An Umbrella Phase 1b, Open-label, Multi-Cohort Study to Evaluate Safety, Pharmacokinetics, and Antiviral Activity of Novel Antiretrovirals in Participants With HIV-1
Phase: PHASE1
Conditions: HIV-1-infection
Sponsor: Gilead Sciences

CLINICAL SUBSTUDY-01 PROTOCOL
Study Title:
An Umbrella Phase 1b, Open-label, Multi-Cohort Study to Evaluate 
Safety, Pharmacokinetics, and Antiviral Activity of Novel 
Antiretrovirals in Participants With HIV-1 Substudy-01: GS-5894 
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
162030
EudraCT Number:
Not Applicable
ClinicalTrials.gov 
Identifier:
Not Available
Indication:
HIV-1 infection
Protocol ID:
GS-US–544–5905-01
Contact Information:
The medical monitor name and contact information will be 
provided in the Key Study Team Contact List.
Protocol 
Version/Date:
Original:
03 August 2022
Amendment 1:
27 September 2022
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 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) and applicable 
regulatory requirements.
GILEAU 

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The information contained in this document, particularly unpublished data, is the property or 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

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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................................3
LIST OF IN-TEXT TABLES .........................................................................................................................................4
LIST OF IN-TEXT FIGURES........................................................................................................................................4
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...................................................................................5
SUBSTUDY PROTOCOL SYNOPSIS..........................................................................................................................7
SUBSTUDY-01 STUDY SCHEMA ............................................................................................................................10
SUBSTUDY-01 STUDY PROCEDURES TABLE.....................................................................................................11
1.
INTRODUCTION................................................................................................................................................13
1.1.
Rationale for Substudy-01.......................................................................................................................13
1.2.
Background on Study Interventions Used in Substudy-01......................................................................13
1.2.1.
GS–5894................................................................................................................................13
1.3.
Rationale for Dose Selection of Study Drug ...........................................................................................18
1.4.
Risk/Benefit Assessment for Substudy-01 ..............................................................................................19
2.
OBJECTIVES AND ENDPOINTS......................................................................................................................20
3.
STUDY DESIGN.................................................................................................................................................21
3.1.
Study Design Overview...........................................................................................................................21
3.1.1.
Dose Selection/Modification.................................................................................................21
3.2.
Duration of Intervention..........................................................................................................................22
3.3.
Substudy-01-Specific Discontinuation Criteria.......................................................................................22
3.4.
Definitions for Time of Primary Endpoint and End of Study .................................................................22
4.
PARTICIPANT POPULATION..........................................................................................................................23
4.1.
Number of Participants and Participant Selection for Substudy-01........................................................23
4.2.
Substudy-01-Specific Inclusion Criteria .................................................................................................23
4.3.
Substudy-01-Specific Exclusion Criteria ................................................................................................23
5.
STUDY INTERVENTIONS AND CONCOMITANT MEDICATIONS ...........................................................24
5.1.
Enrollment and Treatment Code Access .................................................................................................24
5.2.
Description and Handling of GS-5894 and Commercially Available BVY ...........................................24
5.2.1.
Formulation ...........................................................................................................................24
5.2.2.
Packaging and Labeling ........................................................................................................24
5.2.3.
Storage and Handling ............................................................................................................24
5.2.4.
Dosage and Administration ...................................................................................................25
5.3.
Prior and Concomitant Medications........................................................................................................25
5.4.
Accountability for Study Drug Supplies: Study Drug and SOC ART provided by Sponsor 
(BVY)......................................................................................................................................................26
6.
STUDY PROCEDURES......................................................................................................................................27
6.1.
Instructions for Study Procedures ...........................................................................................................27
6.1.1.
Pharmacokinetics...................................................................................................................27
6.1.2.
Suboptimal Virologic Response............................................................................................27
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT................................................................................28
7.1.
Toxicity Management..............................................................................................................................28
7.1.1.
Grade 1 and 2 Laboratory Abnormalities or Clinical Events................................................28
7.1.2.
Grade 3 Laboratory Abnormalities or Clinical Events..........................................................28

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7.1.3.
Grade 4 Laboratory Abnormalities or Clinical Events..........................................................28
8.
STATISTICAL CONSIDERATIONS.................................................................................................................30
9.
RESPONSIBILITIES...........................................................................................................................................31
10.
REFERENCES.....................................................................................................................................................32
11.
APPENDICES......................................................................................................................................................33
11.1.
Pregnancy Precautions, Definition of Childbearing Potential, and Contraceptive Requirements ..........33
11.2.
Management of Clinical and Laboratory Adverse Events ......................................................................36
11.3.
Investigator Signature Page.....................................................................................................................37
LIST OF IN-TEXT TABLES
Table 1.
Substudy-01 Study Procedures Table......................................................................................11
Table 2.
GS-US-544-5906: Preliminary Plasma PK Parameters of GS-5894 Following 
Single-Dose Administration of Oral GS-5894 (N = 6 per Cohort) in the Fasted 
Condition .................................................................................................................................17
Table 3.
GS-US-544-5906: Preliminary Plasma PK Parameters of GS-5894 Following 
Single-Dose Administration of Oral GS-5894 675 mg in the Fasted Condition as 
well as with a Low-Fat or High-Fat Meal ...............................................................................17
Table 4.
GS-5894 Dosage by Cohort.....................................................................................................25
Table 5.
Examples of Medications Prohibited From Day 11 Through Day 39 Because of the 
Potential for Pharmacokinetic Drug-Drug Interaction With GS-5894a...................................26
LIST OF IN-TEXT FIGURES
Figure 1.
Overview of Visits, Dosing, and Key Assessments for Substudy-01 .....................................10
Figure 2.
GS-US-544-5906: Preliminary Mean (SD) GS-5894 Plasma Concentration-Time 
Profiles Following Single-Dose Administration of Oral GS-5894 (N = 6 per Cohort) 
in the Fasted Condition............................................................................................................15
Figure 3.
GS-US-544-5906: Preliminary Mean (SD) GS-5894 Plasma Concentration-Time 
Profiles Following Single-Dose Administration of Oral GS-5894 675 mg in the 
Fasted Condition as well as with a Low-Fat or High-Fat Meal...............................................16

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
%CV 
percentage coefficient of variation
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ART
antiretroviral therapy
ARV
antiretroviral
AUC
area under the concentration versus time curve
AUC0-168 h 
partial area under the concentration versus time curve from time “0” to time “168 h”
BVY
bictegravir/emtricitabine/tenofovir alafenamide (coformulated; Biktarvy®)
Clast
last observed quantifiable concentration of the drug
Cmax
maximum observed concentration of drug
Ct
concentration at specified time “t”
CYP
cytochrome P450 enzyme
ECG
electrocardiogram
eCRF
electronic case report form
ET
early termination
FDA
Food and Drug Administration
FIH
first-in-human
FSH
follicle-stimulating hormone
Gilead
Gilead Sciences/Gilead Sciences, Inc.
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HIV-1
human immunodeficiency virus type 1
IB
investigator’s brochure
IND
investigational new drug
INSTI
integrase strand transfer inhibitor
IQ
inhibitory quotient
mAbs
monoclonal antibodies
LA
long-acting
NNRTI
nonnucleoside reverse transcriptase inhibitor
NRTI
nucleoside reverse transcriptase inhibitor
PD
pharmacodynamic
PEP
postexposure prophylaxis
PI
protease inhibitor
PK
pharmacokinetic
PrEP
pre-exposure prophylaxis
PWH
people with HIV
RNA
ribonucleic acid

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SAE
serious adverse event
SOC
standard of care
SRT
safety review team
t1/2 
terminal elimination half-life
Tlast 
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
US
United States

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SUBSTUDY PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: An Umbrella Phase 1b, Open-label, Multi-Cohort Study to Evaluate Safety, 
Pharmacokinetics, and Antiviral Activity of Novel Antiretrovirals in Participants With HIV-1 
Substudy-01: GS-5894
IND Number: 162030 
EudraCT Number: Not applicable
ClinicalTrials.gov Identifier: Not available
Study Centers Planned:
See master protocol synopsis for study centers planned.
Objectives and Endpoints:
See master protocol synopsis for objectives and endpoints.
Study Design: See master protocol synopsis for the overview of this substudy design.
Substudy-01 is an open-label, Phase 1b, single-dose/multiple-dose, multicohort study to 
evaluate the safety, pharmacokinetics (PK), and antiviral activity of GS-5894 given as 
monotherapy in people with HIV-1 (PWH) who are either treatment-naive or 
treatment-experienced but naive to the study drug class and have not received any 
antiretroviral therapy (ART) within 12 weeks of screening, including medications received for 
pre-exposure prophylaxis (PrEP) or postexposure prophylaxis (PEP). Any current or prior 
receipt of long-acting parenteral ARVs such as monoclonal antibodies (mAbs) targeting 
HIV-1, injectable cabotegravir, or injectable rilpivirine is exclusionary.
After screening and meeting all eligibility criteria, study drug dosing will be initiated on Day 1 
in the clinic for each participant. Participants will be required to return to the clinic for visits 
on Days 2, 3, 4, 7, 8, 9, 10, and 11 (primary endpoint assessment). After assessments on 
Day 11 or upon early termination (ET), participants will initiate a regimen of Biktarvy® 
(bictegravir/emtricitabine/tenofovir alafenamide; BVY) provided by the sponsor or another 
nonnucleoside reverse transcriptase inhibitor (NNRTI)-based standard of care (SOC) ART 
regimen selected by the investigator. If participants are switching to BVY, a 30-day supply 
will be given to provide coverage for up to 5 half-lives of GS-5894. Participants will be 
required to return to the clinic for follow-up visits on Days 18, 25, and 39.

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This substudy will enroll up to approximately 5 cohorts with at least 6 participants in each 
cohort. Participants will be enrolled in Cohort 1 initially and then dosing in subsequent cohorts 
will proceed after safety review team (SRT) review of emerging data.
The doses and dosing regimen for GS-5894 in each cohort will be selected based on a review 
of available PK, cumulative safety and HIV-1 RNA data through the primary endpoint 
(Day 11), and/or relevant and available safety and PK data from the ongoing Phase 1a 
first-in-human (FIH) study of GS-5894.
Number of Participants Planned: Up to 30 participants
Target Population: See master protocol synopsis for the target population. 
Duration of Intervention: Up to 39 days
Diagnosis and Main Eligibility Criteria: See master protocol for diagnosis and main 
eligibility criteria. For inclusion in this substudy, participants must also be willing to initiate 
BVY provided by the sponsor, or a non-NNRTI-based SOC ART regimen selected by the 
investigator, on Day 11 or upon ET, and be willing and able to comply with meal requirements 
on dosing days.
Study Procedures/Frequency:
After screening and meeting all eligibility criteria, study drug dosing will be initiated on Day 1 
in the clinic for each participant. Participants will be required to return to the clinic for visits 
on Days 2, 3, 4, 7, 8, 9, 10, and 11 (primary endpoint assessment). After assessments on 
Day 11 or upon ET, participants will initiate a regimen of BVY provided by the sponsor or 
another non-NNRTI-based SOC ART regimen selected by the investigator. Participants will 
be required to return to the clinic for visits on Days 18, 25, and 39. 
The detailed schedule of procedures for Substudy-01 is provided in Table 1.
Test Product, Dose, and Mode of Administration: 
Single or multiple doses of GS-5894 will be administered starting on Day 1. The dose, dose 
regimen, and meal requirements for administration of GS-5894 in Cohort 1 are provided 
below. Subsequent cohort dosing, dosing regimens (ie, single or multiple doses), meal 
requirements (fasted or with a low-fat or high-fat meal), and progression between cohorts will 
be adaptive. Doses in subsequent cohorts will not exceed the doses indicated below.
Doses of GS-5894 will be administered orally at the clinic under observation by site staff in 
the morning at approximately the same time each day (in the case of multiple-dose regimens).
Single or multiple doses of study drug (GS-5894) will be administered orally in the morning 
with or without regard to food (as appropriate).

Cohort 1: Single dose of GS-5894 675 mg administered on Day 1 with a high-fat meal

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
Cohort 2: Single or multiple doses of GS-5894 up to 2025 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)

Cohort 3: Single or multiple doses of GS-5894 up to 2025 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)

Cohort 4: Single or multiple doses of GS-5894 up to 2025 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)

Cohort 5: Single or multiple doses of GS-5894 up to 2025 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)
Reference Therapy, Dose, and Mode of Administration: Not applicable
Statistical Methods: See master protocol for statistical methods. 

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SUBSTUDY-01 STUDY SCHEMA
Figure 1.
Overview of Visits, Dosing, and Key Assessments for Substudy-01
ART = antiretroviral therapy; BVY = bictegravir/emtricitabine/tenofovir alafenamide (coformulated; Biktarvy®); 
FIH = first in human; PK = pharmacokinetic; SOC = standard of care
a
After assessments on Day 11 or upon early termination, participants will initiate a regimen of BVY provided by the sponsor 
or another non-NNRTI based SOC ART regimen selected by the investigator. 
b
Additional intensive PK visits may be required for cohorts with more than one day of dosing of GS-5894.
For Cohort 1, a single dose of 675 mg dose of GS-5894 will be administered on Day 1 with a high fat meal. The doses, 
dosing regimen (single or multiple doses), and meal requirements for GS-5894 in each subsequent cohort will be selected based 
on a review of available PK, cumulative safety and HIV-1 RNA data through the primary endpoint (Day 11), and/or relevant and 
available safety and PK data from the ongoing Phase 1a FIH study of GS-5894 (Section 3.1.1).
Day 
Treatment 
PK 
GS-5894 Treatment 
1 T T T T T 
-28 
1 
2 
3 
4 
7 
8 
.. 
* 
• 
Clinic visit 
A Initiate GS-5894 dosing (single or multiple doses) 
V Primary endpoint 
Initiate BVY (B/F/TAF) or SOC 
* Intensive PKb 
Single anytime plasma PK 
T 
9 
BVY or SOC ART Treatmenta 
V 
T T 
T 
T 
T 
10 
11 
18 
25 
39 

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SUBSTUDY-01 STUDY PROCEDURES TABLE
Table 1.
Substudy-01 Study Procedures Table
Study Procedure
Screeninga
D1b
D2
D3 b
D4
D7b
D8
D9
D10
D11b
D18b
D25b
D39b
ETc
Visit Window
±1D
±1D
±1D
Written informed consent
X
Medical history and demography
X
Complete physical examination
X
X
X
X
Symptom driven physical examinationd
X
X
X
X
Height 
X
Weight 
X
X
X
X
X
X
X
X
X
Vital signse
X
X
X
X
X
X
X
X
X
X
HBV blood panel and HCV serologyf
X
CD4 cell countf
X
X
X
X
X
X
X
Plasma sample for HIV-1 
genotyping/phenotypingf,g
X
X
X
Plasma HIV-1 RNAf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematologyf,h
X
X
X
X
X
X
X
X
X
Coagulation panelf,h
X
X
X
X
X
X
Chemistryf,h
X
X
X
X
X
X
X
X
X
Urinalysisf,h
X
X
X
X
X
X
X
X
X
Serum pregnancy testf,i
X
Urine pregnancy testf,i, j
X
X
X
Serum FSHf,k
X
12-Lead ECG
X
X
X
X
X
X
Intensive plasma PKl
X
Single anytime plasma PKm
X
X
X
X
X
X
X
X
X
X
X
X
Review AEs and concomitant medicationsn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Initiate study drug (GS-5894) dosingo
X
BVY dispensation
X
BVY or SOC administration
          Xp

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AE = adverse event; BVY = bictegravir/emtricitabine/tenofovir alafenamide (coformulated; Biktarvy®); CLcr = creatinine clearance; D = Day; ECG = electrocardiogram; 
eCRF = electronic case report form; FSH = follicle-stimulating hormone; ET = early termination; HBV = hepatitis B virus; HCV = hepatitis C virus; PK = pharmacokinetic(s); 
SAE = serious adverse event; SOC = standard of care
a
Prospective participants should be screened no more than 28 days prior to administration of the first dose of study drug.
b
Overnight fasting (≥ 6 hours) is required.
c
ET assessments will be performed within 72 hours of prematurely discontinuing from the study or study drug, as applicable.
d
Symptom driven physical examinations will be performed as needed, based on reported signs and symptoms.
e
Vital signs include blood pressure, heart rate, respiration rate, and body temperature. Participants should be sitting down for 5 minutes before vital sign measurements are 
obtained.
f
See detailed list of laboratory assessments in Section 6.3.7 of the master protocol.
g
Participants who meet the criteria for virologic failure after Day 11 will be tested for the potential development of resistance against all components of the treatment regimen, 
including the evaluated compound. See section 6.3.9.1.3 of the master protocol for management of virologic failure.
h
Chemistry, hematology, coagulation, and urinalysis profiles per Section 6.3.7 of the master protocol.
i
Participants assigned female at birth of childbearing potential only. 
j
A negative urine pregnancy test is required prior to study drug dosing on Day 1. Positive urine pregnancy tests will be confirmed with a serum test.
k
Serum FSH test is required for participants assigned female at birth and are < 54 years old, not on hormonal contraception, and who have stopped menstruating for 
≥ 12 months but do not have documentation of hormonal ovarian failure.
l
Intensive PK samples should be collected at these timepoints for all cohorts: predose, 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours postdose 
) on 
respective days of dosing. Additional intensive PK visits may be required for cohorts with more than 1 day of dosing of GS-5894.
m
Single anytime PK sampling will occur relative to study drug dosing on Day 1.
n
From the time of obtaining informed consent through the first administration of study drug, record all SAEs, as well as any nonserious AEs related to protocol-mandated 
procedures, on the AE eCRF. All other untoward medical occurrences observed during the screening period, including exacerbation or changes in medical history are to be 
captured on the medical history eCRF. See Section 7, Adverse Events and Toxicity Management, for additional details.
o
For Cohort 1, a single 675-mg dose of GS-5894 administered on Day 1 with a high-fat meal (Section 5.2.4). Subsequent cohort dose, dosing regimens (ie, single or multiple 
doses), meal requirements (fasted or with a low- or high-fat meal), and progression between cohorts will be adaptive and determined as summarized in Section 3.1.1). 
p
BVY or SOC will be initiated on Day 11. Participants who discontinue study drug before Day 11 should start this regimen at the time of discontinuation (Section 6.4.1 of 
master protocol).
CCI

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1.
INTRODUCTION
Substudy-01 will evaluate the safety, pharmacokinetics (PK), and antiviral activity of GS-5894 
given as monotherapy in people with HIV-1 (PWH), who are either treatment-naive or 
treatment-experienced but naive to nonnucleoside reverse transcriptase inhibitor (NNRTI) class 
and have not received any antiretroviral (ARV) therapy (ART) within 12 weeks of screening 
(full population details provided in Section 4). This is a substudy being conducted as part of the 
GS-US-544-5905 master protocol.
1.1.
Rationale for Substudy-01
Current first-line ART regimens consist of 2 or 3 ARV drugs, often coformulated, allowing a 
one-pill, once-daily oral treatment regimen; these regimens result in virologic suppression in 
more than 80% of PWH {Department of Health and Human Services (DHHS) 2018}, {Gunthard 
2016}, {European Aids Clinical Society (EACS) 2021}, {World Health Organization (WHO) 
2016}. A major factor preventing more widespread success of oral treatment is suboptimal 
adherence, a primary cause of incomplete viral suppression. There are multiple barriers to 
adherence, such as inconvenience, side effects, stigma, and discrimination {Enriquez 2011}.
Long-acting (LA) ARV regimens with less frequent dosing, for example LA injectable or oral 
weekly regimens, have the potential to address challenges with suboptimal adherence and 
treatment fatigue associated with daily oral therapy and improve success rates while also helping 
to prevent transmission of HIV.
An oral weekly regimen could benefit individuals who desire an oral regimen but prefer a 
regimen that can be taken less frequently than daily.
Based on the available PK data (as of 22 June 2022) from the ongoing Phase 1a first-in-human 
(FIH) study GS-US-544-5906, the median terminal elimination half-life (t1/2) of GS-5894 was 
between 4.77 and 7.96 days. GS-5894 also exhibited high metabolic stability and a slow rate of 
metabolism in human hepatocytes. With these supporting data, GS-5894 has the potential to be 
administered orally once weekly and to be combined with other LA agents as part of a 
combination regimen for the treatment of HIV-1 infection.
1.2.
Background on Study Interventions Used in Substudy-01
1.2.1.
GS–5894
1.2.1.1.
General Information
GS-5894 is a novel NNRTI being developed as a once-weekly oral treatment for HIV-1 
infection. In vitro antiviral testing has demonstrated that GS-5894 is a potent and selective 
nonnucleoside inhibitor of HIV-1 replication, showing strong antiviral activity against clinical 
isolates from all major HIV-1 subtypes. GS-5894 maintains full antiviral activity against a broad 
spectrum of HIV-1 mutants resistant to nucleoside reverse transcriptase inhibitors (NRTIs), 

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protease inhibitors (PIs), and integrase strand-transfer inhibitors (INSTIs). 
In addition, reverse transcriptase (RT) mutant viruses that are resistant to the NNRTIs nevirapine 
and efavirenz remain largely sensitive to GS-5894. With the human t1/2, GS-5894 has the 
potential to be administered orally once weekly and to be combined with other LA agents as part 
of a combination regimen for the treatment of HIV-1 infection.
For further information on GS–5894, refer to the current investigator’s brochure (IB), including 
the following:
1. Nonclinical PK
2. Nonclinical pharmacodynamics (PD)
3. Nonclinical toxicology
1.2.1.2.
Nonclinical Pharmacology and Toxicology
Nonclinical pharmacology and toxicology studies are provided in the IB.
1.2.1.3.
Clinical Studies of GS-5894 
1.2.1.3.1.
GS-US-544-5906
Study GS-US-544-5906 is an ongoing, Phase 1a study in healthy volunteers evaluating the 
safety, tolerability, and PK of single and multiple ascending oral doses of a GS-5894. 
Twenty-four unique participants across 3 dosing cohorts have received either GS-5894 or 
placebo (3:1 ratio). Administration of single oral doses of GS-5894 225 mg (Cohort 1), 675 mg 
(Cohort 2), and 2025 mg (Cohort 3) is complete. In addition, 19 participants completed dosing in 
the food-effect Cohort 5. Pharmacokinetic sampling for Cohorts 1, 2, and 3, and Cohort 5 
(through at least Day 7) is complete. Pharmacokinetic data available as of 22 June 2022 are 
summarized below.
Preliminary PK Summary:
Preliminary GS-5894 plasma concentration-time profiles and preliminary PK parameters after 
administration of single oral doses of 225 mg (Cohort 1), 675 mg (Cohort 2), and 2025 mg 
(Cohort 3) in the fasted condition, as well as 675 mg with a low- or high-fat meal (Cohort 5) are 
presented in Figure 2, Figure 3, and Table 2 and Table 3. Median time to maximal plasma 
concentrations of GS-5894 (Cmax) occurred between 3.5 and 5.5 hours (median Tmax). A 9-fold 
increase in dose (from 225 mg to 675 mg and then 2025 mg) resulted in only 2.8-fold higher 
Cmax and 3.2-fold higher AUC0-168h. The increases in Cmax and AUC0-168h were less than dose 
proportional, suggesting GS-5894 exhibits solubility-limited absorption. GS-5894 showed a 
positive food effect; Cmax and AUC0-168h following a 675 mg dose with a low-fat meal were 
3-fold higher and 3.6-fold higher compared with a 675 mg dose in the fasted condition. 
Similarly, Cmax and AUC0-168h following a 675 mg dose with a high-fat meal were 6.1-fold higher 
and 7.7-fold higher compared to a 675 mg dose in the fasted condition.

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Figure 2. 
1000 
GS-US-544-5906: Preliminary Mean (SD) GS-5894 Plasma 
Concentration-Time Profiles Following Single-Dose Administration of 
Oral GS-5894 (N = 6 per Cohort) in the Fasted Condition 
-+- Cohort 2 675 mg; Fasted (N=6) 
---e- Cohort 3: 2025 mg; Fasted (N=6) 
---+- Cohort 1: 225 mg; Fasted (N=6) 
• • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • IQS (254 ng/mL) 
• • · • .. · · • .... • .... • .... • .... • .... • · · • .... • .... • .... • .... • .... • · · • .. · · • .... • .... • .... • .... • · · .. • · · • IQl (50.8 ng/mL) 
Time (h) 
IQl, 5 = inhibito1y quotient 1- or 5-fold higher than the protein adjusted EC95 against wild type HIV-1 virus (paEC95; 
50.8 ng/mL) 
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Figure 3. 
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GS-US-544-5906: Preliminary Mean (SD) GS-5894 Plasma 
Concentration-Time Profiles Following Single-Dose Administration of 
Oral GS-5894 675 mg in the Fasted Condition as well as with a 
Low-Fat or High-Fat Meal 
-+- Cohort 2: 675 mg; Fasted (N=6) 
---e- Cohort 5B: 675 mg; High-fat meal (N=9) 
---+- Cohort 5A: 675 mg; Low-fat meal (N=10) 
• • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • IQS (254 ng/mL) 
• .. • .... • .... • .... • .... • .... • .. • .... • .... • .... • .... • .... • .... • .. • IQl (50.8 ng/mL) 
Time (h) 
IQl, 5 = inhibito1y quotient 1- or 5-fold higher than the protein adjusted EC95 against wild type HIV-1 virus (paEC95; 
50.8 ng/mL) 
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Table 2.
GS-US-544-5906: Preliminary Plasma PK Parameters of GS-5894 
Following Single-Dose Administration of Oral GS-5894 
(N = 6 per Cohort) in the Fasted Condition
Parameter
Cohort 1 
(225 mg, Fasted)
Cohort 2 
(675 mg, Fasted)
Cohort 3
(2025 mg, Fasted)
Cmax (ng/mL)
123 (38.9)
179 (51.3)
349 (19.3)
Tmax (h)
5.00 (3.00, 5.00)
3.50 (2.75, 4.25)
4.50 (4.00, 5.25)
Clast (ng/mL)
8.98 (36.6)
6.73 (10.0)
40.3 (30.3)
Tlast (h)
288 (240, 336)
660 (318, 720)
168 (168, 168)
AUC0-168 h (h•ng/mL)
4080 (33.3)
6520 (57.5)
12900 (22.9)
AUCInf (h•ng/mL)
8350 (50.4)
14200 (53.4)
20200 (25.8)
AUCExtrap (%)
29.8 (36.7)
19.0 (60.2)
35.0 (18.6)
t1/2 (d)
6.68 (5.30, 10.4)
7.96 (6.28, 12.7)
4.77 (4.20, 6.31)
d = days; h = hour; PK = pharmacokinetics; Q1 = first quartile; Q3 = third quartile. PK parameters presented to 
3 significant figures as mean (%CV) except t1/2, Tlast and Tmax which are presented as median (Q1, Q3).
Note: Analysis was conducted using nominal timepoints.
Table 3.
GS-US-544-5906: Preliminary Plasma PK Parameters of GS-5894 
Following Single-Dose Administration of Oral GS-5894 675 mg in the 
Fasted Condition as well as with a Low-Fat or High-Fat Meal
Parameter
Cohort 2 
(225 mg, Fasted)
Cohort 5A 
(675 mg With Low-fat 
Meal)
Cohort 5B
(675 mg With High-fat 
Meal)
Cmax (ng/mL)
179 (51.3)
534 (38.1)
1090 (39.3)
Tmax (h)
3.50 (2.75, 4.25)
5.50 (4.00, 7.50)
5.00 (5.00, 9.00)
Clast (ng/mL)
6.73 (10.0)
39.3 (75.8)
80.4 (46.5)
Tlast (h)
660 (318, 720)
336 (336, 336)
336 (336, 336)
AUC0-168 h (h•ng/mL)
6520 (57.5)
23700 (68.4)
50200 (37.6)
AUCInf (h•ng/mL)
14200 (53.4)
43200 (69.4)
88200 (40.0)
AUCExtrap (%)
19.0 (60.2)
21.3 (36.8)
19.7 (35.1)
t1/2 (d)
7.96 (6.28, 12.7)
6.52 (5.31, 8.35)
5.62 (4.89, 7.31)
d = days; h = hour; PK = pharmacokinetics; Q1 = first quartile; Q3 = third quartile. PK parameters presented to 
3 significant figures as mean (%CV) except t1/2, Tlast and Tmax which are presented as median (Q1, Q3).
Note: Analysis was conducted using nominal timepoints.

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Safety Summary:
In a preliminary blinded review of safety data as of 28 June 2022 (n = 43), no deaths, 
serious adverse events (SAEs), Grade 2 or higher adverse events (AEs), or discontinuations due 
to AEs have been reported to date. Two participants experienced AEs related to study drug; one 
in Cohort 2 (675 mg GS-5894) with proteinuria at Day 2 (resolved at Day 7) and one in Cohort 5 
(675 mg GS-5894, low-fat/moderate-calorie breakfast) with nausea, diarrhea, and vomiting at 
Day 1 (all resolved on same day). 
Grade 3 laboratory abnormalities were reported for 3 participants and were not clinically relevant 
(creatinine clearance: 2 participants; low-density lipoprotein cholesterol: 1 participant).
No notable changes from predose in white bloods cells, eosinophils, or vital signs (systolic blood 
pressure, diastolic blood pressure, pulse, temperature, and respiration rate) have been observed in 
the study. No clinically significant electrocardiogram (ECG) abnormalities have been reported.
1.3.
Rationale for Dose Selection of Study Drug
Selection of the GS-5894 doses for this study takes into consideration the available safety, 
tolerability, and PK data for GS-5894 from the ongoing FIH study with oral single and multiple 
ascending doses in healthy volunteers (Study GS-US-544-5906), as well as emerging preliminary 
safety and antiviral activity data in this substudy.
As of 28 June 2022, 43 participants (37 active and 6 placebo) have received a single oral dose of 
GS-5894 (225 to 2025 mg) or placebo-to-match. All participants have completed at least 7 days 
of follow up. As of the data cut-off date (28 June 2022), there were no deaths, SAEs, Grade 2 or 
higher AEs, or discontinuations due to AEs. GS-5894 was generally well-tolerated.
Available PK data from Study GS-US-544-5906 (as of 22 June 2022), as shown in Figure 2 and 
Figure 3, as well as in Table 2 and Table 3, demonstrates that the highest Cmax and AUC0-168h 
were observed following a 675-mg dose with a high-fat meal (Cohort 5B). Exposure margins 
based on observed data following 675 mg with a high-fat meal (Cohort 5B) were 14-fold and 
11-fold for AUC0-168h and 5-fold and 7-fold for Cmax compared with the dog and mouse 
NOAELs, respectively. Following a 675 mg dose with a high-fat meal, mean GS-5894 
concentrations achieved target IQ5 (that is 5-fold higher than the protein adjusted EC95 against 
wild type HIV-1 virus [paEC95; 50.8 ng/mL]) rapidly, and concentrations were maintained 
(> IQ5) through 72 hours postdose; mean GS-5894 concentrations at Day 8 and Day 12 were 
173.5 ng/mL (maintained above IQ3) and 115.5 ng/mL (maintained above IQ2), respectively. 
Based on these results, 675 mg with a high-fat meal was selected for evaluation in Cohort 1 of 
this substudy. Higher/lower doses (compared to Cohort 1 dose) may be evaluated in subsequent 
cohorts to target a range of IQ values to characterize the PK/PD relationship between GS-5894 
PK parameters and changes in HIV-1 viral load.

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1.4.
Risk/Benefit Assessment for Substudy-01
Potential risks to participants could include prolonged exposure for several weeks to 
subtherapeutic concentrations of the study drug, which can lead to HIV-1 developing resistance 
to the study drug and potentially to the study drug class and could limit future treatment options. 
Strategies to mitigate this risk and additional risk/benefit assessments applicable to Substudy-01 
and GS-5894 are described in Section 1.4 of the master protocol.

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2.
OBJECTIVES AND ENDPOINTS
Objectives and endpoints are described in Section 2 of the master protocol.

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3.
STUDY DESIGN
3.1.
Study Design Overview
This substudy is being conducted as part of an umbrella study as described in the master 
protocol.
Substudy-01 is an open-label, Phase 1b, single/multiple-dose, multicohort study to evaluate the 
safety, PK, and antiviral activity of GS-5894 given as monotherapy in PWH who are either 
treatment-naive or treatment experienced but naive to the study drug class and have not received 
any ART within 12 weeks of screening, including medications received for pre-exposure 
prophylaxis (PrEP) or postexposure prophylaxis (PEP). Any current or prior receipt of long-
acting parenteral ARVs such as monoclonal antibodies (mAbs) targeting HIV-1, injectable 
cabotegravir, or injectable rilpivirine is exclusionary.
After screening and meeting all eligibility criteria, study drug dosing will be initiated on Day 1 in 
the clinic for each participant (Figure 1). Participants will be required to return to the clinic for 
visits on Days 2, 3, 4, 7, 8, 9, 10, and 11 (primary endpoint assessment). After assessments on 
Day 11 or upon early termination (ET), participants will initiate a regimen of 
Biktarvy® (bictegravir [BIC, B]/emtricitabine [FTC, F]/tenofovir alafenamide [TAF]; BVY) 
provided by the sponsor, or other non-NNRTI based standard of care (SOC) ART regimen 
selected by the investigator. If participants are switching to BVY, a 30-day supply will be given 
to provide coverage for up to 5 half-lives of GS-5894. Participants will be required to return to 
the clinic for follow-up visits on Days 18, 25, and 39. Overnight fasting (≥ 6 hours) is required 
for laboratory analyses prior to visit on Days 1, 3, 7, 11, 18, 25, and 39.
The selection of doses and dosing regimen for GS-5894 is described in Section 3.1.1.
This substudy will enroll up to approximately 5 cohorts with at least 6 participants in each 
cohort. Participants will be enrolled in Cohort 1 initially and then dosing in subsequent cohorts 
will proceed after safety review team (SRT) review of emerging data as described in 
Section 3.1.1.
Sequential enrollment in cohorts and order of assignment to substudies is described in 
Section 5.1.1 of the master protocol.
The sponsor may elect to hold dosing, stop/pause substudy enrollment, or stop the study 
(or substudy, or specific cohort) at any time based on review of preliminary safety, efficacy, and 
PK data (see master protocol Section 5.1.1).
3.1.1.
Dose Selection/Modification
Enrollment and dosing with GS-5894 will begin with Cohort 1. The dose and regimen of 
GS-5894 for Cohort 1 is defined in Section 5.2.4. 

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A summary of SRT reviews, dose decisions and cohort progression applicable to this substudy is 
included in Section 3.1.1 of the master protocol.
3.2.
Duration of Intervention
Participants will be under evaluation in this Substudy-01 for 39 days.
Participants will receive single or multiple doses of GS-5894 starting on Day 1. Participants will 
then initiate a BVY or another non-NNRTI-based SOC ART regimen on Day 11 following study 
assessments to provide coverage for up to 5 half-lives of GS-5894. Participants will be required 
to return to the clinic for follow-up visits on Days 18, 25, and 39.
3.3.
Substudy-01-Specific Discontinuation Criteria
Substudy criteria for early discontinuation for the individual participants are described in 
Section 3.3.1 of the master protocol.
3.4.
Definitions for Time of Primary Endpoint and End of Study
The definitions for time of primary endpoint and end of study for each substudy are described 
Section 3.4 of the master protocol.

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4.
PARTICIPANT POPULATION
4.1.
Number of Participants and Participant Selection for Substudy-01
In Substudy-01, up to approximately 5 cohorts of at least 6 participants each will be enrolled. 
Participant replacement is described in Section 4.1.1 of the master protocol.
4.2.
Substudy-01-Specific Inclusion Criteria
Inclusion criteria applicable to all substudies is provided in Section 4.2 of the master protocol. In 
addition to meeting the inclusion criteria in the master protocol, participants must also meet the 
following inclusion criteria to be eligible for participation in this substudy:
S01-1. Willing to initiate an SOC ART regimen on Day 11 or upon ET as stated in Section 4.2 in 
the master protocol. For this substudy, willing to initiate BVY provided by the sponsor or 
a non-NNRTI-based SOC ART regimen selected by the investigator on Day 11 or upon 
ET.
S01-2. Willing and able to comply with meal requirements on dosing days.
4.3.
Substudy-01-Specific Exclusion Criteria
Exclusion criteria applicable to all substudies are provided in Section 4.3 of the master protocol. 
In addition to not meeting any of the exclusion criteria in the master protocol, participants must 
not meet the following exclusion criterion to be eligible for participation in this substudy:
S01-1. Requirement for ongoing therapy with any prohibited medications listed in Section 5.3.

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5.
STUDY INTERVENTIONS AND CONCOMITANT 
MEDICATIONS
5.1.
Enrollment and Treatment Code Access
Participant enrolment procedures are described in Section 5.1 of the master protocol.
5.2.
Description and Handling of GS-5894 and Commercially Available BVY
Commercially available BVY will be provided by the sponsor for use during the study as 
applicable. Further information regarding storage and handling are available in the prescribing 
information for the commercial BVY product.
The description and handling of GS-5894 is described below.
5.2.1.
Formulation
GS-5894 tablets are available in strengths of 75 and 600 mg. GS-5894 tablets, 75 mg, are round, 
plain-faced, film-coated, gray-colored tablets. GS-5894 tablets, 600 mg, are oval, plain-faced, 
film-coated, gray-colored tablets. In addition to the active ingredient, GS-5894 tablets, 75 mg 
and 600 mg, also contain microcrystalline cellulose, crospovidone, magnesium stearate, 
polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and ferrosoferric oxide.
5.2.2.
Packaging and Labeling
GS-5894 tablets are packaged in white, high-density polyethylene bottles containing silica gel 
desiccant and polyester coil packing material. Each bottle is enclosed with a white 
continuous-thread, child-resistant, polypropylene screw cap with an induction-sealed, 
aluminum-faced liner.
Study drugs to be distributed to centers in the United States (US) will be labeled to meet 
applicable requirements of the US Food and Drug Administration (FDA) and/or other local 
regulations as applicable.
5.2.3.
Storage and Handling
GS-5894 tablets should be stored below 30 C. Storage conditions are specified on the label. 
GS-5894 should be stored in a securely locked area, accessible only to authorized site personnel. 
To ensure the stability of GS-5894 and proper identification, the drug product should not be 
stored in a container other than the container in which it is supplied.

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5.2.4.
Dosage and Administration
Single or multiple doses of GS-5894 will be administered starting on Day 1. The dose, 
dose regimen, and meal requirements for administration of GS-5894 in Cohort 1 are provided in 
Table 4. Subsequent cohort dose, dosing regimens (ie, single or multiple doses), meal 
requirements (fasted or with a low- or high-fat meal), and progression between cohorts will be 
adaptive as described in Section 3.1.1. Doses in subsequent cohorts will not exceed the doses 
indicated in Table 4.
Doses of GS-5894 will be administered orally at the clinic under observation by site staff in the 
morning at approximately the same time each day (in the case of multiple-dose regimens).
A low-fat/moderate-calorie breakfast (400-500 calories, 100-125 calories from fat) or a 
high-fat/high-calorie breakfast (800-1000 calories, 500-600 calories from fat) will be initiated 
30 minutes prior to study drug administration, respectively. Participants will be administered 
GS-5894 at or within 5 minutes of participants consuming the meal.
Table 4.
GS-5894 Dosage by Cohort
Cohort
Treatment
Cohort 1
Single 675 mg dose administered on Day 1 with a high-fat meal
Cohort 2
Single or multiple doses of GS-5894 up to 2025 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)
Cohort 3
Single or multiple doses of GS-5894 up to 2025 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)
Cohort 4
Single or multiple doses of GS-5894 up to 2025 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)
Cohort 5
Single or multiple doses of GS-5894 up to 2025 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)
5.3.
Prior and Concomitant Medications
See Section 5.3 of the master protocol for information on prior and concomitant medication rules 
applicable to all substudies including restricted medications through Day 11.
Medications prohibited from after the last dose of study drug on Day 11 through Day 39 in this 
substudy are presented in Table 5. Metabolism of GS-5894 was detectable with 
cytochrome P450 enzyme (CYP)3A in-vitro. Concomitant use of GS-5894 with some 
medications or herbal/natural supplements that are inhibitors of CYP3A may result in increased 
exposure of GS-5894. On the other hand, concomitant use of GS-5894 with some medications or 
herbal/natural supplements that are inducers of CYP3A may result in decreased exposure of 
GS-5894. Representative strong CYP3A inhibitors and strong/moderate CYP3A inducers listed 
in Table 5 are recommended to be excluded while participating in this substudy (Day 11 through 
Day 39). This table is not exhaustive and if there are medications not included in Table 5, 

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the investigator should reach out to the sponsor for guidance to use any concomitant medication 
while participants are on the substudy.
Table 5.
Examples of Medications Prohibited From Day 11 Through Day 39 
Because of the Potential for Pharmacokinetic Drug-Drug Interaction 
With GS-5894a
Medication Class
Prohibited Medications
ARVs 
Amprenavir, lopinavir, ritonavir, indinavir, 
saquinavir, nelfinavir, ritonavir- or cobicistat-
containing regimens, boceprevir, telaprevir, 
efavirenz, etravirine, and nevirapine
Antiandrogens
Apalutamide, enzalutamide
Antibiotics 
Clarithromycin, rifampin, rifapentine, telithromycin, 
troleandomycin
Antifungals 
Itraconazole, ketoconazole, voriconazole, 
posaconazole
Herbal Medications
St. John’s wort
ARVs = antiretrovirals 
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 should consult with the sponsor.
From Day 11 through the last visit, the investigator should follow the current United States 
Prescribing Information to inform the use of concomitant/prohibited medications for 
BVY {BIKTARVY 2021} or other ART taken as the SOC by the individual participant.
5.4.
Accountability for Study Drug Supplies: Study Drug and SOC ART 
provided by Sponsor (BVY)
Guidance related to accountability, return, and disposal for study drug supplies (study drug 
[GS-5894 for this study] and SOC ART provided by the sponsor [BVY for this substudy]) is 
provided in Section 5.4 of the master protocol.

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STUDY PROCEDURES 
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Study procedures applicable to all studies are listed in Section 6 of the master protocol. 
Study procedures specific to Substudy-01 are listed in the sections below. The timepoints for 
study procedures are specified in Table 1. Substudy-specific ICFs will be required for 
Substudy-01. 
6.1. 
6.1.1. 
Instructions for Study Procedures 
Pharmacokinetics 
Blood samples will be collected to detennine GS-5894 PK (and metabolites, if appropriate) in 
plasma as indicated in Table 1. 
6.1.2. 
Suboptimal Virologic Response 
Management of suboptimal virologic response is described in Section 6.3 .9 .1.3 of the master 
protocol. 
6.1.2.1. 
Management of Virologic Rebound 
Management ofvirologic rebound is described in Section 6.3.9.1.3 of the master protocol. 
6.1.2.2. 
Resistance Analysis at Paiiicipant's Last Visit 
Resistance analysis at the pa1iicipant's last visit is described in Section 6.3.9.1.3 of the master 
protocol. 
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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
Adverse events are specified in Section 7 of the master protocol. Information regarding toxicity 
management that is specific to GS-5894 is described below and included in Appendix 11.2. 
Pregnancy precautions, definition of female of childbearing potential, and contraceptive 
requirements specific to GS-5894 are included in Appendix 11.1.
7.1.
Toxicity Management
All clinically significant laboratory toxicities will be managed according to uniform guidelines 
detailed in Appendix 11.2 and as outlined below.

Grade 3 or 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing as soon as possible, and preferably within 3 calendar days after receipt of the 
original test results. The study drug may be continued without dose interruption for multiple 
dose cohorts for a clinically insignificant Grade 3 and 4 laboratory 
abnormality (eg, creatine kinase [CK] elevation after strenuous exercise, triglyceride 
elevation that is nonfasting or that can be medically managed). Recurrence of laboratory 
abnormalities considered unrelated to the study drug may not require permanent 
discontinuation.

Grade 3 or 4 clinical events if considered unrelated to the study drug may not require dose 
interruption; continuation of the investigational product for multiple dose cohorts is at the 
discretion of the investigator.
7.1.1.
Grade 1 and 2 Laboratory Abnormalities or Clinical Events

Continue study drug at the discretion of the investigator for multiple dose cohorts, as 
applicable.
7.1.2.
Grade 3 Laboratory Abnormalities or Clinical Events

For a Grade 3 clinically significant laboratory abnormality confirmed by repeat testing that is 
considered to be related to the study drug, the study drug should be withheld in multiple dose 
cohorts and the medical monitor consulted.
7.1.3.
Grade 4 Laboratory Abnormalities or Clinical Events

For a Grade 4 clinical event or clinically significant laboratory abnormality confirmed by 
repeat testing considered to be related to the study drug, study drug should be permanently 
discontinued in multiple dose cohorts and the participant managed according to local 
practice. The participant should be followed as clinically indicated until the laboratory 
abnormality returns to baseline or is otherwise explained, whichever occurs first. A clinically 
significant Grade 4 laboratory abnormality that is not confirmed by repeat testing should be 
managed according to the algorithm for the new toxicity grade.

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Treatment-emergent toxicities will be noted by the investigator and brought to the attention of 
the sponsor’s medical monitor, and the appropriate course of action will be discussed and 
decided. Whether or not considered treatment related, all participants experiencing AEs must be 
monitored periodically until symptoms subside, any abnormal laboratory values have resolved or 
returned to baseline levels or they are considered irreversible, or until there is a satisfactory 
explanation for the changes observed.
Any questions regarding toxicity management should be directed to the sponsor’s 
medical monitor.

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8.
STATISTICAL CONSIDERATIONS
Details of statistical methods will be provided in the statistical analysis plan for this substudy, 
including any deviations from the original statistical analyses planned. Statistical considerations 
for this substudy are described in Section 8 of the master protocol.

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9.
RESPONSIBILITIES
Details regarding responsibilities are specified in Section 9 of the master protocol.

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10.
REFERENCES
BIKTARVY, Gilead Science Inc. BIKTARVY® bicteoravir 50mo/emtricitabine 20Dmo/ 
tenofovir alafenamide 25mg tablets, U. S. Prescribinig Information. Revised: 
February.  2021:
Department of Health and Human Services (DHHS). Guidelines for the Use of Antiretroviral 
Agents in Adults and Adolescents Living with HIV.  2018:298. 
Enriquez M, McKinsey DS. Strategies to improve HIV treatment adherence in developed 
countries: clinical management at the individual level. HIV AIDS (Auckl) 
2011;3:45-51.
European Aids Clinical Society (EACS). EACS Guidelines, Version 11.0.  2021:
Gunthard HF, Saag MS, Benson CA, del Rio C, Eron JJ, Gallant JE, et al. Antiretroviral Drugs 
for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations 
of the International Antiviral Society-USA Panel. JAMA 2016;316 (2):191-210.
World Health Organization (WHO). Consolidated Guidelines On The Use Of Antiretroviral 
Drugs For Treating And Preventing HIV Infection: Recommendations For A 
Public Health Approach. Second Edition.  2016.

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11.
APPENDICES
11.1.
Pregnancy Precautions, Definition of Childbearing Potential, and 
Contraceptive Requirements
1)
Definitions
a.
Definition of Childbearing Potential
For the purposes of this study, a participant assigned female at birth is considered of childbearing 
potential following the initiation of puberty (Tanner Stage 2) until becoming postmenopausal 
unless the participant is permanently sterile or has medically documented ovarian failure.
Participants assigned female at birth are considered to be in a postmenopausal state when they 
are at least 54 years of age with cessation of previously occurring menses for at least 12 months 
without an alternative cause. In addition, participants assigned female at birth younger than 
54 years of age with amenorrhea of at least 12 months may also be considered postmenopausal if 
their follicle-stimulating hormone (FSH) 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 Fertility in a Participant Assigned Male at Birth
For the purposes of this study, a participant assigned male at birth is considered fertile after the 
initiation of puberty unless the participant is permanently sterile by bilateral orchidectomy or 
medical documentation.
2)
Contraception Requirements for Participants Assigned Female at Birth
a.
Study Drug Effects on Pregnancy and Hormonal Contraception
GS-5894 is contraindicated in pregnancy as a malformative effect is unknown. There is no 
suspicion of human teratogenicity based on class effects or genotoxic potential. GS-5894 has 
insufficient data to exclude the possibility of a clinically relevant interaction with hormonal 
contraception that results in reduced contraception efficacy. Therefore, hormonal contraception 
is not recommended as a contraceptive method either solely or as a part of a contraceptive 
regimen. Refer to the latest version of the IB for additional information.
b.
Contraception Requirements for Participants Assigned Female at Birth of 
Childbearing Potential
The inclusion of participants assigned female at birth of childbearing potential requires the use of 
highly effective contraceptive measures with a failure rate of less than 1% per year. They must 
also not rely on hormone-containing contraceptives as a form of birth control during the study. 
They must have a negative serum pregnancy test at screening and a negative pregnancy test at 

GS–5894
Protocol GS-US–544–5905 Substudy-01
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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the Day 1 visit before enrollment. Pregnancy tests will be performed at monthly intervals 
thereafter until the end of contraception requirement.
Duration of required contraception for female participants in this clinical study should start from 
the screening visit until 39 days after the last study drug dose.
Participants assigned female at birth and of childbearing potential must agree to one of the 
following contraceptive methods:
Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the participant’s preferred and usual 
lifestyle.
Or
Consistent and correct use of 1 of the following methods of birth control listed below:

Nonhormonal intrauterine device (IUD)

Bilateral tubal occlusion (upon medical assessment of surgical success)

Vasectomy in the partner assigned male at birth (upon medical assessment of surgical 
success)
Inclusion of methods of contraception in this list of permitted methods does not imply that the 
method is approved in any country or region. Methods should only be used if locally approved.
Participants assigned female at birth and of childbearing potential must also refrain from egg 
donation and in vitro fertilization during treatment and until the end of contraception 
requirement.
3)
Contraception Requirements for Participants Assigned Male at Birth
It is theoretically possible that a relevant systemic concentration of study drug may be achieved 
in a partner assigned female at birth from exposure to the participant’s seminal fluid and pose a 
potential risk to an embryo/fetus. A participant assigned male at birth with a partner assigned 
female at birth and of childbearing potential must use condoms during treatment and until 
39 days after the last study drug dose. If the partner assigned female at birth and of childbearing 
potential is not pregnant, additional contraception recommendations should also be considered.
Participants assigned male at birth must also refrain from sperm donation and cryopreservation 
of germ cells during treatment and until the end of contraception requirement.

GS–5894
Protocol GS-US–544–5905 Substudy-01
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 35
27 September 2022
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
Participants assigned female at birth will be instructed to notify the investigator if they become 
pregnant or suspect they are pregnant at any time from the start of the study until 39 days after 
the last study drug dose.
Participants assigned male at birth whose partner has become pregnant or suspects they are 
pregnant from start of study until 39 days after the last study drug dose must also report the 
information to the investigator. Instructions for reporting pregnancy, partner pregnancy, and 
pregnancy outcome are outlined in Section 7.4.2.3 of the master protocol.

GS–5894
Protocol GS-US–544–5905 Substudy-01
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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27 September 2022
11.2.
Management of Clinical and Laboratory Adverse Events
G de 1 
... I __ 
G_ra_de_ 2 _ _.I I 
Grade, 3 I 1 .. I __ 
G_r_a_d_e_4_1 __ I 
l 
Continue study 
drug dosing at 
the discretion of 
the i nve!i.lis at Or 
Repe t I b to confirm 
to k1ty gr de 
lrf confirm · d, 
d pos ibl:Y or pro. bly r • ·1 t d lo 
dy 
drug(s), disco,nt nue studv(s} do:s.i g permane 1tly, 
d 
mana e subject accord·n to loca1 pr.actice. Subject 
hould 
- fo low du clini lly "nd1c 
dun i th 
I bora ory bnormal ty ret rns to ba,sellne, or 1s 
o herwise expla'ined 

GS–5894
Protocol GS-US–544–5905 Substudy-01
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 37
27 September 2022
11.3.
Investigator Signature Page
GILEAD SCIENCES, INC.
333 LAKESIDE DRIVE
FOSTER CITY, CA 94404
USA
STUDY ACKNOWLEDGMENT
An Umbrella Phase 1b, Open-label, Multi-Cohort Study to Evaluate Safety, Pharmacokinetics, 
and Antiviral Activity of Novel Antiretrovirals in Participants With HIV-1.
27 September 2022 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Name (Printed)
Exec Director, Clinical Development
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-

Prot GS-US-544-5905-01 amd-1
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Research eSigned 27-Sep-2022
21:43:49
PPD