needed, per Section 6.4.1. 
i 
Participants will complete the questionnaires at the specified visits before completion of other study procedures. Questionnaires are to be completed at Week 4 and not 
completed at Week 8. 
j 
The PP-R will be completed by participants in Treatment Groups 3 and 4 on Day 1, Weeks 4, 8, 12, 24, 36, 48, 60, and every 12 weeks until Week 144. 
k 
The PP-RC will be completed at Weeks 4, 8, 12, 24, 36, 48, 60, and every 12 weeks thereafter. Participants in Treatment Group 4 will complete the PP-RC every 12 weeks 
after switching to ISL+LEN in the Extension Phase until Week 144. 
l 
Vital signs include blood pressure, pulse, temperature, and weight. 
m 
Complete physical examination is required at the screening, Day 1, and ESDD visits. 
n 
Analyses to be performed by the central laboratory. Analytes are presented in Table 25. 
o 
Women of childbearing potential will have a serum pregnancy test at screening and urine pregnancy test at Day 1, Weeks 12, 24, 36, 48, and Post Week 48-Every 12 Weeks in 
Randomized Phase, in Extension Phase (every 12 weeks until Week 144 and every 24 weeks thereafter), and at ESDD. If any pregnancy test is positive, study drugs should be 
immediately discontinued, and participant should come to the site for serum pregnancy test. 
p 
FSH test is required for women who are < 54 years old and have stopped menstruating for ≥ 12 months but do not have documentation of ovarian hormonal failure. 
q 
HBcAb, HBsAg, HBsAb, HBV DNA, HCV RNA. Testing will occur in the Extension Phase at Week 96 and every 48 weeks thereafter. 
r 
For additional safety and virology testing (HIV-1 genotype and phenotype). 
s 
Whole blood sample collected at screening visit for proviral genotype analysis of archived resistance. 
t 
Whole blood sample storage to test for archived resistance. Sampling will occur at the Day 1, Week 24, and Week 48 visits, and every 24 weeks thereafter. 
u 
PK collection: For Treatment Group 3, single anytime plasma PK sampling for ISL and LEN will occur at each onsite visit through Week 72 except at Day 1. Day 1 PK 
sample will be collected 1 hour (± 30 minutes) postdose after onsite study drug administration. The date and time of the previous dose of ISL+LEN will be recorded. PK 
samples collected at Week 60 and 72 will be stored and analyzed only if deemed necessary by the sponsor. 
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w 
Participants will be randomized to 1 of the 2 treatment groups in Cohort 2 on Day 1 after the ICF has been signed, all screening and eligibility tests and assessments have been 
performed, and study eligibility has been confirmed. Participants in Treatment Group 3 will stop B/F/TAF on Day −1. 
x 
Participants will switch to ISL/LEN
 in the Extension Phase when 
 is available. ISL+LEN will no longer be dispensed once a participant switches. 
y 
B/F/TAF dispensation applies only to participants randomized to Treatment Group 4.  
 
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1. 
INTRODUCTION 
1.1. 
Background 
Human immunodeficiency virus type 1 (HIV-1) infection is a life-threatening and serious disease 
of major public health significance, with approximately 39 million people with HIV (PWH) 
worldwide and approximately 29.8 million taking antiretroviral (ARV) treatment 
{UNAIDS 2023}. Advances in combination ARV therapy (ART) for HIV have led to significant 
improvements in morbidity and mortality by suppressing viral replication, preserving 
immunologic function, and averting disease progression to AIDS. Standard-of-care for the 
treatment of HIV-1 infection involves the use of a combination of oral ARV drugs 
(ie, 2 nucleoside reverse transcriptase inhibitors [NRTI] plus a third agent) to suppress viral 
replication to below detectable limits, increase CD4+ T-cell counts, and delay disease 
progression. 
While combination ART for the treatment of HIV-1 infection is efficacious and well-tolerated, 
these agents need to be taken every day and require near perfect adherence to minimize the 
emergence of drug resistant variants. In addition, “treatment fatigue” can occur, defined as 
“decreased desire and motivation to maintain vigilance in adhering to a treatment regimen” 
among PWH prescribed chronic or life-long treatment {Claborn 2015}, which can lead to 
nonadherence and treatment failure. As such, there remains a significant medical need for ARVs 
that can be administered less frequently (ie, long-acting drug products), thereby providing an 
alternative treatment option for PWH. 
1.2. 
Background on Study Interventions 
Islatravir (ISL, MK-8591)/lenacapavir (LEN, GS-6207) fixed-dose combination (
) is being 
developed for the treatment of HIV-1 in collaboration with Merck Sharp & Dohme LLC (MSD).  
1.2.1. 
Information About Islatravir 
Islatravir is a nucleotide reverse transcriptase translocation inhibitor (NRTTI) with potent ARV 
activity, including activity against common NRTI-resistant variants, and favorable nonclinical 
toxicity and pharmacokinetic (PK) profiles. 
1.2.1.1. 
General Information 
For further information on ISL, including information on the following, refer to the current 
investigator’s brochure (IB) for ISL: 
• Nonclinical pharmacology 
• Pharmacokinetics and product metabolism in animals 
• Nonclinical toxicology and toxicokinetics 
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• Clinical experience 
• Changes in absolute lymphocyte and lymphocyte subset counts (see Section 1.6 for 
additional details). 
1.2.2. 
Information About Lenacapavir 
Lenacapavir is a novel, first-in-class, selective inhibitor of HIV-1 capsid function, which has 
potent antiviral activity, low human clearance, and physiochemical properties well suited for 
extended-release parenteral or oral formulations. 
1.2.2.1. 
General Information 
For further information on LEN, including information on the following, refer to the IB for LEN: 
• Nonclinical PK 
• Nonclinical pharmacology and toxicology 
• Clinical experience 
1.2.2.2. 
Clinical Studies of Lenacapavir 
Clinical data from studies not presented in the LEN IB are presented in this section. 
1.2.2.2.1. 
GS-US-563-6148 
Study GS-US-563-6148 is a Phase 1, open-label, parallel-design, single-dose, 3-cohort study 
examining potential DDIs between ISL and LEN following oral coadministration. Fifty-five 
healthy participants received single oral doses of coadministered ISL 20 mg and LEN 600 mg 
(test: N = 18), ISL 20 mg only (reference: N = 18), or LEN 600 mg only (reference: N = 19) 
under fasted conditions. 
Preliminary PK results based on nominal times for percentage geometric least-squares mean 
(%GLSM) ratios of PK parameters AUCinf and Cmax for ISL were 105% and 87.9%, respectively, 
and for LEN were 88.6% and 80.1%, respectively (Table 3). Higher percentage coefficient of 
variation (%CV) was observed for LEN compared with ISL resulting in wider 90% CI. 

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Table 3. 
GS-US-563-6148: Summary Statistics and Statistical Comparisons of 
ISL and LEN PK Parameters 
 
Mean PK Parameter 
(%CV) 
ISL+LEN 
(N=18) 
Reference: ISL Only 
(N=16) or LEN Only 
(N=18) 
ISL+LEN vs Reference 
%GLSM Ratio 
(90% CI) 
ISL 
Cmax, ng/mL 
145 (41.3) 
165 (42.2) 
87.9 (68.7, 113) 
AUCinf, h•ng/mL 
674 (25.4) 
642 (25.8) 
105 (90.2, 123) 
Tmax, ha 
0.75 (0.50, 2.00) 
0.75 (0.50, 2.00) 
ND 
Apparent terminal t1/2, h 
121 (18.7) 
99.1 (14.6) 
ND 
LEN 
Cmax, ng/mL 
33.7 (77.7) 
37.9 (57.0) 
80.1 (50.9, 126) 
AUCinf, h•ng/mL 
9840 (51.0) 
10,800 (56.9) 
88.6 (60.5, 130) 
Tmax, ha 
8.00 (1.00, 48.0) 
10.0 (2.00, 312) 
ND 
Apparent terminal t1/2, h 
296 (23.5) 
308 (24.7) 
ND 
%CV = percentage coefficient of variation; CI = confidence interval; GLSM = geometric least-squares mean; 
ISL = islatravir; LEN = lenacapavir; ND = not determined; PK = pharmacokinetic(s) 
Data are shown to 3 significant digits; results based on nominal time. 
a 
Tmax is presented as median (min, max). 
Overall, oral coadministration of ISL and LEN showed similar PK compared with when 
administered alone and no clinically meaningful PK DDIs were present. 
1.2.2.2.2. 
GS-US-200-4333 
Study 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. The objectives were to evaluate the clinical effects of strong cytochrome P450 enzyme 
(CYP) 3A, P-glycoprotein (P-gp), and uridine diphosphate glucuronosyltransferase 1A1 
(UGT1A1) inhibitors and inducers on LEN exposure; LEN coadministration on sensitive P-gp, 
breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP), and 
CYP3A substrates using tenofovir alafenamide (TAF, Vemlidy®), rosuvastatin (ROS), 
pitavastatin (PIT), and midazolam (MDZ), respectively; and increased gastric pH on LEN 
exposure. Available preliminary data are presented below. Final PK and safety data analyses are 
ongoing. 
Cohort 1 served as a reference arm for Cohorts 2 and 3; participants in Cohort 1 received a single 
dose of LEN 300 mg capsule alone (N = 30). Participants in Cohorts 2 and 3 received up to 
90 days of cobicistat (COBI) 150 mg once daily (mixed CYP3A/P-gp inhibitor), and darunavir 
(DRV)/COBI 800/150 mg once daily (mixed CYP3A/P-gp inhibitor and inducer), respectively, 
with a single dose of LEN 300 mg capsule coadministered in the morning on Day 11 (N = 29 per 
cohort). All doses were administered in the morning under fed conditions. Preliminary PK data 
are presented in Table 4. Median maximum plasma concentrations of LEN (Cmax) occurred 
between 6 to 8 hours (Tmax), and the median t1/2 of LEN administered alone was 11.5 days and 
ranged from 15.4 to 17.9 days following administration with DRV/COBI or COBI. 

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Coadministration of DRV/COBI or COBI with LEN resulted in an approximate 2-fold increase 
in Cmax and AUCinf. This 2-fold increase in LEN exposure was not deemed clinically relevant, 
based on safety data from ongoing Phase 1 studies at or above exposures anticipated to be 
achieved following administration of LEN with strong CYP3A/P-gp inhibitors. Accordingly, the 
use of strong CYP3A and P-gp inhibitors is permitted with LEN. 
Table 4. 
GS-US-200-4333: Preliminary Plasma PK Parameters of LEN 300 mg 
Oral Capsule Following Administration Alone or with DRV/COBI 
(800/150 mg QD) or COBI (150 mg QD) 
PK Parameter 
Mean (%CV) 
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 (42.4) 
AUClast (h•ng/mL) 
10,300 (77.9) 
16,100 (61.3) 
14,200 (47.3) 
AUCinf (h•ng/mL) 
10,600 (77.2) 
22,600 (64.1) 
18,700 (49.5) 
Tmax (hours) 
8.00 (6.00, 48.00) 
6.00 (6.00, 8.00) 
6.00 (4.00, 6.00) 
t1/2 (days) 
11.5 (9.46, 15.0) 
17.9 (15.1, 20.2) 
15.4 (14.2, 17.4) 
%CV = percentage coefficient of variation; COBI = cobicistat; DRV = darunavir; LEN = lenacapavir; PK = pharmacokinetic(s); 
Q1 = first quartile; Q3 = third quartile; QD = once daily 
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. 
Cohort 4 served as a reference arm for Cohort 5; participants in Cohort 4 received a single dose 
of LEN 300 mg tablet alone (N = 27). Participants in Cohort 5 received voriconazole (VORI), a 
CYP3A inhibitor, for 24 days (400 mg twice daily on Day 1, followed by 200 mg twice daily on 
Days 2 through 24), with LEN 300 mg tablet administered on Day 2. All doses were 
administered in the morning under fasted conditions. 
The median t1/2 of LEN administered alone was 13.7 days (Table 5). Coadministration of VORI 
with LEN resulted in an approximate 1.4-fold increase in AUCinf. This increase in LEN exposure 
was not deemed clinically relevant, and further supports the above recommendation permitting 
use of strong CYP3A and P-gp inhibitors with LEN. 

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Table 5. 
GS-US-200-4333: Preliminary Plasma PK Parameters of LEN 300 mg 
Oral Tablet Following Administration Alone or with VORI 
(400/200 mg BID) 
PK Parameter  
Mean (%CV) 
LEN Alone 300 mg 
(N = 27) 
LEN 300 mg + VORI 
(N = 25) 
Cmax (ng/mL) 
20.4 (102) 
20.5 (62.8) 
AUClast (h•ng/mL) 
3640 (70.9)a 
5060 (58.6) 
AUCinf (h•ng/mL) 
5290 (61.1)a 
7300 (51.9) 
Tmax (hours) 
4.00 (4.00, 6.00) 
4.00 (4.00, 8.00) 
t1/2 (days) 
13.7 (9.63, 16.2) 
12.5 (10.4, 16.7) 
%CV = percentage coefficient of variation; BID = twice daily; LEN = lenacapavir; PK = pharmacokinetic(s); Q1 = first quartile; 
Q3 = third quartile; VORI = voriconazole 
a 
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. 
Cohort 6 served as a reference arm for Cohort 7; participants in Cohort 6 received a single dose 
of LEN 300 mg tablet alone (N = 25). Participants in Cohort 7 received up to 60 days of 
atazanavir (ATV)/COBI 300/150 mg once daily, a mixed CYP3A/P-gp/UGT1A1 inhibitor, with 
LEN 300 mg tablet administered on Day 10. All doses were administered in the morning under 
fed conditions. 
The median t1/2 of LEN administered alone was 11.9 days (Table 6). Coadministration of 
ATV/COBI with LEN resulted in an approximate 6.6-fold and 4.2-fold increase in Cmax and 
AUCinf, respectively. In the absence of additional data, coadministration of LEN and strong 
UGT1A1 inhibitors is not recommended. 
Table 6. 
GS-US-200-4333: Preliminary Plasma PK Parameters of LEN 300 mg 
Oral Tablet Following Administration Alone or with ATV/COBI 
(300/150 mg QD) 
PK Parameter  
Mean (%CV) 
LEN Alone 300 mg 
(N = 25) 
LEN 300 mg + ATV/COBI 
(N = 21) 
Cmax (ng/mL) 
17.6 (51) 
120 (55.7) 
AUClast (h•ng/mL) 
5000 (56.6) 
20300 (56.4) 
AUCinf (h•ng/mL) 
5430 (54.4) 
23700 (55.5) 
Tmax (hours) 
6.00 (4.05, 6.00) 
4.00 (4.00, 4.00) 
t1/2 (days) 
11.9 (11.0, 13.4) 
14.9 (13.5, 18.5) 
%CV = percentage coefficient of variation; ATV = atazanavir; COBI = cobicistat; LEN = lenacapavir; PK = pharmacokinetic(s); 
Q1 = first quartile; Q3 = third quartile; QD = once daily 
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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Cohort 4 served as a reference arm for Cohorts 8, 9, and 10; participants in Cohort 4 received a 
single dose of LEN 300 mg tablet alone (N = 27). Participants in Cohorts 8 and 9 received 
rifampin (RIF), a strong CYP3A and P-gp/UGT inducer, and efavirenz (EFV), a moderate 
inducer, respectively, for 25 days (600 mg once daily) with LEN 300 mg tablet administered on 
Day 14 for both cohorts. Participants in Cohort 10 received a single dose of 40 mg famotidine 
(FAM) 2 hours prior to a dose of LEN 300 mg tablet on Day 1. All LEN doses were 
administered in the morning under fasted conditions. 
The median t1/2 of LEN administered alone was 13.7 days (Table 7). Following coadministration 
with RIF, LEN Cmax and AUCinf were approximately 2.5 fold and 6.5 fold lower, respectively, 
with an approximately 5-fold decrease in t1/2. Following coadministration with EFV, LEN Cmax 
and AUCinf were approximately 1.5 fold and 2 fold lower, respectively, with an approximate 
2-fold decrease in t1/2. These data support the recommendations to disallow use of strong and 
moderate CYP3A and P-gp/UGT inducers with LEN. 
Following coadministration with FAM, no change in LEN exposure or t1/2 was observed; 
accordingly, use of FAM and other acid-reducing agents is permitted with LEN. 
Table 7. 
GS-US-200-4333: Preliminary Plasma PK Parameters of LEN 300 mg 
Tablet Following Administration Alone or with RIF (600 mg QD), 
EFV (600 mg QD), or FAM (40 mg) 
PK Parameter  
Mean (%CV) 
LEN Alone 300 mg 
(N = 27) 
LEN 300 mg + RIF 
(N = 25) 
LEN 300 mg + EFV 
(N = 18) 
LEN 300 mg + FAM  
(N = 25) 
Cmax (ng/mL) 
20.4 (102) 
8.20 (59.5) 
13.3 (76.1) 
18.6 (60.2) 
AUClast (h•ng/mL) 
3640 (70.9)a 
720 (51.6) 
1690 (73.5) 
4610 (58.3) 
AUCinf (h•ng/mL) 
5290 (61.1)a 
784 (47.5) 
2480 (80.2) 
6590 (56.5) 
Tmax (hours) 
4.00 (4.00, 6.00) 
24.0 (24.0, 48.0) 
4.00 (4.00, 6.00) 
10.0 (4.00, 48.0) 
t1/2 (days) 
13.7 (9.63, 16.2) 
2.61 (2.36, 2.98) 
6.96 (5.38, 7.75) 
12.3 (10.7, 16.6) 
%CV = percentage coefficient of variation; EFV = efavirenz; FAM = famotidine; LEN = lenacapavir; PK = pharmacokinetic(s); 
Q1 = first quartile; Q3 = third quartile; QD = once daily; RIF = rifampin 
a 
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. 
In Cohort 11, participants received PIT, ROS, TAF, and MDZ alone, or coadministered with oral 
LEN 600 mg tablet. Agents were either codosed with LEN to evaluate the worst-case scenario 
(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 8, 
Table 9, Table 10, and Table 11. 

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Table 8. 
GS-US-200-4333: Preliminary Plasma PK Parameters of PIT (2 mg) 
Following Administration Alone or with LEN 
PK Parameter  
Mean (%CV) 
PIT Alone 
(N = 31) 
PIT + LEN  
(Day 15; Coadministration) 
(N = 30) 
PIT + LEN  
(Day 27; 3 Days Post LEN Dose) 
(N = 28) 
Cmax (ng/mL) 
31.4 (52.8) 
31.0 (48.1) 
26.8 (50.5) 
AUClast (h•ng/mL) 
83.6 (47.5) 
96.8 (47.8) 
73.1 (41.3) 
AUCinf (h•ng/mL) 
90.8 (43.8)a 
102 (47.0) 
81.3 (36.3)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 (8.62, 13.5)a 
10.9 (6.82, 14.6) 
14.1 (10.5, 16.3)b 
%CV = percentage coefficient of variation; LEN = lenacapavir; PIT = pitavastatin; PK = pharmacokinetic(s); Q1 = first quartile; 
Q3 = third quartile 
a 
N = 30 
b 
N = 26 
Pharmacokinetic parameters are presented as mean (%CV) except Tmax and t1/2, which are presented as median (Q1, Q3), and 
shown to 3 significant digits. 
Table 9. 
GS-US-200-4333: Preliminary Plasma PK Parameters of ROS (5 mg) 
Following Administration Alone or with LEN 
PK Parameter  
Mean (%CV) 
ROS Alone 
(N = 30) 
ROS + LEN  
(Day 18; Coadministration) 
(N = 30) 
Cmax (ng/mL) 
1.10 (39.1) 
1.90 (65.7) 
AUClast (h•ng/mL) 
10.2 (41.7) 
13.7 (52.2) 
AUCinf (h•ng/mL) 
12.5 (34.1)a 
16.5 (42.7)b 
Tmax (hours) 
5.00 (5.00, 5.00) 
4.00 (2.00, 4.00) 
t1/2 (hours) 
13.1 (9.14, 20.0)a 
17.1 (13.4, 24.4)b 
%CV = percentage coefficient of variation; LEN = lenacapavir; PK = pharmacokinetic(s); Q1 = first quartile; Q3 = third quartile; 
ROS = rosuvastatin 
a 
N = 28 
b 
N = 29 
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 10. 
GS-US-200-4333: Preliminary Plasma PK Parameters of TAF (25 mg) 
and its Metabolite, TFV, Following Administration Alone or with 
LEN 
PK Parameter  
Mean (%CV) 
TAF Alone 
(N = 30) 
TAF + LEN  
(Day 21; Coadministration) 
(N = 28) 
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 (27.6)b 
Tmax (hours) 
1.00 (0.50, 1.00) 
1.00 (0.50, 1.55) 
t1/2 (hours) 
0.38 (0.34, 0.42)a 
0.41 (0.35, 0.43)b 
TFV 
Cmax (ng/mL) 
6.30 (30.3) 
8.00 (34.1) 
AUClast (h•ng/mL) 
171 (26.3) 
250 (29.2) 
AUCinf (h•ng/mL) 
207 (26.2) 
314 (27.7) 
Tmax (hours) 
2.00 (2.00. 2.00) 
2.00 (1.50, 2.99) 
t1/2 (hours) 
37.3 (34.8, 40.7) 
39.8 (36.0, 45.8) 
%CV = percentage coefficient of variation; LEN = lenacapavir; PK = pharmacokinetic(s); Q1 = first quartile; Q3 = third quartile; 
TAF = tenofovir alafenamide; TFV = tenofovir 
a 
N = 28 
b 
N = 22 
Pharmacokinetic parameters are presented as mean (%CV) except Tmax, and t1/2, which are presented as median (Q1, Q3), and 
shown to 3 significant digits. 
Table 11. 
GS-US-200-4333: Preliminary Plasma PK Parameters of MDZ 
(2.5 mg) and its Metabolite, 1-OH-MDZ, Following Administration 
Alone or with LEN 
PK Parameter  
Mean (%CV) 
MDZ Alone 
(N = 30) 
MDZ + LEN  
(Day 24; Coadministration) 
(N = 28) 
MDZ + LEN  
(Day 25; 1 Day Post LEN Dose) 
(N = 28) 
MDZ 
 
 
 
Cmax (ng/mL) 
9.50 (29.1) 
17.7 (22.7) 
19.7 (23.8) 
AUClast (h•ng/mL) 
50.5 (35.0) 
151 (26.9) 
171 (27.7) 
AUCinf (h•ng/mL) 
53.0 (36.3) 
185 (33.0) 
210 (35.6) 
Tmax (hours) 
2.00 (1.00, 2.00) 
2.00 (1.49, 3.98) 
2.00 (1.00, 2.00) 
t1/2 (hours) 
5.16 (4.20, 7.18) 
9.36 (7.00, 11.3) 
9.38 (7.20, 11.8) 
1-OH-MDZ 
 
 
 
Cmax (ng/mL) 
2.60 (44.5) 
1.40 (34.7) 
1.30 (36.8) 

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PK Parameter  
Mean (%CV) 
MDZ Alone 
(N = 30) 
MDZ + LEN  
(Day 24; Coadministration) 
(N = 28) 
MDZ + LEN  
(Day 25; 1 Day Post LEN Dose) 
(N = 28) 
AUClast (h•ng/mL) 
13.1 (39.3) 
8.80 (32.3) 
9.70 (35.8) 
AUCinf (h•ng/mL) 
14.0 (39.2) 
10.4 (23.5) 
11.6 (43.2) 
Tmax (hours) 
2.00 (1.00, 2.00) 
1.99 (1.00, 2.00) 
2.00 (2.00, 2.00) 
t1/2 (hours) 
4.21(3.15, 4.90) 
6.95 (4.15, 9.85) 
7.18 (5.07, 10.1) 
%CV = percentage coefficient of variation; 1-OH-MDZ = 1-hydroxymidazolam; LEN = lenacapavir; MDZ = midazolam; 
PK = pharmacokinetic(s); 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 8). ROS AUC and Cmax were approximately 1.3 to 1.6 fold 
higher following coadministration with LEN (Table 9), suggesting LEN inhibits BCRP 
transporters. TAF and TFV AUC and Cmax were 1.2- to 1.5-fold higher following 
coadministration with LEN (Table 10), suggesting LEN is a weak inhibitor of P-gp transporters. 
MDZ AUCinf and Cmax were approximately 2- to 4-fold higher, and 1-OH-MDZ AUC and Cmax 
were lower following coadministration with LEN (Table 11), suggesting LEN is a moderate 
inhibitor of CYP3A. Caution is advised if LEN is coadministered with sensitive CYP3A 
substrates, but not for P-gp, BCRP, or OATP substrates. 
1.2.2.2.3. 
GS-US-200-4330 
Study GS-US-200-4330 was a Phase 1, open-label, single-dose, parallel-group study to evaluate 
the PK of oral LEN in participants with impaired renal function and matched healthy control 
participants. The objectives were to evaluate the single-dose PK of LEN and to evaluate the 
safety and tolerability of single-dose LEN in participants with severe renal impairment and 
matched healthy control participants with normal renal function. 
Disposition and Baseline Characteristics 
The study enrolled 20 participants: 10 participants with severe renal impairment (15 ≤ creatinine 
clearance [CLcr] ≤ 29 mL/min using the Cockcroft-Gault equation) and 10 matched healthy 
control participants (CLcr ≥ 90 mL/min). Participants received a single dose of LEN (1  300 mg 
tablet) administered orally on Day 1. All 20 participants completed study drug dosing and 
completed the study. No participants prematurely discontinued the study. 
The majority of participants were male (70.0%, 14 participants), 19 participants were White and 
1 participant was Black, and most participants were Hispanic or Latino (60.0%, 12 participants). 
Overall, the median age of participants was 61 years (range: 18 to 77), and the median (Q1, Q3) 
body mass index (BMI) was 26.6 (24.0, 29.2) kg/m². 

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Safety Results 
Treatment-emergent AEs were reported in 5 of 20 participants. Four participants in the severe 
renal impairment group had at least 1 AE and 1 participant in the normal renal function group 
had an AE. No AE was reported in more than 1 participant in either group (Table 12). 
Four participants had AEs that were Grade 1 or 2 in severity. One Grade 3 AE of hypertension 
was reported in a participant in the severe renal impairment group. 
Table 12. 
GS-US-200-4330: Treatment-Emergent Adverse Events by Preferred 
Term (Safety Analysis Set) 
Preferred Term 
Severe Renal Impairment 
(N = 10) 
Normal Renal Function 
(N = 10) 
Number (%) of Participants with Any Treatment-
Emergent Adverse Event 
4 (40.0%) 
1 (10.0%) 
Diarrhoea 
1 (10.0%) 
0 
Hyperglycaemia 
0 
1 (10.0%) 
Hypertension 
1 (10.0%) 
0 
Infusion site extravasation 
1 (10.0%) 
0 
Melena 
1 (10.0%) 
0 
Pain in extremity 
1 (10.0%) 
0 
Prehypertension 
1 (10.0%) 
0 
AE = adverse event; 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. 
Preferred terms were presented by descending order of total frequencies. 
One AE of hyperglycemia was considered related to study drug and was reported in the normal 
renal function group. One SAE of melena occurred and resolved in the severe renal impairment 
group. No deaths, Grade 4 or Grade 5 AEs, or AEs leading to premature discontinuation of study 
drug or study participation were reported. 
There were no clinically relevant changes from predose in median values for hematology or 
clinical chemistry parameters (including metabolic parameters) in either treatment group. 
Laboratory abnormalities were reported in 19 of 20 participants (10 in the severe renal 
impairment group; 9 in the normal renal function group). The majority of laboratory 
abnormalities were Grade 1 or 2 in severity. Grade 3 or 4 laboratory abnormalities were reported 
for 5 participants in the severe renal impairment group and 3 participants in the normal renal 
function group. Creatinine increase was the most common laboratory abnormality occurring in 
3 participants. One participant in each group had a Grade 3 occurrence and 1 participant in the 
severe renal impairment group had a Grade 4 occurrence. 

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Pharmacokinetic Evaluation 
Intensive PK sampling occurred relative to the morning dose of LEN at the following time points 
for each cohort: 
• Day 1: 0 (predose, ≤ 5 minutes before dose), 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours postdose 
• Days 4, 6, 8, 15, 22, 29, 36, 43, and 50: A single anytime PK sample was collected 
LEN PK parameters with associated exposure comparisons following a single oral dose of 
300 mg under fed conditions in participants with severe renal impairment and their matched 
healthy controls are presented in Table 13. There were no observable differences in the Tmax 
between participants with severe renal impairment and matched healthy controls; the t1/2 values 
were comparable in participants with severe renal impairment compared with their matched 
healthy controls. Lenacapavir exposures increased in participants with severe renal impairment 
as indicated by GLSM ratios for Cmax and AUC. Lenacapavir Cmax and AUCinf increased 
162% and 84%, respectively, in participants with severe renal impairment (N = 10) compared 
with their matched healthy controls (N = 10). 
Table 13. 
GS-US-200-4330: Summary Statistics and Statistical Comparison of 
Plasma PK Parameters (LEN PK Analysis Sets) 
PK Parameter 
Severe Renal 
Impairment 
(N = 10) 
Matched Healthy 
Control 
(N = 10) 
Severe Renal Impairment/Matched 
Healthy Control 
% Geometric Least-Squares 
Mean Ratio (90% CI) 
Cmax (ng/mL)a 
118 (129) 
22.1 (43.6) 
262 (112, 614) 
AUClast (h•ng/mL)a 
18335 (101) 
6844 (48.8) 
189 (95.2, 377) 
AUCinf (h•ng/mL)a 
18997 (98.3) 
7401 (47.6) 
184 (93.6, 360) 
CL/F (mL/h)a 
44063 (138.3) 
51822 (56.3) 
— 
Tmax (h)b 
8.00 (6.00, 24.0) 
6.00 (6.00, 8.00) 
— 
t1/2 (h)b 
234 (178, 354) 
319 (270, 357) 
— 
%CV = percentage coefficient of variation; CI = confidence interval; LEN = lenacapavir; PK = pharmacokinetic(s); Q1 = first 
quartile; Q3 = third quartile 
a 
Data presented as mean (%CV). 
b 
t1/2 and Tmax are presented as median (Q1, Q3). 
Unbound fractions (plasma protein binding) of LEN were measured in predose samples spiked 
with the analyte of interest. Unbound fractions of LEN were similar in the severe renal 
impairment group relative to the matched healthy control group (%unbound fraction [%CV] of 
0.246 [35.3] and 0.206 [27.2], respectively). 
The observed increases in LEN exposure with severe renal impairment (< 2 fold) were not 
deemed clinically meaningful and results from this study do not indicate the necessity for dose 
adjustment in participants with renal impairment. 

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1.2.2.2.4. 
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 subcutaneous (SC) and oral 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 14). 
Table 14. 
GS-US-200-4334: Study Treatments 
Treatment 
Group 
Time Period 
Study Treatments 
1 
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 
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) 
2 
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 
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 3 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. 

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Disposition and Baseline Characteristics 
As of 11 February 2021, 182 participants were randomized and dosed (n = 52, 53, 52, and 25 in 
Treatment Groups 1 to 4, respectively). Most participants were male (93.4%, 170 of 182) and the 
majority were Black (54.4%, 99 of 182) or White (40.7%, 74 of 182). The median age was 
29 years (range: 19 to 72). Mean baseline viral load (VL) was 4.30 log10 copies/mL and 15% had 
VL > 100,000 copies/mL. The mean baseline CD4+ T-cell count was 495 cells/µL 
(range: 175 to 1846). 
Virologic Efficacy Results 
At Week 16, 92.3% (48 of 52), 94.3% (50 of 53), and 94.2% (49 of 52) of the participants in the 
LEN Treatment Groups 1, 2, and 3, respectively, had HIV RNA < 50 copies/mL versus 100% in 
Treatment Group 4 (25 of 25) as assessed by the missing = failure (M = F) analysis. 
Preliminary Safety Results 
Lenacapavir was generally well tolerated. There were no deaths and no participant discontinued 
study drug due to AEs. Serious adverse events (SAEs) were reported in 7 participants in LEN 
Treatment Groups 1 to 3; none were considered related to study drug. 
Grade 3 or higher AEs were reported in 8 participants (5.1%) in LEN Treatment Groups 1, 2, and 
3 (none in Treatment Group 1, 3 in Treatment Group 2, and 5 in Treatment Group 3) and 
1 participant in Treatment Group 4. None of the Grade 3 or higher AEs were reported in more 
than 1 participant. None of the Grade 3 or higher AEs were considered related to study drug. The 
most frequent AEs were injection site erythema (12.7%), and injection site pain and injection site 
swelling (12.1% each). 
All treatment-related AEs of injection site reactions (approximately 36%) were mild or 
moderate. Treatment-related AEs that were reported in > 5% of participants in LEN Groups 1 
and 2 are summarized in Table 15; no events were reported in > 5% of participants in Group 3. 
Table 15. 
GS-US-200-4334: Treatment-Related, Treatment-Emergent Adverse 
Events in > 5% of Participants Overall Receiving SC LEN by 
Preferred Term 
SC LEN + (F/TAF →TAF) 
(N = 52) 
SC LEN + (F/TAF →BIC) 
(N = 53) 
SC LEN Total 1+2 
(N = 105) 
Injection site 
erythema 
10 (19.2%) 
6 (11.3%) 
16 (15.2%) 
Injection site pain 
9 (17.3%) 
5 (9.4%) 
14 (13.3%) 
Injection site 
swelling 
7 (13.5%) 
7 (13.2%) 
14 (13.3%) 
Injection site nodule 
5 (9.6%) 
4 (7.5%) 
9 (8.6%) 
Injection site 
induration 
5 (9.6%) 
3 (5.7%) 
8 (7.6%) 
BIC = bictegravir; F = emtricitabine; LEN = lenacapavir; SC = subcutaneous; TAF = tenofovir alafenamide 

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1.2.2.2.5. 
GS-US-200-4625 
Study GS-US-200-4625 is a Phase 2/3, placebo-controlled, multicenter study of LEN together 
with an optimized background regimen (OBR) in heavily treatment experienced PWH with 
multidrug resistant infection. 
Participants in Cohort 1 were randomized to receive blinded 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 open-label SC LEN (927 mg; 
309 mg/mL; 2  1.5 mL) and OBR, and participants who had received placebo then received 
open-label oral LEN and OBR for 14 days prior to switching to open-label SC LEN (927 mg; 
309 mg/mL; 2  1.5 mL) and OBR. Participants in Cohort 2 received open-label oral LEN and 
OBR for 14 days before switching to open-label SC LEN and OBR. Cohort 2 includes 
participants who 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 
As of 02 February 2021, 72 participants enrolled in Cohorts 1 and 2 and were included in the 
safety analysis set (Cohort 1: LEN 24 participants, placebo 12 participants; 
Cohort 2: LEN + OBR 36 participants). A total of 70 participants completed the Functional 
Monotherapy (Cohort 1: 36 participants) or Oral Lead-in Period (Cohort 2: 34 participants), and 
all received SC LEN. 
Overall in Cohorts 1 and 2, the majority of participants were male (75.0%), 38.0% were Black, 
and the median age was 52 years (range: 23 to 78). Mean baseline VL was 4.17 log10 copies/mL. 
The median (range) baseline CD4+ T-cell count was 150 (3 to 1296) cells/µL. The baseline 
disease characteristics were consistent with the profile of the heavily treatment experienced 
population, and the median (Q1, Q3) number of prior ARV medications taken by participants 
was 11 (8, 16). 
Of the 72 participants in Cohorts 1 and 2 who received oral LEN, 70 participants received SC 
LEN. In Cohort 2, 2 participants remained in the Oral Lead-in Period at the time of the data cut. 
Overall, 25 participants received Week 26 SC LEN and 1 participant received Week 52 SC LEN. 
Virologic Efficacy Results 
The primary efficacy endpoint was the proportion of participants in Cohort 1 achieving 
≥ 0.5 log10 copies/mL reduction from baseline in HIV-1 RNA at the end of the Functional 
Monotherapy Period. 
At the primary endpoint, a significantly greater proportion of participants receiving LEN had a 
VL reduction of at least 0.5 log10 copies/mL from baseline compared with those receiving 
placebo (87.5% vs 16.7%, P < 0.0001). Additionally, the LEN group achieved a statistically 
significant greater mean change in VL versus the placebo group (−1.93 log10 copies/mL vs 
−0.29 log10 copies/mL, P < 0.0001). 

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At Weeks 16, 22, and 26, the proportion of participants who received LEN in Cohorts 1 and 2 
and had HIV-1 RNA < 50 copies/mL, as assessed using the M = F approach, were: 
75.0% (30 of 40), 71.0% (22 of 31), and 73.1% (19 of 26), respectively. 
Preliminary Safety Results 
Lenacapavir was generally well tolerated. Overall, 81.9% (59 of 72) of participants who received 
LEN in Cohorts 1 and 2 had AEs. One participant with a low baseline CD4+ T-cell count 
(7 cells/µL) had an SAE of pneumonia with a fatal outcome; the primary cause of the death is 
unknown at this time; the same participant had a previous SAE of dizziness. Another participant 
had SAEs of abdominal pain and pancreatic mass. No SAEs were considered related to study 
drug. No participant discontinued study drug due to AEs. 
Grade 3 or higher AEs were reported for 10 participants (13.9%). Grade 3 or higher AEs that 
were reported for > 1 participant were as follows: injection site erythema (4.2%, 3 participants), 
injection site edema (2.8%, 2 participants each); 2 of the 3 injections site erythema and both 
injection site edema AEs were attributed to enfuvirtide. One participant had Grade 3 injection 
site swelling and injection site erythema that was considered related to study drug. Another 
participant had Grade 3 AE of rash that was considered related to study drug. 
Injection site reactions related to LEN were reported in 32 of 70 participants (45.7%) (Table 16); 
the majority were Grade 1 (37.1%, 26 of 70); 7.1% were Grade 2 (5 of 70); and 1.4% were 
Grade 3 (1 of 70). The most commonly reported treatment-related AEs were as follows: injection 
site swelling (22.9%, 16 participants), injection site erythema (18.6%, 13 participants), and 
injection site nodule (18.6%, 13 participants). 
Table 16. 
GS-US-200-4625: Treatment-Related, Treatment-Emergent Adverse 
Events in > 5% of Participants Overall by Preferred Term 
 
Total 
(N = 70) 
Any injection site reaction 
32 (45.7%) 
Injection site swelling 
16 (22.9%) 
Injection site erythema 
13 (18.6%) 
Injection site nodule 
13 (18.6%) 
Injection site pain 
10 (14.3%) 
Injection site induration 
6 (8.6%) 
 
1.2.3. 
Clinical Studies of Coadministered ISL and LEN and ISL/LEN Fixed-dose 
Combination 
For information on clinical studies of coadministered ISL and LEN, including the Phase 1 
relative bioavailability (rBA) study for ISL/LEN 
 (GS-US-563-6192), refer to the current 
ISL/LEN IB. 
CCI-

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1.2.4. 
Information About B/F/TAF 
Bictegravir/emtricitabine/tenofovir alafenamide is a tablet approved for the treatment of HIV-1 
infection {BIKTARVY 2021}. The B/F/TAF tablet is a safe and highly effective INSTI-based 
treatment regimen, offering minimal pill burden, once-daily dosing, and excellent tolerability. 
The B/F/TAF is a recommended initial treatment for PWH {Department of Health and Human 
Services (DHHS) 2013}. 
1.2.4.1. 
General Information 
For further information on B/F/TAF, including information on the following, refer to the 
B/F/TAF IB: 
• Nonclinical pharmacology 
• Nonclinical PK and in vitro metabolism 
• Nonclinical toxicology 
• Clinical experience 
1.3. 
Rationale for This Study 
Oral ISL administered with oral LEN has the potential to offer a safe, efficacious, and 
well-tolerated once weekly regimen to treat HIV-1 infection. The 2 agents in combination are 
predicted to be effective for treatment of HIV-1 infection because they have different 
mechanisms of action. Weekly oral dosing is supported by their individual PK profiles. Further, 
clinical evaluation of oral ISL 
 and LEN 
 coadministration showed no clinically 
meaningful PK drug-drug interactions. 
The data from this study are intended to support the ongoing clinical development of an oral 
weekly regimen of ISL and LEN, including Phase 3 studies. 
In the Extension Phase, participants receiving ISL+LEN will switch to ISL/LEN
 when the 
 becomes available. PK data in the single-dose rBA Study GS-US-563-6192 showed 
comparable LEN exposures and a similar extent of ISL exposure with a slower rate of absorption 
for ISL between ISL/LEN
 
 tablet and LEN 
 tablet administered with ISL 
 capsule, supporting the use of ISL/LEN 
 tablets in this Phase 2 and in Phase 3 
studies. For more information, refer to the current ISL/LEN IB. 
An active control group of B/F/TAF is included as a current standard-of-care comparator 
allowing those participants not randomized to ISL+LEN to continue to receive highly effective 
treatment. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
-
-
-
- -

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1.4. 
Rationale for Dose Selection of Islatravir 
Cohort 1: ISL 20 mg once weekly (enrollment and dosing in Cohort 1 were stopped prematurely 
by the sponsor [see Section 1.6]). 
The once weekly dose of 20 mg chosen for ISL in this study is supported by antiviral efficacy, 
PK, and safety data from Phase 1 and 2 oral ISL studies. A single dose of ISL 20 mg once 
weekly achieves a trough concentration comparable to the triphosphate form of islatravir 
(ISL-TP) steady-state levels for a dose of 0.75 mg once daily (the dose selected for the 
doravirine/ISL once daily clinical development program), providing coverage for wild-type 
(WT) and M184V viruses (Figure 2). In addition, ISL 20 mg once weekly provides forgiveness 
for an entire dosing interval, addressing concerns with a late or missed dose. 
Figure 2. 
ISL-TP Concentrations, Achieved with an ISL 20 mg Once-Weekly 
Regimen, Provide Coverage for Both Wild-type and M184V Mutant 
Virus 
IC50 = half-maximal inhibitory concentration; IQ = inhibitory quotient; ISL = islatravir; ISL-TP = triphosphate form of islatravir; 
NRTI = nucleoside reverse transcriptase inhibitor; QW = once weekly; WT = wild type 
The solid lines (black and orange) and the shaded region (grey and orange) correspond to the median and 95% prediction 
interval, respectively (based on simulations, N = 1000). Inhibitory Quotient is defined as Trough Concentration/IC50. The black 
dashed line corresponds to the in vitro intracellular IC50 against WT virus. The red and the blue dashed lines correspond to an IQ 
of 5 based on proof-of-concept monotherapy data for WT virus and a variant bearing the common NRTI M184V 
resistance-associated mutation, respectively. No ISL QW dose is given post Day 70 to demonstrate forgiveness of a missed dose 
(denoted by the vertical dashed line). 
C 
0 
:.::; -
C 
Q) u 
C 
0 
0 
a.. 
I-I 
....J 
Cf) 
100 
10 
0.1 
QW, 20 mg 
QD, 0.75 mg 
_ _ _________________________ :10 = 5 for M184V _ 
I 
: IQ= 5 for WT 
- -------------------------- ~-----------
in vitro IC50 for WT 
---------------------------- i-----------
0 
7 
14 21 
28 35 42 49 56 63 70 77 84 91 
98 105112 119 
Time (day) 

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Plasma ISL exposures on Day 1 and Day 2 
To reach therapeutic levels quickly, loading doses are required for LEN. Loading doses of both 
ISL 40 mg and LEN 600 mg on Day 1 and 2 will be evaluated in this study. While AUC and 
Cmax of plasma ISL following administration of ISL 40 mg on Day 1 and Day 2 are higher than 
the steady-state plasma ISL exposures following ISL 20 mg once weekly, 3 doses of ISL 100 mg 
once weekly (MK-8591-002) and 120 mg once monthly (QM) for 6 months (MK-8591-016) 
have been well-tolerated, and no dose-related toxicities have been identified. Based on available 
data to date, clinically meaningful systemic DDIs with LEN are not expected. The sponsor 
stopped the dosing of ISL+LEN in Cohort 1 due to the laboratory findings of decreases in total 
lymphocyte and CD4+ T-cell counts observed in clinical studies with ISL 60 to 120 mg QM for 
HIV-1 pre-exposure prophylaxis (PrEP), ISL 20 mg (with MK-8507, a nonnucleoside reverse 
transcriptase inhibitor [NNRTI]) once weekly, and ISL 0.75 mg daily (with doravirine 100 mg) 
for HIV-1 treatment. 
Cohort 2: ISL 2 mg once weekly 
The once weekly dose of ISL 2 mg chosen for this study is supported by antiviral efficacy, PK, 
predicted CD4+ T-cell increases, and absolute lymphocyte count increases similar to approved 
ART regimens and safety data from Phase 1, 2, and 3 oral ISL studies. 
Robust antiviral efficacy was observed down to 0.5 mg in the single-dose, proof-of-concept 
study in treatment-naive participants. Additionally, no M184V/I selection was observed across 
any of the doses. In a Phase 2 clinical study, the 0.25 mg once daily dose fully suppressed 
treatment-naive participants through to the end of the study. Predictions from the population PK 
model show 2 mg QW dosing achieves a trough concentration comparable to the ISL-TP 
steady-state trough levels for a dose of 0.25 mg QD (the dose selected for the DOR/ISL QD 
clinical development program), providing coverage for WT and M184V viruses (Figure 3). 

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Figure 3. 
Simulations of ISL-TP Time Series Following Multiple QD and QW 
ISL Dosing 
ISL = islatravir; ISL-TP = triphosphate form of islatravir; PBMC = peripheral blood mononuclear cells; QD = once daily; 
QW = once weekly; TP = triphosphate; WT = wild type 
A PK/pharmacodynamic model capturing the changes in lymphocytes and CD4+ T-cells for ISL 
across the oral Phase 2 and 3 programs was developed. A 2 mg QW oral dose of ISL, in 
combination with LEN, is expected to be well tolerated and will not have a negative effect on 
lymphocytes in participants with HIV-1 who are treatment naive or virologically suppressed. 
Table 17 and Table 18 present the corresponding predicted change from baseline at Week 48 for 
mean absolute lymphocyte cell count in virologically suppressed and treatment-naive 
participants, respectively. At ISL doses below 3 mg QW, the confidence interval for mean 
change from baseline ratio of ISL versus control includes 1, and at doses below 3 mg QW, the 
confidence interval for the mean change from baseline ratio overlaps with the confidence interval 
for participants receiving standard ART. 
Table 19 and Table 20 present the corresponding predicted change from baseline at Week 48 for 
mean CD4+ T-cell count in virologically suppressed and treatment-naive participants, 
respectively. At ISL doses below 3 mg QW, the confidence interval for the mean change from 
baseline ratio of ISL versus control includes 1, and at doses below 3 mg QW, the confidence 
interval for the mean change from baseline ratio overlaps with the confidence interval for 
participants receiving standard ART. 
10.0 
2-
C 
0 
c 
Q) 
u 
1.0 
C 
0 
(.) 
Q. 
I-
(.) 
CD 
Q. 
0.1 
Simulations of ISL-TP Time Series 
Following Multiple QD and QW ISL Dosing 
~ -------------------------------
D~e 
0 
4 
8 
12 
16 
Time (Weeks) 
20 
5·10 for M184V 
-
0.25 mg OD 
-
2mgOW 
S"IQforWT 
24 
28 

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Table 17. 
Week 48 Predicted Mean Absolute Lymphocyte Cell Count and 
Predicted Change From Baseline Ratio Following Once Weekly 
Dosing, Islatravir Versus Control, Virologically Suppressed 
Population 
ISL QW Dose 
(mg) 
Predicted ISL 
Mean Absolute Lymphocyte Cell Count 
(103 cells/mm3) 
(95% CI) 
48 Weeks 
Predicted Change From Baseline 
Ratio of ISL vs Control 
(95% CI) 
48 Weeks 
Standard ARV 
1.98 (1.88, 2.07) 
— 
0.5 
1.96 (1.87, 2.06) 
0.992 (0.948, 1.05) 
1 
1.93 (1.85, 2.02) 
0.978 (0.920, 1.03) 
2 
1.87 (1.78, 1.96) 
0.948 (0.900, 1.01) 
3 
1.82 (1.74, 1.93) 
0.923 (0.875, 0.971) 
5 
1.72 (1.64, 1.79) 
0.872 (0.823, 0.915) 
20 
1.12 (1.04, 1.21) 
0.560 (0.505, 0.610) 
ARV = antiretroviral; CI = confidence interval; ISL = islatravir; QW = once weekly 
Mean (95% CI) for the predicted lymphocyte cell count at baseline in the virologically suppressed group was 1.98 (1.87, 2.06). 
Table 18. 
Week 48 Predicted Mean Absolute Lymphocyte Cell Count and 
Predicted Change From Baseline Ratio Following Once Weekly 
Dosing, Islatravir Versus Control, Treatment-Naive Population 
ISL QW Dose 
(mg) 
Predicted ISL 
Mean Absolute Lymphocyte Cell Count 
(103 cells/mm3) 
(95% CI) 
48 Weeks 
Predicted Change From Baseline 
Ratio of ISL vs Control 
(95% CI) 
48 Weeks 
Standard ARV 
2.09 (1.97, 2.19) 
— 
0.5 
2.08 (1.92, 2.19) 
0.995 (0.945, 1.04) 
1 
2.06 (1.91, 2.18) 
0.990 (0.941, 1.02) 
2 
2.03 (1.85, 2.17) 
0.972 (0.928, 1.02) 
3 
1.98 (1.87, 2.11) 
0.954 (0.908, 1.00) 
5 
1.91 (1.80, 2.00) 
0.918 (0.872, 0.959) 
20 
1.40 (1.27, 1.52) 
0.672 (0.625, 0.719) 
ARV = antiretroviral; CI = confidence interval; ISL = islatravir; QW = once weekly 
Mean (95% CI) for the predicted lymphocyte cell count at baseline in the treatment-naive group was 1.98 (1.87, 2.06). 

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Table 19. 
Week 48 Predicted Mean CD4+ T-Cell Count and Predicted Change 
From Baseline Ratio Following Once Weekly Dosing, Islatravir 
Versus Control, Virologically Suppressed Population 
ISL QW Dose 
(mg) 
Predicted 
Mean CD4+ T-Cell Count (cells/mm3) 
(95% CI) 
48 Weeks  
Predicted Change From Baseline 
Ratio of ISL vs Control 
(95% CI) 
48 Weeks  
Standard ARV 
750 (706, 799) 
— 
0.5 
746 (709, 795) 
0.994 (0.933, 1.04) 
1 
738 (683, 787) 
0.982 (0.916, 1.05) 
2 
725 (683, 775) 
0.959 (0.905, 1.04) 
3 
713 (669, 747) 
0.948 (0.885, 1.01) 
5 
692 (655, 726) 
0.922 (0.858, 0.983) 
20 
568 (513, 618) 
0.742 (0650, 0.819) 
ARV = antiretroviral; CD4 = clusters of differentiation 4; CI = confidence interval; ISL = islatravir; QW = once weekly 
Mean (95%CI) for the predicted CD4+ T-cell count at baseline in the virologically suppressed group was 717 (673, 763). 
Table 20. 
Week 48 Predicted Mean CD4+ T-Cell Count and Predicted Change 
From Baseline Ratio Following Once Weekly Dosing, Islatravir 
Versus Control, Treatment-Naive Population 
ISL QW Dose 
(mg) 
Predicted 
Mean CD4+ T-Cell Count (cells/mm3) 
(95% CI) 
48 Weeks  
Predicted Change From Baseline 
Ratio of ISL vs Control 
(95% CI) 
48 Weeks 
Standard ARV 
715 (670, 759) 
— 
0.5 
711 (669, 751) 
0.991 (0.936, 1.04) 
1 
705 (667, 758) 
0.987 (0.931, 1.03) 
2 
699 (660, 742) 
0.975 (0.929, 1.02) 
3 
687 (648, 730) 
0.962 (0.908, 1.01) 
5 
671 (624, 713) 
0.932 (0.885, 0.980) 
20 
563 (511, 620) 
0.769 (0.703, 0.827) 
ARV = antiretroviral; CD4 = clusters of differentiation 4; CI = confidence interval; ISL = islatravir; QW = once weekly 
Mean (95% CI) for the predicted CD4+ T-cell count at baseline in the treatment-naive group was 589 (548, 628). 
To reach therapeutic levels quickly, loading doses are required for LEN but not for ISL. In 
Cohort 2, no extra doses of ISL will be administered during the loading of LEN. Clinically 
meaningful systemic DDIs with ISL were not observed in a recent clinical DDI study. 

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1.5. 
Rationale for Dose Selection of Lenacapavir 
The dose selection for 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 
modeling indicate that LEN plasma concentration of 15.5 ng/mL, corresponding to inhibitory 
quotient (IQ) of 4, or higher would provide near maximal antiviral activity. The proposed oral 
regimen targets an exposure where the lower bound of the 90% CI of predicted geometric mean 
for LEN Ctau is rapidly achieved and maintained above IQ4 (Figure 4). Participants will receive 
2 loading doses of LEN 600 mg on Day 1 and Day 2 followed by LEN 300 mg on Day 8 and 
once weekly thereafter. LEN has been administered orally at doses up to 1800 mg 
(Study GS-US-200-4701). Preliminary safety data from all ongoing LEN studies indicate that all 
treatments are generally safe and well tolerated. Clinically meaningful systemic DDIs with ISL 
were not observed in a recent clinical DDI study. 
Figure 4. 
Target Exposures are Rapidly Achieved and Maintained with An 
Oral LEN Once-Weekly Regimen 
CI = confidence interval; IQ = inhibitory quotient; LEN = lenacapavir; QW = once weekly 
The solid line and the shaded region correspond to the geometric mean and 90% CI, respectively (based on simulations, 
N = 100). Inhibitory Quotient is defined as Trough Concentration/in vitro protein-adjusted EC95 (paEC95) against wild-type 
virus. Horizontal dashed lines correspond to target IQ values of 4 and 6 based on phenotypic analyses and modeling. 
1.6. 
Risk/Benefit Assessment for the Study 
Potential risks associated with the study include unknown AEs associated with each of the 
investigational drugs, ISL and LEN, and with the novel combination of ISL+LEN, general risks 
associated with frequent clinic visits and laboratory blood draws, and the associated pain and 
discomfort of multiple phlebotomies. Strategies to mitigate these risks include close monitoring 
of laboratory values and AEs. Parameters for monitoring of AEs will be well-defined and closely 
followed. 
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IQ=6 
·•·••··••·••·••···· ····••·••··••·••··••·••··••· ••·····•• ·••···· ····••· ••··••· ••··••·••·••··••·••··•• ·••··••·••··••·••··••· ••··••·••·••··· ·• IQ=4 
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9 
10 
11 

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In addition, potential risks to PWH include virologic breakthrough with exposure to 
subtherapeutic concentrations of ISL+LEN or unrecognized preexisting resistance to ISL and/or 
LEN. These risks could lead to development of resistance to either ISL, LEN, or both. Strategies 
to mitigate these risks include resistance testing of each participant’s latent viral reservoir to 
minimize the risk of enrolling participants with preexisting resistance, and frequent assessments 
of HIV-1 RNA to ensure that virologic breakthrough is rapidly identified, thus limiting the time 
during which drug resistance mutations could emerge. Each component of the study regimen has 
a novel mechanism without predicted cross‑resistance with currently approved ART. 
 
 
Participants will be advised to initiate alternative 
therapy for HIV if they discontinue from the study. 
Decreases in total lymphocyte and lymphocyte subset (including CD4+ T-cell) counts have been 
observed in Phase 2 and Phase 3 studies with ISL given QM (60 and 120 mg), QW (20 mg in 
combination with MK-8507, an NNRTI), and QD (0.75 mg in combination with DOR 100 mg). 
As a result, dosing was stopped in December 2021 for ISL 60 mg QM for HIV-1 PrEP, ISL 
20 mg QW (with MK-8507) for HIV-1 treatment, and DOR/ISL 100 mg/0.75 mg QD for HIV-1 
treatment in pediatric participants. 
Merck has conducted a comprehensive investigation into ISL-related decreases in lymphocyte 
counts to identify possible mechanism(s) of action and to assess the timing and extent of 
lymphocyte decreases while on treatment with ISL and the recovery of lymphocyte counts when 
off-treatment with ISL. 
Investigations of possible mechanisms for the lymphocyte decreases support the conclusion that 
the preferential accumulation of ISL-TP in lymphocytes can lead to inhibition of cell growth and 
apoptosis at high ISL-TP concentrations. Toxicity due to TP levels is a common mechanism 
among HIV nucleoside analog drugs. Mitochondrial toxicity is not a contributing mechanism to 
the decrease in lymphocytes. 
An overall summary of the comprehensive investigation into ISL-related decreases in 
lymphocyte counts is as follows: 
• No changes in general hematology parameters (including hemoglobin, basophils, eosinophils, 
monocytes, leukocytes, neutrophils, platelets) were observed for participants receiving ISL 
alone or in combination with other ARVs in any ISL study. 
• ISL dose-dependent decreases from baseline were observed in mean total lymphocyte counts 
and lymphocyte subset (CD4+ T-cell, CD8+ T-cell, B-cell) counts, with greater decreases 
observed at the higher ISL doses administered QW (20 mg) and QM (60 mg) compared with 
QD (0.75 mg) administration. 
⎯ In virologically suppressed participants in MK-8591A-017 and MK-8591A-018 receiving 
DOR/ISL 100 mg/0.75 mg QD, mean percent changes from baseline were observed in 
total lymphocyte (−10.6% and −8.4%, respectively), CD4+ T-cell (−0.68% and +0.87%, 
respectively), CD8+ T-cell (−8.2% and −7.4%, respectively), and B-cell (−4.4% and 
8.6%, respectively) counts at Week 48. 
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⎯ In virologically suppressed participants in MK-8591-013 receiving ISL 20 mg + 
MK-8507 100 to 400 mg QW, mean percent changes from baseline were observed in 
total lymphocyte (−15.1% to −30.9%), CD4+ T-cell (−7.6% to −28.1%), CD8+ T-cell 
(−18.1% to −32.8%), and B-cell (−36.8% to −46.3%) counts at Week 24. 
⎯ In participants with low risk of HIV-1 infection receiving ISL 60 or 120 mg QM for 
PrEP, the on-treatment mean decreases from baseline in total lymphocyte count were 
−21.3% and −35.6% at Week 24, respectively. 
• Stabilization of the decreases from baseline in mean total lymphocyte count and lymphocyte 
subset counts observed for the DOR/ISL 100 mg/0.75 mg QD program occurred between 
Weeks 48 and 72, depending on the lymphocyte subset. 
• Decreases from baseline in mean total lymphocyte count and lymphocyte subset counts were 
not associated with increased incidence of infection. 
• A return toward baseline in lymphocyte and lymphocyte subset counts has been observed 
across the ISL clinical development program. However, a full recovery was not observed by 
24 weeks after stopping ISL. The most robust data on recovery of the lymphocyte counts 
available at this point was from the studies involving administration of ISL QW (20 mg) and 
QM (60 to 120 mg), as detailed below. Data on recovery to baseline following 
discontinuation of DOR/ISL 100 mg/0.75mg QD in virologically suppressed adults (Studies 
MK-8591A-017 and MK-8591A-018) are not yet available. 
⎯ Approximately 6 months after discontinuation of ISL 20 mg QW in adult virologically 
suppressed participants (MK-8591-013), among those with ≥ 30% decrease in total 
lymphocyte or CD4+ T-cell counts at their last on-treatment measurement and at least 
1 follow-up result, 10 of 40 (25%) and 15of 32 (47%) participants demonstrated an 
increase in total lymphocyte and CD4+ T-cell counts, respectively, to within 10% of 
baseline. 
⎯ Approximately 5 months after discontinuation of ISL 60 mg QM in adults at risk of 
HIV-1 infection, 43 (29.9%) of the 144 participants in MK-8591-022 and MK8591-024 
with a ≥ 30% decrease in total lymphocyte count at the last on-treatment visit 
demonstrated an increase in total lymphocyte counts to within 10% of baseline. 
Overall, the evaluation of data from across the ISL clinical programs to date suggests that the 
decrease in mean total lymphocyte and lymphocyte subset counts is ISL dose-dependent, with 
lower doses less likely to cause decreases. A return toward baseline in lymphocyte and 
lymphocyte subset counts has been observed. 
As a result of these findings and after a review of the totality of the ISL data, Cohort 1 was 
discontinued, and a decreased ISL dose is being implemented in Cohort 2 and loading of ISL has 
been eliminated (see below). Based on modeling and simulation, it is believed that the newly 
selected dose of ISL for Cohort 2 (2 mg once weekly) is unlikely to cause any decrease in 
CD4+ T-cell or absolute lymphocyte counts. Any residual risk for ISL-associated CD4+ T-cell 

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or absolute lymphocyte count decreases will be further mitigated by exclusion of participants 
with CD4+ T-cell count < 350 cells/mm3 or absolute lymphocyte counts < 900 cells/mm3, close 
monitoring and stopping criteria for CD4+ T-cell/absolute lymphocyte count decreases, and 
periodic review of safety and efficacy by an independent data monitoring committee (DMC). 
Details of the planned DMC analyses are provided in Section 8.2.1.2. 
The weekly LEN 300 mg dose selected for evaluation in this study requires that loading doses of 
LEN 600 mg be administered on Days 1 and 2 in order to rapidly achieve exposures predicted to 
be efficacious. In Cohort 1, ISL 40 mg loading doses along with the LEN 600 mg loading doses 
will be evaluated. While the safety profile of ISL under this dosing regimen has not been directly 
studied, the projected exposures were within those observed to be well tolerated in the 
once-monthly oral ISL 120 mg dose administered in the Phase 2 PrEP study (MK-8591-016), 
which supported selection of the ISL 60 mg once-monthly dose for Phase 3 PrEP studies 
(MK-8591-022 and MK-8591-024). However, given the ISL dose-dependent decreases in both 
CD4+ T-cells and absolute lymphocyte counts, ISL loading has been eliminated for Cohort 2 
participants while LEN loading will be maintained. 
Lack of adherence or accidental overdose due to weekly dosing for the treatment of HIV is a 
potential risk in this study, as participants have no experience with an HIV treatment regimen of 
this dosing frequency. Participants will be followed during the first 2 weeks of ISL+LEN dosing 
with phone calls and throughout the study via clinic site visits and may be offered other means of 
adherence support and other medication guides through the remainder of the study. 
Potential benefits of participation in the study include receiving a long-acting weekly regimen, 
thus freeing participants from daily ARV medication, with potentially improved adherence 
leading to improved efficacy and immunologic control. Participants will also be contributing to 
an understanding of the safety and tolerability of a novel long-acting treatment regimen, 
including the PK of the regimen, thus contributing to the development of ART with novel 
mechanisms of action with potential applications for HIV-1 treatment, prevention, and cure. 
Those randomized to receive B/F/TAF the first 48 weeks of the study are not anticipated to have 
any additional therapeutic benefit while taking B/F/TAF but may benefit from increased contact 
with health care providers and close monitoring during this time. 
An infectious disease pandemic may pose additional risks to study drug availability, the 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. 
Considering the above, the benefit-risk balance for this study is considered positive. 
1.7. 
Compliance 
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements. 

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2. 
OBJECTIVES AND ENDPOINTS 
Primary Objective 
Primary Endpoint 
• 
To evaluate the efficacy of oral weekly ISL in 
combination with LEN in virologically suppressed 
PWH at Week 24 
• 
The proportion of participants with HIV-1 RNA 
≥ 50 copies/mL at Week 24 as determined by the 
United States (US) Food and Drug Administration 
(FDA)-defined snapshot algorithm 
Secondary Objectives 
Secondary Endpoints 
• 
To evaluate the efficacy of oral weekly ISL in 
combination with LEN in virologically suppressed 
PWH at Weeks 12, 24, and 48 
• 
The proportion of participants with HIV-1 RNA 
≥ 50 copies/mL at Weeks 12 and 48 as determined 
by the US FDA-defined snapshot algorithm 
• 
The proportions of participants with HIV-1 RNA 
< 50 copies/mL at Weeks 12, 24, and 48 as 
determined by the US FDA-defined snapshot 
algorithm 
• 
The change from baseline in CD4+ T-cell count at 
Weeks 12, 24, and 48 
• 
To evaluate the safety and tolerability of oral 
weekly ISL in combination with LEN 
• 
The incidence of treatment-emergent AEs leading 
to study drug discontinuation 
• 
To evaluate the PK of ISL and LEN administered 
as an oral weekly combination regimen 
• 
ISL and LEN PK parameters (Cmax, Tmax, Ctau, 
AUCtau, and t1/2, as applicable) 
Exploratory Objectives 
Exploratory Endpoints 
• 
To evaluate the development of resistance to ISL 
and LEN administered as an oral weekly 
combination regimen 
• 
Identification of mutations conferring resistance to 
ISL and/or LEN in participants with virologic 
failure 
• 
To assess the effect of treatment with ISL and 
LEN administered as an oral weekly combination 
regimen on patient-reported outcomes (PROs) 
• 
Participant scores on the PRO questionnaires HIV 
Dependent Quality of Life (HIVDQoL), EuroQoL 
5 dimension 5 level (EQ-5D-5L), HIV Treatment 
Satisfaction Questionnaires (HIVTSQc12 and 
HIVTSQs12), the Patient Perspective of Regimen 
and the Patient Perspective of Regimen Change 
 

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3. 
STUDY DESIGN 
3.1. 
Study Design Overview 
A schematic diagram of the study is provided in Figure 1. 
This is a Phase 2, randomized, open-label, active-controlled, multicenter study to evaluate safety, 
efficacy, and PK of a regimen of ISL+LEN in virologically suppressed PWH. 
Cohort 1 (Enrollment and dosing in Cohort 1 were stopped prematurely by the sponsor): 
For Cohort 1, participants who meet all eligibility criteria will be randomized in a 2:1 ratio to 
receive oral weekly ISL+LEN (Treatment Group 1) or oral daily B/F/TAF (Treatment Group 2) 
for 48 weeks. Enrollment and dosing were stopped prematurely by the sponsor. Prior to the 
sponsor discontinuation of Cohort 1, it was planned that following completion of the Week 48 
visit, participants receiving ISL+LEN in Treatment Group 1 were to continue ISL+LEN and 
attend visits every 12 weeks. Participants in Treatment Group 2 were to switch from B/F/TAF to 
the ISL+LEN regimen (starting with the loading doses over 2 days) and continue the study. 
Participants in Treatment Group 2 who did not switch from B/F/TAF to ISL+LEN at Week 48 
were to be discontinued from the study. 
After Week 48, participants taking ISL+LEN were to attend visits every 12 weeks until the 
product became accessible to participants commercially or Gilead Sciences, Inc. (Gilead) elected 
to discontinue the study. 
Cohort 2: 
For Cohort 2, participants who meet all eligibility criteria will be randomized in a 1:1 ratio to 
receive oral weekly ISL (2 mg) capsule + LEN (300 mg) tablet (Treatment Group 3) or oral daily 
B/F/TAF (Treatment Group 4) for 48 weeks. 
At the Week 48 visit, all participants will be given an option to participate in an Extension Phase 
to receive ISL+LEN or ISL/LEN 
 (when available). Participants in Treatment Group 3 may 
continue to receive ISL+LEN, while participants in Treatment Group 4 may switch from 
B/F/TAF to ISL+LEN, starting with the loading doses of LEN over 2 days. During the Extension 
Phase, participants who have started ISL+LEN will switch to ISL/LEN 
 when it becomes 
available and begin taking ISL/LEN 
 starting at their next scheduled dose. Participants who 
do not wish to participate in the Extension Phase will be discontinued from the study. 
Participants in the Extension Phase will attend visits every 12 weeks until Week 144; visits will 
occur every 24 weeks after Week 144 until ISL/LEN 
 becomes available to participants or 
Gilead elects to discontinue the study, whichever occurs first. 
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3.2. 
Study Treatments 
Details regarding the doses and dosing regimens for ISL+LEN, B/F/TAF, and ISL/LEN 
 are 
provided in Sections 5.6 and 5.7, respectively. Details regarding the formulation, packaging, and 
labeling of study drugs are provided in Sections 5.2 to 5.4. 
3.3. 
Duration of Treatment 
Durations of treatment in the Randomized Phases of this study for Cohort 1 and Cohort 2 are 
48 weeks. 
3.4. 
Discontinuation Criteria 
3.4.1. 
Early Discontinuation from Study Treatment 
Study drugs may be discontinued in the following instances: 
• Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a meaningful degree. Following resolution of intercurrent illness, the 
participant may resume study dosing at the discretion of the investigator 
• Reactivation of hepatitis B virus (HBV) infection 
• 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 
• Lack of efficacy 
• Participant request to discontinue for any reason 
• Participant noncompliance 
• Pregnancy during the study; refer to Appendix 3 
• Discontinuation of the study at the request of Gilead or a regulatory agency or institutional 
review board (IRB) 
• Meeting the stopping criteria for changes in CD4+ T-cell or absolute lymphocyte count 
(Treatment Group 3 or Extension Phase only) – see Section 7.7. 
Procedures for participants who discontinue study drugs early are described in Section 6.4.1. 
The Gilead medical monitor should be consulted prior to study drug discontinuation when 
medically feasible. After study drug discontinuation, participants should be switched to an 
appropriate alternative ARV regimen. 
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3.4.2. 
Early Discontinuation from the Study 
A participant may permanently discontinue from the study for reasons including but not limited 
to the following: 
• Death 
• Investigator decision to remove a participant from the study 
• Withdrawal of consent by the participant 
• Participant lost to follow-up (see Section 3.4.3) 
• Study terminated by the sponsor 
Procedures for participants who discontinue the study early are described in Section 6.4. 
3.4.3. 
Lost to Follow-up 
Should the participant fail to return to the investigational site for a scheduled protocol-specific 
visit, sites will need to make at least 2 attempts by a combination of telephone and certified mail 
to contact the participant. If the participant is contacted, the participant should be counseled on 
the importance of maintaining the protocol-specified visit schedule. If the participant does not 
respond within 1 month after the second contact, the participant will be considered lost to 
follow-up and no additional contact will be required. Sites must document all attempts to contact 
the participant. 
3.5. 
Definitions for Time of Primary Endpoint and End of Study 
3.5.1. 
Primary Endpoint 
The date of the last participant’s last visit for the primary endpoint is the date of the last visit to 
perform assessments for the primary analysis. 
3.5.2. 
End of Study 
The end of this study will be the last participant’s last observation (or visit). 
3.6. 
Poststudy Care 
After the participant has completed/terminated their participation in the study, long-term care of 
the participant will remain the responsibility of their primary treating physician. 
3.7. 
Source Data 
The source data for this study will be obtained from electronic data capture (EDC), central 
laboratory, specialty laboratory (eg, for PK and/or pharmacodynamic data), interactive response 
technology (IRT), and electronic clinical outcome assessments 

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4. 
PARTICIPANT POPULATION 
4.1. 
Number of Participants and Participant Selection 
For Cohort 1, approximately 75 virologically suppressed PWH who meet the eligibility criteria 
will be randomized in a 2:1 ratio to receive ISL+LEN or B/F/TAF. Enrollment and dosing in 
Cohort 1 were stopped prematurely by the sponsor. 
For Cohort 2, approximately 100 virologically suppressed PWH who meet the eligibility criteria 
will be randomized in a 1:1 ratio to receive ISL 2 mg + LEN 300 mg or B/F/TAF. 
4.1.1. 
Participant Replacement 
Participants who discontinue before the end of the study will not be replaced. 
4.2. 
Inclusion Criteria (Applicable to Both Cohorts, Unless Specified Otherwise) 
Participants must meet all of the following inclusion criteria to be eligible for participation in this 
study: 
1) Willing and able to provide written informed consent prior to performing study procedures 
2) Aged ≥ 18 years at screening 
3) Received B/F/TAF for HIV-1 infection for ≥ 24 weeks prior to screening 
4) Documented plasma HIV-1 RNA < 50 copies/mL (or undetectable HIV-1 RNA level 
according to the local assay being used if the limit of detection is ≥ 50 copies/mL) for 
≥ 24 weeks before screening 
5) Plasma HIV-1 RNA < 50 copies/mL at screening 
4.3. 
Exclusion Criteria (Applicable to Both Cohorts, Unless Specified Otherwise) 
Participants who meet any of the following exclusion criteria are not eligible to be enrolled in 
this study: 
1) History of prior virologic failure while receiving treatment for HIV-1 
2) Prior use of, or exposure to, ISL or LEN 
3) Active, serious infections requiring parenteral therapy < 30 days before randomization 
4) Active tuberculosis infection 
5) Acute hepatitis < 30 days before randomization 

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6) Active or occult HBV coinfection, defined as hepatitis B core antibody (HBcAb) positive, 
hepatitis B surface antigen (HBsAg) positive, or HBV DNA positive (regardless of prior 
HBsAb status) as determined by the central laboratory 
7) Active hepatitis C virus (HCV) coinfection, defined as detectable HCV RNA. 
Note: Participants with prior/inactive HCV infection (defined as undetectable HCV RNA) 
may be enrolled 
8) History of or current clinical decompensated liver cirrhosis (eg, ascites, encephalopathy, or 
variceal bleeding) 
9) Treatment < 3 months prior to screening or anticipated treatment during the study period with 
immunosuppressant therapies, hydroxyurea, foscarnet, radiation, or cytotoxic 
chemotherapeutic agents without approval from sponsor prior to randomization. Agents 
disallowed in Section 5.8 may not be considered for approval 
10) Active malignancy requiring acute systemic therapy 
11) Abnormal electrocardiogram (ECG) at the screening visit that is clinically significant as 
determined by the investigator 
12) Any of the following laboratory values at screening 
a) CLcr ≤ 30 mL/min according to the Cockcroft-Gault formula {Cockcroft 1976} 
b) Alanine aminotransferase (ALT) > 5  upper limit of normal (ULN) 
c) Direct bilirubin > 1.5  ULN 
d) Platelets < 50,000/mm3 
e) Hemoglobin < 8.0 g/dL 
f) CD4+ T-cells < 200 cells/mm3 (Cohort 1); CD4+ T-cells < 350 cells/mm3 (Cohort 2) 
g) Absolute lymphocyte count < 900 cells/mm3 (Cohort 2) 
13) Participation or planned participation in any other clinical study (including observational 
studies) without prior approval from the sponsor 
14) Known hypersensitivity to any of the study drugs, their metabolites, or formulation 
excipients 
15) Ongoing therapy or anticipated frequent use of any prohibited medications listed in 
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16) Any other clinical 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 
17) Participants of childbearing potential who engage in heterosexual intercourse and do not 
agree to use protocol-specified methods of contraception (Appendix 3) 
18) Participants of childbearing potential (as defined in Appendix 3) who have a positive serum 
pregnancy test at screening or positive urine and serum pregnancy tests at Day 1 prior to 
study drug administration 
19) Participants who plan to continue breastfeeding during the study 
20) Documented historical (if available) or screening (proviral genotype analysis) resistance 
reports showing NRTI or NNRTI resistance mutations in reverse transcriptase, including 
M184V/I (Cohort 2) 
The following substitutions in HIV-1 reverse transcriptase will be considered NRTI 
resistance mutations: M41L, K65E/N/R, D67N, T69 insertions, K70E/R, L74I/V, V75I, 
F77L, Y115F, F116Y, Q151M, M184I/V, L210W, T215F/Y, K219E/N/Q/R. The following 
substitutions in HIV-1 reverse transcriptase will be considered NNRTI resistance mutations: 
L100I, K101E/H/P, K103N/S, V106A/M, V108I, E138A/G/K/Q/R, V179L, Y181C/I/V, 
Y188C/H/L, G190A/Q/S, H221Y, P225H, F227C, M230I/L 

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5. 
STUDY DRUGS 
5.1. 
Randomization, Blinding, and Treatment Codes Access 
5.1.1. 
Randomization 
Participants will be assigned a screening number in the IRT system at the time of consent. 
Once eligibility has been confirmed, the investigator or designee will randomize the participant 
using the IRT system. Once a participant number has been assigned to a participant, it will not be 
reassigned to any other participants. The participant number assignment and randomization may 
be performed up to 3 days prior to the Day 1 visit provided all screening procedures have been 
completed and participant eligibility has been confirmed. 
For Cohort 1, participants who meet eligibility criteria will be randomized in a 2:1 ratio to 
Treatment Group 1 (ISL+LEN) or Treatment Group 2 (B/F/TAF). Enrollment and dosing in 
Cohort 1 were stopped prematurely by the sponsor. 
For Cohort 2, participants who meet all eligibility criteria will be randomized in a 1:1 ratio to 
Treatment Group 3 (ISL 2 mg + LEN) or Treatment Group 4 (B/F/TAF). Randomization will be 
stratified by CD4+ T-cell count (350 to 499 [inclusive] cells/mm3 or ≥ 500 cells/ mm3) at 
screening. 
The IRT will assign study drug bottle numbers of open-label study drugs at Day 1 and 
subsequent visits for each participant. 
5.1.2. 
Blinding 
Blinding of treatment assignments or data will not be performed in this study. 
5.2. 
Description and Handling of Islatravir 
5.2.1. 
Formulation 
Cohort 1: Islatravir capsules, 20 mg, are white opaque capsules. Each capsule contains 20 mg 
ISL drug substance. In addition to the active ingredient, ISL capsules contain the following 
inactive ingredients: gelatin, titanium dioxide, mannitol, microcrystalline cellulose, 
croscarmellose sodium, and magnesium stearate. 
Cohort 2: Islatravir capsules, 1 mg, are white opaque capsules. Each capsule contains 1 mg ISL 
drug substance. In addition to the active ingredient, ISL capsules contain the following inactive 
ingredients: gelatin, titanium dioxide, mannitol, microcrystalline cellulose, croscarmellose 
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5.2.2. 
Packaging and Labeling 
Cohort 1: Islatravir capsules, 20 mg, are packaged in white, high-density polyethylene (HDPE) 
bottles. Each bottle contains 4 capsules. Each bottle is enclosed with a white, continuous-thread, 
child-resistant polypropylene screw cap with an induction-sealed and aluminum-faced liner. 
Cohort 2: Islatravir capsules, 1 mg, are packaged in white, HDPE bottles. Each bottle contains 
4 capsules. Each bottle is enclosed with a white, continuous-thread, child-resistant polypropylene 
screw cap with an induction-sealed and aluminum-faced liner. 
Study drugs to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the US FDA, European Union (EU) Guideline to 
Good Manufacturing Practice – Annex 13 (Investigational Medicinal Products), and/or other 
local regulations. 
5.2.3. 
Storage and Handling 
Cohort 1: Islatravir capsules, 
, should be stored at 2 °C to 30 °C (36 °F to 86 °F). Storage 
conditions are specified on the label. Until dispensed to participants, all bottles of study drugs 
should be stored in a securely locked area, accessible only to authorized site personnel. 
Cohort 2: Islatravir capsules, 1 mg, should be stored at 2 °C to 30 °C (36 °F to 86 °F). Storage 
conditions are specified on the label. Until dispensed to participants, all bottles of study drugs 
should be stored in a securely locked area, accessible only to authorized site personnel. 
To ensure the stability and proper identification, study drugs should not be stored in a container 
other than the container in which they were supplied. Keep the bottle tightly closed to protect 
from moisture. 
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. 
5.3. 
Description and Handling of Lenacapavir 
5.3.1. 
Formulation 
Lenacapavir tablets, 300 mg, are capsule-shaped, film-coated beige tablets, debossed with “GSI” 
on 1 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: copovidone, poloxamer 407, 
mannitol, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyvinyl 
alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide yellow, iron oxide black, and iron 
oxide red. 
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5.3.2. 
Packaging and Labeling 
Lenacapavir tablets, 300 mg, are packaged in white, 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 with an induction-sealed and 
aluminum-faced liner. 
Study drugs to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the US FDA, EU Guideline to Good Manufacturing 
Practice – Annex 13 (Investigational Medicinal Products), and/or other local regulations. 
5.3.3. 
Storage and Handling 
Lenacapavir tablets, 
, should be stored below 30 °C (86 °F). Storage conditions are 
specified on the label. Until dispensed to participants, all bottles of study drugs should be stored 
in a securely locked area, accessible only to authorized site personnel. 
To ensure the stability and proper identification, study drugs should not be stored in a container 
other than the container in which they were supplied. Keep the bottle tightly closed to protect 
from moisture. 
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. 
5.4. 
Description and Handling of B/F/TAF 
5.4.1. 
Formulation 
B/F/TAF 50/200/25 mg tablets are capsule-shaped, film-coated, purplish-brown tablets, debossed 
with “GSI” on one side of the tablet and “9883” on the other side of the tablet. Each tablet core 
contains 50 mg of bictegravir, 200 mg of emtricitabine, and 25 mg of tenofovir alafenamide. In 
addition to the active ingredients, B/F/TAF tablets contain the following inactive ingredients: 
microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, 
titanium dioxide, polyethylene glycol, talc, iron oxide red, and iron oxide black. 
5.4.2. 
Packaging and Labeling 
B/F/TAF 50/200/25 mg tablets are packaged in white, HDPE bottles. 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 with an induction-sealed and 
aluminum-faced liner. 
Study drugs to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the US FDA, EU Guideline to Good Manufacturing 
Practice – Annex 13 (Investigational Medicinal Products), and/or other local regulations. 
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5.4.3. 
Storage and Handling 
B/F/TAF 50/200/25 mg tablets should be stored at 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. Until 
dispensed to participants, all bottles of study drugs should be stored in a securely locked area, 
accessible only to authorized site personnel. 
To ensure the stability and proper identification, study drugs should not be stored in a container 
other than the container in which they were supplied. Keep the bottle tightly closed to protect 
from moisture. 
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. 
5.5. 
Description and Handling of ISL/LEN 
 
5.5.1. 
Formulation 
ISL/LEN 
 tablets are capsule-shaped, film-coated gray tablets. 
ISL/LEN 
 
 tablets are capsule-shaped, debossed, film-coated pink tablets. 
5.5.2. 
Packaging and Labeling 
ISL/LEN 
 tablets are packaged in white, HDPE bottles. Each bottle contains 4 tablets, silica 
gel desiccant, and with or without polyester packing material. Each bottle is enclosed with a 
white, continuous-thread, child-resistant polypropylene screw cap with an induction-sealed and 
aluminum-faced liner. 
Study drugs to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the US FDA, EU Guideline to Good Manufacturing 
Practice – Annex 13 (Investigational Medicinal Products), and/or other local regulations. 
5.5.3. 
Storage and Handling 
ISL/LEN 
 tablets should be stored below 30 °C (86 °F). Storage conditions are specified on 
the label. Until dispensed to participants, all bottles of study drugs should be stored in a securely 
locked area, accessible only to authorized site personnel. 
5.6. 
Dosage and Administration of Islatravir and Lenacapavir 
Cohort 1 (enrollment and dosing in Cohort 1 were stopped prematurely by the sponsor): 
Participants in Treatment Group 1 will take oral ISL 40 mg (2  20 mg capsules) and oral LEN 
600 mg (2  300 mg tablets) on Days 1 and 2 without regard to food. On Day 8 and once a week 
thereafter (ie, on the same day of the week together with LEN), participants will take oral ISL 
20 mg (1  20 mg capsule) and oral LEN 300 mg (1  300 mg tablet) without regard to food. 
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After 48 weeks of on-study B/F/TAF, participants in Treatment Group 2 will take ISL+LEN 
beginning with the loading doses over 2 days and continuing with dosing 7 days after the first 
loading dose and then once a week thereafter. 
Cohort 2 
For Treatment Group 3, oral ISL and oral LEN are to be taken without regard to food and, where 
indicated, taken together. From Day 8 onward, ISL and LEN should be taken weekly on the 
same day of the week. 
During the Extension Phase, participants who are receiving ISL+LEN will switch to the 
ISL/LEN 
 tablet (when available) administered orally on the same schedule, taken weekly 
on the same day of the week, without regard to food. 
Table 21. 
Cohort 2: Treatment Group 3 Dosing Schedule 
  
LENa 
ISLa 
Day 1 
Day 2 
Day 8 (and weekly thereafter) 
 
; ISL = islatravir; LEN = lenacapavir 
a 
Including participants in Treatment Group 4 who continue in the Extension Phase. 
After 48 weeks of on-study B/F/TAF, participants in Treatment Group 4 will be offered to switch 
from B/F/TAF to ISL+LEN, starting with the loading doses of LEN over 2 days. 
Missed dose recommendations for ISL, LEN, and ISL/LEN 
 for Cohort 2 are provided in 
Table 22 and Table 23. These recommendations apply to missing both ISL and LEN as well as to 
missing only ISL, only LEN, or ISL/LEN 
 The scheduled dosing day of the week should 
not change due to the missed dose of ISL and/or LEN or ISL/LEN 
 
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Table 22. 
Cohort 2: Missed Dose Recommendations for ISL and LEN 
Number of Days 
Since Initial 
Missed 
Scheduled Dose 
Recommendation 
Examples 
1 to 6 days 
(1 missed dose) 
For both ISL and LEN, take 1 dose each 
(ie, 2 capsules of 1 mg ISL and 1 tablet of 
300 mg LEN) as soon as possible, then 
resume normal schedule, taking 1 dose on 
the next scheduled day. 
Participant forgets to take dose on Monday 
(scheduled) but remembers before the next 
scheduled dose day (ie, Tuesday-Sunday). 
Take 1 dose as soon as possible, then take 
1 dose on the following Monday as scheduled. 
7 to 14 days 
(1 – 2 missed 
doses) 
NOTE: Separate instructions for ISL and 
LEN 
 
ISL: Take 1 dose (ie, 2 capsules of 1 mg 
ISL) as soon as possible, then resume 
normal schedule, taking 1 dose on the next 
scheduled day. If participant remembers on 
scheduled dosing day, then take 1 dose 
only. Do not take 2 doses on the same day. 
 
LEN: Take 2 doses (ie, 2 tablets of 300 mg 
LEN) as soon as possible, then resume 
normal schedule on the next scheduled day. 
If participant remembers on scheduled 
dosing day, then take 2 doses only. Never 
take 3 doses on the same day. 
Participant forgets to take both doses on 
Monday (scheduled) but remembers the 
following Monday. Take 1 dose of ISL and 
2 doses of LEN on that Monday and resume 
dosing schedule (1 dose each on Mondays). 
Participant forgets to take both doses on 
2 consecutive Mondays (scheduled) but 
remembers a few days later 
(ie, Tuesday-Sunday following second missed 
dose) before the third Monday. Take 1 dose of 
ISL and 2 doses of LEN as soon as possible, 
then resume dosing schedule (1 dose each the 
next Monday as scheduled). 
Participant forgets to take both doses on 
2 consecutive Mondays (scheduled) but 
remembers on the third Monday. Take 1 dose 
of ISL and 2 doses of LEN on the third 
Monday and resume dosing schedule (1 dose 
on Mondays). Do not take 2 doses of ISL or 
3 doses of LEN on the same day. 
More than 
14 days 
(3 or more 
missed doses) 
Assess whether clinically appropriate to 
restart oral weekly regimen. Consider 
checking HIV-1 RNA. 
Participant forgets to take dose on 
3 consecutive Mondays (scheduled). Clinical 
assessment needed. 
HIV-1 = human immunodeficiency virus type 1; ISL = islatravir; LEN = lenacapavir; RNA = ribonucleic acid 

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Table 23. 
Cohort 2: Missed Dose Recommendations for ISL/LEN 
 
Number of Days 
Since Initial 
Missed 
Scheduled Dose 
Recommendation 
Examples 
1 to 6 days 
(1 missed dose) 
Take the usual maintenance dose 
(ie, 1 tablet of ISL/LEN 
 2/300 mg) 
as soon as possible, then resume normal 
schedule, taking 1 dose on the next 
scheduled day. 
Participant forgets to take dose on Monday 
(scheduled) but remembers before the next 
scheduled dose day (ie, Tuesday-Sunday). Take 
1 dose as soon as possible, then take 1 dose on 
the following Monday as scheduled. 
7 days 
(1 full missed 
dose) 
Take the usual maintenance dose 
(ie, 1 tablet of ISL/LEN 
 2/300 mg) 
on that day, then resume normal schedule, 
taking 1 dose on the next scheduled day. 
Participant has been taking doses every 
Monday. Participant forgets to take dose on 
Monday (scheduled) but does not realize this 
until the following Monday. The participant 
should take a single dose on that Monday and 
resume the previous dosing schedule (1 dose on 
each Monday). 
More than 7 days 
(2 or more missed 
doses) 
Participant to contact the clinic. 
Investigator to consider checking HIV-1 
RNA and assess whether clinically 
appropriate to restart oral weekly 
regimen. If appropriate, initiate reloading 
(ie, 2 tablets of ISL/LEN 0.5/300 mg or 
 on 2 consecutive days) as soon as 
possible followed by once weekly 
maintenance doses. The site should 
contact the sponsor medical monitor. 
Participant has been taking doses every 
Monday. Participant forgets to take dose on 
2 consecutive Mondays. Participant should 
contact the clinic. If clinically appropriate, 
participant will be asked for a clinic visit to 
restart the loading regimen (ie, 2 tablets of 
ISL/LEN 0.5/300 mg or 
 on 2 consecutive 
days) as soon as possible, followed by once 
weekly maintenance doses. 
; HIV-1 = human immunodeficiency virus type 1; ISL = islatravir; LEN = lenacapavir; 
RNA = ribonucleic acid 
 
 
 
 
 
 
ISL/LEN
 
 tablet administered orally should be taken weekly on the same day of 
the week, without regard to food. 
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5.7. 
Dosage and Administration of B/F/TAF 
Participants in Treatment Groups 2 and 4 will take oral daily B/F/TAF (1  50/200/25 mg tablet) 
without regard to food. 
If a participant misses a dose of B/F/TAF and notices within 18 hours of the usual dosing time, 
the participant should take the missed dosed as soon as possible, then take the next dose at the 
next usual dosing time. If a participant misses a dose of B/F/TAF and notices after 18 hours or 
more past the usual dosing time, the participant should skip the missed dose and wait to take the 
next dose at the next usual dosing time. 
5.8. 
Prior and Concomitant Medications 
Medications in Table 24 are prohibited or should be used with caution while participants are 
taking study drugs. Should participants have a need to initiate treatment with any prohibited 
concomitant medication, the Gilead medical monitor must be consulted, and approval granted 
before initiation of the new medication. In instances where a prohibited medication is initiated 
before discussion with the Gilead medical monitor, the investigator must notify Gilead as soon as 
he/she/they is/are aware of the use of the prohibited medication. 
For guidance on prior and concomitant medications for participants in Treatment Groups 2 
and 4, the investigator is directed to refer to the FDA-approved B/F/TAF product labeling 
package insert for complete information {BIKTARVY 2021}. 
Islatravir metabolism occurs primarily via adenosine deaminase, a non–cytochrome 
P450 enzyme (CYP)-mediated process. Given the very low propensity for people with HIV-1 to 
require an adenosine deaminase inhibitor (eg, pentostatin), the likelihood of ISL being a victim 
of DDI is low. Islatravir is not metabolized by CYP enzymes and, therefore, is not expected to be 
a victim of CYP-mediated drug interactions. In vitro studies show that ISL is not an inhibitor of 
major CYP enzymes, transporters, or UGT1A1, nor a time-dependent inhibitor of CYP3A4 at 
clinically meaningful concentrations. No clinically significant interactions were seen in DDI 
studies of ISL and dolutegravir/tenofovir disoproxil fumarate, ISL and levonorgestrel/ethinyl 
estradiol, ISL and doravirine, or ISL and pantoprazole, ISL and methadone, or ISL and 
metformin/atorvastatin. Islatravir, like many other nucleosides, is phosphorylated initially by 
deoxycytidine kinase (dCK), an enzyme for which ISL has relatively low affinity and, therefore, 
is not converted to ISL-TP when exogenous nucleosides with a higher affinity for dCK (eg, 
lamivudine [3TC], emtricitabine [FTC]) are also administered. Islatravir has the potential to be 
an object of a dCK-mediated interaction when coadministered with 3TC or FTC, or other high 
affinity substrates of dCK. Coadministration of 3TC or FTC with ISL/LEN 
 is prohibited. 
Clinical data indicate LEN is a substrate of CYP3A, P-gp, and UGT1A1, a moderate inhibitor of 
CYP3A, and a weak inhibitor of P-gp and BCRP. Current clinical recommendations for LEN 
allow coadministration of LEN with strong CYP3A or CYP3A/P-gp inhibitors without dose 
modification, but coadministration with strong UGT1A1 inhibitors or UGT1A1/CYP3A/P-gp 
inhibitors is not recommended. Strong and moderate inducers of CYP/P-gp/UGT should also be 
avoided with LEN. Caution is advised if LEN is coadministered with sensitive CYP3A 
substrates, but not P-gp, BCRP, or OATP substrates. 
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Concomitant use of LEN with medications or herbal/natural supplements that are substrates of 
CYP3A may result in increased exposure of these medications. Representative medications and 
herbal/natural supplements listed in Table 24 are currently excluded or should be used with caution 
while participating in this study; this table is not exhaustive. For medications not listed below that 
may be sensitive substrates of CYP3A, strong or moderate inducers, strong UGT1A1/CYP3A/P-gp 
inhibitors, or strong UGT1A1 inhibitors, the investigator should reach out to Gilead for guidance. 
Participants should discontinue disallowed concomitant medications 30 days prior to initiation of 
study drugs, except for their baseline B/F/TAF regimen. 
Table 24. 
Examples of Prior and Concomitant Medications That are to be Used 
With Caution or That Are Prohibited due to the Potential for PK DDI 
With Islatravir or Lenacapavira 
Medication Class 
Medications to be Used With Caution 
Prohibited Medications 
Adenosine deaminase inhibitors 
 
Pentostatin 
Anticonvulsants 
 
Carbamazepine, oxcarbazepine, 
phenobarbital, phenytoin 
Antihyperlipidemic agents 
(HMG-CoA reductase 
inhibitors) 
Coadministration may increase certain statin 
concentrations, which is associated with increased 
risk of myopathy, including rhabdomyolysis. Start 
with the lowest dose and titrate to clinical response 
with careful monitoring. In particular, Gilead 
recommends maximum doses for the following 
statins: simvastatin 10 mg, lovastatin 20 mg, and 
atorvastatin 20 mg. 
 
Antimycobacterials 
 
Rifampin, rifabutin, rifapentine 
ARV 
 
Any nonstudy HIV-1 ARV 
Corticosteroids 
 
Any chronic systemic 
corticosteroid (> 2 weeks)  
dCK substrates 
Coadministration with cladribine, clofarabine, 
cytarabine, fludarabine, and gemcitabine is not 
recommended. 
Coadministration is 
contraindicated with 3TC or FTC. 
Ergot derivatives 
 
Ergotamine, dihydroergotamine, 
methylergonovine, ergometrine 
Herbal/natural supplements 
 
St. John’s wort, echinacea, milk 
thistle  
Immunomodulators 
 
Interferons 
Phosphodiesterase-5 inhibitors 
Recommended maximum doses are as follows: 
sildenafil 25 mg in 24 hours, vardenafil 5 mg in 24 
hours, and tadalafil 10 mg in 72 hours. 
 
Sedatives/hypnotics 
Midazolam, triazolam 
 
3TC = lamivudine; ARV = antiretroviral; dCK = deoxycytidine kinase; DDI = drug-drug interactions; FTC = emtricitabine; 
HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A; PK = pharmacokinetic(s) 
a 
This table represents examples of the most common concomitant medications and is not meant to be exhaustive. If the 
investigator is unsure if a medication is allowed per protocol, he/she/they should consult with the sponsor. 

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5.9. 
Accountability for Study Drugs 
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug supplies (drugs and bottles). This includes acknowledgment of receipt of each shipment of 
study drug supplies (quantity and condition). All used and unused study drug supplies dispensed 
to participants must be returned to the site. 
Each investigational site must keep accountability records that capture the following: 
• The date received, quantity, and condition of study drug bottles 
• The date, participant number, and the study drug bottle numbers or lots dispensed 
• The date, quantity of used and unused study drug bottles returned, along with the initials of 
the person recording the information 
5.9.1. 
Study Drug Return or Disposal 
Gilead recommends that used and unused study drugs, which includes bottles, be destroyed at the 
site. If the site has an appropriate standard operating procedure for drug destruction as 
determined by Gilead, the site may destroy used (empty or partially empty) and unused study 
drug bottles in accordance with that site’s approved procedural documents. A copy of the site’s 
approved procedural document will be obtained for the electronic trial master file. If the study 
drug supply is destroyed at the site, the investigator must maintain accurate records for all study 
drug supplies 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 supplies. 
Upon study completion, copies of the study drug accountability records must be filed at the site. 
Another copy will be provided to Gilead. 
If the site does not have an appropriate standard operating procedure 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 study drug 
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6. 
STUDY PROCEDURES 
The study procedures to be conducted for each participant screened or enrolled in the study are 
presented in tabular form in Table 1, Table 2, and described in the sections below. 
The investigator must document any deviation from the protocol procedures and notify Gilead or 
the contract research organization. 
6.1. 
Informed Consent 
Written informed consent must be obtained from each participant before initiation of any 
study-related procedures. Refer to Section 9.1.4 for further information regarding informed 
consent. 
6.2. 
Screening, Participant Enrollment, and Treatment Assignment 
Participants will be screened within 35 days before enrollment in the study. Each participant will 
be assigned a unique screening number using the IRT. Participants meeting all of the inclusion 
criteria and none of the exclusion criteria will return to the clinic within 35 days for 
randomization into the study. It is the responsibility of the investigator to ensure that participants 
are eligible to participate in the study prior to enrollment and continue to remain eligible 
throughout the study. The medical monitor may be contacted regarding any questions related to 
eligibility. 
If the screening window is exceeded in an otherwise eligible participant, the participant is 
allowed to rescreen 1 time after approval from the sponsor. Once a participant has started the 
rescreening process, a new screening window (35 days) will begin, during which time screening 
procedures will be repeated. 
Participants who are considered screen failures because the duration of baseline B/F/TAF was 
< 24 weeks are allowed to rescreen if they have continued to receive B/F/TAF therapy. 
For all participants, the last day of baseline B/F/TAF prior to randomization will be Day −1. 
Entry into screening does not guarantee enrollment into 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. 
Once the informed consent form (ICF) has been signed, all screening and eligibility tests and 
assessments have been assessed, and study eligibility has been confirmed, participants will be 
randomized to receive study drugs on Day 1. 
Participants will receive the study treatments as described in Sections 5.6 and 5.7. 

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6.3. 
Instructions for Study Procedures 
Study procedures and assessments are outlined in Table 1 and Table 2. 
6.3.1. 
Adverse Events 
From the time informed consent is obtained through the first administration of study drugs, 
record all SAEs, as well as any AEs related to protocol-required 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. After study drug administration, report all AEs and SAEs. Additional details are 
provided in Section 7. 
6.3.2. 
Concomitant Medications 
Review of concomitant medications will occur at the time points presented in Table 1 and 
Table 2. Further information about concomitant medications is provided in Sections 4.3 and 5.8. 
6.3.3. 
Electrocardiograms 
Participants should rest quietly in the supine position for a minimum of 10 minutes before ECG 
acquisition and should remain in that position until the recording is complete. 
The investigator or other qualified individual at the study center will review the ECG for 
abnormalities. 
6.3.4. 
Medical History and Demographic Information 
Medical history and demographic information are to be collected for each participant at 
screening as follows: 
• Review medical history including HIV-1 disease-related events, available historical 
genotype/phenotype reports, available HIV-1 treatment history, substance (ie, illicit drug) 
use, and medications taken within 30 days of the screening visit 
• Obtain demographic information, including sex at birth, sexual orientation, and gender 
identity 
• If available, investigators are asked to document prior resistance data from available HIV-1 
genotype and/or phenotype reports (see Exclusion Criterion 20 in Section 4.3) 
6.3.5. 
Physical Examination 
Physical examinations conducted throughout the study will be complete or symptom driven 
(Table 1 and Table 2). 

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The complete physical examination will include source documentation of general appearance, 
and the following body systems: head, neck, and thyroid; eyes, ears, nose, throat, mouth, and 
tongue; chest (excluding breasts); respiratory; cardiovascular; lymph nodes; abdomen; skin, hair, 
nails; musculoskeletal; neurological. Genito-urinary and breast examinations should not be 
conducted unless clinically indicated. 
6.3.6. 
Clinical Laboratory Assessments 
Blood and urine samples will be collected throughout the study as outlined in Table 1 and 
Table 2. Laboratory assessments are listed in Table 25. 
Table 25. 
Laboratory Assessments 
Safety Laboratory Measurements 
Other Laboratory Measurements 
Chemistry 
(Serum or Plasma) 
Hematology 
Urinalysis 
ALT  
AST  
Albumin 
Alkaline phosphatase 
Creatine kinase 
Creatininea 
Direct bilirubin  
Total bilirubin 
Glucose 
Lipase 
Phosphorus 
Potassium 
Sodium 
Hemoglobin 
Platelets 
White cell count 
5-part differentialb 
Color & clarity 
Specific gravity 
pH 
Glucose 
Protein 
Blood and microscopic 
(reflex if positive) 
Leukocyte esterase and 
microscopic (reflex if 
positive) 
Pregnancy testc 
Serum pregnancy testc 
Serum FSHd 
CD4+ T-cell/TBNK panel (Cohort 2)  
Plasma HIV-1 RNA  
HBcAb, HBsAg, HBsAb, HBV DNA, 
HCV Ab (Cohort 2), HCV RNA  
Plasma storage samples 
Whole blood storage sample 
Pharmacokinetics 
HIV-1 proviral genotypee 
HIV-1 genotype and phenotype at 
virologic failure 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CD4+ = clusters of differentiation 4; CLcr = creatinine 
clearance; FSH = follicle-stimulating hormone; HBcAb = hepatitis B core antibody; HBsAb = hepatitis B surface antibody; 
HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HCV Ab = hepatitis C antibody; 
TBNK = T, B, and natural killer cells 
a 
Creatinine clearance to be calculated according to the Cockcroft-Gault formula for Creatinine clearance: male: 
[(140 – age in years)  (weight in kg)]/[72  (serum creatinine in mg/dL)] = CLcr (mL/min); female: 
[(140 – age in years)  (weight in kg)  0.85]/[72  (serum creatinine in mg/dL)] = CLcr (mL/min). 
b 
Count and percent (neutrophils, lymphocytes, monocytes, basophils, eosinophils). 
c 
For participants of childbearing potential. 
d 
For participants who were female sex at birth and are < 54 years old and have stopped menstruating for ≥ 12 months but do 
not have documentation of ovarian hormonal failure. 
e 
For all participants enrolled in Cohort 2, to be performed at the screening visit. 
Refer to Table 1 and Table 2 for collection time points. 
HIV-1 RNA will be measured using the COBAS Ampliprep/COBAS Taqman v. 2.0 assay. 
Gilead reserves the right to use alternate assays for HIV-1 RNA should this assay become 
unavailable. 

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6.3.7. 
Pharmacokinetics Assessments 
6.3.7.1. 
Single Anytime Plasma PK Sampling 
Single anytime plasma PK sampling for ISL and LEN will occur in Treatment Group 1 and 
Treatment Group 3 participants at each onsite visit through Week 72 except Day 1. Day 1 PK 
sample will be collected 1 hour (± 30 minutes) postdose after onsite drug administration. The 
date and time of ISL and LEN dosing on Day 1 and previous ISL and LEN dosing for subsequent 
visits will be recorded. PK collections after Week 48 will be stored and analyzed only if deemed 
necessary by sponsor. 
6.3.7.2. 
Pharmacokinetics Substudy 
A PK substudy will be conducted in approximately 10 participants in Treatment Group 1 and 
approximately 15 participants in Treatment Group 3 who provide consent. Samples will be 
collected on Day 1, Day 2, and Week 12 at the time points presented in Table 26. Study drugs 
will be administered during the onsite visits on Day 1, Day 2, and Week 12. For Day 2, only 
LEN samples will be collected; both ISL and LEN samples will be collected for Day 1 and 
Week 12. Week 12 PK substudy sample collection may be performed at Week 18 if the 
participant took the Week 12 study drugs prior to the clinic visit instead of administered onsite. 
Additional single anytime PK sampling will not be collected for participants in the substudy 
during PK substudy visits (Day 1, Week 12, or Week 18). 
Table 26. 
PK Substudy Sample Collection Time Points 
Visita 
Sampling Time Points 
Day 1 
predose (within 30 minutes prior to dosing), 0.5, 1, 2, 4, 6, and 8 hours postdose 
Day 2 b 
predose (within 30 minutes prior to dosing), 0.5, 1, 2, 4, 6, and 8 hours postdose 
Week 12c, d 
predose (within 30 minutes prior to dosing), 0.5, 1, 2, 4, 6, 8, 72, 120, and 168 hours postdose 
LEN = lenacapavir; PK = pharmacokinetic(s) 
a 
The study drugs will be administered at the site during the study visit. 
b 
For Day 2, only LEN samples will be collected after LEN only (2  300 mg) administration onsite. 
c 
Week 12 PK substudy sample collection may be performed at Week 18 if the participant took the Week 12 study drugs prior 
to the clinic visit instead of administered onsite. 
d 
168-hour sample must be collected prior to next dose to capture trough concentration. 
6.3.8. 
Clinical Virology Analyses 
6.3.8.1. 
Virology Testing 
6.3.8.1.1. 
Virology Samples to Address Study Objectives 
Stored plasma and whole blood samples may be used to assess HIV-1 genotype at baseline 
HIV-1 genotype and phenotype in confirmed cases of virologic failure as defined in 
Section 6.3.8.2. 

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6.3.8.2. 
Virologic Failure 
Virologic failure is defined as virologic rebound, as defined below, or having HIV-1 RNA 
≥ 50 copies/mL at study discontinuation or at last visit. 
6.3.8.2.1. 
Management of Virologic Rebound 
Participants who meet the criteria listed below will be considered to have virologic rebound: 
• At any post Day 1 visit, a rebound in HIV-1 RNA ≥ 50 copies/mL, which is subsequently 
confirmed at the following scheduled or unscheduled visit; OR 
• Any participant with HIV-1 RNA ≥ 50 copies/mL at study drug discontinuation or at the last 
visit 
At Day 1 visit or any post Day 1 visit, if the HIV-1 RNA is ≥ 50 copies/mL and 
< 200 copies/mL, a reflex HIV-1 RNA repeat test will be conducted on stored plasma samples, if 
available. If the repeat result is < 50 copies/mL, no further action is required. If the repeat result 
is ≥ 50 copies/mL, participants will be asked to return to the clinic for a scheduled or 
unscheduled blood draw (2 to 3 weeks after the date of the original test with HIV-1 RNA 
≥ 50 copies/mL) for confirmation of virologic rebound. If virologic rebound is confirmed and 
HIV-1 RNA is ≥ 200 copies/mL, the plasma sample from the confirmation visit will be the 
primary sample used for HIV-1 genotypic and phenotypic testing. After a participant’s first post 
Day 1 resistance test, additional testing will be conducted on a case-by-case basis. 
If no resistance is detected from the genotype or phenotype, the participant may remain on study 
drugs and the HIV-1 RNA test should be repeated (2 to 3 weeks after the date of confirmed test 
with HIV-1 RNA ≥ 50 copies/mL). If genotypic or phenotypic resistance to study drug is 
documented and the participant resuppresses HIV-1 RNA to < 50 copies/mL at a subsequent 
visit, the participant may continue on study drugs. If resistance to study drug is detected and 
HIV-1 RNA levels remain ≥ 50 copies/mL, investigators should carefully evaluate the benefits 
and risks of remaining on study drugs for each individual participant and document this 
assessment in the onsite medical record. Investigators who opt to discontinue study drugs for an 
individual participant must discuss with the medical monitor prior to study drug discontinuation. 
Refer to Figure 5 for the management of participants who meet the criteria for virologic rebound. 
CCI

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Figure 5. 
Virologic Rebound Schema 
ARV = antiretroviral; HIV-1 = human immunodeficiency virus type 1; RNA = ribonucleic acid 
a 
If virologic rebound is not confirmed, the participant will remain on their current regimen. 
b 
If virologic rebound is confirmed and the HIV-1 RNA is ≥ 200 copies/mL, the HIV-1 genotype and phenotype 
(capsid, reverse transcriptase, and integrase) will be analyzed. 
c 
Based on the results of the genotypic and phenotypic assays, the participant will remain on study drugs or study drugs will 
be discontinued. If the genotyping or phenotyping assay shows resistance, a new ARV regimen may be configured at the 
discretion of the investigator, in consultation with the medical monitor. 
d 
If no resistance is detected, HIV-1 RNA will be repeated (2 to 3 weeks later). 
e 
Investigator reviews study drug continuation/discontinuation options and discusses with the medical monitor prior to study 
drug discontinuation. 
f 
If study drugs are discontinued, a new ARV regimen will be configured, at the investigator’s discretion, and the participant 
will remain in the study through the 30- and 60-day (as applicable) follow-up visits. 
6.3.8.3. 
Resistance Analysis at a Participant’s Last Visit 
Participants with HIV-1 RNA ≥ 50 copies/mL at their last study visit while taking study drugs 
(ie, rebound not confirmable) will be considered to have virologic failure. Participants with 
HIV-1 RNA ≥ 200 copies/mL at the last visit will be evaluated for resistance. 
6.3.9. 
Patient-Reported Outcomes 
Patient-reported outcome questionnaires (if available) will be completed by participants in both 
cohorts at the visits specified in Table 1 and Table 2, and include HIVDQoL, the HIV Treatment 
Satisfaction Questionnaires (HIVTSQc12 and HIVTSQs12), EQ-5D-5L, the Patient Perspective 
of Regimen (PP-R), and the Patient Perspective of Regimen Change (PP-RC). The PP-R and 
PP-RC questionnaires are novel 10-item treatment preference questionnaire developed by MSD, 
following the FDA PRO development guidance and are intended to explore patient perceptions 
of weekly oral ART and how those perceptions may differ from perceptions of those taking daily 
oral ART. The PP-R will be administered to participants in Treatment Groups 3 and 4; for 
Treatment Group 3, participants will also be administered the PP-RC after completing the PP-R. 
Screening 
Treatment Period 
30- and 60-Day Follow-up 
Day I 
At any post Day I visit. a rebound in HJV-1 RNA to ?: 50 copies/mL 
Unconfirmed virologic rebound: 
remain on cun-ent regimen• 
Rcn1111 for schcdulcd/unschcdulcd HJV- 1 RNA and 
potential genotyp phenotype (2-3 weeks later) 
If virnl load 
Confirmed virologic rebom1d• 
50 - <200 copies/mL 
Remain on study without 
HIV- I genotype/phenotype 
If ,·iral load ?: 200 copies/mL 
If !!Q capsid. reverse trauscriptase. or 
integrase resistance detected. may 
continue on study drngs<l'" 
Remain on study with 
~0V- 1 genol)•p phenotype' 
If capsid. reverse transcriplase, or 
integrase resistance detected. and HJV-1 
RNA resuppresses to < SO copie mL, 
may continue on snidy dnigsc: 
If capsid, reverse transcriptase. or 
integrase resistance detected. and HJV- 1 
RNA ?: 50 copie mL. discuss 
discontinuation of study chugs with 
Medical Monitord 

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6.4. 
Assessments for Early Discontinuation from Study Treatment or from the 
Study 
If a participant discontinues study drugs, every attempt should be made to keep the participant in 
the study and continue to perform the required 30- and 60-day (as applicable) follow-up visit 
procedures. If this is not possible or acceptable to the participant or investigator, the participant 
may be withdrawn from the study. 
6.4.1. 
Assessments for Early Discontinuation from Study Treatment 
Participants who permanently discontinue study drugs before the end of the study are required to 
return to the investigational site to complete an early study drug discontinuation (ESDD) visit 
within 3 days (+1 day) after their last dose. If early discontinuation occurs during the timeframe 
of a scheduled study visit, the assessments for the ESDD visit should be conducted. Assessments 
and procedures for the ESDD visit are specified in Table 1 and Table 2. 
At the ESDD visit, any assessment showing abnormal results (except those meeting stopping 
criteria due to CD4+ T-cell and/or absolute lymphocyte count declines) that the investigator 
determines to have a possible or probable causal relationship with the study drugs, 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. 
Participants in Treatment Group 3 or any Cohort 2 participant in the Extension Phase who has 
been discontinued from the study due to CD4+ T-cell declines will have the laboratory test 
repeated as specified in the study procedures (Section 7.7) until it is at least 75% (or higher) of 
the average baseline (based on screening and Day 1 values, with average baseline equal to 100%) 
or until the 200-day follow-up visit, whichever comes first. Participants who have been 
discontinued from the study due to absolute lymphocyte count declines will have the laboratory 
test repeated as specified in the study procedures until it is above the lower limit of normal based 
on age (per central laboratory) or until the 200-day follow-up visit, whichever comes first. 
For participants who discontinued study drugs and are confirmed to have HIV-1 RNA 
≥ 50 copies/mL at the ESDD visit, the participant will be followed until resuppression of HIV-1 
RNA to < 50 copies/mL or for 3 months, whichever occurs first. 
6.4.2. 
Assessments for End of Study 
Participants who received ISL+LEN or ISL/LEN
 are required to return to the clinic for 
follow-up visits 30 and 60 days after the last ISL+LEN or ISL/LEN 
 dose. Participants who 
received only B/F/TAF (ie, did not switch to ISL+LEN or ISL/LEN 
) are required to return 
to the clinic for a follow-up visit 30 days after the last on-study B/F/TAF dose. Assessments and 
procedures for the 30- and 60-day follow-up visits are specified in Table 1 and the 100- and 
200-day follow-up visits in Table 2. 
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At the 30- and 60-day follow-up visits, as applicable, any assessment showing abnormal results 
that the investigator determines to have a possible or probable causal relationship with the study 
drugs, 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. Gilead may request that 
certain AEs be followed beyond the protocol-defined follow-up period. 
6.5. 
Poststudy Care 
After the participant has completed/terminated their participation in the study, long-term care of 
the participant will remain the responsibility of their primary treating physician. 
6.6. 
Sample Storage 
The stored biological samples may be used by Gilead or its research partner for additional testing 
to provide supplemental 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 or per 
country requirements. 

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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 7.1.4). 
An AE does not include the following: 
• Medical or surgical procedures such as surgery, endoscopy, tooth extraction, or 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 7.1.4) 
• 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. 
7.1.2. 
Serious Adverse Events 
An SAE is defined as an event that, at any dose, results in the following: 
• Death 
• A life-threatening situation (Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the participant was at risk of death at the time of the event; it does 
not refer to an event that hypothetically might have caused death if it were more severe) 
• In-patient hospitalization or prolongation of existing hospitalization 

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• 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 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 
7.1.3. 
Adverse Events of Special Interest 
Not applicable. 
7.1.4. 
Study Drugs and Gilead Concomitant Medications 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 or falsified medicine, and 
pregnancy regardless of an associated AE. Any sequelae from a special situation event must be 
reported as an AE/SAE in accordance with Sections 7.3 and 7.4 in addition to being captured in 
the SSR. 
Below are the definitions for special situation events that require reporting in accordance with 
Section 7.4.3. 
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, participant, 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 

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when it is clear that the participant has taken the excess dose(s). Overdose cannot be established 
when the participant cannot account for the discrepancy, except in cases in which the 
investigator has reason to suspect that the participant has taken the additional dose(s). 
Occupational exposure is defined as exposure to a study drug as a result of one’s professional or 
nonprofessional occupation. 
Drug interaction is defined as any drug/drug, drug/food, drug/alcohol, or drug/device interaction. 
Unexpected benefit is defined as an unintended therapeutic effect where the results are judged to 
be desirable and beneficial. 
Transmission of infectious agents is defined as any suspected transmission of an infected agent 
through a Gilead study drug. 
Counterfeit or falsified medicine is defined as 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 adverse event may have been caused by the 
study drug. 
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 and laboratory abnormalities will be graded using the Division of AIDS 
(DAIDS) Toxicity Grading Scale, Version 2.1 dated July 2017, available as follows: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
For each episode, the highest grade attained should be reported as defined in the Toxicity 
Grading Scale. 
7.3. 
Investigator Reporting Requirements and Instructions 
7.3.1. 
Requirements for Collection Before Study Drug Initiation 
After informed consent, but before initiation of study drug, the following types of events must be 
reported on the applicable eCRF: all SAEs and any AEs that are related to protocol-required 
procedures. 
7.3.2. 
Adverse Events 
Following initiation of study drug, collect all AE, regardless of cause or relationship, until the 
end of the protocol-defined follow-up period and report the AEs on the eCRF as instructed. 
All AEs and clinically significant laboratory abnormalities 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 posttreatment follow-up visit(s), must be reported on the applicable electronic case report 
forms and to Gilead Patient Safety as instructed below in this section. This also includes any 
SAEs resulting from protocol-associated procedures performed after the ICF is signed. The 
investigator must report the primary cause of death as an SAE for any participant who dies 
during the follow-up period to the sponsor. The primary cause of death will be reported as the 
SAE term(s) unless the cause of death cannot be obtained. 
Any SAEs and deaths that occur after the posttreatment follow-up visit(s) until the end of 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 Patient Safety. 
Instructions for reporting SAEs are described in Section 7.4.1. 

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7.3.4. 
Adverse Events of Special Interest 
Not applicable. 
7.3.5. 
Study Drug Special Situations Reports 
All study drug SSRs that occur from study drug initiation and throughout the duration of the 
study, including the posttreatment follow-up visit(s), must be reported to Gilead Patient Safety 
(Section 7.4.3). Adverse events and SAEs resulting from SSRs must be reported in accordance to 
the AE and SAE reporting guidance (Section 7.3). 
7.3.6. 
Concomitant Medications Reports 
7.3.6.1. 
Gilead Concomitant Medications Special Situations Report 
Special situation reports involving a Gilead concomitant medication (not considered study drug), 
that occurs after the participant first consents to participate in the study (ie, signing of the ICF) 
and throughout the duration of the study, including the posttreatment follow-up visit(s), must be 
reported to Gilead Patient Safety utilizing the paper SSR (Section 7.4.3.1). 
7.3.6.2. 
Non-Gilead Concomitant Medications 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 eCRF. 
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 eCRF. Details of the symptoms and signs, clinical 
management, and outcome will be reported, when available. 
7.4. 
Reporting Process for Serious Adverse Events, Adverse Events of Special 
Interest, and Special Situations 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 CRFs within 24 hours of the investigator’s knowledge of the 
initial event/update in order for the SAE information to be transmitted timely to Gilead Patient 
Safety. 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 Patient Safety. 
7.4.2. 
Adverse Events of Special Interest Reporting Process 
Not applicable. 
7.4.3. 
Special Situations Reporting Process 
7.4.3.1. 
Paper Special Situations Reporting Process for Study Drug 
All SSRs will be recorded on the SSR form and transmitted by emailing or faxing the report 
form within 24 hours of the investigator’s knowledge of the event to the attention of Gilead 
Patient Safety (contact information provided in Section 7.4.1.1) from study drug initiation 
throughout the duration of the study, including the protocol-required posttreatment follow-up 
period. 
7.4.3.2. 
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 Patient Safety (contact information provided in Section 7.4.1.1) utilizing the paper SSR 
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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 because of a non-Gilead 
concomitant medication, must be reported on the AE eCRF. 
7.4.3.3. 
Pregnancy Reporting Process 
The investigator should report pregnancies in female study participants who are identified after 
initiation of study drug and throughout the study, including the protocol-required posttreatment 
follow-up period, to Gilead Patient Safety (contact information provided in Section 7.4.1.1) 
within 24 hours of becoming aware of the pregnancy using the pregnancy report form. 
The pregnancy itself is not considered an AE, nor is an induced elective abortion to terminate a 
pregnancy without medical reasons. 
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 Gilead Patient Safety. 
The participant should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome of the pregnancy should be reported to Gilead Patient Safety using the 
pregnancy outcome report form. If the end of the pregnancy occurs after the study has been 
completed, the outcome should be reported directly to Gilead Patient Safety (contact information 
provided in Section 7.4.1.1). 
Refer to Appendix 3 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements. 
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 suspected unexpected serious adverse reactions. In accordance with 
the EU Clinical Trials Directive (2001/20/EC), Gilead or a specified designee will notify 
worldwide regulatory agencies and the relevant independent ethics committee in concerned 
Member States of applicable suspected unexpected serious adverse reactions as outlined in 
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In the intended study population, Gilead anticipates the occurrence of SAEs that are 
manifestations of the underlying disease, commonly occur in the study population independent 
of drug exposure, or are components of the study endpoints. The anticipated SAEs, unless 
life-threatening/fatal, will not be reported to FDA. 
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 reports associated with any study drug. The investigator should notify 
the IRB or independent ethics committee of suspected unexpected serious adverse reaction 
reports as soon as is practical, where this is required by local regulatory agencies, and in 
accordance with the local institutional policy. 
Details for the role of the DMC are provided in Section 8.10. 
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 of either AEs or laboratory abnormalities should be recorded and graded according to 
the DAIDS Toxicity Grading Scale, Version 2.1 dated July 2017, available as follows: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
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. 
7.7. 
Toxicity Management 
All clinical and clinically significant laboratory toxicities – except for CD4+ T-cells and absolute 
lymphocyte counts delineated later in this section – will be managed according to uniform 
guidelines detailed in Appendix 4 and the timing described below. 
Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing within 3 calendar days of receipt of results and before investigational medicinal product 
discontinuation, unless such a delay is not consistent with good medical practice. If repeat testing 
is not possible within 3 calendar days of receipt of results, it may be completed within 
14 calendar days of receipt of results per the investigator’s discretion. 

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For Treatment Group 3 participants in the Randomized Phase or any Cohort 2 participants in the 
Extension Phase meeting either the CD4+ T-cell or absolute lymphocyte count criteria below, the 
Gilead medical monitor should be consulted to discuss study drug discontinuation when 
medically feasible: 
• For those with an average baseline CD4+ T-cell count ≥ 500 cells/mm3, a decline to 
< 350 cells/mm3 that is confirmed by a repeat measure at least 10 weeks apart and in the absence 
of a plausible alternative cause (eg, concurrent illness, immunosuppressive medications, radiation 
therapy, HIV viral rebound). Average baseline is defined as the mean CD4+ T-cell count 
between screening and Day 1. 
• For those with an average baseline CD4+ T-cell count ≥ 350 and ≤ 499 cells/mm3 (inclusive), a 
decline to < 200 cells/mm3 that is confirmed by a repeat measure at least 10 weeks apart and in 
the absence of a plausible alternative cause (eg, concurrent illness, immunosuppressive 
medications, radiation therapy, HIV viral rebound). Average baseline is defined as the mean 
CD4+ T-cell count between screening and Day 1. 
OR 
• A Grade 2 or above (per DAIDS toxicity grading scale) absolute lymphocyte count that is 
confirmed by a repeat measure at least 10 weeks apart and in the absence of a plausible 
alternative cause for the decline (eg, concurrent illness, immunosuppressive medications, 
radiation therapy, HIV viral rebound). 
If an alternative etiology is suspected for either CD4+ T-cell or absolute lymphocyte count 
declines, a participant may continue study drug with ongoing monitoring. However, at any time, 
if a participant receiving ISL+LEN or ISL/LEN 
 experiences CD4+ T-cell or absolute 
lymphocyte count declines that are clinically meaningful (eg, infections occurring as a result of 
such declines), out of proportion to normal clinical practice intraparticipant variability (eg, 
confirmed 30% decline), and/or do not have a plausible alternative cause as determined by the 
investigator, study drug discontinuation may be considered regardless of the above criteria. 
The Gilead medical monitor should be consulted prior to study drug discontinuation when 
medically feasible. After study drug discontinuation, participants should be switched to an 
appropriate alternative ARV regimen. 
Refer to Section 6.4.1 for monitoring procedures after study drug discontinuation due to 
CD4+ T-cell or absolute lymphocyte count decline. 
See Section 7.6 for AE reporting requirements for laboratory abnormalities. 
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8. 
STATISTICAL CONSIDERATIONS 
Additional details for the planned analyses will be provided in the statistical analysis plan (SAP). 
8.1. 
Analysis Objectives and Endpoints 
Objectives and endpoints are listed in Section 2. 
8.2. 
Planned Analyses 
8.2.1. 
Interim Analysis 
Before the final analysis, interim analyses, including analyses supporting DMC evaluation, may 
be conducted and the analyses may be submitted to regulatory agencies to seek guidance for the 
overall clinical development program and to support regulatory filings. 
8.2.1.1. 
Planned Interim Analyses 
In addition to the primary analysis, there will be 2 planned interim analyses: 
• Week 48 analysis after all participants have completed their Week 48 visits or prematurely 
discontinued study drug 
• Week 96 (Extension Phase Week 48) analysis after all participants who entered the 
Extension Phase have completed their Week 96 visits or prematurely discontinued study drug 
8.2.1.2. 
Data Monitoring Committee Analysis 
Planned DMC analyses are to be conducted after all participants have completed their Week 12, 
24, and 48 visits, or prematurely discontinued study drugs during the Randomized Phase. 
Additionally, if 5 or more participants receiving ISL+LEN experience virologic rebound (as 
defined in Section 6.3.8.2.1) unrelated to poor adherence before Week 12, a DMC meeting will 
be convened to assess the data. If 3 or more participants receiving ISL+LEN discontinue study 
drug due to meeting the stopping criteria for ISL-associated CD4+ T-cell and/or absolute 
lymphocyte count decline (Section 7.7) at any time, a DMC meeting will be convened to assess 
the data. 
A DMC meeting may be convened, and the supporting analyses may be conducted at other times 
during the study as deemed necessary. Clinical assessments will be made to determine if the 
nature, frequency, and severity of AEs associated with a study regimen warrant the early 
termination of the study in the best interest of the participants. No formal stopping rules will be 
used by the DMC for safety or efficacy outcomes. No alpha penalty will be applied for the 
primary analysis of the primary efficacy endpoint given that the study is not adequately powered 
for a formal efficacy evaluation. Data from these analyses may be used to support the planning 
of other studies. 

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8.2.2. 
Primary Analysis 
The primary analysis of the primary endpoint will be conducted after all participants within each 
cohort have completed the Week 24 visit or have prematurely discontinued study drugs, 
outstanding data queries have been resolved or adjudicated as unresolvable, and the data have 
been cleaned and finalized for the analysis. This analysis of the primary endpoint will serve as 
the final analysis for this endpoint and will be used to evaluate the efficacy of ISL+LEN. 
8.2.3. 
Final Analysis 
The final analysis will be performed after all participants within each cohort have completed or 
prematurely discontinued from the study, outstanding data queries have been resolved or 
adjudicated as unresolvable, and the data have been cleaned and finalized. 
8.3. 
Analysis Conventions 
8.3.1. 
Analysis Sets 
The following analysis sets are defined for each cohort respectively. 
8.3.1.1. 
Efficacy 
The primary analysis set for efficacy analyses is defined as the full analysis set (FAS), which 
will include all participants who (1) are randomized into the study and (2) have received at least 
1 dose of study drugs. Participants will be grouped according to the treatment to which they were 
randomized. 
8.3.1.2. 
Safety 
The primary analysis set for safety analyses is defined as the safety analysis set, which will 
include all participants who have received at least 1 dose of study drugs. Participants will be 
grouped according to the treatment they actually received. 
8.3.1.3. 
Pharmacokinetics 
8.3.1.3.1. 
Pharmacokinetic Analysis Set 
The primary analysis set for general PK analyses is defined as the PK analysis set, which will 
include all participants who (1) are randomized into the study, (2) have received at least 1 dose 
of study drugs, and (3) have at least 1 nonmissing PK concentration value for the analyte under 
evaluation reported by the PK laboratory. The PK analysis set will be used for analyses of 
general PK. 

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8.3.1.3.2. 
Pharmacokinetic Substudy Analysis Set 
The primary analysis set for intensive PK analyses is defined as the PK substudy analysis set, 
which will include all participants who (1) are randomized into the study, (2) enrolled into the 
PK substudy, (3) have received at least 1 dose of study drugs, and (4) have at least 1 nonmissing 
intensive PK concentration value for the analyte under evaluation reported by the PK laboratory. 
The PK substudy analysis set will be used for detailed PK analyses. 
8.3.1.4. 
All ISL+LEN Analysis Set 
This analysis set is defined for All ISL+LEN analysis and will include all participants who 
(1) are randomized into the study and (2) have received at least 1 dose of ISL+LEN or ISL/LEN 
. Participants who received ISL+LEN or ISL/LEN 
by error as partial treatment during 
the Randomized Phase will be excluded from the All ISL+LEN analysis set. 
8.3.2. 
Data Handling Conventions 
HIV-1 RNA reported results of ‘No HIV-1 RNA detected’ and ‘< 20 copies/mL HIV-1 RNA 
Detected’ will be imputed as 19 copies/mL for analysis purposes. Logarithm (base 10) 
transformation will be applied to HIV-1 RNA levels for analysis of change from baseline in 
HIV-1 RNA. The HIV-1 RNA reported results will be used for listing purposes. 
Laboratory data (other than HIV-1 RNA) that are continuous in nature but are above the upper 
limit of quantitation or less than the lower limit of quantitation (LLOQ) will be imputed to the 
value of the upper or lower limit plus or minus 1 significant digit, respectively (eg, if the result of 
a continuous laboratory test is < 5.4, a value of 5.3 will be assigned). 
Pharmacokinetic plasma concentration values below the limit of quantification (BLQ) will be 
treated as zero at predose and one-half of LLOQ for postdose time points, where LLOQ is 
corrected for the dilution factor (ie, reported dilution/dilution factor), for analysis purposes. The 
PK plasma concentrations will be transformed using natural logarithm for PK analysis. The 
report values that are BLQ will be presented as “BLQ” in the concentration data listing. 
Missing data can have an impact upon the interpretation of the study data. In general, values for 
missing data will not be imputed. However, a missing pretreatment laboratory result would be 
treated as normal (ie, no toxicity grade) for the laboratory abnormality summary. 
8.4. 
Demographic and Baseline Characteristics Analysis 
Demographic and baseline measurements will be summarized using standard descriptive 
methods including sample size, mean, SD, median, Q1, Q3, minimum, and maximum for 
continuous variables and frequency and percentages for categorical variables. 
Demographic summaries will include sex at birth, sexual orientation, gender identity, race, 
ethnicity, and age. 
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Baseline data will include a summary of body weight, height, BMI, and HIV-1 infection 
(eg, CD4+ T-cell count). 
For categorical demographic and baseline characteristics, a Fisher exact test will be used to 
compare the ISL+LEN group and B/F/TAF group within each cohort. For continuous 
demographic and baseline characteristics, a Wilcoxon rank sum test will be used to compare the 
ISL+LEN group and B/F/TAF group within each cohort. 
8.5. 
Efficacy Analysis 
8.5.1. 
Primary Analysis 
The primary efficacy endpoint is the proportion of participants with HIV-1 RNA ≥ 50 copies/mL 
at Week 24 as determined by the US FDA-defined snapshot algorithm {U. S. Department of 
Health and Human Services 2015}. The primary analysis of the efficacy will be based on the 
FAS. 
The 95% CI of the difference in the proportion of participants with HIV-1 RNA ≥ 50 copies/mL 
at Week 24 between the ISL+LEN group and B/F/TAF group within each cohort will be 
constructed based on an unconditional exact method using 2 inverted 1-sided tests {Chan 1999}. 
8.5.2. 
Secondary Analyses 
The same methods used to analyze the primary efficacy endpoint, as determined by the 
US FDA-defined snapshot algorithm, will be used to assess the proportion of participants with 
HIV1 RNA ≥ 50 copies/mL at Weeks 12 and 48 and the proportion of participants with HIV-1 
RNA <50 copies/mL at Weeks 12, 24, and 48. 
Changes from baseline in CD4+ T-cell count at Weeks 12, 24, and 48 will be summarized by 
treatment group within each cohort using descriptive statistics. The differences in changes from 
baseline in CD4+ T-cell count between the ISL+LEN group and B/F/TAF group within each 
cohort and the associated 95% CIs will be constructed using analysis of covariance (ANCOVA) 
models, including baseline CD4+ T-cell count as a covariate and treatment (ISL+LEN vs 
B/F/TAF) as a fixed-effect in the models. 
8.5.3. 
All ISL+LEN Analysis 
The following efficacy endpoints will be summarized for All ISL+LEN analysis using All 
ISL+LEN analysis set: (1) the proportion of participants with HIV-1 RNA categories (< 50, 50 to 
< 200 copies/mL, etc) by missing = excluded and missing = failure approaches by visit, (2) the 
change from baseline in CD4+ T-cell count by visits, and (3) the percentage change from 
baseline in CD4+ T-cells by visits. No statistical comparison will be conducted.  

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8.6. 
Safety Analysis 
All safety analyses will be performed using the safety analysis set for the Randomized Phase 
analysis and using the All ISL+LEN analysis set for the All ISL+LEN analysis, unless specified 
otherwise. 
For the Randomized Phase analysis, all safety data collected on or after the date that study drugs 
are first dispensed up to the date of last dose of study drugs plus 60 days for the ISL+LEN group 
and 30 days for the B/F/TAF group (before switching to ISL+LEN) will be summarized by 
treatment group (according to the study drugs received) within each cohort.  
For the All ISL+LEN analysis, all safety data collected on or after the first dose date of ISL or 
LEN, up to the last dose date of ISL, LEN, or ISL/LEN 
 plus 60 days, will be summarized 
by treatment group. 
All collected data will be included in data listings for all enrolled participants. 
8.6.1. 
Extent of Exposure 
A participant’s extent of exposure to study drug will be generated from the study drug 
administration data in the eCRF. Exposure data will be summarized by treatment group within 
each cohort. 
Dosing information for individual participants will be listed. 
8.6.2. 
Adverse Events 
Clinical and laboratory AEs will be coded using the current version of the Medical Dictionary 
for Regulatory Activities (MedDRA). System organ class, high-level group term, high-level 
term, preferred term, 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 drugs up to 
the date of last dose of study drugs plus 60 days (for ISL+LEN or ISL/LEN 
 or 30 days (for 
B/F/TAF), or any AE leading to study drug discontinuation. 
Summaries (number and percentage of participants) of treatment-emergent AEs (by system 
organ class, high-level term [if applicable], and preferred term) will be provided by treatment 
group within each cohort. Additional summaries will include summaries for AEs by grade, 
investigator’s assessment of relationship to study drugs, and effect on study drug dosing. 
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8.6.3. 
Laboratory Evaluations 
Selected laboratory test data (using conventional units) will be summarized using only observed 
data. Absolute values and changes from baseline at all scheduled visits will be summarized. 
Graded laboratory abnormalities will be defined using the grading scheme in the DAIDS Table 
for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 dated July 2017, 
available as follows: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at 
least 1 toxicity grade from baseline at any time post baseline up to and including the date of last 
dose of study drugs plus 60 days (for ISL+LEN or ISL/LEN
 or 30 days (for B/F/TAF), 
will be summarized by treatment group within each cohort. If baseline data are missing, then any 
postbaseline graded abnormality (ie, at least a Grade 1) will be considered treatment-emergent. 
The maximum postbaseline toxicity grade will be summarized by laboratory parameter. 
8.6.4. 
Other Safety Evaluations 
Vital signs and safety ECG data will be summarized by treatment group within each cohort as 
appropriate. 
8.7. 
Adjustments for Multiplicity 
No adjustments will be made for multiplicity. Nominal 95% CIs and tests performed at the 
nominal 0.05 alpha level will be provided. 
8.8. 
Pharmacokinetic Analysis 
For the general PK analyses, the PK of ISL and LEN may be evaluated using descriptive 
statistics or population analysis approaches. For the intensive PK substudy, plasma 
concentrations of ISL and LEN will be summarized by nominal sampling time. Pharmacokinetic 
parameters (Cmax, Tmax, Ctau, AUCtau, and t1/2, as appropriate) will be listed and summarized using 
descriptive statistics. 
8.9. 
Sample Size 
A sample size of 50 participants in the ISL+LEN treatment group was chosen to estimate the 
proportion of participants with HIV-1 RNA ≥ 50 copies/mL at Week 24 as determined by the 
US FDA-defined snapshot algorithm to allow for the planning of Phase 3 studies. This study is 
not formally powered. 
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Cohort 1 
Assuming no failure (0%) in Treatment Group 2 (B/F/TAF) at Week 24, the number of failures 
in Treatment Group 1 (ISL+LEN) at Week 24 would need to be ≥ 8 (16%) for the 95% CI for the 
between-treatment difference in the proportion of participants with HIV-1 RNA ≥ 50 copies/mL 
to exclude 0. Similarly, assuming 1 failure (4%) in Treatment Group 2 at Week 24, the number 
of failures in Treatment Group 1 at Week 24 would need to be ≥ 12 (24%) for the 95% CI for the 
between-treatment difference in the proportion of participants with HIV-1 RNA ≥ 50 copies/mL 
to exclude 0. The 95% CI is calculated based on an exact unconditional method {Chan 1999}. 
If the underlying incidence of a specific AE is 5%, there is a 92.3% chance of observing at least 
1 AE among 50 participants in Treatment Group 1 and a 72.3% chance of observing at least 
1 AE among 25 participants in Treatment Group 2. 
Cohort 2 
Assuming no failure (0%) in Treatment Group 4 (B/F/TAF) at Week 24, the number of failures 
in Treatment Group 3 (ISL+LEN) at Week 24 would need to be ≥ 4 (8%) for the 95% CI for the 
between-treatment difference in the proportion of participants with HIV-1 RNA ≥ 50 copies/mL 
to exclude 0. Similarly, assuming 1 failure (2%) in Treatment Group 4 at Week 24, the number 
of failures in Treatment Group 3 at Week 24 would need to be ≥ 7 (14%) for the 95% CI for the 
between-treatment difference in the proportion of participants with HIV-1 RNA ≥ 50 copies/mL 
to exclude 0. The 95% CI is calculated based on an exact unconditional method {Chan 1999}. 
If the underlying incidence of a specific AE is 5%, there is a 92.3% chance of observing 
at least 1 AE among 50 participants in Treatment Groups 3 and 4. 
8.10. 
Data Monitoring Committee 
A multidisciplinary DMC consisting of non-Gilead personnel will review the progress of the 
study, perform interim reviews of safety and efficacy data at a minimum at Weeks 12, 24, and 
48, and provide recommendations to Gilead whether the nature, frequency, and severity of AEs 
associated with study treatment 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. The DMC may also provide recommendations as needed regarding 
study design. The DMC’s specific activities will be defined by a mutually agreed charter, which 
will define the DMC’s membership, conduct, 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. If the DMC determines that discontinuation of one or both treatment groups is 
warranted, it will recommend to do so. 

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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 (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 the sponsor or MSD, or of any proprietary interests in the 
study drugs. This documentation must be provided before 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. The investigator will not begin any study participant activities until 
approval from the IRB 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 any modifications made to the protocol or any accompanying material to be provided to 
the participant after initial institution review board 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-approved ICF for documenting written informed consent. Each 
ICF 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 local requirements). 

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The ICF will inform participants about laboratory testing and/or planned sample retention. 
 
 
 
 
 The results of the tests performed on the 
stored biological samples will not be given to the participant or the investigator unless requested. 
The stored biological samples will be destroyed no later than 15 years after the end of study or 
per country requirements, but participants may at any time request that their stored samples be 
destroyed. 
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, IRB, 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, 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 investigational 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, eCRFs, IRB, 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 drugs, 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, the 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 investigational 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. 
Case Report Forms 
An eCRF casebook will be completed by an authorized study personnel member whose training 
for this function is completed in the EDC system unless otherwise directed. The eCRF casebook 
will only capture the data required per the protocol schedule of events and procedures, unless 
collected by a nonelectronic data capture vendor system (eg, central laboratory). The 
inclusion/exclusion criteria and enrollment eCRFs should be completed only after all data related 
to eligibility are available. Data entry should be performed in accordance with the CRF 
Completion Guidelines provided by the sponsor. Subsequent to data entry, a study monitor may 
perform source data verification. System-generated or manual queries will be issued in the EDC 
system as data discrepancies are identified by the study monitor or Gilead personnel who 
routinely review the data for completeness, correctness, and consistency. The site investigator, 
site coordinator, or other designee is responsible for responding to the queries in a timely 
manner, within the system, either by confirming the data as correct or updating the original entry, 
and providing the reason for the update (eg, data entry error). Original entries as well as any 
changes to data fields will be stored in the audit trail of the system. Regular oversight by the 
principal investigator of the data entered into the EDC system is expected to occur on an ongoing 
basis throughout the study to ensure quality and completeness. At a minimum, before any 
interim, final, or other time points (as instructed by Gilead), the investigator will apply his/her 
electronic signature to confirm that the forms have been reviewed and that the entries accurately 
reflect the information in the source documents. At the conclusion of the study, Gilead will 
provide the site investigator with a read-only archive copy of the data entered. 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 IRB, 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 
in accordance with local requirements and receive documented IRB approval before 
modifications can be implemented. 

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9.2.2. 
Study Reports 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. 
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 personnel 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 
and/or travel expenses or reimbursements, consulting fees, and any other transfer of value. 
9.3.2. 
Access to Information for Monitoring 
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation and any participant records in order to verify the adherence 
to the protocol and the accuracy of the data recorded in the electronic case report form. The study 
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 investigator agrees to cooperate with the study monitor to 
ensure that any problems detected through any type of monitoring (central, off site, 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 study 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(ies), and IRB. 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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9.3.5. 
Data Protection 
The sponsor has developed enterprise level technical and organizational controls for the purpose 
of data protection. This includes user authentication and identification, fine grained access 
controls, end-to-end data encryption, security monitoring, network segregation, and physical 
security controls. Users of the sponsor’s systems are provided training for security awareness and 
privacy.  
To prepare for the possibility of a data security breach, the sponsor maintains a business 
continuity and disaster recovery plan and conducts regular disaster recovery testing to ensure that 
the sponsor’s systems are recoverable if a cyber or data security incident is experienced. The 
sponsor’s detailed incident response plan for any cyber or data security incident is based on the 
following 5 steps: detection, analysis, containment, eradication, and recovery. The sponsor’s 
standard clinical trial agreements with study sites and vendors also obligate each party to comply 
with applicable data protection laws and to promptly notify the other in the event of a personal 
data breach. 

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10. 
REFERENCES 
BIKTARVY, Gilead Sciences Inc. BIKTARVY® (bictegravir, emtricitabine, and tenofovir 
alafenamide) tablets, for oral use. U.S. Prescribing Information. Foster City, CA. 
Revised March.  2021: 
Chan IS, Zhang Z. Test-based exact confidence intervals for the difference of two binomial 
proportions. Biometrics 1999;55 (4):1202-9. 
Claborn KR, Meier E, Miller MB, Leffingwell TR. A Systematic Review Of Treatment Fatigue 
Among HIV-Infected Patients Prescribed Antiretroviral Therapy. Psychol Health 
Med 2015;20 (3):1-11. 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41. 
Department of Health and Human Services (DHHS). Guidelines for the Use of Antiretroviral 
Agents in HIV-1-Infected Adults and Adolescents. Developed by the HHS Panel 
on Antiretroviral Guidelines for Adults and Adolescents – A Working Group of 
the Office of AIDS Research Advisory Council (OARAC). Revised 12 February 
2013. Available at: http://aidsinfo.nih.gov/guidelines. Accessed: 2013 February 
12.  2013. 
U. S. Department of Health and Human Services, Food and Drug Administration (FDA), Center 
for Drug Evaluation and Research (CDER). Human Immunodeficiency Virus-1 
Infection: Developing Antiretroviral Drugs for Treatment. Guidance for Industry. 
Silver Spring, MD.  November, 2015. 
UNAIDS. The path that ends AIDS: UNAIDS Global AIDS Update 2023. Available at: 
https://www.unaids.org/en/resources/documents/2023/global-aids-update-2023. 
Accessed: 15 August 2023. Last Updated: 13 July.  2023: 
 

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11. 
APPENDICES 
Appendix 1. 
Investigator Signature Page 
Appendix 2. 
Pandemic Risk Assessment and Mitigation Plan 
Appendix 3. 
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements 
Appendix 4. 
Management of Clinical and Laboratory Adverse Events 
Appendix 5. 
Country-Specific Requirements 
Appendix 6. 
Amendment History 
 

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Appendix 1. 
Investigator Signature Page 
 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
USA 
 
STUDY ACKNOWLEDGMENT 
 
A Phase 2 Randomized, Open-Label, Active-Controlled Study Evaluating the Safety and 
Efficacy of an Oral Weekly Regimen of Islatravir in Combination with Lenacapavir in 
Virologically Suppressed People with HIV 
GS-US-563-6041, Amendment 6, 02 December 2025 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
 
 
[See appended electronic signature] 
Name (Printed) 
 
 
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 an ongoing pandemic, potential risks associated with participants being unable to attend 
study visits have been identified for this study. 
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 
drugs, or the site may be unable to accept any participant visits. Without study drugs, the 
participant would not be able to continue receiving the study drugs as planned per 
protocol. 
Mitigation plan: Study drug supplies 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 drugs as determined by the principal investigator. A remote study visit, via phone 
or video conferencing, must be performed before remote study drug resupply. 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 drugs from sites to study participants if permitted by the local ethics 
committee/IRB/regulatory authority as applicable and with sponsor’s approval. 
b) Shipments of study drugs could be delayed because of transportation issues. Without 
study drugs, the participant would not be able to continue receiving the study drugs as 
planned per protocol. 
Mitigation plan: The site’s study drug inventory 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 investigational sites. Manual shipments will be 
triggered as necessary. 
2) Participant safety monitoring and follow-up: 
a) Participants may be unable or unwilling to come to the investigational site for their 
scheduled study visits as required per protocol. 

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Mitigation plan: For participants who may be unable or unwilling to visit the 
investigational site for their scheduled study visits as required per protocol, the principal 
investigator or qualified delegate will conduct a remote study visit, via phone or video 
conferencing, to assess the participant within the target visit window date whenever 
possible. During the remote study visit, the following information at minimum will be 
reviewed: 
i) Confirm if participant has experienced any AEs/SAEs/special situations (including 
pregnancy) and follow-up on any unresolved AEs/SAEs. 
ii) Review the current list of concomitant medications and document any new 
concomitant medications. 
iii) If applicable, confirm electronic diary questionnaires and PROs have been completed 
and transmitted. 
iv) If applicable, confirm the participant’s study drug supply is sufficient to last until the 
next planned visit date. If study drug resupply is needed, it will be provided as 
described above in (1). 
v) If applicable, remind the participant to maintain current dosing and to keep all 
dispensed study drug kits for return at the next onsite 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: Local laboratories or other vendors 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 changes in the party conducting laboratory assessments for 
the study due to the pandemic will be documented accordingly. Pregnancy testing may be 
performed using a home urine pregnancy test if local laboratory pregnancy testing is not 
feasible. 
c) Participants may be unable or unwilling to attend the study visit to sign an updated ICF 
version. 
Mitigation plan: The site staff will follow their approved consent process and remain in 
compliance with the local ethics committee/IRB and national laws and regulations. 
Remote consent will be allowed if has been approved by the local ethics committee/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 be conducted 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 and described in the CSR. Any remote 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) Study monitors may be unable to carry out source data review or source data verification, 
or study drug accountability or assess protocol and GCP compliance. This may lead to 
delays in source data verification, 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 source data verification may be arranged 
if allowed by local regulation and the Study Monitoring Plan. The study monitor is to 
reference the Study Monitoring Plan for guidance on how to conduct an off-site 
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 study 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 
(eg, modification of the SAP) and in compliance with regulatory authorities’ guidance. 
Overall, the CSR 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 ISL, LEN, and B/F/TAF in study participants remains 
unchanged. 

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Appendix 3. 
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements 
1) Definitions 
a. Definition of Childbearing Potential 
For the purposes of this study, a female-born participant is considered of childbearing potential 
until becoming postmenopausal unless the participant is permanently sterile or has medically 
documented ovarian failure. 
Women are considered to be in a postmenopausal state when they are ≥ 54 years of age with 
cessation of previously occurring menses for ≥ 12 months without an alternative cause. In 
addition, women < 54 years of age with amenorrhea of ≥ 12 months also may be considered 
postmenopausal if their follicle-stimulating hormone level is in the postmenopausal range and 
they are not using hormonal contraception or hormonal replacement therapy. 
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female participant of any age. 
b. Definition of Male Fertility 
For the purposes of this study, a male-born participant is considered fertile after the initiation of 
puberty unless the participant is permanently sterile by bilateral orchidectomy or with medical 
documentation. 
2) Contraception Requirements for Female Participants 
a. Study Drug Effects on Pregnancy and Hormonal Contraception 
Islatravir data on pregnant women are limited or not available. Data from nonclinical toxicity 
studies of ISL have demonstrated no adverse effect on fertility or embryo-fetal development. 
Available data indicate that ISL has demonstrated there is no reduction in the clinical efficacy of 
hormonal contraception. Please refer to the latest version of the ISL IB for additional 
information. 
Lenacapavir data on pregnant women are not available. Data from nonclinical toxicity studies of 
LEN have demonstrated no adverse effect on fertility or embryo-fetal development. Available 
data indicate that LEN has demonstrated there is no reduction in the clinical efficacy of 
hormonal contraception. Please refer to the latest version of the LEN IB for additional 
information. 
ISL/LEN 
 data on pregnant women are limited. Data from nonclinical toxicity studies of 
ISL have demonstrated no adverse effect on fertility or embryo-fetal development. Available 
data indicate that ISL has demonstrated there is no reduction in the clinical efficacy of hormonal 
contraception. Please refer to the latest version of the ISL/LEN 
 IB for additional 
information. 
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b. Contraception Requirements for Female Participants of Childbearing Potential 
The inclusion of female participants of childbearing potential requires using at least an 
acceptable effective contraceptive measure. They must have a negative serum pregnancy test at 
screening and a negative urine pregnancy test on the admission (Day 1) visit before 
randomization. In the event of a delayed menstrual period (over 1 month between 
menstruations), a pregnancy test must be performed to rule out pregnancy. This is applicable also 
for female participants of childbearing potential with infrequent or irregular periods. 
Duration of required contraception for female participants enrolled in this clinical study should 
start from the screening visit until 60 days following the last dose of ISL+LEN or ISL/LEN 
 
Female participants must agree to 1 of the following contraceptive methods: 
• Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the participant’s preferred and usual 
lifestyle. 
Or 
• Consistent and correct use of 1 of the following methods of birth control listed below: 
• Hormonal and nonhormonal intrauterine device (IUD) 
• Bilateral tubal occlusion (upon medical assessment of surgical success) 
• Vasectomy in the male partner (upon medical assessment of surgical success) 
• Or 
Female participants who initiate use of a hormonal contraceptive > 7 days after onset of menses 
as one of their birth control methods should use additional back-up contraception (eg, condoms) 
or avoid sexual intercourse for 7 days. Hormonally based contraceptives and barrier methods 
permitted for use in this protocol are as follows: 
• Hormonal methods 
⎯ Oral contraceptives (either combined or progesterone only) 
⎯ Injectable progesterone 
⎯ Subdermal contraceptive implant 
⎯ Transdermal contraceptive patch 
⎯ Contraceptive vaginal ring 
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• Barrier methods 
⎯ Male condom (with or without spermicide) 
⎯ Female condom (with or without spermicide) 
⎯ Diaphragm with spermicide 
⎯ Cervical cap with spermicide 
⎯ Sponge with spermicide 
Inclusion of methods of contraception in this list of permitted methods does not imply that the 
method is approved in any country or region. Methods should only be used if locally approved. 
Female participants must also refrain from egg donation and in vitro fertilization during 
treatment and until the end of contraception requirement. 
3) Contraception Requirements for Male Participants 
No contraception measures are needed. 
4) Unacceptable Birth Control Methods 
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method. A female condom and a male condom should not be used 
together. 
5) Procedures to be Followed in the Event of Pregnancy 
Female participants will be instructed to notify the investigator if they become pregnant or 
suspect they are pregnant at any time from start of the study to 60 days following the last dose of 
ISL+LEN or ISL/LEN 
. Study drugs must be discontinued immediately. 
Instructions for reporting pregnancy and pregnancy outcome are outlined in Section 7.4.3.3. 
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Appendix 4. 
Management of Clinical and Laboratory Adverse Events 
 
I 
Grade 1 
I 
Grade 2 
I 
I 
Grade3 
I 
I 
, 1, 
, 1, 
It 
May continue dosing 
Repeat lab to 
Repeat lab to 
at the discretion of 
confirm toxicity 
confirm toxicity 
the investigator 
grade 
grade 
' 
If confirmed, and possibly or probably related to investigational 
If confirmed, and unrelated to 
products: 
investigational medical 
I. Withhold investigational medicinal products until :S Grade 2 
products, dosing may continue 
2. Restart all investigational medicinal products at full dose 
at the discretion of the 
upon discussion with the Gilead Sciences Medical Monitor 
investigator 
l 
If Grade 3 or 4 recurrence is 
If Grade 3 or 4 recurrence is 
confirmed, and possibly or 
confirmed, and unrelated to 
probably related to 
investigational medical 
investigational products, 
products, continue all 
discontinue all investigational 
investigational medicinal 
medicinal products dosing 
products at the same dose, at 
permanently, and manage the 
the discretion of the 
participant according to local 
investigator 
practice 
Grade 4 
I 
If confirmed, and 
bably 
possibly or pro 
related to 
investigational 
products, disco ntinue 
investigational 
medicinal prod ucts 
ntly, 
dosing permane 
and manage 
participant acco rding 
e. 
to local practic 
Participant sho uld be 
mically 
the 
followed as er 
indicated until 
laboratory 
abnormality re turns 
s 
ined 
to baseline, or i 
otherwise expla 

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Appendix 5. 
Country-Specific Requirements 
Not applicable. 

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Appendix 6. 
Amendment History 
A high-level summary of this amendment history is provided in tabular form below. Minor 
changes such as the correction of typographic errors, grammar, or formatting are not detailed. 
Separate summary of change documents for earlier amendments are available upon request. 
A separate tracked change (red-lined) document comparing the previous version of the protocol 
to this amendment will be made available upon the publication of this protocol. 
Appendix Table 1. 
Amendment 6 ( ) 
Rationale for Key Changes Included in Amendment 6 
Affected Sections 
Frequency of visits in Extension Phase changed to every 24 weeks after 
Week 144 to ease participant burden.  
Synopsis, Study Schema, 
Table 2, Section 3.1 
Text was added to indicate that islatravir (ISL)/lenacapavir is being developed 
for the treatment of HIV-1 in collaboration with Merck Sharp & Dohme LLC 
(MSD) and that investigators and subinvestigators will provide documentation 
of any financial interest or arrangements with the sponsor or MSD. 
Merck Sharp & Dohme LLC’s name was updated to be referred to “MSD” 
throughout the document. 
Sections 1.2, 6.3.9, and 9.1.2  
Information was added relative to drug-drug interactions between lamivudine or 
emtricitabine and ISL-triphosphate; drug-drug interactions between 
deoxycytidine kinase substrates and islatravir triphosphate. 
Section 5.8 
Added text regarding the responsibilities of the investigator in confirming 
participant eligibility. 
Section 6.2 
New sections for Adverse Events of Special Interest were added as per new 
updates in the Gilead protocol template and mentioned as not applicable. 
Section 7 
Language regarding reporting of any sequelae from a special situation event 
was added for clarity. 
Section 7.1.4 
Clarified text related to death as a serious adverse event. 
Section 7.3.3 
Added section regarding data protection as per Gilead protocol template. 
Section 9.3.5 
Minor grammatical and typographical changes. 
Throughout as needed. 
 
Appendix Table 2. 
Amendment 5 (19 November 2024) 
Rationale for Key Changes Included in Amendment 5 
Affected Sections 
Dosing instructions for ISL/LEN fixed-dose combination (
) 2/300 mg 
added in Cohort 2. 
Throughout as needed 
Added new section providing reference to clinical studies of coadministered ISL 
and LEN, as well as ISL/LEN 
. 
Section 1.4 
Additional rationale language inserted to clarify the switch to ISL/LEN 
 
Section 1.6 
Updated study schematic to better reflect treatment regimen of Cohort 2 
transitioning from ISL+LEN to ISL/LEN 
 during Extension Phase. 
Figure 1 
ISL/LEN 
 dispensation row added in Study Procedure Table of Cohort 2. 
Table 2 
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Rationale for Key Changes Included in Amendment 5 
Footnote x was updated and footnote y was added to Study Procedme Table of 
Coho1t 2. 
Section pe1taining to Description and Handling ofISIJLEN-
added. 
Language regarding Planned Interim Analysis was updated to include Week 48 
analysis for Extension Phase (Study Week 96) instead of Week 24. 
Added new section for an analysis set with consideration to the addition of 
ISIJLEN-. 
Added new efficacy analysis section for All ISL+LEN analysis. 
Updated safety analysis section for the Randomized Phase analysis regarding 
All ISL+LEN analyses. 
.
, rBA, and NNRTI added to List of Abbreviations and Definition ofTemis. 
Included mention ofISL/LEN-
where appropriate. 
Added new table for ISIJL~ 
missed dose recommendations for Cohort 2 
and introduced the use of an 
dose under special 
circulllStances. 
Added language to clarify the process for repo1ting SAE info1mation using 
electronic fo1ms. 
Added language specific to contraception requirements for female participants 
administered ISIJLE1'911111. 
Appendix Table 3. 
Amendment 4 (21 February 2024) 
Rationale for Key Changes Included in Amendment 4 
Study Procedures Table for Coho1t 2 updated for accuracy to include urine 
pregnancy test at early study drng discontinuation (ESDD) visit, to remove time 
point Week 48 for B/F/fAF dispensation, and to remove HCV Ab from the 
screening assessments. In addition, footnotes 'j ' and 'k' were updated to clarify 
the time points for the PP-Rand PP-RC PROs. 
Clarified that pa1ticipants assigned female at bitth of childbearing potential 
must have a negative urine pregnancy test at Day 1. 
Language regarding the number of planned interim analyses was updated to 
remove the Week 12 planned interitn analysis as the key summa1y tables 
including the Week 12 snapshot (secondaty endpoint) are provided in the 
Week 12 DMC analysis (Section 8.10). 
Language regarding an internal Safety Assessment Committee was deleted due 
to a template update and is not applicable to this open-label study. 
Minor grammatical and typographical changes. 
CONFIDENTIAL 
Page 110 
Final 
Amendment 6 
Affected Sections 
Table 2 
Section 5.5 
Section 8.2.1.1 
Section 8.3.1.3.4 
Section 8.5.3 
Section 8.6 
List of Abbreviations and 
Definition of Terms 
Throughout as needed 
Figure 1, Table 23 
Section 7.4.1.1 
Appendix 3 
Affected Sections 
Study Procedures for Cohort 2 
(Table 2) 
Appendix 3 
Section 8.2.1.1 
Section 7.8 
Throughout as needed. 
02 December 2025 

Islatravir + Lenacapavir 
 
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Gilead Sciences, Inc.  
Amendment 6 
CONFIDENTIAL 
Page 111 
02 December 2025 
Appendix Table 4. 
Amendment 3 (26 October 2022) 
Rationale for Key Changes Included in Amendment 3 
Affected Sections 
An ISL dose of 
 capsules) was implemented 
for Cohort 2 in the Randomized Phase. 
• 
Treatment groups in Cohort 2 were changed to 
 
ISL 
) + LEN group (current Treatment 
Group 3; previously 1 mg ISL+LEN) or B/F/TAF 
group (current Treatment Group 4; previously treatment 
Group 5). 
• 
The 3 mg ISL+LEN dose (previously Treatment Group 
3) was removed from Cohort 2. 
Synopsis; Study Schema (Figure 1); Study 
Procedures for Cohort 2 (Table 2); Sections 3.1, 
5.1.1, and 5.5 
An ISL dose of
) + LEN was implemented 
for participants in the Extension Phase. 
Synopsis; Section 3.1; Table 21 
The Cohort 2 ISL dose selection rationale was revised, 
including the predicted ISL exposures and predicted 
changes in mean lymphocytes and CD4+ T cells, based on 
an ISL dosage of
) QW. 
Section 1.6 
The General Information section was revised to update the 
location of additional information regarding changes in 
absolute lymphocyte and lymphocyte subset counts (ie, 
information is available in the IB for ISL). A cross-
reference to Section 1.8 Risk/Benefit Assessment) was also 
added. 
Section 1.2.1 
The Risk/Benefit Assessment section was revised to include 
information related to the scope of the observed lymphocyte 
and lymphocyte subset decreases across the ISL program. 
Section 1.8 
The frequency of HBV/HCV screening was expanded into 
the Extension Phase to repeat every 48 weeks after the 
Week 48 visit of the Randomized Phase. 
Study Procedures for Cohort 2 (Table 2); Section 
6.3.6  
HCV Ab was added to the list of HBV/HCV tests for 
Cohort 2. 
Study Procedures for Cohort 2 (Table 2); Table 24 
The description of ISL drug product and labeling were 
revised to accommodate the 
) dose. 
The description and labeling of ISL 3 mg drug product were 
removed. 
Synopsis; Sections 5.2.1, 5.2.2, and 5.2.3  
The missed dose recommendations were revised in order to 
specify the number of ISL 1 mg capsules and LEN 300 mg 
tablets to be taken for each missed dose. 
Table 22 
The End of Randomized Treatment Visit was removed since 
the dose of ISL in the Extension Phase will be the same as 
in the Randomized Phase (ie,
  
Synopsis; Study Schema (Figure 1); Study 
Procedures for Cohort 2 (Table 2); Section 5.5 
The number of participants planned in Cohort 2 was revised 
from 150 (50 participants randomized in a 1:1:1 ratio to 
Treatment Groups 3, 4, and 5) to 100 participants in a 1:1 
ratio (50 participants in Treatment Group 3 [
 
Synopsis; Sections 4.1 and 5.1.1  
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
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Islatravir + Lenacapavir 
 
Protocol GS-US-563-6041 
Final 
Gilead Sciences, Inc.  
Amendment 6 
CONFIDENTIAL 
Page 112 
02 December 2025 
Rationale for Key Changes Included in Amendment 3 
Affected Sections 
ISL+LEN] and 50 participants in Treatment Group 4 
[B/F/TAF]). 
The study procedures/frequency section of the Synopsis for 
Cohort 2 was updated to clarify occurrence of onsite and 
telephone visits in the Randomized and Extension Phases.  
Synopsis 
Exclusion criterion no. 6 was revised to add active or occult 
HBV coinfection as exclusionary. 
Section 4.3 
Minor grammatical and typographical changes. 
Throughout as needed. 
 

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